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Sample records for 50-528 stn 50-529

  1. STN1-POLA2 interaction provides a basis for primase-pol α stimulation by human STN1.

    PubMed

    Ganduri, Swapna; Lue, Neal F

    2017-09-19

    The CST (CTC1-STN1-TEN1) complex mediates critical functions in maintaining telomere DNA and overcoming genome-wide replication stress. A conserved biochemical function of the CST complex is its primase-Pol α (PP) stimulatory activity. In this report, we demonstrate the ability of purified human STN1 alone to promote PP activity in vitro. We show that this regulation is mediated primarily by the N-terminal OB fold of STN1, but does not require the DNA-binding activity of this domain. Rather, we observed a strong correlation between the PP-stimulatory activity of STN1 variants and their abilities to bind POLA2. Remarkably, the main binding target of STN1 in POLA2 is the latter's central OB fold domain. In the substrate-free structure of PP, this domain is positioned so as to block nucleic acid entry to the Pol α active site. Thus the STN1-POLA2 interaction may promote the necessary conformational change for nucleic acid delivery to Pol α and subsequent DNA synthesis. A disease-causing mutation in human STN1 engenders a selective defect in POLA2-binding and PP stimulation, indicating that these activities are critical for the in vivo function of STN1. Our findings have implications for the molecular mechanisms of PP, STN1 and STN1-related molecular pathology. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  2. Brittle Dyskinesia Following STN but not GPi Deep Brain Stimulation

    PubMed Central

    Sriram, Ashok; Foote, Kelly D.; Oyama, Genko; Kwak, Joshua; Zeilman, Pam R.; Okun, Michael S.

    2014-01-01

    Background The aim was to describe the prevalence and characteristics of difficult to manage dyskinesia associated with subthalamic nucleus (STN) deep brain stimulation (DBS). A small subset of STN DBS patients experience troublesome dyskinesia despite optimal programming and medication adjustments. This group of patients has been referred to by some practitioners as brittle STN DBS-induced dyskinesia, drawing on comparisons with brittle diabetics experiencing severe blood sugar regulation issues and on a single description by McLellan in 1982. We sought to describe, and also to investigate how often the “brittle” phenomenon occurs in a relatively large DBS practice. Methods An Institutional Review Board-approved patient database was reviewed, and all STN and globus pallidus internus (GPi) DBS patients who had surgery at the University of Florida from July 2002 to July 2012 were extracted for analysis. Results There were 179 total STN DBS patients and, of those, four STN DBS (2.2%) cases were identified as having dyskinesia that could not be managed without the induction of an “off state,” or by the precipitation of a severe dyskinesia despite vigorous stimulation and medication adjustments. Of 75 GPi DBS cases reviewed, none (0%) was identified as having brittle dyskinesia. One STN DBS patient was successfully rescued by bilateral GPi DBS. Discussion Understanding the potential risk factors for postoperative troublesome and brittle dyskinesia may have an impact on the initial surgical target selection (STN vs. GPI) in DBS therapy. Rescue GPi DBS therapy may be a viable treatment option, though more cases will be required to verify this observation. PMID:24932426

  3. The Student Telescope Network (STN) experiment

    NASA Astrophysics Data System (ADS)

    Hannahoe, Ryan M.; Stencel, Robert E.; Bisque, Steve; Rice, Mike

    2003-02-01

    support of this effort, and acknowleedge in-kind support from the estate of William Herschel Womble. Details at website www.du.edu/~rstencel/stn.htm.

  4. Amantadine improves gait in PD patients with STN stimulation.

    PubMed

    Chan, Hiu-Fai; Kukkle, Prashanth L; Merello, Marcelo; Lim, Shen-Yang; Poon, Yu-Yan; Moro, Elena

    2013-03-01

    In advanced Parkinson's disease (PD), axial symptoms such as speech, gait, and balance impairment often become levodopa-unresponsive and they are difficult to manage, even in patients with subthalamic nucleus deep brain stimulation (STN-DBS). We anecdotally observed that oral administration of amantadine was very effective in treating both residual and stimulation-induced axial symptoms after bilateral STN-DBS in one PD patient. Therefore, we conducted a prospective multicenter observational study to evaluate the effects of amantadine on speech, gait and balance in PD patients with STN-DBS and incomplete axial benefit. Primary outcomes were changes in speech (UPDRS III, item 18), gait (item 29) and postural stability (item 30) with amantadine treatment compared to baseline. Secondary outcome was the patients' subjective scoring of axial symptoms with amantadine compared to baseline. Forty-six PD patients with STN-DBS were enrolled in the study and followed for 10.35 ± 8.21 months (median: 9.00; range: 1-31). The mean daily dose of amantadine was 273.44 ± 47.49 mg. Gait scores significantly improved (from 1.51 ± 0.89 to 1.11 ± 0.92, P = 0.015) with amantadine treatment, whereas postural stability and speech scores were similar before and after treatment. Thirty-five (76.1%) patients reported subjective improvement in speech, gait or balance with amantadine, whereas thirty (65.2%) patients reported improvement in gait and balance. In conclusion, our data suggest that amantadine may have new beneficial effects on axial symptoms in PD patients with STN-DBS.

  5. Comparative phosphoproteome profiling reveals a function of the STN8 kinase in fine-tuning of cyclic electron flow (CEF)

    PubMed Central

    Reiland, Sonja; Finazzi, Giovanni; Endler, Anne; Willig, Adrian; Baerenfaller, Katja; Grossmann, Jonas; Gerrits, Bertran; Rutishauser, Dorothea; Gruissem, Wilhelm; Rochaix, Jean-David; Baginsky, Sacha

    2011-01-01

    Important aspects of photosynthetic electron transport efficiency in chloroplasts are controlled by protein phosphorylation. Two thylakoid-associated kinases, STN7 and STN8, have distinct roles in short- and long-term photosynthetic acclimation to changes in light quality and quantity. Although some substrates of STN7 and STN8 are known, the complexity of this regulatory kinase system implies that currently unknown substrates connect photosynthetic performance with the regulation of metabolic and regulatory functions. We performed an unbiased phosphoproteome-wide screen with Arabidopsis WT and stn8 mutant plants to identify unique STN8 targets. The phosphorylation status of STN7 was not affected in stn8, indicating that kinases other than STN8 phosphorylate STN7 under standard growth conditions. Among several putative STN8 substrates, PGRL1-A is of particular importance because of its possible role in the modulation of cyclic electron transfer. The STN8 phosphorylation site on PGRL1-A is absent in both monocotyledonous plants and algae. In dicots, spectroscopic measurements with Arabidopsis WT, stn7, stn8, and stn7/stn8 double-mutant plants indicate a STN8-mediated slowing down of the transition from cyclic to linear electron flow at the onset of illumination. This finding suggests a possible link between protein phosphorylation by STN8 and fine-tuning of cyclic electron flow during this critical step of photosynthesis, when the carbon assimilation is not commensurate to the electron flow capacity of the chloroplast. PMID:21768351

  6. Stn1-Ten1 is an Rpa2-Rpa3-like complex at telomeres

    SciTech Connect

    Sun, Jia; Yu, Eun Young; Yang, Yuting; Confer, Laura A; Sun, Steven H; Wan, Ke; Lue, Neal F; Lei, Ming

    2010-09-02

    In budding yeast, Cdc13, Stn1, and Ten1 form a heterotrimeric complex (CST) that is essential for telomere protection and maintenance. Previous bioinformatics analysis revealed a putative oligonucleotide/oligosaccharide-binding (OB) fold at the N terminus of Stn1 (Stn1N) that shows limited sequence similarity to the OB fold of Rpa2, a subunit of the eukaryotic ssDNA-binding protein complex replication protein A (RPA). Here we present functional and structural analyses of Stn1 and Ten1 from multiple budding and fission yeast. The crystal structure of the Candida tropicalis Stn1N complexed with Ten1 demonstrates an Rpa2N-Rpa3-like complex. In both structures, the OB folds of the two components pack against each other through interactions between two C-terminal helices. The structure of the C-terminal domain of Saccharomyces cerevisiae Stn1 (Stn1C) was found to comprise two related winged helix-turn-helix (WH) motifs, one of which is most similar to the WH motif at the C terminus of Rpa2, again supporting the notion that Stn1 resembles Rpa2. The crystal structure of the fission yeast Schizosaccharomyces pombe Stn1N-Ten1 complex exhibits a virtually identical architecture as the C. tropicalis Stn1N-Ten1. Functional analyses of the Candida albicans Stn1 and Ten1 proteins revealed critical roles for these proteins in suppressing aberrant telomerase and recombination activities at telomeres. Mutations that disrupt the Stn1-Ten1 interaction induce telomere uncapping and abolish the telomere localization of Ten1. Collectively, our structural and functional studies illustrate that, instead of being confined to budding yeast telomeres, the CST complex may represent an evolutionarily conserved RPA-like telomeric complex at the 3' overhangs that works in parallel with or instead of the well-characterized POT1-TPP1/TEBP{alpha}-{beta} complex.

  7. Comparison of weight changes following unilateral and staged bilateral STN DBS for advanced PD.

    PubMed

    Lee, Eric M; Kurundkar, Ashish; Cutter, Gary R; Huang, He; Guthrie, Barton L; Watts, Ray L; Walker, Harrison C

    2011-09-01

    Unilateral and bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) result in weight gain in the initial postoperative months, but little is known about the changes in weight following unilateral and staged bilateral STN DBS over longer time intervals. A case-control comparison evaluated weight changes over 2 years in 43 consecutive unilateral STN DBS patients, among whom 25 elected to undergo staged bilateral STN DBS, and 21 age-matched and disease severity matched PD controls without DBS. Regression analyses incorporating age, gender, and baseline weight in case or control were conducted to assess weight changes 2 years after the initial unilateral surgery. Unilateral STN DBS and staged bilateral STN DBS patients gained 3.9 ± 2.0 kg and 5.6 ± 2.1 kg versus their preoperative baseline weight (P < 0.001, respectively) while PD controls without DBS lost 0.8 ± 1.1 kg. Although bilateral STN DBS patients gained 1.7 kg more than unilateral STN DBS patients at 2 years, this difference was not statistically significant (P = 0.885). Although there was a trend toward greater weight gain in staged bilateral STN DBS patients versus unilateral patients, we found no evidence for an equivalent or synergistic increase in body weight following placement of the second DBS electrode.

  8. SOURCE APPORTIONMENT OF SEATTLE PM 2.5: A COMPARISON OF IMPROVE AND ENHANCED STN DATA SETS

    EPA Science Inventory

    Seattle, WA, STN and IMPROVE data sets with STN temperature resolved carbon peaks were analyzed with both the PMF and Unmix receptor models. In addition, the IMPROVE trace element data was combined with the major STN species to examine the role of IMPROVE metals. To compare the ...

  9. SOURCE APPORTIONMENT OF SEATTLE PM 2.5: A COMPARISON OF IMPROVE AND ENHANCED STN DATA SETS

    EPA Science Inventory

    Seattle, WA, STN and IMPROVE data sets with STN temperature resolved carbon peaks were analyzed with both the PMF and Unmix receptor models. In addition, the IMPROVE trace element data was combined with the major STN species to examine the role of IMPROVE metals. To compare the ...

  10. Stn1 is critical for telomere maintenance and long-term viability of somatic human cells.

    PubMed

    Boccardi, Virginia; Razdan, Neetu; Kaplunov, Jessica; Mundra, Jyoti J; Kimura, Masayuki; Aviv, Abraham; Herbig, Utz

    2015-06-01

    Disruption of telomere maintenance pathways leads to accelerated entry into cellular senescence, a stable proliferative arrest that promotes aging-associated disorders in some mammals. The budding yeast CST complex, comprising Cdc13, Stn1, and Ctc1, is critical for telomere replication, length regulation, and end protection. Although mammalian homologues of CST have been identified recently, their role and function for telomere maintenance in normal somatic human cells are still incompletely understood. Here, we characterize the function of human Stn1 in cultured human fibroblasts and demonstrate its critical role in telomere replication, length regulation, and function. In the absence of high telomerase activity, shRNA-mediated knockdown of hStn1 resulted in aberrant and fragile telomeric structures, stochastic telomere attrition, increased telomere erosion rates, telomere dysfunction, and consequently accelerated entry into cellular senescence. Oxidative stress augmented the defects caused by Stn1 knockdown leading to almost immediate cessation of cell proliferation. In contrast, overexpression of hTERT suppressed some of the defects caused by hStn1 knockdown suggesting that telomerase can partially compensate for hStn1 loss. Our findings reveal a critical role for human Stn1 in telomere length maintenance and function, supporting the model that efficient replication of telomeric repeats is critical for long-term viability of normal somatic mammalian cells.

  11. Stn1 is critical for telomere maintenance and long-term viability of somatic human cells

    PubMed Central

    Boccardi, Virginia; Razdan, Neetu; Kaplunov, Jessica; Mundra, Jyoti J; Kimura, Masayuki; Aviv, Abraham; Herbig, Utz

    2015-01-01

    Disruption of telomere maintenance pathways leads to accelerated entry into cellular senescence, a stable proliferative arrest that promotes aging-associated disorders in some mammals. The budding yeast CST complex, comprising Cdc13, Stn1, and Ctc1, is critical for telomere replication, length regulation, and end protection. Although mammalian homologues of CST have been identified recently, their role and function for telomere maintenance in normal somatic human cells are still incompletely understood. Here, we characterize the function of human Stn1 in cultured human fibroblasts and demonstrate its critical role in telomere replication, length regulation, and function. In the absence of high telomerase activity, shRNA-mediated knockdown of hStn1 resulted in aberrant and fragile telomeric structures, stochastic telomere attrition, increased telomere erosion rates, telomere dysfunction, and consequently accelerated entry into cellular senescence. Oxidative stress augmented the defects caused by Stn1 knockdown leading to almost immediate cessation of cell proliferation. In contrast, overexpression of hTERT suppressed some of the defects caused by hStn1 knockdown suggesting that telomerase can partially compensate for hStn1 loss. Our findings reveal a critical role for human Stn1 in telomere length maintenance and function, supporting the model that efficient replication of telomeric repeats is critical for long-term viability of normal somatic mammalian cells. PMID:25684230

  12. Effects of antidromic and orthodromic activation of STN afferent axons during DBS in Parkinson's disease: a simulation study.

    PubMed

    Kang, Guiyeom; Lowery, Madeleine M

    2014-01-01

    Recent studies suggest that subthalamic nucleus (STN)-Deep Brain Stimulation (DBS) may exert at least part of its therapeutic effect through the antidromic suppression of pathological oscillations in the cortex in 6-OHDA treated rats and in parkinsonian patients. STN-DBS may also activate STN neurons by initiating action potential propagation in the orthodromic direction, similarly resulting in suppression of pathological oscillations in the STN. While experimental studies have provided strong evidence in support of antidromic stimulation of cortical neurons, it is difficult to separate relative contributions of antidromic and orthodromic effects of STN-DBS. The aim of this computational study was to examine the effects of antidromic and orthodromic activation on neural firing patterns and beta-band (13-30 Hz) oscillations in the STN and cortex during DBS of STN afferent axons projecting from the cortex. High frequency antidromic stimulation alone effectively suppressed simulated beta activity in both the cortex and STN-globus pallidus externa (GPe) network. High frequency orthodromic stimulation similarly suppressed beta activity within the STN and GPe through the direct stimulation of STN neurons driven by DBS at the same frequency as the stimulus. The combined effect of both antidromic and orthodromic stimulation modulated cortical activity antidromically while simultaneously orthodromically driving STN neurons. While high frequency DBS reduced STN beta-band power, low frequency stimulation resulted in resonant effects, increasing beta-band activity, consistent with previous experimental observations. The simulation results indicate effective suppression of simulated oscillatory activity through both antidromic stimulation of cortical neurons and direct orthodromic stimulation of STN neurons. The results of the study agree with experimental recordings of STN and cortical neurons in rats and support the therapeutic potential of stimulation of cortical neurons.

  13. Effects of antidromic and orthodromic activation of STN afferent axons during DBS in Parkinson's disease: a simulation study

    PubMed Central

    Kang, Guiyeom; Lowery, Madeleine M.

    2014-01-01

    Recent studies suggest that subthalamic nucleus (STN)-Deep Brain Stimulation (DBS) may exert at least part of its therapeutic effect through the antidromic suppression of pathological oscillations in the cortex in 6-OHDA treated rats and in parkinsonian patients. STN-DBS may also activate STN neurons by initiating action potential propagation in the orthodromic direction, similarly resulting in suppression of pathological oscillations in the STN. While experimental studies have provided strong evidence in support of antidromic stimulation of cortical neurons, it is difficult to separate relative contributions of antidromic and orthodromic effects of STN-DBS. The aim of this computational study was to examine the effects of antidromic and orthodromic activation on neural firing patterns and beta-band (13-30 Hz) oscillations in the STN and cortex during DBS of STN afferent axons projecting from the cortex. High frequency antidromic stimulation alone effectively suppressed simulated beta activity in both the cortex and STN-globus pallidus externa (GPe) network. High frequency orthodromic stimulation similarly suppressed beta activity within the STN and GPe through the direct stimulation of STN neurons driven by DBS at the same frequency as the stimulus. The combined effect of both antidromic and orthodromic stimulation modulated cortical activity antidromically while simultaneously orthodromically driving STN neurons. While high frequency DBS reduced STN beta-band power, low frequency stimulation resulted in resonant effects, increasing beta-band activity, consistent with previous experimental observations. The simulation results indicate effective suppression of simulated oscillatory activity through both antidromic stimulation of cortical neurons and direct orthodromic stimulation of STN neurons. The results of the study agree with experimental recordings of STN and cortical neurons in rats and support the therapeutic potential of stimulation of cortical neurons

  14. Efficacy and Safety of Elective Conversion From Sotrastaurin (STN) to Tacrolimus (TAC) or Mycophenolate (MPS) in Stable Kidney Transplant Recipients.

    PubMed

    Hannun, Pedro; Felipe, Claudia; Ferreira, Alexandra; Sandes-Freitas, Tainá; Cristelli, Marina; Aguiar, Wilson; Franco, Marcello; Campos, Erika; Gerbase de Lima, Maria; Tedesco-Silva, Hélio; Medina-Pestana, José

    2016-06-01

    This study aimed to evaluate the efficacy and safety outcomes of conversion strategies in stable kidney transplant recipients after premature termination of the sotrastaurin (STN) development program. This is an exploratory and prospective study, including 38 stable renal transplant recipients. Tacrolimus (TAC) group [STN → mycophenolate sodium (MPS)] consisted of 9 patients receiving TAC, STN, and prednisone that were converted from STN to MPS. Everolimus (EVR) group (STN → TAC) consisted of 29 patients receiving EVR, STN, and prednisone that were converted from STN to TAC. In TAC (STN → MPS) group, dose-adjusted TAC concentrations decreased from baseline to first week (2.3 ± 1.1 versus 1.5 ± 1.0 ng·mL·mg, P < 0.05). Two patients experienced a first acute rejection episode. Conversion to MPS was associated with a higher incidence of adverse events. In EVR (STN → TAC) group, dose-adjusted EVR concentrations decreased from baseline to first week (3.6 ± 2.3 ng·mL·mg versus 1.9 ± 0.8 ng·mL·mg, P < 0.01). The proportion of patients with donor-specific antibodies was lower in TAC (STN → MPS) (11%) compared to EVR (STN → TAC) (31%) before conversion. Conversion from STN to TAC was associated with a reduction in estimated glomerular filtration rate (69.6 ± 16.9 versus 61.0 ± 18.8 mL·min·1.73 m, P < 0.01) and a decreased proportion of patients with donor-specific antibodies (31% versus 14%) at 12 months. Conversion from TAC/STN to TAC/MPS or from EVR/STN to TAC/EVR was associated with significant pharmacokinetic changes in both TAC and EVR whole-blood trough concentrations due to known drug-to-drug interaction, which were associated with changes in efficacy and safety.

  15. Stn1–Ten1 is an Rpa2–Rpa3-like complex at telomeres

    PubMed Central

    Sun, Jia; Yu, Eun Young; Yang, Yuting; Confer, Laura A.; Sun, Steven H.; Wan, Ke; Lue, Neal F.; Lei, Ming

    2009-01-01

    In budding yeast, Cdc13, Stn1, and Ten1 form a heterotrimeric complex (CST) that is essential for telomere protection and maintenance. Previous bioinformatics analysis revealed a putative oligonucleotide/oligosaccharide-binding (OB) fold at the N terminus of Stn1 (Stn1N) that shows limited sequence similarity to the OB fold of Rpa2, a subunit of the eukaryotic ssDNA-binding protein complex replication protein A (RPA). Here we present functional and structural analyses of Stn1 and Ten1 from multiple budding and fission yeast. The crystal structure of the Candida tropicalis Stn1N complexed with Ten1 demonstrates an Rpa2N–Rpa3-like complex. In both structures, the OB folds of the two components pack against each other through interactions between two C-terminal helices. The structure of the C-terminal domain of Saccharomyces cerevisiae Stn1 (Stn1C) was found to comprise two related winged helix–turn–helix (WH) motifs, one of which is most similar to the WH motif at the C terminus of Rpa2, again supporting the notion that Stn1 resembles Rpa2. The crystal structure of the fission yeast Schizosaccharomyces pombe Stn1N–Ten1 complex exhibits a virtually identical architecture as the C. tropicalis Stn1N–Ten1. Functional analyses of the Candida albicans Stn1 and Ten1 proteins revealed critical roles for these proteins in suppressing aberrant telomerase and recombination activities at telomeres. Mutations that disrupt the Stn1–Ten1 interaction induce telomere uncapping and abolish the telomere localization of Ten1. Collectively, our structural and functional studies illustrate that, instead of being confined to budding yeast telomeres, the CST complex may represent an evolutionarily conserved RPA-like telomeric complex at the 3′ overhangs that works in parallel with or instead of the well-characterized POT1–TPP1/TEBPα–β complex. PMID:20008938

  16. Articulatory Changes in Vowel Production following STN DBS and Levodopa Intake in Parkinson's Disease.

    PubMed

    Martel Sauvageau, Vincent; Roy, Johanna-Pascale; Cantin, Léo; Prud'Homme, Michel; Langlois, Mélanie; Macoir, Joël

    2015-01-01

    Purpose. To investigate the impact of deep brain stimulation of the subthalamic nucleus (STN DBS) and levodopa intake on vowel articulation in dysarthric speakers with Parkinson's disease (PD). Methods. Vowel articulation was assessed in seven Quebec French speakers diagnosed with idiopathic PD who underwent STN DBS. Assessments were conducted on- and off-medication, first prior to surgery and then 1 year later. All recordings were made on-stimulation. Vowel articulation was measured using acoustic vowel space and formant centralization ratio. Results. Compared to the period before surgery, vowel articulation was reduced after surgery when patients were off-medication, while it was better on-medication. The impact of levodopa intake on vowel articulation changed with STN DBS: before surgery, levodopa impaired articulation, while it no longer had a negative effect after surgery. Conclusions. These results indicate that while STN DBS could lead to a direct deterioration in articulation, it may indirectly improve it by reducing the levodopa dose required to manage motor symptoms. These findings suggest that, with respect to speech production, STN DBS and levodopa intake cannot be investigated separately because the two are intrinsically linked. Along with motor symptoms, speech production should be considered when optimizing therapeutic management of patients with PD.

  17. Articulatory Changes in Vowel Production following STN DBS and Levodopa Intake in Parkinson's Disease

    PubMed Central

    Cantin, Léo; Prud'Homme, Michel; Langlois, Mélanie

    2015-01-01

    Purpose. To investigate the impact of deep brain stimulation of the subthalamic nucleus (STN DBS) and levodopa intake on vowel articulation in dysarthric speakers with Parkinson's disease (PD). Methods. Vowel articulation was assessed in seven Quebec French speakers diagnosed with idiopathic PD who underwent STN DBS. Assessments were conducted on- and off-medication, first prior to surgery and then 1 year later. All recordings were made on-stimulation. Vowel articulation was measured using acoustic vowel space and formant centralization ratio. Results. Compared to the period before surgery, vowel articulation was reduced after surgery when patients were off-medication, while it was better on-medication. The impact of levodopa intake on vowel articulation changed with STN DBS: before surgery, levodopa impaired articulation, while it no longer had a negative effect after surgery. Conclusions. These results indicate that while STN DBS could lead to a direct deterioration in articulation, it may indirectly improve it by reducing the levodopa dose required to manage motor symptoms. These findings suggest that, with respect to speech production, STN DBS and levodopa intake cannot be investigated separately because the two are intrinsically linked. Along with motor symptoms, speech production should be considered when optimizing therapeutic management of patients with PD. PMID:26558134

  18. Comparative study of microelectrode recording-based STN location and MRI-based STN location in low to ultra-high field (7.0 T) T2-weighted MRI images

    NASA Astrophysics Data System (ADS)

    Verhagen, Rens; Schuurman, P. Richard; van den Munckhof, Pepijn; Fiorella Contarino, M.; de Bie, Rob M. A.; Bour, Lo J.

    2016-12-01

    Objective. The correspondence between the anatomical STN and the STN observed in T2-weighted MRI images used for deep brain stimulation (DBS) targeting remains unclear. Using a new method, we compared the STN borders seen on MRI images with those estimated by intraoperative microelectrode recordings (MER). Approach. We developed a method to automatically generate a detailed estimation of STN shape and the location of its borders, based on multiple-channel MER measurements. In 33 STNs of 19 Parkinson patients, we quantitatively compared the dorsal and lateral borders of this MER-based STN model with the STN borders visualized by 1.5 T (n = 14), 3.0 T (n = 10) and 7.0 T (n = 9) T2-weighted MRI. Main results. The dorsal border was identified more dorsally on coronal T2 MRI than by the MER-based STN model, with a significant difference in the 3.0 T (range 0.97-1.19 mm) and 7.0 T (range 1.23-1.25 mm) groups. The lateral border was significantly more medial on 1.5 T (mean: 1.97 mm) and 3.0 T (mean: 2.49 mm) MRI than in the MER-based STN; a difference that was not found in the 7.0 T group. Significance. The STN extends further in the dorsal direction on coronal T2 MRI images than is measured by MER. Increasing MRI field strength to 3.0 T or 7.0 T yields similar discrepancies between MER and MRI at the dorsal STN border. In contrast, increasing MRI field strength to 7.0 T may be useful for identification of the lateral STN border and thereby improve DBS targeting.

  19. Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects.

    PubMed

    Simon, Amos J; Lev, Atar; Zhang, Yong; Weiss, Batia; Rylova, Anna; Eyal, Eran; Kol, Nitzan; Barel, Ortal; Cesarkas, Keren; Soudack, Michalle; Greenberg-Kushnir, Noa; Rhodes, Michele; Wiest, David L; Schiby, Ginette; Barshack, Iris; Katz, Shulamit; Pras, Elon; Poran, Hana; Reznik-Wolf, Haike; Ribakovsky, Elena; Simon, Carlos; Hazou, Wadi; Sidi, Yechezkel; Lahad, Avishay; Katzir, Hagar; Sagie, Shira; Aqeilan, Haifa A; Glousker, Galina; Amariglio, Ninette; Tzfati, Yehuda; Selig, Sara; Rechavi, Gideon; Somech, Raz

    2016-07-25

    The analysis of individuals with telomere defects may shed light on the delicate interplay of factors controlling genome stability, premature aging, and cancer. We herein describe two Coats plus patients with telomere and genomic defects; both harbor distinct, novel mutations in STN1, a member of the human CTC1-STN1-TEN1 (CST) complex, thus linking this gene for the first time to a human telomeropathy. We characterized the patients' phenotype, recapitulated it in a zebrafish model and rescued cellular and clinical aspects by the ectopic expression of wild-type STN1 or by thalidomide treatment. Interestingly, a significant lengthy control of the gastrointestinal bleeding in one of our patients was achieved by thalidomide treatment, exemplifying a successful bed-to-bench-and-back approach.

  20. Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects

    PubMed Central

    Simon, Amos J.; Lev, Atar; Zhang, Yong; Weiss, Batia; Rylova, Anna; Eyal, Eran; Kol, Nitzan; Cesarkas, Keren; Rhodes, Michele; Schiby, Ginette; Barshack, Iris; Katz, Shulamit; Reznik-Wolf, Haike; Ribakovsky, Elena; Simon, Carlos; Hazou, Wadi; Katzir, Hagar; Sagie, Shira; Amariglio, Ninette; Rechavi, Gideon

    2016-01-01

    The analysis of individuals with telomere defects may shed light on the delicate interplay of factors controlling genome stability, premature aging, and cancer. We herein describe two Coats plus patients with telomere and genomic defects; both harbor distinct, novel mutations in STN1, a member of the human CTC1–STN1–TEN1 (CST) complex, thus linking this gene for the first time to a human telomeropathy. We characterized the patients’ phenotype, recapitulated it in a zebrafish model and rescued cellular and clinical aspects by the ectopic expression of wild-type STN1 or by thalidomide treatment. Interestingly, a significant lengthy control of the gastrointestinal bleeding in one of our patients was achieved by thalidomide treatment, exemplifying a successful bed-to-bench-and-back approach. PMID:27432940

  1. Inhibition of Serratia marcescens Smj-11 biofilm formation by Alcaligenes faecalis STN17 crude extract

    SciTech Connect

    Lutfi, Zainal; Ahmad, Asmat; Usup, Gires

    2014-09-03

    Serratia marcescens biofilms are formed when they are bound to surfaces in aqueous environments. S. marcescens utilizes N-acylhomoserine lactone (AHL) as its quorum sensing signal molecule. The accumulation of AHL indicates the bacteria to produce matrices to form biofilms. Prodigiosin (2-methyl-3-pentyl-6-methoxyprodigiosin), which causes red pigmentation in the colonies, are also produced when the AHL reaches a certain threshold. The Alcaligenes faecalis STN17 crude extract is believed to inhibit quorum sensing in the S. marcescens Smj-11 and, thus, impedes its biofilm formation ability. A. faecalis STN17 was grown in marine broth, and ethyl acetate extraction was carried out. The crude compound of A. faecalis STN17 was diluted at high concentration (0.2-6.4 mg/mL) and was taken to confirm anti-biofilm activity through the crystal violet method in 96-wells plate. Then, the crude extract underwent purification using simple solvents partitioning test to discern the respective compounds that had the anti-biofilm activity under the crystal violet method. The crystal violet test showed that the crude did have anti-biofilm activity on S. marcescens Smj-11, but did not kill the cells. This finding signifies that the suppression of biofilm formation in S. marcescens by A. faecalis STN17 has a strong correlation. The partitioning test showed that A. faecalis STN17 crude extract has several compounds and only the compound(s) in chloroform showed activities. In conclusion, the crude extract of A. faecalis STN17 has the ability to inhibit S. marcescens Smj-11 biofilm formation.

  2. Inhibition of Serratia marcescens Smj-11 biofilm formation by Alcaligenes faecalis STN17 crude extract

    NASA Astrophysics Data System (ADS)

    Lutfi, Zainal; Usup, Gires; Ahmad, Asmat

    2014-09-01

    Serratia marcescens biofilms are formed when they are bound to surfaces in aqueous environments. S. marcescens utilizes N-acylhomoserine lactone (AHL) as its quorum sensing signal molecule. The accumulation of AHL indicates the bacteria to produce matrices to form biofilms. Prodigiosin (2-methyl-3-pentyl-6-methoxyprodigiosin), which causes red pigmentation in the colonies, are also produced when the AHL reaches a certain threshold. The Alcaligenes faecalis STN17 crude extract is believed to inhibit quorum sensing in the S. marcescens Smj-11 and, thus, impedes its biofilm formation ability. A. faecalis STN17 was grown in marine broth, and ethyl acetate extraction was carried out. The crude compound of A. faecalis STN17 was diluted at high concentration (0.2-6.4 mg/mL) and was taken to confirm anti-biofilm activity through the crystal violet method in 96-wells plate. Then, the crude extract underwent purification using simple solvents partitioning test to discern the respective compounds that had the anti-biofilm activity under the crystal violet method. The crystal violet test showed that the crude did have anti-biofilm activity on S. marcescens Smj-11, but did not kill the cells. This finding signifies that the suppression of biofilm formation in S. marcescens by A. faecalis STN17 has a strong correlation. The partitioning test showed that A. faecalis STN17 crude extract has several compounds and only the compound(s) in chloroform showed activities. In conclusion, the crude extract of A. faecalis STN17 has the ability to inhibit S. marcescens Smj-11 biofilm formation.

  3. Using STN DBS and medication reduction as a strategy to treat pathological gambling in Parkinson's disease.

    PubMed

    Bandini, Fabio; Primavera, Alberto; Pizzorno, Matteo; Cocito, Leonardo

    2007-08-01

    We describe two patients with Parkinson's disease (PD) who developed clinical criteria of pathological gambling addiction in the setting of increased dopamine replacement therapy (levodopa and dopamine agonist medications). The second patient showed also signs of dopamine dysregulation syndrome, with an addiction to dopaminergic medication. Neither patients responded to the standard therapy for gambling behavior, but dramatically improved after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) and early postoperative withdrawal of dopaminergic therapy. The possible therapeutic role of subthalamic nucleus deep brain stimulation (STN-DBS) on such a disabling behavior needs to be investigated prospectively.

  4. STN vs. GPi Deep Brain Stimulation: Translating the Rematch into Clinical Practice

    PubMed Central

    Williams, Nolan R.; Foote, Kelly D.; Okun, Michael S.

    2014-01-01

    When formulating a deep brain stimulation (DBS) treatment plan for a patient with Parkinson’s disease (PD), two critical questions should be addressed: 1- Which brain target should be chosen to optimize this patient’s outcome? and 2- Should this patient’s DBS operation be unilateral or bilateral? Over the past two decades, two targets have emerged as leading contenders for PD DBS; the subthalamic nucleus (STN) and the globus pallidus internus (GPi). While the GPi target does have a following, most centers have uniformly employed bilateral STN DBS for all Parkinson’s disease cases (Figure 1). This bilateral STN “one-size-fits-all” approach was challenged by an editorial entitled “STN vs. GPi: The Rematch,” which appeared in the Archives of Neurology in 2005. Since 2005, a series of well designed clinical trials and follow-up studies have addressed the question as to whether a more tailored approach to DBS therapy might improve overall outcomes. Such a tailored approach would include the options of targeting the GPi, or choosing a unilateral operation. The results of the STN vs. GPi ‘rematch’ studies support the conclusion that bilateral STN DBS may not be the best option for every Parkinson’s disease surgical patient. Off period motor symptoms and tremor improve in both targets, and with either unilateral or bilateral stimulation. Advantages of the STN target include more medication reduction, less frequent battery changes, and a more favorable economic profile. Advantages of GPi include more robust dyskinesia suppression, easier programming, and greater flexibility in adjusting medications. In cases where unilateral stimulation is anticipated, the data favor GPi DBS. This review summarizes the accumulated evidence regarding the use of bilateral vs. unilateral DBS and the selection of STN vs. GPi DBS, including definite and possible advantages of different targets and approaches. Based on this evidence, a more patient-tailored, symptom specific

  5. Role of STN1 and DNA Polymerase α in Telomere Stability and Genome-Wide Replication in Arabidopsis

    PubMed Central

    Derboven, Elisa; Ekker, Heinz; Kusenda, Branislav; Bulankova, Petra; Riha, Karel

    2014-01-01

    The CST (Cdc13/CTC1-STN1-TEN1) complex was proposed to have evolved kingdom specific roles in telomere capping and replication. To shed light on its evolutionary conserved function, we examined the effect of STN1 dysfunction on telomere structure in plants. STN1 inactivation in Arabidopsis leads to a progressive loss of telomeric DNA and the onset of telomeric defects depends on the initial telomere size. While EXO1 aggravates defects associated with STN1 dysfunction, it does not contribute to the formation of long G-overhangs. Instead, these G-overhangs arise, at least partially, from telomerase-mediated telomere extension indicating a deficiency in C-strand fill-in synthesis. Analysis of hypomorphic DNA polymerase α mutants revealed that the impaired function of a general replication factor mimics the telomeric defects associated with CST dysfunction. Furthermore, we show that STN1-deficiency hinders re-replication of heterochromatic regions to a similar extent as polymerase α mutations. This comparative analysis of stn1 and pol α mutants suggests that STN1 plays a genome-wide role in DNA replication and that chromosome-end deprotection in stn1 mutants may represent a manifestation of aberrant replication through telomeres. PMID:25299252

  6. The Role of Stn1p in Saccharomyces cerevisiae Telomere Capping Can Be Separated From Its Interaction With Cdc13p

    PubMed Central

    Petreaca, Ruben C.; Chiu, Huan-Chih; Nugent, Constance I.

    2007-01-01

    The function of telomeres is twofold: to facilitate complete chromosome replication and to protect chromosome ends against fusions and illegitimate recombination. In the budding yeast Saccharomyces cerevisiae, interactions among Cdc13p, Stn1p, and Ten1p are thought to be critical for promoting these processes. We have identified distinct Stn1p domains that mediate interaction with either Ten1p or Cdc13p, allowing analysis of whether the interaction between Cdc13p and Stn1p is indeed essential for telomere capping or length regulation. Consistent with the model that the Stn1p essential function is to promote telomere end protection through Cdc13p, stn1 alleles that truncate the C-terminal 123 residues fail to interact with Cdc13p and do not support viability when expressed at endogenous levels. Remarkably, more extensive deletions that remove an additional 185 C-terminal residues from Stn1p now allow cell growth at endogenous expression levels. The viability of these stn1-t alleles improves with increasing expression level, indicating that increased stn1-t dosage can compensate for the loss of Cdc13p–Stn1p interaction. However, telomere length is misregulated at all expression levels. Thus, an amino-terminal region of Stn1p is sufficient for its essential function, while a central region of Stn1p either negatively regulates the STN1 essential function or destabilizes the mutant Stn1 protein. PMID:17947422

  7. SOURCE APPORTIONMENT OF SEATTLE PM 2.5 USING STN ORGANIC CARBON PEAKS

    EPA Science Inventory

    Results from the Source Apportionment of Seattle PM2.5 Using STN Organic Carbon Peaks study will be presented at the American Association for Aerosol Research (AAAR) 24th Annual Conference in Austin, Texas (Oct 17 - 21, 2005). Receptor modeling results from Seattle us...

  8. STN area detection using K-NN classifiers for MER recordings in Parkinson patients during neurostimulator implant surgery

    NASA Astrophysics Data System (ADS)

    Schiaffino, L.; Rosado Muñoz, A.; Guerrero Martínez, J.; Francés Villora, J.; Gutiérrez, A.; Martínez Torres, I.; Kohan, y. D. R.

    2016-04-01

    Deep Brain Stimulation (DBS) applies electric pulses into the subthalamic nucleus (STN) improving tremor and other symptoms associated to Parkinson’s disease. Accurate STN detection for proper location and implant of the stimulating electrodes is a complex task and surgeons are not always certain about final location. Signals from the STN acquired during DBS surgery are obtained with microelectrodes, having specific characteristics differing from other brain areas. Using supervised learning, a trained model based on previous microelectrode recordings (MER) can be obtained, being able to successfully classify the STN area for new MER signals. The K Nearest Neighbours (K-NN) algorithm has been successfully applied to STN detection. However, the use of the fuzzy form of the K-NN algorithm (KNN-F) has not been reported. This work compares the STN detection algorithm of K-NN and KNN-F. Real MER recordings from eight patients where previously classified by neurophysiologists, defining 15 features. Sensitivity and specificity for the classifiers are obtained, Wilcoxon signed rank non-parametric test is used as statistical hypothesis validation. We conclude that the performance of KNN-F classifier is higher than K-NN with p<0.01 in STN specificity.

  9. Coordinated reset stimulation in a large-scale model of the STN-GPe circuit

    PubMed Central

    Ebert, Martin; Hauptmann, Christian; Tass, Peter A.

    2014-01-01

    Synchronization of populations of neurons is a hallmark of several brain diseases. Coordinated reset (CR) stimulation is a model-based stimulation technique which specifically counteracts abnormal synchrony by desynchronization. Electrical CR stimulation, e.g., for the treatment of Parkinson's disease (PD), is administered via depth electrodes. In order to get a deeper understanding of this technique, we extended the top-down approach of previous studies and constructed a large-scale computational model of the respective brain areas. Furthermore, we took into account the spatial anatomical properties of the simulated brain structures and incorporated a detailed numerical representation of 2 · 104 simulated neurons. We simulated the subthalamic nucleus (STN) and the globus pallidus externus (GPe). Connections within the STN were governed by spike-timing dependent plasticity (STDP). In this way, we modeled the physiological and pathological activity of the considered brain structures. In particular, we investigated how plasticity could be exploited and how the model could be shifted from strongly synchronized (pathological) activity to strongly desynchronized (healthy) activity of the neuronal populations via CR stimulation of the STN neurons. Furthermore, we investigated the impact of specific stimulation parameters especially the electrode position on the stimulation outcome. Our model provides a step forward toward a biophysically realistic model of the brain areas relevant to the emergence of pathological neuronal activity in PD. Furthermore, our model constitutes a test bench for the optimization of both stimulation parameters and novel electrode geometries for efficient CR stimulation. PMID:25505882

  10. Reduction of influence of task difficulty on perceptual decision making by STN deep brain stimulation.

    PubMed

    Green, Nikos; Bogacz, Rafal; Huebl, Julius; Beyer, Ann-Kristin; Kühn, Andrea A; Heekeren, Hauke R

    2013-09-09

    Neurocomputational models of optimal decision making ascribe a crucial role-the computation of conflict between choice alternatives-to the subthalamic nucleus (STN). Specifically, these models predict that deep brain stimulation (DBS) of the STN will diminish the influence of decision conflict on decision making. In this work, patients with Parkinson's disease judged the direction of motion in random dot stimuli while ON and OFF DBS. To induce decision conflict, we varied the task difficulty (motion coherence), leading to increased reaction time (RT) in trials with greater task difficulty in healthy subjects. Results indicate that DBS significantly influences performance for perceptual decisions under high decision conflict. RT increased substantially OFF DBS as the task became more difficult, and a diffusion model best accounted for behavioral data. In contrast, ON DBS, the influence of task difficulty on RT was significantly reduced and a race model best accounted for the observed data. Individual data fits of evidence accumulation models demonstrate different information processing under distinct DBS states. Furthermore, ON DBS, speed-accuracy tradeoffs affected the magnitude of decision criterion adjustment significantly less compared to OFF DBS. Together, these findings suggest a crucial role for the STN in adjusting decision making during high-conflict trials in perceptual decision making.

  11. Locating the STN-DBS electrodes and resolving their subsequent networks using coherent source analysis on EEG.

    PubMed

    Muthuraman, M; Paschen, S; Hellriegel, H; Groppa, S; Deuschl, G; Raethjen, J

    2012-01-01

    The deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most effective surgical therapy for Parkinson's disease (PD). The first aim of the study was to locate the STN-DBS electrode by applying source analysis on EEG. Secondly, to identify tremor related areas which are associated with the STN. The Dynamic imaging of coherent sources (DICS) was used to find the coherent sources in the brain. The capability of the source analysis to detect deep sources like STN in the brain using EEG data was tested with two model dipole simulations. The simulations were concentrated on two aspects, the angle of the dipole orientation and the disturbance of the cortical areas on locating subcortical regions. In all the DBS treated Parkinsonian tremor patients the power spectrum showed a clear peak at the stimulated frequency and followed by there harmonics. The DBS stimulated frequency constituted a network of primary sensory motor cortex, supplementary motor area, prefrontal cortex, diencephalon, cerebellum and brainstem. Thus the STN was located in the region of the diencephalon. The resolved network may give better understanding to the pathophysiology of the effected tremor network in PD patients with STN-DBS.

  12. Differential modulation of STN-cortical and cortico-muscular coherence by movement and levodopa in Parkinson's disease.

    PubMed

    Hirschmann, J; Özkurt, T E; Butz, M; Homburger, M; Elben, S; Hartmann, C J; Vesper, J; Wojtecki, L; Schnitzler, A

    2013-03-01

    Previous research suggests that oscillatory coupling between cortex, basal ganglia and muscles plays an important role in motor behavior. Furthermore, there is evidence that oscillatory coupling is altered in patients with movement disorders such as Parkinson's disease (PD). In this study, we performed simultaneous magnetoencephalography (MEG), local field potential (LFP) and electromyogram (EMG) recordings in PD patients selected for therapeutic subthalamic nucleus (STN) stimulation. Patients were recorded (i) after withdrawal of anti-parkinsonian medication (OFF) and (ii) after levodopa administration (ON). We analyzed STN-cortical and cortico-muscular coherence during static forearm contraction and repetitive hand movement in order to evaluate modulations of coherence by movement and medication. Based on previous results from studies investigating resting state coherence in PD patients, we selected primary motor cortex (M1) and superior temporal gyrus (STG) as regions of interest. We found beta coherence between M1 and STN to be suppressed by administration of levodopa. M1-muscular coherence was strongly reduced in the alpha and beta band during repetitive movement compared to static contraction, but was unaffected by administration of levodopa. Strong STG-STN but not STG-muscular coherence could be observed in the alpha band. Coherence with STG was modulated neither by movement nor by medication. Finally, we found both M1-STN and M1-muscular beta coherence to be negatively correlated with UPDRS akinesia and rigidity sub-scores in the OFF state. The present study provides new insights into the functional roles of STN-cortical and cortico-muscular coherence and their relationship to PD symptoms. The results indicate that STN-cortical and cortico-muscular coupling are correlated, but can be modulated independently. Moreover, they show differences in their frequency-specific topography. We conclude that they represent partly independent sub-loops within the motor

  13. ATR cooperates with CTC1 and STN1 to maintain telomeres and genome integrity in Arabidopsis.

    PubMed

    Boltz, Kara A; Leehy, Katherine; Song, Xiangyu; Nelson, Andrew D; Shippen, Dorothy E

    2012-04-01

    The CTC1/STN1/TEN1 (CST) complex is an essential constituent of plant and vertebrate telomeres. Here we show that CST and ATR (ataxia telangiectasia mutated [ATM] and Rad3-related) act synergistically to maintain telomere length and genome stability in Arabidopsis. Inactivation of ATR, but not ATM, temporarily rescued severe morphological phenotypes associated with ctc1 or stn1. Unexpectedly, telomere shortening accelerated in plants lacking CST and ATR. In first-generation (G1) ctc1 atr mutants, enhanced telomere attrition was modest, but in G2 ctc1 atr, telomeres shortened precipitously, and this loss coincided with a dramatic decrease in telomerase activity in G2 atr mutants. Zeocin treatment also triggered a reduction in telomerase activity, suggesting that the prolonged absence of ATR leads to a hitherto-unrecognized DNA damage response (DDR). Finally, our data indicate that ATR modulates DDR in CST mutants by limiting chromosome fusions and transcription of DNA repair genes and also by promoting programmed cell death in stem cells. We conclude that the absence of CST in Arabidopsis triggers a multifaceted ATR-dependent response to facilitate maintenance of critically shortened telomeres and eliminate cells with severe telomere dysfunction.

  14. Distinct effects of dopamine vs STN stimulation therapies in associative learning and retention in Parkinson disease.

    PubMed

    Ventre-Dominey, Jocelyne; Mollion, Hélène; Thobois, Stephane; Broussolle, Emmanuel

    2016-04-01

    Evidence has been provided in Parkinson's disease patients of cognitive impairments including visual memory and learning which can be partially compensated by dopamine medication or subthalamic nucleus stimulation. The effects of these two therapies can differ according to the learning processes involving the dorsal vs ventral part of the striatum. Here we aimed to investigate and compare the outcomes of dopamine vs stimulation treatment in Parkinson patient's ability to acquire and maintain over successive days their performance in visual working memory. Parkinson patients performed conditional associative learning embedded in visual (spatial and non spatial) working memory tasks over two consecutive days either ON or OFF dopaminergic drugs or STN stimulation depending on the group of patients studied. While Parkinson patients were more accurate and faster in memory tasks ON vs OFF stimulation independent of the day of testing, performance in medicated patients differed depending on the medication status during the initial task acquisition. Patients who learnt the task ON medication the first day were able to maintain or even improve their memory performance both OFF and ON medication on the second day after consolidation. These effects were observed only in patients with dopamine replacement with or without motor fluctuations. This enhancement in memory performance after having learnt under dopamine medication and not under STN stimulation was mostly significant in visuo-spatial working memory tasks suggesting that dopamine replacement in the depleted dorsal striatum is essential for retention and consolidation of learnt skill. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Crystal Structure of StnA for the Biosynthesis of Antitumor Drug Streptonigrin Reveals a Unique Substrate Binding Mode

    PubMed Central

    Qian, Tianle; Wo, Jing; Zhang, Yan; Song, Quanwei; Feng, Guoqiang; Luo, Ray; Lin, Shuangjin; Wu, Geng; Chen, Hai-Feng

    2017-01-01

    Streptonigrin methylesterase A (StnA) is one of the tailoring enzymes that modify the aminoquinone skeleton in the biosynthesis pathway of Streptomyces species. Although StnA has no significant sequence homology with the reported α/β-fold hydrolases, it shows typical hydrolytic activity in vivo and in vitro. In order to reveal its functional characteristics, the crystal structures of the selenomethionine substituted StnA (SeMet-StnA) and the complex (S185A mutant) with its substrate were resolved to the resolution of 2.71 Å and 2.90 Å, respectively. The overall structure of StnA can be described as an α-helix cap domain on top of a common α/β hydrolase domain. The substrate methyl ester of 10′-demethoxystreptonigrin binds in a hydrophobic pocket that mainly consists of cap domain residues and is close to the catalytic triad Ser185-His349-Asp308. The transition state is stabilized by an oxyanion hole formed by the backbone amides of Ala102 and Leu186. The substrate binding appears to be dominated by interactions with several specific hydrophobic contacts and hydrogen bonds in the cap domain. The molecular dynamics simulation and site-directed mutagenesis confirmed the important roles of the key interacting residues in the cap domain. Structural alignment and phylogenetic tree analysis indicate that StnA represents a new subfamily of lipolytic enzymes with the specific binding pocket located at the cap domain instead of the interface between the two domains. PMID:28074848

  16. Emotion recognition in Parkinson's disease after subthalamic deep brain stimulation: differential effects of microlesion and STN stimulation.

    PubMed

    Aiello, Marilena; Eleopra, Roberto; Lettieri, Christian; Mondani, Massimo; D'Auria, Stanislao; Belgrado, Enrico; Piani, Antonella; De Simone, Luca; Rinaldo, Sara; Rumiati, Raffaella I

    2014-02-01

    Deep brain stimulation of the subthalamic nucleus (STN-DBS) has acquired a relevant role in the treatment of Parkinson's disease (PD). Despite being a safe procedure, it may expose patients to an increased risk to experience cognitive and emotional difficulties. Impairments in emotion recognition, mediated both by facial and prosodic expressions, have been reported in PD patients treated with such procedure. However, it is still unclear whether the STN per se is responsible for such changes or whether others factors like the microlesion produced by the electrode implantation may also play a role. In this study we evaluated facial emotions discrimination and emotions recognition using both facial and prosodic expressions in 12 patients with PD and 13 matched controls. Patients' were tested in four conditions: before surgery, both in on and off medication, and after surgery, respectively few days after STN implantation before turning stimulator on and few months after with stimulation on. We observed that PD patients were impaired in discriminating and recognizing facial emotions, especially disgust, even before DBS implant. Microlesion caused by surgical procedure was found to influence patients' performance on the discrimination task and recognition of sad facial expression while, after a few months of STN stimulation, impaired disgust recognition was again prominent. No impairment in emotional prosody recognition was observed both before and after surgery. Our study confirms that PD patients may experience a deficit in disgust recognition and provides insight into the differential effect of microlesion and stimulation of STN on several tasks assessing emotion recognition. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. A Multiple Kernel Learning approach for human behavioral task classification using STN-LFP signal.

    PubMed

    Golshan, Hosein M; Hebb, Adam O; Hanrahan, Sara J; Nedrud, Joshua; Mahoor, Mohammad H

    2016-08-01

    Deep Brain Stimulation (DBS) has gained increasing attention as an effective method to mitigate Parkinson's disease (PD) disorders. Existing DBS systems are open-loop such that the system parameters are not adjusted automatically based on patient's behavior. Classification of human behavior is an important step in the design of the next generation of DBS systems that are closed-loop. This paper presents a classification approach to recognize such behavioral tasks using the subthalamic nucleus (STN) Local Field Potential (LFP) signals. In our approach, we use the time-frequency representation (spectrogram) of the raw LFP signals recorded from left and right STNs as the feature vectors. Then these features are combined together via Support Vector Machines (SVM) with Multiple Kernel Learning (MKL) formulation. The MKL-based classification method is utilized to classify different tasks: button press, mouth movement, speech, and arm movement. Our experiments show that the lp-norm MKL significantly outperforms single kernel SVM-based classifiers in classifying behavioral tasks of five subjects even using signals acquired with a low sampling rate of 10 Hz. This leads to a lower computational cost.

  18. Compensatory stepping in Parkinson's disease is still a problem after deep brain stimulation randomized to STN or GPi

    PubMed Central

    St George, R. J.; Carlson-Kuhta, P.; King, L. A.; Burchiel, K. J.

    2015-01-01

    The effects of deep brain stimulation (DBS) on balance in people with Parkinson's disease (PD) are not well established. This study examined whether DBS randomized to the subthalamic nucleus (STN; n = 11) or globus pallidus interna (GPi; n = 10) improved compensatory stepping to recover balance after a perturbation. The standing surface translated backward, forcing subjects to take compensatory steps forward. Kinematic and kinetic responses were recorded. PD-DBS subjects were tested off and on their levodopa medication before bilateral DBS surgery and retested 6 mo later off and on DBS, combined with off and on levodopa medication. Responses were compared with PD-control subjects (n = 8) tested over the same timescale and 17 healthy control subjects. Neither DBS nor levodopa improved the stepping response. Compensatory stepping in the best-treated state after surgery (DBS+DOPA) was similar to the best-treated state before surgery (DOPA) for the PD-GPi group and the PD-control group. For the PD-STN group, there were more lateral weight shifts, a delayed foot-off, and a greater number of steps required to recover balance in DBS+DOPA after surgery compared with DOPA before surgery. Within the STN group five subjects who did not fall during the experiment before surgery fell at least once after surgery, whereas the number of falls in the GPi and PD-control groups were unchanged. DBS did not improve the compensatory step response needed to recover from balance perturbations in the GPi group and caused delays in the preparation phase of the step in the STN group. PMID:26108960

  19. Cdk1 Regulates the Temporal Recruitment of Telomerase and Cdc13-Stn1-Ten1 Complex for Telomere Replication

    PubMed Central

    Liu, Chang-Ching; Gopalakrishnan, Veena; Poon, Lai-Fong; Yan, TingDong

    2014-01-01

    In budding yeast (Saccharomyces cerevisiae), the cell cycle-dependent telomere elongation by telomerase is controlled by the cyclin-dependent kinase 1 (Cdk1). The telomere length homeostasis is balanced between telomerase-unextendable and telomerase-extendable states that both require Cdc13. The recruitment of telomerase complex by Cdc13 promotes telomere elongation, while the formation of Cdc13-Stn1-Ten1 (CST) complex at the telomere blocks telomere elongation by telomerase. However, the cellular signaling that regulates the timing of the telomerase-extendable and telomerase-unextendable states is largely unknown. Phosphorylation of Cdc13 by Cdk1 promotes the interaction between Cdc13 and Est1 and hence telomere elongation. Here, we show that Cdk1 also phosphorylates Stn1 at threonine 223 and serine 250 both in vitro and in vivo, and these phosphorylation events are essential for the stability of the CST complexes at the telomeres. By controlling the timing of Cdc13 and Stn1 phosphorylations during cell cycle progression, Cdk1 regulates the temporal recruitment of telomerase complexes and CST complexes to the telomeres to facilitate telomere maintenance. PMID:24164896

  20. The role of cancer vaccines following autologous stem cell rescue in breast and ovarian cancer patients: experience with the STn-KLH vaccine (Theratope).

    PubMed

    Holmberg, Leona A; Oparin, Dimitri V; Gooley, Ted; Sandmaier, Brenda M

    2003-02-01

    The success of high-dose chemotherapy followed by autologous stem-cell rescue as treatment for breast and ovarian cancer is limited by a high incidence of relapse. After autologous transplantation, patients are likely to have a low tumor burden and thus would be more likely to respond immunologically to a cancer vaccine. Sialyl-Tn (STn) is a carbohydrate associated with the MUC1 mucin on breast and ovarian cancer and is an ideal candidate for vaccine immunotherapy. Sialyl-Tn-keyhole limpet hemocyanin (STn-KLH) vaccine (Theratope) incorporates a synthetic STn antigen that mimics the unique tumor-associated STn carbohydrate and is designed to stimulate tumor antigen-specific immune responses in patients with mucin-expressing tumors. Between 1995 and 2000, 70 patients (16 with stage II/III breast cancer, 17 with stage III/IV ovarian cancer, and 37 with stage IV breast cancer) were treated with 2 different formulations of STn-KLH. Toxicity, outcome, and immune response data are reported. STn-KLH was well-tolerated with minimal toxicity. The most common side effects were indurations and erythema at the sites of injections. Humoral and cellular responses were elicited in the majority of patients. Overall, these data indicate that post-autologous transplant patients are able to mount an effective immune response to vaccine immunotherapy with minimal side effects, and that vaccine immunotherapy may be a useful addition to high-dose chemotherapy regimens.

  1. Weight Changes in STN versus GPi DBS: Results from the COMPARE Parkinson’s Disease DBS Cohort

    PubMed Central

    Locke, Maren; Wu, Samuel; Foote, Kelly; Sassi, Marco; Jacobson, Charles; Rodriguez, Ramon; Fernandez, Hubert; Okun, Michael

    2011-01-01

    Background Parkinson’s patients, on average, gain weight following DBS. Objective To determine potential differences in weight gain when comparing the STN versus the GPi target. Methods A retrospective analysis was performed on the prospective randomized cohort of NIH COMPARE DBS patients who received unilateral STN or GPi DBS. Baseline weights were recorded prior to DBS surgery and at 6, 12, and 18 months post-operatively. Relationships between weight change and changes in BDI score, UPDRS motor score (part III) (also the dyskinesia duration and disability subscores from UPDRS IV), and HY stage were determined via Spearman’s rank order correlation coefficients. Regression analyses were performed to investigate the effects of potential factors on weight change over time. Results Patients in the COMPARE DBS cohort gained a significant amount of weight-a mean of 4.86 lbs (SD 8.73) (p-value = 0.0006), but there was no significant difference between STN and GPi targets (weight gain of 4.29± 6.79 and 5.38±10.32 pounds, respectively; p-value = 0.684). Weight gain did not correlate with BDI score change, UPDRS motor score, dyskinesia duration, dyskinesia disability change, or the HY stage (p-values were0.617, 0.210, and 0.305 respectively). No specific variable was associated with weight gain, and there were no differences in binge eating post-surgery in either target. Conclusion There were significant changes in weight over time following DBS therapy. However, neither BDI score change nor UPDRS score change or dyskinesia was correlated with weight gain. No significant factor was associated with the weight change. PMID:21273927

  2. Intracranial air correlates with preoperative cerebral atrophy and stereotactic error during bilateral STN DBS surgery for Parkinson's disease.

    PubMed

    Azmi, Hooman; Machado, Andre; Deogaonkar, Milind; Rezai, Ali

    2011-01-01

    We examine the effect of intracranial air on stereotactic accuracy during bilateral deep brain stimulation (DBS) surgery for Parkinson's disease (PD). We also assess factors that may predict an increased risk of intracranial air during these surgeries. 32 patients with PD underwent bilateral DBS surgery. The technique used for implantation of the leads has been standardized in over 800 subthalamic nucleus (STN) implantations. For lead implantation, the goal of the neurophysiological technique is identification of the STN and its borders with 3 microelectrode recording (MER) tracks. We examined the number of tracks and the degree of deviation from the planned target on each side. Total intracranial air (TIA) was then compared in these groups. We also examined the relationship between the TIA and length of surgery, ventricular volume and the degree of atrophy. Side 2 in this series required more MER tracks. The TIA was larger in patients with more than 3 MER tracks on side 2 of surgery. There was more deviation from the target on side 2. In addition, the TIA in patients with >1 mm of vector deviation on side 2 was more than in those without. The TIA correlated with the number of tracks on side 2 as well as with the degree of the second euclidean deviation on side 2. There was a correlation of degree of atrophy with TIA. In bilateral STN DBS for PD, intracranial air may contribute to error in stereotactic accuracy especially on the second side. In addition, there is a correlation between the accumulated volume of intracranial air and the degree of cerebral atrophy. Copyright © 2011 S. Karger AG, Basel.

  3. Reappraising contemporary theories of subcortical participation in language: proposing an interhemispheric regulatory function for the subthalamic nucleus (STN) in the mediation of high-level linguistic processes.

    PubMed

    Whelan, Brooke-Mai; Murdoch, Bruce E; Theodoros, Deborah G; Silburn, Peter; Hall, Bruce

    2004-02-01

    Apropos the basal ganglia, the dominant striatum and globus pallidus internus (GPi) have been hypothesised to represent integral components of subcortical language circuitry. Working subcortical language theories, however, have failed thus far to consider a role for the STN in the mediation of linguistic processes, a structure recently defined as the driving force of basal ganglia output. The aim of this research was to investigate the impact of surgically induced functional inhibition of the STN upon linguistic abilities, within the context of established models of basal ganglia participation in language. Two males with surgically induced 'lesions' of the dominant and non-dominant dorsolateral STN, aimed at relieving Parkinsonian motor symptoms, served as experimental subjects. General and high-level language profiles were compiled for each subject up to 1 month prior to and 3 months following neurosurgery, within the drug-on state (i.e., when optimally medicated). Comparable post-operative alterations in linguistic performance were observed subsequent to surgically induced functional inhibition of the left and right STN. More specifically, higher proportions of reliable decline as opposed to improvement in post-operative performance were demonstrated by both subjects on complex language tasks, hypothesised to entail the interplay of cognitive-linguistic processes. The outcomes of the current research challenge unilateralised models of functional basal ganglia organisation with the proposal of a potential interhemispheric regulatory function for the STN in the mediation of high-level linguistic processes.

  4. The STN8 kinase-PBCP phosphatase system is responsible for high-light-induced reversible phosphorylation of the PSII inner antenna subunit CP29 in rice.

    PubMed

    Betterle, Nico; Poudyal, Roshan Sharma; Rosa, Anthony; Wu, Guangxi; Bassi, Roberto; Lee, Choon-Hwan

    2017-02-01

    Reversible phosphorylation of thylakoid light-harvesting proteins is a mechanism to compensate for unbalanced excitation of photosystem I (PSI) versus photosystem II (PSII) under limiting light. In monocots, an additional phosphorylation event on the PSII antenna CP29 occurs upon exposure to excess light, enhancing resistance to light stress. Different from the case of the major LHCII antenna complex, the STN7 kinase and its related PPH1 phosphatase were proven not to be involved in CP29 phosphorylation, indicating that a different set of enzymes act in the high-light (HL) response. Here, we analyze a rice stn8 mutant in which both PSII core proteins and CP29 phosphorylation are suppressed in HL, implying that STN8 is the kinase catalyzing this reaction. In order to identify the phosphatase involved, we produced a recombinant enzyme encoded by the rice ortholog of AtPBCP, antagonist of AtSTN8, which catalyzes the dephosphorylation of PSII core proteins. The recombinant protein was active in dephosphorylating P-CP29. Based on these data, we propose that the activities of the OsSTN8 kinase and the antagonistic OsPBCP phosphatase, in addition to being involved in the repair of photo-damaged PSII, are also responsible for the HL-dependent reversible phosphorylation of the inner antenna CP29.

  5. Effects of L-DOPA and STN-HFS dyskinesiogenic treatments on NR2B regulation in basal ganglia in the rat model of Parkinson's disease.

    PubMed

    Quintana, Adrien; Sgambato-Faure, Véronique; Savasta, Marc

    2012-12-01

    Dyskinesia is a major side effect of chronic levodopa (L-DOPA) administration, the reference treatment for Parkinson's disease (PD). High-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing L-DOPA requirement. However, inadequate stimulation can also trigger dyskinetic movements in PD patients and animal models. Here, we investigated the possible association between L-DOPA- and STN-HFS-induced dyskinesia and regulation of the NR2B subunit of NMDA receptors in the rodent model of PD. We subjected 6-OHDA-lesioned rats to HFS for 1h, at an intensity triggering forelimb dyskinesia. Other 6-OHDA-lesioned rats were treated with chronic high doses of L-DOPA for ten days, to induce abnormal involuntary movements. The 6-OHDA lesion regulated NR2B only in the SNr, where the activation of NR2B was observed (as assessed by phosphorylation of the Tyr1472 residue). Both STN-HFS and L-DOPA dyskinesiogenic treatments induced NR2B activation in the STN and EP, but only L-DOPA triggered NR2B hyperphosphorylation in the striatum. Finally, the use of CP-101,606 exacerbated L-DOPA-induced motor behavior and associated NR2B hyperphosphorylation in the striatum, STN and EP. Thus, NR2B activation in basal ganglia structures is correlated with dyskinesia.

  6. Maintenance of very long telomeres by recombination in the Kluyveromyces lactis stn1-M1 mutant involves extreme telomeric turnover, telomeric circles, and concerted telomeric amplification.

    PubMed

    Xu, Jianing; McEachern, Michael J

    2012-08-01

    Some cancers utilize the recombination-dependent process of alternative lengthening of telomeres (ALT) to maintain long heterogeneous telomeres. Here, we studied the recombinational telomere elongation (RTE) of the Kluyveromyces lactis stn1-M1 mutant. We found that the total amount of the abundant telomeric DNA in stn1-M1 cells is subject to rapid variation and that it is likely to be primarily extrachromosomal. Rad50 and Rad51, known to be required for different RTE pathways in Saccharomyces cerevisiae, were not essential for the production of either long telomeres or telomeric circles in stn1-M1 cells. Circles of DNA containing telomeric repeats (t-circles) either present at the point of establishment of long telomeres or introduced later into stn1-M1 cells each led to the formation of long tandem arrays of the t-circle's sequence, which were incorporated at multiple telomeres. These tandem arrays were extraordinarily unstable and showed evidence of repeated rounds of concerted amplification. Our results suggest that the maintenance of telomeres in the stn1-M1 mutant involves extreme turnover of telomeric sequences from processes including both large deletions and the copying of t-circles.

  7. Activation of the Stt7/STN7 Kinase through Dynamic Interactions with the Cytochrome b6f Complex1[OPEN

    PubMed Central

    Shapiguzov, Alexey; Chai, Xin; Fucile, Geoffrey; Longoni, Paolo; Zhang, Lixin

    2016-01-01

    Photosynthetic organisms have the ability to adapt to changes in light quality by readjusting the cross sections of the light-harvesting systems of photosystem II (PSII) and photosystem I (PSI). This process, called state transitions, maintains the redox poise of the photosynthetic electron transfer chain and ensures a high photosynthetic yield when light is limiting. It is mediated by the Stt7/STN7 protein kinase, which is activated through the cytochrome b6f complex upon reduction of the plastoquinone pool. Its probable major substrate, the light-harvesting complex of PSII, once phosphorylated, dissociates from PSII and docks to PSI, thereby restoring the balance of absorbed light excitation energy between the two photosystems. Although the kinase is known to be inactivated under high-light intensities, the molecular mechanisms governing its regulation remain unknown. In this study we monitored the redox state of a conserved and essential Cys pair of the Stt7/STN7 kinase and show that it forms a disulfide bridge. We could not detect any change in the redox state of these Cys during state transitions and high-light treatment. It is only after prolonged anaerobiosis that this disulfide bridge is reduced. It is likely to be mainly intramolecular, although kinase activation may involve a transient covalently linked kinase dimer with two intermolecular disulfide bonds. Using the yeast two-hybrid system, we have mapped one interaction site of the kinase on the Rieske protein of the cytochrome b6f complex. PMID:26941194

  8. Cognitive and Psychiatric Effects of STN versus GPi Deep Brain Stimulation in Parkinson's Disease: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Zhang, Xiao-Hua; Wang, Yun-Peng; Li, Ji-Ping; Li, Yong-Jie

    2016-01-01

    Background Deep brain stimulation (DBS) of either the subthalamic nucleus (STN) or the globus pallidus interna (GPi) can reduce motor symptoms in patients with Parkinson’s disease (PD) and improve their quality of life. However, the effects of STN DBS and GPi DBS on cognitive functions and their psychiatric effects remain controversial. The present meta-analysis was therefore performed to clarify these issues. Methods We searched the PUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials databases. Other sources, including internet-based clinical trial registries and grey literature sources, were also searched. After searching the literature, two investigators independently performed literature screens to assess the quality of the included trials and to extract the data. The outcomes included the effects of STN DBS and GPi DBS on multiple cognitive domains, depression, anxiety, and quality of life. Results Seven articles related to four randomized controlled trials that included 521 participants were incorporated into the present meta-analysis. Compared with GPi DBS, STN DBS was associated with declines in selected cognitive domains after surgery, including attention, working memory and processing speed, phonemic fluency, learning and memory, and global cognition. However, there were no significant differences in terms of quality of life or psychiatric effects, such as depression and anxiety, between the two groups. Conclusions A selective decline in frontal-subcortical cognitive functions is observed after STN DBS in comparison with GPi DBS, which should not be ignored in the target selection for DBS treatment in PD patients. In addition, compared to GPi DBS, STN DBS does not affect depression, anxiety, and quality of life. PMID:27248139

  9. Gait analysis in patients with advanced Parkinson disease: different or additive effects on gait induced by levodopa and chronic STN stimulation.

    PubMed

    Lubik, S; Fogel, W; Tronnier, V; Krause, M; König, J; Jost, W H

    2006-02-01

    The aim of our study was to observe the effects on gait parameters induced by STN stimulation and levodopa medication in patients with advanced Parkinson's disease in order to determine different or additive effects. Therefore we examined 12 patients with advanced Parkinson disease after bilateral implantation of DBS into the STN. We assessed the motor score of the UPDRS and quantitative gait analysis under 4 treatment conditions: with and without stimulation as well as with and without levodopa. The mean improvement of the UPDRS motor score was almost the same with levodopa and DBS. Combining both therapies we saw a further improvement of the motor score. Gait parameters of patients with PD treated either with levodopa or STN stimulation were greatly improved. A significant difference between levodopa and STN stimulation could only be shown for the parameters velocity and step length. These parameters improved more with levodopa than with stimulation. The combination of both therapeutic methods showed the best results on the UPDRS motor score and gait parameters.

  10. Closed-loop stimulation of a delayed neural fields model of parkinsonian STN-GPe network: a theoretical and computational study

    PubMed Central

    Detorakis, Georgios Is.; Chaillet, Antoine; Palfi, Stéphane; Senova, Suhan

    2015-01-01

    Several disorders are related to pathological brain oscillations. In the case of Parkinson's disease, sustained low-frequency oscillations (especially in the β-band, 13–30 Hz) correlate with motor symptoms. It is still under debate whether these oscillations are the cause of parkinsonian motor symptoms. The development of techniques enabling selective disruption of these β-oscillations could contribute to the understanding of the underlying mechanisms, and could be exploited for treatments. A particularly appealing technique is Deep Brain Stimulation (DBS). With clinical electrical DBS, electrical currents are delivered at high frequency to a region made of potentially heterogeneous neurons (the subthalamic nucleus (STN) in the case of Parkinson's disease). Even more appealing is DBS with optogenetics, which is until now a preclinical method using both gene transfer and deep brain light delivery and enabling neuromodulation at the scale of one given neural network. In this work, we rely on delayed neural fields models of STN and the external Globus Pallidus (GPe) to develop, theoretically validate and test in silico a closed-loop stimulation strategy to disrupt these sustained oscillations with optogenetics. First, we rely on tools from control theory to provide theoretical conditions under which sustained oscillations can be attenuated by a closed-loop stimulation proportional to the measured activity of STN. Second, based on this theoretical framework, we show numerically that the proposed closed-loop stimulation efficiently attenuates sustained oscillations, even in the case when the photosensitization effectively affects only 50% of STN neurons. We also show through simulations that oscillations disruption can be achieved when the same light source is used for the whole STN population. We finally test the robustness of the proposed strategy to possible acquisition and processing delays, as well as parameters uncertainty. PMID:26217171

  11. Closed-loop stimulation of a delayed neural fields model of parkinsonian STN-GPe network: a theoretical and computational study.

    PubMed

    Detorakis, Georgios Is; Chaillet, Antoine; Palfi, Stéphane; Senova, Suhan

    2015-01-01

    Several disorders are related to pathological brain oscillations. In the case of Parkinson's disease, sustained low-frequency oscillations (especially in the β-band, 13-30 Hz) correlate with motor symptoms. It is still under debate whether these oscillations are the cause of parkinsonian motor symptoms. The development of techniques enabling selective disruption of these β-oscillations could contribute to the understanding of the underlying mechanisms, and could be exploited for treatments. A particularly appealing technique is Deep Brain Stimulation (DBS). With clinical electrical DBS, electrical currents are delivered at high frequency to a region made of potentially heterogeneous neurons (the subthalamic nucleus (STN) in the case of Parkinson's disease). Even more appealing is DBS with optogenetics, which is until now a preclinical method using both gene transfer and deep brain light delivery and enabling neuromodulation at the scale of one given neural network. In this work, we rely on delayed neural fields models of STN and the external Globus Pallidus (GPe) to develop, theoretically validate and test in silico a closed-loop stimulation strategy to disrupt these sustained oscillations with optogenetics. First, we rely on tools from control theory to provide theoretical conditions under which sustained oscillations can be attenuated by a closed-loop stimulation proportional to the measured activity of STN. Second, based on this theoretical framework, we show numerically that the proposed closed-loop stimulation efficiently attenuates sustained oscillations, even in the case when the photosensitization effectively affects only 50% of STN neurons. We also show through simulations that oscillations disruption can be achieved when the same light source is used for the whole STN population. We finally test the robustness of the proposed strategy to possible acquisition and processing delays, as well as parameters uncertainty.

  12. Comparison of imaging modalities and source-localization algorithms in locating the induced activity during deep brain stimulation of the STN.

    PubMed

    Mideksa, K G; Singh, A; Hoogenboom, N; Hellriegel, H; Krause, H; Schnitzler, A; Deuschl, G; Raethjen, J; Schmidt, G; Muthuraman, M

    2016-08-01

    One of the most commonly used therapy to treat patients with Parkinson's disease (PD) is deep brain stimulation (DBS) of the subthalamic nucleus (STN). Identifying the most optimal target area for the placement of the DBS electrodes have become one of the intensive research area. In this study, the first aim is to investigate the capabilities of different source-analysis techniques in detecting deep sources located at the sub-cortical level and validating it using the a-priori information about the location of the source, that is, the STN. Secondly, we aim at an investigation of whether EEG or MEG is best suited in mapping the DBS-induced brain activity. To do this, simultaneous EEG and MEG measurement were used to record the DBS-induced electromagnetic potentials and fields. The boundary-element method (BEM) have been used to solve the forward problem. The position of the DBS electrodes was then estimated using the dipole (moving, rotating, and fixed MUSIC), and current-density-reconstruction (CDR) (minimum-norm and sLORETA) approaches. The source-localization results from the dipole approaches demonstrated that the fixed MUSIC algorithm best localizes deep focal sources, whereas the moving dipole detects not only the region of interest but also neighboring regions that are affected by stimulating the STN. The results from the CDR approaches validated the capability of sLORETA in detecting the STN compared to minimum-norm. Moreover, the source-localization results using the EEG modality outperformed that of the MEG by locating the DBS-induced activity in the STN.

  13. Freestanding rGO-SWNT-STN Composite Film as an Anode for Li Ion Batteries with High Energy and Power Densities

    PubMed Central

    Song, Taeseup; Choi, Junghyun; Paik, Ungyu

    2015-01-01

    Freestanding Si-Ti-Ni alloy particles/reduced graphene oxide/single wall carbon nanotube composites have been prepared as an anode for lithium ion batteries via a simple filtration method. This composite electrode showed a 9% increase in reversible capacity, a two-fold higher cycle retention at 50 cycles and a two-fold higher rate capability at 2 C compared to pristine Si-Ti-Ni (STN) alloy electrodes. These improvements were attributed to the suppression of the pulverization of the STN active material by the excellent mechanical properties of the reduced graphene oxide-single wall carbon nanotube networks and the enhanced kinetics associated with both electron and Li ion transport.

  14. Freestanding rGO-SWNT-STN Composite Film as an Anode for Li Ion Batteries with High Energy and Power Densities.

    PubMed

    Song, Taeseup; Choi, Junghyun; Paik, Ungyu

    2015-12-18

    Freestanding Si-Ti-Ni alloy particles/reduced graphene oxide/single wall carbon nanotube composites have been prepared as an anode for lithium ion batteries via a simple filtration method. This composite electrode showed a 9% increase in reversible capacity, a two-fold higher cycle retention at 50 cycles and a two-fold higher rate capability at 2 C compared to pristine Si-Ti-Ni (STN) alloy electrodes. These improvements were attributed to the suppression of the pulverization of the STN active material by the excellent mechanical properties of the reduced graphene oxide-single wall carbon nanotube networks and the enhanced kinetics associated with both electron and Li ion transport.

  15. Prevalence of multiple drug resistance and screening of enterotoxin (stn) gene in Salmonella enterica serovars from water sources in Lagos, Nigeria.

    PubMed

    Akinyemi, K O; Iwalokun, B A; Foli, F; Oshodi, K; Coker, A O

    2011-02-01

    To determine the prevalence, antibiotic resistance and carriage of enterotoxin (stn) gene among strains of Salmonella isolated from water sources in Lagos. A total of 200 samples (60 well water, 60 pipe-borne water and 80 different brands of sachet water) were collected at random from various locations in Lagos. The samples were evaluated bacteriologically using standard methods. The identified isolates were subjected to antimicrobial susceptibility tests and were further screened for the presence of stn gene using standard procedures. Thirty-seven of the samples analysed were positive for Salmonella isolates. Seven serotypes were found -Salmonella typhi (n = 3, 8.1%), Salmonella typhimurium (n = 8, 21.6%), Salmonella choleraesuis (n = 5, 13.5%), Salmonella enteritidis (n = 9, 24.3%), Salmonella paratyphi (n = 8, 21.6%) and Salmonella arizonae (n = 4, 10.8%) - with at least one serotype present in all water sources. Over 60% of Salmonella isolates carried stn gene and the risk was higher in pipe-borne water. There was no relationship (P > 0.05) between enterotoxin-producing gene and antibiotic resistance in Salmonella isolates. Thirteen resistance patterns were exhibited by the isolates, with Str. Amp.Tet.Chl.Amo.Gen, Str. Amp.Tet.Amo.Chl.Amo.Nal.Nit, Str.Tet and Str. Amp.Tet.Chl.Amo being the most notable resistance patterns observed. Isolates that carried stn gene developed resistance to more antibiotics. Although reduced susceptibility to ciproflocacin was observed in two strains, none of the isolates developed resistance to ofloxacin. Emerging multidrug-resistant Salmonella serotypes with stn gene were found in the water samples, which may pose a threat to public health. Constant monitoring of pipe leakages, the quality of various wells and the quality of sachet water is advocated to avoid possible future outbreaks of salmonellosis due to consumption of contaminated water. Copyright © 2010 The Royal Society for Public Health. Published by

  16. 76 FR 24064 - Arizona Public Service Company, Palo Verde Nuclear Generating Station, Units 1, 2, and 3, Notice...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-29

    ... COMMISSION [Docket Nos. 50-528, 50-529, 50-530; NRC-2009-0012 Arizona Public Service Company, Palo Verde... of the Palo Verde Nuclear Generating Station, Units 1, 2, and 3 (PVNGS). Renewed Facility Operating... Palo Verde Nuclear Generating Station,'' issued January 2011, discusses the Commission's...

  17. Re-appraising contemporary theories of subcortical participation in language: proposing an interhemispheric regulatory function for the subthalamic nucleus (STN) in the mediation of high-level linguistic processes.

    PubMed

    Whelan, Brooke-Mai; Murdoch, Bruce E; Theodoros, Deborah; Silburn, Peter; Hall, Bruce

    2004-10-01

    Apropos the basal ganglia, the dominant striatum and globus pallidus internus (GPi) have been hypothesized to represent integral components of subcortical language circuitry. Working subcortical language theories, however, have failed thus far to consider a role for the STN in the mediation of linguistic processes, a structure recently defined as the driving force of basal ganglia output. The aim of this research was to investigate the impact of surgically induced functional inhibition of the STN upon linguistic abilities, within the context of established models of basal ganglia participation in language. Two males with surgically induced'lesions'of the dominant and non-dominant dorsolateral STN, aimed at relieving Parkinsonian motor symptoms, served as experimental subjects. General and high-level language profiles were compiled for each subject up to 1 month prior to and 3 months following neurosurgery, within the drug-on state (i.e., when optimally medicated). Comparable post-operative alterations in linguistic performance were observed subsequent to surgically induced functional inhibition of the left and right STN. More specifically, higher proportions of reliable decline as opposed to improvement in post-operative performance were demonstrated by both subjects on complex language tasks, hypothesised to entail the interplay of cognitive-linguistic processes. The outcomes of the current research challenge unilateralised models of functional basal ganglia organisation with the proposal of a potential interhemispheric regulatory function for the STN in the mediation of high-level linguistic processes.

  18. SUMOylation regulates telomere length by targeting the shelterin subunit Tpz1Tpp1 to modulate shelterin–Stn1 interaction in fission yeast

    PubMed Central

    Miyagawa, Keisuke; Low, Ross S.; Santosa, Venny; Tsuji, Hiroki; Moser, Bettina A.; Fujisawa, Shiho; Harland, Jennifer L.; Raguimova, Olga N.; Go, Andrew; Ueno, Masaru; Matsuyama, Akihisa; Yoshida, Minoru; Nakamura, Toru M.; Tanaka, Katsunori

    2014-01-01

    Telomeres protect DNA ends of linear eukaryotic chromosomes from degradation and fusion, and ensure complete replication of the terminal DNA through recruitment of telomerase. The regulation of telomerase is a critical area of telomere research and includes cis regulation by the shelterin complex in mammals and fission yeast. We have identified a key component of this regulatory pathway as the SUMOylation [the covalent attachment of a small ubiquitin-like modifier (SUMO) to target proteins] of a shelterin subunit in fission yeast. SUMOylation is known to be involved in the negative regulation of telomere extension by telomerase; however, how SUMOylation limits the action of telomerase was unknown until now. We show that SUMOylation of the shelterin subunit TPP1 homolog in Schizosaccharomyces pombe (Tpz1) on lysine 242 is important for telomere length homeostasis. Furthermore, we establish that Tpz1 SUMOylation prevents telomerase accumulation at telomeres by promoting recruitment of Stn1-Ten1 to telomeres. Our findings provide major mechanistic insights into how the SUMOylation pathway collaborates with shelterin and Stn1-Ten1 complexes to regulate telomere length. PMID:24711392

  19. Xenopus laevis Ctc1-Stn1-Ten1 (xCST) Protein Complex Is Involved in Priming DNA Synthesis on Single-stranded DNA Template in Xenopus Egg Extract*

    PubMed Central

    Nakaoka, Hidenori; Nishiyama, Atsuya; Saito, Motoki; Ishikawa, Fuyuki

    2012-01-01

    The Ctc1-Stn1-Ten1 (CST) complex is an RPA (replication protein A)-like protein complex that binds to single-stranded (ss) DNA. It localizes at telomeres and is involved in telomere end protection in mammals and plants. It is also known to stimulate DNA polymerase α-primase in vitro. However, it is not known how CST accomplishes these functions in vivo. Here, we report the identification and characterization of Xenopus laevis CST complex (xCST). xCST showed ssDNA binding activity with moderate preference for G (guanine)-rich sequences. xStn1-immunodepleted Xenopus egg extracts supported chromosomal DNA replication in in vitro reconstituted sperm nuclei, suggesting that xCST is not a general replication factor. However, the immunodepletion or neutralization of xStn1 compromised DNA synthesis on ssDNA template. Because primed ssDNA template was replicated in xStn1-immunodepleted extracts as efficiently as in control ones, we conclude that xCST is involved in the priming step on ssDNA template. These results are consistent with the current model that CST is involved in telomeric C-strand synthesis through the regulation of DNA polymerase α-primase. PMID:22086929

  20. Production of superoxide from photosystem II-light harvesting complex II supercomplex in STN8 kinase knock-out rice mutants under photoinhibitory illumination.

    PubMed

    Poudyal, Roshan Sharma; Nath, Krishna; Zulfugarov, Ismayil S; Lee, Choon-Hwan

    2016-09-01

    When phosphorylation of Photosystem (PS) II core proteins is blocked in STN8 knock-out mutants of rice (Oryza sativa) under photoinhibitory illumination, the mobilization of PSII supercomplex is prevented. We have previously proposed that more superoxide (O2(-)) is produced from PSII in the mutant (Nath et al., 2013, Plant J. 76, 675-686). Here, we clarify the type and site for the generation of reactive oxygen species (ROS). Using both histochemical and fluorescence probes, we observed that, compared with wild-type (WT) leaves, levels of ROS, including O2(-) and hydrogen peroxide (H2O2), were increased when leaves from mutant plants were illuminated with excess light. However, singlet oxygen production was not enhanced under such conditions. When superoxide dismutase was inhibited, O2(-) production was increased, indicating that it is the initial event prior to H2O2 production. In thylakoids isolated from WT leaves, kinase was active in the presence of ATP, and spectrophotometric analysis of nitrobluetetrazolium absorbance for O2(-) confirmed that PSII-driven superoxide production was greater in the mutant thylakoids than in the WT. This contrast in levels of PSII-driven superoxide production between the mutants and the WT plants was confirmed by conducting protein oxidation assays of PSII particles from osstn8 leaves under strong illumination. Those assays also demonstrated that PSII-LHCII supercomplex proteins were oxidized more in the mutant, thereby implying that PSII particles incur greater damage even though D1 degradation during PSII-supercomplex mobilization is partially blocked in the mutant. These results suggest that O2(-) is the major form of ROS produced in the mutant, and that the damaged PSII in the supercomplex is the primary source of O2(-).

  1. The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer

    PubMed Central

    Munkley, Jennifer; Oltean, Sebastian; Vodák, Daniel; Wilson, Brian T.; Livermore, Karen E.; Zhou, Yan; Star, Eleanor; Floros, Vasileios I.; Johannessen, Bjarne; Knight, Bridget; McCullagh, Paul; McGrath, John; Crundwell, Malcolm; Skotheim, Rolf I.; Robson, Craig N.; Leung, Hing Y.; Harries, Lorna W.; Rajan, Prabhakar; Mills, Ian G.; Elliott, David J.

    2015-01-01

    Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, being significantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression. PMID:26452038

  2. Retraction: Sophocleous, M. (2012). On understanding and predicting groundwater response time. Ground Water, 50: 528–540. doi: 10.1111/j.1745-6584.2011.00876.x.

    PubMed

    2014-01-01

    The above article, published online on October 24, 2011 on Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the author's sponsoring institution, the journal Editor in Chief, Franklin W. Schwartz, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation by the Kansas Geological Survey (a research and service division of the University of Kansas), which identified unattributed areas of overlap with a number of other publications.

  3. COMPARISON OF DATA FROM THE STN AND IMPROVE NETWORKS

    EPA Science Inventory

    Two national chemical speciation-monitoring networks operate currently within the United States. The Interagency Monitoring of Protected Visual Environments (IMPROVE) monitoring network operates primarily in rural areas collecting aerosol and optical data to better understand th...

  4. Cost Comparison of Online Searching in Four Hosts: Data-Star, Dialog, ESA-IRS and STN.

    ERIC Educational Resources Information Center

    Eskola, Pirkko; Sormunen, Eero

    1990-01-01

    Describes study that compared the costs of online searching on six databases in four systems. Costs of the search phase and the output phase are analyzed separately; transmission rate and telecommunication costs are examined; and the effects of pricing structures on online searches are discussed. (five references) (LRW)

  5. Resting-state functional connectivity of subthalamic nucleus in different Parkinson's disease phenotypes.

    PubMed

    Wang, Zhan; Chen, Huimin; Ma, Huizi; Ma, Lingyan; Wu, Tao; Feng, Tao

    2016-12-15

    Previous studies showed that the subthalamic nucleus (STN) plays a crucial role in Parkinson's disease (PD) pathophysiology. During rest, PD phenotypes exhibit different STN functional connectivity. STN functional connectivity was examined in 31 PD patients [12 tremor-dominant (TD) and 19 posture instability gait difficulty (PIGD)] and 22 healthy controls (HC). Compared with controls and PIGD patients, the TD patients exhibited higher functional connectivity between the bilateral STN and the left cerebellar anterior lobe. Compared with the TD and HC groups, in the PIGD subgroup functional connectivity was lower between the left putamen and the STN, as well as between the pons and the STN. In the PIGD subgroup, functional connectivity was greater between the STN and bilateral occipital lobe, which positively correlated with PIGD scores in PD patients. Additionally, STN-cerebellum connectivity positively correlated with the tremor score, and STN-putamen connectivity negatively correlated with the PIGD score in PD patients. PD subtypes with distinguished STN functional connectivity might explain the various pathophysiological mechanisms in tremor and gait disorders. Increased coupling between the STN and cerebellum might underlie the neural substrate of PD tremors. Lower functional connectivity between the STN and putamen might underpin PD gait and posture disturbances, while higher functional connectivity between the STN and visual cortex might play a compensatory role.

  6. The effects of unilateral versus bilateral subthalamic nucleus deep brain stimulation on prosaccades and antisaccades in Parkinson's disease.

    PubMed

    Goelz, Lisa C; David, Fabian J; Sweeney, John A; Vaillancourt, David E; Poizner, Howard; Metman, Leonard Verhagen; Corcos, Daniel M

    2017-02-01

    Unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson's disease improves skeletomotor function assessed clinically, and bilateral STN DBS improves motor function to a significantly greater extent. It is unknown whether unilateral STN DBS improves oculomotor function and whether bilateral STN DBS improves it to a greater extent. Further, it has also been shown that bilateral, but not unilateral, STN DBS is associated with some impaired cognitive-motor functions. The current study compared the effect of unilateral and bilateral STN DBS on sensorimotor and cognitive aspects of oculomotor control. Patients performed prosaccade and antisaccade tasks during no stimulation, unilateral stimulation, and bilateral stimulation. There were three sets of findings. First, for the prosaccade task, unilateral STN DBS had no effect on prosaccade latency and it reduced prosaccade gain; bilateral STN DBS reduced prosaccade latency and increased prosaccade gain. Second, for the antisaccade task, neither unilateral nor bilateral stimulation had an effect on antisaccade latency, unilateral STN DBS increased antisaccade gain, and bilateral STN DBS increased antisaccade gain to a greater extent. Third, bilateral STN DBS induced an increase in prosaccade errors in the antisaccade task. These findings suggest that while bilateral STN DBS benefits spatiotemporal aspects of oculomotor control, it may not be as beneficial for more complex cognitive aspects of oculomotor control. Our findings are discussed considering the strategic role the STN plays in modulating information in the basal ganglia oculomotor circuit.

  7. Cortico-subthalamic white matter tract strength predicts interindividual efficacy in stopping a motor response.

    PubMed

    Forstmann, Birte U; Keuken, Max C; Jahfari, Sara; Bazin, Pierre-Louis; Neumann, Jane; Schäfer, Andreas; Anwander, Alfred; Turner, Robert

    2012-03-01

    The subthalamic nucleus (STN) is a small but vitally important structure in the basal ganglia. Because of its small volume, and its localization in the basal ganglia, the STN can best be visualized using ultra-high resolution 7 Tesla (T) magnetic resonance imaging (MRI). In the present study, first we individually segmented 7 T MRI STN masks to generate atlas probability maps. Secondly, the individually segmented STN masks and the probability maps were used to derive cortico-subthalamic white matter tract strength. Tract strength measures were then taken to test two functional STN hypotheses which account for the efficiency in stopping a motor response: the right inferior fronto-subthalamic (rIFC-STN) hypothesis and the posterior medial frontal cortex-subthalamic (pMFC-STN) hypothesis. Results of two independent experiments show that increased white matter tract strength between the pMFC and STN results in better stopping behaviour. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Pedunculopontine nucleus evoked potentials from subthalamic nucleus stimulation in Parkinson's disease.

    PubMed

    Neagu, Bogdan; Tsang, Eric; Mazzella, Filomena; Hamani, Clement; Moro, Elena; Hodaie, Mojgan; Lozano, Andres M; Chen, Robert

    2013-12-01

    The effects of subthalamic nucleus (STN) stimulation on the pedunculopontine nucleus area (PPNR) evoked activities were examined in two patients with Parkinson's disease. The patients had previously undergone bilateral STN deep brain stimulation (DBS) and subsequently received unilateral DBS electrodes in the PPNR. Evoked potentials were recorded from the local field potentials (LFP) from the PPNR with STN stimulation at different frequencies and bipolar contacts. Ipsilateral and contralateral short latency (<2ms) PPNR responses were evoked from left but not from right STN stimulation. In both patients, STN stimulation evoked contralateral PPNR responses at medium latencies between 41 and 45ms. Cortical evoked potentials to single pulse STN stimulation were observed at latencies between 18 and 27ms. These results demonstrate a functional connection between the STN and the PPNR. It likely involves direct projections between the STN and PPNR or polysynaptic pathways with thalamic or cortical relays.

  9. Facilitating effects of deep brain stimulation on feedback learning in Parkinson's disease.

    PubMed

    Meissner, Sarah Nadine; Südmeyer, Martin; Keitel, Ariane; Pollok, Bettina; Bellebaum, Christian

    2016-10-15

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) provides an effective treatment for Parkinson's disease (PD) motor symptoms. However, findings of effects on cognitive function such as feedback learning remain controversial and rare. The aim of the present study was to gain a better understanding of cognitive alterations associated with STN-DBS. Therefore, we investigated effects of STN-DBS on active and observational feedback learning in PD. 18 PD patients with STN-DBS and 18 matched healthy controls completed active and observational feedback learning tasks. Patients were investigated ON and OFF STN-DBS. Tasks consisted of learning (with feedback) and test phases (without feedback). STN-DBS improved active learning during feedback trials and PD patients ON (but not OFF) STN-DBS showed comparable performance patterns as healthy controls. No STN-DBS effect was found when assessing performance during active test trials without feedback. In this case, however, STN-DBS effects were found to depend on symptom severity. While more impaired patients benefited from STN-DBS, stimulation had no facilitating effect on patients with less severe symptoms. Along similar lines, the severity of motor symptoms tended to be significantly correlated with differences in active test performance due to STN-DBS. For observational feedback learning, there was a tendency for a positive STN-DBS effect with patients reaching the performance level of healthy controls only ON STN-DBS. The present data suggest that STN-DBS facilitates active feedback learning in PD patients. Furthermore, they provide first evidence that STN-DBS might not only affect learning from own but also from observed actions and outcomes.

  10. Hypersexuality following subthalamic nucleus stimulation for Parkinson's disease.

    PubMed

    Doshi, Paresh; Bhargava, Pranshu

    2008-01-01

    Subthalamic nucleus (STN) stimulation is an established surgical treatment for Parkinson's disease (PD). Though the motor benefits of STN stimulation are well understood, its cognitive and behavioral effects are still not fully understood. Manic psychosis, hypersexuality, pathological gambling and mood swings are associated with advanced PD. There have been reports to suggest improvement or worsening in these symptoms following STN deep brain stimulation (DBS). We report two cases as the sole behavioral side-effects of STN stimulation despite good clinical improvement on long-term follow-up. These patients and literature review suggests the complex role of STN stimulation in motor and behavioral control.

  11. Mucin-associated sialosyl-Tn antigen expression in gastric cancer correlates with an adverse outcome.

    PubMed Central

    Werther, J. L.; Rivera-MacMurray, S.; Bruckner, H.; Tatematsu, M.; Itzkowitz, S. H.

    1994-01-01

    The expression of sialosyl-Tn (STn) antigen was evaluated by immunohistochemistry in primary gastric cancers. Twenty-one of 31 (68%) gastric cancers expressed STn, regardless of tumour location, stage or histological type. Eighty-one per cent of patients with STn-positive tumours died of their disease or had recurrent cancer, compared with 20% of patients with STn-negative tumours (P < 0.002). STn may be a useful prognostic marker in patients with gastric cancer. Images Figure 1 PMID:8123499

  12. High frequency stimulation of the subthalamic nucleus has beneficial antiparkinsonian effects on motor functions in rats, but less efficiency in a choice reaction time task.

    PubMed

    Darbaky, Yassine; Forni, Claude; Amalric, Marianne; Baunez, Christelle

    2003-08-01

    Chronic subthalamic nucleus high frequency stimulation (STN HFS) improves motor function in Parkinson's disease. However, its efficacy on cognitive function and the mechanisms involved are less known. The aim of this study was to assess the effects of STN HFS in hemiparkinsonian awake rats performing different specific motor tests and a cognitive operant task. Unilateral STN HFS applied in unilaterally DA-depleted rats decreased the apomorphine-induced circling behaviour and reduced catalepsy induced by the neuroleptic haloperidol. DA-depleted rats exhibited severe deficits in the operant task, among which the inability to perform the task was not alleviated by STN HFS. However, in a few animals showing less impairment, STN HFS significantly reduced the contralateral neglect induced by the lesion. These results are the first to demonstrate a beneficial effect of STN HFS applied in awake rats on basic motor functions. However, STN HFS appears to be less effective on impaired cognitive functions.

  13. Asymmetric right/left encoding of emotions in the human subthalamic nucleus

    PubMed Central

    Eitan, Renana; Shamir, Reuben R.; Linetsky, Eduard; Rosenbluh, Ovadya; Moshel, Shay; Ben-Hur, Tamir; Bergman, Hagai; Israel, Zvi

    2013-01-01

    Emotional processing is lateralized to the non-dominant brain hemisphere. However, there is no clear spatial model for lateralization of emotional domains in the basal ganglia. The subthalamic nucleus (STN), an input structure in the basal ganglia network, plays a major role in the pathophysiology of Parkinson's disease (PD). This role is probably not limited only to the motor deficits of PD, but may also span the emotional and cognitive deficits commonly observed in PD patients. Beta oscillations (12–30 Hz), the electrophysiological signature of PD, are restricted to the dorsolateral part of the STN that corresponds to the anatomically defined sensorimotor STN. The more medial, more anterior and more ventral parts of the STN are thought to correspond to the anatomically defined limbic and associative territories of the STN. Surprisingly, little is known about the electrophysiological properties of the non-motor domains of the STN, nor about electrophysiological differences between right and left STNs. In this study, microelectrodes were utilized to record the STN spontaneous spiking activity and responses to vocal non-verbal emotional stimuli during deep brain stimulation (DBS) surgeries in human PD patients. The oscillation properties of the STN neurons were used to map the dorsal oscillatory and the ventral non-oscillatory regions of the STN. Emotive auditory stimulation evoked activity in the ventral non-oscillatory region of the right STN. These responses were not observed in the left ventral STN or in the dorsal regions of either the right or left STN. Therefore, our results suggest that the ventral non-oscillatory regions are asymmetrically associated with non-motor functions, with the right ventral STN associated with emotional processing. These results suggest that DBS of the right ventral STN may be associated with beneficial or adverse emotional effects observed in PD patients and may relieve mental symptoms in other neurological and psychiatric

  14. Prior pallidotomy reduces and modifies neuronal activity in the subthalamic nucleus of Parkinson's disease patients.

    PubMed

    Zaidel, A; Moran, A; Marjan, G; Bergman, H; Israel, Z

    2008-01-01

    Parkinson's disease (PD) patients with prior radio-frequency lesions in the internal segment of the globus pallidus (GPi, pallidotomy), whose symptoms have deteriorated, may be candidates for further invasive treatment such as subthalamic deep brain stimulation (STN DBS). Six patients with prior pallidotomy (five unilaterally; one bilaterally) underwent bilateral STN DBS. The microelectrode recordings (MERs, used intraoperatively for STN verification), ipsilateral and contralateral to pallidotomy, and MERs from 11 matched PD patients who underwent bilateral STN DBS without prior pallidotomy were compared. For each trajectory, average, variance and mean successive difference (MSD, a measure of irregularity) of the root mean square (RMS) of the STN MER were calculated. The RMS in trajectories ipsilateral to pallidotomy showed significant reduction of the mean average and MSD of STN activity when compared with trajectories from patients without prior pallidotomy. The RMS parameters contralateral to pallidotomy tend to lie between those ipsilateral to pallidotomy and those without prior pallidotomy. The average STN power spectral density of oscillatory activity was notably lower ipsilateral to pallidotomy than contralateral, or without prior pallidotomy. The finding that pallidotomy reduces STN activity and changes firing characteristics, in conjunction with the effectiveness of STN DBS despite prior pallidotomy, calls for reappraisal and modification of the current model of the basal ganglia (BG) cortical network. It highlights the critical role of direct projections from the BG to brain-stem structures and suggests a possible GPi-STN reciprocal positive-feedback mechanism.

  15. Tremor-correlated neuronal activity in the subthalamic nucleus of Parkinsonian patients.

    PubMed

    Amtage, Florian; Henschel, Kathrin; Schelter, Björn; Vesper, Jan; Timmer, Jens; Lücking, Carl Hermann; Hellwig, Bernhard

    2008-09-19

    Tremor in Parkinson's disease (PD) is generated by an oscillatory neuronal network consisting of cortex, basal ganglia and thalamus. The subthalamic nucleus (STN) which is part of the basal ganglia is of particular interest, since deep brain stimulation of the STN is an effective treatment for PD including Parkinsonian tremor. It is controversial if and how the STN contributes to tremor generation. In this study, we analyze neuronal STN activity in seven patients with Parkinsonian rest tremor who underwent stereotactic surgery for deep brain stimulation. Surface EMG was recorded from the wrist flexors and extensors. Simultaneously, neuronal spike activity was registered in different depths of the STN using an array of five microelectrodes. After spike-sorting, spectral coherence was analyzed between spike activity of STN neurons and tremor activity. Significant coherence at the tremor frequency was detected between EMG and neuronal STN activity in 76 out of 145 neurons (52.4%). In contrast, coherence in the beta band occurred only in 10 out of 145 neurons (6.9%). Tremor-coherent STN activity was widely distributed over the STN being more frequent in its dorsal parts (70.8-88.9%) than in its ventral parts (25.0-48.0%). Our results suggest that synchronous neuronal STN activity at the tremor frequency contributes to the pathogenesis of Parkinsonian tremor. The wide-spread spatial distribution of tremor-coherent spike activity argues for the recruitment of an extended network of subthalamic neurons for tremor generation.

  16. Bilateral high-frequency stimulation of the subthalamic nucleus on attentional performance: transient deleterious effects and enhanced motivation in both intact and parkinsonian rats

    PubMed Central

    Baunez, Christelle; Christakou, Anastasia; Chudasama, Yogita; Forni, Claude; Robbins, Trevor W.

    2007-01-01

    It is now well established that subthalamic nucleus high-frequency stimulation (STN HFS) alleviates motor problems in Parkinson's disease. However, its efficacy for cognitive function remains a matter of debate. The aim of this study was to assess the effects of STN HFS in rats performing a visual attentional task. Bilateral STN HFS was applied in intact and in bilaterally dopamine (DA)-depleted rats. In all animals, STN HFS had a transient debilitating effect on all the variables measured in the task. In DA-depleted rats, STN HFS did not alleviate the deficits induced by the DA lesion such as omissions and latency to make correct responses, but induced perseverative approaches to the food magazine, an indicator of enhanced motivation. In sham-operated controls, STN HFS significantly reduced accuracy and induced perseverative behaviour, mimicking partially the effects of bilateral STN lesions in the same task. These results are in line with the hypothesis that STN HFS only partially mimics inactivation of STN produced by lesioning and confirm the motivational exacerbation induced by STN inactivation. PMID:17331214

  17. Antifibrotic effect of atorvastatin on paraquat-induced pulmonary fibrosis: role of PPARγ receptors.

    PubMed

    Malekinejad, Hassan; Mehrabi, Masoud; Khoramjouy, Mona; Rezaei-Golmisheh, Ali

    2013-11-15

    This study was carried out to highlight the role of PPARγ in the paraquat (PQ)-induced pulmonary fibrosis. Forty-two male Wistar rats were exposed either against saline as a control group or PQ (3.5mg/kg, i.p.) as test groups. The test groups were nominated as PQ (PQ-exposed non-treated animals), pioglitazone (PGT, 10mg/kg, orally), atorvastatin (STN, 10mg/kg, orally), PGT+STN, PGT+GW9662 (1mg/kg, i.p.) and STN+GW9662 (1mg/kg). Atorvastatin but not PGT was able to reverse significantly (P<0.05) the PQ-increased ratio of lung to body weight. STN was successfully able to recover the PQ-reduced antioxidant potency and the GW9662 administration resulted in antagonizing the protective effect of both PGT and STN. Although both PGT and STN were able to reduce the hydrxoproline content of the lungs, GW9662, however, could reverse only STN-related effect. Histochemical studies revealed that PQ exposure resulted in a remarkable increase of fibroblasts and collagen fibers in the interstitial tissue and around vessels and bronchioles, which was improved by the STN administration. Only STN-received animals showed the down-regulation of the TGF-β1 expression and GW9662 was able to antagonize this down-regulation. Co-administration of PGT and STN could not exert any synergistic protective effect. These data suggest that the PQ-induced pulmonary fibrosis could be more effectively reversed by STN rather than PGT. Moreover, STN-induced protective effects might attribute to the regulation of TGF-β1 expression, which is antagonized by PPARγ antagonist, suggesting that STN may improve the PQ-induced damages via PPARγ. © 2013 Published by Elsevier B.V.

  18. Can We Rely on Susceptibility-Weighted Imaging for Subthalamic Nucleus Identification in Deep Brain Stimulation Surgery?

    PubMed

    Bot, Maarten; Bour, Lo; de Bie, Rob M; Contarino, Maria Fiorella; Schuurman, P Richard; van den Munckhof, Pepijn

    2016-03-01

    Susceptibility-weighted imaging (SWI) offers significantly improved visibility of the subthalamic nucleus (STN) compared with traditional T2-weighted imaging. However, it is unknown whether the representation of the nucleus on SWI corresponds to the neurophysiological location of the STN. To determine the correlation between the intraoperative electrophysiological activity of the STN and the representation of the nucleus on different magnetic resonance imaging (MRI) sequences used for deep brain stimulation target planning. At stereotactic target depth, microelectrode recordings (MERs) of typical STN neuronal activity were mapped on 3 different preoperative MRI sequences: 1.5-T SWI, 1.5-T T2-weighted, and 3-T T2-weighted MRI. For each MRI sequence, it was determined whether the MER signal was situated inside or outside the contour of the STN. A total of 196 MER tracks in 34 patients were evaluated. In 165 tracks (84%), typical electrophysiological STN activity was measured. MER activity was situated more consistently inside hypointense STN contour representation on 1.5- and 3-T T2-weighted images compared with SWI (99% and 100% vs 79%, respectively). The 21% incongruence of electrophysiological STN activity outside the STN contour on SWI was seen almost exclusively in the anterior and lateral microelectrode channels. STN representation on SWI does not correspond to electrophysiological STN borders. SWI does not correctly display the lateral part of the STN. When aiming to target the superolateral sensorimotor part of the STN during deep brain stimulation surgery, SWI does not offer an advantage but a disadvantage compared with conventional T2. Future research is needed to determine whether these findings may also apply for high-field SWI.

  19. Reduced Vglut2/Slc17a6 Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption

    PubMed Central

    Smith-Anttila, Casey J.A.; Nordenankar, Karin; Arvidsson, Emma; Mahmoudi, Souha; Zampera, André; Wärner Jonsson, Hanna; Bergquist, Jonas; Lévesque, Daniel; Andersson, Malin; Dumas, Sylvie

    2016-01-01

    The subthalamic nucleus (STN) plays a central role in motor, cognitive, and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention for advanced Parkinson’s disease (PD), and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders, and addiction. Animal studies using STN-DBS, lesioning, or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry, and function of the STN. Recent studies in rodent STN models have exposed different roles for STN neurons in reward-related functions. We have previously shown that the majority of STN neurons express the vesicular glutamate transporter 2 gene (Vglut2/Slc17a6) and that reduction of Vglut2 mRNA levels within the STN of mice [conditional knockout (cKO)] causes reduced postsynaptic activity and behavioral hyperlocomotion. The cKO mice showed less interest in fatty rewards, which motivated analysis of reward-response. The current results demonstrate decreased sugar consumption and strong rearing behavior, whereas biochemical analyses show altered dopaminergic and peptidergic activity in the striatum. The behavioral alterations were in fact correlated with opposite effects in the dorsal versus the ventral striatum. Significant cell loss and disorganization of the STN structure was identified, which likely accounts for the observed alterations. Rare genetic variants of the human VGLUT2 gene exist, and this study shows that reduced Vglut2/Slc17a6 gene expression levels exclusively within the STN of mice is sufficient to cause strong modifications in both the STN and the mesostriatal dopamine system. PMID:27699212

  20. Subthalamic 6-OHDA-induced lesion attenuates levodopa-induced dyskinesias in the rat model of Parkinson's disease.

    PubMed

    Marin, C; Bonastre, M; Mengod, G; Cortés, R; Rodríguez-Oroz, M C; Obeso, J A

    2013-12-01

    The subthalamic nucleus (STN) receives direct dopaminergic innervation from the substantia nigra pars compacta that degenerates in Parkinson's disease. The present study aimed to investigate the role of dopaminergic denervation of STN in the origin of levodopa-induced dyskinesias. Rats were distributed in four groups which were concomitantly lesioned with 6-OHDA or vehicle (sham) in the STN and in the medial forebrain bundle (MFB) as follows: a) MFB-sham plus STN-sham, b) MFB-sham plus STN-lesion, c) MFB-lesion plus STN-sham, and d) MFB-lesion plus STN-lesion. Four weeks after lesions, animals were treated with levodopa (6mg/kg with 15mg/kg benserazide i.p.) twice daily for 22 consecutive days. Abnormal involuntary movements were measured. In situ hybridization was performed measuring the expression of striatal preproenkephalin, preprodynorphin, STN cytochrome oxidase (CO) and nigral GAD67 mRNAs. STN 6-OHDA denervation did not induce dyskinesias in levodopa-treated MFB-sham animals but attenuated axial (p<0.05), limb (p<0.05) and orolingual (p<0.01) dyskinesias in rats with a concomitant lesion of the nigrostriatal pathway. The attenuation of dyskinesias was associated with a decrease in the ipsilateral STN CO mRNA levels (p<0.05). No significant differences between MFB-lesion plus STN-sham and MFB-lesion plus STN-lesion groups in the extent of STN dopaminergic denervation were observed. Moreover, intrasubthalamic microinfusion of dopamine in the MFB-lesion plus STN-lesion group triggered orolingual (p<0.01), but not axial or limb, dyskinesias. These results suggest that dopaminergic STN innervation influences the expression of levodopa-induced dyskinesias but also the existence of non dopaminergic-mediated mechanisms. STN noradrenergic depletion induced by 6-OHDA in the STN needs to be taken in account as a possible mechanism explaining the attenuation of dyskinesias in the combined lesion group.

  1. Deep Brain Stimulation of the Subthalamic Nucleus Alters Frontal Activity during Spatial Working Memory Maintenance of Patients with Parkinson’s Disease

    PubMed Central

    Mayer, Jutta S.; Neimat, Joseph; Folley, Bradley S.; Bourne, Sarah K.; Konrad, Peter E.; Charles, David; Park, Sohee

    2016-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves the motor symptoms of Parkinson’s disease (PD). The STN may represent an important relay station not only in the motor but also the associative cortico-striato-thalamocortical pathway. Therefore, STN stimulation may alter cognitive functions such as working memory (WM). We examined cortical effects of STN-DBS on WM in early PD patients using functional near-infrared spectroscopy. The effects of dopaminergic medication on WM were also examined. Lateral frontal activity during WM maintenance was greater when patients were taking dopaminergic medication. STN-DBS led to a trend-level worsening of WM performance, accompanied by increased lateral frontal activity during WM maintenance. These findings suggest that STN-DBS in PD might lead to functional modifications of the basal ganglia-thalamocortical pathway during WM maintenance. PMID:27337498

  2. The subthalamic nucleus during decision-making with multiple alternatives.

    PubMed

    Keuken, Max C; Van Maanen, Leendert; Bogacz, Rafal; Schäfer, Andreas; Neumann, Jane; Turner, Robert; Forstmann, Birte U

    2015-10-01

    Several prominent neurocomputational models predict that an increase of choice alternatives is modulated by increased activity in the subthalamic nucleus (STN). In turn, increased STN activity allows prolonged accumulation of information. At the same time, areas in the medial frontal cortex such as the anterior cingulate cortex (ACC) and the pre-SMA are hypothesized to influence the information processing in the STN. This study set out to test concrete predictions of STN activity in multiple-alternative decision-making using a multimodal combination of 7 Tesla structural and functional Magnetic Resonance Imaging, and ancestral graph (AG) modeling. The results are in line with the predictions in that increased STN activity was found with an increasing amount of choice alternatives. In addition, our study shows that activity in the ACC is correlated with activity in the STN without directly modulating it. This result sheds new light on the information processing streams between medial frontal cortex and the basal ganglia.

  3. Effects of deep brain stimulation and medication on strength, bradykinesia, and electromyographic patterns of the ankle joint in Parkinson's disease.

    PubMed

    Vaillancourt, David E; Prodoehl, Janey; Sturman, Molly M; Bakay, Roy A E; Metman, Leo Verhagen; Corcos, Daniel M

    2006-01-01

    We investigated the control of movement in 12 patients with Parkinson's disease (PD) after they received surgically implanted high-frequency stimulating electrodes in the subthalamic nucleus (STN). The experiment studied ankle strength, movement velocity, and the associated electromyographic patterns in PD patients, six of whom had tremor at the ankle. The patients were studied off treatment, ON STN deep brain stimulation (DBS), on medication, and on medication plus STN DBS. Twelve matched control subjects were also examined. Medication alone and STN DBS alone increased patients' ankle strength, ankle velocity, agonist muscle burst amplitude, and agonist burst duration, while reducing the number of agonist bursts during movement. These findings were similar for PD patients with and without tremor. The combination of medication plus STN DBS normalized maximal strength at the ankle joint, but ankle movement velocity and electromyographic patterns were not normalized. The findings are the first to demonstrate that STN DBS and medication increase strength and movement velocity at the ankle joint.

  4. Subthalamic nucleus lesions increase impulsive action and decrease impulsive choice - mediation by enhanced incentive motivation?

    PubMed

    Uslaner, Jason M; Robinson, Terry E

    2006-10-01

    The subthalamic nucleus (STN) is traditionally thought of as part of a system involved in motor control but recent evidence suggests that it may also play a role in other psychological processes. Here we examined the effects of STN lesions on two measures of impulsivity and found that STN lesions increased 'impulsive action' (produced behavioral disinhibition), as measured by performance on a differential reinforcement of low rates of responding task, but decreased 'impulsive choice' (impulsive decision making), as measured by a delay discounting task. In addition, amphetamine and food restriction increased 'impulsive action' and decreased 'impulsive choice' to a greater extent in STN-lesioned animals than in sham controls. We speculate that these apparently discrepant effects may be because STN lesions enhance the incentive salience assigned to rewards. These findings suggest that the STN may serve as a novel target for the treatment of psychological disorders characterized by deficits in behavioral control, such as drug addiction and attention deficit hyperactivity disorder.

  5. The Subthalamic Nucleus During Decision-Making With Multiple Alternatives

    PubMed Central

    Bogacz, Rafal; Schäfer, Andreas; Neumann, Jane; Turner, Robert; Forstmann, Birte U.

    2016-01-01

    Several prominent neurocomputational models predict that an increase of choice alternatives is modulated by increased activity in the subthalamic nucleus (STN). In turn, increased STN activity allows prolonged accumulation of information. At the same time, areas in the medial frontal cortex such as the anterior cingulate cortex (ACC) and the pre-SMA are hypothesized to influence the information processing in the STN. This study set out to test concrete predictions of STN activity in multiple-alternative decision-making using a multimodal combination of 7 Tesla structural and functional Magnetic Resonance Imaging, and ancestral graph (AG) modeling. The results are in line with the predictions in that increased STN activity was found with an increasing amount of choice alternatives. In addition, our study shows that activity in the ACC is correlated with activity in the STN without directly modulating it. This result sheds new light on the information processing streams between medial frontal cortex and the basal ganglia. PMID:26178078

  6. High-frequency stimulation of the subthalamic nucleus selectively reverses dopamine denervation-induced cellular defects in the output structures of the basal ganglia in the rat.

    PubMed

    Salin, Pascal; Manrique, Christine; Forni, Claude; Kerkerian-Le Goff, Lydia

    2002-06-15

    High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is now recognized as an effective treatment for advanced Parkinson's disease, but the molecular basis of its effects remains unknown. This study examined the effects of unilateral STN HFS (2 hr of continuous stimulation) in intact and hemiparkinsonian awake rats on STN neuron metabolic activity and on neurotransmitter-related gene expression in the basal ganglia, by means of in situ hybridization histochemistry and immunocytochemistry. In both intact and hemiparkinsonian rats, this stimulation was found to induce c-fos protein expression but to decrease cytochrome oxidase subunit I mRNA levels in STN neurons. STN HFS did not affect the dopamine lesion-mediated overexpression of enkephalin mRNA or the decrease in substance P in the ipsilateral striatum. The lesion-induced increases in intraneuronal glutamate decarboxylase 67 kDa isoform (GAD67) mRNA levels on the lesion side were reversed by STN HFS in the substantia nigra, partially antagonized in the entopeduncular nucleus but unaffected in the globus pallidus. The stimulation did not affect neuropeptide or GAD67 mRNA levels in the side contralateral to the dopamine lesion or in intact animals. These data furnish the first evidence that STN HFS decreases the metabolic activity of STN neurons and antagonizes dopamine lesion-mediated cellular defects in the basal ganglia output structures. They provide molecular substrate to the therapeutic effects of this stimulation consistent with the current hypothesis that HFS blocks STN neuron activity. However, the differential impact of STN HFS on the effects of dopamine lesion among structures receiving direct STN inputs suggests that this stimulation may not cause simply interruption of STN outflow.

  7. Spatial heterogeneity distribution of soil total nitrogen and total phosphorus in the Yaoxiang watershed in a hilly area of northern China based on geographic information system and geostatistics.

    PubMed

    Liu, Yu; Gao, Peng; Zhang, Liyong; Niu, Xiang; Wang, Bing

    2016-10-01

    Soil total nitrogen (STN) and total phosphorus (STP) are important indicators of soil nutrients and the important indexes of soil fertility and soil quality evaluation. Using geographic information system (GIS) and geostatistics, the spatial heterogeneity distribution of STN and STP in the Yaoxiang watershed in a hilly area of northern China was studied. The results showed that: (1) The STN and STP contents showed a declining trend with the increase in soil depth; the variation coefficients (Cv) of STN and STP in the 0- to 10-cm soil layer (42.25% and 14.77%, respectively) were higher than in the 10- to 30-cm soil layer (28.77% and 11.60%, respectively). Moreover, the Cv of STN was higher than that of STP. (2) The maximum C0/(C0 + C1) of STN and STP in the soil layers was less than 25%, this indicated that a strong spatial distribution autocorrelation existed for STN and STP; and the STP showed higher intensity and more stable variation than the STN. (3) From the correlation analysis, we concluded that the topographic indexes such as elevation and slope direction all influenced the spatial distribution of STN and STP (correlation coefficients were 0.688 and 0.518, respectively). (4) The overall distribution of STN and STP in the Yaoxiang watershed decreased from the northwest to the southeast. This variation trend was similar to the watershed DEM trend and was significantly influenced by vegetation and topographic factors. These results revealed the spatial heterogeneity distribution of STN and STP, and addressed the influences of forest vegetation coverage, elevation, and other topographic factors on the spatial distribution of STN and STP at the watershed scale.

  8. In Parkinson's disease on a probabilistic Go/NoGo task deep brain stimulation of the subthalamic nucleus only interferes with withholding of the most prepotent responses.

    PubMed

    Georgiev, Dejan; Dirnberger, Georg; Wilkinson, Leonora; Limousin, Patricia; Jahanshahi, Marjan

    2016-04-01

    The evidence on the impact of subthalamic nucleus deep brain stimulation (STN-DBS) on action restraint on Go/NoGO reaction time (RT) tasks in Parkinson's disease (PD) is inconsistent; with some studies reporting no effect and others finding that STN stimulation interferes with withholding of responses and results in more commission errors relative to STN-DBS off. We used a task in which the probability of Go stimuli varied from 100% (simple RT task) to 80, 50 and 20% (probabilistic Go/NoGo RT task), thus altering the prepotency of the response and the difficulty in withholding it on NoGo trials. Twenty PD patients with STN-DBS, ten unoperated PD patients and ten healthy controls participated in the study. All participants were tested twice; the order of on versus off stimulation for STN-DBS PD patients was counterbalanced. Both STN-DBS and unoperated PD patients were tested on medication. The results indicated that STN-DBS selectively decreased discriminability when the response was most prepotent (high--80%, as compared to low Go probability trials--50 and 20%). Movement times were faster with STN stimulation than with DBS off across different Go probability levels. There was neither an overall nor a selective effect of STN-DBS on RTs depending on the level of Go probability. Furthermore, compared to healthy controls, both STN-DBS and unoperated PD patients were more prone to making anticipatory errors; which was not influenced by STN stimulation. The results provide evidence for 'load-dependent' effects of STN stimulation on action restraint as a function of the prepotency of the Go response.

  9. Tremor reduction by subthalamic nucleus stimulation and medication in advanced Parkinson's disease.

    PubMed

    Blahak, Christian; Wöhrle, Johannes C; Capelle, Hans-Holger; Bäzner, Hansjörg; Grips, Eva; Weigel, Ralf; Hennerici, Michael G; Krauss, Joachim K

    2007-02-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has proved to be effective for tremor in Parkinson's disease (PD). Most of the recent studies used only clinical data to analyse tremor reduction. The objective of our study was to quantify tremor reduction by STN DBS and antiparkinsonian medication in elderly PD patients using an objective measuring system. Amplitude and frequency of resting tremor and re-emergent resting tremor during postural tasks were analysed using an ultrasound-based measuring system and surface electromyography. In a prospective study design nine patients with advanced PD were examined preoperatively off and on medication, and twice postoperatively during four treatment conditions: off treatment, on STN DBS, on medication, and on STN DBS plus medication. While both STN DBS and medication reduced tremor amplitude, STN DBS alone and the combination of medication and STN DBS were significantly superior to pre- and postoperative medication. STN DBS but not medication increased tremor frequency, and off treatment tremor frequency was significantly reduced postoperatively compared to baseline. These findings demonstrate that STN DBS is highly effective in elderly patients with advanced PD and moderate preoperative tremor reduction by medication. Thus, with regard to the advanced impact on the other parkinsonian symptoms, STN DBS can replace thalamic stimulation in this cohort of patients. Nevertheless, medication was still effective postoperatively and may act synergistically. The significantly superior efficacy of STN DBS on tremor amplitude and its impact on tremor frequency in contrast to medication might be explained by the influence of STN DBS on additional neural circuits independent from dopaminergic neurotransmission.

  10. Impact of chronic subthalamic high-frequency stimulation on metabolic basal ganglia activity: a 2-deoxyglucose uptake and cytochrome oxidase mRNA study in a macaque model of Parkinson's disease.

    PubMed

    Meissner, Wassilios; Guigoni, Celine; Cirilli, Laetitia; Garret, Maurice; Bioulac, Bernard H; Gross, Christian E; Bezard, Erwan; Benazzouz, Abdelhamid

    2007-03-01

    The mechanisms of action of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) remain only partially understood. Hitherto, experimental studies have suggested that STN-HFS reduces the activity of STN neurons. However, some recent reports have challenged this view, showing that STN-HFS might also increase the activity of globus pallidus internalis (GPi) neurons that are under strong excitatory drive of the STN. In addition, most results emanate from studies applying acute STN-HFS, while parkinsonian patients receive chronic stimulation. Thus, the present study was designed to assess the effect of chronic (10 days) STN-HFS in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primate. For this purpose, 2-deoxyglucose (2-DG) uptake, a measure of global synaptic activity, was assessed in the basal ganglia and the motor thalamus after chronic unilateral STN-HFS. Cytochrome oxidase subunit 1 (COI) mRNA expression, a marker of efferent metabolic activity, was additionally assessed in the globus pallidus. Chronic STN-HFS (i) reversed abnormally decreased 2-DG uptake in the STN of parkinsonian nonhuman primates, (ii) reversed abnormally increased 2-DG accumulation in the GPi while COI mRNA expression was increased, suggesting global activation of GPi neurons, and (iii) reversed abnormally increased 2-DG uptake in the ventrolateral motor thalamus nucleus. The simultaneous decrease in 2-DG uptake and increase in COI mRNA expression are difficult to reconcile with the current model of basal ganglia function and suggest that the mechanisms by which STN-HFS exerts its clinical benefits are more complex than a simple reversal of abnormal activity in the STN and its targets.

  11. Subthalamic nucleus deep brain stimulation induces impulsive action when patients with Parkinson's disease act under speed pressure.

    PubMed

    Pote, Inês; Torkamani, Mariam; Kefalopoulou, Zinovia-Maria; Zrinzo, Ludvic; Limousin-Dowsey, Patricia; Foltynie, Thomas; Speekenbrink, Maarten; Jahanshahi, Marjan

    2016-07-01

    The subthalamic nucleus (STN) is proposed to modulate response thresholds and speed-accuracy trade-offs. In situations of conflict, the STN is considered to raise response thresholds, allowing time for the accumulation of information to occur before a response is selected. Conversely, speed pressure is thought to reduce the activity of the STN and lower response thresholds, resulting in fast, errorful responses. In Parkinson's disease (PD), subthalamic nucleus deep brain stimulation (STN-DBS) reduces the activity of the nucleus and improves motor symptoms. We predicted that the combined effects of STN stimulation and speed pressure would lower STN activity and lead to fast, errorful responses, hence resulting in impulsive action. We used the motion discrimination 'moving-dots' task to assess speed-accuracy trade-offs, under both speed and accuracy instructions. We assessed 12 patients with PD and bilateral STN-DBS and 12 age-matched healthy controls. Participants completed the task twice, and the patients completed it once with STN-DBS on and once with STN-DBS off, with order counterbalanced. We found that STN stimulation was associated with significantly faster reaction times but more errors under speed instructions. Application of the drift diffusion model showed that stimulation resulted in lower response thresholds when acting under speed pressure. These findings support the involvement of the STN in the modulation of speed-accuracy trade-offs and establish for the first time that speed pressure alone, even in the absence of conflict, can result in STN stimulation inducing impulsive action in PD.

  12. Effects of neurostimulation for advanced Parkinson’s disease patients on motor symptoms: A multiple-treatments meta-analysas of randomized controlled trials

    PubMed Central

    Xie, Cheng-Long; Shao, Bei; Chen, Jie; Zhou, Yi; Lin, Shi-Yi; Wang, Wen-Wen

    2016-01-01

    Deep brain stimulation (DBS) is the surgical procedure of choice for patients with advanced Parkinson disease (PD). We aim to evaluate the efficacy of GPi (globus pallidus internus), STN (subthalamic nucleus)-DBS and medical therapy for PD. We conducted a systematic review and multiple-treatments meta-analysis to investigate the efficacy of neurostimulation and medical therapy for PD patients. Sixteen eligible studies were included in this analysis. We pooled the whole data and found obvious difference between GPi-DBS versus medical therapy and STN-DBS versus medical therapy in terms of UPDRS scores (Unified Parkinson’s Disease Rating Scale). Meanwhile, we found GPi-DBS had the similar efficacy on the UPDRS scores when compared with STN-DBS. What is more, quality of life, measured by PDQ-39 (Parkinson’s disease Questionnaire) showed greater improvement after GPi-DBS than STN-DBS. Five studies showed STN-DBS was more effective for reduction in medication than GPi-DBS. Overall, either GPi-DBS or STN-DBS was an effective technique to control PD patients’ symptoms and improved their functionality and quality of life. Meanwhile, the UPDRS scores measuring parkinsonian symptoms revealed no significant difference between GPi-DBS and STN-DBS. STN-DBS was more effective for reduction in medication than GPi-DBS. Alternatively, GPi-DBS was more effective for improving the PDQ-39 score than STN-DBS. PMID:27142183

  13. Neuronal activity in the human subthalamic nucleus encodes decision conflict during action selection

    PubMed Central

    Zaghloul, Kareem A.; Weidemann, Christoph T.; Lega, Bradley C.; Jaggi, Jurg L.; Baltuch, Gordon H.; Kahana, Michael J.

    2012-01-01

    The subthalamic nucleus (STN), which receives excitatory inputs from the cortex and has direct connections with the inhibitory pathways of the basal ganglia, is well positioned to efficiently mediate action selection. Here, we use microelectrode recordings captured during deep brain stimulation surgery as participants engage in a decision task to examine the role of the human STN in action selection. We demonstrate that spiking activity in the STN increases when participants engage in a decision, and that the level of spiking activity increases with the degree of decision conflict. These data implicate the STN as an important mediator of action selection during decision processes. PMID:22396419

  14. Pallidotomy suppresses beta power in the subthalamic nucleus of Parkinson's disease patients.

    PubMed

    Contarino, Maria Fiorella; Bour, Lo J; Bot, Maarten; Van Den Munckhof, Pepijn; Speelman, Johannes D; Schuurman, P Richard; De Bie, Rob M A

    2011-04-01

    Parkinsonian patients, who have had a unilateral pallidotomy, may require bilateral deep brain stimulation of the subthalamic nucleus (STN), due to disease progression. The current model of the basal ganglia circuitry does not predict a direct effect of pallidotomy on the neuronal activity of the ipsilateral STN. To date, only three studies have investigated the effect of pallidotomy on overall activity of the STN or neuronal firing rate, but not on the spectral content of the neuronal oscillatory activity. Moreover, none of these studies attempted to differentiate the effects on the dorsal (sensory-motor) and ventral (associative-limbic) parts of the STN. We studied the effect of pallidotomy on spectral power in six frequency bands in the STN ipsilateral and contralateral to pallidotomy from seven patients and in 60 control nuclei of patients without prior functional neurosurgery, and investigated whether this effect is different on the dorsal and ventral STN. The data show that pallidotomy suppresses beta power (13-30 Hz) in the ipsilateral STN. This effect tends predominantly to be present in the dorsal part of the STN. In addition, spectral power in the frequency range 3-30 Hz is significantly higher in the dorsal part than in the ventral part. The effect of pallidotomy on STN neural activity is difficult to explain with the current model of basal ganglia circuitry and should be envisaged in the context of complex modulatory interactions in the basal ganglia.

  15. Targeting of the Subthalamic Nucleus for Deep Brain Stimulation: A Survey Among Parkinson Disease Specialists.

    PubMed

    Hamel, Wolfgang; Köppen, Johannes A; Alesch, François; Antonini, Angelo; Barcia, Juan A; Bergman, Hagai; Chabardes, Stephan; Contarino, Maria Fiorella; Cornu, Philippe; Demmel, Walter; Deuschl, Günther; Fasano, Alfonso; Kühn, Andrea A; Limousin, Patricia; McIntyre, Cameron C; Mehdorn, H Maximilian; Pilleri, Manuela; Pollak, Pierre; Rodríguez-Oroz, Maria C; Rumià, Jordi; Samuel, Michael; Timmermann, Lars; Valldeoriola, Francesc; Vesper, Jan; Visser-Vandewalle, Veerle; Volkmann, Jens; Lozano, Andres M

    2017-03-01

    Deep brain stimulation within or adjacent to the subthalamic nucleus (STN) represents the most common stereotactic procedure performed for Parkinson disease. Better STN imaging is often regarded as a requirement for improving stereotactic targeting. However, it is unclear whether there is consensus about the optimal target. To obtain an expert opinion on the site regarded optimal for "STN stimulation," movement disorder specialists were asked to indicate their preferred position for an active contact on hard copies of the Schaltenbrand and Wahren atlas depicting the STN in all 3 planes. This represented an idealized setting, and it mimicked optimal imaging for direct target definition in a perfectly delineated STN. The suggested targets were heterogeneous, although some clustering was observed in the dorsolateral STN and subthalamic area. In particular, in the anteroposterior direction, the intended targets differed to a great extent. Most of the indicated targets are thought to also result in concomitant stimulation of structures adjacent to the STN, including the zona incerta, fields of Forel, and internal capsule. This survey illustrates that most sites regarded as optimal for STN stimulation are close to each other, but there appears to be no uniform perception of the optimal anatomic target, possibly influencing surgical results. The anatomic sweet zone for STN stimulation needs further specification, as this information is likely to make magnetic resonance imaging-based target definition less variable when applied to individual patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Observations of minor planets.

    NASA Astrophysics Data System (ADS)

    Observations made at the following stations are published: Bucharest, Catania, Caussols, Cent. Astron. Yebes, Cerro Tololo Interam. Obs., Chirorin, Crimean Astrophys. Obs. (52nd Report), Eur. South. Obs., Falkensee, Geisei, Goethe Link Obs., Göttingen, Haute Provence, Hemingford Abbots, JCPM Oi Stn., Kambah (near Canberra), Kitt Peak, Klet', Le Creusot, Lick Obs., Lincoln Lab., Lowell Obs., Lowell Obs. Anderson Mesa Stn., Madonnna di Dossobuono, Mt. John Obs., Mt. Palomar, Oak Ridge Obs., Purple Mountain Obs., Quonochontaug Stn. (Rhode Island), Reintal, S. Vittore (Bologna), Seewalchen, Siding Spring, Skalnaté Pleso, Spec. Astrophys. Obs., Steward Obs., Sydney, Tautenburg, Telford, Tokyo Obs. Kiso Stn., Turku, Zimmerwald.

  17. Effects of subthalamic nucleus stimulation and medication on resting and postural tremor in Parkinson's disease.

    PubMed

    Sturman, Molly M; Vaillancourt, David E; Metman, Leo Verhagen; Bakay, Roy A E; Corcos, Daniel M

    2004-09-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and antiparkinsonian medication have proved to be effective treatments for tremor in Parkinson's disease. To date it is not known how and to what extent STN DBS alone and in combination with antiparkinsonian medication alters the pathophysiology of resting and postural tremor in idiopathic Parkinson's disease. The purpose of this study was to examine the effects of STN DBS and antiparkinsonian medication on the neurophysiological characteristics of resting and postural hand tremor in Parkinson's disease. Resting and postural hand tremor were recorded using accelerometry and surface electromyography (EMG) from 10 Parkinson's disease patients and 10 matched control subjects. The Parkinson's disease subjects were examined under four treatment conditions: (i) off treatment; (ii) STN DBS; (iii) medication; and (iv) medication plus STN DBS. The amplitude, EMG frequency, regularity, and 1-8 Hz tremor-EMG coherence were analysed. Both STN DBS and medication reduced the amplitude, regularity and tremor-EMG coherence, and increased the EMG frequency of resting and postural tremor in Parkinson's disease. STN DBS was more effective than medication in reducing the amplitude and increasing the frequency of resting and postural tremor to healthy physiological levels. These findings provide strong evidence that effective STN DBS normalizes the amplitude and frequency of tremor. The findings suggest that neural activity in the STN is an important modulator of the neural network(s) responsible for both resting and postural tremor genesis in Parkinson's disease.

  18. Quantitative analysis of axon bouton distribution of subthalamic nucleus neurons in the rat by single neuron visualization with a viral vector.

    PubMed

    Koshimizu, Yoshinori; Fujiyama, Fumino; Nakamura, Kouichi C; Furuta, Takahiro; Kaneko, Takeshi

    2013-06-15

    The subthalamic nucleus (STN) of the basal ganglia plays a key role in motor control, and STN efferents are known to mainly target the external segment of the globus pallidus (GPe), entopeduncular nucleus (Ep), and substantia nigra (SN) with some axon collaterals to the other regions. However, it remains to be clarified how each STN neuron projects axon fibers and collaterals to those target nuclei of the STN. Here we visualized the whole axonal arborization of single STN neurons in the rat brain by using a viral vector expressing membrane-targeted green fluorescent protein, and examined the distribution of axon boutons in those target nuclei. The vast majority (8-9) of 10 reconstructed STN neurons projected to the GPe, SN, caudate-putamen (CPu), and Ep, which received, on average ± SD, 457 ± 425, 400 ± 347, 126 ± 143, and 106 ± 100 axon boutons per STN neuron, respectively. Furthermore, the density of axon boutons in the GPe was highest among these nuclei. Although these target nuclei were divided into calbindin-rich and -poor portions, STN projection showed no exclusive preference for those portions. Since STN neurons mainly projected not only to the GPe, SN, and Ep but also to the CPu, the subthalamostriatal projection might serve as a positive feedback path for the striato-GPe-subthalamic disinhibitory pathway, or work as another route of cortical inputs to the striatum through the corticosubthalamostriatal disynaptic excitatory pathway.

  19. Verbal fluency in patients receiving bilateral versus left-sided deep brain stimulation of the subthalamic nucleus for Parkinson's disease.

    PubMed

    Sjöberg, Rickard L; Lidman, Elin; Häggström, Björn; Hariz, Marwan I; Linder, Jan; Fredricks, Anna; Blomstedt, Patric

    2012-05-01

    The purpose of this study was to investigate the relative effects of unilateral (left-sided) versus bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) on verbal fluency. To do this, 10 Parkinson's disease patients with predominantly bilateral motor symptoms who received bilateral STN DBS were compared with 6 patients suffering from predominantly unilateral symptoms who received STN DBS on the left side only. The results suggest that unilateral STN DBS of the speech dominant hemisphere is associated with significantly less declines in measures of verbal fluency as compared to bilateral stimulation.

  20. Subthalamic nucleus high-frequency stimulation modulates neuronal reactivity to cocaine within the reward circuit.

    PubMed

    Hachem-Delaunay, Sabira; Fournier, Marie-Line; Cohen, Candie; Bonneau, Nicolas; Cador, Martine; Baunez, Christelle; Le Moine, Catherine

    2015-08-01

    The subthalamic nucleus (STN) is a critical component of a complex network controlling motor, associative and limbic functions. High-frequency stimulation (HFS) of the STN is an effective therapy for motor symptoms in Parkinsonian patients and can also reduce their treatment-induced addictive behaviors. Preclinical studies have shown that STN HFS decreases motivation for cocaine while increasing that for food, highlighting its influence on rewarding and motivational circuits. However, the cellular substrates of these effects remain unknown. Our objectives were to characterize the cellular consequences of STN HFS with a special focus on limbic structures and to elucidate how STN HFS may interfere with acute cocaine effects in these brain areas. Male Long-Evans rats were subjected to STN HFS (130 Hz, 60 μs, 50-150 μA) for 30 min before an acute cocaine injection (15 mg/kg) and sacrificed 10 min following the injection. Neuronal reactivity was analyzed through the expression of two immediate early genes (Arc and c-Fos) to decipher cellular responses to STN HFS and cocaine. STN HFS only activated c-Fos in the globus pallidus and the basolateral amygdala, highlighting a possible role on emotional processes via the amygdala, with a limited effect by itself in other structures. Interestingly, and despite some differential effects on Arc and c-Fos expression, STN HFS diminished the c-Fos response induced by acute cocaine in the striatum. By preventing the cellular effect of cocaine in the striatum, STN HFS might thus decrease the reinforcing properties of the drug, which is in line with the inhibitory effect of STN HFS on the rewarding and reinforcing properties of cocaine. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Computational Model of Recurrent Subthalamo-Pallidal Circuit for Generation of Parkinsonian Oscillations

    PubMed Central

    Shouno, Osamu; Tachibana, Yoshihisa; Nambu, Atsushi; Doya, Kenji

    2017-01-01

    Parkinson's disease is a movement disorder caused by dopamine depletion in the basal ganglia. Abnormally synchronized neuronal oscillations between 8 and 15 Hz in the basal ganglia are implicated in motor symptoms of Parkinson's disease. However, how these abnormal oscillations are generated and maintained in the dopamine-depleted state is unknown. Based on neural recordings in a primate model of Parkinson's disease and other experimental and computational evidence, we hypothesized that the recurrent circuit between the subthalamic nucleus (STN) and the external segment of the globus pallidus (GPe) generates and maintains parkinsonian oscillations, and that the cortical excitatory input to the STN amplifies them. To investigate this hypothesis through computer simulations, we developed a spiking neuron model of the STN-GPe circuit by incorporating electrophysiological properties of neurons and synapses. A systematic parameter search by computer simulation identified regions in the space of the intrinsic excitability of GPe neurons and synaptic strength from the GPe to the STN that reproduce normal and parkinsonian states. In the parkinsonian state, reduced firing of GPe neurons and increased GPe-STN inhibition trigger burst activities of STN neurons with strong post-inhibitory rebound excitation, which is usually subject to short-term depression. STN neuronal bursts are shaped into the 8–15 Hz, synchronous oscillations via recurrent interactions of STN and GPe neurons. Furthermore, we show that cortical excitatory input to the STN can amplify or suppress pathological STN oscillations depending on their phase and strength, predicting conditions of cortical inputs to the STN for suppressing oscillations. PMID:28377699

  2. Delimiting subterritories of the human subthalamic nucleus by means of microelectrode recordings and a Hidden Markov Model.

    PubMed

    Zaidel, Adam; Spivak, Alexander; Shpigelman, Lavi; Bergman, Hagai; Israel, Zvi

    2009-09-15

    Positive therapeutic response without adverse side effects to subthalamic nucleus deep brain stimulation (STN DBS) for Parkinson's disease (PD) depends to a large extent on electrode location within the STN. The sensorimotor region of the STN (seemingly the preferred location for STN DBS) lies dorsolaterally, in a region also marked by distinct beta (13-30 Hz) oscillations in the parkinsonian state. In this study, we present a real-time method to accurately demarcate subterritories of the STN during surgery, based on microelectrode recordings (MERs) and a Hidden Markov Model (HMM). Fifty-six MER trajectories were used, obtained from 21 PD patients who underwent bilateral STN DBS implantation surgery. Root mean square (RMS) and power spectral density (PSD) of the MERs were used to train and test an HMM in identifying the dorsolateral oscillatory region (DLOR) and nonoscillatory subterritories within the STN. The HMM demarcations were compared to the decisions of a human expert. The HMM identified STN-entry, the ventral boundary of the DLOR, and STN-exit with an error of -0.09 +/- 0.35, -0.27 +/- 0.58, and -0.20 +/- 0.33 mm, respectively (mean +/- standard deviation), and with detection reliability (error < 1 mm) of 95, 86, and 91%, respectively. The HMM was successful despite a very coarse clustering method and was robust to parameter variation. Thus, using an HMM in conjunction with RMS and PSD measures of intraoperative MER can provide improved refinement of STN entry and exit in comparison with previously reported automatic methods, and introduces a novel (intra-STN) detection of a distinct DLOR-ventral boundary.

  3. Effect of unilateral versus bilateral electrostimulation in subthalamic nucleus on speech in Parkinsons disease

    NASA Astrophysics Data System (ADS)

    Wang, Emily; Verhagen Metman, Leo; Bakay, Roy; Arzbaecher, Jean; Bernard, Bryan

    2004-05-01

    Previously, it was found that 16 right-handed patients with idiopathic Parkinsons disease who underwent unilateral implantation of deep brain stimulator in subthalamic nucleus (STN) showed significant improvement in their nonspeech motor functions. Eight of the 16 patients had stimulator in the left STN and eight in the right STN. In contrast, their speech function showed very mild improvement that was limited to the respiratory/phonotory subsystems. Further, there seemed a trend that the patients with right STN stimulation did better than those with left STN stimulation. It was speculated that the difference might be due to a micro lesion caused by the surgical procedure to the corticobulbar fibers run in the left internal capsule. This paper reports speech changes associated with bilateral DBS in STN in four of the 16 subjects who elected to have deep brain stimulator implanted in STN on the opposite side of the brain at a later time. Results show negative changes in speech after bilateral DBS in STN. The changes were not limited to the micro lesion effect due to the surgery itself, but also related to the active stimulation on the dominant hemisphere for speech processing. [Work supported by NIH.

  4. The supraorbital region revisited: An anatomic exploration of the neuro-vascular bundle with regard to frontal migraine headache.

    PubMed

    Berchtold, Valeria; Stofferin, Hannes; Moriggl, Bernhard; Brenner, Erich; Pauzenberger, Reinhard; Konschake, Marko

    2017-09-01

    Recent findings on the pathogenesis of frontal migraine headache support, besides a central vasogenic cause, an alternative peripheral mechanism involving compressed craniofacial nerves. This is further supported by the efficiency of botulinum toxin injections as a new treatment option in frontal migraine headache patients. The supraorbital regions of 22 alcohol-glycerine-embalmed facial halves of both sexes were dissected. Both the supratrochlear and supraorbital nerves (STN and SON, respectively) were identified, and their relationship with the corrugator supercilii muscle (CSM) was investigated by dissection and ultrasound. The course of both nerves was defined, and the interaction between the supraorbital artery (SOA) and SON was determined. We discovered a new possible compression point of the STN passing through the orbital septum and verified previously described compression points of both STN and SON. Osteofibrous channels used by the STN and SON were found constantly. We described the varying topography of the STN and CSM, the SON and CSM, and the SON and SOA. Further, we provide an algorithm for the ultrasound visualization of the supraorbital neurovascular bundle. Our data support the hypothesis of a peripheral mechanism for frontal migraine headache because of following potential irritation points: first, the CSM is constantly perforated by the SON and frequently by the STN; second, the topographic proximity between SOA and SON and the osteofibrous channels is used by the SON and STN; and third, the STN passes through the orbital septum. Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

  5. Subthalamic Nucleus Stimulation and Dysarthria in Parkinson's Disease: A PET Study

    ERIC Educational Resources Information Center

    Pinto, Serge; Thobois, Stephane; Costes, Nicolas; Le Bars, Didier; Benabid, Alim-Louis; Broussolle, Emmanuel; Pollak, Pierre; Gentil, Michele

    2004-01-01

    In Parkinson's disease, functional imaging studies during limb motor tasks reveal cerebral activation abnormalities that can be reversed by subthalamic nucleus (STN) stimulation. The effect of STN stimulation on parkinsonian dysarthria has not, however, been investigated using PET. The aim of the present study was to evaluate the effect of STN…

  6. Subthalamic Nucleus Deep Brain Stimulation Changes Velopharyngeal Control in Parkinson's Disease

    ERIC Educational Resources Information Center

    Hammer, Michael J.; Barlow, Steven M.; Lyons, Kelly E.; Pahwa, Rajesh

    2011-01-01

    Purpose: Adequate velopharyngeal control is essential for speech, but may be impaired in Parkinson's disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on velopharyngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of velopharyngeal…

  7. Chronic stress-like syndrome as a consequence of medial site subthalamic stimulation in Parkinson's disease.

    PubMed

    Růžička, Filip; Jech, Robert; Nováková, Lucie; Urgošík, Dušan; Bezdíček, Ondřej; Vymazal, Josef; Růžička, Evžen

    2015-02-01

    Considering the functional organization of the subthalamic nucleus (STN), we hypothesized that subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease might have a differential impact on the hypothalamic-pituitary-adrenal axis in relation to the position of active stimulating contact within the STN. In addition, we searched for any STN-DBS-related morning plasma cortisol changes in association with postoperative anxiety and weight gain. A plasma cortisol measurement was performed on the day of initiation of bilateral STN-DBS and repeated after 1 and 17 months in twenty patients with advanced Parkinson's disease. The body weight change and anxiety scores following the implantation were assessed as well. The electrode positions in the STN were determined on T1-weighted magnetic resonance images. After initiation of stimulation, cortisol levels significantly decreased and the cortisol changes after 1 and 17 months strongly correlated with the position of active contact in the subthalamic area. Patients with at least one contact located more medially in the STN experienced a significantly greater decrease of cortisol than those with one or both active contacts more laterally. Furthermore, the lower cortisol levels were strongly associated with higher trait anxiety and weight gain. These changes mimicked the effects of chronic stress and suggest the disturbing impact of STN-DBS on limbic and motivational systems.

  8. Axonal and synaptic failure suppress the transfer of firing rate oscillations, synchrony and information during high frequency deep brain stimulation.

    PubMed

    Rosenbaum, Robert; Zimnik, Andrew; Zheng, Fang; Turner, Robert S; Alzheimer, Christian; Doiron, Brent; Rubin, Jonathan E

    2014-02-01

    High frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used treatment for Parkinson's disease, but its effects on neural activity in basal ganglia circuits are not fully understood. DBS increases the excitation of STN efferents yet decouples STN spiking patterns from the spiking patterns of STN synaptic targets. We propose that this apparent paradox is resolved by recent studies showing an increased rate of axonal and synaptic failures in STN projections during DBS. To investigate this hypothesis, we combine in vitro and in vivo recordings to derive a computational model of axonal and synaptic failure during DBS. Our model shows that these failures induce a short term depression that suppresses the synaptic transfer of firing rate oscillations, synchrony and rate-coded information from STN to its synaptic targets. In particular, our computational model reproduces the widely reported suppression of parkinsonian β oscillations and synchrony during DBS. Our results support the idea that short term depression is a therapeutic mechanism of STN DBS that works as a functional lesion by decoupling the somatic spiking patterns of STN neurons from spiking activity in basal ganglia output nuclei.

  9. Effect of unilateral versus bilateral electrostimulation in subthalamic nucleus on speech in Parkinsons disease

    NASA Astrophysics Data System (ADS)

    Wang, Emily; Verhagen Metman, Leo; Bakay, Roy; Arzbaecher, Jean; Bernard, Bryan

    2001-05-01

    Previously, it was found that 16 right-handed patients with idiopathic Parkinsons disease who underwent unilateral implantation of deep brain stimulator in subthalamic nucleus (STN) showed significant improvement in their nonspeech motor functions. Eight of the 16 patients had stimulator in the left STN and eight in the right STN. In contrast, their speech function showed very mild improvement that was limited to the respiratory/phonotory subsystems. Further, there seemed a trend that the patients with right STN stimulation did better than those with left STN stimulation. It was speculated that the difference might be due to a micro lesion caused by the surgical procedure to the corticobulbar fibers run in the left internal capsule. This paper reports speech changes associated with bilateral DBS in STN in four of the 16 subjects who elected to have deep brain stimulator implanted in STN on the opposite side of the brain at a later time. Results show negative changes in speech after bilateral DBS in STN. The changes were not limited to the micro lesion effect due to the surgery itself, but also related to the active stimulation on the dominant hemisphere for speech processing. [Work supported by NIH.

  10. Effects of Medication and Subthalamic Nucleus Deep Brain Stimulation on Tongue Movements in Speakers with Parkinson's Disease Using Electropalatography: A Pilot Study

    ERIC Educational Resources Information Center

    Hartinger, Mariam; Tripoliti, Elina; Hardcastle, William J.; Limousin, Patricia

    2011-01-01

    Parkinson's disease (PD) affects speech in the majority of patients. Subthalamic nucleus deep brain stimulation (STN-DBS) is particularly effective in reducing tremor and rigidity. However, its effect on speech is variable. The aim of this pilot study was to quantify the effects of bilateral STN-DBS and medication on articulation, using…

  11. Subthalamic Nucleus Deep Brain Stimulation Changes Velopharyngeal Control in Parkinson's Disease

    ERIC Educational Resources Information Center

    Hammer, Michael J.; Barlow, Steven M.; Lyons, Kelly E.; Pahwa, Rajesh

    2011-01-01

    Purpose: Adequate velopharyngeal control is essential for speech, but may be impaired in Parkinson's disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on velopharyngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of velopharyngeal…

  12. "The little engine that could": voltage-dependent Na(+) channels and the subthalamic nucleus.

    PubMed

    Surmeier, D James; Bevan, Mark D

    2003-07-03

    The most effective treatment for late-stage Parkinson's disease is to electrically stimulate the subthalamic nucleus (STN) at high frequencies. Why this strategy works is unclear. The work by Do and Bean shows that the Na channels in STN neurons have distinctive features--like resurgence--that regulate their spiking behavior, providing new insights into the mechanism of DBS.

  13. Subthalamic nucleus involvement in executive functions with increased cognitive load: a subthalamic nucleus and anterior cingulate cortex depth recording study.

    PubMed

    Aulická, Stefania Rusnáková; Jurák, Pavel; Chládek, Jan; Daniel, Pavel; Halámek, Josef; Baláž, Marek; Bočková, Martina; Chrastina, Jan; Rektor, Ivan

    2014-10-01

    We studied the appearance of broadband oscillatory changes (ranging 2-45 Hz) induced by a cognitive task with two levels of complexity. The event-related de/synchronizations (ERD/S) in the subthalamic nucleus (STN) and in the anterior cingulate cortex (ACC) were evaluated in an executive function test. Four epilepsy surgery candidates with intracerebral electrodes implanted in the ACC and three Parkinson's disease patients with externalized deep brain stimulation electrodes implanted in the STN participated in the study. A Flanker test (FT) with visual stimuli (arrows) was performed. Subjects reacted to four types of stimuli presented on the monitor by pushing the right or left button: congruent arrows to the right or left side (simple task) and incongruent arrows to the right or left side (more difficult complex task). We explored the activation of STN and the activation of the ACC while processing the FT. Both conditions, i.e. congruent and incongruent, induced oscillatory changes in the ACC and also STN with significantly higher activation during incongruent trial. At variance with the ACC, in the STN not only the ERD beta but also the ERD alpha activity was significantly more activated by the incongruent condition. In line with our earlier studies, the STN appears to be involved in activities linked with increased cognitive load. The specificity and complexity of task-related activation of the STN might indicate the involvement of the STN in processes controlling human behaviour, e.g. in the selection and inhibition of competing alternatives.

  14. The human subthalamic nucleus and globus pallidus internus differentially encode reward during action control.

    PubMed

    Justin Rossi, Peter; Peden, Corinna; Castellanos, Oscar; Foote, Kelly D; Gunduz, Aysegul; Okun, Michael S

    2017-04-01

    The subthalamic nucleus (STN) and globus pallidus internus (GPi) have recently been shown to encode reward, but few studies have been performed in humans. We investigated STN and GPi encoding of reward and loss (i.e., valence) in humans with Parkinson's disease. To test the hypothesis that STN and GPi neurons would change their firing rate in response to reward- and loss-related stimuli, we recorded the activity of individual neurons while participants performed a behavioral task. In the task, action choices were associated with potential rewarding, punitive, or neutral outcomes. We found that STN and GPi neurons encode valence-related information during action control, but the proportion of valence-responsive neurons was greater in the STN compared to the GPi. In the STN, reward-related stimuli mobilized a greater proportion of neurons than loss-related stimuli. We also found surprising limbic overlap with the sensorimotor regions in both the STN and GPi, and this overlap was greater than has been previously reported. These findings may help to explain alterations in limbic function that have been observed following deep brain stimulation therapy of the STN and GPi. Hum Brain Mapp 38:1952-1964, 2017. © 2017 Wiley Periodicals, Inc.

  15. Deep brain stimulation and medication for parkinsonian tremor during secondary tasks.

    PubMed

    Sturman, Molly M; Vaillancourt, David E; Metman, Leo Verhagen; Sierens, Diane K; Bakay, Roy A E; Corcos, Daniel M

    2007-06-15

    This study examined the efficacy of subthalamic nucleus (STN), deep brain stimulation (DBS), and medication for resting tremor during performance of secondary tasks. Hand tremor was recorded using accelerometry and electromyography (EMG) from 10 patients with Parkinson's disease (PD) and ten matched control subjects. The PD subjects were examined off treatment, on STN DBS, on medication, and on STN DBS plus medication. In the first experiment, tremor was recorded in a quiet condition and during a cognitive task designed to enhance tremor. In the second experiment, tremor was recorded in a quiet condition and during isometric finger flexion (motor task) with the contralateral limb at 5% of the maximal voluntary contraction (MVC) that was designed to suppress tremor. Results showed that: (1) STN DBS and medication reduced tremor during a cognitive task that exacerbated tremor, (2) STN DBS normalized tremor frequency in both the quiet and cognitive task conditions, whereas tremor amplitude was only normalized in the quiet condition, (3) a secondary motor task reduced tremor in a similar manner to STN DBS. These findings demonstrate that STN DBS still suppresses tremor in the presence of a cognitive task. Furthermore, a secondary motor task of the opposite limb suppresses tremor to levels comparable to STN DBS.

  16. Effects of Electrodes on the Switching Behavior of Strontium Titanate Nickelate Resistive Random Access Memory

    PubMed Central

    Lee, Ke-Jing; Wang, Li-Wen; Chiang, Te-Kung; Wang, Yeong-Her

    2015-01-01

    Strontium titanate nickelate (STN) thin films on indium tin oxide (ITO)/glass substrate were synthesized using the sol-gel method for resistive random access memory (RRAM) applications. Aluminum (Al), titanium (Ti), tungsten (W), gold (Au) and platinum (Pt) were used as top electrodes in the STN-based RRAM to probe the switching behavior. The bipolar resistive switching behavior of the set and reset voltages is in opposite bias in the Al/STN/ITO and Pt/STN/ITO RRAMs, which can be partly ascribed to the different work functions of top electrodes in the ITO. Analyses of the fitting results and temperature-dependent performances showed that the Al/STN/ITO switching was mainly attributed to the absorption/release of oxygen-based functional groups, whereas the Pt/STN/ITO switching can be associated with the diffusion of metal electrode ions. The Al/STN/ITO RRAM demonstrated a high resistance ratio of >106 between the high-resistance state (HRS) and the low-resistance state (LRS), as well as a retention ability of >105 s. Furthermore, the Pt/STN/ITO RRAM displayed a HRS/LRS resistance ratio of >103 and a retention ability of >105 s. PMID:28793630

  17. Polymorphism in electrospun poly(vinylidene fluoride)/nanoclay composite nanofibers

    NASA Astrophysics Data System (ADS)

    Yu, Lei; Cebe, Peggy

    2009-03-01

    We investigated the morphology and polymorphism behavior of electrospun (ES) composite nanofibers of poly(vinylidene fluoride) (PVDF) with two nanoclays: Lucentite^TM STN and SWN. Lucentite^TM STN and SWN synthetic nanoclays are based on hectrite structure, but only STN contains an organic modifier between the hectrite layers. The PVDF was dissolved, and nanoclay was dispersed, in N,N-dimethylformamide/acetone and then electrospun into nanofibers with diameters ranging from 100˜1000 nm. The nanoclay content ranged from 0.2% to 10%. The addition of STN can greatly decrease the number of beads and makes the diameter of the ES nanofibers more uniform due to an increase of solution conductivity. From wide angle X-ray scattering and Fourier transform infrared spectroscopy, we found both STN and SWN can induce more beta phase PVDF crystals and TTT conformers, while reducing the alpha phase crystal content in ES PVDF/nanoclay composite nanofibers. STN can completely eliminate the alpha phase crystals, even at low STN content. The ionic organic modifier makes STN much more effective than SWN in promoting beta phase PVDF crystals.

  18. Effect of electrical and chemical stimulation of the subthalamic nucleus on the release of striatal dopamine.

    PubMed

    Pazo, Jorge H; Höcht, Cristian; Barceló, Ana C; Fillipini, Bárbara; Lomastro, María J

    2010-12-01

    High-frequency stimulation (HFS) of the subthalamic nucleus (STN) alleviates the cardinal symptoms of Parkinson's disease, but the mechanisms underlying these clinical results remain to be clarified. The HFS of STN is associated with the release of dopamine (DA) in the striatum. This study examines possible mechanisms by which HFS-STN release DA. The experiments were performed in rats anesthetized with urethane. The STN was stimulated by electrical HF and chemical microinjections of an antagonist and an agonist of GABA(A) receptors, the bicuculline, and the muscimol, respectively. The extracellular striatal DA-DOPAC (3-4-dihydroxyphenilacetic acid) content was collected by means of intracerebral microdialysis cannula and analyzed with HPLC with an electrochemical detector. The HFS of STN and microinjection of bicuculline intrasubthalamic produced a significant increase of extracellular striatal DA, whereas DOPAC levels were unchanged. The microinjection of muscimol depresses spontaneous release of DA, without changes in DOPAC. The kainic acid lesion of the globus pallidus (GP) and the substantia nigra pars reticulata (SNr), ipsilateral to dialyzed striatum, did not modify the release of DA-DOPAC. These data provide evidence that the STN has a tonic action on the substantia nigra pars compacta (SNc), and the release of striatal DA by HFS-STN may be due to activation of the STN acting directly on SNc neurons. © 2010 Wiley-Liss, Inc.

  19. Effects of Medication and Subthalamic Nucleus Deep Brain Stimulation on Tongue Movements in Speakers with Parkinson's Disease Using Electropalatography: A Pilot Study

    ERIC Educational Resources Information Center

    Hartinger, Mariam; Tripoliti, Elina; Hardcastle, William J.; Limousin, Patricia

    2011-01-01

    Parkinson's disease (PD) affects speech in the majority of patients. Subthalamic nucleus deep brain stimulation (STN-DBS) is particularly effective in reducing tremor and rigidity. However, its effect on speech is variable. The aim of this pilot study was to quantify the effects of bilateral STN-DBS and medication on articulation, using…

  20. Subthalamic nucleus deep brain stimulation changes velopharyngeal control in Parkinson’s disease

    PubMed Central

    Hammer, Michael J.; Barlow, Steven M.; Lyons, Kelly E.; Pahwa, Rajesh

    2010-01-01

    Purpose Adequate velopharyngeal control is essential for speech, but may be impaired in Parkinson’s disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on velopharyngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of velopharyngeal control, and whether these changes were correlated with limb function and stimulation settings. Methods Seventeen PD participants with bilateral STN DBS were tested within a morning session after a minimum of 12 h since their most recent dose of anti-PD medication. Testing occurred when STN DBS was on, and again 1 h after STN DBS was turned off, and included aerodynamic measures during syllable production, and standard neurological ratings of limb function. Results We found that PD participants exhibited changes with STN DBS, primarily consistent with increased intraoral pressure (n = 7) and increased velopharyngeal closure (n = 5). These changes were modestly correlated with measures of limb function, and were correlated with stimulation frequency. Conclusion Our findings suggest that STN DBS may change velopharyngeal control during syllable production in PD, with greater benefit associated with low frequency stimulation. However, DBS demonstrates a more subtle influence on speech-related velopharyngeal control than limb motor control. This distinction and its underlying mechanisms are important to consider when assessing the impact of STN DBS on PD. PMID:20708741

  1. Subthalamic Nucleus Stimulation and Dysarthria in Parkinson's Disease: A PET Study

    ERIC Educational Resources Information Center

    Pinto, Serge; Thobois, Stephane; Costes, Nicolas; Le Bars, Didier; Benabid, Alim-Louis; Broussolle, Emmanuel; Pollak, Pierre; Gentil, Michele

    2004-01-01

    In Parkinson's disease, functional imaging studies during limb motor tasks reveal cerebral activation abnormalities that can be reversed by subthalamic nucleus (STN) stimulation. The effect of STN stimulation on parkinsonian dysarthria has not, however, been investigated using PET. The aim of the present study was to evaluate the effect of STN…

  2. Early dysfunction and progressive degeneration of the subthalamic nucleus in mouse models of Huntington's disease

    PubMed Central

    Atherton, Jeremy F; McIver, Eileen L; Mullen, Matthew RM; Wokosin, David L; Surmeier, D James; Bevan, Mark D

    2016-01-01

    The subthalamic nucleus (STN) is an element of cortico-basal ganglia-thalamo-cortical circuitry critical for action suppression. In Huntington's disease (HD) action suppression is impaired, resembling the effects of STN lesioning or inactivation. To explore this potential linkage, the STN was studied in BAC transgenic and Q175 knock-in mouse models of HD. At <2 and 6 months of age autonomous STN activity was impaired due to activation of KATP channels. STN neurons exhibited prolonged NMDA receptor-mediated synaptic currents, caused by a deficit in glutamate uptake, and elevated mitochondrial oxidant stress, which was ameliorated by NMDA receptor antagonism. STN activity was rescued by NMDA receptor antagonism or the break down of hydrogen peroxide. At 12 months of age approximately 30% of STN neurons had been lost, as in HD. Together, these data argue that dysfunction within the STN is an early feature of HD that may contribute to its expression and course. DOI: http://dx.doi.org/10.7554/eLife.21616.001 PMID:27995895

  3. Inhibiting subthalamic nucleus decreases cocaine demand and relapse: therapeutic potential.

    PubMed

    Bentzley, Brandon S; Aston-Jones, Gary

    2017-07-01

    Preclinical evidence indicates that inactivation of subthalamic nucleus (STN) may be effective for treating cocaine addiction, and therapies that target STN, e.g. deep brain stimulation, are available indicating that this may have clinical promise. Here, we assessed the therapeutic potential of STN inactivation using a translationally relevant economic approach that quantitatively describes drug-taking behavior, and tested these results with drug-seeking tasks. Economic demand for cocaine was assessed in rats (n = 11) using a within-session threshold procedure in which cocaine price (responses/mg cocaine) was sequentially increased throughout the session. Cocaine demand was assessed in this manner immediately after bilateral microinfusions into STN of either vehicle (artificial cerebrospinal fluid) or the GABAA receptor agonist muscimol. A separate group of animals (n = 8) was tested for changes in cocaine seeking either during extinction or in response to cocaine-associated cues. Muscimol-induced inhibition of STN significantly attenuated cocaine consumption at high prices, drug seeking during extinction and cued reinstatement of cocaine seeking. In contrast, STN inhibition did not reduce cocaine consumption at low prices or locomotor activity. Thus, STN inactivation reduced economic demand for cocaine and multiple measures of drug seeking during extinction. In view of the association between economic demand and addiction severity in both rat and human, these results indicate that STN inactivation has substantial clinical potential for treatment of cocaine addiction. © 2016 Society for the Study of Addiction.

  4. Facial expression recognition and subthalamic nucleus stimulation

    PubMed Central

    Schroeder, U; Kuehler, A; Hennenlotter, A; Haslinger, B; Tronnier, V; Krause, M; Pfister, R; Sprengelmeyer, R; Lange, K; Ceballos-Baumann, A

    2004-01-01

    Objective: To study the impact of STN stimulation in Parkinson's disease on perception of facial expressions. Results: There was a selective reduction in recognition of angry faces, but not other expressions, during STN stimulation. Conclusions: The findings may have important implications for social adjustment in these patients. PMID:15026519

  5. The effects of subthalamic deep brain stimulation on metaphor comprehension and language abilities in Parkinson's disease.

    PubMed

    Tremblay, Christina; Macoir, Joël; Langlois, Mélanie; Cantin, Léo; Prud'homme, Michel; Monetta, Laura

    2015-02-01

    The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) on different language abilities are still controversial and its impact on high-level language abilities such as metaphor comprehension has been overlooked. The aim of this study was to determine the effects of STN electrical stimulation on metaphor comprehension and language abilities such as lexical and semantic capacities. Eight PD individuals with bilateral STN-DBS were first evaluated OFF-DBS and, at least seven weeks later, ON-DBS. Performance on metaphor comprehension, lexical decision, word association and verbal fluency tasks were compared ON and OFF-DBS in addition to motor symptoms evaluation. STN stimulation had a significant beneficial effect on motor symptoms in PD. However, this stimulation did not have any effect on metaphor comprehension or any other cognitive ability evaluated in this study. These outcomes suggest that STN stimulation may have dissociable effects on motor and language functions.

  6. Parkinson's disease patients with bilateral subthalamic deep brain stimulation gain weight.

    PubMed

    Macia, Frédéric; Perlemoine, Caroline; Coman, Irène; Guehl, Dominique; Burbaud, Pierre; Cuny, Emmanuel; Gin, Henri; Rigalleau, Vincent; Tison, François

    2004-02-01

    Weight, body mass index (BMI) and energy expenditure/energy intake (EE/EI) was studied in 19 Parkinson's disease (PD) patients after subthalamic deep brain stimulation (STN-DBS) versus 14 nonoperated ones. Operated patients had a significant weight gain (WG, + 9.7 +/- 7 kg) and BMI increase (+ 4.7 kg/m2). The fat mass was higher after STN-DBS. Resting EE (REE; offdrug/ON stimulation) was significantly decreased in STN-DBS patients, while their daily energy expenditure (DEI) was not significantly different. A significant correlation was found among WG, BMI increase, and pre-operative levodopa-equivalent daily dose, their reduction after STN-DBS, and the differential REE related to stimulation and the REE in the offdrug/OFF stimulation condition. In conclusion, STN-DBS in PD induces a significant WG associated with a reduction in REE without DEI adjustment.

  7. Deep brain stimulation effect on freezing of gait.

    PubMed

    Ferraye, Murielle U; Debû, Bettina; Pollak, Pierre

    2008-01-01

    The majority of patients with Parkinson's disease suffer from freezing of gait (FOG), which responds more or less to levodopa. Thalamic stimulation, mainly used in the treatment of tremor dominant Parkinson's disease is ineffective in FOG. GPi stimulation moderately improves FOG, but this effect may abate in the long term. STN stimulation was reported to improve levodopa-responsive FOG. In some patients, the benefit from levodopa is greater than that from STN stimulation, and levodopa and STN stimulation can have additive effects. On the contrary, STN stimulation is ineffective on levodopa-resistant FOG. In the few cases of levodopa-induced FOG, STN stimulation can indirectly be effective, thanks to a great decrease or arrest of levodopa. Stimulation of the pedunculopontine nucleus has recently been performed in small groups of patients suffering from both off- and on-levodopa gait impairments. The first results appear encouraging, but they need to be confirmed by controlled studies in larger series of patients.

  8. Soil Carbon and Nitrogen Changes following Afforestation of Marginal Cropland across a Precipitation Gradient in Loess Plateau of China

    PubMed Central

    Lü, Yihe; Liu, Guohua; Fu, Bojie

    2014-01-01

    Cropland afforestation has been widely found to increase soil organic carbon (SOC) and soil total nitrogen (STN); however, the magnitudes of SOC and STN accumulation and regulating factors are less studied in dry, marginal lands, and therein the interaction between soil carbon and nitrogen is not well understood. We examined the changes in SOC and STN in younger (5–9-year-old) and older (25–30-year-old) black locust (Robinia pseudoacacia L., an N-fixing species) plantations that were established on former cropland along a precipitation gradient (380 to 650 mm) in the semi-arid Loess Plateau of China. The SOC and STN stocks of cropland and plantations increased linearly with precipitation increase, respectively, accompanying an increase in the plantation net primary productivity and the soil clay content along the increasing precipitation gradient. The SOC stock of cropland decreased in younger plantations and increased in older plantations after afforestation, and the amount of the initial loss of SOC during the younger plantations’ establishment increased with precipitation increasing. By contrast, the STN stock of cropland showed no decrease in the initial afforestation while tending to increase with plantation age, and the changes in STN were not related to precipitation. The changes in STN and SOC showed correlated and were precipitation-dependent following afforestation, displaying a higher relative gain of SOC to STN as precipitation decreased. Our results suggest that the afforestation of marginal cropland in Loess Plateau can have a significant effect on the accumulation of SOC and STN, and that precipitation has a significant effect on SOC accumulation but little effect on STN retention. The limitation effect of soil nitrogen on soil carbon accumulation is more limited in the drier area rather than in the wetter sites. PMID:24416408

  9. The subthalamic nucleus keeps you high on emotion: behavioral consequences of its inactivation.

    PubMed

    Pelloux, Yann; Meffre, Julie; Giorla, Elodie; Baunez, Christelle

    2014-01-01

    The subthalamic nucleus (STN) belongs to the basal ganglia and is the current target for the surgical treatment of neurological and psychiatric disorders such as Parkinson's Disease (PD) and obsessive compulsive disorders (OCD), but also a proposed site for the treatment of addiction. It is therefore very important to understand its functions in order to anticipate and prevent possible side-effects in the patients. Although the involvement of the STN is well documented in motor, cognitive and motivational processes, less is known regarding emotional processes. Here we have investigated the direct consequences of STN inactivation by excitotoxic lesions on emotional processing and reinforcement in the rat. We have used various behavioral procedures to assess affect for neutral, positive and negative reinforcers in STN lesioned rats. STN lesions reduced affective responses for positive (sweet solutions) and negative (electric foot shock, Lithium Chloride-induced sickness) reinforcers while they had no effect on responses for a more neutral reinforcer (novelty induced place preference (NIPP)). Furthermore, when given the choice between saccharine, a sweet but non caloric solution, and glucose, a more bland but caloric solution, in contrast to sham animals that preferred saccharine, STN lesioned animals preferred glucose over saccharine. Taken altogether these results reveal that STN plays a critical role in emotional processing. These results, in line with some clinical observations in PD patients subjected to STN surgery, suggest possible emotional side-effects of treatments targeting the STN. They also suggest that the increased motivation for sucrose previously reported cannot be due to increased pleasure, but could be responsible for the decreased motivation for cocaine reported after STN inactivation.

  10. Electrode Position and Current Amplitude Modulate Impulsivity after Subthalamic Stimulation in Parkinsons Disease—A Computational Study

    PubMed Central

    Mandali, Alekhya; Chakravarthy, V. Srinivasa; Rajan, Roopa; Sarma, Sankara; Kishore, Asha

    2016-01-01

    Background: Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) is highly effective in alleviating motor symptoms of Parkinson's disease (PD) which are not optimally controlled by dopamine replacement therapy. Clinical studies and reports suggest that STN-DBS may result in increased impulsivity and de novo impulse control disorders (ICD). Objective/Hypothesis: We aimed to compare performance on a decision making task, the Iowa Gambling Task (IGT), in healthy conditions (HC), untreated and medically-treated PD conditions with and without STN stimulation. We hypothesized that the position of electrode and stimulation current modulate impulsivity after STN-DBS. Methods: We built a computational spiking network model of basal ganglia (BG) and compared the model's STN output with STN activity in PD. Reinforcement learning methodology was applied to simulate IGT performance under various conditions of dopaminergic and STN stimulation where IGT total and bin scores were compared among various conditions. Results: The computational model reproduced neural activity observed in normal and PD conditions. Untreated and medically-treated PD conditions had lower total IGT scores (higher impulsivity) compared to HC (P < 0.0001). The electrode position that happens to selectively stimulate the part of the STN corresponding to an advantageous panel on IGT resulted in de-selection of that panel and worsening of performance (P < 0.0001). Supratherapeutic stimulation amplitudes also worsened IGT performance (P < 0.001). Conclusion(s): In our computational model, STN stimulation led to impulsive decision making in IGT in PD condition. Electrode position and stimulation current influenced impulsivity which may explain the variable effects of STN-DBS reported in patients. PMID:27965590

  11. Neural Correlates of Decision Thresholds in the Human Subthalamic Nucleus.

    PubMed

    Herz, Damian M; Zavala, Baltazar A; Bogacz, Rafal; Brown, Peter

    2016-04-04

    If humans are faced with difficult choices when making decisions, the ability to slow down responses becomes critical in order to avoid suboptimal choices. Current models of decision making assume that the subthalamic nucleus (STN) mediates this function by elevating decision thresholds, thereby requiring more evidence to be accumulated before responding [1-9]. However, direct electrophysiological evidence for the exact role of STN during adjustment of decision thresholds is lacking. Here, we show that trial-by-trial variations in STN low-frequency oscillatory activity predict adjustments of decision thresholds before subjects make a response. The relationship between STN activity and decision thresholds critically depends on the subjects' level of cautiousness. While increased oscillatory activity of the STN predicts elevated decision thresholds during high levels of cautiousness, it predicts decreased decision thresholds during low levels of cautiousness. This context-dependent relationship may be mediated by increased influence of the medial prefrontal cortex (mPFC)-STN pathway on decision thresholds during high cautiousness. Subjects who exhibit a stronger increase in phase alignment of low-frequency oscillatory activity in mPFC and STN before making a response have higher decision thresholds and commit fewer erroneous responses. Together, our results demonstrate that STN low-frequency oscillatory activity and corresponding mPFC-STN coupling are involved in determining how much evidence subjects accumulate before making a decision. This finding might explain why deep-brain stimulation of the STN can impair subjects' ability to slow down responses and can induce impulsive suboptimal decisions.

  12. Subthalamic nucleus long-range synchronization-an independent hallmark of human Parkinson's disease.

    PubMed

    Moshel, Shay; Shamir, Reuben R; Raz, Aeyal; de Noriega, Fernando R; Eitan, Renana; Bergman, Hagai; Israel, Zvi

    2013-01-01

    Beta-band synchronous oscillations in the dorsolateral region of the subthalamic nucleus (STN) of human patients with Parkinson's disease (PD) have been frequently reported. However, the correlation between STN oscillations and synchronization has not been thoroughly explored. The simultaneous recordings of 2390 multi-unit pairs recorded by two parallel microelectrodes (separated by fixed distance of 2 mm, n = 72 trajectories with two electrode tracks >4 mm STN span) in 57 PD patients undergoing STN deep brain stimulation surgery were analyzed. Automatic procedures were utilized to divide the STN into dorsolateral oscillatory and ventromedial non-oscillatory regions, and to quantify the intensity of STN oscillations and synchronicity. Finally, the synchronicity of simultaneously vs. non-simultaneously recorded pairs were compared using a shuffling procedure. Synchronization was observed predominately in the beta range and only between multi-unit pairs in the dorsolateral oscillatory region (n = 615). In paired recordings between sites in the dorsolateral and ventromedial (n = 548) and ventromedial-ventromedial region pairs (n = 1227), no synchronization was observed. Oscillation and synchronicity intensity decline along the STN dorsolateral-ventromedial axis suggesting a fuzzy border between the STN regions. Synchronization strength was significantly correlated to the oscillation power, but synchronization was no longer observed following shuffling. We conclude that STN long-range beta oscillatory synchronization is due to increased neuronal coupling in the Parkinsonian brain and does not merely reflect the outcome of oscillations at similar frequency. The neural synchronization in the dorsolateral (probably the motor domain) STN probably augments the pathological changes in firing rate and patterns of subthalamic neurons in PD patients.

  13. NMDA Receptors Containing the GluN2D Subunit Control Neuronal Function in the Subthalamic Nucleus.

    PubMed

    Swanger, Sharon A; Vance, Katie M; Pare, Jean-François; Sotty, Florence; Fog, Karina; Smith, Yoland; Traynelis, Stephen F

    2015-12-02

    The GluN2D subunit of the NMDA receptor is prominently expressed in the basal ganglia and associated brainstem nuclei, including the subthalamic nucleus (STN), globus pallidus, striatum, and substantia nigra. However, little is known about how GluN2D-containing NMDA receptors contribute to synaptic activity in these regions. Using Western blotting of STN tissue punches, we demonstrated that GluN2D is expressed in the rat STN throughout development [age postnatal day 7 (P7)-P60] and in the adult (age P120). Immunoelectron microscopy of the adult rat brain showed that GluN2D is predominantly expressed in dendrites, unmyelinated axons, and axon terminals within the STN. Using subunit-selective allosteric modulators of NMDA receptors (TCN-201, ifenprodil, CIQ, and DQP-1105), we provide evidence that receptors containing the GluN2B and GluN2D subunits mediate responses to exogenously applied NMDA and glycine, as well as synaptic NMDA receptor activation in the STN of rat brain slices. EPSCs in the STN were mediated primarily by AMPA and NMDA receptors and GluN2D-containing NMDA receptors controlled the slow deactivation time course of EPSCs in the STN. In vivo recordings from the STN of anesthetized adult rats demonstrated that the spike firing rate was increased by the GluN2C/D potentiator CIQ and decreased by the GluN2C/D antagonist DQP-1105, suggesting that NMDA receptor activity can influence STN output. These data indicate that the GluN2B and GluN2D NMDA receptor subunits contribute to synaptic activity in the STN and may represent potential therapeutic targets for modulating subthalamic neuron activity in neurological disorders such as Parkinson's disease. Copyright © 2015 the authors 0270-6474/15/3515971-13$15.00/0.

  14. Load-Dependent Interference of Deep Brain Stimulation of the Subthalamic Nucleus with Switching from Automatic to Controlled Processing During Random Number Generation in Parkinson's Disease.

    PubMed

    Williams, Isobel Anne; Wilkinson, Leonora; Limousin, Patricia; Jahanshahi, Marjan

    2015-01-01

    Deep brain stimulation of the subthalamic nucleus (STN DBS) ameliorates the motor symptoms of Parkinson's disease (PD). However, some aspects of executive control are impaired with STN DBS. We tested the prediction that (i) STN DBS interferes with switching from automatic to controlled processing during fast-paced random number generation (RNG) (ii) STN DBS-induced cognitive control changes are load-dependent. Fifteen PD patients with bilateral STN DBS performed paced-RNG, under three levels of cognitive load synchronised with a pacing stimulus presented at 1, 0.5 and 0.33 Hz (faster rates require greater cognitive control), with DBS on or off. Measures of output randomness were calculated. Countscore 1 (CS1) indicates habitual counting in steps of one (CS1). Countscore 2 (CS2) indicates a more controlled strategy of counting in twos. The fastest rate was associated with an increased CS1 score with STN DBS on compared to off. At the slowest rate, patients had higher CS2 scores with DBS off than on, such that the differences between CS1 and CS2 scores disappeared. We provide evidence for a load-dependent effect of STN DBS on paced RNG in PD. Patients could switch to more controlled RNG strategies during conditions of low cognitive load at slower rates only when the STN stimulators were off, but when STN stimulation was on, they engaged in more automatic habitual counting under increased cognitive load. These findings are consistent with the proposal that the STN implements a switch signal from the medial frontal cortex which enables a shift from automatic to controlled processing.

  15. Deep brain stimulation of the subthalamic nucleus increases premature responding in a rat gambling task.

    PubMed

    Aleksandrova, Lily R; Creed, Meaghan C; Fletcher, Paul J; Lobo, Daniela S S; Hamani, Clement; Nobrega, José N

    2013-05-15

    Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a treatment option for the motor symptoms of Parkinson's disease (PD). However, several recent studies have found an association between STN-DBS and increased impulsivity. Currently, it is not clear whether the observed increase in impulsivity results from STN-DBS per se, or whether it involves an interaction with the underlying PD neuropathology and/or intake of dopaminergic drugs. We investigated the effects of STN-DBS on performance of intact rats on two tasks measuring impulsive responding: a novel rat gambling task (rGT) and a differential reinforcement of low rate responding (DRL20s) schedule. Following initial behavioural training, animals received electrode implantation into the STN (n=24) or sham surgery (n=24), and were re-tested on their assigned behavioural task, with or without STN-DBS. Bilateral STN-DBS administered for two hours immediately prior to testing, had no effects on rGT choice behaviour or on DRL response inhibition (p>0.05). However, STN-DBS significantly increased premature responding in the rGT task (p=0.0004), an effect that took several sessions to develop and persisted in subsequent trials when no stimulation was given. Consistent with the notion of distinct facets of impulsivity with unique neurochemical underpinnings, we observed differential effects of STN-DBS in the two tasks employed. These results suggest that STN-DBS in the absence of parkinsonism may not lead to a general loss of inhibitory control, but may instead affect impulsivity under specific conditions.

  16. Load-Dependent Interference of Deep Brain Stimulation of the Subthalamic Nucleus with Switching from Automatic to Controlled Processing During Random Number Generation in Parkinson’s Disease

    PubMed Central

    Williams, Isobel Anne; Wilkinson, Leonora; Limousin, Patricia; Jahanshahi, Marjan

    2015-01-01

    Background: Deep brain stimulation of the subthalamic nucleus (STN DBS) ameliorates the motor symptoms of Parkinson’s disease (PD). However, some aspects of executive control are impaired with STN DBS. Objective: We tested the prediction that (i) STN DBS interferes with switching from automatic to controlled processing during fast-paced random number generation (RNG) (ii) STN DBS-induced cognitive control changes are load-dependent. Methods: Fifteen PD patients with bilateral STN DBS performed paced-RNG, under three levels of cognitive load synchronised with a pacing stimulus presented at 1, 0.5 and 0.33 Hz (faster rates require greater cognitive control), with DBS on or off. Measures of output randomness were calculated. Countscore 1 (CS1) indicates habitual counting in steps of one (CS1). Countscore 2 (CS2) indicates a more controlled strategy of counting in twos. Results: The fastest rate was associated with an increased CS1 score with STN DBS on compared to off. At the slowest rate, patients had higher CS2 scores with DBS off than on, such that the differences between CS1 and CS2 scores disappeared. Conclusions: We provide evidence for a load-dependent effect of STN DBS on paced RNG in PD. Patients could switch to more controlled RNG strategies during conditions of low cognitive load at slower rates only when the STN stimulators were off, but when STN stimulation was on, they engaged in more automatic habitual counting under increased cognitive load. These findings are consistent with the proposal that the STN implements a switch signal from the medial frontal cortex which enables a shift from automatic to controlled processing. PMID:25720447

  17. Neural Correlates of Decision Thresholds in the Human Subthalamic Nucleus

    PubMed Central

    Herz, Damian M.; Zavala, Baltazar A.; Bogacz, Rafal; Brown, Peter

    2016-01-01

    Summary If humans are faced with difficult choices when making decisions, the ability to slow down responses becomes critical in order to avoid suboptimal choices. Current models of decision making assume that the subthalamic nucleus (STN) mediates this function by elevating decision thresholds, thereby requiring more evidence to be accumulated before responding [1, 2, 3, 4, 5, 6, 7, 8, 9]. However, direct electrophysiological evidence for the exact role of STN during adjustment of decision thresholds is lacking. Here, we show that trial-by-trial variations in STN low-frequency oscillatory activity predict adjustments of decision thresholds before subjects make a response. The relationship between STN activity and decision thresholds critically depends on the subjects’ level of cautiousness. While increased oscillatory activity of the STN predicts elevated decision thresholds during high levels of cautiousness, it predicts decreased decision thresholds during low levels of cautiousness. This context-dependent relationship may be mediated by increased influence of the medial prefrontal cortex (mPFC)-STN pathway on decision thresholds during high cautiousness. Subjects who exhibit a stronger increase in phase alignment of low-frequency oscillatory activity in mPFC and STN before making a response have higher decision thresholds and commit fewer erroneous responses. Together, our results demonstrate that STN low-frequency oscillatory activity and corresponding mPFC-STN coupling are involved in determining how much evidence subjects accumulate before making a decision. This finding might explain why deep-brain stimulation of the STN can impair subjects’ ability to slow down responses and can induce impulsive suboptimal decisions. PMID:26996501

  18. Stop! border ahead: Automatic detection of subthalamic exit during deep brain stimulation surgery.

    PubMed

    Valsky, Dan; Marmor-Levin, Odeya; Deffains, Marc; Eitan, Renana; Blackwell, Kim T; Bergman, Hagai; Israel, Zvi

    2017-01-01

    Microelectrode recordings along preplanned trajectories are often used for accurate definition of the subthalamic nucleus (STN) borders during deep brain stimulation (DBS) surgery for Parkinson's disease. Usually, the demarcation of the STN borders is performed manually by a neurophysiologist. The exact detection of the borders is difficult, especially detecting the transition between the STN and the substantia nigra pars reticulata. Consequently, demarcation may be inaccurate, leading to suboptimal location of the DBS lead and inadequate clinical outcomes. We present machine-learning classification procedures that use microelectrode recording power spectra and allow for real-time, high-accuracy discrimination between the STN and substantia nigra pars reticulata. A support vector machine procedure was tested on microelectrode recordings from 58 trajectories that included both STN and substantia nigra pars reticulata that achieved a 97.6% consistency with human expert classification (evaluated by 10-fold cross-validation). We used the same data set as a training set to find the optimal parameters for a hidden Markov model using both microelectrode recording features and trajectory history to enable real-time classification of the ventral STN border (STN exit). Seventy-three additional trajectories were used to test the reliability of the learned statistical model in identifying the exit from the STN. The hidden Markov model procedure identified the STN exit with an error of 0.04 ± 0.18 mm and detection reliability (error < 1 mm) of 94%. The results indicate that robust, accurate, and automatic real-time electrophysiological detection of the ventral STN border is feasible. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

  19. Early versus delayed bilateral subthalamic deep brain stimulation for parkinson's disease: a decision analysis.

    PubMed

    Espay, Alberto J; Vaughan, Jennifer E; Marras, Connie; Fowler, Rob; Eckman, Mark H

    2010-07-30

    The long-term benefits of subthalamic nucleus deep brain stimulation (STN DBS) applied earlier in the disease course, before significant disability accumulates, remain to be determined. We developed a Markov state transition decision analytic model to compare effectiveness in quality-adjusted life years (QALYs) of STN DBS applied to patients with PD at an "early" ("off time" 10-20%) versus "delayed" stage ("off time" >40%). A lifelong time horizon and societal perspective were assumed. Probabilities and rates were obtained from literature review; utilities were derived using the time trade-off technique and a computer-assisted utility assessment software tool applied to a cohort of 22 STN-DBS and 21 non-STN-DBS PD patients. Uncertainty was assessed through one- and two-way sensitivity analyses and probabilistic sensitivity analysis using second-order Monte Carlo simulations. Early STN DBS was preferred with a quality-adjusted life expectancy of 22.3 QALYs, a gain of 2.5 QALYs over those with delayed surgery (19.8 QALYs). Early STN DBS was preferred in 69% of 5,000 Monte Carlo simulations. Early surgery was robustly favored through most sensitivity analyses. Delayed STN DBS afforded greater QALYs when using utility estimates exclusively from non-STN-DBS patients and, for the entire group, if the rate of motor progression were to exceed 25% per year. Although decision modeling requires assumptions and simplifications, our exploratory analysis suggests that STN DBS performed in early PD may convey greater quality-adjusted life expectancy when compared to a delayed procedure. These findings support further evaluation of early STN DBS in a controlled clinical trial. (c) 2010 Movement Disorder Society.

  20. NMDA Receptors Containing the GluN2D Subunit Control Neuronal Function in the Subthalamic Nucleus

    PubMed Central

    Swanger, Sharon A.; Vance, Katie M.; Pare, Jean-François; Sotty, Florence; Fog, Karina; Smith, Yoland

    2015-01-01

    The GluN2D subunit of the NMDA receptor is prominently expressed in the basal ganglia and associated brainstem nuclei, including the subthalamic nucleus (STN), globus pallidus, striatum, and substantia nigra. However, little is known about how GluN2D-containing NMDA receptors contribute to synaptic activity in these regions. Using Western blotting of STN tissue punches, we demonstrated that GluN2D is expressed in the rat STN throughout development [age postnatal day 7 (P7)–P60] and in the adult (age P120). Immunoelectron microscopy of the adult rat brain showed that GluN2D is predominantly expressed in dendrites, unmyelinated axons, and axon terminals within the STN. Using subunit-selective allosteric modulators of NMDA receptors (TCN-201, ifenprodil, CIQ, and DQP-1105), we provide evidence that receptors containing the GluN2B and GluN2D subunits mediate responses to exogenously applied NMDA and glycine, as well as synaptic NMDA receptor activation in the STN of rat brain slices. EPSCs in the STN were mediated primarily by AMPA and NMDA receptors and GluN2D-containing NMDA receptors controlled the slow deactivation time course of EPSCs in the STN. In vivo recordings from the STN of anesthetized adult rats demonstrated that the spike firing rate was increased by the GluN2C/D potentiator CIQ and decreased by the GluN2C/D antagonist DQP-1105, suggesting that NMDA receptor activity can influence STN output. These data indicate that the GluN2B and GluN2D NMDA receptor subunits contribute to synaptic activity in the STN and may represent potential therapeutic targets for modulating subthalamic neuron activity in neurological disorders such as Parkinson's disease. SIGNIFICANCE STATEMENT The subthalamic nucleus (STN) is a key component of the basal ganglia, a group of subcortical nuclei that control movement and are dysregulated in movement disorders such as Parkinson's disease. Subthalamic neurons receive direct excitatory input, but the pharmacology of excitatory

  1. Deep Brain Stimulation Frequency of the Subthalamic Nucleus Affects Phonemic and Action Fluency in Parkinson's Disease.

    PubMed

    Fagundes, Valéria de Carvalho; Rieder, Carlos R M; da Cruz, Aline Nunes; Beber, Bárbara Costa; Portuguez, Mirna Wetters

    2016-01-01

    Introduction. Deep brain stimulation of the subthalamic nucleus (STN-DBS) in Parkinson's disease (PD) has been linked to a decline in verbal fluency. The decline can be attributed to surgical effects, but the relative contributions of the stimulation parameters are not well understood. This study aimed to investigate the impact of the frequency of STN-DBS on the performance of verbal fluency tasks in patients with PD. Methods. Twenty individuals with PD who received bilateral STN-DBS were evaluated. Their performances of verbal fluency tasks (semantic, phonemic, action, and unconstrained fluencies) upon receiving low-frequency (60 Hz) and high-frequency (130 Hz) STN-DBS were assessed. Results. The performances of phonemic and action fluencies were significantly different between low- and high-frequency STN-DBS. Patients showed a decrease in these verbal fluencies for high-frequency STN-DBS. Conclusion. Low-frequency STN-DBS may be less harmful to the verbal fluency of PD patients.

  2. [Single and Network Neuron Activity of Subthalamic Nucleus at Impulsive and Delayed (Self-Control) Reactions in Choice Behavior].

    PubMed

    Sidorina, V V; Gerasimova, Yu A; Kuleshova, E P; Merzhanova, G Kh

    2015-01-01

    During our experiments on cats was investigated the subthalamic neuron activity at different types of behavior in case of reinforcement choice depending on its value and availability. In chronic experiences the multiunit activity in subthalamic nucleus (STN) and orbitofrontal cortex (FC) has been recorded. Multiunit activity was analyzed over frequency and network properties of spikes. It was shown, that STN neurons reaction to different reinforcements and conditional stimulus at short- or long-delay reactions was represented by increasing or decreasing of frequency of single neurons. However the same STN neu- rons responded with increasing of frequency of single neuron during expectation of mix-bread-meat and decreasing--during the meat expectation. It has been revealed, that the number of STN interneuron interactions was authentic more at impulsive behavior than at self-control choice of behavior. The number of interactions between FC and STN neurons within intervals of 0-30 Ms was authentic more at display impulsive than during self-control behavior. These results suppose that FC and STN neurons participate in integration of reinforcement estimation; and distinctions in a choice of behavior are defined by the local and distributed interneuron interactions of STN and FC.

  3. Structural and functional connectivity of the subthalamic nucleus during vocal emotion decoding

    PubMed Central

    Frühholz, Sascha; Ceravolo, Leonardo; Grandjean, Didier

    2016-01-01

    Our understanding of the role played by the subthalamic nucleus (STN) in human emotion has recently advanced with STN deep brain stimulation, a neurosurgical treatment for Parkinson’s disease and obsessive-compulsive disorder. However, the potential presence of several confounds related to pathological models raises the question of how much they affect the relevance of observations regarding the physiological function of the STN itself. This underscores the crucial importance of obtaining evidence from healthy participants. In this study, we tested the structural and functional connectivity between the STN and other brain regions related to vocal emotion in a healthy population by combining diffusion tensor imaging and psychophysiological interaction analysis from a high-resolution functional magnetic resonance imaging study. As expected, we showed that the STN is functionally connected to the structures involved in emotional prosody decoding, notably the orbitofrontal cortex, inferior frontal gyrus, auditory cortex, pallidum and amygdala. These functional results were corroborated by probabilistic fiber tracking, which revealed that the left STN is structurally connected to the amygdala and the orbitofrontal cortex. These results confirm, in healthy participants, the role played by the STN in human emotion and its structural and functional connectivity with the brain network involved in vocal emotions. PMID:26400857

  4. Dorsolateral subthalamic neuronal activity enhanced by median nerve stimulation characterizes Parkinson's disease during deep brain stimulation with general anesthesia.

    PubMed

    Tsai, Sheng-Tzung; Chuang, Wei-Yi; Kuo, Chung-Chih; Chao, Paul C P; Chen, Tsung-Ying; Hung, Hsiang-Yi; Chen, Shin-Yuan

    2015-12-01

    Deep brain stimulation (DBS) surgery under general anesthesia is an alternative option for patients with Parkinson's disease (PD). However, few studies are available that report whether neuronal firing can be accurately recorded during this condition. In this study the authors attempted to characterize the neuronal activity of the subthalamic nucleus (STN) and elucidate the influence of general anesthetics on neurons during DBS surgery in patients with PD. The benefit of median nerve stimulation (MNS) for localization of the dorsolateral subterritory of the STN, which is involved in sensorimotor function, was explored. Eight patients with PD were anesthetized with desflurane and underwent contralateral MNS at the wrist during microelectrode recording of the STN. The authors analyzed the spiking patterns and power spectral density (PSD) of the background activity along each penetration track and determined the spatial correlation to the target location, estimated mated using standard neurophysiological procedures. The dorsolateral STN spiking pattern showed a more prominent bursting pattern without MNS and more oscillation with MNS. In terms of the neural oscillation of the background activity, beta-band oscillation dominated within the sensorimotor STN and showed significantly more PSD during MNS (p < 0.05). Neuronal firing within the STN could be accurately identified and differentiated when patients with PD received general anesthetics. Median nerve stimulation can enhance the neural activity in beta-band oscillations, which can be used as an index to ensure optimal electrode placement via successfully tracked dorsolateral STN topography.

  5. Subthalamic nucleus activity dissociates proactive and reactive inhibition in patients with Parkinson's disease.

    PubMed

    Benis, Damien; David, Olivier; Lachaux, Jean-Philippe; Seigneuret, Eric; Krack, Paul; Fraix, Valérie; Chabardès, Stéphan; Bastin, Julien

    2014-05-01

    Models of action selection postulate the critical involvement of the subthalamic nucleus (STN), especially in reactive inhibition processes when inappropriate responses to a sudden stimulus must be overridden. The STN could also play a key role during proactive inhibition, when subjects prepare to potentially suppress their actions. Here, we hypothesized that STN responses to reactive and proactive inhibitory control might be driven by different underlying mechanisms with specific temporal profiles. Direct neural recordings in twelve Parkinson's disease patients during a modified stop signal task (SST) revealed a decrease of beta band activity (βA, 13-35Hz) in the STN during reactive inhibition of smaller amplitude and shorter duration than during motor execution. Crucially, the onset latency of this relative increase of βA took place before the stop signal reaction time. It could thus be thought of as a "stop" signal inhibiting thalamo-cortical activity that would have supported motor execution. Finally, results also revealed a higher level of βA in the STN during proactive inhibition, which correlated with patient's inhibitory performances. We propose that βA in the STN would here participate in the implementation of a "hold your horse" signal to delay motor responses, thus prioritizing accuracy as compared to speed. In brief, our results provide strong electrophysiological support for the hypothesized role of the STN during executive control underlying proactive and reactive response suppression.

  6. High-frequency stimulation of the subthalamic nucleus counteracts cortical expression of major histocompatibility complex genes in a rat model of Parkinson's disease.

    PubMed

    Grieb, Benjamin; Engler, Gerhard; Sharott, Andrew; von Nicolai, Constantin; Streichert, Thomas; Papageorgiou, Ismini; Schulte, Alexander; Westphal, Manfred; Lamszus, Katrin; Engel, Andreas K; Moll, Christian K E; Hamel, Wolfgang

    2014-01-01

    High-frequency stimulation of the subthalamic nucleus (STN-HFS) is widely used as therapeutic intervention in patients suffering from advanced Parkinson's disease. STN-HFS exerts a powerful modulatory effect on cortical motor control by orthodromic modulation of basal ganglia outflow and via antidromic activation of corticofugal fibers. However, STN-HFS-induced changes of the sensorimotor cortex are hitherto unexplored. To address this question at a genomic level, we performed mRNA expression analyses using Affymetrix microarray gene chips and real-time RT-PCR in sensorimotor cortex of parkinsonian and control rats following STN-HFS. Experimental parkinsonism was induced in Brown Norway rats by bilateral nigral injections of 6-hydroxydopamine and was assessed histologically, behaviorally, and electrophysiologically. We applied prolonged (23h) unilateral STN-HFS in awake and freely moving animals, with the non-stimulated hemisphere serving as an internal control for gene expression analyses. Gene enrichment analysis revealed strongest regulation in major histocompatibility complex (MHC) related genes. STN-HFS led to a cortical downregulation of several MHC class II (RT1-Da, Db1, Ba, and Cd74) and MHC class I (RT1CE) encoding genes. The same set of genes showed increased expression levels in a comparison addressing the effect of 6-hydroxydopamine lesioning. Hence, our data suggest the possible association of altered microglial activity and synaptic transmission by STN-HFS within the sensorimotor cortex of 6-hydroxydopamine treated rats.

  7. Rearrangement of the dendritic morphology of the neurons from prefrontal cortex and hippocampus after subthalamic lesion in Sprague-Dawley rats.

    PubMed

    Camacho-Abrego, Israel; Tellez-Merlo, Gullermina; Melo, Angel I; Rodríguez-Moreno, Antonio; Garcés, Linda; De La Cruz, Fidel; Zamudio, Sergio; Flores, Gonzalo

    2014-03-01

    Several studies in rodents have suggested the inactivation of the subthalamic nucleus (STN) as an alternative strategy to Parkinson's disease (PD) treatment. The STN is part of the basal ganglia and plays an important role in the motor function; however, recent data suggest that this structure has a critical role in the cognitive function of the limbic system. The STN receives direct projection from the prefrontal cortex (PFC), structure interconnected with the hippocampus and both structures send excitatory projections to the nucleus accumbens (NAcc). Here, we determined whether and which changes occurred 4 weeks after a STN lesion in the dendritic morphology of pyramidal neurons of the layers 3 and 5 of the PFC and basolateral amygdala, neurons of the ventral hippocampus, and the medium spiny neurons of the NAcc and caudate-putamen. Dendritic morphology was measured using the Golgi-Cox procedure followed by Sholl analysis. We also evaluated the effects of STN lesion on locomotor behavior assessed by an open field test, social interaction, acoustic startle response, prepulse inhibition, and locomotor activity induced by a novel environment and amphetamine. We found that STN damage induced a deficit in locomotion measured by open field test with neuronal hypertrophy in PFC (layer 5) and reduced spinogenesis in CA1 ventral hippocampus and PFC (layer 3). Taken together, these data suggest that the behavioral and morphological effects of STN lesion are, at least partially, mediated by limbic subregions with possible consequences for cognitive-related behaviors observed in PD treatment. Copyright © 2013 Wiley Periodicals, Inc.

  8. Expression of sialyl-Tn antigen in breast cancer cells transfected with the human CMP-Neu5Ac: GalNAc alpha2,6-sialyltransferase (ST6GalNac I) cDNA.

    PubMed

    Julien, S; Krzewinski-Recchi, M A; Harduin-Lepers, A; Gouyer, V; Huet, G; Le Bourhis, X; Delannoy, P

    2001-01-01

    Sialyl-Tn antigen (STn) is a cancer associated carbohydrate antigen over-expressed in several cancers including breast cancer, and currently associated with more aggressive diseases and poor prognosis. However, the commonly used breast cancer cell lines (MDA-MB-231, T47-D and MCF7) do not express STn antigen. The key step in the biosynthesis of STn is the transfer of a sialic acid residue in alpha2,6-linkage to GalNAc alpha-O-Ser/Thr. This reaction is mainly catalyzed by a CMP-Neu5Ac GalNAc alpha2,6-sialyltransferase: ST6GalNAc I. In order to generate STn-positive breast cancer cells, we have cloned a cDNA encoding the full-length human ST6GalNAc I from HT-29-MTX cells. The stable transfection of MDA-MB-231 with an expression vector encoding ST6GalNAc I induces the expression of STn antigen at the cell surface. The expression of STn short cuts the initial O-glycosylation pattern of these cell lines, by competing with the Core-1 beta1,3-galactosyltransferase, the first enzyme involved in the elongation of O-glycan chains. Moreover, we show that STn expression is associated with morphological changes, decreased growth and increased migration of MDA-MB-231 cells.

  9. A functionally relevant and long-term model of deep brain stimulation of the rat subthalamic nucleus: advantages and considerations.

    PubMed

    Spieles-Engemann, A L; Collier, T J; Sortwell, C E

    2010-10-01

    In this review we outline some relevant considerations with regards to the rat model of deep brain stimulation of the subthalamic nucleus (STN DBS). In order to optimize the rat STN DBS model in terms of predictive validity for the clinical situation we propose that the STN stimulation experimental design parameters in rodents should incorporate the following features: (i) stimulation parameters that demonstrate functional alleviation of symptoms induced by nigrostriatal dopamine (DA) denervation; (ii) stimulation duration that is relatively long-term and continuous; (iii) stimulation that is initiated at a time when the denervation status of the nigrostriatal system is known to be partial and progressing; (iv) stimulation current spread that is minimized and optimized to closely approximate the clinical situation; (v) the appropriate control conditions are included; and (vi) implantation to the STN target is verified post-mortem. Further research that examines the effect of long-term STN DBS on the neurophysiology and neurochemistry of STN circuitry is warranted. The rat model of functionally relevant long-term STN DBS provides a most favorable preclinical experimental platform in which to conduct these studies.

  10. Deep Brain Stimulation Frequency of the Subthalamic Nucleus Affects Phonemic and Action Fluency in Parkinson's Disease

    PubMed Central

    da Cruz, Aline Nunes; Beber, Bárbara Costa

    2016-01-01

    Introduction. Deep brain stimulation of the subthalamic nucleus (STN-DBS) in Parkinson's disease (PD) has been linked to a decline in verbal fluency. The decline can be attributed to surgical effects, but the relative contributions of the stimulation parameters are not well understood. This study aimed to investigate the impact of the frequency of STN-DBS on the performance of verbal fluency tasks in patients with PD. Methods. Twenty individuals with PD who received bilateral STN-DBS were evaluated. Their performances of verbal fluency tasks (semantic, phonemic, action, and unconstrained fluencies) upon receiving low-frequency (60 Hz) and high-frequency (130 Hz) STN-DBS were assessed. Results. The performances of phonemic and action fluencies were significantly different between low- and high-frequency STN-DBS. Patients showed a decrease in these verbal fluencies for high-frequency STN-DBS. Conclusion. Low-frequency STN-DBS may be less harmful to the verbal fluency of PD patients. PMID:28050309

  11. Deep Brain Stimulation of the subthalamic nucleus does not negatively affect social cognitive abilities of patients with Parkinson's disease.

    PubMed

    Enrici, Ivan; Mitkova, Antonia; Castelli, Lorys; Lanotte, Michele; Lopiano, Leonardo; Adenzato, Mauro

    2017-08-25

    Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a treatment option for patients with advanced idiopathic PD successful at alleviating disabling motor symptoms. Nevertheless, the effects of STN-DBS on cognitive functions remain controversial and few studies have investigated modification of social cognitive abilities in patients with PD treated with STN-DBS. Here we expanded the typically-investigated spectrum of these abilities by simultaneously examining emotion recognition, and both affective and cognitive Theory of Mind (ToM). By means of a cross-sectional study, 20 patients with PD under dopaminergic replacement therapy, 18 patients with PD treated with STN-DBS, and 20 healthy controls performed the Ekman 60-Faces test, the full version of the Reading the Mind in the Eyes test, and the Protocol for the Attribution of Communicative Intentions. There were no differences between the PD groups (treated and not treated with STN-DBS) on any of the social cognitive tests. Our results suggest that patients with PD who are treated with STN-DBS do not experience detrimental effects on their social cognitive abilities. The present study, the first one examining a wide spectrum of social cognitive abilities after DBS of the STN, suggests that this surgical procedure can be considered safe from this standpoint.

  12. The modulatory role of subthalamic nucleus in cognitive functions - a viewpoint.

    PubMed

    Rektor, Ivan; Bočková, Martina; Chrastina, Jan; Rektorová, Irena; Baláž, Marek

    2015-04-01

    The modifications of electrophysiological activities of subthalamic nucleus (STN) by non-motor tasks, i.e. movement observation, emotional stimuli and impulse control, were reported repeatedly. Despite being a small structure, STN is apparently involved in a variety of functions. Based on our own electrophysiological recordings and results of other groups we believe that it acts as an indirect modulator which may be involved in tuning the functional systems. STN may modulate specific cognitive activities via contextual modulation of certain cortical areas. Our findings support the hypothesis of a cortical-STN bypass (via hyperdirect pathway) of "classical" basal ganglia-thalamocortical circuitry, at least during the processing of certain cognitive functions. The modulation of cognitive functions appears to be selective, probably determined by the involvement of cortical neuronal populations interconnected with STN. There could also exist a spatial overlap of areas within STN regulating various functions. That may explain the fact that some non-motor symptoms of Parkinson's disease may improve after deep brain stimulation of STN. These improvements are likely caused by combination of direct stimulation effect on non-motor function and overall beneficial effect of motor improvement on quality of life.

  13. Determination of vertical dimension of occlusion using lateral profile photographs: A pilot study.

    PubMed

    Vinnakota, Dileep Nag; Kanneganti, Krishna Chaitanya; Pulagam, Mahesh; Keerthi, Gopala Krishna

    2016-01-01

    To hypothesize a new theory based on soft tissue reference points on lateral profile photographs (LPPs) for determining the vertical dimension of occlusion (VDO), as there is need to explore for simple strategies. Fifty-three participants in the age range of 20-27 years who met the inclusion criteria were recruited. LPPs were taken for all participants using standard protocol and duplicate copies obtained, on which five soft tissue reference points, nasion (Stn), subnasale (Stsn), porion (Stp), gnathion (Stgn), and gonion (Stg) (Stg prenoted on the face) were marked and joined to form angles; distance between Stsn and Stgn was considered as VDO in LPP (VDO-LP). The angle formed between Stn-Stsn-Stgn and Stn-Stsn-Stg; Stp-Stg-Stgn and Stp-Stg-Stsn was correlated; two simple linear regression models were developed to predict Stn-Stsn-Stgn and Stp-Stg-Stgn using Stn-Stsn-Stg and Stp-Stg-Stsn as independent variables. Using the formulae, VDO-LP predicted was constructed and correlated with the actual values. The angle Stn-Stsn-Stgn had a statistically significant moderate positive correlation with Stn-Stsn-Stg (r = 0.57, P < 0.001) and angle Stp-Stg-Stgn, a significant strong positive correlation with Stp-Stg-Stsn (r = 0.81, P < 0.001). Using simple linear regression analysis, the following formulae were obtained: Stn-Stsn-Stgn (in degrees) = 0.776 Stn-Stsn-Stg (in degrees) +79.01 and Stp-Stg-Stgn (in degrees) =1.331 Stp-Stg-Stsn (in degrees) +10.2. The predicted and actual VDO-LP values were in strong positive correlation with a coefficient of 0.8. With the use of simple landmarks on LPP, it is possible to reconstruct the lost facial dimensions during prosthetic replacement of lost teeth.

  14. Deep-Brain Stimulation of the Subthalamic Nucleus Selectively Decreases Risky Choice in Risk-Preferring Rats.

    PubMed

    Adams, Wendy K; Vonder Haar, Cole; Tremblay, Melanie; Cocker, Paul J; Silveira, Mason M; Kaur, Sukhbir; Baunez, Christelle; Winstanley, Catharine A

    2017-01-01

    Deep brain stimulation of the subthalamic nucleus (STN-DBS) can improve the motor symptoms of Parkinson's disease (PD) and negate the problematic side effects of dopamine replacement therapy. Although there is concern that STN-DBS may enhance the development of gambling disorder and other impulse control disorders in this patient group, recent data suggest that STN-DBS may actually reduce iatrogenic impulse control disorders, and alleviate obsessive-compulsive disorder (OCD). Here, we sought to determine whether STN-DBS was beneficial or detrimental to performance of the rat gambling task (rGT), a rodent analogue of the Iowa Gambling Task (IGT) used to assess risky decision making clinically. Rats chose between four options associated with different amounts and probabilities of sugar pellet rewards versus timeout punishments. As in the IGT, the optimal approach was to favor options associated with smaller per-trial gains but lower timeout penalties. Once a stable behavioral baseline was established, electrodes were implanted bilaterally into the STN, and the effects of STN-DBS assessed on-task over 10 consecutive sessions using an A-B-A design. STN-DBS did not affect choice in optimal decision makers that correctly favored options associated with smaller per-trial gains but also lower penalties. However, a minority (∼25%) preferred the maladaptive "high-risk, high-reward" options at baseline. STN-DBS significantly and progressively improved choice in these risk-preferring rats. These data support the hypothesis that STN-DBS may be beneficial in ameliorating maladaptive decision making associated with compulsive and addiction disorders.

  15. Anatomic correlates of deep brain stimulation electrode impedance.

    PubMed

    Satzer, David; Maurer, Eric W; Lanctin, David; Guan, Weihua; Abosch, Aviva

    2015-04-01

    The location of the optimal target for deep brain stimulation (DBS) of the subthalamic nucleus (STN) remains controversial. Electrode impedance affects tissue activation by DBS and has been found to vary by contact number, but no studies have examined association between impedance and anatomic location. To evaluate the relationship between electrode impedance and anatomic contact location, and to assess the clinical significance of impedance. We gathered retrospective impedance data from 101 electrodes in 73 patients with Parkinson's disease. We determined contact location using microelectrode recording (MER) and high-field 7T MRI, and assessed the relationship between impedance and contact location. For contact location as assessed via MER, impedance was significantly higher for contacts in STN, at baseline (111 Ω vs STN border, p=0.03; 169 Ω vs white matter, p<0.001) and over time (90 Ω vs STN border, p<0.001; 54 Ω vs white matter, p<0.001). Over time, impedance was lowest in contacts situated at STN border (p=0.03). Impedance did not vary by contact location as assessed via imaging. Location determination was 75% consistent between MER and imaging. Impedance was inversely related to absolute symptom reduction during stimulation (-2.5 motor portion of the Unified Parkinson's Disease Rating Scale (mUPDRS) points per 1000 Ω, p=0.01). In the vicinity of DBS electrodes chronically implanted in STN, impedance is lower at the rostral STN border and in white matter, than in STN. This finding suggests that current reaches white matter fibres more readily than neuronal cell bodies in STN, which may help explain anatomic variation in stimulation efficacy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  16. Spatial distribution of soil organic carbon and total nitrogen based on GIS and geostatistics in a small watershed in a hilly area of northern China.

    PubMed

    Peng, Gao; Bing, Wang; Guangpo, Geng; Guangcan, Zhang

    2013-01-01

    The spatial variability of soil organic carbon (SOC) and total nitrogen (STN) levels is important in both global carbon-nitrogen cycle and climate change research. There has been little research on the spatial distribution of SOC and STN at the watershed scale based on geographic information systems (GIS) and geostatistics. Ninety-seven soil samples taken at depths of 0-20 cm were collected during October 2010 and 2011 from the Matiyu small watershed (4.2 km(2)) of a hilly area in Shandong Province, northern China. The impacts of different land use types, elevation, vegetation coverage and other factors on SOC and STN spatial distributions were examined using GIS and a geostatistical method, regression-kriging. The results show that the concentration variations of SOC and STN in the Matiyu small watershed were moderate variation based on the mean, median, minimum and maximum, and the coefficients of variation (CV). Residual values of SOC and STN had moderate spatial autocorrelations, and the Nugget/Sill were 0.2% and 0.1%, respectively. Distribution maps of regression-kriging revealed that both SOC and STN concentrations in the Matiyu watershed decreased from southeast to northwest. This result was similar to the watershed DEM trend and significantly correlated with land use type, elevation and aspect. SOC and STN predictions with the regression-kriging method were more accurate than those obtained using ordinary kriging. This research indicates that geostatistical characteristics of SOC and STN concentrations in the watershed were closely related to both land-use type and spatial topographic structure and that regression-kriging is suitable for investigating the spatial distributions of SOC and STN in the complex topography of the watershed.

  17. Bilateral subthalamic stimulation effects on oral force control in Parkinson's disease.

    PubMed

    Pinto, Serge; Gentil, Michèle; Fraix, Valérie; Benabid, Alim-Louis; Pollak, Pierre

    2003-02-01

    Dysarthria in Parkinson's disease (PD) consists of articulatory, phonatory and respiratory impairment. Bilateral subthalamic nucleus (STN) stimulation greatly improves motor disability, but its long-term effect on speech within a large group of patients has not been precisely evaluated. The aim of this study was to determine the effect of bilateral STN stimulation on oral force control in PD. We measured forces of the upper lip, lower lip and tongue in twenty-six PD patients treated with bilateral STN stimulation. Measurements of the articulatory organ force, as well as a motor evaluation using the Unified Parkinson's Disease Rating Scale (UPDRS), were made with and without STN stimulation. Maximal voluntary force (MVF), reaction time (RT), movement time (MT), imprecision of the peak force (PF) and the hold phase (HP) were all improved with STN stimulation during the articulatory force task, as well as the motor examination scores of the UPDRS. It seems that the beneficial STN stimulation-induced effect on articulatory forces persisted whatever the duration of post-surgical follow-up. However, dysarthria evaluated by the UPDRS was worse in two subgroups of patients with a one to two year and three to five year post-surgical follow-up, in comparison with a subgroup of patients with a three month follow-up. STN stimulation has a beneficial long-term effect on the articulatory organs involved in speech production, and this indicates that parkinsonian dysarthria is associated, at least in part, with an alteration in STN neuronal activity. Nevertheless, to confirm the persistence of the beneficial effect of STN stimulation on parkinsonian dysarthria, a longitudinal evaluation is still needed.

  18. Subthalamic nucleus stimulation effects on single and combined task performance in Parkinson's disease patients: a PET study.

    PubMed

    Atkinson-Clement, Cyril; Maillet, Audrey; LeBars, Didier; Lavenne, Franck; Redouté, Jérôme; Krainik, Alexandre; Pollak, Pierre; Thobois, Stéphane; Pinto, Serge

    2016-10-04

    Subthalamic nucleus deep brain stimulation (STN-DBS) represents one of the most efficacious treatments for Parkinson's disease, along with L-dopa therapy. The objective of the present work was to identify the cerebral networks associated with hand movement and speech production tasks performed alone and simultaneously, as well as the effects of STN-DBS on these profiles. Clinical, behavioral, and neuroimaging (oxygen 15-labeled water and Positron Emission Tomography) investigations were used to study single and combined performances of unilateral hand movements and speech production in 11 unmedicated individuals with PD, both off and on STN-DBS. Specifically, a flexible factorial design with the tasks (hand movement, speech production, combined task) and the STN-DBS conditions (off, on) as main factors was chosen for brain activation statistical analysis, using a Family-Wise Error corrected p-value at the cluster level of at least 10 contiguous voxels. Increased activation of fronto-parietal and cingulate areas was observed under STN-DBS for hand movement in single and combined tasks, respectively, reflecting a partial restoration of cortico-sub-cortical connections. The lack of results for speech production for both off and on STN-DBS could illustrate its relatively poor response to the treatment. STN-DBS tended to restore the additive function capacity that can be achieved when performing the combined task. We confirmed with original neuroimaging data that speech is much less responsive to STN-DBS than any other motor function and we concluded that speech outcomes following STN-DBS can be different from those observed pre-operatively following L-dopa administration.

  19. Identification of target areas for deep brain stimulation in human basal ganglia substructures based on median nerve sensory evoked potential criteria

    PubMed Central

    Klostermann, F; Vesper, J; Curio, G

    2003-01-01

    Objective: In the interventional treatment of movement disorders, the thalamic ventral intermediate nucleus (VIM) and the subthalamic nucleus (STN) are the most relevant electrode targets for deep brain stimulation (DBS). This study tested the value of somatosensory evoked potentials (SEP) for the functional identification of VIM and STN. Methods: Median nerve SEP were recorded from the final stimulation electrodes targeted at STN and VIM. Throughout the stereotactic procedure SEP were recorded during short electrode stops above STN/VIM and within the presumed target areas. After digital filtering, high and low frequency SEP components were analysed separately to parameterise both the 1000 Hz SEP burst and low frequency (<100 Hz) components. Results: SEP recorded in the VIM target region could unequivocally be distinguished from SEP recorded in STN. The 1000 Hz burst signal was significantly larger in VIM than in STN without any overlap of amplitude values. In the low frequency band, a primary high amplitude negativity was obtained in VIM, contrasting with a low amplitude positivity in STN. SEP waveshapes in recordings above target positions resembled SEP obtained in STN. When entering VIM, a sharp amplitude increase was observed over a few millimetres only. Conclusions: Based on SEP criteria, the VIM target but not the STN region can be identified by typical SEP configuration changes, when penetrating the target zone. The approach is independent of the patient's cooperation and vigilance and therefore feasible in general anaesthesia. It provides an easy, reliable, and robust tool for the final assessment of electrode positions at the last instance during electrode implantation when eventual electrode revisions can easily be performed. PMID:12876229

  20. Sixty Hertz Neurostimulation Amplifies Subthalamic Neural Synchrony in Parkinson’s Disease

    PubMed Central

    Blumenfeld, Zack; Velisar, Anca; Miller Koop, Mandy; Hill, Bruce C.; Shreve, Lauren A.; Quinn, Emma J.; Kilbane, Camilla; Yu, Hong; Henderson, Jaimie M.; Brontë-Stewart, Helen

    2015-01-01

    High frequency subthalamic nucleus (STN) deep brain stimulation (DBS) improves the cardinal motor signs of Parkinson’s disease (PD) and attenuates STN alpha/beta band neural synchrony in a voltage-dependent manner. While there is a growing interest in the behavioral effects of lower frequency (60 Hz) DBS, little is known about its effect on STN neural synchrony. Here we demonstrate for the first time that during intra-operative 60 Hz STN DBS, one or more bands of resting state neural synchrony were amplified in the STN in PD. We recorded intra-operative STN resting state local field potentials (LFPs) from twenty-eight STNs in seventeen PD subjects after placement of the DBS lead (model 3389, Medtronic, Inc.) before and during three randomized neurostimulation sets (130 Hz/1.35V, 130 Hz/2V, 60 Hz/2V). During 130 Hz/2V DBS, baseline (no DBS) STN alpha (8 – 12 Hz) and beta (13 – 35 Hz) band power decreased (N=14, P < 0.001 for both), whereas during 60 Hz/2V DBS, alpha band and peak frequency power increased (P = 0.012, P = 0.007, respectively). The effect of 60 Hz/2V DBS opposed that of power-equivalent (130 Hz/1.35V) DBS (alpha: P < 0.001, beta: P = 0.006). These results show that intra-operative 60 Hz STN DBS amplified whereas 130 Hz STN DBS attenuated resting state neural synchrony in PD; the effects were frequency-specific. We demonstrate that neurostimulation may be useful as a tool to selectively modulate resting state resonant bands of neural synchrony and to investigate its influence on motor and non-motor behaviors in PD and other neuropsychiatric diseases. PMID:25807463

  1. High incidence of carpal tunnel syndrome after deep brain stimulation in Parkinson's disease.

    PubMed

    Loizon, Marine; Laurencin, Chloé; Vial, Christophe; Danaila, Teodor; Thobois, Stéphane

    2016-12-01

    We observed several cases of carpal tunnel syndrome (CTS) revealed after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). 115 consecutive PD patients who underwent STN-DBS between 2010 and 2014 at the Neurological Hospital in Lyon were retrospectively included. CTS was accepted as the diagnosis only if clinical examination and ENMG both confirmed it. Nine patients (7.8 %) developed CTS in the 2 years following surgery, which is far beyond the 2.7/1000 incidence in the general population. The present study shows an overrepresentation of CTS occurrence after STN-DBS in PD.

  2. Mood Response to Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson Disease

    PubMed Central

    Campbell, Meghan C.; Black, Kevin J.; Weaver, Patrick M.; Lugar, Heather M.; Videen, Tom O.; Tabbal, Samer D.; Karimi, Morvarid; Perlmutter, Joel S.; Hershey, Tamara

    2012-01-01

    Deep brain stimulation of the subthalamic nucleus (STN DBS) in Parkinson disease (PD) improves motor function but has variable effects on mood. Little is known about the relationship between electrode contact location and mood response. We identified the anatomical location of electrode contacts and measured mood response to stimulation with the Visual Analog Scale in 24 STN DBS PD patients. Participants reported greater positive mood, decreased anxiety and apathy with bilateral and unilateral stimulation. Left DBS improved mood more than right DBS. Right DBS-induced increase in positive mood was related to more medial and dorsal contact locations. These results highlight the functional heterogeneity of the STN. PMID:22450611

  3. Effects of dopaminergic and subthalamic stimulation on musical performance.

    PubMed

    van Vugt, Floris T; Schüpbach, Michael; Altenmüller, Eckart; Bardinet, Eric; Yelnik, Jérôme; Hälbig, Thomas D

    2013-05-01

    Although subthalamic-deep brain stimulation (STN-DBS) is an efficient treatment for Parkinson's disease (PD), its effects on fine motor functions are not clear. We present the case of a professional violinist with PD treated with STN-DBS. DBS improved musical articulation, intonation and emotional expression and worsened timing relative to a timekeeper (metronome). The same effects were found for dopaminergic treatment. These results suggest that STN-DBS, mimicking the effects of dopaminergic stimulation, improves fine-tuned motor behaviour whilst impairing timing precision.

  4. Combined pallidal and subthalamic nucleus stimulation in sporadic dystonia-parkinsonism.

    PubMed

    Wöhrle, Johannes C; Blahak, Christian; Capelle, Hans-Holger; Fogel, Wolfgang; Bäzner, Hansjoerg; Krauss, Joachim K

    2012-01-01

    Multifocal deep brain stimulation (DBS) is a new technique that has been introduced recently. A 39-year-old man with dystonia-parkinsonism underwent the simultaneous implantation of subthalamic nucleus (STN) and globus pallidus internus (GPi) DBS electrodes. While bilateral STN DBS controlled the parkinsonian symptoms well and allowed for a reduction in levodopa, the improvement of dystonia was only temporary. Additional GPi DBS also alleviated dystonic symptoms. Formal assessment at the 1-year follow-up showed that both the parkinsonian symptoms and the dystonia were markedly improved via continuous bilateral combined STN and GPi stimulation. Sustained benefit was achieved at 3 years postoperatively.

  5. Other Types Of LCDs

    NASA Astrophysics Data System (ADS)

    Kobayashi, Shunsuke; Mochizuki, Akihiro

    The following sections are included: * INTRODUCTION * TUNABLE BIREFRINGENCE LCDs * Nematic Device with Homogeneous Alignment * Nematic Device with Homeotropic Alignment * ELECTRICALLY CONTROLLED BIREFRINGENCE EFFECT LCDs WITH A COMPENSATING CELL OR POLYMER LAYERS * Super Homeotropic LCDs * Black and White STN LCDs * Optical mode interference * Guest-host mode * Double-layered STN * Retardation film compensated STN * DUAL FREQUENCY ADDRESSING LCDs * Application for DSM LCDs * Application for TN LCDs * PI-CELL * CHOLESTERIC-NEMATIC PHASE CHANGE LCDs * Storage Mode LCDs * Stabilized Hysteresis Mode LCDs * THERMALLY ADDRESSED LCDs (CHOLESTERIC) * BISTABLE LCD * WIDE VIEWING ANGLE TN LCDs USING RETARDATION SHEETS * Type 1 Cells * Type 2 Cells * REFERENCES

  6. The Mathematics of Dispatchability, Revisited

    NASA Technical Reports Server (NTRS)

    Morris, Paul

    2016-01-01

    Dispatchability is an important property for the efficient execution of temporal plans where the temporal constraints are represented as a Simple Temporal Network (STN). It has been shown that every STN may be reformulated as a dispatchable STN, and dispatchability ensures that the temporal constraints need only be satisfied locally during execution. Recently, it has also been shown that Simple Temporal Networks with Uncertainty, augmented with wait edges, are Dynamically Controllable provided every projection is dispatchable. Thus, dispatchability has considerable theoretical as well as practical significance. One thing that hampers further work in this area is the underdeveloped theory. Moreover, the existing foundation is inadequate in certain respects. In this paper, we develop a new mathematical theory of dispatchability and its relationship to execution. We also provide several characterizations of dispatchability, including characterizations in terms of the structural properties of the STN graph. This facilitates the potential application of the theory to other areas.

  7. The Mathematics of Dispatchability Revisited

    NASA Technical Reports Server (NTRS)

    Morris, Paul

    2016-01-01

    Dispatchability is an important property for the efficient execution of temporal plans where the temporal constraints are represented as a Simple Temporal Network (STN). It has been shown that every STN may be reformulated as a dispatchable STN, and dispatchability ensures that the temporal constraints need only be satisfied locally during execution. Recently it has also been shown that Simple Temporal Networks with Uncertainty, augmented with wait edges, are Dynamically Controllable provided every projection is dispatchable. Thus, the dispatchability property has both theoretical and practical interest. One thing that hampers further work in this area is the underdeveloped theory. The existing definitions are expressed in terms of algorithms, and are less suitable for mathematical proofs. In this paper, we develop a new formal theory of dispatchability in terms of execution sequences. We exploit this to prove a characterization of dispatchability involving the structural properties of the STN graph. This facilitates the potential application of the theory to uncertainty reasoning.

  8. Oscillatory entrainment of subthalamic nucleus neurons and behavioural consequences in rodents and primates.

    PubMed

    Syed, E C J; Benazzouz, A; Taillade, M; Baufreton, J; Champeaux, K; Falgairolle, M; Bioulac, B; Gross, C E; Boraud, T

    2012-11-01

    We investigated the functional role of oscillatory activity in the local field potential (LFP) of the subthalamic nucleus (STN) in the pathophysiology of Parkinson's disease (PD). It has been postulated that beta (15-30 Hz) oscillatory activity in the basal ganglia induces PD motor symptoms. To assess this hypothesis, an LFP showing significant power in the beta frequency range (23 Hz) was used as a stimulus both in vitro and in vivo. We first demonstrated in rat brain slices that STN neuronal activity was driven by the LFP stimulation. We then applied beta stimulation to the STN of 16 rats and two monkeys while quantifying motor behaviour. Although stimulation-induced behavioural effects were observed, stimulation of the STN at 23 Hz induced no significant decrease in motor performance in either rodents or primates. This study is the first to show LFP-induced behaviour in both rats and primates, and highlights the complex relationship between beta power and parkinsonian symptoms.

  9. Nonmotor outcomes in Parkinson’s disease: is deep brain stimulation better than dopamine replacement therapy?

    PubMed Central

    Kandadai, Rukmini Mridula; Jabeen, Afshan; Kannikannan, Meena A.

    2012-01-01

    Nonmotor symptoms are an integral part of Parkinson’s disease and cause significant morbidity. Pharmacological therapy helps alleviate the disease but produces nonmotor manifestations. While deep brain stimulation (DBS) has emerged as the treatment of choice for motor dysfunction, the effect on nonmotor symptoms is not well known. Compared with pharmacological therapy, bilateral subthalamic nucleus (STN)-DBS or globus pallidum interna (GPi)-DBS has significant beneficial effects on pain, sleep, gastrointestinal and urological symptoms. STN-DBS is associated with a mild worsening in verbal fluency while GPi-DBS has no effect on cognition. STN-DBS may improve cardiovascular autonomic disturbances by reducing the dose of dopaminergic drugs. Because the motor effects of STN-DBS and GPi-DBS appear to be similar, nonmotor symptoms may determine the target choice in surgery of future patients. PMID:22276074

  10. New Versions of Old Favorites.

    ERIC Educational Resources Information Center

    Tenopir, Carol

    1999-01-01

    Describes Web versions of online systems and considers advantages and trade-offs for information professionals and other searchers. Web versions highlighted include Dow Jones Interactive; Dialog; LEXIS-NEXIS; and STN. (LRW)

  11. Treatment of dysarthria following subthalamic nucleus deep brain stimulation for Parkinson’s disease

    PubMed Central

    Tripoliti, Elina; Strong, Laura; Hickey, Freya; Foltynie, Tom; Zrinzo, Ludvic; Candelario, Joseph; Hariz, Marwan; Limousin, Patricia

    2011-01-01

    Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established treatment for patients with Parkinson’s disease (PD). Speech impairment is a frequent side effect of the surgery. This study examined the efficacy of an intensive speech treatment (the Lee Silverman Voice Treatment, LSVT) on dysarthria after STN-DBS. The LSVT was administered in ten patients with STN-DBS (surgical group) and ten patients without (medical group). Patients were assessed before, immediately after and six months following the speech treatment using sustained phonation, a speech intelligibility scale and monologue. Vocal loudness, speech intelligibility and perceptual ratings were the primary outcome measures. Vocal loudness and perceptual scores improved significantly across tasks for the medical group only. Speech intelligibility did not significantly change for either group. Results in the surgical group were variable with some patients deteriorating. Treatment of dysarthria following STN-DBS needs further investigation due to the variable response to LSVT. PMID:21953693

  12. An active contour-based atlas registration model applied to automatic subthalamic nucleus targeting on MRI: method and validation.

    PubMed

    Duay, Valérie; Bresson, Xavier; Castro, Javier Sanchez; Pollo, Claudio; Cuadra, Meritxell Bach; Thiran, Jean-Philippe

    2008-01-01

    This paper presents a new non parametric atlas registration framework, derived from the optical flow model and the active contour theory, applied to automatic subthalamic nucleus (STN) targeting in deep brain stimulation (DBS) surgery. In a previous work, we demonstrated that the STN position can be predicted based on the position of surrounding visible structures, namely the lateral and third ventricles. A STN targeting process can thus be obtained by registering these structures of interest between a brain atlas and the patient image. Here we aim to improve the results of the state of the art targeting methods and at the same time to reduce the computational time. Our simultaneous segmentation and registration model shows mean STN localization errors statistically similar to the most performing registration algorithms tested so far and to the targeting expert's variability. Moreover, the computational time of our registration method is much lower, which is a worthwhile improvement from a clinical point of view.

  13. Deep brain stimulation of the subthalamic nucleus improves pain in Parkinson's disease.

    PubMed

    Pellaprat, Jean; Ory-Magne, Fabienne; Canivet, Cindy; Simonetta-Moreau, Marion; Lotterie, Jean-Albert; Radji, Fatai; Arbus, Christophe; Gerdelat, Angélique; Chaynes, Patrick; Brefel-Courbon, Christine

    2014-06-01

    In Parkinson's disease (PD), chronic pain is a common symptom which markedly affects the quality of life. Some physiological arguments proposed that Deep Brain Stimulation of the Subthalamic Nucleus (STN-DBS) could improve pain in PD. We investigated in 58 PD patients the effect of STN-DBS on pain using the short McGill Pain Questionnaire and other pain parameters such as the Bodily discomfort subscore of the Parkinson's disease Questionnaire 39 and the Unified Parkinson's Disease Rating Scale section II (UPDRS II) item 17. All pain scores were significantly improved 12 months after STN-DBS. This improvement was not correlated with motor improvement, depression scores or L-Dopa reduction. STN-DBS induced a substantial beneficial effect on pain in PD, independently of its motor effects and mood status of patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Subthalamic nucleus gamma activity increases not only during movement but also during movement inhibition.

    PubMed

    Fischer, Petra; Pogosyan, Alek; Herz, Damian M; Cheeran, Binith; Green, Alexander L; Fitzgerald, James; Aziz, Tipu Z; Hyam, Jonathan; Little, Simon; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Brown, Peter; Tan, Huiling

    2017-07-25

    Gamma activity in the subthalamic nucleus (STN) is widely viewed as a pro-kinetic rhythm. Here we test the hypothesis that rather than being specifically linked to movement execution, gamma activity reflects dynamic processing in this nucleus. We investigated the role of gamma during fast stopping and recorded scalp electroencephalogram and local field potentials from deep brain stimulation electrodes in 9 Parkinson's disease patients. Patients interrupted finger tapping (paced by a metronome) in response to a stop-signal sound, which was timed such that successful stopping would occur only in ~50% of all trials. STN gamma (60-90 Hz) increased most strongly when the tap was successfully stopped, whereas phase-based connectivity between the contralateral STN and motor cortex decreased. Beta or theta power seemed less directly related to stopping. In summary, STN gamma activity may support flexible motor control as it did not only increase during movement execution but also during rapid action-stopping.

  15. Intermuscular coherence in Parkinson's disease: effects of subthalamic nucleus stimulation.

    PubMed

    Marsden, J; Limousin-Dowsey, P; Fraix, V; Pollak, P; Odin, P; Brown, P

    2001-05-08

    It remains unclear how high frequency stimulation of the subthalamic nucleus (STN) improves parkinsonism. We hypothesized that stimulation may affect the organization of the cortical drive to voluntarily activated muscle. Normally this is characterized by oscillations at 15-30 Hz, manifest in coherence between muscles in the same frequency band. We therefore investigated the effects of STN stimulation on electromyographic (EMG) activity in co-contracting distal arm muscles in nine subjects with Parkinson's disease off drugs. Without stimulation, coherence between EMG signals was diminished at 15-30 Hz compared with nine controls. STN stimulation increased coherence in the 15-30 Hz band, so that it approached that in healthy subjects. The results suggest that STN stimulation facilitates the normal cortical drive to muscles.

  16. A PC-based system for predicting movement from deep brain signals in Parkinson's disease.

    PubMed

    Loukas, Constantinos; Brown, Peter

    2012-07-01

    There is much current interest in deep brain stimulation (DBS) of the subthalamic nucleus (STN) for the treatment of Parkinson's disease (PD). This type of surgery has enabled unprecedented access to deep brain signals in the awake human. In this paper we present an easy-to-use computer based system for recording, displaying, archiving, and processing electrophysiological signals from the STN. The system was developed for predicting self-paced hand-movements in real-time via the online processing of the electrophysiological activity of the STN. It is hoped that such a computerised system might have clinical and experimental applications. For example, those sites within the STN most relevant to the processing of voluntary movement could be identified through the predictive value of their activities with respect to the timing of future movement.

  17. Cross validation of experts versus registration methods for target localization in deep brain stimulation.

    PubMed

    Sánchez Castro, F Javier; Pollo, Claudio; Meuli, Reto; Maeder, Philippe; Cuadra, Meritxell Bach; Cuisenaire, Olivier; Villemure, Jean-Guy; Thiran, Jean-Philippe

    2005-01-01

    In the last five years, Deep Brain Stimulation (DBS) has become the most popular and effective surgical technique for the treatent of Parkinson's disease (PD). The Subthalamic Nucleus (STN) is the usual target involved when applying DBS. Unfortunately, the STN is in general not visible in common medical imaging modalities. Therefore, atlas-based segmentation is commonly considered to locate it in the images. In this paper, we propose a scheme that allows both, to perform a comparison between different registration algorithms and to evaluate their ability to locate the STN automatically. Using this scheme we can evaluate the expert variability against the error of the algorithms and we demonstrate that automatic STN location is possible and as accurate as the methods currently used.

  18. Targeting the subthalamic nucleus for deep brain stimulation: technical approach and fusion of pre- and postoperative MR images to define accuracy of lead placement.

    PubMed

    Hamid, N A; Mitchell, R D; Mocroft, P; Westby, G W M; Milner, J; Pall, H

    2005-03-01

    To define the role of magnetic resonance imaging (MRI) and intraoperative electrophysiological recording in targeting the subthalamic nucleus (STN) in Parkinson's disease and to determine accuracy of electrode placement. We implanted 54 electrodes into the STN in 27 patients. Target planning was done by coordinate guidelines and visualising the STN on MRI and defined in relation to the mid-point of the AC-PC line. Intraoperative microelectrode recording was used. We adjusted electrode positions for placement in the centre of the STN electrical activity and verified this on postoperative MRI in 16 cases, which were fused to the preoperative images to measure actual error in electrode placement in the three axes. Based on coordinate calculation and MRI localisation, the mean of the target was 11.5 mm lateral, 2.5 mm posterior and 4.1 mm inferior to the mid-point of the AC-PC line. Fifty good electrophysiological recordings of the STN (average length 4.65 mm) were achieved and target point adjusted in 90% of lead placements. The mean of the final target after electrophysiological correction was 11.7 mm lateral, 2.1 mm posterior, and 3.8 mm inferior to the mid-point. The distance from the centre of the electrode artefact to the final target used after electrophysiological recording on the fused images was 0.48 mm, 0.69 mm, and 2.9 mm in the x, y, and z axes, respectively. No postoperative MRI related complication was observed. Both direct visualisation of the STN on MRI and intraoperative electrophysiological recording are important in defining the best target. Individual variations exist in the location of the STN target. Fewer tracks were required to define STN activity on the side operated first. Our current stereotactic method of electrode placement is relatively accurate.

  19. Effects of dopamine depletion on information flow between the subthalamic nucleus and external globus pallidus.

    PubMed

    Cruz, Ana V; Mallet, Nicolas; Magill, Peter J; Brown, Peter; Averbeck, Bruno B

    2011-10-01

    Abnormal oscillatory synchrony is increasingly acknowledged as a pathophysiological hallmark of Parkinson's disease, but what promotes such activity remains unclear. We used novel, nonlinear time series analyses and information theory to capture the effects of dopamine depletion on directed information flow within and between the subthalamic nucleus (STN) and external globus pallidus (GPe). We compared neuronal activity recorded simultaneously from these nuclei in 6-hydroxydopamine-lesioned Parkinsonian rats with that in dopamine-intact control rats. After lesioning, both nuclei displayed pronounced augmentations of beta-frequency (∼20 Hz) oscillations and, critically, information transfer between STN and GPe neurons was increased. Furthermore, temporal profiles of the directed information transfer agreed with the neurochemistry of these nuclei, being "excitatory" from STN to GPe and "inhibitory" from GPe to STN. Separation of the GPe population in lesioned animals into "type-inactive" (GP-TI) and "type-active" (GP-TA) neurons, according to definitive firing preferences, revealed distinct temporal profiles of interaction with STN and each other. The profile of GP-TI neurons suggested their output is of greater causal significance than that of GP-TA neurons for the reduced activity that periodically punctuates the spiking of STN neurons during beta oscillations. Moreover, STN was identified as a key candidate driver for recruiting ensembles of GP-TI neurons but not GP-TA neurons. Short-latency interactions between GP-TI and GP-TA neurons suggested mutual inhibition, which could rhythmically dampen activity and promote anti-phase firing across the two subpopulations. Results thus indicate that information flow around the STN-GPe circuit is exaggerated in Parkinsonism and further define the temporal interactions underpinning this.

  20. Basal ganglia dysfunction in OCD: subthalamic neuronal activity correlates with symptoms severity and predicts high-frequency stimulation efficacy.

    PubMed

    Welter, M-L; Burbaud, P; Fernandez-Vidal, S; Bardinet, E; Coste, J; Piallat, B; Borg, M; Besnard, S; Sauleau, P; Devaux, B; Pidoux, B; Chaynes, P; Tézenas du Montcel, S; Bastian, A; Langbour, N; Teillant, A; Haynes, W; Yelnik, J; Karachi, C; Mallet, L

    2011-05-03

    Functional and connectivity changes in corticostriatal systems have been reported in the brains of patients with obsessive-compulsive disorder (OCD); however, the relationship between basal ganglia activity and OCD severity has never been adequately established. We recently showed that deep brain stimulation of the subthalamic nucleus (STN), a central basal ganglia nucleus, improves OCD. Here, single-unit subthalamic neuronal activity was analysed in 12 OCD patients, in relation to the severity of obsessions and compulsions and response to STN stimulation, and compared with that obtained in 12 patients with Parkinson's disease (PD). STN neurons in OCD patients had lower discharge frequency than those in PD patients, with a similar proportion of burst-type activity (69 vs 67%). Oscillatory activity was present in 46 and 68% of neurons in OCD and PD patients, respectively, predominantly in the low-frequency band (1-8 Hz). In OCD patients, the bursty and oscillatory subthalamic neuronal activity was mainly located in the associative-limbic part. Both OCD severity and clinical improvement following STN stimulation were related to the STN neuronal activity. In patients with the most severe OCD, STN neurons exhibited bursts with shorter duration and interburst interval, but higher intraburst frequency, and more oscillations in the low-frequency bands. In patients with best clinical outcome with STN stimulation, STN neurons displayed higher mean discharge, burst and intraburst frequencies, and lower interburst interval. These findings are consistent with the hypothesis of a dysfunction in the associative-limbic subdivision of the basal ganglia circuitry in OCD's pathophysiology.

  1. Effects of subthalamic nucleus deep brain stimulation and levodopa on energy production rate and substrate oxidation in Parkinson's disease.

    PubMed

    Perlemoine, Caroline; Macia, Frédéric; Tison, François; Coman, Isabelle; Guehl, Dominique; Burbaud, Pierre; Cuny, Emmanuel; Baillet, Laurence; Gin, Henri; Rigalleau, Vincent

    2005-02-01

    Patients with Parkinson's disease (PD) often lose weight, but after subthalamic nucleus deep brain stimulation (STN-DBS), they gain weight. We compared daily energy intake (DEI), resting energy expenditure (REE) and substrate oxidation rates (measured by indirect calorimetry) in nineteen STN-DBS-treated patients (Group S), thirteen others on pharmacologic treatment by levodopa (Group L) and eight control subjects. We also determined the acute effects of STN-DBS and levodopa on REE and substrate oxidation rates. STN-DBS treated patients gained 9.7 (SEM 7.1) kg after surgery, whereas patients on pharmacologic treatment lost 3.8 (SEM 10.0) kg since diagnosis. In STN-DBS-treated patients, REE (-16.5 %; P<0.001), lipid oxidation (-27 %; P<0.05) and protein oxidation (-46 %; P<0.05) were decreased, whereas glucose oxidation was elevated (+81 %; P<0.05) as compared to patients on pharmacologic treatment. Levodopa acutely reduced REE (-8.3 %; P<0.05) and glucose oxidation (-37 %; P<0.01) with a slight hyperglycaemic effect (after levodopa challenge: 5.6 (SEM 0.8) v. before levodopa challenge: 5.3 (SEM 0.6) mmol/l; P<0.01). Switching 'on' STN-DBS acutely reduced REE (-17.5 %; P<0.01) and lipid oxidation (-24 %; P<0.001) 30 min after starting stimulation. Fasting glycaemia was slightly but significantly reduced (5.4 (SEM 1.4) v. 5.5 (SEM 1.3) mmol/l; P<0.01). After STN-DBS, the normalization of REE and the reduction in lipid and protein oxidation contribute to the restoration of weight. As levodopa decreases glucose oxidation, the reduction in daily dose of levodopa in STN-DBS-treated patients helps prevent the effect of weight gain on glycaemia.

  2. Mismatch negativity-like potential (MMN-like) in the subthalamic nuclei in Parkinson's disease patients.

    PubMed

    Minks, Eduard; Jurák, Pavel; Chládek, Jan; Chrastina, Jan; Halámek, Josef; Shaw, Daniel J; Bareš, Martin

    2014-12-01

    An infrequent change to an otherwise repetitive sequence of stimuli leads to the generation of mismatch negativity (MMN), even in the absence of attention. This evoked negative response occurs in the scalp-recorded electroencephalogram (EEG) over the temporal and frontal cortices, 100-250 ms after onset of the deviant stimulus. The MMN is used to detect sensory information processing. The aim of our study was to investigate whether MMN can be recorded in the subthalamic nuclei (STN) as evidence of auditory information processing on an unconscious level within this structure. To our knowledge, MMN has never been recorded in the human STN. We recorded intracerebral EEG using a MMN paradigm in five patients with Parkinson's disease (PD) who were implanted with depth electrodes in the subthalamic nuclei (STN). We found far-field MMN when intracerebral contacts were connected to an extracranial reference electrode. In all five PD patients (and nine of ten intracerebral electrodes), we also found near-field MMN-like potentials when intracerebral contacts were referenced to one another, and in some electrodes, we observed phase reversals in these potentials. The mean time-to-peak latency of the intracerebral MMN-like potentials was 214 ± 38 ms (median 219 ms). We reveal MMN-like potentials in bilateral STN. This finding provides evidence that STN receives sensory (auditory) information from other structures. The question for further research is whether STN receives such signals through a previously described hyperdirect pathway between STN and frontal cortex (a known generator of the MMN potential) and if the STN contributes to sensorimotor integration.

  3. NMDA receptor antagonism potentiates the L-DOPA-induced extracellular dopamine release in the subthalamic nucleus of hemi-parkinson rats.

    PubMed

    El Arfani, Anissa; Bentea, Eduard; Aourz, Najat; Ampe, Ben; De Deurwaerdère, Philippe; Van Eeckhaut, Ann; Massie, Ann; Sarre, Sophie; Smolders, Ilse; Michotte, Yvette

    2014-10-01

    Long term treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) is associated with several motor complications. Clinical improvement of this treatment is therefore needed. Lesions or high frequency stimulation of the hyperactive subthalamic nucleus (STN) in Parkinson's disease (PD), alleviate the motor symptoms and reduce dyskinesia, either directly and/or by allowing the reduction of the L-DOPA dose. N-methyl-D-aspartate (NMDA) receptor antagonists might have similar actions. However it remains elusive how the neurochemistry changes in the STN after a separate or combined administration of L-DOPA and a NMDA receptor antagonist. By means of in vivo microdialysis, the effect of L-DOPA and/or MK 801, on the extracellular dopamine (DA) and glutamate (GLU) levels was investigated for the first time in the STN of sham and 6-hydroxydopamine-lesioned rats. The L-DOPA-induced DA increase in the STN was significantly higher in DA-depleted rats compared to shams. MK 801 did not influence the L-DOPA-induced DA release in shams. However, MK 801 enhanced the L-DOPA-induced DA release in hemi-parkinson rats. Interestingly, the extracellular STN GLU levels remained unchanged after nigral degeneration. Furthermore, administration of MK 801 alone or combined with L-DOPA did not alter the STN GLU levels in both sham and DA-depleted rats. The present study does not support the hypothesis that DA-ergic degeneration influences the STN GLU levels neither that MK 801 alters the GLU levels in lesioned and non-lesioned rats. However, NMDA receptor antagonists could be used as a beneficial adjuvant treatment for PD by enhancing the therapeutic efficacy of l-DOPA at least in part in the STN.

  4. Hypoxia enhances the malignant nature of bladder cancer cells and concomitantly antagonizes protein O-glycosylation extension

    PubMed Central

    Lima, Luís; Azevedo, Rita; Soares, Janine; Cotton, Sofia; Parreira, Beatriz; Neves, Manuel; Amaro, Teresina; Tavares, Ana; Teixeira, Filipe; Palmeira, Carlos; Rangel, Maria; Silva, André M.N.; Reis, Celso A.; Santos, Lúcio Lara; Oliveira, Maria José; Ferreira, José Alexandre

    2016-01-01

    Invasive bladder tumours express the cell-surface Sialyl-Tn (STn) antigen, which stems from a premature stop in protein O-glycosylation. The STn antigen favours invasion, immune escape, and possibly chemotherapy resistance, making it attractive for target therapeutics. However, the events leading to such deregulation in protein glycosylation are mostly unknown. Since hypoxia is a salient feature of advanced stage tumours, we searched into how it influences bladder cancer cells glycophenotype, with emphasis on STn expression. Therefore, three bladder cancer cell lines with distinct genetic and molecular backgrounds (T24, 5637 and HT1376) were submitted to hypoxia. To disclose HIF-1α-mediated events, experiments were also conducted in the presence of Deferoxamine Mesilate (Dfx), an inhibitor of HIF-1α proteasomal degradation. In both conditions all cell lines overexpressed HIF-1α and its transcriptionally-regulated protein CA-IX. This was accompanied by increased lactate biosynthesis, denoting a shift toward anaerobic metabolism. Concomitantly, T24 and 5637 cells acquired a more motile phenotype, consistent with their more mesenchymal characteristics. Moreover, hypoxia promoted STn antigen overexpression in all cell lines and enhanced the migration and invasion of those presenting more mesenchymal characteristics, in an HIF-1α-dependent manner. These effects were reversed by reoxygenation, demonstrating that oxygen affects O-glycan extension. Glycoproteomics studies highlighted that STn was mainly present in integrins and cadherins, suggesting a possible role for this glycan in adhesion, cell motility and invasion. The association between HIF-1α and STn overexpressions and tumour invasion was further confirmed in bladder cancer patient samples. In conclusion, STn overexpression may, in part, result from a HIF-1α mediated cell-survival strategy to adapt to the hypoxic challenge, favouring cell invasion. In addition, targeting STn-expressing glycoproteins may

  5. Identification of (2S,3S)-β-Methyltryptophan as the Real Biosynthetic Intermediate of Antitumor Agent Streptonigrin

    PubMed Central

    Kong, Dekun; Zou, Yi; Zhang, Zhang; Xu, Fei; Brock, Nelson L.; Zhang, Liping; Deng, Zixin; Lin, Shuangjun

    2016-01-01

    Streptonigrin is a potent antitumor antibiotic, active against a wide range of mammalian tumor cells. It was reported that its biosynthesis relies on (2S,3R)-β-methyltryptophan as an intermediate. In this study, the biosynthesis of (2S,3R)-β-methyltryptophan and its isomer (2S,3S)-β-methyltryptophan by enzymes from the streptonigrin biosynthetic pathway is demonstrated. StnR is a pyridoxal 5′-phosphate (PLP)-dependent aminotransferase that catalyzes a transamination between L-tryptophan and β-methyl indolepyruvate. StnQ1 is an S-adenosylmethionine (SAM)-dependent C-methyltransferase and catalyzes β-methylation of indolepyruvate to generate (R)-β-methyl indolepyruvate. Although StnR exhibited a significant preference for (S)-β-methyl indolepyruvate over the (R)-epimer, StnQ1 and StnR together catalyze (2S,3R)-β-methyltryptophan formation from L-tryptophan. StnK3 is a cupin superfamily protein responsible for conversion of (R)-β-methyl indolepyruvate to its (S)-epimer and enables (2S,3S)-β-methyltryptophan biosynthesis from L-tryptophan when combined with StnQ1 and StnR. Most importantly, (2S,3S)-β-methyltryptophan was established as the biosynthetic intermediate of the streptonigrin pathway by feeding experiments with a knockout mutant, contradicting the previous proposal that stated (2S,3R)-β-methyltryptophan as the intermediate. These data set the stage for the complete elucidation of the streptonigrin biosynthetic pathway, which would unlock the potential of creating new streptonigrin analogues by genetic manipulation of the biosynthetic machinery. PMID:26847951

  6. Movement-related changes in local and long-range synchronization in Parkinson’s disease revealed by simultaneous magnetoencephalography and intracranial recordings

    PubMed Central

    Litvak, Vladimir; Eusebio, Alexandre; Jha, Ashwani; Oostenveld, Robert; Barnes, Gareth; Foltynie, Tom; Limousin, Patricia; Zrinzo, Ludvic; Hariz, Marwan I.; Friston, Karl; Brown, Peter

    2012-01-01

    Functional neurosurgery has afforded the opportunity to assess interactions between populations of neurons in the human cerebral cortex and basal ganglia in patients with Parkinson’s disease (PD). Interactions occur over a wide range of frequencies, and the functional significance of those above 30 Hz is particularly unclear. Do they improve movement and, if so, in what way? We acquired simultaneously magnetoencephalography (MEG) and direct recordings from the subthalamic nucleus (STN) in 17 PD patients. We examined the effect of synchronous and sequential finger movements and of the dopamine prodrug levodopa on induced power in the contralateral primary motor cortex (M1) and STN and on the coherence between the two structures. We observed discrete peaks in M1 and STN power over 60-90 Hz and 300-400 Hz. All these power peaks increased with movement and levodopa treatment. Only STN activity over 60-90 Hz was coherent with activity in M1. Directionality analysis showed that STN gamma activity at 60-90 Hz tended to drive gamma activity in M1. The effects of levodopa on both local and distant synchronisation over 60-90 Hz correlated with the degree of improvement in bradykinesia-rigidity, as did local STN activity at 300-400 Hz. Despite this, there were no effects of movement type, nor interactions between movement type and levodopa in the STN, nor in the coherence between STN and M1. We conclude that synchronisation over 60-90 Hz in the basal ganglia cortical network is prokinetic, but likely through a modulatory effect rather than any involvement in explicit motor processing. PMID:22855804

  7. The relationship between clinical phenotype and early staged bilateral deep brain stimulation in Parkinson disease.

    PubMed

    Sung, Victor W; Watts, Ray L; Schrandt, Christian J; Guthrie, Stephanie; Wang, Deli; Amara, Amy W; Guthrie, Barton L; Walker, Harrison C

    2013-12-01

    While many centers place bilateral deep brain stimulation (DBS) systems simultaneously, unilateral subthalamic nucleus (STN) DBS followed by a staged contralateral procedure has emerged as a treatment option for many patients. However, little is known about whether the preoperative phenotype predicts when staged placement of a DBS electrode in the opposite STN will be required. The authors aimed to determine whether preoperative clinical phenotype predicts early staged placement of a second STN DBS electrode in patients who undergo unilateral STN DBS for Parkinson disease (PD). Eighty-two consecutive patients with advanced PD underwent unilateral STN DBS contralateral to the most affected hemibody and had at least 2 years of follow-up. Multivariate logistic regression analysis determined preoperative characteristics that predicted staged placement of a second electrode in the opposite STN. Preoperative measurements included aspects of the Unified Parkinson's Disease Rating Scale (UPDRS), motor asymmetry index, and body weight. At 2-year follow-up, 28 (34%) of the 82 patients had undergone staged placement of a contralateral electrode while the remainder chose to continue with unilateral stimulation. Statistically significant improvements in UPDRS total and Part 3 scores were retained at the end of the 2-year follow-up period in both subsets of patients. Multivariate logistic regression analysis showed that the most important predictors for early staged placement of a second subthalamic stimulator were low asymmetry index (OR 13.4, 95% CI 2.8-64.9), high tremor subscore (OR 7.2, CI 1.5-35.0), and low body weight (OR 5.5, 95% CI 1.4-22.3). This single-center study provides evidence that elements of the preoperative PD phenotype predict whether patients will require early staged bilateral STN DBS. These data may aid in the management of patients with advanced PD who undergo STN DBS.

  8. Subthalamic nucleus neurons are synchronized to primary motor cortex local field potentials in Parkinson’s disease

    PubMed Central

    Shimamoto, Shoichi; Ryapolova-Webb, Elena S.; Ostrem, Jill L.; Galifianakis, Nicholas B.; Miller, Kai J.; Starr, Philip A.

    2013-01-01

    In Parkinson’s disease (PD), striatal dopamine denervation results in a cascade of abnormalities in the single unit activity of downstream basal ganglia nuclei that include increased firing rate, altered firing patterns, and increased oscillatory activity. However, the effects of these abnormalities on cortical function are poorly understood. Here, in humans undergoing deep brain stimulator implantation surgery, we utilize the novel technique of subdural electrocorticography in combination with subthalamic nucleus (STN) single unit recording to study basal ganglia-cortex interactions at the millisecond time scale. We show that in patients with PD, STN spiking is synchronized with primary motor cortex (M1) local field potentials in two distinct patterns: First, STN spikes are phase-synchronized with M1 rhythms in the theta, alpha, or beta (4-30 Hz) bands. Second, STN spikes are synchronized with M1 gamma activity over a broad spectral range (50-200 Hz). The amplitude of STN spike-synchronized gamma activity in M1 is itself rhythmically modulated by the phase of a lower frequency rhythm (phase-amplitude coupling), such that “waves” of phase-synchronized gamma activity precede the occurrence of STN spikes. We show the disease specificity of these phenomena in PD, by comparison with STN-M1 paired recordings performed in a group of patients with a different disorder, primary cranio-cervical dystonia. Our findings support a model of the basal ganglia-thalamocortical loop in PD in which gamma activity in primary motor cortex, modulated by the phase of low frequency rhythms, drives STN unit discharge. PMID:23616531

  9. Hypoxia enhances the malignant nature of bladder cancer cells and concomitantly antagonizes protein O-glycosylation extension.

    PubMed

    Peixoto, Andreia; Fernandes, Elisabete; Gaiteiro, Cristiana; Lima, Luís; Azevedo, Rita; Soares, Janine; Cotton, Sofia; Parreira, Beatriz; Neves, Manuel; Amaro, Teresina; Tavares, Ana; Teixeira, Filipe; Palmeira, Carlos; Rangel, Maria; Silva, André M N; Reis, Celso A; Santos, Lúcio Lara; Oliveira, Maria José; Ferreira, José Alexandre

    2016-09-27

    Invasive bladder tumours express the cell-surface Sialyl-Tn (STn) antigen, which stems from a premature stop in protein O-glycosylation. The STn antigen favours invasion, immune escape, and possibly chemotherapy resistance, making it attractive for target therapeutics. However, the events leading to such deregulation in protein glycosylation are mostly unknown. Since hypoxia is a salient feature of advanced stage tumours, we searched into how it influences bladder cancer cells glycophenotype, with emphasis on STn expression. Therefore, three bladder cancer cell lines with distinct genetic and molecular backgrounds (T24, 5637 and HT1376) were submitted to hypoxia. To disclose HIF-1α-mediated events, experiments were also conducted in the presence of Deferoxamine Mesilate (Dfx), an inhibitor of HIF-1α proteasomal degradation. In both conditions all cell lines overexpressed HIF-1α and its transcriptionally-regulated protein CA-IX. This was accompanied by increased lactate biosynthesis, denoting a shift toward anaerobic metabolism. Concomitantly, T24 and 5637 cells acquired a more motile phenotype, consistent with their more mesenchymal characteristics. Moreover, hypoxia promoted STn antigen overexpression in all cell lines and enhanced the migration and invasion of those presenting more mesenchymal characteristics, in an HIF-1α-dependent manner. These effects were reversed by reoxygenation, demonstrating that oxygen affects O-glycan extension. Glycoproteomics studies highlighted that STn was mainly present in integrins and cadherins, suggesting a possible role for this glycan in adhesion, cell motility and invasion. The association between HIF-1α and STn overexpressions and tumour invasion was further confirmed in bladder cancer patient samples. In conclusion, STn overexpression may, in part, result from a HIF-1α mediated cell-survival strategy to adapt to the hypoxic challenge, favouring cell invasion. In addition, targeting STn-expressing glycoproteins may

  10. The Good and Bad Differentially Encoded within the Subthalamic Nucleus in Rats

    PubMed Central

    Breysse, Emmanuel; Pelloux, Yann

    2015-01-01

    Abstract The subthalamic nucleus (STN) has only recently been added into the reward circuit. It has been shown to encode information regarding rewards (4% sucrose, 32% cocaine). To investigate the encoding of negative value, STN neurons were recorded in rats performing a task using discriminative stimuli predicting various rewards and especially during the replacement of a positive reinforcer (4% sucrose) by an aversive reinforcer (quinine). The results show that STN neurons encode information relative to both positive and aversive reinforcers via specialized subpopulations. The specialization is reset when the context is modified (change from a favorable context (4% vs 32% sucrose) to an unfavorable context (quinine vs 32% sucrose). An excitatory response to the cue light predicting the reward seems to be associated with the preferred situation, suggesting that STN plays a role in encoding the relative value of rewards. STN also seems to play a critical role in the encoding of execution error. Indeed, various subpopulations of neurons responding exclusively at early (i.e., “oops neurons”) or at correct lever release were identified. The oops neurons respond mostly when the preferred reward (32% sucrose) is missed. Furthermore, STN neurons respond to reward omission, suggesting a role in reward prediction error. These properties of STN neurons strengthen its position in the reward circuit as a key cerebral structure through which reward-related processes are mediated. It is particularly important given the fact that STN is the target of surgical treatment for Parkinson’s disease and obsessive compulsive disorders, and has been suggested for the treatment of addiction as well. PMID:26478913

  11. The Subthalamic Nucleus becomes a Generator of Bursts in the Dopamine-Depleted State. Its High Frequency Stimulation Dramatically Weakens Transmission to the Globus Pallidus

    PubMed Central

    Ammari, Rachida; Bioulac, Bernard; Garcia, Liliana; Hammond, Constance

    2011-01-01

    Excessive burst firing in the dopamine-depleted basal ganglia correlates with severe motor symptoms of Parkinson's disease that are attenuated by high frequency electrical stimulation of the subthalamic nucleus (STN). Here we test the hypothesis that pathological bursts in dopamine-deprived basal ganglia are generated within the STN and transmitted to globus pallidus neurons. To answer this question we recorded excitatory synaptic currents and potentials from subthalamic and pallidal neurons in the basal ganglia slice (BGS) from dopamine-depleted mice while continuously blocking GABAA receptors. In control mice, a single electrical stimulus delivered to the internal capsule or the rostral pole of the STN evoked a short duration, small amplitude, monosynaptic EPSC in subthalamic neurons. In contrast, in the dopamine-depleted BGS, this monosynaptic EPSC was amplified and followed by a burst of polysynaptic EPSCs that eventually reverberated three to seven times, providing a long lasting response that gave rise to bursts of EPSCs and spikes in GP neurons. Repetitive (10–120 Hz) stimulation delivered to the STN in the dopamine-depleted BGS attenuated STN-evoked bursts of EPSCs in pallidal neurons after several minutes of stimulation but only high frequency (90–120 Hz) stimulation replaced them with small amplitude EPSCs at 20 Hz. We propose that the polysynaptic pathway within the STN amplifies subthalamic responses to incoming excitation in the dopamine-depleted basal ganglia, thereby transforming the STN into a burst generator and entraining pallidal neurons in pathogenic bursting activities. High frequency stimulation of the STN prevents the transmission of this pathological activity to globus pallidus and imposes a new glutamatergic synaptic noise on pallidal neurons. PMID:21716635

  12. Neuronal Activity in the Subthalamic Nucleus Modulates the Release of Dopamine in the Monkey Striatum

    PubMed Central

    Shimo, Yasushi; Wichmann, Thomas

    2009-01-01

    The primate subthalamic nucleus (STN) is commonly seen as a relay nucleus between the external and internal pallidal segments, and as an input station for cortical and thalamic information into the basal ganglia. In rodents, STN activity is also known to influence neuronal activity in the dopaminergic substantia nigra pars compacta (SNc) through inhibitory and excitatory mono- and polysynaptic pathways. Although the anatomical connections between STN and SNc are not entirely the same in primates as in rodents, the electrophysiologic and microdialysis experiments presented here show directly that this functional interaction can also be demonstrated in primates. In three Rhesus monkeys, extracellular recordings from SNc during microinjections into the STN revealed that transient pharmacologic activation of the subthalamic nucleus by the acetylcholine-receptor agonist carbachol substantially increased burst firing of single nigral neurons. Transient inactivation of the STN with microinjections of the GABA-A-receptor agonist muscimol had the opposite effect. While the firing rates of individual SNc neurons changed in response to the activation or inactivation of the STN, these changes were not consistent across the entire population of SNc cells. Permanent lesions of the STN, produced in two animals with the fiber-sparing neurotoxin ibotenic acid, reduced burst firing and firing rates of SNc neurons, and substantially decreased dopamine levels in the primary recipient area of SNc projections, the striatum, as measured with microdialysis. These results suggest that activity in the primate SNc is prominently influenced by neuronal discharge in the STN, which may thus alter dopamine release in the striatum. PMID:19087163

  13. The Subthalamic Nucleus, Limbic Function, and Impulse Control.

    PubMed

    Rossi, P Justin; Gunduz, Aysegul; Okun, Michael S

    2015-12-01

    It has been well documented that deep brain stimulation (DBS) of the subthalamic nucleus (STN) to address some of the disabling motor symptoms of Parkinson's disease (PD) can evoke unintended effects, especially on non-motor behavior. This observation has catalyzed more than a decade of research concentrated on establishing trends and identifying potential mechanisms for these non-motor effects. While many issues remain unresolved, the collective result of many research studies and clinical observations has been a general recognition of the role of the STN in mediating limbic function. In particular, the STN has been implicated in impulse control and the related construct of valence processing. A better understanding of STN involvement in these phenomena could have important implications for treating impulse control disorders (ICDs). ICDs affect up to 40% of PD patients on dopamine agonist therapy and approximately 15% of PD patients overall. ICDs have been reported to be associated with STN DBS. In this paper we will focus on impulse control and review pre-clinical, clinical, behavioral, imaging, and electrophysiological studies pertaining to the limbic function of the STN.

  14. Subthalamic deep brain stimulation in Parkinson׳s disease has no significant effect on perceptual timing in the hundreds of milliseconds range

    PubMed Central

    Cope, Thomas E.; Grube, Manon; Mandal, Arnab; Cooper, Freya E.; Brechany, Una; Burn, David J.; Griffiths, Timothy D.

    2014-01-01

    Bilateral, high-frequency stimulation of the basal ganglia (STN-DBS) is in widespread use for the treatment of the motor symptoms of Parkinson׳s disease (PD). We present here the first psychophysical investigation of the effect of STN-DBS upon perceptual timing in the hundreds of milliseconds range, with both duration-based (absolute) and beat-based (relative) tasks; 13 patients with PD were assessed with their STN-DBS ‘on’, ‘off’, and then ‘on’ again. Paired parametric analyses revealed no statistically significant differences for any task according to DBS status. We demonstrate, from the examination of confidence intervals, that any functionally relevant effect of STN-DBS on relative perceptual timing is statistically unlikely. For absolute, duration-based timing, we demonstrate that the activation of STN-DBS may either worsen performance or have no effect, but that it is unlikely to lead to significant improvement. Although these results are negative they have important implications for our understanding of perceptual timing and its relationship to motor functions within the timing network of the brain. They imply that the mechanisms involved in the perceptual processing of temporal information are likely to be functionally independent from those that underpin movement. Further, they suggest that the connections between STN and the subtantia nigra and globus pallidus are unlikely to be critical to beat-based perceptual timing. PMID:24613477

  15. Effects of subthalamic deep brain stimulation on noun/verb generation and selection from competing alternatives in Parkinson's disease.

    PubMed

    Castner, J E; Chenery, H J; Silburn, P A; Coyne, T J; Sinclair, F; Smith, E R; Copland, D A

    2008-06-01

    Impaired generation of verbs relative to nouns has been reported in Parkinson's disease (PD) and has been associated with the frontal pathophysiology of PD. The aim of the present study was to measure noun/verb generation abilities in PD and to determine whether noun/verb generation is affected by stimulation of the subthalamic nucleus (STN). 8 participants who had been diagnosed with PD and had received surgery for deep brain stimulation (DBS) of the STN as well as 15 control participants completed a noun/verb generation task with four probe-response conditions-namely, noun-noun, verb-noun, noun-verb and verb-verb conditions. Patients with PD were assessed while receiving STN stimulation and without stimulation. During the off stimulation condition, patients with PD presented with a selective deficit in verb generation compared with control participants. However, when receiving STN stimulation, patients with PD produced significantly more errors than controls during the noun-noun and verb-verb conditions, supporting evidence from previous studies that STN stimulation modulates a frontotemporal network associated with word generation. Finally, errors during verb generation were significantly correlated with item selection constraint (ie, the degree to which a response competes with other response alternatives) in the on stimulation condition, but not the off stimulation condition. Our results suggest that STN stimulation affects the ability to select from many competing lexical alternatives during verb generation.

  16. Human Subthalamic Nucleus Theta and Beta Oscillations Entrain Neuronal Firing During Sensorimotor Conflict

    PubMed Central

    Zavala, Baltazar; Damera, Srikanth; Dong, Jian Wilson; Lungu, Codrin; Brown, Peter; Zaghloul, Kareem A.

    2017-01-01

    Recent evidence has suggested that prefrontal cortical structures may inhibit impulsive actions during conflict through activation of the subthalamic nucleus (STN). Consistent with this hypothesis, deep brain stimulation to the STN has been associated with altered prefrontal cortical activity and impaired response inhibition. The interactions between oscillatory activity in the STN and its presumably antikinetic neuronal spiking, however, remain poorly understood. Here, we simultaneously recorded intraoperative local field potential and spiking activity from the human STN as participants performed a sensorimotor action selection task involving conflict. We identified several STN neuronal response types that exhibited different temporal dynamics during the task. Some neurons showed early, cue-related firing rate increases that remained elevated longer during high conflict trials, whereas other neurons showed late, movement-related firing rate increases. Notably, the high conflict trials were associated with an entrainment of individual neurons by theta- and beta-band oscillations, both of which have been observed in cortical structures involved in response inhibition. Our data suggest that frequency-specific activity in the beta and theta bands influence STN firing to inhibit impulsivity during conflict. PMID:26494798

  17. Neuropsychology Review Submission

    PubMed Central

    Rossi, P. Justin; Okun, Michael S.

    2016-01-01

    It has been well documented that deep brain stimulation (DBS) of the subthalamic nucleus (STN) to address some of the disabling motor symptoms of Parkinson’s disease (PD) can evoke unintended effects, especially on non-motor behavior. This observation has catalyzed more than a decade of research concentrated on establishing trends and identifying potential mechanisms for these non-motor effects. While many issues remain unresolved, the collective result of many research studies and clinical observations has been a general recognition of the role of the STN in mediating limbic function. In particular, the STN has been implicated in impulse control and the related construct of valence processing. A better understanding of STN involvement in these phenomena could have important implications for treating impulse control disorders (ICDs). ICDs affect up to 40% of PD patients on dopamine agonist therapy and approximately 15% of PD patients overall. ICDs have been reported to be associated with STN DBS. In this paper we will focus on impulse control and review pre-clinical, clinical, behavioral, imaging, and electrophysiological studies pertaining to the limbic function of the STN. PMID:26577509

  18. Impact of Bilateral Subthalamic Stimulation on Motor/Cognitive Functions in Parkinson's Disease

    PubMed Central

    ASAHI, Takashi; NAKAMICHI, Naomi; TAKAIWA, Akiko; KASHIWAZAKI, Daina; KOH, Masaki; DOUGU, Nobuhiro; TAKASHIMA, Shutaro; TANAKA, Kortaro; KURODA, Satoshi

    2014-01-01

    It is still unclear whether deep brain stimulation targeted to the bilateral subthalamic nucleus (STN-DBS) affects cognitive function in Parkinson's disease (PD). This prospective study was aimed to systemically evaluate the impact of bilateral STN-DBS on motor and cognitive functions in patients with PD. This study included totally 11 Japanese patients with medically intolerant PD. Neurological and cognitive status was precisely evaluated before and 1 year after bilateral STN-DBS, using unified Parkinson's disease rating scale (UPDRS), levodopa equivalent doses, mini-mental state examination (MMSE), Japanese adult reading test (JART), repeatable battery for the assessment of neuropsychological status (RBANS), and Wechsler adult intelligence scale-revised (WAIS-R). Preoperative RBANS and WAIS-R identified cognitive dysfunction that could not be detected by MMSE and JART. Before surgery, PD patients had significantly impaired immediate memory and attention. Motor function significantly improved 1 year after bilateral STN-DBS. Bilateral STN-DBS did not affect any score on cognitive examinations. However, postoperative improvements of total score on RBANS and performance intelligence quotient (PIQ) scores on WAIS-R were closely related to those of UPDRS part III off (R2 = 0.61, P < 0.01; R2 = 0.39, P < 0.05, respectively). These findings strongly suggest that bilateral STN-DBS may significantly improve cognitive function in a certain subgroup of patients whose therapeutic effects on motor function are prominent. PMID:24872253

  19. Emerging Points of the Supraorbital and Supratrochlear Nerves in the Supraorbital Margin With Reference to the Lacrimal Caruncle: Implications for Regional Nerve Block in Upper Eyelid and Dermatologic Surgery.

    PubMed

    Shin, Kang-Jae; Shin, Hyun Jin; Lee, Shin-Hyo; Song, Wu-Chul; Koh, Ki-Seok; Gil, Young-Chun

    2016-08-01

    Blocking the supraorbital nerve (SON) and supratrochlear nerve (STN) by injecting anesthetic distal to the surgical site has the advantage in upper eyelid surgery that avoids obscuring the surgical landmarks and compromising the levator function. To identify the emerging points of the SON and STN in the supraorbital margin with reference to the lacrimal caruncle. Forty-nine orbits from 27 embalmed Korean cadavers were dissected. The lacrimal caruncle and facial midline were used as landmarks. The emerging points of the SON and STN in the supraorbital margin were determined. The emerging points of the SON and STN were, respectively, located at 3.0 mm lateral and 3.3 mm medial to the vertical line through the apex of the lacrimal caruncle along the supraorbital margin. The horizontal distances from the facial midline to the emerging points of the SON and STN were 22.8 and 15.2 mm, respectively. The optimum sites for achieving SON and STN block are, respectively, located approximately 3 mm lateral and 3 mm medial to the vertical line through the apex of lacrimal caruncle along the supraorbital margin. This knowledge will help the surgeon achieve an easy and accurate approach for regional nerve block.

  20. Cholesterol stimulates and ceramide inhibits Sticholysin II-induced pore formation in complex bilayer membranes.

    PubMed

    Alm, Ida; García-Linares, Sara; Gavilanes, José G; Martínez-Del-Pozo, Álvaro; Slotte, J Peter

    2015-04-01

    The pore forming capacity of Sticholysin II (StnII; isolated from Stichodactyla helianthus) in bilayer membranes containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), palmitoylsphingomyelin (PSM) and either cholesterol or palmitoyl ceramide (PCer) has been examined. The aim of the study was to elucidate how the presence of differently ordered PSM domains affected StnII oligomerization and pore formation. Cholesterol is known to enhance pore formation by StnII, and our results confirmed this and provide kinetic information for the process. The effect of cholesterol on bilayer permeabilization kinetics was concentration-dependent. In the concentration regime used (2.5-10nmol cholesterol in POPC:PSM 80:20 by nmol), cholesterol also increased the acyl chain order in the fluid PSM domain and thus decreased bilayer fluidity, suggesting that fluidity per se was not responsible for cholesterol's effect. Addition of PCer (2.5-10nmol) to the POPC:PSM (80:20 by nmol) bilayers attenuated StnII-induced pore formation, again in a concentration-dependent fashion. This addition also led to the formation of a PCer-rich gel phase. Addition of cholesterol to PCer-containing membranes could partially reduce the inhibitory effect of PCer on StnII pore formation. We conclude that the physical state of PSM (as influenced by either cholesterol or PCer) affected StnII binding and pore formation under the conditions examined.

  1. Frontosubthalamic Circuits for Control of Action and Cognition.

    PubMed

    Aron, Adam R; Herz, Damian M; Brown, Peter; Forstmann, Birte U; Zaghloul, Kareem

    2016-11-09

    The subthalamic nucleus (STN) of the basal ganglia appears to have a potent role in action and cognition. Anatomical and imaging studies show that different frontal cortical areas directly project to the STN via so-called hyperdirect pathways. This review reports some of the latest findings about such circuits, including simultaneous recordings from cortex and the STN in humans, single-unit recordings in humans, high-resolution fMRI, and neurocomputational modeling. We argue that a major function of the STN is to broadly pause behavior and cognition when stop signals, conflict signals, or surprise signals occur, and that the fronto-STN circuits for doing this, at least for stopping and conflict, are dissociable anatomically and in terms of their spectral reactivity. We also highlight recent evidence for synchronization of oscillations between prefrontal cortex and the STN, which may provide a preferential "window in time" for single neuron communication via long-range connections. Copyright © 2016 the authors 0270-6474/16/3611489-07$15.00/0.

  2. Subthalamic Nucleus Stimulation Modulates Thalamic Neuronal Activity

    PubMed Central

    Xu, Weidong; Russo, Gary S.; Hashimoto, Takao; Zhang, Jianyu; Vitek, Jerrold L.

    2009-01-01

    Deep brain stimulation (DBS) in the subthalamic nucleus (STN) is an effective tool for the treatment of advanced Parkinson’s disease. The mechanism by which STN DBS elicits its beneficial effect, however, remains unclear. We previously reported STN stimulation increased the rate and produced a more regular and periodic pattern of neuronal activity in the internal segment of the globus pallidus (GPi). Here we extend our observations to neurons in the pallidal (ventralis lateralis pars oralis (VLo) and ventralis anterior (VA)) and cerebellar (ventralis lateralis posterior pars oralis (VPLo)) receiving areas of the motor thalamus during STN DBS. Stimulation parameters that produced improvement in rigidity and bradykinesia resulted in changes in the pattern and power of oscillatory activity of neuronal activity that were similar in both regions of the motor thalamus. Neurons in both VA/VLo and VPLo tended to become more periodic and regular with a shift in oscillatory activity from low to high frequencies. Burst activity was reduced in VA/VLo, but was not significantly changed in VPLo. There was also a significant shift in the population of VA/VLo neurons that were inhibited during STN DBS, while VPLo neurons tended to be activated. These data are consistent with the hypothesis that STN DBS increases output from the nucleus and produces a change in the pattern and periodicity of neuronal activity in the basal ganglia thalamic network, and that these changes include cerebellar pathways likely via activation of adjacent cerebello-thalamic fiber bundles. PMID:19005057

  3. Long-Term Task- and Dopamine-Dependent Dynamics of Subthalamic Local Field Potentials in Parkinson’s Disease

    PubMed Central

    Hanrahan, Sara J.; Nedrud, Joshua J.; Davidson, Bradley S.; Farris, Sierra; Giroux, Monique; Haug, Aaron; Mahoor, Mohammad H.; Silverman, Anne K.; Zhang, Jun Jason; Hebb, Adam Olding

    2016-01-01

    Subthalamic nucleus (STN) local field potentials (LFP) are neural signals that have been shown to reveal motor and language behavior, as well as pathological parkinsonian states. We use a research-grade implantable neurostimulator (INS) with data collection capabilities to record STN-LFP outside the operating room to determine the reliability of the signals over time and assess their dynamics with respect to behavior and dopaminergic medication. Seven subjects were implanted with the recording augmented deep brain stimulation (DBS) system, and bilateral STN-LFP recordings were collected in the clinic over twelve months. Subjects were cued to perform voluntary motor and language behaviors in on and off medication states. The STN-LFP recorded with the INS demonstrated behavior-modulated desynchronization of beta frequency (13–30 Hz) and synchronization of low gamma frequency (35–70 Hz) oscillations. Dopaminergic medication did not diminish the relative beta frequency oscillatory desynchronization with movement. However, movement-related gamma frequency oscillatory synchronization was only observed in the medication on state. We observed significant inter-subject variability, but observed consistent STN-LFP activity across recording systems and over a one-year period for each subject. These findings demonstrate that an INS system can provide robust STN-LFP recordings in ambulatory patients, allowing for these signals to be recorded in settings that better represent natural environments in which patients are in a variety of medication states. PMID:27916831

  4. The effect of low frequency stimulation of the pedunculopontine tegmental nucleus on basal ganglia in a rat model of Parkinson's disease.

    PubMed

    Park, Eunkyoung; Song, Inho; Jang, Dong Pyo; Kim, In Young

    2014-08-08

    The pedunculopontine nucleus (PPN) has recently been introduced as an alternative target to the subthalamic nucleus (STN) or globus pallidus internus (GPi) for the treatment of advanced Parkinson's disease with severe and medically intractable axial symptoms such as gait and postural impairment. However, it is little known about how electrical stimulation of the PPN affects control of neuronal activities between the PPN and basal ganglia. We examined how low frequency stimulation of the pedunculopontine tegmental nucleus (PPTg) affects control of neuronal activities between the PPN and basal ganglia in 6-OHDA lesioned rats. In order to identify the effect of low frequency stimulation on the PPTg, neuronal activity in both the STN and substantia nigra par reticulata (SNr) were recorded and subjected to quantitative analysis, including analysis of firing rates and firing patterns. In this study, we found that the firing rates of the STN and SNr were suppressed during low frequency stimulation of the PPTg. However, the firing pattern, in contrast to the firing rate, did not exhibit significant changes in either the STN or SNr of 6-OHDA lesioned rats during low frequency stimulation of the PPTg. In addition, we also found that the firing rate of STN and SNr neurons displaying burst and random pattern were decreased by low frequency stimulation of PPTg, while the neurons displaying regular pattern were not affected. These results indicate that low frequency stimulation of the PPTg affects neuronal activity in both the STN and SNr, and may represent electrophysiological efficacy of low frequency PPN stimulation.

  5. Depression and intelligence in patients with Parkinson's disease and deep-brain stimulation.

    PubMed

    Schadt, Courtney R; Cox, Katie L; Tramontana, Michael G; Byrne, Daniel W; Davis, Thomas L; Fang, John Y; Konrad, Peter E; Padaliya, Bhavna; Mutter, Robert W; Gill, Chandler E; Richardson, Caralee R; Charles, P David

    2006-07-01

    The goal of this study is to examine the association of depression with intelligence and education in patients with Parkinson's disease treated with bilateral subthalamic nucleus stimulation (STN-DBS). The literature has been contradictory concerning depression in Parkinson's disease patients. Some studies have shown less depression in Parkinson's disease patients with more education not treated with STN-DBS. Other recently published studies indicate that STN-DBS improves the depression associated with Parkinson's disease. No studies have examined the correlation of these factors with depression in Parkinson's disease patients treated with STN-DBS. We administered the Beck Depression Inventory (BDI) pre- and postoperatively to 21 Parkinson's disease patients (seven women, 14 men, ages 49-75) who underwent STN-DBS. The postoperative scores of the lower 50th percentile (n=8) of the Verbal Comprehensive Index of the Wechsler Adult Intelligence Scale (WAIS-III) decreased significantly (P=0.036), while the upper 50th percentile (n=13) remained nearly constant (P=0.802). Furthermore, as the education increased from highschool to graduate level, patients demonstrated less improvement in depressive symptoms postoperatively. These findings suggest that Parkinson's disease patients with lower intelligence test scores and less education benefit more with regards to depressive symptomatology after STN-DBS than patients with higher scores and education.

  6. Subthalamic nucleus stimulation affects incentive salience attribution in Parkinson's disease.

    PubMed

    Serranová, Tereza; Jech, Robert; Dušek, Petr; Sieger, Tomáš; Růžička, Filip; Urgošík, Dušan; Růžička, Evžen

    2011-10-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can induce nonmotor side effects such as behavioral and mood disturbances or body weight gain in Parkinson's disease (PD) patients. We hypothesized that some of these problems could be related to an altered attribution of incentive salience (ie, emotional relevance) to rewarding and aversive stimuli. Twenty PD patients (all men; mean age ± SD, 58.3 ± 6 years) in bilateral STN DBS switched ON and OFF conditions and 18 matched controls rated pictures selected from the International Affective Picture System according to emotional valence (unpleasantness/pleasantness) and arousal on 2 independent visual scales ranging from 1 to 9. Eighty-four pictures depicting primary rewarding (erotica and food) and aversive fearful (victims and threat) and neutral stimuli were selected for this study. In the STN DBS ON condition, the PD patients attributed lower valence scores to the aversive pictures compared with the OFF condition (P < .01) and compared with controls (P < .01). The difference between the OFF condition and controls was less pronounced (P < .05). Furthermore, postoperative weight gain correlated with arousal ratings from the food pictures in the STN DBS ON condition (P < .05 compensated for OFF condition). Our results suggest that STN DBS increases activation of the aversive motivational system so that more relevance is attributed to aversive fearful stimuli. In addition, STN DBS-related sensitivity to food reward stimuli cues might drive DBS-treated patients to higher food intake and subsequent weight gain.

  7. Comparison of weight gain and energy intake after subthalamic versus pallidal stimulation in Parkinson's disease.

    PubMed

    Sauleau, Paul; Leray, Emmanuelle; Rouaud, Tiphaine; Drapier, Sophie; Drapier, Dominique; Blanchard, Sophie; Drillet, Gwenolla; Péron, Julie; Vérin, Marc

    2009-10-30

    To compare body mass index (BMI) and daily energy intake (DEI) after subthalamic versus pallidal deep brain stimulation (DBS). Weight gain following DBS in Parkinson's disease patients remains largely unexplained and no comparison of subthalamic and pallidal (GPi) stimulation has yet been performed. BMI and DEI, dopaminergic drug administration and motor scores were recorded in 46 patients with PD before STN (n = 32) or GPi (n = 14) DBS and 3 and 6 months after. At M6, BMI had increased by an average of 8.4% in the STN group and 3.2% in the GPi group. BMI increased in 28 STN and 9 GPi patients. This increase was significantly higher in the STN group (P < 0.048) and the difference remained significant after adjustment for reduced dopaminergic medication; 28.6% of GPi patients were overweight at 6 months (14.3% preoperatively) versus 37.5% of STN patients (21.9% preoperatively). Changes in BMI were negatively correlated with changes in dyskinesia in the GPi-DBS group. Food intake did not change in the two groups, either quantitatively or qualitatively. Frequent weight gain, inadequately explained by motor improvement or reduced dopaminergic drug dosage, occurred in subthalamic DBS patients. The difference between groups suggests additional factors in the STN group, such as homeostatic control center involvement.

  8. Increase in body weight is a non-motor side effect of deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

    PubMed

    Novakova, Lucie; Ruzicka, Evzen; Jech, Robert; Serranova, Tereza; Dusek, Petr; Urgosik, Dusan

    2007-02-01

    Deep brain stimulation of the subthalamic nucleus (DBS STN) is an effective treatment method in advanced Parkinson's disease (PD) providing marked improvement of its major motor symptoms. In addition, non-motor effects have been reported including weight gain in PD patients after DBS STN. Using retrospective survey, we aimed to evaluate weight changes in our patients with advanced PD treated with DBS STN. We inquired 25 PD patients (16 men, 9 women), of mean age 55 (42-65) years, mean PD duration 15 (9-21) years, who previously received bilateral DBS STN. We obtained valid data from 23 patients. In the first survey, 1 to 45 months after DBS, weight gain was found in all patients comparing to pre-DBS period. The mean increase was 9.4 kg (from 1 to 25 kg). The patients' mean body mass index (BMI) increased from 23.7 to 27.0 kg/m2, i.e. by 3.3 kg/m2 (+2 to +6.1 kg/m2). In the repeated survey one year later, in 12 of the patients body weight moderately decreased, 3 did not change, and 6 patients further increased their weight. Possible explanations of body weight gain after DBS STN include a reduction of energy output related to elimination of dyskinesias, improved alimentation or direct influence on function of lateral hypothalamus by DBS STN.

  9. Deep brain stimulation of the pedunculopontine tegmental nucleus modulates neuronal hyperactivity and enhanced beta oscillatory activity of the subthalamic nucleus in the rat 6-hydroxydopamine model.

    PubMed

    Alam, Mesbah; Heissler, Hans E; Schwabe, Kerstin; Krauss, Joachim K

    2012-01-01

    Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) area has been introduced as a novel surgical therapy for dopamine refractory gait problems, freezing and postural instability in the late stage of Parkinson's disease (PD). Lesions of the pedunculopontine tegmental (PPTg) nucleus, the equivalent of the PPN in rodents, were shown to reduce the elevated discharge rate of the subthalamic nucleus (STN) in the 6-hydroxydopamine (6-OHDA) rat model of PD. In order to further elucidate the modulatory effect of the PPTg on the STN we examined the effect of 25 Hz low frequency PPTg stimulation on neuronal single unit activity and oscillatory local field potentials (LFPs) of the STN, and on the electrocorticogram (ECoG) of the primary motor cortex region in rats with unilateral 6-OHDA induced nigrostriatal lesions. Stimulation of the PPTg reduced the enhanced firing rate in the STN, without affecting the firing pattern or approximate entropy (ApEn). It also reduced the activity in the beta band (15-30 Hz) of the STN, which is elevated in 6-OHDA lesioned rats, without affecting beta activity in the motor cortex. We showed a modulatory effect of PPTg stimulation on altered neuronal STN activity in the PD 6-OHDA rat model, indicating that PPTg DBS may alter activity of the basal ganglia circuitry at least partially. It remains unclear, however, how these changes are exactly mediated and whether they are relevant with regard to the descending PPTg projections in the lower brainstem.

  10. Different cerebral cortical areas influence the effect of subthalamic nucleus stimulation on parkinsonian motor deficits and freezing of gait.

    PubMed

    Lyoo, Chul Hyoung; Aalto, Sargo; Rinne, Juha O; Lee, Ki Ook; Oh, Seung Hun; Chang, Jin Woo; Lee, Myung Sik

    2007-11-15

    Inconsistent response in freezing of gait (FOG) with levodopa treatment or STN DBS makes the pathogenesis difficult to understand. We studied brain areas associated with the expression of STN DBS effect on parkinsonian motor deficits and FOG. Ten Parkinson's disease patients with typical FOG were included. One month before STN DBS, we performed [(18)F]-deoxyglucose PET scans and measured the UPDRS motor and modified FOG (mFOG) scores during levodopa off and on periods. At two months after STN DBS, same rating scores were measured. The percentage improvement of mFOG and UPDRS motor scores by STN DBS during levodopa off period was calculated. We searched for brain areas in which glucose metabolism correlated with the improvement of mFOG and UPDRS motor scores by DBS. During levodopa off period, STN DBS improved the UPDRS motor scores by 32.3% and the mFOG scores by 56.6%. There was no correlation between the improvements of both scores. The improvement of UPDRS motor score by DBS correlated with the metabolic activities of rostral supplementary motor area (Brodmann's area 8; BA8), anterior cingulate cortex (BA32), and prefrontal cortex (BA9). On the other hand, there was a positive correlation between the improvement of mFOG score by DBS and the metabolic activity of the parietal, occipital, and temporal sensory association cortices. In conclusion, dysfunction of different cerebral cortical areas limits the beneficial effects of DBS on parkinsonian motor deficits and FOG.

  11. Expression of sialyl-Tn in gastric cancer: correlation with known prognostic factors.

    PubMed Central

    Miles, D. W.; Linehan, J.; Smith, P.; Filipe, I.

    1995-01-01

    Sialyl-Tn (STn) is a core region carcinoma-associated carbohydrate determinant expressed on cancer-associated mucins. Expression of STn has been associated with poor prognosis in colon and ovarian cancer, independent of other prognostic factors such as tumour grade, stage or histological type. Recent studies have suggested that STn expression may be an independent prognostic variable in gastric cancer. We have examined 158 patients with gastric cancer using the antibody B72.3 (Biomira, Edmonton, Alberta, Canada). Of these, 110 patients (70%) expressed STn. Expression of STn did not correlate with tumour differentiation or the Ming classification, but expression was noted more frequently in the relatively good prognosis intestinal type of tumours (chi 2 = 6.9, P = 0.03). Conversely, early-stage cancers showed a significantly lower frequency of expression than more advanced cases (chi 2 = 13.75, P = 0.003). In this patient group, STn expression did not influence survival, and in multivariate regression analysis only tumour stage and Lauren classification were found to be independent prognostic variables. Images Figure 1 Figure 2 Figure 3 PMID:7734303

  12. Successful Management of Hemorrhage-Associated Hemiballism After Subthalamic Nucleus Deep Brain Stimulation with Pallidal Stimulation: a Case Report.

    PubMed

    Pabaney, Aqueel; Ali, Rushna; Lewitt, Peter A; Sidiropoulos, Christos; Schwalb, Jason M

    2015-10-01

    Deep brain stimulation has been widely used for treating several movement disorders including idiopathic Parkinson disease (IPD). The development of hemiballism after an iatrogenic injury to the subthalamic nucleus (STN) such as postoperative hemorrhage or stroke is rare. Employing pallidal DBS to manage hemiballism arising as a result of STN injury is a unique application of this therapeutic modality, which has only been reported twice in the literature. We present a case of a 54-year-old male with levodopa-responsive IPD who underwent STN electrode placement for deep brain stimulation. The immediate postoperative course was uneventful, but the patient suffered a fall 12 weeks after electrode implantation, leading to electrode displacement and subsequent STN hemorrhage, which led to hemiballism. The hemiballism was then subsequently treated with pallidal DBS after medical management was unsuccessful. In our case pallidal DBS was effective in treating hemiballism that arose as a result of traumatic displacement of STN DBS electrodes. Medical management and changes in stimulation parameters failed to produce any significant change in the hemiballism. This report is only the third of its kind in the literature wherein hemiballism arising as a result of STN damage after DBS was successfully treated with pallidal stimulation. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Physical activity in advanced Parkinson's disease: impact of subthalamic deep brain stimulation.

    PubMed

    Daneault, Jean-François; Sadikot, Abbas F; Barbat-Artigas, Sébastien; Aubertin-Leheudre, Mylène; Jodoin, Nicolas; Panisset, Michel; Duval, Christian

    2015-01-01

    Maintaining a physically active lifestyle promotes general health. Recent studies have demonstrated that patients with Parkinson's disease (PD) fail to meet the suggested levels of physical activity and that targeted interventions do not always improve this behavior. One validated treatment for motor symptoms in PD is subthalamic stimulation (STN DBS). Assess whether motor symptom improvement following STN DBS translated into increased physical activity behavior. Twenty patients with PD scheduled for bilateral STN DBS filled-out the Phone-FITT physical activity questionnaire and the SF-36 quality of life questionnaire prior to surgery and 6 to 9 months postoperatively. Data were compared to age- and gender-matched healthy controls. Our results demonstrate that PD patients' quality of life is significantly lower than healthy controls. While STN DBS improves motor symptoms in the intermediate term, it only improves some aspects of quality of life related to physical function. Furthermore, STN DBS does not modify physical activity behavior measured by the Phone-FITT, whether for household or recreational activities. The current study demonstrates that the motor improvements observed after STN DBS do not lead to systematic improvements in all aspects of quality of life or increased levels of physical activity. This highlights the need to develop and implement intervention strategies to promote an active lifestyle in this population, even if clinical improvement is evident following surgery.

  14. Fear recognition is impaired by subthalamic nucleus stimulation in Parkinson's disease.

    PubMed

    Biseul, Isabelle; Sauleau, Paul; Haegelen, Claire; Trebon, Pascale; Drapier, Dominique; Raoul, Sylvie; Drapier, Sophie; Lallement, François; Rivier, Isabelle; Lajat, Youenn; Verin, Marc

    2005-01-01

    Behavioural disturbances such as disorders of mood, apathy or indifference are often observed in Parkinson's disease (PD) patients with chronic high frequency deep brain stimulation of subthalamic nucleus (STN DBS). Neuropsychological modifications causing these adverse events induced by STN DBS remain unknown, even if limbic disturbances are hypothesised. The limbic system supports neural circuits processing emotional information. The aim of this work is to evaluate changes of emotional recognition in PD patients induced by STN DBS. Thirty PD patients were assessed using a computerised paradigm of recognition of emotional facial expressions [Ekman, P., & Friesen, W. V. (1976). Pictures of facial affect. Palo Alto, CA: Consulting Psychologists Press], 15 before STN DBS and 15 after. The two patients groups were compared to a group of 15 healthy control subjects. One series of 55 pictures of emotional facial expressions was presented to each patient. Patients had to classify the pictures according to seven basic emotions (happiness, sadness, fear, surprise, disgust, anger and no emotion). The intact ability to percept faces was firstly assured using the Benton Recognition Test. Recognition of fear expressions was significantly and selectively reduced in the post-operative group in comparison to both pre-operative and control groups. Our results demonstrate for the first time a selective reduction of recognition of facial expressions of fear by STN DBS. This impairment could be the first neuropsychological marker of a more general limbic dysfunction, thought to be responsible for the behavioural disorders reported after STN DBS.

  15. Effects of deep brain stimulation on vocal fold immobility in Parkinson's disease

    PubMed Central

    Arocho-Quinones, Elsa V.; Hammer, Michael J.; Bock, Jonathan M.; Pahapill, Peter A.

    2017-01-01

    Background: Vocal fold (VF) immobility is a rare, potentially fatal complication of advanced Parkinson's disease (PD). Previous reports suggest that subthalamic nucleus deep brain stimulation (STN-DBS) may influence laryngeal function, yet the role of STN-DBS on VF immobility remains unexplored. Case Description: We report a case of a patient with advanced PD and bilateral VF immobility ultimately requiring a tracheostomy. To assess the effects of STN-DBS on vocal cord function and to correlate these effects with peripheral motor symptoms at different stimulation settings, the patient was evaluated before and after initiation of bilateral STN-DBS. Measures included direct observation of VF mobility via transnasal laryngoscopy, levodopa equivalent dose of anti-PD medication, and motor scores. High frequency (150 Hz) STN-DBS resulted in improved motor scores, reduced medication requirement, and modestly improved right VF abduction although insufficient for safe decannulation. Low frequency (60 Hz) stimulation resulted in lower motor scores, but without worsening VF abduction. Conclusions: STN-DBS may play an important role in the neuromodulation of PD-induced laryngeal dysfunction, including VF mobility. Characterization of these axial symptoms is important when programming and evaluating responsiveness to DBS. PMID:28303202

  16. Interactions between the breast cancer-associated MUC1 mucins and C-type lectin characterized by optical tweezers.

    PubMed

    Hadjialirezaei, Soosan; Picco, Gianfranco; Beatson, Richard; Burchell, Joy; Stokke, Bjørn Torger; Sletmoen, Marit

    2017-01-01

    Carbohydrate-protein interactions govern many crucial processes in biological systems including cell recognition events. We have used the sensitive force probe optical tweezers to quantify the interactions occurring between MGL lectins and MUC1 carrying the cancer-associated glycan antigens mucins Tn and STn. Unbinding forces of 7.6 pN and 7.1 pN were determined for the MUC1(Tn)-MGL and MUC1(STn)-MGL interactions, at a force loading rate of ~40 pN/s. The interaction strength increased with increasing force loading rate, to 27 and 37 pN at a force loading rate of ~ 310 pN/s. No interactions were detected between MGL and MUC1(ST), a glycoform of MUC1 also expressed by breast carcinoma cells. Interestingly, this glycan (ST) can be found on proteins expressed by normal cells, although in this case not on MUC1. Additionally, GalNAc decorated polyethylene glycol displayed similar rupture forces as observed for MUC1(Tn) and MUC1(STn) when forced to unbind from MGL, indicating that GalNAc is an essential group in these interactions. Since the STn glycan decoration is more frequently found on the surface of carcinomas than the Tn glycan, the binding of MUC1 carrying STn to MGL may be more physiologically relevant and may be in part responsible for some of the characteristics of STn expressing tumours.

  17. Foxa1 is essential for development and functional integrity of the subthalamic nucleus

    PubMed Central

    Gasser, Emanuel; Johannssen, Helge C.; Rülicke, Thomas; Zeilhofer, Hanns Ulrich; Stoffel, Markus

    2016-01-01

    Inactivation of transcription factor Foxa1 in mice results in neonatal mortality of unknown cause. Here, we report that ablation of Foxa1 causes impaired development and loss of the subthalamic nucleus (STN). Functional deficits in the STN have been implicated in the etiology of Huntington’s and Parkinson’s disease. We show that neuronal ablation by Synapsin1-Cre-mediated Foxa1 deletion is sufficient to induce hyperlocomotion in mice. Transcriptome profiling of STN neurons in conditional Foxa1 knockout mice revealed changes in gene expression reminiscent of those in neurodegenerative diseases. We identified Ppargc1a, a transcriptional co-activator that is implicated in neurodegeneration, as a Foxa1 target. These findings were substantiated by the observation of Foxa1-dependent demise of STN neurons in conditional models of Foxa1 mutant mice. Finally, we show that the spontaneous firing activity of Foxa1-deficient STN neurons is profoundly impaired. Our data reveal so far elusive roles of Foxa1 in the development and maintenance of STN function. PMID:27934886

  18. The Striatum and Subthalamic Nucleus as Independent and Collaborative Structures in Motor Control

    PubMed Central

    Tewari, Alia; Jog, Rachna; Jog, Mandar S.

    2016-01-01

    The striatum and the subthalamic nucleus (STN) are two separate input structures into the basal ganglia (BG). Accordingly, research to date has primarily focused on the distinct roles of these structures in motor control and cognition, often through investigation of Parkinson’s disease (PD). Both structures are divided into sensorimotor, associative, and limbic subdivisions based on cortical connectivity. The more recent discovery of the STN as an input structure into the BG drives comparison of these two structures and their respective roles in cognition and motor control. This review compares the role of the striatum and STN in motor response inhibition and execution, competing motor programs, feedback based learning, and response planning. Through comparison, it is found that the striatum and STN have highly independent roles in motor control but also collaborate in order to execute desired actions. There is also the possibility that inhibition or activation of one of these structures indirectly contributes to the function of other connected anatomical structures. Both structures contribute to selective motor response inhibition, which forms the basis of many tasks, but the STN additionally contributes to global inhibition through the hyperdirect pathway. Research is warranted on the functional connectivity of the network for inhibition involving the rIFG, preSMA, striatum, and STN. PMID:26973474

  19. Visualizing the mobility and distribution of chlorophyll proteins in higher plant thylakoid membranes: effects of photoinhibition and protein phosphorylation.

    PubMed

    Goral, Tomasz K; Johnson, Matthew P; Brain, Anthony P R; Kirchhoff, Helmut; Ruban, Alexander V; Mullineaux, Conrad W

    2010-06-01

    The diffusion of proteins in chloroplast thylakoid membranes is believed to be important for processes including the photosystem-II repair cycle and the regulation of light harvesting. However, to date there is very little direct information on the mobility of thylakoid proteins. We have used fluorescence recovery after photobleaching in a laser-scanning confocal microscope to visualize in real time the exchange of chlorophyll proteins between grana in intact spinach (Spinacia oleracea L.) and Arabidopsis chloroplasts. Most chlorophyll proteins in the grana appear immobile on the 10-min timescale of our measurements. However, a limited population of chlorophyll proteins (accounting for around 15% of chlorophyll fluorescence) can exchange between grana on this timescale. In intact, wild-type chloroplasts this mobile population increases significantly after photoinhibition, consistent with a role for protein diffusion in the photosystem-II repair cycle. No such increase in mobility is seen in isolated grana membranes, or in the Arabidopsis stn8 and stn7 stn8 mutants, which lack the protein kinases required for phosphorylation of photosystem II core proteins and light-harvesting complexes. Furthermore, mobility under low-light conditions is significantly lower in stn8 and stn7 stn8 plants than in wild-type Arabidopsis. The changes in protein mobility correlate with changes in the packing density and size of thylakoid protein complexes, as observed by freeze-fracture electron microscopy. We conclude that protein phosphorylation switches the membrane system to a more fluid state, thus facilitating the photosystem-II repair cycle.

  20. Nigrostriatal denervation changes the effect of cannabinoids on subthalamic neuronal activity in rats.

    PubMed

    Morera-Herreras, Teresa; Ruiz-Ortega, José Angel; Linazasoro, Gurutz; Ugedo, Luisa

    2011-03-01

    It is known that dopaminergic cell loss leads to increased endogenous cannabinoid levels and CB1 receptor density. The aim of this study was to evaluate the influence of dopaminergic cell loss, induced by injection of 6-hydroxydopamine, on the effects exerted by cannabinoid agonists on neuron activity in the subthalamic nucleus (STN) of anesthetized rats. We have previously shown that Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and anandamide induce both stimulation and inhibition of STN neuron activity and that endocannabinoids mediate tonic control of STN activity. Here, we show that in intact rats, the cannabinoid agonist WIN 55,212-2 stimulated all recorded STN neurons. Conversely, after dopaminergic depletion, WIN 55,212-2, Δ(9)-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed. Moreover, anandamide exerted a more intense inhibitory effect in lesioned rats in comparison to control rats. Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway. These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits.

  1. The effects of high frequency subthalamic stimulation on balance performance and fear of falling in patients with Parkinson's disease.

    PubMed

    Nilsson, Maria H; Fransson, Per-Anders; Jarnlo, Gun-Britt; Magnusson, Måns; Rehncrona, Stig

    2009-04-30

    Balance impairment is one of the most distressing symptoms in Parkinson's disease (PD) even with pharmacological treatment (levodopa). A complementary treatment is high frequency stimulation in the subthalamic nucleus (STN). Whether STN stimulation improves postural control is under debate. The aim of this study was to explore the effects of STN stimulation alone on balance performance as assessed with clinical performance tests, subjective ratings of fear of falling and posturography. Ten patients (median age 66, range 59-69 years) with bilateral STN stimulation for a minimum of one year, had their anti-PD medications withdrawn overnight. Assessments were done both with the STN stimulation turned OFF and ON (start randomized). In both test conditions, the following were assessed: motor symptoms (descriptive purposes), clinical performance tests, fear of falling ratings, and posturography with and without vibratory proprioceptive disturbance. STN stimulation alone significantly (p = 0.002) increased the scores of the Berg balance scale, and the median increase was 6 points. The results of all timed performance tests, except for sharpened Romberg, were significantly (p STN stimulation was turned ON, but three patients were unable to do so when it was turned OFF. The seven patients with complete data showed no statistical significant difference (p values >or= 0.109) in torque variance values when comparing the two test situations. This applied both during quiet stance and during the periods with vibratory stimulation, and it was irrespective of visual input and sway direction. In this sample, STN stimulation alone significantly improved the results of the clinical performance tests that mimic activities in daily living. This improvement was

  2. Effects of subthalamic stimulation on speech of consecutive patients with Parkinson disease

    PubMed Central

    Zrinzo, L.; Martinez-Torres, I.; Frost, E.; Pinto, S.; Foltynie, T.; Holl, E.; Petersen, E.; Roughton, M.; Hariz, M.I.; Limousin, P.

    2011-01-01

    Objective: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson disease (PD). Following STN-DBS, speech intelligibility can deteriorate, limiting its beneficial effect. Here we prospectively examined the short- and long-term speech response to STN-DBS in a consecutive series of patients to identify clinical and surgical factors associated with speech change. Methods: Thirty-two consecutive patients were assessed before surgery, then 1 month, 6 months, and 1 year after STN-DBS in 4 conditions on- and off-medication with on- and off-stimulation using established and validated speech and movement scales. Fifteen of these patients were followed up for 3 years. A control group of 12 patients with PD were followed up for 1 year. Results: Within the surgical group, speech intelligibility significantly deteriorated by an average of 14.2% ± 20.15% off-medication and 16.9% ± 21.8% on-medication 1 year after STN-DBS. The medical group deteriorated by 3.6% ± 5.5% and 4.5% ± 8.8%, respectively. Seven patients showed speech amelioration after surgery. Loudness increased significantly in all tasks with stimulation. A less severe preoperative on-medication motor score was associated with a more favorable speech response to STN-DBS after 1 year. Medially located electrodes on the left STN were associated with a significantly higher risk of speech deterioration than electrodes within the nucleus. There was a strong relationship between high voltage in the left electrode and poor speech outcome at 1 year. Conclusion: The effect of STN-DBS on speech is variable and multifactorial, with most patients exhibiting decline of speech intelligibility. Both medical and surgical issues contribute to deterioration of speech in STN-DBS patients. Classification of evidence: This study provides Class III evidence that STN-DBS for PD results in deterioration in speech intelligibility in all combinations of medication and stimulation states at 1

  3. Late Consequential Surgical Bed Soft Tissue Necrosis in Advanced Oropharyngeal Squamous Cell Carcinomas Treated With Transoral Robotic Surgery and Postoperative Radiation Therapy

    SciTech Connect

    Lukens, J. Nicholas; Lin, Alexander; Gamerman, Victoria; Mitra, Nandita; Grover, Surbhi; McMenamin, Erin M.; Weinstein, Gregory S.; O'Malley, Bert W.; Cohen, Roger B.; Orisamolu, Abimbola; Ahn, Peter H.; Quon, Harry

    2014-08-01

    Purpose: A subset of patients with oropharyngeal squamous cell carcinoma (OP-SCC) managed with transoral robotic surgery (TORS) and postoperative radiation therapy (PORT) developed soft tissue necrosis (STN) in the surgical bed months after completion of PORT. We investigated the frequency and risk factors. Materials and Methods: This retrospective analysis included 170 consecutive OP-SCC patients treated with TORS and PORT between 2006 and 2012, with >6 months' of follow-up. STN was defined as ulceration of the surgical bed >6 weeks after completion of PORT, requiring opioids, biopsy, or hyperbaric oxygen therapy. Results: A total of 47 of 170 patients (28%) had a diagnosis of STN. Tonsillar patients were more susceptible than base-of-tongue (BOT) patients, 39% (41 of 104) versus 9% (6 of 66), respectively. For patients with STN, median tumor size was 3.0 cm (range 1.0-5.6 cm), and depth of resection was 2.2 cm (range 1.0-5.1 cm). Median radiation dose and dose of fraction to the surgical bed were 6600 cGy and 220 cGy, respectively. Thirty-one patients (66%) received concurrent chemotherapy. Median time to STN was 2.5 months after PORT. All patients had resolution of STN after a median of 3.7 months. Multivariate analysis identified tonsillar primary (odds ratio [OR] 4.73, P=.01), depth of resection (OR 3.12, P=.001), total radiation dose to the resection bed (OR 1.51 per Gy, P<.01), and grade 3 acute mucositis (OR 3.47, P=.02) as risk factors for STN. Beginning May 2011, after implementing aggressive avoidance of delivering >2 Gy/day to the resection bed mucosa, only 8% (2 of 26 patients) experienced STN (all grade 2). Conclusions: A subset of OP-SCC patients treated with TORS and PORT are at risk for developing late consequential surgical bed STN. Risk factors include tonsillar location, depth of resection, radiation dose to the surgical bed, and severe mucositis. STN risk is significantly decreased with carefully avoiding a radiation dosage of >2 Gy/day to the

  4. Late consequential surgical bed soft tissue necrosis in advanced oropharyngeal squamous cell carcinomas treated with transoral robotic surgery and postoperative radiation therapy.

    PubMed

    Lukens, J Nicholas; Lin, Alexander; Gamerman, Victoria; Mitra, Nandita; Grover, Surbhi; McMenamin, Erin M; Weinstein, Gregory S; O'Malley, Bert W; Cohen, Roger B; Orisamolu, Abimbola; Ahn, Peter H; Quon, Harry

    2014-08-01

    A subset of patients with oropharyngeal squamous cell carcinoma (OP-SCC) managed with transoral robotic surgery (TORS) and postoperative radiation therapy (PORT) developed soft tissue necrosis (STN) in the surgical bed months after completion of PORT. We investigated the frequency and risk factors. This retrospective analysis included 170 consecutive OP-SCC patients treated with TORS and PORT between 2006 and 2012, with >6 months' of follow-up. STN was defined as ulceration of the surgical bed >6 weeks after completion of PORT, requiring opioids, biopsy, or hyperbaric oxygen therapy. A total of 47 of 170 patients (28%) had a diagnosis of STN. Tonsillar patients were more susceptible than base-of-tongue (BOT) patients, 39% (41 of 104) versus 9% (6 of 66), respectively. For patients with STN, median tumor size was 3.0 cm (range 1.0-5.6 cm), and depth of resection was 2.2 cm (range 1.0-5.1 cm). Median radiation dose and dose of fraction to the surgical bed were 6600 cGy and 220 cGy, respectively. Thirty-one patients (66%) received concurrent chemotherapy. Median time to STN was 2.5 months after PORT. All patients had resolution of STN after a median of 3.7 months. Multivariate analysis identified tonsillar primary (odds ratio [OR] 4.73, P=.01), depth of resection (OR 3.12, P=.001), total radiation dose to the resection bed (OR 1.51 per Gy, P<.01), and grade 3 acute mucositis (OR 3.47, P=.02) as risk factors for STN. Beginning May 2011, after implementing aggressive avoidance of delivering >2 Gy/day to the resection bed mucosa, only 8% (2 of 26 patients) experienced STN (all grade 2). A subset of OP-SCC patients treated with TORS and PORT are at risk for developing late consequential surgical bed STN. Risk factors include tonsillar location, depth of resection, radiation dose to the surgical bed, and severe mucositis. STN risk is significantly decreased with carefully avoiding a radiation dosage of >2 Gy/day to the surgical bed. Copyright © 2014 Elsevier Inc. All

  5. Effects of subthalamic stimulation on speech of consecutive patients with Parkinson disease.

    PubMed

    Tripoliti, E; Zrinzo, L; Martinez-Torres, I; Frost, E; Pinto, S; Foltynie, T; Holl, E; Petersen, E; Roughton, M; Hariz, M I; Limousin, P

    2011-01-04

    Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson disease (PD). Following STN-DBS, speech intelligibility can deteriorate, limiting its beneficial effect. Here we prospectively examined the short- and long-term speech response to STN-DBS in a consecutive series of patients to identify clinical and surgical factors associated with speech change. Thirty-two consecutive patients were assessed before surgery, then 1 month, 6 months, and 1 year after STN-DBS in 4 conditions on- and off-medication with on- and off-stimulation using established and validated speech and movement scales. Fifteen of these patients were followed up for 3 years. A control group of 12 patients with PD were followed up for 1 year. Within the surgical group, speech intelligibility significantly deteriorated by an average of 14.2%±20.15% off-medication and 16.9%±21.8% on-medication 1 year after STN-DBS. The medical group deteriorated by 3.6%±5.5% and 4.5%±8.8%, respectively. Seven patients showed speech amelioration after surgery. Loudness increased significantly in all tasks with stimulation. A less severe preoperative on-medication motor score was associated with a more favorable speech response to STN-DBS after 1 year. Medially located electrodes on the left STN were associated with a significantly higher risk of speech deterioration than electrodes within the nucleus. There was a strong relationship between high voltage in the left electrode and poor speech outcome at 1 year. The effect of STN-DBS on speech is variable and multifactorial, with most patients exhibiting decline of speech intelligibility. Both medical and surgical issues contribute to deterioration of speech in STN-DBS patients. This study provides Class III evidence that STN-DBS for PD results in deterioration in speech intelligibility in all combinations of medication and stimulation states at 1 month, 6 months, and 1 year compared to baseline and to control subjects

  6. L-DOPA-induced dyskinesia in adult rats with a unilateral 6-OHDA lesion of dopamine neurons is paralleled by increased c-fos gene expression in the subthalamic nucleus.

    PubMed

    Soghomonian, Jean-Jacques

    2006-05-01

    Levodopa (L-DOPA), the metabolic precursor of dopamine, is widely used as a pharmacological agent for the symptomatic treatment of Parkinson's disease. However, long-term L-DOPA use results in abnormal involuntary movements such as dyskinesias. There is evidence that abnormal cell signaling in the basal ganglia is involved in L-DOPA-induced dyskinesia. The subthalamic nucleus (STN) plays a key role in the circuitry of the basal ganglia and in the pathophysiology of Parkinson's disease. However, the contribution of the STN to L-DOPA-induced dyskinesias remains unclear. The objective of this work was to study the effects of acute or chronic systemic administration of L-DOPA to adult rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of dopamine neurons on c-fos expression in the STN and test the hypothesis that these effects correlate with L-DOPA-induced dyskinesias. c-fos mRNA expression was measured in the STN by in situ hybridization histochemistry at the single cell level. Our results confirm earlier evidence that the chronic administration of L-DOPA to rats with a unilateral 6-OHDA lesion increases c-fos expression in the STN. We also report that c-fos expression can be increased following an acute injection of L-DOPA to 6-OHDA-lesioned rats but not following a chronic injection of L-DOPA to sham-operated, unlesioned rats. Finally, we provide evidence that the occurrence and severity of dyskinesia is correlated with c-fos mRNA levels in the ipsilateral STN. These results suggest that altered cell signaling in the STN is involved in some of the behavioral effects induced by systemic L-DOPA administration.

  7. Timing and direction selectivity of subthalamic and pallidal neurons in patients with Parkinson disease.

    PubMed

    Williams, Ziv M; Neimat, Joseph S; Cosgrove, G Rees; Eskandar, Emad N

    2005-05-01

    Current models of basal ganglia function suggest that some manifestations of Parkinson disease (PD) arise from abnormal activity and decreased selectivity of neurons in the subthalamic nucleus (STN) and globus pallidus internus (Gpi). Our goal was to examine the timing and direction selectivity of neuronal activity relative to visually guided movements in the STN and Gpi of patients with PD. Recordings were made from 152 neurons in the STN and 33 neurons in the Gpi of awake subjects undergoing surgery for PD. Corresponding EMG data were obtained for half the cells. We employed a structured behavioral task in which the subjects used a joystick to guide a cursor to one of four targets displayed on a monitor. Each direction was tested over multiple trials. Movement-related modulation of STN activity began on average 264+/-10 ms before movement initiation and 92+/-13 ms before initial EMG activity, while modulation of Gpi activity began 204+/-21 ms before overt movement initiation. In the STN, 40% of cells demonstrated perimovement activity, and of these 64% were directionally selective. In Gpi, 45% of cells showed perimovement activity of which 80% were selective. In both nuclei, directionally selective cells had significantly lower baseline firing rates than nonselective cells (41+/-5 vs 59+/-4 spikes/s in STN, and 50+/-9 vs 74+/-15 spikes/s in Gpi). These results suggest that STN activity occurs earlier than previously reported, and that higher neuronal firing rates maybe associated with decreased direction selectivity in PD patients.

  8. Effects of Subthalamic Nucleus Lesions and Stimulation upon Corticostriatal Afferents in the 6-Hydroxydopamine-Lesioned Rat

    PubMed Central

    Walker, Ruth H.; Moore, Cindy; Davies, Georgia; Dirling, Lisa B.; Koch, Rick J.; Meshul, Charles K.

    2012-01-01

    Abnormalities of striatal glutamate neurotransmission may play a role in the pathophysiology of Parkinson's disease and may respond to neurosurgical interventions, specifically stimulation or lesioning of the subthalamic nucleus (STN). The major glutamatergic afferent pathways to the striatum are from the cortex and thalamus, and are thus likely to be sources of striatal neuronally-released glutamate. Corticostriatal terminals can be distinguished within the striatum at the electron microscopic level as their synaptic vesicles contain the vesicular glutamate transporter, VGLUT1. The majority of terminals which are immunolabeled for glutamate but are not VGLUT1 positive are likely to be thalamostriatal afferents. We compared the effects of short term, high frequency, STN stimulation and lesioning in 6-hydroxydopamine (6OHDA)-lesioned rats upon striatal terminals immunolabeled for both presynaptic glutamate and VGLUT1. 6OHDA lesions resulted in a small but significant increase in the proportions of VGLUT1-labeled terminals making synapses on dendritic shafts rather than spines. STN stimulation for one hour, but not STN lesions, increased the proportion of synapses upon spines. The density of presynaptic glutamate immuno-gold labeling was unchanged in both VGLUT1-labeled and -unlabeled terminals in 6OHDA-lesioned rats compared to controls. Rats with 6OHDA lesions+STN stimulation showed a decrease in nerve terminal glutamate immuno-gold labeling in both VGLUT1-labeled and -unlabeled terminals. STN lesions resulted in a significant decrease in the density of presynaptic immuno-gold-labeled glutamate only in VGLUT1-labeled terminals. STN interventions may achieve at least part of their therapeutic effect in PD by normalizing the location of corticostriatal glutamatergic terminals and by altering striatal glutamatergic neurotransmission. PMID:22427909

  9. Quantitative analysis of axonal fiber activation evoked by deep brain stimulation via activation density heat maps

    PubMed Central

    Hartmann, Christian J.; Chaturvedi, Ashutosh; Lujan, J. Luis

    2015-01-01

    Background: Cortical modulation is likely to be involved in the various therapeutic effects of deep brain stimulation (DBS). However, it is currently difficult to predict the changes of cortical modulation during clinical adjustment of DBS. Therefore, we present a novel quantitative approach to estimate anatomical regions of DBS-evoked cortical modulation. Methods: Four different models of the subthalamic nucleus (STN) DBS were created to represent variable electrode placements (model I: dorsal border of the posterolateral STN; model II: central posterolateral STN; model III: central anteromedial STN; model IV: dorsal border of the anteromedial STN). Axonal fibers of passage near each electrode location were reconstructed using probabilistic tractography and modeled using multi-compartment cable models. Stimulation-evoked activation of local axon fibers and corresponding cortical projections were modeled and quantified. Results: Stimulation at the border of the STN (models I and IV) led to a higher degree of fiber activation and associated cortical modulation than stimulation deeply inside the STN (models II and III). A posterolateral target (models I and II) was highly connected to cortical areas representing motor function. Additionally, model I was also associated with strong activation of fibers projecting to the cerebellum. Finally, models III and IV showed a dorsoventral difference of preferentially targeted prefrontal areas (models III: middle frontal gyrus; model IV: inferior frontal gyrus). Discussion: The method described herein allows characterization of cortical modulation across different electrode placements and stimulation parameters. Furthermore, knowledge of anatomical distribution of stimulation-evoked activation targeting cortical regions may help predict efficacy and potential side effects, and therefore can be used to improve the therapeutic effectiveness of individual adjustments in DBS patients. PMID:25713510

  10. A novel lead design enables selective deep brain stimulation of neural populations in the subthalamic region

    NASA Astrophysics Data System (ADS)

    van Dijk, Kees J.; Verhagen, Rens; Chaturvedi, Ashutosh; McIntyre, Cameron C.; Bour, Lo J.; Heida, Ciska; Veltink, Peter H.

    2015-08-01

    Objective. The clinical effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) as a treatment for Parkinson’s disease are sensitive to the location of the DBS lead within the STN. New high density (HD) lead designs have been created which are hypothesized to provide additional degrees of freedom in shaping the stimulating electric field. The objective of this study is to compare the performances of a new HD lead with a conventional cylindrical contact (CC) lead. Approach. A computational model, consisting of a finite element electric field model combined with multi-compartment neuron and axon models representing different neural populations in the subthalamic region, was used to evaluate the two leads. We compared ring-mode and steering-mode stimulation with the HD lead to single contact stimulation with the CC lead. These stimulation modes were tested for the lead: (1) positioned in the centroid of the STN, (2) shifted 1 mm towards the internal capsule (IC), and (3) shifted 2 mm towards the IC. Under these conditions, we quantified the number of STN neurons that were activated without activating IC fibers, which are known to cause side-effects. Main results. The modeling results show that the HD lead is able to mimic the stimulation effect of the CC lead. Additionally, in steering-mode stimulation there was a significant increase of activated STN neurons compared to the CC mode. Significance. From the model simulations we conclude that the HD lead in steering-mode with optimized stimulation parameter selection can stimulate more STN cells. Next, the clinical impact of the increased number of activated STN cells should be tested and balanced across the increased complexity of identifying the optimized stimulation parameter settings for the HD lead.

  11. Different patterns of medication change after subthalamic or pallidal stimulation for Parkinson's disease: target related effect or selection bias?

    PubMed Central

    Minguez-Castellan..., A; Escamilla-Sevilla, F; Katati, M; Martin-Linares, J; Meersmans, M; Ortega-Moreno, A; Arjona, V

    2005-01-01

    Background: Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is favoured over bilateral globus pallidus internus (Gpi) DBS for symptomatic treatment of advanced Parkinson's disease (PD) due to the possibility of reducing medication, despite lack of definitive comparative evidence. Objective: To analyse outcomes after one year of bilateral Gpi or STN DBS, with consideration of influence of selection bias on the pattern of postsurgical medication change. Methods: The first patients to undergo bilateral Gpi (n = 10) or STN (n = 10) DBS at our centre were studied. They were assessed presurgically and one year after surgery (CAPIT protocol). Results: Before surgery the Gpi DBS group had more dyskinesias and received lower doses of medication. At one year, mean reduction in UPDRS off medication score was 35% and 39% in the Gpi and STN groups, respectively (non-significant difference). Dyskinesias reduced in proportion to presurgical severity. The levodopa equivalent dose was significantly reduced only in the STN group (24%). This study high-lights the absence of significant differences between the groups in clinical scales and medication dose at one year. In the multivariate analysis of predictive factors for off-state motor improvement, the presurgical levodopa equivalent dose showed a direct relation in the STN and an inverse relation in the Gpi group. Conclusion: Differences in the patterns of medication change after Gpi and STN DBS may be partly due to a patient selection bias. Both procedures may be equally useful for different subgroups of patients with advanced PD, Gpi DBS especially for patients with lower threshold for dyskinesia. PMID:15607992

  12. Expectation modulates the effect of deep brain stimulation on motor and cognitive function in tremor-dominant Parkinson's disease.

    PubMed

    Keitel, Ariane; Ferrea, Stefano; Südmeyer, Martin; Schnitzler, Alfons; Wojtecki, Lars

    2013-01-01

    Expectation contributes to placebo and nocebo responses in Parkinson's disease (PD). While there is evidence for expectation-induced modulations of bradykinesia, little is known about the impact of expectation on resting tremor. Subthalamic nucleus (STN) deep brain stimulation (DBS) improves cardinal PD motor symptoms including tremor whereas impairment of verbal fluency (VF) has been observed as a potential side-effect. Here we investigated how expectation modulates the effect of STN-DBS on resting tremor and its interaction with VF. In a within-subject-design, expectation of 24 tremor-dominant PD patients regarding the impact of STN-DBS on motor symptoms was manipulated by verbal suggestions (positive [placebo], negative [nocebo], neutral [control]). Patients participated with (MedON) and without (MedOFF) antiparkinsonian medication. Resting tremor was recorded by accelerometry and bradykinesia of finger tapping and diadochokinesia were assessed by a 3D ultrasound motion detection system. VF was quantified by lexical and semantic tests. In a subgroup of patients, the effect of STN-DBS on tremor was modulated by expectation, i.e. tremor decreased (placebo response) or increased (nocebo response) by at least 10% as compared to the control condition while no significant effect was observed for the overall group. Interestingly, nocebo responders in MedON were additionally characterized by significant impairment in semantic verbal fluency. In contrast, bradykinesia was not affected by expectation. These results indicate that the therapeutic effect of STN-DBS on tremor can be modulated by expectation in a subgroup of patients and suggests that tremor is also among the parkinsonian symptoms responsive to placebo and nocebo interventions. While positive expectations enhanced the effect of STN-DBS by further decreasing the magnitude of tremor, negative expectations counteracted the therapeutic effect and at the same time exacerbated a side-effect often associated with STN

  13. A cross validation study of deep brain stimulation targeting: from experts to atlas-based, segmentation-based and automatic registration algorithms.

    PubMed

    Castro, F Javier Sanchez; Pollo, Claudio; Meuli, Reto; Maeder, Philippe; Cuisenaire, Olivier; Cuadra, Meritxell Bach; Villemure, Jean-Guy; Thiran, Jean-Philippe

    2006-11-01

    Validation of image registration algorithms is a difficult task and open-ended problem, usually application-dependent. In this paper, we focus on deep brain stimulation (DBS) targeting for the treatment of movement disorders like Parkinson's disease and essential tremor. DBS involves implantation of an electrode deep inside the brain to electrically stimulate specific areas shutting down the disease's symptoms. The subthalamic nucleus (STN) has turned out to be the optimal target for this kind of surgery. Unfortunately, the STN is in general not clearly distinguishable in common medical imaging modalities. Usual techniques to infer its location are the use of anatomical atlases and visible surrounding landmarks. Surgeons have to adjust the electrode intraoperatively using electrophysiological recordings and macrostimulation tests. We constructed a ground truth derived from specific patients whose STNs are clearly visible on magnetic resonance (MR) T2-weighted images. A patient is chosen as atlas both for the right and left sides. Then, by registering each patient with the atlas using different methods, several estimations of the STN location are obtained. Two studies are driven using our proposed validation scheme. First, a comparison between different atlas-based and nonrigid registration algorithms with a evaluation of their performance and usability to locate the STN automatically. Second, a study of which visible surrounding structures influence the STN location. The two studies are cross validated between them and against expert's variability. Using this scheme, we evaluated the expert's ability against the estimation error provided by the tested algorithms and we demonstrated that automatic STN targeting is possible and as accurate as the expert-driven techniques currently used. We also show which structures have to be taken into account to accurately estimate the STN location.

  14. GABAA-receptor activation in the subthalamic nucleus compensates behavioral asymmetries in the hemiparkinsonian rat.

    PubMed

    Petri, David; Pum, Martin; Vesper, Jan; Huston, Joseph P; Schnitzler, Alfons

    2013-09-01

    The subthalamic nucleus (STN) has a pivotal role in the pathophysiology of Parkinson's disease (PD). Modulation of STN activity (by lesions, pharmacological or electrical stimulation) has been shown to improve motor parameters in PD patients and in animal models of PD. In an attempt to characterize the neurochemical bases for such antiparkinsonian action, we address specific neurotransmitter systems via local pharmacological manipulation of the STN in hemiparkinsonian rats. Here, we have focused on the GABAergic and glutamatergic receptors in the STN. In animals with unilateral 6-hydroxydopamine lesions of the nigro-striatal tract, we administered either the selective GABAA-agonist muscimol (0.5 μg and 1.0 μg), the non-competitive N-methyl-d-aspartate (NMDA)-antagonist MK-801 (dizocilpine; 2.5 μg), or vehicle (0.25 μl) into the STN. The effects of GABAergic and glutamatergic modulation of the STN on motor parameters were assessed by gauging rotational behavior and locomotion. Application of muscimol ipsilateral to the side of dopamine-depletion influenced turning behavior in a dose-dependent fashion, with the low dose re-adjusting turning behavior to a non-biased distribution, and the high dose evoking contraversive turning. The administration of MK-801 did not have such effects. These findings give evidence for the involvement of GABAergic activation in the STN in the compensation of motor asymmetries in the hemiparkinsonian rat, whereas N-methyl-d-aspartate (NMDA)-antagonism was ineffective in this model of PD.

  15. The prefrontal cortex achieves inhibitory control by facilitating subcortical motor pathway connectivity.

    PubMed

    Rae, Charlotte L; Hughes, Laura E; Anderson, Michael C; Rowe, James B

    2015-01-14

    Communication between the prefrontal cortex and subcortical nuclei underpins the control and inhibition of behavior. However, the interactions in such pathways remain controversial. Using a stop-signal response inhibition task and functional imaging with analysis of effective connectivity, we show that the lateral prefrontal cortex influences the strength of communication between regions in the frontostriatal motor system. We compared 20 generative models that represented alternative interactions between the inferior frontal gyrus, presupplementary motor area (preSMA), subthalamic nucleus (STN), and primary motor cortex during response inhibition. Bayesian model selection revealed that during successful response inhibition, the inferior frontal gyrus modulates an excitatory influence of the preSMA on the STN, thereby amplifying the downstream polysynaptic inhibition from the STN to the motor cortex. Critically, the strength of the interaction between preSMA and STN, and the degree of modulation by the inferior frontal gyrus, predicted individual differences in participants' stopping performance (stop-signal reaction time). We then used diffusion-weighted imaging with tractography to assess white matter structure in the pathways connecting these three regions. The mean diffusivity in tracts between preSMA and the STN, and between the inferior frontal gyrus and STN, also predicted individual differences in stopping efficiency. Finally, we found that white matter structure in the tract between preSMA and STN correlated with effective connectivity of the same pathway, providing important cross-modal validation of the effective connectivity measures. Together, the results demonstrate the network dynamics and modulatory role of the prefrontal cortex that underpin individual differences in inhibitory control.

  16. A novel lead design enables selective deep brain stimulation of neural populations in the subthalamic region.

    PubMed

    van Dijk, Kees J; Verhagen, Rens; Chaturvedi, Ashutosh; McIntyre, Cameron C; Bour, Lo J; Heida, Ciska; Veltink, Peter H

    2015-08-01

    The clinical effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) as a treatment for Parkinson's disease are sensitive to the location of the DBS lead within the STN. New high density (HD) lead designs have been created which are hypothesized to provide additional degrees of freedom in shaping the stimulating electric field. The objective of this study is to compare the performances of a new HD lead with a conventional cylindrical contact (CC) lead. A computational model, consisting of a finite element electric field model combined with multi-compartment neuron and axon models representing different neural populations in the subthalamic region, was used to evaluate the two leads. We compared ring-mode and steering-mode stimulation with the HD lead to single contact stimulation with the CC lead. These stimulation modes were tested for the lead: (1) positioned in the centroid of the STN, (2) shifted 1 mm towards the internal capsule (IC), and (3) shifted 2 mm towards the IC. Under these conditions, we quantified the number of STN neurons that were activated without activating IC fibers, which are known to cause side-effects. The modeling results show that the HD lead is able to mimic the stimulation effect of the CC lead. Additionally, in steering-mode stimulation there was a significant increase of activated STN neurons compared to the CC mode. From the model simulations we conclude that the HD lead in steering-mode with optimized stimulation parameter selection can stimulate more STN cells. Next, the clinical impact of the increased number of activated STN cells should be tested and balanced across the increased complexity of identifying the optimized stimulation parameter settings for the HD lead.

  17. No Effect of Subthalamic Deep Brain Stimulation on Intertemporal Decision-Making in Parkinson Patients123

    PubMed Central

    Wojtecki, Lars; Storzer, Lena; Schnitzler, Alfons

    2016-01-01

    Abstract Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used treatment for the motor symptoms of Parkinson’s disease (PD). DBS or pharmacological treatment is believed to modulate the tendency to, or reverse, impulse control disorders. Several brain areas involved in impulsivity and reward valuation, such as the prefrontal cortex and striatum, are linked to the STN, and activity in these areas might be affected by STN-DBS. To investigate the effect of STN-DBS on one type of impulsive decision-making—delay discounting (i.e., the devaluation of reward with increasing delay until its receipt)—we tested 40 human PD patients receiving STN-DBS treatment and medication for at least 3 months. Patients were pseudo-randomly assigned to one of four groups to test the effects of DBS on/off states as well as medication on/off states on delay discounting. The delay-discounting task consisted of a series of choices among a smaller. sooner or a larger, later monetary reward. Despite considerable effects of DBS on motor performance, patients receiving STN-DBS did not choose more or less impulsively compared with those in the off-DBS group, as well as when controlling for risk attitude. Although null results have to be interpreted with caution, our findings are of significance to other researchers studying the effects of PD treatment on impulsive decision-making, and they are of clinical relevance for determining the therapeutic benefits of using STN-DBS. PMID:27257622

  18. Subthalamic nucleus activity in the awake hemiparkinsonian rat: relationships with motor and cognitive networks.

    PubMed

    Delaville, Claire; McCoy, Alex J; Gerber, Colin M; Cruz, Ana V; Walters, Judith R

    2015-04-29

    Oscillatory activity in both beta and gamma ranges has been recorded in the subthalamic nucleus (STN) of Parkinson's disease (PD) patients and linked to motor function, with beta activity considered antikinetic, and gamma activity, prokinetic. However, the extent to which nonmotor networks contribute to this activity is unclear. This study uses hemiparkinsonian rats performing a treadmill walking task to compare synchronized STN local field potential (LFP) activity with activity in motor cortex (MCx) and medial prefrontal cortex (mPFC), areas involved in motor and cognitive processes, respectively. Data show increases in STN and MCx 29-36 Hz LFP spectral power and coherence after dopamine depletion, which are reduced by apomorphine and levodopa treatments. In contrast, recordings from mPFC 3 weeks after dopamine depletion failed to show peaks in 29-36 Hz LFP power. However, mPFC and STN both showed peaks in the 45-55 Hz frequency range in LFP power and coherence during walking before and 21 days after dopamine depletion. Interestingly, power in this low gamma range was transiently reduced in both mPFC and STN after dopamine depletion but recovered by day 21. In contrast to the 45-55 Hz activity, the amplitude of the exaggerated 29-36 Hz rhythm in the STN was modulated by paw movement. Furthermore, as in PD patients, after dopamine treatment a third band (high gamma) emerged in the lesioned hemisphere. The results suggest that STN integrates activity from both motor and cognitive networks in a manner that varies with frequency, behavioral state, and the integrity of the dopamine system.

  19. Decisions Made with Less Evidence Involve Higher Levels of Corticosubthalamic Nucleus Theta Band Synchrony

    PubMed Central

    Zavala, Baltazar; Tan, Huiling; Little, Simon; Ashkan, Keyoumars; Green, Alexander L.; Aziz, Tipu; Foltynie, Thomas; Zrinzo, Ludvic; Zaghloul, Kareem; Brown, Peter

    2016-01-01

    The switch between automatic action selection and more controlled forms of decision-making is a dynamic process thought to involve both cortical and subcortical structures. During sensory conflict, medial pFC oscillations in the theta band (<8 Hz) drive those of the subthalamic nucleus (STN), and this is thought to increase the threshold of evidence needed for one competing response to be selected over another. Here, we were interested in testing whether STN activity is also altered by the rate at which evidence is presented during a congruent dot motion task absent of any explicit sensory conflict. By having a series of randomly moving dots gradually transform to congruent motion at three different rates (slow, medium, fast), we were able to show that a slower rate increased the time it took participants to make a response but did not alter the total amount of evidence that was integrated before the response. Notably, this resulted in a decision being made with a lower amount of instantaneous evidence during the slow and medium trials. Consistent with the idea that medial pFC–STN activity is involved in executing cognitive control, the higher levels of ambiguity during these trials were associated with increased theta band synchrony between the cortex and the STN, with the cortical oscillations Granger-causal to those of the STN. These results further confirm the involvement of the STN in decision-making and suggest that the disruption of this network may underlie some of the unwanted cognitive deficits associated with STN deep brain stimulation. PMID:26845109

  20. The Prefrontal Cortex Achieves Inhibitory Control by Facilitating Subcortical Motor Pathway Connectivity

    PubMed Central

    Hughes, Laura E.; Anderson, Michael C.; Rowe, James B.

    2015-01-01

    Communication between the prefrontal cortex and subcortical nuclei underpins the control and inhibition of behavior. However, the interactions in such pathways remain controversial. Using a stop-signal response inhibition task and functional imaging with analysis of effective connectivity, we show that the lateral prefrontal cortex influences the strength of communication between regions in the frontostriatal motor system. We compared 20 generative models that represented alternative interactions between the inferior frontal gyrus, presupplementary motor area (preSMA), subthalamic nucleus (STN), and primary motor cortex during response inhibition. Bayesian model selection revealed that during successful response inhibition, the inferior frontal gyrus modulates an excitatory influence of the preSMA on the STN, thereby amplifying the downstream polysynaptic inhibition from the STN to the motor cortex. Critically, the strength of the interaction between preSMA and STN, and the degree of modulation by the inferior frontal gyrus, predicted individual differences in participants' stopping performance (stop-signal reaction time). We then used diffusion-weighted imaging with tractography to assess white matter structure in the pathways connecting these three regions. The mean diffusivity in tracts between preSMA and the STN, and between the inferior frontal gyrus and STN, also predicted individual differences in stopping efficiency. Finally, we found that white matter structure in the tract between preSMA and STN correlated with effective connectivity of the same pathway, providing important cross-modal validation of the effective connectivity measures. Together, the results demonstrate the network dynamics and modulatory role of the prefrontal cortex that underpin individual differences in inhibitory control. PMID:25589771

  1. Neuronal activity in the medial associative-limbic and lateral motor part of the rat subthalamic nucleus and the effect of 6-hydroxydopamine-induced lesions of the dorsolateral striatum.

    PubMed

    Lindemann, Christoph; Alam, Mesbah; Krauss, Joachim K; Schwabe, Kerstin

    2013-10-01

    Lesions of the rat nigrostriatal dopamine system by injection of 6-hydroxydopamine (6-OHDA) lead to abnormal neuronal activity in the basal ganglia (BG) motor loop similar to that found in Parkinson's disease (PD). In the BG motor loop the subthalamic nucleus (STN) represents an important structure, which, however, also comprises areas of the BG associative and limbic loops. We were interested whether neuronal activity would differ between the STN medial associative-limbic and lateral motor part, and whether selective 6-OHDA-induced lesions of the dorsolateral striatum, the entrance region of the BG motor loop, would differently affect these subregions. In male Sprague-Dawley rats 6-OHDA (n = 12) or vehicle (n = 10) was bilaterally injected in the dorsolateral striatum. Four weeks later extracellular single-unit activity and local field potentials were recorded in medial and lateral STN neurons of urethane-anesthetized rats. In sham-lesioned rats the discharge rate and burst activity were higher in the lateral compared to the medial STN. Similar differences were found for other neuronal activity measures (coefficient of variation of interspike interval, skewness, kurtosis, approximate entropy). After 6-OHDA injection neuronal burst activity was enhanced, while the discharge rate was not affected. In addition, in 6-OHDA-lesioned rats β-band oscillatory activity was enhanced, with no difference between STN subregions. We found important differences of neuronal activity between STN subregions, indicating functional segregation. However, selective 6-OHDA lesions of the dorsolateral striatum also had a pronounced effect on the medial STN subregion, indicating interaction between BG loops. © 2013 Wiley Periodicals, Inc.

  2. Human Subthalamic Nucleus in Movement Error Detection and Its Evaluation during Visuomotor Adaptation

    PubMed Central

    Zavala, Baltazar; Pogosyan, Alek; Ashkan, Keyoumars; Zrinzo, Ludvic; Foltynie, Thomas; Limousin, Patricia; Brown, Peter

    2014-01-01

    Monitoring and evaluating movement errors to guide subsequent movements is a critical feature of normal motor control. Previously, we showed that the postmovement increase in electroencephalographic (EEG) beta power over the sensorimotor cortex reflects neural processes that evaluate motor errors consistent with Bayesian inference (Tan et al., 2014). Whether such neural processes are limited to this cortical region or involve the basal ganglia is unclear. Here, we recorded EEG over the cortex and local field potential (LFP) activity in the subthalamic nucleus (STN) from electrodes implanted in patients with Parkinson's disease, while they moved a joystick-controlled cursor to visual targets displayed on a computer screen. After movement offsets, we found increased beta activity in both local STN LFP and sensorimotor cortical EEG and in the coupling between the two, which was affected by both error magnitude and its contextual saliency. The postmovement increase in the coupling between STN and cortex was dominated by information flow from sensorimotor cortex to STN. However, an information drive appeared from STN to sensorimotor cortex in the first phase of the adaptation, when a constant rotation was applied between joystick inputs and cursor outputs. The strength of the STN to cortex drive correlated with the degree of adaption achieved across subjects. These results suggest that oscillatory activity in the beta band may dynamically couple the sensorimotor cortex and basal ganglia after movements. In particular, beta activity driven from the STN to cortex indicates task-relevant movement errors, information that may be important in modifying subsequent motor responses. PMID:25505327

  3. Differential Effect of Bilayer Thickness on Sticholysin Activity.

    PubMed

    Palacios-Ortega, Juan; García-Linares, Sara; Rivera-de-Torre, Esperanza; Gavilanes, José G; Martínez-Del-Pozo, Álvaro; Slotte, J Peter

    2017-10-04

    In this study, we examined the influence of bilayer thickness on the activity of the actinoporin toxins sticholysin I and II (StnI and StnII) at 25 °C. Bilayer thickness was varied using dimonounsaturated phosphatidylcholine (PC) analogues (with 14:1, 16:1, 18:1, 20:1, and 22:1 acyl chains). In addition, N-14:0-sphingomyelin (SM) was always included because StnI and StnII are SM specific. Cholesterol was also incorporated as indicated. In cholesterol-free large unilamellar vesicles (LUVs) the PC:SM molar ratio was 4:1, and when cholesterol was included, the complete molar ratio was 4:1:0.5 (PC:SM:cholesterol, respectively). Stn toxins promote bilayer leakage through pores formed by oligomerized toxin monomers. Initial calcein leakage was moderately dependent on bilayer PC acyl chain length (and thus bilayer thickness), with higher rates observed with di-16:1 and di-18:1 PC bilayers. In the presence of cholesterol, the maximum rates of calcein leakage were observed in di-14:1 and di-16:1 PC bilayers. Using isothermal titration calorimetry to study the Stn-LUV interaction, we observed that the bilayer affinity constant (Ka) peaked with LUVs containing di-18:1 PC, and was lower in shorter and longer PC acyl chain bilayers. The presence of cholesterol increased the binding affinity approximately 30-fold at the optimal bilayer thickness (di-18:1-PC). We conclude that bilayer thickness affects both functional and conformational aspects of Stn membrane binding and pore formation. Moreover, the length of the actinoporins' N-terminal α-helix, which penetrates the membrane to form a functional pore, appears to be optimal for the membrane thickness represented by di-18:1 PC.

  4. The organization of prefrontal-subthalamic inputs in primates provides an anatomical substrate for both functional specificity and integration: implications for basal ganglia models and deep brain stimulation

    PubMed Central

    Haynes, William I. A.; Haber, Suzanne N.

    2013-01-01

    The identification of a hyperdirect cortico-subthalamic nucleus connection highlighted the important role of the subthalamic nucleus (STN) in regulating behavior. However, this pathway was shown primarily from motor areas. Hyperdirect pathways associated with cognitive and motivational cortical regions are particularly relevant given recent data from deep brain stimulation, both for neurological and psychiatric disorders. Our experiments were designed to: demonstrate the existence and organization of prefrontal-STN projections, help delineate the ‘limbic’ STN, and determine whether convergence between cortico-STN fibers from functionally diverse cortical areas exists in the STN. We injected anterograde tracers in the ventromedial prefrontal, orbitofrontal, anterior cingulate and dorsal prefrontal cortices of Macaca nemestrina & M. fascicularis to analyze the organization of terminals and passing fibers in the STN. Results show a topographically organized prefrontal hyperdirect pathway in primates. Limbic areas project to the medial tip of the nucleus, straddling its border and extending into the lateral hypothalamus. Associative areas project to the medial half, motor areas to the lateral half. Limbic projections terminated primarily rostrally and motor projections more caudally. The extension of limbic projections into the lateral hypothalamus, suggests that this region be included in the STN. A high degree of convergence exists between projections from functionally diverse cortical areas, creating potentially important interfaces between terminal fields. Taken together, the results provide an anatomical substrate to extend the role of the hyperdirect pathway in models of basal ganglia function, and new keys for understanding deep brain stimulation effects on cognitive and motivational aspects of behavior. PMID:23486951

  5. Cholinergic and non-cholinergic mesopontine tegmental neurons projecting to the subthalamic nucleus in the rat

    PubMed Central

    Kita, Takako; Kita, Hitoshi

    2010-01-01

    The subthalamic nucleus (STN) receives cholinergic and non-cholinergic projections from the mesopontine tegmentum. This study investigated the numbers and distributions of neurons involved in these projections in rats using Fluorogold (FG) retrograde tracing combined with immunostaining of choline acetyltransferase and a neuron-specific nuclear protein. The results suggest that a small population of cholinergic neurons mainly in the caudoventral part of the pedunculopontine tegmental nucleus (PPN), approximately 360 neurons (≈10% of total) in the homolateral and 80 neurons (≈2%) in the contralateral PPN, projects to the STN. In contrast, the number of non-cholinergic neurons projecting to the STN was estimated to be 9 times as much, with approximately 3300 in the homolateral side and 1300 neurons in the contralateral side. A large gathering of the FG-labeled non-cholinergic neurons was found rostrodorsomedial to the caudolateral PPN. The biotinylated dextran amine (BDA) anterograde tracing method was used to substantiate the mesopontine-STN projections. Injection of BDA into the caudoventral PPN labeled numerous thin fibers with small en-passant varicosities in the STN. Injection of BDA into the non-cholinergic neuron-rich area labeled a moderate number of thicker fibers with patches of aggregates of larger boutons. The densities of labeled fibers and the number of retrogradely labeled cells in the mesopontine tegmentum suggested that the terminal field formed in the STN by each cholinergic neuron is more extensive than that by each non-cholinergic neuron. The findings suggest that cholinergic and non-cholinergic mesopontine afferents may carry different information to the STN. PMID:21198985

  6. Connectivity of the subthalamic nucleus and globus pallidus pars interna to regions within the speech network: a meta-analytic connectivity study.

    PubMed

    Manes, Jordan L; Parkinson, Amy L; Larson, Charles R; Greenlee, Jeremy D; Eickhoff, Simon B; Corcos, Daniel M; Robin, Donald A

    2014-07-01

    Cortico-basal ganglia connections are involved in a range of behaviors within motor, cognitive, and emotional domains; however, the whole-brain functional connections of individual nuclei are poorly understood in humans. The first aim of this study was to characterize and compare the connectivity of the subthalamic nucleus (STN) and globus pallidus pars interna (GPi) using meta-analytic connectivity modeling. Structure-based activation likelihood estimation meta-analyses were performed for STN and GPi seeds using archived functional imaging coordinates from the BrainMap database. Both regions coactivated with caudate, putamen, thalamus, STN, GPi, and GPe, SMA, IFG, and insula. Contrast analyses also revealed coactivation differences within SMA, IFG, insula, and premotor cortex. The second aim of this study was to examine the degree of overlap between the connectivity maps derived for STN and GPi and a functional activation map representing the speech network. To do this, we examined the intersection of coactivation maps and their respective contrasts (STN > GPi and GPi > STN) with a coordinate-based meta-analysis of speech function. In conjunction with the speech map, both STN and GPi coactivation maps revealed overlap in the anterior insula with GPi map additionally showing overlap in the supplementary motor area (SMA). Among cortical regions activated by speech tasks, STN was found to have stronger connectivity than GPi with regions involved in cognitive linguistic processes (pre-SMA, dorsal anterior insula, and inferior frontal gyrus), while GPi demonstrated stronger connectivity to regions involved in motor speech processes (middle insula, SMA, and premotor cortex).

  7. Improved Subthalamic Nucleus Depiction with Quantitative Susceptibility Mapping

    PubMed Central

    Liu, Tian; Eskreis-Winkler, Sarah; Schweitzer, Andrew D.; Chen, Weiwei; Kaplitt, Michael G.; Tsiouris, A. John

    2013-01-01

    Purpose: To assess quantitative susceptibility mapping (QSM) in the depiction of the subthalamic nucleus (STN) by using 3-T magnetic resonance (MR) imaging. Materials and Methods: This study was HIPAA compliant and institutional review board approved. Ten healthy subjects (five men, five women; mean age, 24 years ± 3 [standard deviation]; age range, 21–33 years) and eight patients with Parkinson disease (five men, three women; mean age, 57 years ± 14; age range, 25–69 years) who were referred by neurologists for preoperative navigation MR imaging prior to deep brain stimulator placement were included in this study. T2-weighted (T2w), T2*-weighted (T2*w), R2* mapping (R2*), phase, susceptibility-weighted (SW), and QSM images were reconstructed for STN depiction. Qualitative visualization scores of STN and internal globus pallidus (GPi) were recorded by two neuroradiologists on all images. Contrast-to-noise ratios (CNRs) of the STN and GPi were also measured. Measurement differences were assessed by using the Wilcoxon rank sum test and the signed rank test. Results: Qualitative scores were significantly higher on QSM images than on T2w, T2*w, R2*, phase, or SW images (P < .05) for STN and GPi visualization. Median CNR was 6.4 and 10.7 times higher on QSM images than on T2w images for differentiation of STN from the zona incerta and substantia nigra, respectively, and was 22.7 and 9.1 times higher on QSM images than on T2w images for differentiation of GPi from the internal capsule and external globus pallidus, respectively. CNR differences between QSM images and all other images were significant (P < .01). Conclusion: QSM at 3-T MR imaging performs significantly better than current standard-of-care sequences in the depiction of the STN. © RSNA, 2013 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13121991/-/DC1 PMID:23674786

  8. Modulation of motor cortex neuronal activity and motor behavior during subthalamic nucleus stimulation in the normal primate.

    PubMed

    Johnson, Luke A; Xu, Weidong; Baker, Kenneth B; Zhang, Jianyu; Vitek, Jerrold L

    2015-04-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established surgical therapy for advanced Parkinson's disease (PD). An emerging hypothesis is that the therapeutic benefit of DBS is derived from direct modulation of primary motor cortex (M1), yet little is known about the influence of STN DBS on individual neurons in M1. We investigated the effect of STN DBS, delivered at discrete interval intensities (20, 40, 60, 80, and 100%) of corticospinal tract threshold (CSTT), on motor performance and M1 neuronal activity in a naive nonhuman primate. Motor performance during a food reach and retrieval task improved during low-intensity stimulation (20% CSTT) but worsened as intensity approached the threshold for activation of corticospinal fibers (80% and 100% CSTT). To assess cortical effects of STN DBS, spontaneous, extracellular neuronal activity was collected from M1 neurons before, during, and after DBS at the same CSTT stimulus intensities. STN DBS significantly modulated the firing of a majority of M1 neurons; however, the direction of effect varied with stimulus intensity such that, at 20% CSTT, most neurons were suppressed, whereas at the highest stimulus intensities the majority of neurons were activated. At a population level, firing rates increased as stimulus intensity increased. These results show that STN DBS influences both motor performance and M1 neuronal activity systematically according to stimulus intensity. In addition, the unanticipated reduction in reach times suggests that STN DBS, at stimulus intensities lower than typically used for treatment of PD motor signs, can enhance normal motor performance.

  9. Deep brain stimulation improves movement amplitude but not hastening of repetitive finger movements.

    PubMed

    Stegemöller, Elizabeth L; Zadikoff, Cindy; Rosenow, Joshua M; Mackinnon, Colum D

    2013-09-27

    External pacing cues, dopaminergic medication, and bilateral subthalamic nucleus deep brain stimulation (STN-DBS) improve repetitive movements performed at low rates. When the pacing rate is increased to frequencies near 2 Hz and above, both external pacing cues and Parkinson's medication were shown to be ineffective at improving repetitive finger movement performance. It remains unclear if STN-DBS improves the performance of repetitive finger movements at high pacing rates. This study examined the effects of STN-DBS on the amplitude and rate of repetitive finger movement across a range of external pacing rates. Nine participants with STN-DBS (OFF and ON stimulation) and nine matched healthy adults performed repetitive index finger flexion movements paced by an acoustic tone that increased from 1.0 to 3.0 Hz. OFF stimulation, most subjects moved at rates that were substantially higher (hastening pattern) or lower (bradykinesia pattern) than the tone rate, particularly at high pacing rates. ON stimulation, movement rate improved in subjects with the bradykinesia pattern, but not in those with the hastening pattern. Overall, STN-DBS did not significantly affect movement rate. In contrast, STN-DBS significantly (p<0.05) improved movement amplitude across all pacing rates. These findings demonstrate that STN-DBS improves movement amplitude, but had no effect on the rate of movement in participants with a hastening pattern. Separately testing movement amplitude and movement rate using both high and low rate externally paced cues in the clinical environment may aid in the diagnosis and treatment of people with Parkinson's disease. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  10. Cognition and Depression Following Deep Brain Stimulation of the Subthalamic Nucleus and Globus Pallidus Pars Internus in Parkinson's Disease: A Meta-Analysis.

    PubMed

    Combs, Hannah L; Folley, Bradley S; Berry, David T R; Segerstrom, Suzanne C; Han, Dong Y; Anderson-Mooney, Amelia J; Walls, Brittany D; van Horne, Craig

    2015-12-01

    Parkinson's disease (PD) is a common, degenerative disorder of the central nervous system. Individuals experience predominantly extrapyramidal symptoms including resting tremor, rigidity, bradykinesia, gait abnormalities, cognitive impairment, depression, and neurobehavioral concerns. Cognitive impairments associated with PD are diverse, including difficulty with attention, processing speed, executive functioning, memory recall, visuospatial functions, word-retrieval, and naming. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) is FDA approved and has been shown to be effective in reducing motor symptoms of PD. Studies have found that stimulating STN and GPi are equally effective at improving motor symptoms and dyskinesias; however, there has been discrepancy as to whether the cognitive, behavioral, and mood symptoms are affected differently between the two targets. The present study used random-effects meta-analytic models along with a novel p-curve analytic procedure to compare the potential cognitive and emotional impairments associated with STN-DBS in the current literature to those associated with GPi-DBS. Forty-one articles were reviewed with an aggregated sample size of 1622 patients. Following STN-DBS, small declines were found in psychomotor speed, memory, attention, executive functions, and overall cognition; and moderate declines were found in both semantic and phonemic fluency. However, GPi-DBS resulted in fewer neurocognitive declines than STN-DBS (small declines in attention and small-moderate declines in verbal fluency). With regards to its effect on depression symptomatology, both GPi-DBS and STN-DBS resulted in lower levels of depressive symptoms post-surgery. From a neurocognitive standpoint, both GPi-DBS and STN-DBS produce subtle cognitive declines but appears to be relatively well tolerated.

  11. Characterization of Ca(2+) channels in rat subthalamic nucleus neurons.

    PubMed

    Song, W J; Baba, Y; Otsuka, T; Murakami, F

    2000-11-01

    The subthalamic nucleus (STN) plays a key role in motor control. Although previous studies have suggested that Ca(2+) conductances may be involved in regulating the activity of STN neurons, Ca(2+) channels in this region have not yet been characterized. We have therefore investigated the subtypes and functional characteristics of Ca(2+) conductances in STN neurons, in both acutely isolated and slice preparations. Acutely isolated STN cells were identified by retrograde filling with the fluorescent dye, Fluoro-Gold. In acutely isolated STN neurons, Cd(2+)-sensitive, depolarization-activated Ba(2+) currents were observed in all cells studied. The current-voltage relationship and current kinetics were characteristic of high-voltage-activated Ca(2+) channels. The steady-state voltage-dependent activation curves and inactivation curves could both be fitted with a single Boltzmann function. Currents evoked with a prolonged pulse, however, inactivated with multiple time constants, suggesting either the presence of more than one Ca(2+) channel subtype or multiple inactivation processes with a single channel type in STN neurons. Experiments using organic Ca(2+) channel blockers revealed that on average, 21% of the current was nifedipine sensitive, 52% was sensitive to omega-conotoxin GVIA, 16% was blocked by a high concentration of omega-agatoxin IVA (200 nM), and the remainder of the current (9%) was resistant to the co-application of all blockers. These currents had similar voltage dependencies, but the nifedipine-sensitive current and the resistant current activated at slightly lower voltages. omega-Agatoxin IVA at 20 nM was ineffective in blocking the current. Together, the above results suggest that acutely isolated STN neurons have all subtypes of high-voltage-activated Ca(2+) channels except for P-type, but have no low-voltage-activated channels. Although acutely isolated neurons provide a good preparation for whole cell voltage-clamp study, dendritic processes are

  12. High Frequency Stimulation of the Subthalamic Nucleus Leads to Presynaptic GABA(B)-Dependent Depression of Subthalamo-Nigral Afferents

    PubMed Central

    Dvorzhak, Anton; Gertler, Christoph; Harnack, Daniel; Grantyn, Rosemarie

    2013-01-01

    Patients with akinesia benefit from chronic high frequency stimulation (HFS) of the subthalamic nucleus (STN). Among the mechanisms contributing to the therapeutic success of HFS-STN might be a suppression of activity in the output region of the basal ganglia. Indeed, recordings in the substantia nigra pars reticulata (SNr) of fully adult mice revealed that HFS-STN consistently produced a reduction of compound glutamatergic excitatory postsynaptic currents at a time when the tetrodotoxin-sensitive components of the local field potentials had already recovered after the high frequency activation. These observations suggest that HFS-STN not only alters action potential conduction on the way towards the SNr but also modifies synaptic transmission within the SNr. A classical conditioning-test paradigm was then designed to better separate the causes from the indicators of synaptic depression. A bipolar platinum-iridium macroelectrode delivered conditioning HFS trains to a larger group of fibers in the STN, while a separate high-ohmic glass micropipette in the rostral SNr provided test stimuli at minimal intensity to single fibers. The conditioning-test interval was set to 100 ms, i.e. the time required to recover the excitability of subthalamo-nigral axons after HFS-STN. The continuity of STN axons passing from the conditioning to the test sites was examined by an action potential occlusion test. About two thirds of the subthalamo-nigral afferents were occlusion-negative, i.e. they were not among the fibers directly activated by the conditioning STN stimulation. Nonetheless, occlusion-negative afferents exhibited signs of presynaptic depression that could be eliminated by blocking GABA(B) receptors with CGP55845 (1 µM). Further analysis of single fiber-activated responses supported the proposal that the heterosynaptic depression of synaptic glutamate release during and after HFS-STN is mainly caused by the tonic release of GABA from co-activated striato

  13. Cortical Plasticity Induction by Pairing Subthalamic Nucleus Deep-Brain Stimulation and Primary Motor Cortical Transcranial Magnetic Stimulation in Parkinson's Disease.

    PubMed

    Udupa, Kaviraja; Bahl, Nina; Ni, Zhen; Gunraj, Carolyn; Mazzella, Filomena; Moro, Elena; Hodaie, Mojgan; Lozano, Andres M; Lang, Anthony E; Chen, Robert

    2016-01-13

    Noninvasive brain stimulation studies have shown abnormal motor cortical plasticity in Parkinson's disease (PD). These studies used peripheral nerve stimulation paired with transcranial magnetic stimulation (TMS) to primary motor cortex (M1) at specific intervals to induce plasticity. Induction of cortical plasticity through stimulation of the basal ganglia (BG)-M1 connections has not been studied. In the present study, we used a novel technique of plasticity induction by repeated pairing of deep-brain stimulation (DBS) of the BG with M1 stimulation using TMS. We hypothesize that repeated pairing of subthalamic nucleus (STN)-DBS and M1-TMS at specific time intervals will lead to plasticity in the M1. Ten PD human patients with STN-DBS were studied in the on-medication state with DBS set to 3 Hz. The interstimulus intervals (ISIs) between STN-DBS and TMS that produced cortical facilitation were determined individually for each patient. Three plasticity induction conditions with repeated pairings (180 times) at specific ISIs (∼ 3 and ∼ 23 ms) that produced cortical facilitation and a control ISI of 167 ms were tested in random order. Repeated pairing of STN-DBS and M1-TMS at short (∼ 3 ms) and medium (∼ 23 ms) latencies increased M1 excitability that lasted for at least 45 min, whereas the control condition (fixed ISI of 167 ms) had no effect. There were no specific changes in motor thresholds, intracortical circuits, or recruitment curves. Our results indicate that paired-associative cortical plasticity can be induced by repeated STN and M1 stimulation at specific intervals. These results show that STN-DBS can modulate cortical plasticity. We introduced a new experimental paradigm to test the hypothesis that pairing subthalamic nucleus deep-brain stimulation (STN-DBS) with motor cortical transcranial magnetic stimulation (M1-TMS) at specific times can induce cortical plasticity in patients with Parkinson's disease (PD). We found that repeated pairing of STN

  14. Regulation of Sticholysin II-Induced Pore Formation by Lipid Bilayer Composition, Phase State, and Interfacial Properties.

    PubMed

    Palacios-Ortega, Juan; García-Linares, Sara; Åstrand, Mia; Al Sazzad, Md Abdullah; Gavilanes, José G; Martínez-del-Pozo, Álvaro; Slotte, J Peter

    2016-04-12

    Sticholysin II (StnII) is a pore-forming toxin that uses sphingomyelin (SM) as the recognition molecule in targeting membranes. After StnII monomers bind to SM, several toxin monomers act in concert to oligomerize into a functional pore. The regulation of StnII binding to SM, and the subsequent pore-formation process, is not fully understood. In this study, we examined how the biophysical properties of bilayers, originating from variations in the SM structure, from the presence of sterol species, or from the presence of increasingly polyunsaturated glycerophospholipids, affected StnII-induced pore formation. StnII-induced pore formation, as determined from calcein permeabilization, was fastest in the pure unsaturated SM bilayers. In 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/saturated SM bilayers (4:1 molar ratio), pore formation became slower as the chain length of the saturated SMs increased from 14 up to 24 carbons. In the POPC/palmitoyl-SM (16:0-SM) 4:1 bilayers, SM could not support pore formation by StnII if dimyristoyl-PC was included at 1:1 stoichiometry with 16:0-SM, suggesting that free clusters of SM were required for toxin binding and/or pore formation. Cholesterol and other sterols facilitated StnII-induced pore formation markedly, but the efficiency did not appear to correlate with the sterol structure. Benzyl alcohol was more efficient than sterols in enhancing the pore-formation process, suggesting that the effect on pore formation originated from alcohol-induced alteration of the hydrogen-bonding network in the SM-containing bilayers. Finally, we observed that pore formation by StnII was enhanced in the PC/16:0-SM 4:1 bilayers, in which the PC was increasingly unsaturated. We conclude that the physical state of bilayer lipids greatly affected pore formation by StnII. Phase boundaries were not required for pore formation, although SM in a gel state attenuated pore formation.

  15. Two opposite effects of Delta(9)-tetrahydrocannabinol on subthalamic nucleus neuron activity: involvement of GABAergic and glutamatergic neurotransmission.

    PubMed

    Morera-Herreras, Teresa; Ruiz-Ortega, Jose Angel; Ugedo, Luisa

    2010-01-01

    Activation of CB1 cannabinoid receptors in the basal ganglia interferes with movement regulation. The aim of this study was to characterize the effect of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) on neurons in the subthalamic nucleus (STN) and to elucidate the mechanisms involved in this effect using single-unit extracellular recordings in anesthetized rats. Administration of Delta(9)-THC (0.25-2 mg/kg, i.v.) stimulated (by 107% +/- 32%) neurons mainly recorded in the ventromedial portion of the caudal STN, whereas it inhibited (by 65% +/- 4%) neurons recorded in the dorsolateral portion of the rostral STN. The CB1 receptor antagonist rimonabant (1 mg/kg, i.v.) completely reverted these effects. The excitatory effect of Delta(9)-THC on STN neurons was not observed after antagonism of GABA(A) receptors by bicuculline administration (10 ng, icv.) or after chemical lesion of the globus pallidus with ibotenic acid. The inhibitory effect was abolished when excitatory amino acid receptors were blocked by kynurenic acid (0.5 mumol, icv.). These results indicate that CB1 receptor activation modulates STN neuron activity by indirect mechanisms involving glutamatergic and GABAergic neurotransmission.

  16. Impulse control and related disorders in Parkinson's disease patients treated with bilateral subthalamic nucleus stimulation: a review.

    PubMed

    Broen, Martijn; Duits, Annelien; Visser-Vandewalle, Veerle; Temel, Yasin; Winogrodzka, Ania

    2011-07-01

    Recently, impulse control and related disorders including punding and the dopamine dysregulation syndrome (DDS) have been increasingly recognized in treated patients with Parkinson's disease (PD). Especially the impulse control disorders (ICD) such as pathological gambling, hypersexuality, compulsive eating and buying may have dramatic repercussions on family, personal and professional life. Drug replacement therapy (DRT) is believed to play an important role in the onset of these behavioral disturbances. Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) might be a therapeutic option for those patients with DRT-related behavior, it may also induce ICD. So far, little is known about the relationship between STN DBS and impulse control and related disorders. Our aim was to review the current knowledge on this relationship in PD patients. The available studies showed that stimulation of the STN is associated with both favorable and negative outcome in terms of impulse control and related disorders. Preoperative disorders may resolve or improve after STN DBS, but these can also worsen or show no change at all. Moreover, STN DBS can also reveal or even induce ICD. Possible explanations for this variability are proposed and suggestions for clinical management are given. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. Subthalamic nucleus local field potential activity helps encode motor effort rather than force in parkinsonism.

    PubMed

    Tan, Huiling; Pogosyan, Alek; Ashkan, Keyoumars; Cheeran, Binith; FitzGerald, James J; Green, Alexander L; Aziz, Tipu; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Brown, Peter

    2015-04-15

    Local field potential (LFP) recordings from patients with deep brain stimulation electrodes in the basal ganglia have suggested that frequency-specific activities correlate with force or effort, but previous studies have not been able to disambiguate the two. Here, we dissociated effort from actual force generated by contrasting the force generation of different fingers while recording LFP activity from the subthalamic nucleus (STN) in patients with Parkinson's disease who had undergone functional surgery. Patients were studied while on their normal dopaminergic medication. We investigated the relationship between frequency-specific oscillatory activity in the STN and voluntary flexion of either the index or little finger at different effort levels. At each tested effort level (10%, 25%, and 40% of the maximal voluntary contraction force of each individual finger), the index finger generated larger force than the little finger. Movement-related suppression of beta-band power in the STN LFP was significantly modulated by effort, but not by which finger was used, suggesting that the beta suppression in the STN LFP during sustained contraction serves as a proxy for effort. The absolute force scaled with beta power suppression, but with the scaling determined by the maximal voluntary contraction force of the motor effector. Our results argue against the hypothesis that the basal ganglia are directly involved in the parameterization of force during movement and support a role of the STN in the control of motor effort to be attributed to a response.

  18. A Non-Invasive Imaging Approach to Understanding Speech Changes following Deep Brain Stimulation in Parkinson’s Disease

    PubMed Central

    Narayana, Shalini; Jacks, Adam; Robin, Donald A.; Poizner, Howard; Zhang, Wei; Franklin, Crystal; Liotti, Mario; Vogel, Deanie; Fox, Peter T.

    2009-01-01

    Purpose To explore the use of non-invasive functional imaging and “virtual” lesion techniques to study the neural mechanisms underlying motor speech disorders in Parkinson’s disease. Here, we report the use of Positron Emission Tomography (PET) and transcranial magnetic stimulation (TMS) to explain exacerbated speech impairment following subthalamic nucleus deep brain stimulation (STN-DBS) in a patient with Parkinson’s disease. Method Perceptual and acoustic speech measures as well as cerebral blood flow (CBF) during speech as measured by PET were obtained with STN-DBS on and off. TMS was applied to a region in the speech motor network found to be abnormally active during DBS. Speech disruption by TMS was compared both perceptually and acoustically with that resulting from DBS on. Results Speech production was perceptually inferior and acoustically less contrastive during left STN stimulation compared to no stimulation. Increased neural activity in left dorsal premotor cortex (PMd) was observed during DBS on. “Virtual” lesioning of this region resulted in speech characterized by decreased speech segment duration, increased pause duration, and decreased intelligibility. Conclusions This case report provides evidence that impaired speech production accompanying STN-DBS may be resulting from unintended activation of PMd. Clinical application of functional imaging and TMS may lead to optimizing the delivery of STN-DBS to improve outcomes for speech production as well as general motor abilities. PMID:19029533

  19. The subthalamic nucleus modulates the early phase of probabilistic classification learning.

    PubMed

    Weiss, Daniel; Lam, Judith M; Breit, Sorin; Gharabaghi, Alireza; Krüger, Rejko; Luft, Andreas R; Wächter, Tobias

    2014-07-01

    Previous models proposed that the subthalamic nucleus (STN) is critical in the early phase of skill acquisition. We hypothesized that subthalamic deep brain stimulation modulates the learning curve in early classification learning. Thirteen idiopathic Parkinson's disease patients (iPD) with subthalamic deep brain stimulation (STN-DBS), 9 medically treated iPD, and 21 age-matched healthy controls were tested with a probabilistic classification task. STN-DBS patients were tested with stimulation OFF and ON, and medically treated patients with medication OFF and ON, respectively. Performance and reaction time were analyzed on the first 100 consecutive trials as early learning phase. Moreover, data were separated for low and high-probability patterns, and more differentiated strategy analyses were used. The major finding was a significant modulation of the learning curve in DBS patients with stimulation ON: although overall learning was similar to healthy controls, only the stimulation ON group showed a transient significant performance dip from trials '41-60' that rapidly recovered. Further analysis indicated that this might be paralleled by a modulation of the learning strategy, particularly on the high-probability patterns. The reaction time was unchanged during the dip. Our study supports that the STN serves as a relay in early classification learning and directs attention toward unacquainted content. The STN might play a role in balancing the short-term success against strategy optimization for improved long-term outcome.

  20. Fiber type composition of the sternomastoid and diaphragm muscles of dystrophin-deficient mdx mice.

    PubMed

    Guido, Anderson Neri; Campos, Gerson Eduardo Rocha; Neto, Humberto Santo; Marques, Maria Julia; Minatel, Elaine

    2010-10-01

    The muscle fiber phenotype is mainly determined by motoneuron innervation and changes in neuromuscular interaction alter the muscle fiber type. In dystrophin-deficient mdx mice, changes in the molecular assembly of the neuromuscular junction and in nerve terminal sprouting occur in the sternomastoid (STN) muscle during early stages of the disease. In this study, we were interested to see whether early changes in neuromuscular assembly are correlated with alterations in fiber type in dystrophic STN at 2 months of age. A predominance of hybrid fast myofibers (about 52% type IIDB) was observed in control (C57Bl/10) STN. In mdx muscle, the lack of dystrophin did not change this profile (about 54% hybrid type IIDB). Pure fast type IID fibers predominated in normal and dystrophic diaphragm (DIA; about 39% in control and 30% in mdx muscle) and a population of slow Type I fibers was also present (about 10% in control and 13% in mdx muscle). In conclusion, early changes in neuromuscular assembly do not affect the fiber type composition of dystrophic STN. In contrast to the pure fast fibers of the more affected DIA, the hybrid phenotype of the STN may permit dynamic adaptations during progression of the disease.

  1. Hypoxia-inducible factor-1α activation improves renal oxygenation and mitochondrial function in early chronic kidney disease.

    PubMed

    Thomas, Joanna L; Pham, Hai; Li, Ying; Hall, Elanore; Perkins, Guy A; Ali, Sameh S; Patel, Hemal H; Singh, Prabhleen

    2017-08-01

    The pathophysiology of chronic kidney disease (CKD) is driven by alterations in surviving nephrons to sustain renal function with ongoing nephron loss. Oxygen supply-demand mismatch, due to hemodynamic adaptations, with resultant hypoxia, plays an important role in the pathophysiology in early CKD. We sought to investigate the underlying mechanisms of this mismatch. We utilized the subtotal nephrectomy (STN) model of CKD to investigate the alterations in renal oxygenation linked to sodium (Na) transport and mitochondrial function in the surviving nephrons. Oxygen delivery was significantly reduced in STN kidneys because of lower renal blood flow. Fractional oxygen extraction was significantly higher in STN. Tubular Na reabsorption was significantly lower per mole of oxygen consumed in STN. We hypothesized that decreased mitochondrial bioenergetic capacity may account for this and uncovered significant mitochondrial dysfunction in the early STN kidney: higher oxidative metabolism without an attendant increase in ATP levels, elevated superoxide levels, and alterations in mitochondrial morphology. We further investigated the effect of activation of hypoxia-inducible factor-1α (HIF-1α), a master regulator of cellular hypoxia response. We observed significant improvement in renal blood flow, glomerular filtration rate, and tubular Na reabsorption per mole of oxygen consumed with HIF-1α activation. Importantly, HIF-1α activation significantly lowered mitochondrial oxygen consumption and superoxide production and increased mitochondrial volume density. In conclusion, we report significant impairment of renal oxygenation and mitochondrial function at the early stages of CKD and demonstrate the beneficial role of HIF-1α activation on renal function and metabolism.

  2. Forelimb dyskinesia mediated by high-frequency stimulation of the subthalamic nucleus is linked to rapid activation of the NR2B subunit of N-methyl-D-aspartate receptors.

    PubMed

    Quintana, Adrien; Melon, Christophe; Kerkerian-Le Goff, Lydia; Salin, Pascal; Savasta, Marc; Sgambato-Faure, Véronique

    2010-08-01

    Dyskinesia is a major side-effect of chronic l-DOPA administration, the reference treatment for Parkinson's disease. High-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing the L-DOPA requirement. However, inappropriate stimulation can also trigger dyskinetic movements, in both human and rodents. We investigated whether STN-HFS-evoked forelimb dyskinesia involved changes in glutamatergic neurotransmission as previously reported for L-DOPA-induced dyskinesias, focusing on the role of NR2B-containing N-methyl-D-aspartate receptors (NR2B/NMDARs). We applied STN-HFS in normal rats at intensities above and below the threshold for triggering forelimb dyskinesia. Dyskinesiogenic STN-HFS induced the activation of NR2B (as assessed by immunodetection of the phosphorylated residue Tyr(1472)) in neurons of the subthalamic nucleus, entopeduncular nucleus, motor thalamus and forelimb motor cortex. The severity of STN-HFS-induced forelimb dyskinesia was decreased in a dose-dependent manner by systemic injections of CP-101,606, a selective blocker of NR2B/NMDARs, but was either unaffected or increased by the non-selective N-methyl-D-aspartate receptor antagonist, MK-801.

  3. Distinct mechanisms mediate speed-accuracy adjustments in cortico-subthalamic networks

    PubMed Central

    Herz, Damian M; Tan, Huiling; Brittain, John-Stuart; Fischer, Petra; Cheeran, Binith; Green, Alexander L; FitzGerald, James; Aziz, Tipu Z; Ashkan, Keyoumars; Little, Simon; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Bogacz, Rafal; Brown, Peter

    2017-01-01

    Optimal decision-making requires balancing fast but error-prone and more accurate but slower decisions through adjustments of decision thresholds. Here, we demonstrate two distinct correlates of such speed-accuracy adjustments by recording subthalamic nucleus (STN) activity and electroencephalography in 11 Parkinson’s disease patients during a perceptual decision-making task; STN low-frequency oscillatory (LFO) activity (2–8 Hz), coupled to activity at prefrontal electrode Fz, and STN beta activity (13–30 Hz) coupled to electrodes C3/C4 close to motor cortex. These two correlates differed not only in their cortical topography and spectral characteristics but also in the relative timing of recruitment and in their precise relationship with decision thresholds. Increases of STN LFO power preceding the response predicted increased thresholds only after accuracy instructions, while cue-induced reductions of STN beta power decreased thresholds irrespective of instructions. These findings indicate that distinct neural mechanisms determine whether a decision will be made in haste or with caution. DOI: http://dx.doi.org/10.7554/eLife.21481.001 PMID:28137358

  4. Modulations on cortical oscillations by subthalamic deep brain stimulation in patients with Parkinson disease: A MEG study.

    PubMed

    Cao, Chun-Yan; Zeng, Ke; Li, Dian-You; Zhan, Shi-Kun; Li, Xiao-Li; Sun, Bo-Min

    2017-01-01

    The study aimed to explore the modification to cortical oscillations of Parkinson disease (PD) patients by subthalamic nucleus deep brain stimulation (STN DBS). With Magnetoencephalogram (MEG) detection, we examined the changes in absolute power spectrum of cortical oscillations in the PD patients with the treatment of STN DBS. The power analysis of PD patients showed a dominant over-synchronization of alpha and beta bands in temporal and occipital areas relative to the healthy control subjects. STN DBS on-state showed marked power increase in the gamma band of PD patients in the frontal and parietal relative to the DBS off-state. The alleviation of motor symptoms by STN DBS negatively correlated to the increase of high gamma oscillation in the right frontal cortex, and also correlated to the suppression of the alpha and beta oscillations in the right temporal cortex. The treatment of STN DBS to PD patients might involve the augmentation of gamma activity and suppression of alpha and beta activities in cortical oscillations. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Comparison of oscillatory activity in subthalamic nucleus in Parkinson's disease and dystonia

    PubMed Central

    Jiang, Yin; Ashkan, Keyoumars; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Green, Alexander; Aziz, Tipu; Brown, Peter; Wang, Shouyan

    2017-01-01

    Objectives Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been successfully used to treat both Parkinson's disease (PD) and dystonia. Local field potentials (LFPs) recorded from the STN of PD patients demonstrate prominent beta frequency band activity. It is unclear whether such activity occurs in the STN in dystonia, and, if not, whether dystonia has another distinctive neural population activity in the STN. Methods Twelve patients with PD, and eight patients with dystonia underwent DBS electrode implantation targeting the STN. Seven dystonia patients were off medication and one was on aripiprazole and clonazepam. LFPs were recorded from the DBS electrodes in PD in the on/off medication states and in dystonia. Power spectra and temporal dynamics measured by the with Lempel-Ziv complexity of the LFPs were compared among these states. Results Normalised power spectra and Lempel-Ziv complexity of subthalamic LFPs differed between dystonia off and PD on/off, and between PD off and on over the low frequency, beta and high gamma bands. Patients with dystonia and off medication had lower beta power but higher low frequency and high gamma power than PD. Spectral power in the low beta frequency (11–20 Hz) range was attenuated in medicated PD. Conclusion The results suggest that dystonia and PD are characterized by different patterns of oscillatory activities even within the same nucleus, and exaggerated beta activity may relate to hypo-dopaminergic status. PMID:27940307

  6. Conditions for the generation of beta oscillations in the subthalamic nucleus-globus pallidus network.

    PubMed

    Holgado, Alejo J Nevado; Terry, John R; Bogacz, Rafal

    2010-09-15

    The advance of Parkinson's disease is associated with the existence of abnormal oscillations within the basal ganglia with frequencies in the beta band (13-30 Hz). While the origin of these oscillations remains unknown, there is some evidence suggesting that oscillations observed in the basal ganglia arise due to interactions of two nuclei: the subthalamic nucleus (STN) and the globus pallidus pars externa (GPe). To investigate this hypothesis, we develop a computational model of the STN-GPe network based upon anatomical and electrophysiological studies. Significantly, our study shows that for certain parameter regimes, the model intrinsically oscillates in the beta range. Through an analytical study of the model, we identify a simple set of necessary conditions on model parameters that guarantees the existence of beta oscillations. These conditions for generation of oscillations are described by a set of simple inequalities and can be summarized as follows: (1) The excitatory connections from STN to GPe and the inhibitory connections from GPe to STN need to be sufficiently strong. (2) The time required by neurons to react to their inputs needs to be short relative to synaptic transmission delays. (3) The excitatory input from the cortex to STN needs to be high relative to the inhibition from striatum to GPe. We confirmed the validity of these conditions via numerical simulation. These conditions describe changes in parameters that are consistent with those expected as a result of the development of Parkinson's disease, and predict manipulations that could inhibit the pathological oscillations.

  7. Customizing deep brain stimulation to the patient using computational models.

    PubMed

    McIntyre, Cameron C; Frankenmolle, Anneke M; Wu, Jennifer; Noecker, Angela M; Alberts, Jay L

    2009-01-01

    Bilateral subthalamic (STN) deep brain stimulation (DBS) is effective in improving the cardinal motor signs of advanced Parkinson's disease (PD); however declines in cognitive function have been associated with this procedure. The aim of this study was to assess cognitive-motor performance of 10 PD patients implanted with STN DBS systems during either clinically determined stimulation settings or settings derived from a computational model. Cicerone DBS software was used to define the model parameters such that current spread to non-motor areas of the STN was minimized. Clinically determined and model defined parameters were equally effective in improving motor scores on the traditional clinical rating scale (UPDRS-III). Under modest dual-task conditions, cognitive-motor performance was worse with clinically determined compared to model derived parameters. In addition, the model parameters provided a 66% reduction in power consumption. These results indicate that the cognitive-motor declines associated with bilateral STN can be mitigated, without compromising motor benefits, utilizing stimulation parameters that minimize current spread into non-motor regions of the STN.

  8. Effects of DBS in parkinsonian patients depend on the structural integrity of frontal cortex

    PubMed Central

    Muthuraman, Muthuraman; Deuschl, Günther; Koirala, Nabin; Riedel, Christian; Volkmann, Jens; Groppa, Sergiu

    2017-01-01

    While deep brain stimulation of the subthalamic nucleus (STN-DBS) has evolved to an evidence-based standard treatment for Parkinson’s disease (PD), the targeted cerebral networks are poorly described and no objective predictors for the postoperative clinical response exist. To elucidate the systemic mechanisms of DBS, we analysed cerebral grey matter properties using cortical thickness measurements and addressed the dependence of structural integrity on clinical outcome. Thirty one patients with idiopathic PD without dementia (23 males, age: 63.4 ± 9.3, Hoehn and Yahr: 3.5 ± 0.8) were selected for DBS treatment. The patients underwent whole-brain preoperative T1 MR-Imaging at 3 T. Grey matter integrity was assessed by cortical thickness measurements with FreeSurfer. The clinical motor outcome markedly improved after STN-DBS in comparison to the preoperative condition. The cortical thickness of the frontal lobe (paracentral area and superior frontal region) predicted the clinical improvement after STN-DBS. Moreover, in patients with cortical atrophy of these areas a higher stimulation voltage was needed for an optimal clinical response. Our data suggest that the effects of STN-DBS in PD directly depend on frontal lobe grey matter integrity. Cortical atrophy of this region might represent a distinct predictor of a poor motor outcome after STN-DBS in PD patients. PMID:28262813

  9. Customizing Deep Brain Stimulation to the Patient Using Computational Models

    PubMed Central

    McIntyre, Cameron C.; Frankenmolle, Anneke; Wu, Jennifer; Noecker, Angela M.; Alberts, Jay L.

    2011-01-01

    Bilateral subthalamic (STN) deep brain stimulation (DBS) is effective in improving the cardinal motor signs of advanced Parkinson's disease (PD); however declines in cognitive function have been associated with this procedure. The aim of this study was to assess cognitive-motor performance of 10 PD patients implanted with STN DBS systems during either clinically determined stimulation settings or settings derived from a computational model. Cicerone DBS software was used to define the model parameters such that current spread to non-motor areas of the STN was minimized. Clinically determined and model defined parameters were equally effective in improving motor scores on the traditional clinical rating scale (UPDRS-III). Under modest dual-task conditions, cognitive-motor performance was worse with clinically determined compared to model derived parameters. In addition, the model parameters provided a 33% reduction in power consumption. These results indicate that the cognitivemotor declines associated with bilateral STN can be mitigated, without compromising motor benefits, utilizing stimulation parameters that minimize current spread into non-motor regions of the STN. PMID:19965023

  10. O-glycan sialylation alters galectin-3 subcellular localization and decreases chemotherapy sensitivity in gastric cancer

    PubMed Central

    Santos, Sofia N.; Junqueira, Mara S.; Francisco, Guilherme; Vilanova, Manuel; Magalhães, Ana; Baruffi, Marcelo Dias; Chammas, Roger; Harris, Adrian L.; Reis, Celso A.; Bernardes, Emerson S.

    2016-01-01

    ST6GalNAc-I, the sialyltransferase responsible for sialyl-Tn (sTn) synthesis, has been previously reported to be positively associated with cancer aggressiveness. Here we describe a novel sTn-dependent mechanism for chemotherapeutic resistance. We show that sTn protects cancer cells against chemotherapeutic-induced cell death by decreasing the interaction of cell surface glycan receptors with galectin-3 and increasing its intracellular accumulation. Moreover, exogenously added galectin-3 potentiated the chemotherapeutics-induced cytotoxicity in sTn non-expressing cells, while sTn overexpressing cells were protected. We also found that the expression of sTn was associated with a reduction in galectin-3-binding sites in human gastric samples tumors. ST6GalNAc-I knockdown restored galectin-3-binding sites on the cell surface and chemotherapeutics sensibility. Our results clearly demonstrate that an interruption of O-glycans extension caused by ST6GalNAc-I enzymatic activity leads to tumor cells resistance to chemotherapeutic drugs, highlighting the need for the development of novel strategies to target galectin-3 and/or ST6GalNAc-I. PMID:27835877

  11. Personality Changes after Deep Brain Stimulation in Parkinson's Disease

    PubMed Central

    Pham, Uyen; Solbakk, Anne-Kristin; Skogseid, Inger-Marie; Pripp, Are Hugo; Konglund, Ane Eidahl; Andersson, Stein; Haraldsen, Ira Ronit; Aarsland, Dag; Dietrichs, Espen; Malt, Ulrik Fredrik

    2015-01-01

    Objectives. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a recognized therapy that improves motor symptoms in advanced Parkinson's disease (PD). However, little is known about its impact on personality. To address this topic, we have assessed personality traits before and after STN-DBS in PD patients. Methods. Forty patients with advanced PD were assessed with the Temperament and Character Inventory (TCI): the Urgency, Premeditation, Perseverance, Sensation Seeking impulsive behaviour scale (UPPS), and the Neuroticism and Lie subscales of the Eysenck Personality Questionnaire (EPQ-N, EPQ-L) before surgery and after three months of STN-DBS. Collateral information obtained from the UPPS was also reported. Results. Despite improvement in motor function and reduction in dopaminergic dosage patients reported lower score on the TCI Persistence and Self-Transcendence scales, after three months of STN-DBS, compared to baseline (P = 0.006; P = 0.024). Relatives reported significantly increased scores on the UPPS Lack of Premeditation scale at follow-up (P = 0.027). Conclusion. STN-DBS in PD patients is associated with personality changes in the direction of increased impulsivity. PMID:25705545

  12. Behavioral and electrophysiological evidence for early and automatic detection of phonological equivalence in variable speech inputs.

    PubMed

    Kharlamov, Viktor; Campbell, Kenneth; Kazanina, Nina

    2011-11-01

    Speech sounds are not always perceived in accordance with their acoustic-phonetic content. For example, an early and automatic process of perceptual repair, which ensures conformity of speech inputs to the listener's native language phonology, applies to individual input segments that do not exist in the native inventory or to sound sequences that are illicit according to the native phonotactic restrictions on sound co-occurrences. The present study with Russian and Canadian English speakers shows that listeners may perceive phonetically distinct and licit sound sequences as equivalent when the native language system provides robust evidence for mapping multiple phonetic forms onto a single phonological representation. In Russian, due to an optional but productive t-deletion process that affects /stn/ clusters, the surface forms [sn] and [stn] may be phonologically equivalent and map to a single phonological form /stn/. In contrast, [sn] and [stn] clusters are usually phonologically distinct in (Canadian) English. Behavioral data from identification and discrimination tasks indicated that [sn] and [stn] clusters were more confusable for Russian than for English speakers. The EEG experiment employed an oddball paradigm with nonwords [asna] and [astna] used as the standard and deviant stimuli. A reliable mismatch negativity response was elicited approximately 100 msec postchange in the English group but not in the Russian group. These findings point to a perceptual repair mechanism that is engaged automatically at a prelexical level to ensure immediate encoding of speech inputs in phonological terms, which in turn enables efficient access to the meaning of a spoken utterance.

  13. Subthalamic nucleus--sensorimotor cortex functional connectivity in de novo and moderate Parkinson's disease.

    PubMed

    Kurani, Ajay S; Seidler, Rachael D; Burciu, Roxana G; Comella, Cynthia L; Corcos, Daniel M; Okun, Michael S; MacKinnon, Colum D; Vaillancourt, David E

    2015-01-01

    Previous research has indicated increased functional connectivity between subthalamic nucleus (STN) and sensorimotor cortex in off-medication Parkinson's disease (PD) compared with control subjects. It is not clear if the increase in functional connectivity between STN and sensorimotor cortex occurs in de novo PD, which is before patients begin dopamine therapy. Resting-state functional magnetic resonance imaging was carried out in 20 de novo (drug naïve) patients with PD (Hoehn and Yahr stage: I-II), 19 patients with moderate PD (Hoehn and Yahr stage: II-III), and 19 healthy controls. The functional connectivity analysis in de novo and moderate PD patients focused on the connectivity of the more affected STN and the sensorimotor cortex. Using resting-state functional connectivity analysis, we provide new evidence that people with de novo PD and off-medicated moderate PD have increased functional connectivity between the more affected STN and different regions within the sensorimotor cortex. The overlapping sensorimotor cortex found in both de novo and moderate PD had functional connectivity values that correlated positively with the Unified Parkinson's Disease Rating Scale part III. This key finding suggests that changes in functional connectivity between STN and sensorimotor cortex occur early in the disease following diagnosis and before dopamine therapy.

  14. Striatal Glutamate and GABA after High Frequency Subthalamic Stimulation in Parkinsonian Rat

    PubMed Central

    Lee, Kyung Jin; Shim, Insop; Sung, Jae Hoon; Hong, Jae Taek; Kim, Il sup; Cho, Chul Bum

    2017-01-01

    Objective High frequency stimulation (HFS) of the subthalamic nucleus (STN) is recognized as an effective treatment of advanced Parkinson’s disease. However, the neurochemical basis of its effects remains unknown. The aim of this study is to investigate the effects of STN HFS in intact and 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rat model on changes of principal neurotransmitters, glutamate, and gamma-aminobutyric acid (GABA) in the striatum. Methods The authors examined extracellular glutamate and GABA change in the striatum on sham group, 6-OHDA group, and 6-OHDA plus deep brain stimulation (DBS) group using microdialysis methods. Results High-pressure liquid chromatography was used to quantify glutamate and GABA. The results show that HFS-STN induces a significant increase of extracellular glutamate and GABA in the striatum of 6-OHDA plus DBS group compared with sham and 6-OHDA group. Conclusion Therefore, the clinical results of STN-HFS are not restricted to the direct STN targets but involve widespread adaptive changes within the basal ganglia. PMID:28264233

  15. Choreatic Side Effects of Deep Brain Stimulation of the Anteromedial Subthalamic Nucleus for Treatment-Resistant Obsessive-Compulsive disorder.

    PubMed

    Mulders, Anne E P; Leentjens, Albert F G; Schruers, Koen; Duits, Annelien; Ackermans, Linda; Temel, Yasin

    2017-08-01

    Patients with treatment-resistant obsessive-compulsive disorder (OCD) are potential candidates for deep brain stimulation (DBS). The anteromedial subthalamic nucleus (STN) is among the most commonly used targets for DBS in OCD. We present a patient with a 30-year history of treatment-resistant OCD who underwent anteromedial STN-DBS. Despite a clear mood-enhancing effect, stimulation caused motor side effects, including bilateral hyperkinesia, dyskinesias, and sudden large amplitude choreatic movements of arms and legs when stimulating at voltages greater than approximately 1.5 V. DBS at lower amplitudes and at other contact points failed to result in a significant reduction of obsessions and compulsions without inducing motor side effects. Because of this limitation in programming options, we decided to reoperate and target the ventral capsule/ventral striatum (VC/VS), which resulted in a substantial reduction in key obsessive and compulsive symptoms without serious side effects. Choreatic movements and hemiballismus have previously been linked to STN dysfunction and have been incidentally reported as side effects of DBS of the dorsolateral STN in Parkinson disease (PD). However, in PD, these side effects were usually transient, and they rarely interfered with DBS programming. In our patient, the motor side effects were persistent, and they made optimal DBS programming impossible. To our knowledge, such severe and persistent motor side effects have not been described previously for anteromedial STN-DBS. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Impulsivity in Parkinson's disease is associated with altered subthalamic but not globus pallidus internus activity.

    PubMed

    Rossi, Peter Justin; Shute, Jonathan B; Opri, Enrico; Molina, Rene; Peden, Corinna; Castellanos, Oscar; Foote, Kelly D; Gunduz, Aysegul; Okun, Michael S

    2017-08-19

    A significant subset of patients with Parkinson's disease (PD) suffer from impulse control disorders (ICDs). A hallmark feature of many ICDs is the pursuit of rewarding behaviours despite negative consequences. Recent evidence implicates the subthalamic nucleus (STN) and globus pallidus internus (GPi) in reward and punishment processing, and deep brain stimulation (DBS) of these structures has been associated with changes in ICD symptoms. We tested the hypothesis that in patients with PD diagnosed with ICD, neurons in the STN and GPi would be more responsive to reward-related stimuli and less responsive to loss-related stimuli. We studied a cohort of 43 patients with PD (12 with an ICD and 31 without) undergoing DBS electrode placement surgery. Patients performed a behavioural task in which their action choices were motivated by the potential for either a monetary reward or a monetary loss. During task performance, the activity of individual neurons was recorded in either the STN (n=100) or the GPi (n=100). The presence of an ICD was associated with significantly greater proportions of reward responsive neurons (p<0.01) and significantly lower proportions of loss responsive neurons (p<0.05) in the STN, but not in the GPi. These findings provide further evidence of STN involvement in impulsive behaviour in the PD population. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  17. Subthalamic nucleus - sensorimotor cortex functional connectivity in de novo and moderate Parkinson’s disease

    PubMed Central

    Kurani, A.S.; Seidler, R.D.; Burciu, R.G.; Comella, C.L.; Corcos, D.M.; Okun, M.S.; MacKinnon, C.D.; Vaillancourt, D.E.

    2014-01-01

    Previous research has indicated increased functional connectivity between subthalamic nucleus (STN) and sensorimotor cortex in off-medication Parkinson’s disease (PD) compared with control subjects. It is not clear if the increase in functional connectivity between STN and sensorimotor cortex occurs in de novo PD, which is prior to when patients begin dopamine therapy. Resting state functional magnetic resonance imaging was carried out in 20 de novo (drug-naïve) patients with PD (HY stage: I-II), 19 patients with moderate PD (HY stage: II-III), and 19 healthy controls. The functional connectivity analysis in de novo and moderate PD patients focused on the connectivity of the more affected STN and the sensorimotor cortex. Using resting state functional connectivity analysis, we provide new evidence that people with de novo PD and off-medicated moderate PD have increased functional connectivity between the more affected STN and different regions within the sensorimotor cortex. The overlapping sensorimotor cortex found in both de novo and moderate PD had functional connectivity values that correlated positively with the Unified Parkinson’s Disease Rating Scale part III. This key finding suggests that changes in functional connectivity between STN and sensorimotor cortex occur early in the disease following diagnosis and prior to dopamine therapy. PMID:25095723

  18. Vocal emotion decoding in the subthalamic nucleus: An intracranial ERP study in Parkinson's disease.

    PubMed

    Péron, Julie; Renaud, Olivier; Haegelen, Claire; Tamarit, Lucas; Milesi, Valérie; Houvenaghel, Jean-François; Dondaine, Thibaut; Vérin, Marc; Sauleau, Paul; Grandjean, Didier

    2017-01-12

    Using intracranial local field potential (LFP) recordings in patients with Parkinson's disease (PD) undergoing deep brain stimulation (DBS), we explored the electrophysiological activity of the subthalamic nucleus (STN) in response to emotional stimuli in the auditory modality. Previous studies focused on the influence of visual stimuli. To this end, we recorded LFPs within the STN in response to angry, happy, and neutral prosodies in 13 patients with PD who had just undergone implantation of DBS electrodes. We observed specific modulation of the right STN in response to anger and happiness, as opposed to neutral prosody, occurring at around 200-300ms post-onset, and later at around 850-950ms post-onset for anger and at around 3250-3350ms post-onset for happiness. Taken together with previous reports of modulated STN activity in response to emotional visual stimuli, the present results appear to confirm that the STN is involved in emotion processing irrespective of stimulus valence and sensory modality.

  19. Ethical safety of deep brain stimulation: A study on moral decision-making in Parkinson's disease.

    PubMed

    Fumagalli, Manuela; Marceglia, Sara; Cogiamanian, Filippo; Ardolino, Gianluca; Picascia, Marta; Barbieri, Sergio; Pravettoni, Gabriella; Pacchetti, Claudio; Priori, Alberto

    2015-07-01

    The possibility that deep brain stimulation (DBS) in Parkinson's disease (PD) alters patients' decisions and actions, even temporarily, raises important clinical, ethical and legal questions. Abnormal moral decision-making can lead to ethical rules violations. Previous experiments demonstrated the subthalamic (STN) activation during moral decision-making. Here we aim to study whether STN DBS can affect moral decision-making in PD patients. Eleven patients with PD and bilateral STN DBS implant performed a computerized moral task in ON and OFF stimulation conditions. A control group of PD patients without DBS implant performed the same experimental protocol. All patients underwent motor, cognitive and psychological assessments. STN stimulation was not able to modify neither reaction times nor responses to moral task both when we compared the ON and the OFF state in the same patient (reaction times, p = .416) and when we compared DBS patients with those treated only with the best medical treatment (reaction times: p = .408, responses: p = .776). Moral judgment is the result of a complex process, requiring cognitive executive functions, problem-solving, anticipations of consequences of an action, conflict processing, emotional evaluation of context and of possible outcomes, and involving different brain areas and neural circuits. Our data show that STN DBS leaves unaffected moral decisions thus implying relevant clinical and ethical implications for DBS consequences on patients' behavior, on decision-making and on judgment ability. In conclusion, the technique can be considered safe on moral behavior. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Subthalamic nucleus deep brain stimulation changes speech respiratory and laryngeal control in Parkinson's disease

    PubMed Central

    Barlow, Steven M.; Lyons, Kelly E.; Pahwa, Rajesh

    2010-01-01

    Adequate respiratory and laryngeal motor control are essential for speech, but may be impaired in Parkinson's disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on respiratory and laryngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of respiratory and laryngeal control, and whether these changes were correlated with limb function and stimulation parameters. Eighteen PD participants with bilateral STN DBS were tested within a morning session after a minimum of 12 h since their most recent dose of anti-PD medication. Testing occurred when DBS was on, and again 1 h after DBS was turned off, and included aerodynamic measures during syllable production, and standard clinical ratings of limb function. We found that PD participants exhibited changes with DBS, consistent with increased respiratory driving pressure (n = 9) and increased vocal fold closure (n = 9). However, most participants exceeded a typical operating range for these respiratory and laryngeal control variables with DBS. Changes were uncorrelated with limb function, but showed some correlation with stimulation frequency and pulse width, suggesting that speech may benefit more from low-frequency stimulation and shorter pulse width. Therefore, high-frequency STN DBS may be less beneficial for speech-related respiratory and laryngeal control than for limb motor control. It is important to consider these distinctions and their underlying mechanisms when assessing the impact of STN DBS on PD. PMID:20582431

  1. Effect of subthalamic nucleus stimulation during exercise on the mesolimbocortical dopaminergic region in Parkinson's disease: a positron emission tomography study.

    PubMed

    Nozaki, Takao; Sugiyama, Kenji; Yagi, Shunsuke; Yoshikawa, Etsuji; Kanno, Toshihiko; Asakawa, Tetsuya; Ito, Tae; Terada, Tatsuhiro; Namba, Hiroki; Ouchi, Yasuomi

    2013-03-01

    To elucidate the dynamic effects of deep brain stimulation (DBS) in the subthalamic nucleus (STN) during activity on the dopaminergic system, 12 PD patients who had STN-DBS operations at least 1 month prior, underwent two positron emission tomography scans during right-foot movement in DBS-off and DBS-on conditions. To quantify motor performance changes, the motion speed and mobility angle of the foot at the ankle were measured twice. Estimations of the binding potential of [(11)C]raclopride (BP(ND)) were based on the Logan plot method. Significant motor recovery was found in the DBS-on condition. The STN-DBS during exercise significantly reduced the [(11)C]raclopride BP(ND) in the caudate and the nucleus accumbens (NA), but not in the dorsal or ventral putamen. The magnitude of dopamine release in the NA correlated negatively with the magnitude of motor load, indicating that STN-DBS facilitated motor behavior more smoothly and at less expense to dopamine neurons in the region. The lack of dopamine release in the putamen and the significant dopamine release in the ventromedial striatum by STN-DBS during exercise indicated dopaminergic activation occurring in the motivational circuit during action, suggesting a compensatory functional activation of the motor loop from the nonmotor to the motor loop system.

  2. Ex Situ Investigation of Anisotropic Interconnection in Silicon-Titanium-Nickel Alloy Anode Material

    DOE PAGES

    Cho, Jong -Soo; Alaboina, Pankaj Kumar; Kang, Chan -Soon; ...

    2017-03-10

    Herein we investigate the nanostructural evolution of Silicon-Titanium-Nickel (Si-Ti-Ni) ternary alloy material synthesized by melt spinning process for advanced lithium-ion battery anode. The synthesized material was found to have nano-Silicon particles dispersed in the Ti4Ni4Si7 (STN) alloy buffering matrix and was characterized by X-ray diffraction (XRD), High resolution- transmission electron microscope (HR-TEM), Scanning transmission electron microscopes - energy dispersive X-ray spectrometer (STEM-EDS), and electrochemical performance test. The role of STN matrix is to accommodate the volume expansion stresses of the dispersed Si nanoparticles. However, an interesting behavior was observed during cycling. The Si nanoparticles were observed to form interconnection channelsmore » growing through the weak STN matrix cracks and evolving to a network isolating the STN matrix into small puddles. In conclusion, this unique nanostructural evolution of Si particles and isolation of the STN matrix failing to offer significant buffering effect to the grown Si network eventually accelerates more volume expansions during cycling due to less mechanical confinement and leads to performance degradation and poor cycle stability.« less

  3. Cortico-subthalamic inputs from the motor, limbic, and associative areas in normal and dopamine-depleted rats are not fully segregated.

    PubMed

    Janssen, Marcus L F; Temel, Yasin; Delaville, Claire; Zwartjes, Daphne G M; Heida, Tjitske; De Deurwaerdère, Philippe; Visser-Vandewalle, Veerle; Benazzouz, Abdelhamid

    2017-08-01

    The subthalamic nucleus (STN) receives monosynaptic glutamatergic afferents from different areas of the cortex, known as the "hyperdirect" pathway. The STN has been divided into three distinct subdivisions, motor, limbic, and associative parts in line with the concept of parallel information processing. The extent to which the parallel information processing coming from distinct cortical areas overlaps in the different territories of the STN is still a matter of debate and the proposed role of dopaminergic neurons in maintaining the coherence of responses to cortical inputs in each territory is not documented. Using extracellular electrophysiological approaches, we investigated to what degree the motor and non-motor regions in the STN are segregated in control and dopamine (DA) depleted rats. We performed electrical stimulation of different cortical areas and recorded STN neuronal responses. We showed that motor and non-motor cortico-subthalamic pathways are not fully segregated, but partially integrated in the rat. This integration was mostly present through the indirect pathway. The spatial distribution and response latencies were the same in sham and 6-hydroxydopamine lesioned animals. The inhibitory phase was, however, less apparent in the lesioned animals. In conclusion, this study provides the first evidence that motor and non-motor cortico-subthalamic pathways in the rat are not fully segregated, but partially integrated. This integration was mostly present through the indirect pathway. We also show that the inhibitory phase induced by GABAergic inputs from the external segment of the globus pallidus is reduced in the DA-depleted animals.

  4. Telomere Capping Proteins are Structurally Related to RPA with an additional Telomere-Specific Domain

    SciTech Connect

    Gelinas, A.; Paschini, M; Reyes, F; Heroux, A; Batey, R; Lundblad, V; Wuttke, D

    2009-01-01

    Telomeres must be capped to preserve chromosomal stability. The conserved Stn1 and Ten1 proteins are required for proper capping of the telomere, although the mechanistic details of how they contribute to telomere maintenance are unclear. Here, we report the crystal structures of the C-terminal domain of the Saccharomyces cerevisiae Stn1 and the Schizosaccharomyces pombe Ten1 proteins. These structures reveal striking similarities to corresponding subunits in the replication protein A complex, further supporting an evolutionary link between telomere maintenance proteins and DNA repair complexes. Our structural and in vivo data of Stn1 identify a new domain that has evolved to support a telomere-specific role in chromosome maintenance. These findings endorse a model of an evolutionarily conserved mechanism of DNA maintenance that has developed as a result of increased chromosomal structural complexity.

  5. Subthalamic nucleus-deep brain stimulation for early motor complications in Parkinson's disease-the EARLYSTIM trial: early is not always better.

    PubMed

    Mestre, Tiago A; Espay, Alberto J; Marras, Connie; Eckman, Mark H; Pollak, Pierre; Lang, Anthony E

    2014-12-01

    Subthalamic nucleus deep brain stimulation (STN-DBS) has revolutionized the management of disabling motor complications in Parkinson's disease. The EARLYSTIM trial applied this treatment to patients who had been experiencing motor complications for less than three years. STN-DBS significantly improved all primary and secondary outcome measures while best medical therapy failed to provide any improvement at the two-year follow-up time point. On face value these results strongly favor the application of STN-DBS far earlier than is currently applied, when patients are just beginning to experience problems with motor complications. Here we review the application of early DBS and the EARLYSTIM trial from the perspectives of clinical issues, health economics and study design and patient expectation of benefit. We conclude that the most relevant issue is not when to operate but on whom and that early is not always better. © 2014 International Parkinson and Movement Disorder Society.

  6. What neurophysiological recordings tell us about cognitive and behavioral functions of the human subthalamic nucleus.

    PubMed

    Marceglia, Sara; Fumagalli, Manuela; Priori, Alberto

    2011-01-01

    The behavioral implications of deep brain stimulation (DBS) observed in Parkinson's disease patients provided evidence for a possible nonexclusively motor role of the subthalamic nucleus (STN) in basal ganglia circuitry. Basal ganglia pathophysiology can be studied directly by the analysis of neural rhythms measured in local field potentials recorded through DBS electrodes. Recent studies demonstrated that specific oscillations in the STN are involved in cognitive and behavioral information processing: action representation is mediated through β oscillations (13-35 Hz); cognitive information related to decision-making processes is mediated through the low-frequency oscillation (5-12 Hz); and limbic and emotional information is mediated through the α oscillation (8-12 Hz). These results revealed an important involvement of STN in decisional processes, cognitive functions, emotion control and conflict that could explain the post-DBS occurrence of behavioral disturbances.

  7. Subthalamic nucleus stimulation reverses mediofrontal influence over decision threshold.

    PubMed

    Cavanagh, James F; Wiecki, Thomas V; Cohen, Michael X; Figueroa, Christina M; Samanta, Johan; Sherman, Scott J; Frank, Michael J

    2011-09-25

    It takes effort and time to tame one's impulses. Although medial prefrontal cortex (mPFC) is broadly implicated in effortful control over behavior, the subthalamic nucleus (STN) is specifically thought to contribute by acting as a brake on cortico-striatal function during decision conflict, buying time until the right decision can be made. Using the drift diffusion model of decision making, we found that trial-to-trial increases in mPFC activity (EEG theta power, 4-8 Hz) were related to an increased threshold for evidence accumulation (decision threshold) as a function of conflict. Deep brain stimulation of the STN in individuals with Parkinson's disease reversed this relationship, resulting in impulsive choice. In addition, intracranial recordings of the STN area revealed increased activity (2.5-5 Hz) during these same high-conflict decisions. Activity in these slow frequency bands may reflect a neural substrate for cortico-basal ganglia communication regulating decision processes.

  8. Older Candidates for Subthalamic Deep Brain Stimulation in Parkinson's Disease Have a Higher Incidence of Psychiatric Serious Adverse Events

    PubMed Central

    Cozac, Vitalii V.; Ehrensperger, Michael M.; Gschwandtner, Ute; Hatz, Florian; Meyer, Antonia; Monsch, Andreas U.; Schuepbach, Michael; Taub, Ethan; Fuhr, Peter

    2016-01-01

    Objective: To investigate the incidence of serious adverse events (SAE) of subthalamic deep brain stimulation (STN-DBS) in elderly patients with Parkinson's disease (PD). Methods: We investigated a group of 26 patients with PD who underwent STN-DBS at mean age 63.2 ± 3.3 years. The operated patients from the EARLYSTIM study (mean age 52.9 ± 6.6) were used as a comparison group. Incidences of SAE were compared between these groups. Results: A higher incidence of psychosis and hallucinations was found in these elderly patients compared to the younger patients in the EARLYSTIM study (p < 0.01). Conclusions: The higher incidence of STN-DBS-related psychiatric complications underscores the need for comprehensive psychiatric pre- and postoperative assessment in older DBS candidates. However, these psychiatric SAE were transient, and the benefits of DBS clearly outweighed its adverse effects. PMID:27375478

  9. Decoding gripping force based on local field potentials recorded from subthalamic nucleus in humans.

    PubMed

    Tan, Huiling; Pogosyan, Alek; Ashkan, Keyoumars; Green, Alexander L; Aziz, Tipu; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Hariz, Marwan; Brown, Peter

    2016-11-18

    The basal ganglia are known to be involved in the planning, execution and control of gripping force and movement vigour. Here we aim to define the nature of the basal ganglia control signal for force and to decode gripping force based on local field potential (LFP) activities recorded from the subthalamic nucleus (STN) in patients with deep brain stimulation (DBS) electrodes. We found that STN LFP activities in the gamma (55-90 Hz) and beta (13-30m Hz) bands were most informative about gripping force, and that a first order dynamic linear model with these STN LFP features as inputs can be used to decode the temporal profile of gripping force. Our results enhance the understanding of how the basal ganglia control gripping force, and also suggest that deep brain LFPs could potentially be used to decode movement parameters related to force and movement vigour for the development of advanced human-machine interfaces.

  10. The Evolution of the Society of Trauma Nurses' Leadership Institute.

    PubMed

    Krichten, Amy; Kyle, Amber

    2015-01-01

    The Society of Trauma Nurses (STN) understands the increasing complexity of trauma care and the vital leadership role nurses play. In 2009, the STN took the initiative to form a Leadership Committee tasked with researching the possibility of developing a mechanism to offer trauma leaders opportunities in leadership development. Investigation and collaboration among the committee members, with input from the Board of Directors and the organization's executive director, resulted in the STN Leadership Institute. The Leadership Institute design is to equip trauma nurses with the tools needed to effectively lead from the bedside to the boardroom and beyond through web-based modules. Operationalization of the plan took intense focus and dedicated leadership. Following a pilot study, the initial cohort ran the first quarter of 2015. Because of the positive feedback and identified opportunities for improvement, the program will continue to be offered with further expansion planning underway.

  11. Differential effects of deep brain stimulation on verbal fluency.

    PubMed

    Ehlen, Felicitas; Schoenecker, Thomas; Kühn, Andrea A; Klostermann, Fabian

    2014-07-01

    We aimed at gaining insights into principles of subcortical lexical processing. Therefore, effects of deep brain stimulation (DBS) in different target structures on verbal fluency (VF) were tested. VF was assessed with active vs. inactivated DBS in 13 and 14 patients with DBS in the vicinity of the thalamic ventral intermediate nucleus (VIM) and, respectively, of the subthalamic nucleus (STN). Results were correlated to electrode localizations in postoperative MRI, and compared to those of 12 age-matched healthy controls. Patients' VF performance was generally below normal. However, while activation of DBS in the vicinity of VIM provoked marked VF decline, it induced subtle phonemic VF enhancement in the vicinity of STN. The effects correlated with electrode localizations in left hemispheric stimulation sites. The results show distinct dependencies of VF on DBS in the vicinity of VIM vs. STN. Particular risks for deterioration occur in patients with relatively ventromedial thalamic electrodes. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Bilateral subthalamic nucleus deep brain stimulation for refractory total body dystonia secondary to metabolic autopallidotomy in a 4-year-old boy with infantile methylmalonic acidemia: case report.

    PubMed

    Chakraborti, Santo; Hasegawa, Harutomo; Lumsden, Daniel E; Ali, Wisam; Kaminska, Margaret; Lin, Jean-Pierre; Ashkan, Keyoumars

    2013-10-01

    The methylmalonic acidemias (MMAs) are a group of inborn errors of metabolism resulting in the accumulation of methylmalonic acid in body tissues and fluids. A recognized complication of MMA is bilateral liquefaction of the globus pallidi, resulting in a fulminant total body dystonia of childhood often refractory to medical treatment. This case of total body dystonia due to MMA in a 4-year-old boy had been medically refractory for 15 months. Complete metabolic destructive liquefaction of the pallidi, that is, autopallidotomy, necessitated an alternative, bilateral subthalamic nucleus (STN) target for deep brain stimulation (DBS) with a marked improvement in dystonia and reduction in pain. The case illustrates the efficacy of STN DBS in this condition and the technical challenges in targeting the STN in a small child.

  13. Investigation of morphometric variability of subthalamic nucleus, red nucleus, and substantia nigra in advanced Parkinson's disease patients using automatic segmentation and PCA-based analysis.

    PubMed

    Xiao, Yiming; Jannin, Pierre; D'Albis, Tiziano; Guizard, Nicolas; Haegelen, Claire; Lalys, Florent; Vérin, Marc; Collins, D Louis

    2014-09-01

    Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective surgical therapy to treat Parkinson's disease (PD). Conventional methods employ standard atlas coordinates to target the STN, which, along with the adjacent red nucleus (RN) and substantia nigra (SN), are not well visualized on conventional T1w MRIs. However, the positions and sizes of the nuclei may be more variable than the standard atlas, thus making the pre-surgical plans inaccurate. We investigated the morphometric variability of the STN, RN and SN by using label-fusion segmentation results from 3T high resolution T2w MRIs of 33 advanced PD patients. In addition to comparing the size and position measurements of the cohort to the Talairach atlas, principal component analysis (PCA) was performed to acquire more intuitive and detailed perspectives of the measured variability. Lastly, the potential correlation between the variability shown by PCA results and the clinical scores was explored.

  14. Perceived articulatory precision in patients with Parkinson's disease after deep brain stimulation of subthalamic nucleus and caudal zona incerta.

    PubMed

    Eklund, Elisabeth; Qvist, Johanna; Sandström, Lena; Viklund, Fanny; Van Doorn, Jan; Karlsson, Fredrik

    2015-02-01

    The effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and caudal zona incerta (cZi) on speech articulation in patients with Parkinson's disease (PD) was investigated. Read speech samples were collected from nine patients with STN-DBS and 10 with cZi-DBS. The recordings were made pre-operatively and 12 months post-operatively with stimulator on and off (on medication). Blinded, randomised, repeated perceptual assessments were performed on words and isolated fricatives extracted from the recordings to assess (1) overall articulatory quality ratings, (2) frequency of occurrence of misarticulation patterns and (3) fricative production. Statistically significant worsening of articulatory measures on- compared with off-stimulation occurred in the cZi-DBS group, with deteriorated articulatory precision ratings, increased presence of misarticulations (predominately altered realisations of plosives and fricatives) and a reduced accuracy in fricative production. A similar, but not significant, trend was found for the STN-DBS group.

  15. Imaging Impulsivity in Parkinson's Disease and the Contribution of the Subthalamic Nucleus

    PubMed Central

    Ray, Nicola; Antonelli, Francesca; Strafella, Antonio P.

    2011-01-01

    Taking risks is a natural human response, but, in some, risk taking is compulsive and may be detrimental. The subthalamic nucleus (STN) is thought to play a large role in our ability to inhibit responses. Differences between individuals' ability to inhibit inappropriate responses may underlie both the normal variation in trait impulsivity in the healthy population, as well as the pathological compulsions experienced by those with impulse control disorders (ICDs). Thus, we review the role of the STN in response inhibition, with a particular focus on studies employing imaging methodology. We also review the latest evidence that disruption of the function of the STN by deep brain stimulation in patients with Parkinson's disease can increase impulsivity. PMID:21765999

  16. [Surgery of the subthalamic nucleus in Parkinson's disease].

    PubMed

    Linazasoro, G; Guridi, J; Rodríguez, M C; Gorospe, A; Ramos, E; Ruibal, M; Obeso, J A

    The subthalamic nucleus (STN) plays a crucial part in the pathophysiology of Parkinsonism. Its inactivation improves all the main signs and symptoms of Parkinson's disease. Surgery of the STN in patients with the disease is effective and the benefit/risk relationship very favorable. Although the dyskinesias are not a definite limitation, it seems most reasonable to use techniques of deep cerebral stimulation until greater experience has been obtained with subthalamotomy. The long term efficacy is being studied and preliminary data indicate that the clinical benefit obtained is maintained in the long term. More studies are necessary to determine the mechanism of action of surgery on the STN. The potential neuroprotector effect of subthalamic surgery requires more extensive study.

  17. Neural Circuit Modulation During Deep Brain Stimulation at the Subthalamic Nucleus for Parkinson's Disease: What Have We Learned from Neuroimaging Studies?

    PubMed Central

    Albaugh, Daniel L.

    2014-01-01

    Abstract Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) represents a powerful clinical tool for the alleviation of many motor symptoms that are associated with Parkinson's disease. Despite its extensive use, the underlying therapeutic mechanisms of STN-DBS remain poorly understood. In the present review, we integrate and discuss recent literature examining the network effects of STN-DBS for Parkinson's disease, placing emphasis on neuroimaging findings, including functional magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography. These techniques enable the noninvasive detection of brain regions that are modulated by DBS on a whole-brain scale, representing a key experimental strength given the diffuse and far-reaching effects of electrical field stimulation. By examining these data in the context of multiple hypotheses of DBS action, generally developed through clinical and physiological observations, we define a multitude of consistencies and inconsistencies in the developing literature of this rapidly moving field. PMID:24147633

  18. Interaction of noradrenergic pharmacological manipulation and subthalamic stimulation on movement initiation control in Parkinson's disease.

    PubMed

    Albares, Marion; Thobois, Stéphane; Favre, Emilie; Broussolle, Emmanuel; Polo, Gustavo; Domenech, Philippe; Boulinguez, Philippe; Ballanger, Bénédicte

    2015-01-01

    Slowness in movement initiation (akinesia) is a cardinal feature of Parkinson's disease (PD), which is still poorly understood. Notably, akinesia is restored by subthalamic nucleus deep brain stimulation (STN-DBS) but not fully reversed by current dopaminergic treatments. It was recently suggested that this disorder is of executive nature (related to inhibitory control of response) and of non-dopaminergic origin (possibly noradrenergic). To test the double hypothesis that: 1) the ability to control movement initiation is modified by noradrenergic neurotransmission modulation, and 2) this effect is mediated by the regulation of STN activity. Sixteen STN-DBS PD patients were enrolled in a placebo-controlled study investigating the effects of noradrenergic attenuation by clonidine (∝2-adrenergic receptor agonist). Movement initiation latency was assessed by means of a cue-target reaction time task. Patients, who remained on their chronic dopaminergic medication, were tested on four sessions: two with placebo (ON- or OFF-DBS), and two with a 150 μg oral dose of clonidine (ON- or OFF-DBS). In the OFF stimulation condition, patients were locked into a mode of control maintaining inappropriate response inhibition. This dysfunctional executive setting was overcome by STN-DBS. Clonidine, however, was found to impair specifically the ability to release inhibitory control in the ON-DBS state. Overall our results suggest an important implication of the noradrenergic system in the pathophysiology of akinesia in PD. Reducing the noradrenergic "tonus" may even block the positive action of STN-DBS on akinesia, suggesting, at least by part, a noradrenergic-dependent STN-DBS efficiency. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. The rotenone-induced rat model of Parkinson's disease: behavioral and electrophysiological findings.

    PubMed

    von Wrangel, Christof; Schwabe, Kerstin; John, Nadine; Krauss, Joachim K; Alam, Mesbah

    2015-02-15

    Exposure to rotenone leads to parkinsonian features, such as loss of dopaminergic neurons in the substantia nigra and motor impairment, however, the validity of this model has recently been questioned. In rodent and monkey models of Parkinson's disease (PD) abnormal neuronal activity in the basal ganglia motor loop has been described, with hyperactivity of the subthalamic nucleus (STN) similar to that found in PD. The present study aims at providing new and more specific evidence for the validity of the rotenone rat model of PD by examining whether neuronal activity in the STN is altered. Male Sprague Dawley rats were treated with rotenone injections (2.5mg/kg bodyweight intraperitoneally) for 60 days. Behavioral analysis showed an impairment in the rotarod and hanging wire test in the rotenone group (p<0.05), accompanied by a decline in tyrosine hydroxylase immunoreactive neurons in the nigro-striatal region (p<0.001). Thereafter, single unit (SU) activities and local field potentials were recorded in the STN in urethane anesthetized rats. The SU analysis revealed a higher neuronal discharge rate (p<0.001), more bursts per minute (p=0.006) and a higher oscillatory activity (p=0.008) in the STN of rotenone treated rats. Spectral analysis showed an increase of relative beta power in the STN as well as in the motor cortex. We found electrophysiological key features of PD pathology and pathophysiology in the STN of rotenone treated rats. Therefore, the rotenone-induced rat model of PD deserves further attention since it covers more aspects than dopamine depletion and implies the reproducibility of PD specific features. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Comparison of frequencies of non motor symptoms in Indian Parkinson’s disease patients on medical management versus deep brain stimulation: A case-control study

    PubMed Central

    Rukmini Mridula, Kandadai; Borgohain, Rupam; Jabeen, Shaik Afshan; Padmaja, Gaddamanugu; Bandaru, VCS Srinivasarao; Ankathi, Praveen; Kanikannan, Meena A; Ali Khan, Mohammed Shujath

    2015-01-01

    Background: Non motor symptoms (NMS) of idiopathic Parkinson’s disease (PD) are a major cause of disability and recognition of these symptoms and treatment is important for comprehensive health care. Deep brain stimulation of bilateral subthalamic nucleus deep brain stimulation (STN DBS) has been shown to improve motor symptoms in PD and effects on NMS are unknown. To investigate the NMS among PD patients who underwent STN DBS. Methods: We recruited prospectively 56 patients with PD, who had undergone bilateral STN DBS and 53 age and duration of illness matched PD patients on dopaminergic therapy (controls). NMS were assessed using 30 item questionnaire NMS Quest. These questions evaluated 9 domains, gastrointestinal, urinary, cardiovascular, sexual, cognition (apathy/attention/memory), anxiety/depression, hallucinations/delusions, sleep and miscellaneous. Comparison was done on individual symptoms as well as in various domains. This study was carried at Nizam’s Institution of Medical Sciences and study period was from January 2011 to December 2012. Results: Patients who underwent STN DBS had a significantly lower mean total score on NMS quest (6.7 ± 3.8) compared to controls (8.4 ± 3.7) (P < 0.00100). Symptoms in the domains of cardiovascular, gastrointestinal, sleep were significantly less frequent while sexual disturbances were significantly more frequent among patients compared to controls. On individual symptom analysis, nocturia  (P < 0.00010), unexplained pains (P < 0.00010), nausea and vomiting, constipation, lightheadedness, depression, and insomnia were less prevalent, while sexual disturbances were significantly more common in STN DBS group compared to controls. Conclusion: Bilateral STN DBS not only improves the motor symptoms but also improves many NMS in PD patients. PMID:26056553

  1. Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys.

    PubMed

    Masilamoni, Gunasingh Jeyaraj; Groover, Olivia; Smith, Yoland

    2017-04-01

    There is anatomical and functional evidence that ventral midbrain dopaminergic (DA) cell groups and the subthalamic nucleus (STN) receive noradrenergic innervation in rodents, but much less is known about these interactions in primates. Degeneration of NE neurons in the locus coeruleus (LC) and related brainstem NE cell groups is a well-established pathological feature of Parkinson's disease (PD), but the development of such pathology in animal models of PD has been inconsistent across species and laboratories. We recently demonstrated 30-40% neuronal loss in the LC, A5 and A6 NE cell groups of rhesus monkeys rendered parkinsonian by chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study, we used dopamine-beta-hydroxylase (DβH) immunocytochemistry to assess the impact of this neuronal loss on the number of NE terminal-like varicosities in the substantia nigra pars compacta (SNC), ventral tegmental area (VTA), retrorubral field (RRF) and STN of MPTP-treated parkinsonian monkeys. Our findings reveal that the NE innervation of the ventral midbrain and STN of normal monkeys is heterogeneously distributed being far more extensive in the VTA, RRF and dorsal tier of the SNC than in the ventral SNC and STN. In parkinsonian monkeys, all regions underwent a significant (~50-70%) decrease in NE innervation. At the electron microscopic level, some DβH-positive terminals formed asymmetric axo-dendritic synapses in VTA and STN. These findings demonstrate that the VTA, RRF and SNCd are the main ventral midbrain targets of ascending NE inputs, and that these connections undergo a major break-down in chronically MPTP-treated parkinsonian monkeys. This severe degeneration of the ascending NE system may contribute to the pathophysiology of ventral midbrain and STN neurons in PD.

  2. Subthalamic Stimulation Reduces Vowel Space at the Initiation of Sustained Production: Implications for Articulatory Motor Control in Parkinson's Disease.

    PubMed

    Sidtis, John J; Alken, Amy G; Tagliati, Michele; Alterman, Ron; Van Lancker Sidtis, Diana

    2016-03-19

    Stimulation of the subthalamic nuclei (STN) is an effective treatment for Parkinson's disease, but complaints of speech difficulties after surgery have been difficult to quantify. Speech measures do not convincingly account for such reports. This study examined STN stimulation effects on vowel production, in order to probe whether DBS affects articulatory posturing. The objective was to compare positioning during the initiation phase with the steady prolongation phase by measuring vowel spaces for three "corner" vowels at these two time frames. Vowel space was measured over the initial 0.25 sec of sustained productions of high front (/i/), high back (/u/) and low vowels (/a/), and again during a 2 sec segment at the midpoint. Eight right-handed male subjects with bilateral STN stimulation and seven age-matched male controls were studied based on their participation in a larger study that included functional imaging. Mean values: age = 57±4.6 yrs; PD duration = 12.3±2.7 yrs; duration of DBS = 25.6±21.2 mos, and UPDRS III speech score = 1.6±0.7. STN subjects were studied off medication at their therapeutic DBS settings and again with their stimulators off, counter-balanced order. Vowel space was larger in the initiation phase compared to the midpoint for both the control and the STN subjects off stimulation. With stimulation on, however, the initial vowel space was significantly reduced to the area measured at the mid-point. For the three vowels, the acoustics were differentially affected, in accordance with expected effects of front versus back position in the vocal tract. STN stimulation appears to constrain initial articulatory gestures for vowel production, raising the possibility that articulatory positions normally used in speech are similarly constrained.

  3. Effect of low-frequency deep brain stimulation on sensory thresholds in Parkinson's disease.

    PubMed

    Belasen, Abigail; Rizvi, Khizer; Gee, Lucy E; Yeung, Philip; Prusik, Julia; Ramirez-Zamora, Adolfo; Hanspal, Era; Paiva, Priscilla; Durphy, Jennifer; Argoff, Charles E; Pilitsis, Julie G

    2017-02-01

    OBJECTIVE Chronic pain is a major distressing symptom of Parkinson's disease (PD) that is often undertreated. Subthalamic nucleus (STN) deep brain stimulation (DBS) delivers high-frequency stimulation (HFS) to patients with PD and has been effective in pain relief in a subset of these patients. However, up to 74% of patients develop new pain concerns while receiving STN DBS. Here the authors explore whether altering the frequency of STN DBS changes pain perception as measured through quantitative sensory testing (QST). METHODS Using QST, the authors measured thermal and mechanical detection and pain thresholds in 19 patients undergoing DBS via HFS, low-frequency stimulation (LFS), and off conditions in a randomized order. Testing was performed in the region of the body with the most pain and in the lower back in patients without chronic pain. RESULTS In the patients with chronic pain, LFS significantly reduced heat detection thresholds as compared with thresholds following HFS (p = 0.029) and in the off state (p = 0.010). Moreover, LFS resulted in increased detection thresholds for mechanical pressure (p = 0.020) and vibration (p = 0.040) compared with these thresholds following HFS. Neither LFS nor HFS led to changes in other mechanical thresholds. In patients without chronic pain, LFS significantly increased mechanical pain thresholds in response to the 40-g pinprick compared with thresholds following HFS (p = 0.032). CONCLUSIONS Recent literature has suggested that STN LFS can be useful in treating nonmotor symptoms of PD. Here the authors demonstrated that LFS modulates thermal and mechanical detection to a greater extent than HFS. Low-frequency stimulation is an innovative means of modulating chronic pain in PD patients receiving STN DBS. The authors suggest that STN LFS may be a future option to consider when treating Parkinson's patients in whom pain remains the predominant complaint.

  4. Increasing extracellular potassium results in subthalamic neuron activity resembling that seen in a 6-hydroxydopamine lesion.

    PubMed

    Strauss, Ulf; Zhou, Fu-Wen; Henning, Jeannette; Battefeld, Arne; Wree, Andreas; Köhling, Rüdiger; Haas, Stefan Jean-Pierre; Benecke, Reiner; Rolfs, Arndt; Gimsa, Ulrike

    2008-06-01

    Abnormal neuronal activity in the subthalamic nucleus (STN) plays a crucial role in the pathophysiology of Parkinson's disease (PD). Although altered extracellular potassium concentration ([K+]o) and sensitivity to [K+]o modulates neuronal activity, little is known about the potassium balance in the healthy and diseased STN. In vivo measurements of [K+]o using ion-selective electrodes demonstrated a twofold increase in the decay time constant of lesion-induced [K+]o transients in the STN of adult Wistar rats with a unilateral 6-hydroxydopamine (6-OHDA) median forebrain bundle lesion, employed as a model of PD, compared with nonlesioned rats. Various [K+]o concentrations (1.5-12.5 mM) were applied to in vitro slice preparations of three experimental groups of STN slices from nonlesioned control rats, ipsilateral hemispheres, and contralateral hemispheres of lesioned rats. The majority of STN neurons of nonlesioned rats and in slices contralateral to the lesion fired spontaneously, predominantly in a regular pattern, whereas those in slices ipsilateral to the lesion fired more irregularly or even in bursts. Experimentally increased [K+]o led to an increase in the number of spontaneously firing neurons and action potential firing rates in all groups. This was accompanied by a decrease in the amplitude of post spike afterhyperpolarization (AHP) and the amplitude and duration of the posttrain AHP. Lesion effects in ipsilateral neurons at physiological [K+]o resembled the effects of elevated [K+]o in nonlesioned rats. Our data suggest that changed potassium sensitivity due to conductivity alterations and delayed clearance may be critical for shaping STN activity in parkinsonian states.

  5. Different effectiveness of subthalamic deep brain stimulation in Parkinson's disease: A comparative cohort study at 1 year and 5 years.

    PubMed

    Jiang, Jiin-Ling; Chen, Shin-Yuan; Hsieh, Tsung-Cheng; Lee, Chi-Wei; Lin, Sheng-Huang; Tsai, Sheng-Tzung

    2015-09-01

    Subthalamic nucleus deep brain stimulation (STN-DBS) has been shown to produce long-term symptom improvement in Parkinson's disease. The aim of this study was to identify the target symptoms that show the most improvement at 1 year and at 5 years after STN-DBS. This was a 5-year cohort study of 41 consecutive patients treated with bilateral STN-DBS. Clinical evaluations were performed 1 month prior to surgery and 1 year and 5 years after surgery. The outcome measurements at 1 year and 5 years were the changes compared with the baseline in Unified Parkinson's Disease Rating Scale (UPDRS) parts I, II, III, and IV scores, the Hoehn and Yahr stage, and Schwab and England Activities of Daily Living (SEADL) scores in the conditions of off-medication/on-stimulation and off-medication/off-stimulation. Further analysis included changes in the levodopa equivalent daily dose. When compared to the preoperative baseline off-medication condition, significant improvements were observed in the UPDRS parts I, II, III, and IV and SEADL (p < 0.001) scores in the off-medication/on-stimulation condition 1 year after STN-DBS. Five years after STN-DBS, improvements in UPDRS scores were observed only for parts II, III, and IV (p < 0.001). In the off-medication/off-stimulation condition, no significant improvement was observed. At 5 years, significant deteriorations were observed in scores for the UPDRS part III axial subitem (p = 0.005), UPDRS part I (p = 0.005), UPDRS part II (p < 0.001), and SEADL (p = 0.001). The long-term effect of STN-DBS on motor function is promising, although the magnitude of its effectiveness varied over the 5-year period. Copyright © 2013. Published by Elsevier B.V.

  6. Myths and facts about the EARLYSTIM study.

    PubMed

    Schüpbach, W M Michael; Rau, Jörn; Houeto, Jean-Luc; Krack, Paul; Schnitzler, Alfons; Schade-Brittinger, Carmen; Timmermann, Lars; Deuschl, Günther

    2014-12-01

    DBS of the STN improves quality of life (QoL) and motor function not only in advanced Parkinson's disease (PD), but also in PD with early motor complications, as shown in the recent EARLYSTIM study. In spite of the evidence in favor of STN-DBS, the findings of the EARLYSTIM study have recently been controversially debated. Here, we argue that a placebo or lessebo effect is unlikely to have relevantly contributed to the favorable outcome of STN-DBS in the EARLYSTIM study. The method of quantification of the placebo effect of DBS in a previous publication reveals flaws leading to implausible results, and therefore the placebo effect of DBS remains currently elusive, especially because blinding of PD patients with STN-DBS as a crucial preassumption for assessing a placebo effect is practically impossible. Moreover, we claim that the extent of such a placebo effect is most likely very small. Specific challenges of STN-DBS at an earlier stage of PD and inclusion criteria are the risk of inclusion of patients who later evolve to atypical parkinsonism, the risk of a floor effect for the benefit from DBS, the need for experienced multidisciplinary care including prevention of suicidal behavior, and the need for highly qualified long-term follow-up. The EARLYSTIM study has shown that STN-DBS may be proposed earlier on in the course of PD, as soon as motor complications start to cause relevant disability despite proper medical management. This can lead to a gain of several years of improved QoL.

  7. Effective connectivity of the subthalamic nucleus–globus pallidus network during Parkinsonian oscillations

    PubMed Central

    Nevado-Holgado, Alejo J; Mallet, Nicolas; Magill, Peter J; Bogacz, Rafal

    2014-01-01

    In Parkinsonism, subthalamic nucleus (STN) neurons and two types of external globus pallidus (GP) neuron inappropriately synchronise their firing in time with slow (∼1 Hz) or beta (13–30 Hz) oscillations in cortex. We recorded the activities of STN, Type-I GP (GP-TI) and Type-A GP (GP-TA) neurons in anaesthetised Parkinsonian rats during such oscillations to constrain a series of computational models that systematically explored the effective connections and physiological parameters underlying neuronal rhythmic firing and phase preferences in vivo. The best candidate model, identified with a genetic algorithm optimising accuracy/complexity measures, faithfully reproduced experimental data and predicted that the effective connections of GP-TI and GP-TA neurons are quantitatively different. Estimated inhibitory connections from striatum were much stronger to GP-TI neurons than to GP-TA neurons, whereas excitatory connections from thalamus were much stronger to GP-TA and STN neurons than to GP-TI neurons. Reciprocal connections between GP-TI and STN neurons were matched in weight, but those between GP-TA and STN neurons were not; only GP-TI neurons sent substantial connections back to STN. Different connection weights between and within the two types of GP neuron were also evident. Adding to connection differences, GP-TA and GP-TI neurons were predicted to have disparate intrinsic physiological properties, reflected in distinct autonomous firing rates. Our results elucidate potential substrates of GP functional dichotomy, and emphasise that rhythmic inputs from striatum, thalamus and cortex are important for setting activity in the STN–GP network during Parkinsonian beta oscillations, suggesting they arise from interactions between most nodes of basal ganglia–thalamocortical circuits. PMID:24344162

  8. High-Frequency Stimulation at the Subthalamic Nucleus Suppresses Excessive Self-Grooming in Autism-Like Mouse Models

    PubMed Central

    Chang, Andrew D; Berges, Victoria A; Chung, Sunho J; Fridman, Gene Y; Baraban, Jay M; Reti, Irving M

    2016-01-01

    Approximately one quarter of individuals with an autism spectrum disorder (ASD) display self-injurious behavior (SIB) ranging from head banging to self-directed biting and punching. Sometimes, these behaviors are extreme and unresponsive to pharmacological and behavioral therapies. We have found electroconvulsive therapy (ECT) can produce life-changing results, with more than 90% suppression of SIB frequency. However, these patients typically require frequent maintenance ECT (mECT), as often as every 5 days, to sustain the improvement gained during the acute course. Long-term consequences of such frequent mECT started as early as childhood in some cases are unknown. Accordingly, there is a need for alternative forms of chronic stimulation for these patients. To explore the feasibility of deep brain stimulation (DBS) for intractable SIB seen in some patients with an ASD, we utilized two genetically distinct mouse models demonstrating excessive self-grooming, namely the Viaat-Mecp2−/y and Shank3B−/− lines, and administered high-frequency stimulation (HFS) via implanted electrodes at the subthalamic nucleus (STN-HFS). We found that STN-HFS significantly suppressed excessive self-grooming in both genetic lines. Suppression occurs both acutely when stimulation is switched on, and persists for several days after HFS is stopped. This effect was not explained by a change in locomotor activity, which was unaffected by STN-HFS. Likewise, social interaction deficits were not corrected by STN-HFS. Our data show STN-HFS suppresses excessive self-grooming in two autism-like mouse models, raising the possibility DBS might be used to treat intractable SIB associated with ASDs. Further studies are required to explore the circuitry engaged by STN-HFS, as well as other potential stimulation sites. Such studies might also yield clues about pathways, which could be modulated by non-invasive stimulatory techniques. PMID:26606849

  9. High-Frequency Stimulation of the Subthalamic Nucleus Restores Neural and Behavioral Functions During Reaction Time Task in a Rat Model of Parkinson’s Disease

    PubMed Central

    Li, Xiang-Hong; Wang, Jin-Yan; Gao, Ge; Chang, Jing-Yu; Woodward, Donald J.; Luo, Fei

    2015-01-01

    Deep brain stimulation (DBS) has been used in the clinic to treat Parkinson’s disease (PD) and other neuropsychiatric disorders. Our previous work has shown that DBS in the subthalamic nucleus (STN) can improve major motor deficits, and induce a variety of neural responses in rats with unilateral dopamine (DA) lesions. In the present study, we examined the effect of STN DBS on reaction time (RT) performance and parallel changes in neural activity in the cortico-basal ganglia regions of partially bilateral DA- lesioned rats. We recorded neural activity with a multiple-channel single-unit electrode system in the primary motor cortex (MI), the STN, and the substantia nigra pars reticulata (SNr) during RT test. RT performance was severely impaired following bilateral injection of 6-OHDA into the dorsolateral part of the striatum. In parallel with such behavioral impairments, the number of responsive neurons to different behavioral events was remarkably decreased after DA lesion. Bilateral STN DBS improved RT performance in 6-OHDA lesioned rats, and restored operational behavior-related neural responses in cortico-basal ganglia regions. These behavioral and electrophysiological effects of DBS lasted nearly an hour after DBS termination. These results demonstrate that a partial DA lesion-induced impairment of RT performance is associated with changes in neural activity in the cortico-basal ganglia circuit. Furthermore, STN DBS can reverse changes in behavior and neural activity caused by partial DA depletion. The observed long-lasting beneficial effect of STN DBS suggests the involvement of the mechanism of neural plasticity in modulating corticobasal ganglia circuits. PMID:20025062

  10. Modulation of beta oscillations in the subthalamic area during motor imagery in Parkinson's disease.

    PubMed

    Kühn, Andrea A; Doyle, Louise; Pogosyan, Alek; Yarrow, Kielan; Kupsch, Andreas; Schneider, Gerd-Helge; Hariz, Marwan I; Trottenberg, Thomas; Brown, Peter

    2006-03-01

    Activation of the basal ganglia has been shown during the preparation and execution of movement. However, the extent to which the activation during movement is related to efferent processes or feedback-related motor control remains unclear. We used motor imagery (MI), which eliminates peripheral feedback, to further investigate the role of the subthalamic area in the feedforward organization of movement. We recorded local field potential (LPF) activity from the region of the subthalamic nucleus (STN) in eight patients with Parkinson's disease off dopaminergic medication during performance of a warned reaction time task. Patients were instructed to either extend the wrist [motor execution (ME)], to imagine performing the same task without any overt movement (MI), or, in a subgroup, to perform a non-motor visual imagery (VI) task. MI led to event-related desynchronization (ERD) of oscillatory beta activity in the region of the STN in all patients that was similar in frequency, time course and degree to the ERD occurring during ME. The degree of ERD during MI correlated with the ERD in trials of ME and, like ME, was accompanied by a decrease in cortico-STN coherence, so that STN LFP activity during MI was similar to that in ME. The ERD in ME and MI were both significantly larger than the ERD in VI. In contrast, event-related synchronization (ERS) was significantly smaller in trials of MI, and even smaller in trials of VI, than during ME. The data suggest that the activity in the region of the human STN indexed by the ERD during movement is related to the feedforward organization of movement and is relatively independent of peripheral feedback. In contrast, sensorimotor feedback is an important factor in the ERS occurring in the STN area after completion of movement, consistent with a role for this region in trial-to-trial motor learning or the re-establishment of postural set following movements.

  11. Increased extracellular dopamine and 5-hydroxytryptamine levels contribute to enhanced subthalamic nucleus neural activity during exhausting exercise

    PubMed Central

    Hu, Y; Liu, X

    2015-01-01

    The purpose of the study was to explore the mechanism underlying the enhanced subthalamic nucleus (STN) neural activity during exhausting exercise from the perspective of monoamine neurotransmitters and changes of their corresponding receptors. Rats were randomly divided into microdialysis and immunohistochemistry study groups. For microdialysis study, extracellular fluid of the STN was continuously collected with a microdialysis probe before, during and 90 min after one bout of exhausting exercise. Dopamine (DA) and 5-hydroxytryptamine (5-HT) levels were subsequently detected with high-performance liquid chromatography (HPLC). For immunohistochemistry study, the expression of DRD2 and HT2C receptors in the STN, before, immediately after and 90 min after exhaustion was detected through immunohistochemistry technique. Microdialysis study results showed that the extracellular DA and 5-HT neurotransmitters increased significantly throughout the procedure of exhausting exercise and the recovery period (P<0.05 or P<0.01). Immunohistochemistry study results showed that the expression levels of DRD2 and HT2C in the rat STN immediately after exhausting exercise and at the time point of 90 min after exhaustion were both higher than those of the rest condition, but the difference was not significant (P>0.05). Our results suggest that the increased extracellular DA and 5-HT in the STN might be one important factor leading to the enhanced STN neural activity and the development of fatigue during exhausting exercise. This study may essentially offer useful evidence for better understanding of the mechanism of the central type of exercise-induced fatigue. PMID:26424920

  12. Resveratrol suppresses glial activation and alleviates trigeminal neuralgia via activation of AMPK.

    PubMed

    Yang, Yan-jing; Hu, Liang; Xia, Ye-peng; Jiang, Chun-yi; Miao, Chen; Yang, Chun-qing; Yuan, Miao; Wang, Lin

    2016-04-19

    Glial activation and neuroinflammation in the spinal trigeminal nucleus (STN) play a pivotal role in the genesis and maintenance of trigeminal neuralgia (TN). Resveratrol, a natural compound from grape and red wine, has a potential anti-inflammatory effect. We hypothesized that resveratrol could significantly suppress neuroinflammation in the STN mediated by glial activation and further relieve TN. In this study, we evaluated whether resveratrol could alleviate trigeminal allodynia and explore the mechanism underlying the antinociceptive effect of resveratrol. Animals were orally injected with resveratrol after chronic constriction injury (CCI) of the infraorbital nerve. Mechanical thresholds of the affected whisker pad were measured to assess nociceptive behaviors. The STN was harvested to quantify the changing levels of p-NR1, p-PKC, TNF-α, and IL1-β by western blotting and detect the expression of calcitonin gene-related peptide (CGRP) and c-Fos by immunofluorescence. Glial activation was observed by immunofluorescence and western blotting. Mitogen-activated protein kinase (MAPK) phosphorylation in vivo and in vitro was examined by western blotting. We found that resveratrol significantly attenuated trigeminal allodynia dose-dependently and decreased the increased expression of CGRP and c-Fos in the STN. Additionally, resveratrol showed an inhibitory effect on CCI-evoked astrocyte and microglia activation and reduced production of pro-inflammatory cytokines in the STN. Furthermore, the antinociceptive effect of resveratrol was partially mediated by reduced phosphorylation of MAP kinases via adenosine monophosphate-activated protein kinase (AMPK) activation. AMPK activation in the STN glia via resveratrol has utility in the treatment of CCI-induced neuroinflammation and further implicates AMPK as a novel target for the attenuation of trigeminal neuralgia.

  13. Subthalamic Stimulation Reduces Vowel Space at the Initiation of Sustained Production: Implications for Articulatory Motor Control in Parkinson’s Disease

    PubMed Central

    Sidtis, John J.; Alken, Amy G.; Tagliati, Michele; Alterman, Ron; Van Lancker Sidtis, Diana

    2016-01-01

    Background: Stimulation of the subthalamic nuclei (STN) is an effective treatment for Parkinson’s disease, but complaints of speech difficulties after surgery have been difficult to quantify. Speech measures do not convincingly account for such reports. Objective: This study examined STN stimulation effects on vowel production, in order to probe whether DBS affects articulatory posturing. The objective was to compare positioning during the initiation phase with the steady prolongation phase by measuring vowel spaces for three “corner” vowels at these two time frames. Methods: Vowel space was measured over the initial 0.25 sec of sustained productions of high front (/i/), high back (/u/) and low vowels (/a/), and again during a 2 sec segment at the midpoint. Eight right-handed male subjects with bilateral STN stimulation and seven age-matched male controls were studied based on their participation in a larger study that included functional imaging. Mean values: age = 57±4.6 yrs; PD duration = 12.3±2.7 yrs; duration of DBS = 25.6±21.2 mos, and UPDRS III speech score = 1.6±0.7. STN subjects were studied off medication at their therapeutic DBS settings and again with their stimulators off, counter-balanced order. Results: Vowel space was larger in the initiation phase compared to the midpoint for both the control and the STN subjects off stimulation. With stimulation on, however, the initial vowel space was significantly reduced to the area measured at the mid-point. For the three vowels, the acoustics were differentially affected, in accordance with expected effects of front versus back position in the vocal tract. Conclusions: STN stimulation appears to constrain initial articulatory gestures for vowel production, raising the possibility that articulatory positions normally used in speech are similarly constrained. PMID:27003219

  14. Motor behaviors in the sheep evoked by electrical stimulation of the subthalamic nucleus.

    PubMed

    Lentz, Linnea; Zhao, Yan; Kelly, Matthew T; Schindeldecker, William; Goetz, Steven; Nelson, Dwight E; Raike, Robert S

    2015-11-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is used to treat movement disorders, including advanced Parkinson's disease (PD). The pathogenesis of PD and the therapeutic mechanisms of DBS are not well understood. Large animal models are essential for investigating the mechanisms of PD and DBS. The purpose of this study was to develop a novel sheep model of STN DBS and quantify the stimulation-evoked motor behaviors. To do so, a large sample of animals was chronically-implanted with commercial DBS systems. Neuroimaging and histology revealed that the DBS leads were implanted accurately relative to the neurosurgical plan and also precisely relative to the STN. It was also possible to repeatedly conduct controlled evaluations of stimulation-evoked motor behavior in the awake-state. The evoked motor responses depended on the neuroanatomical location of the electrode contact selected for stimulation, as contacts proximal to the STN evoked movements at significantly lower voltages. Tissue stimulation modeling demonstrated that selecting any of the contacts stimulated the STN, whereas selecting the relatively distal contacts often also stimulated thalamus but only the distal-most contact stimulated internal capsule. The types of evoked motor behaviors were specific to the stimulation frequency, as low but not high frequencies consistently evoked movements resembling human tremor or dyskinesia. Electromyography confirmed that the muscle activity underlying the tremor-like movements in the sheep was consistent with human tremor. Overall, this work establishes that the sheep is a viable a large-animal platform for controlled testing of STN DBS with objective motor outcomes. Moreover, the results support the hypothesis that exaggerated low-frequency activity within individual nodes of the motor network can drive symptoms of human movement disorders, including tremor and dyskinesia. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Effects of varying subthalamic nucleus stimulation on apraxia of lid opening in Parkinson's disease.

    PubMed

    Tommasi, Giorgio; Krack, Paul; Fraix, Valérie; Pollak, Pierre

    2012-09-01

    Apraxia of lid opening (ALO) is a non-paralytic inability to open the eyes or sustain lid elevation at will. The exact pathophysiological mechanisms underlying the syndrome are still unknown. ALO has been reported in patients with Parkinson's disease (PD) after subthalamic nucleus (STN) deep brain stimulation (DBS), suggesting a possible involvement of the basal ganglia. We aimed to assess the effects of varying STN stimulation voltage on ALO in PD patients. Seven out of 14 PD patients with bilateral STN stimulation consecutively seen in our centre presented with ALO. We progressively increased voltage on each STN, using either 130 Hz (high-frequency stimulation, HFS) or 2 or 3 Hz (low-frequency stimulation, LFS). In five patients, HFS induced ALO time-locked to stimulation in 7 out of 10 STNs at a voltage higher than that used for chronic stimulation. LFS induced myoclonus in the pretarsal orbicularis oculi muscle (pOOm) with a rhythm synchronous to the frequency. In the other two patients with ALO already present at the time of the study, HFS improved ALO in 3 out of 4 STNs. ALO recurred within minutes of stimulation arrest. Our findings show that STN-DBS can have opposite effects on ALO. On the one hand, ALO is thought to be a corticobulbar side effect due to lateral current spreading from the STN, in which case it is necessary to use voltages below the ALO-inducing threshold. On the other hand, ALO may be considered a form of off-phase focal dystonia possibly improved by increasing the stimulation voltages.

  16. D2-like dopamine receptor-mediated modulation of activity-dependent plasticity at GABAergic synapses in the subthalamic nucleus

    PubMed Central

    Baufreton, Jérôme; Bevan, Mark D

    2008-01-01

    Reciprocally connected glutamatergic subthalamic nucleus (STN) and GABAergic external globus pallidus (GP) neurons normally exhibit weakly correlated, irregular activity but following the depletion of dopamine in Parkinson's disease they express more highly correlated, rhythmic bursting activity. Patch clamp recording was used to test the hypothesis that dopaminergic modulation reduces the capability of GABAergic inputs to pattern ‘pathological’ activity in STN neurons. Electrically evoked GABAA receptor-mediated IPSCs exhibited activity-dependent plasticity in STN neurons, i.e. IPSCs evoked at frequencies between 1 and 50 Hz exhibited depression that increased with the frequency of activity. Dopamine, the D2-like dopamine receptor agonist quinpirole and external media containing a low [Ca2+] reduced both the magnitude of IPSCs evoked at 1–50 Hz and synaptic depression at 10–50 Hz. Dopamine/quinpirole also reduced the frequency but not the amplitude of miniature IPSCs recorded in the presence of tetrodotoxin. D1-like and D4 agonists were ineffective and D2/3 but not D4 receptor antagonists reversed the effects of dopamine or quinpirole. Together these data suggest that presynaptic D2/3 dopamine receptors modulate the short-term dynamics of GABAergic transmission in the STN by lowering the initial probability of transmitter release. Simulated GABAA receptor-mediated synaptic conductances representative of control or modulated transmission were then generated in STN neurons using the dynamic clamp technique. Dopamine-modulated transmission was less effective at resetting autonomous activity or generating rebound burst firing than control transmission. The data therefore support the conclusion that dopamine acting at presynaptic D2-like receptors reduces the propensity for GABAergic transmission to generate correlated, bursting activity in STN neurons. PMID:18292127

  17. Subthalamic nucleus neuronal activity in Parkinson's disease and epilepsy subjects.

    PubMed

    Montgomery, Erwin B

    2008-01-01

    Activity from 113 subthalamic nucleus (STN) neurons from two epilepsy patients and 103 neurons from 9 Parkinson's disease (PD) patients undergoing DBS surgery showed no significant differences in frequencies (PD, mean 7.5+/-7.0 spikes/s (sps), epilepsy mean 7.8+/-8.5 sps) or in the coefficients of variation of mean discharge frequencies per 1s epochs. A striking relationship between mean discharge frequencies per 1 s epochs and the standard deviations for both groups were consistent with a random Poisson processes. These and similar findings call into question theories that posit increased STN activity is causal to parkinsonism.

  18. Addiction in Parkinson's disease: impact of subthalamic nucleus deep brain stimulation.

    PubMed

    Witjas, Tatiana; Baunez, Christelle; Henry, Jean Marc; Delfini, Marie; Regis, Jean; Cherif, André Ali; Peragut, Jean Claude; Azulay, Jean Philippe

    2005-08-01

    In Parkinson's disease, dopamine dysregulation syndrome (DDS) is characterized by severe dopamine addiction and behavioral disorders such as manic psychosis, hypersexuality, pathological gambling, and mood swings. Here, we describe the case of 2 young parkinsonian patients suffering from disabling motor fluctuations and dyskinesia associated with severe DDS. In addition to alleviating the motor disability in both patients, subthalamic nucleus (STN) deep brain stimulation greatly reduced the behavioral disorders as well as completely abolished the addiction to dopaminergic treatment. Dopaminergic addiction in patients with Parkinson's disease, therefore, does not constitute an obstacle to high-frequency STN stimulation, and this treatment may even cure the addiction.

  19. Dominant efficiency of nonregular patterns of subthalamic nucleus deep brain stimulation for Parkinson’s disease and obsessive-compulsive disorder in a data-driven computational model

    NASA Astrophysics Data System (ADS)

    Karamintziou, Sofia D.; Deligiannis, Nick G.; Piallat, Brigitte; Polosan, Mircea; Chabardès, Stephan; David, Olivier; Stathis, Pantelis G.; Tagaris, George A.; Boviatsis, Efstathios J.; Sakas, Damianos E.; Polychronaki, Georgia E.; Tsirogiannis, George L.; Nikita, Konstantina S.

    2016-02-01

    Objective. Almost 30 years after the start of the modern era of deep brain stimulation (DBS), the subthalamic nucleus (STN) still constitutes a standard stimulation target for advanced Parkinson’s disease (PD), but the use of STN-DBS is also now supported by level I clinical evidence for treatment-refractory obsessive-compulsive disorder (OCD). Disruption of neural synchronization in the STN has been suggested as one of the possible mechanisms of action of standard and alternative patterns of STN-DBS at a local level. Meanwhile, recent experimental and computational modeling evidence has signified the efficiency of alternative patterns of stimulation; however, no indications exist for treatment-refractory OCD. Here, we comparatively simulate the desynchronizing effect of standard (regular at 130 Hz) versus temporally alternative (in terms of frequency, temporal variability and the existence of bursts or pauses) patterns of STN-DBS for PD and OCD, by means of a stochastic dynamical model and two microelectrode recording (MER) datasets. Approach. The stochastic model is fitted to subthalamic MERs acquired during eight surgical interventions for PD and eight surgical interventions for OCD. For each dynamical system simulated, we comparatively assess the invariant density (steady-state phase distribution) as a measure inversely related to the desynchronizing effect yielded by the applied patterns of stimulation. Main results. We demonstrate that high (130 Hz)—and low (80 Hz)—frequency irregular patterns of stimulation, and low-frequency periodic stimulation interrupted by bursts of pulses, yield in both pathologic conditions a significantly stronger desynchronizing effect compared with standard STN-DBS, and distinct alternative patterns of stimulation. In PD, values of the invariant density measure are proven to be optimal at the dorsolateral oscillatory region of the STN including sites with the optimal therapeutic window. Significance. In addition to providing

  20. The VLSI-PLM Board: Design, Construction, and Testing

    DTIC Science & Technology

    1989-03-01

    Computer Aided Design CB- Xenologic Corporation’s X-1 cache board DAS - Digital Analysis System EECS - Electrical Engineering and Computer...PLM Board is to debug the VLSI-PLM Chip [STN88] and to interface the chip to the Xenologic Corporation’s X-1 cache board. The chip is a high...a wire-wrapped board designed for debugging VLSI-PLM [STN88] and connecting VLSI- PLM to the cache board of Xenologic Corporation’s X-1 system. The

  1. Response of high-risk of recurrence/progression bladder tumours expressing sialyl-Tn and sialyl-6-T to BCG immunotherapy.

    PubMed

    Lima, L; Severino, P F; Silva, M; Miranda, A; Tavares, A; Pereira, S; Fernandes, E; Cruz, R; Amaro, T; Reis, C A; Dall'Olio, F; Amado, F; Videira, P A; Santos, L; Ferreira, J A

    2013-10-15

    High risk of recurrence/progression bladder tumours is treated with Bacillus Calmette-Guérin (BCG) immunotherapy after complete resection of the tumour. Approximately 75% of these tumours express the uncommon carbohydrate antigen sialyl-Tn (Tn), a surrogate biomarker of tumour aggressiveness. Such changes in the glycosylation of cell-surface proteins influence tumour microenvironment and immune responses that may modulate treatment outcome and the course of disease. The aim of this work is to determine the efficiency of BCG immunotherapy against tumours expressing sTn and sTn-related antigen sialyl-6-T (s6T). In a retrospective design, 94 tumours from patients treated with BCG were screened for sTn and s6T expression. In vitro studies were conducted to determine the interaction of BCG with high-grade bladder cancer cell line overexpressing sTn. From the 94 cases evaluated, 36 had recurrence after BCG treatment (38.3%). Treatment outcome was influenced by age over 65 years (HR=2.668; (1.344-5.254); P=0.005), maintenance schedule (HR=0.480; (0.246-0.936); P=0.031) and multifocality (HR=2.065; (1.033-4.126); P=0.040). sTn or s6T expression was associated with BCG response (P=0.024; P<0.0001) and with increased recurrence-free survival (P=0.001). Multivariate analyses showed that sTn and/or s6T were independent predictive markers of recurrence after BCG immunotherapy (HR=0.296; (0.148-0.594); P=0.001). In vitro studies demonstrated higher adhesion and internalisation of the bacillus to cells expressing sTn, promoting cell death. s6T is described for the first time in bladder tumours. Our data strongly suggest that BCG immunotherapy is efficient against sTn- and s6T-positive tumours. Furthermore, sTn and s6T expression are independent predictive markers of BCG treatment response and may be useful in the identification of patients who could benefit more from this immunotherapy.

  2. Three-dimensional SPACE fluid-attenuated inversion recovery at 3 T to improve subthalamic nucleus lead placement for deep brain stimulation in Parkinson's disease: from preclinical to clinical studies.

    PubMed

    Senova, Suhan; Hosomi, Koichi; Gurruchaga, Jean-Marc; Gouello, Gaëtane; Ouerchefani, Naoufel; Beaugendre, Yara; Lepetit, Hélène; Lefaucheur, Jean-Pascal; Badin, Romina Aron; Dauguet, Julien; Jan, Caroline; Hantraye, Philippe; Brugières, Pierre; Palfi, Stéphane

    2016-08-01

    OBJECTIVE Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established therapy for motor symptoms in patients with pharmacoresistant Parkinson's disease (PD). However, the procedure, which requires multimodal perioperative exploration such as imaging, electrophysiology, or clinical examination during macrostimulation to secure lead positioning, remains challenging because the STN cannot be reliably visualized using the gold standard, T2-weighted imaging (T2WI) at 1.5 T. Thus, there is a need to improve imaging tools to better visualize the STN, optimize DBS lead implantation, and enlarge DBS diffusion. METHODS Gradient-echo sequences such as those used in T2WI suffer from higher distortions at higher magnetic fields than spin-echo sequences. First, a spin-echo 3D SPACE (sampling perfection with application-optimized contrasts using different flip angle evolutions) FLAIR sequence at 3 T was designed, validated histologically in 2 nonhuman primates, and applied to 10 patients with PD; their data were clinically compared in a double-blind manner with those of a control group of 10 other patients with PD in whom STN targeting was performed using T2WI. RESULTS Overlap between the nonhuman primate STNs segmented on 3D-histological and on 3D-SPACE-FLAIR volumes was high for the 3 most anterior quarters (mean [± SD] Dice scores 0.73 ± 0.11, 0.74 ± 0.06, and 0.60 ± 0.09). STN limits determined by the 3D-SPACE-FLAIR sequence were more consistent with electrophysiological edges than those determined by T2WI (0.9 vs 1.4 mm, respectively). The imaging contrast of the STN on the 3D-SPACE-FLAIR sequence was 4 times higher (p < 0.05). Improvement in the Unified Parkinson's Disease Rating Scale Part III score (off medication, on stimulation) 12 months after the operation was higher for patients who underwent 3D-SPACE-FLAIR-guided implantation than for those in whom T2WI was used (62.2% vs 43.6%, respectively; p < 0.05). The total electrical energy

  3. Excitatory postsynaptic potentials trigger a plateau potential in rat subthalamic neurons at hyperpolarized states.

    PubMed

    Otsuka, T; Murakami, F; Song, W J

    2001-10-01

    The subthalamic nucleus (STN) directly innervates the output structures of the basal ganglia, playing a key role in basal ganglia function. It is therefore important to understand the regulatory mechanisms for the activity of STN neurons. In the present study, we aimed to investigate how the intrinsic membrane properties of STN neurons interact with their synaptic inputs, focusing on their generation and the properties of the long-lasting, plateau potential. Whole cell recordings were obtained from STN neurons in slices prepared from postnatal day 14 (P14) to P20 rats. We found that activation of glutamate receptor-mediated excitatory synaptic potentials (EPSPs) evoked a plateau potential in a subpopulation of STN neurons (n = 13/22), in a voltage-dependent manner. Plateau potentials could be induced only when the cell was hyperpolarized to more negative than about -75 mV. Plateau potentials, evoked with a depolarizing current pulse, again only from a hyperpolarized state, were observed in about half of STN neurons tested (n = 162/327). Only in neurons in which a plateau potential could be evoked by current injection did EPSPs evoke plateau potentials. L-type Ca(2+) channels, Ca(2+)-dependent K(+) channels, and TEA-sensitive K(+) channels were found to be involved in the generation of the potential. The stability of the plateau potential, tested by the injection of a negative pulse current during the plateau phase, was found to be robust at the early phase of the potential, but decreased toward the end. As a result the early part of the plateau potential was resistant to membrane potential perturbations and would be able to support a train of action potentials. We conclude that excitatory postsynaptic potentials, evoked in a subpopulation of STN neurons at a hyperpolarized state, activate L-type Ca(2+) and other channels, leading to the generation of a plateau potential. Thus about half of STN neurons can transform short-lasting synaptic excitation into a long

  4. Effect of bilateral subthalamic nucleus stimulation on gait in Parkinson's disease.

    PubMed

    Faist, M; Xie, J; Kurz, D; Berger, W; Maurer, C; Pollak, P; Lücking, C H

    2001-08-01

    The fundamental disturbance of the parkinsonian gait is the reduction in walking velocity. This is mainly due to reduction in stride length, while cadence (steps/min) is slightly enhanced. Treatment with L-dopa increases stride length while cadence is unchanged. Chronic stimulation of the thalamus has no effect on Parkinsonian gait. The efficacy of electrical stimulation of the subthalamic nucleus (STN) on gait in advanced Parkinson's disease has been clearly demonstrated clinically. The aim of the present study was to quantify the changes in gait measures induced by STN stimulation and L-dopa and to assess possible differential or additive effects. Eight Parkinson's disease patients (mean +/- SD age 48.1 +/- 7.3 years) with chronic bilateral STN stimulation (mean duration of disease 13.3 +/- 2.4 years, mean stimulation time 15.4 +/- 10.6 months) and 12 age-matched controls were investigated. Subjects walked on a special treadmill with a closed-loop ultrasound control system that used the subject's position to adjust treadmill speed continuously for the actual walking velocity. In an appropriate crossover design, spatiotemporal gait measures and leg joint angle movements were assessed for at least 120 stride cycles in four treatment conditions: with and without stimulation and with and without a suprathreshold dose of L-dopa. With STN stimulation, there were increases of almost threefold in mean walking velocity (from 0.35 to 0.96 m/s) and stride length (from 0.34 to 0.99 m). Cadence remained constant. The range of motion of the major leg joints also increased. L-Dopa alone had a slightly weaker effect, with an increase in walking velocity to 0.94 m/s and in stride length to 0.92 m at a similar cadence. These increased values were in the range of those for healthy age-matched subjects performing the same task. The combination of both treatments further increased the mean walking velocity to 1.19 m/s and stride length to 1.20 m at an unchanged cadence. However, not

  5. Effects of nigral stimulation on locomotion and postural stability in patients with Parkinson's disease.

    PubMed

    Chastan, N; Westby, G W M; Yelnik, J; Bardinet, E; Do, M C; Agid, Y; Welter, M L

    2009-01-01

    The physiopathology of gait and balance disorders in Parkinson's disease patients is still poorly understood. Levodopa treatment and subthalamic nucleus (STN) stimulation improve step length and walking speed, with less effect on postural instability. These disorders have been linked to dysfunction of the descending basal ganglia outputs to brainstem structures. In this study, we evaluated the effects of stimulation of the substantia nigra pars reticulata (SNr), on locomotion and balance in Parkinson's disease patients. Biomechanical parameters and leg muscle activity were recorded during gait initiation in seven selected patients operated for bilateral STN stimulation, out of 204 stimulated patients, with one contact of each electrode located within the SNr. Step length, anteroposterior and vertical velocities of the centre of gravity were studied, with special reference to the subjects' ability to brake the centre of gravity fall before foot-contact, and compared to seven controls. In Parkinson's disease patients, five treatment conditions were tested: (i) no treatment, (ii) levodopa treatment, (iii) STN stimulation, (iv) SNr stimulation and (v) combined levodopa treatment and STN stimulation. The effects of these treatments on motor parkinsonian disability were assessed with the UPDRS III scale, separated into 'axial' (rising from chair, posture, postural stability and gait) and 'distal' scores. Whereas levodopa and/or STN stimulation improved 'axial' and 'distal' motor symptoms, SNr stimulation improved only the 'axial' symptoms. Compared to controls, untreated Parkinson's disease patients showed reduced step length and velocity, and poor braking just prior to foot-contact, with a decrease in both soleus (S) and anterior tibialis (AT) muscle activity. Step length and velocity significantly increased with levodopa treatment alone or in combination with STN stimulation in both natural and fast gait conditions, and with STN stimulation alone in the fast gait

  6. A Simple Method to Measure the Twist Elastic Constant of a Nematic Liquid Crystal

    DTIC Science & Technology

    2015-01-01

    as 180° super- twisted nematic (STN) cell. Next, we assume the helical twisting power ( HTP ) of chiral dopant is also unknown, same as K22. To solve...threshold voltages of these two 180° STN cells, both K22 and HTP can be obtained simultaneously. In the whole process, there is no need to measure...Equation (1), if we sub- stitute ϕ = π and pitch length P = 1/( HTP · c) (where c is chiral concentration), then the critical voltage can be rewritten

  7. Response of high-risk of recurrence/progression bladder tumours expressing sialyl-Tn and sialyl-6-T to BCG immunotherapy

    PubMed Central

    Lima, L; Severino, P F; Silva, M; Miranda, A; Tavares, A; Pereira, S; Fernandes, E; Cruz, R; Amaro, T; Reis, C A; Dall'Olio, F; Amado, F; Videira, P A; Santos, L; Ferreira, J A

    2013-01-01

    Background: High risk of recurrence/progression bladder tumours is treated with Bacillus Calmette-Guérin (BCG) immunotherapy after complete resection of the tumour. Approximately 75% of these tumours express the uncommon carbohydrate antigen sialyl-Tn (Tn), a surrogate biomarker of tumour aggressiveness. Such changes in the glycosylation of cell-surface proteins influence tumour microenvironment and immune responses that may modulate treatment outcome and the course of disease. The aim of this work is to determine the efficiency of BCG immunotherapy against tumours expressing sTn and sTn-related antigen sialyl-6-T (s6T). Methods: In a retrospective design, 94 tumours from patients treated with BCG were screened for sTn and s6T expression. In vitro studies were conducted to determine the interaction of BCG with high-grade bladder cancer cell line overexpressing sTn. Results: From the 94 cases evaluated, 36 had recurrence after BCG treatment (38.3%). Treatment outcome was influenced by age over 65 years (HR=2.668; (1.344–5.254); P=0.005), maintenance schedule (HR=0.480; (0.246–0.936); P=0.031) and multifocallity (HR=2.065; (1.033–4.126); P=0.040). sTn or s6T expression was associated with BCG response (P=0.024; P<0.0001) and with increased recurrence-free survival (P=0.001). Multivariate analyses showed that sTn and/or s6T were independent predictive markers of recurrence after BCG immunotherapy (HR=0.296; (0.148–0.594); P=0.001). In vitro studies demonstrated higher adhesion and internalisation of the bacillus to cells expressing sTn, promoting cell death. Conclusion: s6T is described for the first time in bladder tumours. Our data strongly suggest that BCG immunotherapy is efficient against sTn- and s6T-positive tumours. Furthermore, sTn and s6T expression are independent predictive markers of BCG treatment response and may be useful in the identification of patients who could benefit more from this immunotherapy. PMID:24064971

  8. Dominant efficiency of nonregular patterns of subthalamic nucleus deep brain stimulation for Parkinson's disease and obsessive-compulsive disorder in a data-driven computational model.

    PubMed

    Karamintziou, Sofia D; Deligiannis, Nick G; Piallat, Brigitte; Polosan, Mircea; Chabardès, Stephan; David, Olivier; Stathis, Pantelis G; Tagaris, George A; Boviatsis, Efstathios J; Sakas, Damianos E; Polychronaki, Georgia E; Tsirogiannis, George L; Nikita, Konstantina S

    2016-02-01

    Almost 30 years after the start of the modern era of deep brain stimulation (DBS), the subthalamic nucleus (STN) still constitutes a standard stimulation target for advanced Parkinson's disease (PD), but the use of STN-DBS is also now supported by level I clinical evidence for treatment-refractory obsessive-compulsive disorder (OCD). Disruption of neural synchronization in the STN has been suggested as one of the possible mechanisms of action of standard and alternative patterns of STN-DBS at a local level. Meanwhile, recent experimental and computational modeling evidence has signified the efficiency of alternative patterns of stimulation; however, no indications exist for treatment-refractory OCD. Here, we comparatively simulate the desynchronizing effect of standard (regular at 130 Hz) versus temporally alternative (in terms of frequency, temporal variability and the existence of bursts or pauses) patterns of STN-DBS for PD and OCD, by means of a stochastic dynamical model and two microelectrode recording (MER) datasets. The stochastic model is fitted to subthalamic MERs acquired during eight surgical interventions for PD and eight surgical interventions for OCD. For each dynamical system simulated, we comparatively assess the invariant density (steady-state phase distribution) as a measure inversely related to the desynchronizing effect yielded by the applied patterns of stimulation. We demonstrate that high (130 Hz)-and low (80 Hz)-frequency irregular patterns of stimulation, and low-frequency periodic stimulation interrupted by bursts of pulses, yield in both pathologic conditions a significantly stronger desynchronizing effect compared with standard STN-DBS, and distinct alternative patterns of stimulation. In PD, values of the invariant density measure are proven to be optimal at the dorsolateral oscillatory region of the STN including sites with the optimal therapeutic window. In addition to providing novel insights into the efficiency of low

  9. Implantation of electrodes for deep brain stimulation of the subthalamic nucleus in advanced Parkinson's disease with the aid of intraoperative microrecording under general anesthesia.

    PubMed

    Hertel, Frank; Züchner, Mark; Weimar, Inge; Gemmar, Peter; Noll, Bernhard; Bettag, Martin; Decker, Christian

    2006-11-01

    Deep brain stimulation (DBS) is widely accepted in the treatment of advanced Parkinson's disease (PD) and other movement disorders. The standard implantation procedure is performed under local anesthesia (LA). Certain groups of patients may not be eligible for surgery under LA because of clinical reasons, such as massive fear, reduced cooperativity, or coughing attacks. Microrecording (MER) has been shown to be helpful in DBS surgery. The purpose of this study was to evaluate the feasibility of MER for DBS surgery under general anesthesia (GA) and to compare the data of intraoperative MER as well as the clinical data with that of the current literature of patients undergoing operation under LA. The data of nine patients with advanced PD (mean Hoehn and Yahr status, 4.2) who were operated with subthalamic nucleus (STN) DBS under GA, owing to certain clinical circumstances ruling out DBS under LA, were retrospectively analyzed. All operations were performed under analgosedation with propofol or remifentanil and intraoperative MER. For MER, remifentanil was ceased completely and propofol was lowered as far as possible. The STN could be identified intraoperatively in all patients with MER. The typical bursting pattern was identified, whereas a widening of the baseline noise could not be as adequately detected as in patients under LA. The daily off phases of the patients were reduced from 50 to 17%, whereas the Unified Parkinson's Disease Rating Scale III score was reduced from 43 (preoperative, medication off) to 19 (stimulation on, medication off) and 12 (stimulation on, medication on). Two patients showed a transient neuropsychological deterioration after surgery, but both also had preexisting episodes of disorientation. One implantable pulse generator infection was noticed. No further significant clinical complications were observed. STN surgery for advanced PD with MER guidance is possible with good clinical results under GA. Intraoperative MER of the STN region

  10. Analysis of Air Flow in the Ventilated Insulating Air Layer of the External Wall

    NASA Astrophysics Data System (ADS)

    Katunská, Jana; Bullová, Iveta; Špaková, Miroslava

    2016-12-01

    The paper deals with problems of impact of air flow in ventilated insulating air layer of the external wall on behaviour of thermal-technical parameters of the proposed external structure (according principles of STN 73 0549, which is not valid now), by comparing them in the calculation according to the valid STN standards, where air flow in the ventilated air layer is not taken into account, as well as by comparing them with behavior of thermal-technical parameters in the proposal of sandwich external wall with the contact heat insulation system without air cavity.

  11. Deep brain stimulation and continuous dopaminergic stimulation in advanced Parkinson's disease.

    PubMed

    Wolters, Erik Ch

    2007-09-01

    Patients receiving oral levodopa, the standard treatment for Parkinson's disease (PD), eventually develop motor fluctuations and dyskinesias. Treatment options for patients with these symptoms include high-frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) or continuous dopaminergic stimulation (CDS). STN-DBS is the prevalent surgical therapy for PD and has shown efficacy, but behavioural disorders, including cognitive problems, depression and suicidality have been reported. CDS can be achieved with oral dopamine agonists with a long half-life, transdermal or subcutaneous delivery of dopamine agonists, or intestinal levodopa infusion. Of these, duodenal levodopa infusion appears to be the most promising option in terms of both efficacy and safety.

  12. Subthalamic Nucleus Deep Brain Stimulation Modulate Catecholamine Levels with Significant Relations to Clinical Outcome after Surgery in Patients with Parkinson’s Disease

    PubMed Central

    Yamamoto, Tatsuya; Uchiyama, Tomoyuki; Higuchi, Yoshinori; Asahina, Masato; Hirano, Shigeki; Yamanaka, Yoshitaka; Kuwabara, Satoshi

    2015-01-01

    Aims Although subthalamic nucleus deep brain stimulation (STN-DBS) is effective in patients with advanced Parkinson’s disease (PD), its physiological mechanisms remain unclear. Because STN-DBS is effective in patients with PD whose motor symptoms are dramatically alleviated by L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, the higher preoperative catecholamine levels might be related to the better clinical outcome after surgery. We aimed to examine the correlation between the preoperative catecholamine levels and postoperative clinical outcome after subthalamic nucleus deep brain stimulation. The effectiveness of STN-DBS in the patient who responded well to dopaminergic medication suggest the causal link between the dopaminergic system and STN-DBS. We also examined how catecholamine levels were modulated after subthalamic stimulation. Methods In total 25 patients with PD were enrolled (Mean age 66.2 ± 6.7 years, mean disease duration 11.6 ± 3.7 years). Mean levodopa equivalent doses were 1032 ± 34.6 mg before surgery. Cerebrospinal fluid and plasma catecholamine levels were measured an hour after oral administration of antiparkinsonian drugs before surgery. The mean Unified Parkinson’s Disease Rating Scale scores (UPDRS) and the Parkinson’s disease Questionnaire-39 (PDQ-39) were obtained before and after surgery. Of the 25 patients, postoperative cerebrospinal fluid and plasma were collected an hour after oral administration of antiparkinsonian drugs during on stimulation at follow up in 11 patients. Results Mean levodopa equivalent doses significantly decreased after surgery with improvement in motor functions and quality of life. The preoperative catecholamine levels had basically negative correlations with postoperative motor scores and quality of life, suggesting that higher preoperative catecholamine levels were related to better outcome after STN-DBS. The preoperative plasma levels of L-DOPA had significantly negative correlations with

  13. Cost of deep brain stimulation for the treatment of Parkinson's disease by surgical stimulation sites.

    PubMed

    Stroupe, Kevin T; Weaver, Frances M; Cao, Lishan; Ippolito, Dolores; Barton, Brandon R; Burnett-Zeigler, Inger E; Holloway, Robert G; Vickrey, Barbara G; Simuni, Tanya; Follett, Kenneth A

    2014-11-01

    To assess costs and effectiveness of deep brain stimulation (DBS) of the internal globus pallidum (GPi) versus subthalamic nucleus (STN) from the provider and societal perspectives for Parkinson's disease (PD) patients in a multicenter randomized trial. All costs from randomization to 36 months were included. Costs were from Department of Veterans Affairs (VA) and Medicare databases and clinical trial data. Quality adjusted life years (QALYs) were from Quality of Well Being questionnaires. Provider costs were similar for the 144 GPi and 130 STN patients (GPi: $138,044 vs. STN: $131,822; difference = $6,222, 95% confidence interval [CI]: -$42,125 to $45,343). Societal costs were also similar (GPi: $171,061 vs. STN: $167,706; difference = $3,356, 95% CI: -$57,371 to $60,294). The GPi patients had nonsignificantly more QALYs. The QALYs and costs were similar; the level of uncertainty given the sample size suggests that these factors should not direct treatment or resource allocation decisions in selecting or making available either procedure for eligible PD patients. © 2014 International Parkinson and Movement Disorder Society.

  14. A role for the subthalamic nucleus in response inhibition during conflict.

    PubMed

    Brittain, John-Stuart; Watkins, Kate E; Joundi, Raed A; Ray, Nicola J; Holland, Peter; Green, Alexander L; Aziz, Tipu Z; Jenkinson, Ned

    2012-09-26

    The subthalamic nucleus (STN) is a key node in the network that supports response inhibition. It is suggested that the STN rapidly inhibits basal ganglia activity, to pause motor output during conflict until an appropriate motor plan is ready. Here, we recorded neural activity during a Stroop task from deep brain stimulation electrodes implanted in the human STN. We intended to determine whether cognitive psychological phenomena such as the Stroop effect can be explained via mechanisms of response inhibition involving the STN, or whether higher cognitive centers are alone responsible. We show stimulus-driven desychronization in the beta band (15-35 Hz) that lasts throughout the verbal response, in keeping with the idea that beta-band synchrony decreases to allow motor output to occur. During incongruent trials--in which response times were elongated due to the Stroop effect--a resynchronization was seen in the beta band before response. Crucially, in the incongruent trials during which the participant was unable to withhold the prepotent response, this resynchronization occurred after response onset. We suggest that this beta-band resynchronization pauses the motor system until conflict can be resolved.

  15. Dialog Alternatives: A Power Searcher's Checklist.

    ERIC Educational Resources Information Center

    Kassel, Amelia; Drebes, Karen Ann

    1998-01-01

    Discusses Dialog's recent new pricing structure and its effects on librarians and other information professionals. Presents charts that compare Dialog databases with other search services (Dow Jones Interactive, LEXIS-NEXIS, OCLC FirstSearch, Ovid, Questel-Orbit, SilverPlatter, and STN) and Dialog via other channels (DataStar, Dialog Select,…

  16. Resonant antidromic cortical circuit activation as a consequence of high-frequency subthalamic deep-brain stimulation.

    PubMed

    Li, S; Arbuthnott, G W; Jutras, M J; Goldberg, J A; Jaeger, D

    2007-12-01

    Deep brain stimulation (DBS) is an effective treatment of Parkinson's disease (PD) for many patients. The most effective stimulation consists of high-frequency biphasic stimulation pulses around 130 Hz delivered between two active sites of an implanted depth electrode to the subthalamic nucleus (STN-DBS). Multiple studies have shown that a key effect of STN-DBS that correlates well with clinical outcome is the reduction of synchronous and oscillatory activity in cortical and basal ganglia networks. We hypothesized that antidromic cortical activation may provide an underlying mechanism responsible for this effect, because stimulation is usually performed in proximity to cortical efferent pathways. We show with intracellular cortical recordings in rats that STN-DBS did in fact lead to antidromic spiking of deep layer cortical neurons. Furthermore, antidromic spikes triggered a dampened oscillation of local field potentials in cortex with a resonant frequency around 120 Hz. The amplitude of antidromic activation was significantly correlated with an observed suppression of slow wave and beta band activity during STN-DBS. These findings were seen in ketamine-xylazine or isoflurane anesthesia in both normal and 6-hydroxydopamine (6-OHDA)-lesioned rats. Thus antidromic resonant activation of cortical microcircuits may make an important contribution toward counteracting the overly synchronous and oscillatory activity characteristic of cortical activity in PD.

  17. Efficient chemoenzymatic synthesis of sialyl Tn-antigens and derivatives.

    PubMed

    Ding, Li; Yu, Hai; Lau, Kam; Li, Yanhong; Muthana, Saddam; Wang, Junru; Chen, Xi

    2011-08-14

    An N-terminal and C-terminal truncated recombinant α2-6-sialyltransferase cloned from Photobacterium sp. JH-ISH-224, Psp2,6ST(15-501)-His(6), was shown to be an efficient catalyst for one-pot three-enzyme synthesis of sialyl Tn (STn) antigens and derivatives containing natural and non-natural sialic acid forms.

  18. Characteristic laryngoscopic findings in Parkinson's disease patients after subthalamic nucleus deep brain stimulation and its correlation with voice disorder.

    PubMed

    Tsuboi, Takashi; Watanabe, Hirohisa; Tanaka, Yasuhiro; Ohdake, Reiko; Yoneyama, Noritaka; Hara, Kazuhiro; Ito, Mizuki; Hirayama, Masaaki; Yamamoto, Masahiko; Fujimoto, Yasushi; Kajita, Yasukazu; Wakabayashi, Toshihiko; Sobue, Gen

    2015-12-01

    Speech and voice disorders are one of the most common adverse effects in Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS). However, the pathophysiology of voice and laryngeal dysfunction after STN-DBS remains unclear. We assessed 47 PD patients (22 treated with bilateral STN-DBS (PD-DBS) and 25 treated medically (PD-Med); all patients in both groups matched by age, sex, disease duration, and motor and cognitive function) using the objective and subjective voice assessment batteries (GRBAS scale and Voice Handicap Index), and laryngoscopy. Laryngoscopic examinations revealed that PD-DBS patients showed a significantly higher incidence of incomplete glottal closure (77 vs 48 %; p = 0.039), hyperadduction of the false vocal folds (73 vs 44 %; p = 0.047), anteroposterior hypercompression (50 vs 20 %; p = 0.030) and asymmetrical glottal movement (50 vs 16 %; p = 0.002) than PD-Med patients. On- and off-stimulation assessment revealed that STN-DBS could induce or aggravate incomplete glottal closure, hyperadduction of the false vocal folds, anteroposterior hypercompression, and asymmetrical glottal movement. Incomplete glottal closure and hyperadduction of the false vocal folds significantly correlated with breathiness and strained voice, respectively (r = 0.590 and 0.539). We should adjust patients' DBS settings in consideration of voice and laryngeal functions as well as motor function.

  19. Reward circuit DBS improves Parkinson's gait along with severe depression and OCD.

    PubMed

    Williams, Nolan R; Hopkins, Thomas R; Short, E Baron; Sahlem, Gregory L; Snipes, Jonathan; Revuelta, Gonzalo J; George, Mark S; Takacs, Istvan

    2016-01-01

    A 59-year-old Caucasian man with a past history of Parkinson's disease (PD) status post-bilateral subthalamic nucleus (STN) deep brain stimulation (DBS), who also had treatment-resistant (TR) obsessive-compulsive disorder (OCD), and treatment-resistant depression (TRD), presented for further evaluation and management of his TR OCD. After an unsuccessful attempt to treat his OCD by reprogramming his existing STN DBS, he was offered bilateral ventral capsule/ventral striatum (VC/VS) DBS surgery. In addition to the expected improvement in OCD symptoms, he experienced significant improvement in both PD-related apathy and depression along with resolution of suicidal ideation. Furthermore, the patient's festinating gait dramatically improved. This case demonstrates that DBS of both the STN and VC/VS appears to have an initial signal of safety and tolerability. This is the first instance where both the STN and the VC/VS DBS targets have been implanted in an individual and the first case where a patient with PD has received additional DBS in mood-regulatory circuitry.

  20. Coping with Chemical Nomenclature in the Age of Computers.

    ERIC Educational Resources Information Center

    Dess, Howard M.

    1988-01-01

    Reviews nomenclature-related problems for users of Chemical Abstracts (CA) and describes online techniques for searching with generic/trade/common names, non-CA index names, and CA index names using CAS-Online via STN (Scientific and Technical Information Network). Terms used in the online substance display format are explained. (10 references)…

  1. Chemical Substructure Searching: Comparing Three Commercially Available Databases.

    ERIC Educational Resources Information Center

    Wagner, A. Ben

    1986-01-01

    Compares the differences in coverage and utility of three substructure databases--Chemical Abstracts, Index Chemicus, and Chemical Information System's Nomenclature Search System. The differences between Chemical Abstracts with two different vendors--STN International and Questel--are described and a summary guide for choosing between databases is…

  2. Software for Information Storage and Retrieval Tested, Evaluated and Compared: Part VI--Various Additional Programs.

    ERIC Educational Resources Information Center

    Sieverts, Eric G.; And Others

    1993-01-01

    Reports on tests evaluating nine microcomputer software packages designed for information storage and retrieval: BRS-Search, dtSearch, InfoBank, Micro-OPC, Q&A, STN-PFS, Strix, TINman, and ZYindex. Tables and narrative evaluations detail results related to security, hardware, user features, search capability, indexing, input, maintenance of files,…

  3. Functional MRI reveals frequency-dependent responses during deep brain stimulation at the subthalamic nucleus or internal globus pallidus.

    PubMed

    Lai, Hsin-Yi; Younce, John R; Albaugh, Daniel L; Kao, Yu-Chieh Jill; Shih, Yen-Yu Ian

    2014-01-01

    Deep brain stimulation (DBS) represents a widely used therapeutic tool for the symptomatic treatment of movement disorders, most commonly Parkinson's disease (PD). High frequency stimulation at both the subthalamic nucleus (STN) and internal globus pallidus (GPi) has been used with great success for the symptomatic treatment of PD, although the therapeutic mechanisms of action remain elusive. To better understand how DBS at these target sites modulates neural circuitry, the present study used functional blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to map global brain responses to DBS at the STN and GPi of the rat. Robust activation centered in the ipsilateral motor cortex was observed during high frequency stimulation at either target site, with peak responses observed at a stimulation frequency of 100Hz. Of note, frequency tuning curves were generated, demonstrating that cortical activation was maximal at clinically-relevant stimulation frequencies. Divergent responses to stimulation were noted in the contralateral hemisphere, with strong cortical and striatal negative BOLD signal during stimulation of the GPi, but not STN. The frequency-dependence of the observed motor cortex activation at both targets suggests a relationship with the therapeutic effects of STN and GPi DBS, with both DBS targets being functionally connected with motor cortex at therapeutic stimulation frequencies.

  4. Cognitive Changes following Bilateral Deep Brain Stimulation of Subthalamic Nucleus in Parkinson's Disease: A Meta-Analysis.

    PubMed

    Xie, Yi; Meng, Xiangyu; Xiao, Jinsong; Zhang, Jie; Zhang, Junjian

    2016-01-01

    Background. Nowadays, it has been largely acknowledged that deep brain stimulation of subthalamic nucleus (STN DBS) can alleviate motor symptoms of Parkinson's disease, but its effects on cognitive function remain unclear, which are not given enough attention by many clinical doctors and researchers. To date, 3 existing meta-analyses focusing on this issue included self-control studies and have not drawn consistent conclusions. The present study is the first to compare effect sizes of primary studies that include control groups, hoping to reveal the net cognitive outcomes after STN DBS and the clinical significance. Methods. A structured literature search was conducted using strict criteria. Only studies with control group could be included. Data on age, duration of disease, levodopa equivalent dosage (LED), and multiple cognitive scales were collected and pooled. Results. Of 172 articles identified, 10 studies (including 3 randomized controlled trials and 7 nonrandomized controlled studies) were eligible for inclusion. The results suggest that STN DBS results in decreased global cognition, memory, verbal fluency, and executive function compared with control group. No significant difference is found in other cognitive domains. Conclusions. STN DBS seems relatively safe with respect to cognitive function, and further studies should focus on the exact mechanisms of possible verbal deterioration after surgery in the future.

  5. Subthalamic deep brain stimulation reduces pathological information transmission to the thalamus in a rat model of parkinsonism.

    PubMed

    Anderson, Collin J; Sheppard, Daylan T; Huynh, Rachel; Anderson, Daria Nesterovich; Polar, Christian A; Dorval, Alan D

    2015-01-01

    The degeneration of dopaminergic neurons in the substantia nigra pars compacta leads to parkinsonian motor symptoms via changes in electrophysiological activity throughout the basal ganglia. High-frequency deep brain stimulation (DBS) partially treats these symptoms, but the mechanisms are unclear. We hypothesize that motor symptoms of Parkinson's disease (PD) are associated with increased information transmission from basal ganglia output neurons to motor thalamus input neurons and that therapeutic DBS of the subthalamic nucleus (STN) treats these symptoms by reducing this extraneous information transmission. We tested these hypotheses in a unilateral, 6-hydroxydopamine-lesioned rodent model of hemiparkinsonism. Information transfer between basal ganglia output neurons and motor thalamus input neurons increased in both the orthodromic and antidromic directions with hemiparkinsonian (hPD) onset, and these changes were reversed by behaviorally therapeutic STN-DBS. Omnidirectional information increases in the parkinsonian state underscore the detrimental nature of that pathological information and suggest a loss of information channel independence. Therapeutic STN-DBS reduced that pathological information, suggesting an effective increase in the number of independent information channels. We interpret these data with a model in which pathological information and fewer information channels diminishes the scope of possible motor activities, driving parkinsonian symptoms. In this model, STN-DBS restores information-channel independence by eliminating or masking the parkinsonism-associated information, and thus enlarges the scope of possible motor activities, alleviating parkinsonian symptoms.

  6. Method to Select Metropolitan Areas of Epidemiologic Interest for Enhanced Air Quality Monitoring

    EPA Science Inventory

    The U.S. Environmental Protection Agency’s current Speciation Trends Network (STN) covers most major U.S. metropolitan areas and a wide range of particulate matter (PM) constituents and gaseous co-pollutants. However, using filter-based methods, most PM constituents are measured ...

  7. Deep brain stimulation of pedunculopontine tegmental nucleus: role in sleep modulation in advanced Parkinson disease patients: one-year follow-up.

    PubMed

    Peppe, Antonella; Pierantozzi, Mariangela; Baiamonte, Valentina; Moschella, Vincenzo; Caltagirone, Carlo; Stanzione, Paolo; Stefani, Alessandro

    2012-12-01

    Sleep disorders are frequent non-motor symptoms in Parkinson disease (PD), probably due to multifactorial pathogeneses including disease progression, dopaminergic drugs, or concomitant illness. In recent years, the pedunculopontine tegmental (PPTg) nucleus has been considered a surgical target for deep brain stimulation (DBS) in advanced PD patients. As it is involved in controlling the sleep-wake cycle, we investigated the long-lasting effects of PPTg-DBS on the sleep of five PD patients implanted in both the PPTg and the subthalamic nucleus (STN) by rating two subjective clinical scales for sleep: the Parkinson's Disease Sleep Scale (PDSS), and the Epworth Sleepiness Scale (ESS). Sleep scales were administered a week before surgery (T0), three months after DBS (T1), and one year later (T2). In this study, STN-DBS was kept constantly in ON, and three different patterns of PPTg-DBS were investigated: STN-ON (PPTg switched off); PPTg-ON (PPTg stimulated 24 h/day); PPTg-cycle (PPTg stimulated only at night). In post-surgery follow-up, PD patients reported a marked improvement of sleep quality in all DBS conditions. In particular, stimulation of the PPTg nucleus produced not only a remarkable long-term improvement of nighttime sleep, but unlike STN-DBS, also produced significant amelioration of daytime sleepiness. Our study suggests that PPTg-DBS plays an important role in reorganizing regular sleep in PD patients.

  8. Two cycles of recurrent maternal half-sib selection reduce foliar late blight in a diploid hybrid Solanum phureja-S. stenotomum population by two-thirds

    USDA-ARS?s Scientific Manuscript database

    Foliar late blight, caused by Phytophthora infestans, is an important disease problem worldwide. Foliar resistance to late blight was found in a hybrid population of the cultivated diploid species Solanum phureja-S. stenotomum (phu-stn). The objective of this study was to determine if resistance t...

  9. MDMA modulates spontaneous firing of subthalamic nucleus neurons in vitro.

    PubMed

    Liebig, Luise; von Ameln-Mayerhofer, Andreas; Hentschke, Harald

    2015-01-01

    3,4-Methylene-dioxy-N-methylamphetamine (MDMA, 'ecstasy') has a broad spectrum of molecular targets in the brain, among them receptors and transporters of the serotonergic (5-hydroxytryptamine, 5-HT) and noradrenergic systems. Its action on the serotonergic system modulates motor systems in rodents and humans. Although parts of the basal ganglia could be identified as mediators of the motor effects of MDMA, very little is known about the role of the subthalamic nucleus (STN). Therefore, this study investigated the modulation of spontaneous action potential activity of the STN by MDMA (2.5-20 µM) in vitro. MDMA had very heterogeneous effects, ranging from a complete but reversible inhibition to a more than twofold increase in firing at 5 µM. On average, MDMA excited STN neurons moderately, but lost its excitatory effect in the presence of the 5-HT(2A) antagonist MDL 11,939. 5-HT(1A) receptors did not appear to play a major role. Effects of MDMA on transporters for serotonin (SERT) and norepinephrine (NET) were investigated by coapplication of the reuptake inhibitors citalopram and desipramine, respectively. Similar to the effects of 5-HT(2A) receptor blockade, antagonism of SERT and NET bestowed an inhibitory effect on MDMA. From these results, we conclude that both the 5-HT and the noradrenergic system mediate MDMA-induced effects on STN neurons.

  10. Effects of Black Rock Harbor Dredged Material on the Scope for Growth of the Blue Mussel, Mytilus edulis after Laboratory and Field Exposures

    DTIC Science & Technology

    1987-09-01

    maintained in all five llaboratory exposure treatment:s,. Thisi concentration 21 ... . . ....... N air i~ne 2mrm capillary lubing polycorbonole . jugs stn... air stones to provide sufficient oxygen and to ensure even distribution of suspended particulates (Figure 5). 22...ability of the mussel to depurate or metabolize this compound. Field Exposure 97. Estimated from residues. The first method used to determine pos

  11. A Novel Concept for the Search and Retrieval of the Derwent Markush Resource Database.

    PubMed

    Barth, Andreas; Stengel, Thomas; Litterst, Edwin; Kraut, Hans; Matuszczyk, Henry; Ailer, Franz; Hajkowski, Steve

    2016-05-23

    The representation of and search for generic chemical structures (Markush) remains a continuing challenge. Several research groups have addressed this problem, and over time a limited number of practical solutions have been proposed. Today there are two large commercial providers of Markush databases: Chemical Abstracts Service (CAS) and Thomson Reuters. The Thomson Reuters "Derwent" Markush database is currently offered via the online services Questel and STN and as a data feed for in-house use. The aim of this paper is to briefly review the existing Markush systems (databases plus search engines) and to describe our new approach for the implementation of the Derwent Markush Resource on STN. Our new approach demonstrates the integration of the Derwent Markush Resource database into the existing chemistry-focused STN platform without loss of detail. This provides compatibility with other structure and Markush databases on STN and at the same time makes it possible to deploy the specific features and functions of the Derwent approach. It is shown that the different Markush languages developed by CAS and Derwent can be combined into a single general Markush description. In this concept the generic nodes are grouped together in a unique hierarchy where all chemical elements and fragments can be integrated. As a consequence, both systems are searchable using a single structure query. Moreover, the presented concept could serve as a promising starting point for a common generalized description of Markush structures.

  12. Two-dimensional crystallization on lipid monolayers and three-dimensional structure of sticholysin II, a cytolysin from the sea anemone Stichodactyla helianthus.

    PubMed Central

    Martín-Benito, J; Gavilanes, F; de Los Ríos, V; Mancheño, J M; Fernández, J J; Gavilanes, J G

    2000-01-01

    Sticholysin II (Stn II), a potent cytolytic protein isolated from the sea anemone Stichodactyla helianthus, has been crystallized on lipid monolayers. With Fourier-based methods, a three-dimensional (3D) model of Stn II, up to a resolution of 15 A, has been determined. The two-sided plane group is p22(1)2, with dimensions a = 98 A, b = 196 A. The 3D model of Stn II displays a Y-shaped structure, slightly flattened, with a small curvature along its longest dimension (51 A). This protein, with a molecular mass of 19. 2 kDa, is one of the smallest structures reconstructed with this methodology. Two-dimensional (2D) crystals of Stn II on phosphatidylcholine monolayers present a unit cell with two tetrameric motifs, with the monomers in two different orientations: one with its longest dimension lying on the crystal plane and the other with this same axis leaning at an angle of approximately 60 degrees with the crystal plane. PMID:10827995

  13. Influence of composted dairy manure and perennial forage on soil carbon and nitrogen fractions during transition into organic management

    USDA-ARS?s Scientific Manuscript database

    Composted dairy manure (CDM) is among the management practices used in transitioning from a conventional to an organic agricultural system. The objectives of this study are to evaluate the impact of several organic nitrogen (N) sources on: (i) soil organic C (SOC) and soil total N (STN) content; (ii...

  14. Intensive Voice Treatment (LSVT[R]LOUD) for Parkinson's Disease Following Deep Brain Stimulation of the Subthalamic Nucleus

    ERIC Educational Resources Information Center

    Spielman, Jennifer; Mahler, Leslie; Halpern, Angela; Gilley, Phllip; Klepitskaya, Olga; Ramig, Lorraine

    2011-01-01

    Purpose: Intensive voice therapy (LSVT[R]LOUD) can effectively manage voice and speech symptoms associated with idiopathic Parkinson disease (PD). This small-group study evaluated voice and speech in individuals with and without deep brain stimulation of the subthalamic nucleus (STN-DBS) before and after LSVT LOUD, to determine whether outcomes…

  15. Pitch Variability in Patients with Parkinson's Disease: Effects of Deep Brain Stimulation of Caudal Zona Incerta and Subthalamic Nucleus

    ERIC Educational Resources Information Center

    Karlsson, Fredrik; Olofsson, Katarina; Blomstedt, Patric; Linder, Jan; van Doorn, Jan

    2013-01-01

    Purpose: The purpose of the present study was to examine the effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) pitch characteristics of connected speech in patients with Parkinson's disease (PD). Method: The authors evaluated 16 patients preoperatively and 12 months after DBS surgery. Eight…

  16. Articulatory Closure Proficiency in Patients with Parkinson's Disease Following Deep Brain Stimulation of the Subthalamic Nucleus and Caudal Zona Incerta

    ERIC Educational Resources Information Center

    Karlsson, Fredrik; Olofsson, Katarina; Blomstedt, Patric; Linder, Jan; Nordh, Erik; van Doorn, Jan

    2014-01-01

    Purpose: The present study aimed at comparing the effects of deep brain stimulation (DBS) treatment of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) on the proficiency in achieving oral closure and release during plosive production of people with Parkinson's disease. Method: Nineteen patients participated preoperatively and…

  17. Locations of movement-related cells in the human subthalamic nucleus in Parkinson's disease.

    PubMed

    Theodosopoulos, Philip V; Marks, William J; Christine, Chadwick; Starr, Philip A

    2003-07-01

    The subthalamic nucleus (STN) is an emerging target for deep brain stimulator (DBS) implantation for the treatment of advanced Parkinson's disease (PD). Understanding the somatotopic organization of the STN is important for surgical navigation within the nucleus. We analyzed intraoperative data obtained during 54 procedures for the implantation of STN stimulators to assess the locations of movement-related cells. Cells were considered movement-related if they exhibited modulation of the cell discharge during passive movement of the contralateral upper or lower extremity. Microelectrode track reconstructions were plotted on a human brain atlas, using the location of the DBS electrode from postoperative magnetic resonance images as a registration mark in reconstructing microelectrode track locations. Movement-related cells were predominantly located in the dorsal part of the nucleus. The majority of the cells were related to proximal joint manipulation. Arm-related cells were located laterally and at the rostral and caudal poles, whereas leg-related cells were located medially and centrally. The finding of three or more leg-related cells on a given microelectrode track was predictive of a medial localization within the motor area. Our findings are consistent with the small number of published studies on STN somatopy in the human and the nonhuman primate.

  18. Effects of lesions of the subthalamic nucleus/zona incerta area and dorsomedial striatum on attentional set-shifting in the rat.

    PubMed

    Tait, David S; Phillips, Janice M; Blackwell, Andrew D; Brown, Verity J

    2017-03-14

    Patients with Parkinson's disease (PD) show cognitive impairments, including difficulty in shifting attention between perceptual dimensions of complex stimuli. Inactivation of the subthalamic nucleus (STN) has been shown to be effective in ameliorating the motor abnormalities associated with striatal dopamine (DA) depletion, but it is possible that STN inactivation might result in additional, perhaps attentional, deficits. This study examined the effects of: DA depletion from the dorsomedial striatum (DMS); lesions of the STN area; and the effects of the two lesions together, on the ability to shift attentional set in the rat. In a single session, rats performed the intradimensional/extradimensional (ID/ED) test of attentional set-shifting. This comprises a series of seven, two-choice discriminations, including acquisitions of novel discriminations in which the relevant stimulus is either in the currently attended dimension (ID) or the currently unattended dimension (ED shift) and reversals (REVs) following each acquisition stage. Bilateral lesions were made by injection of 6-hydroxydopamine (6-OHDA) into the DMS, resulting in a selective impairment in reversal learning. Large bilateral ibotenic acid lesions centered on the STN resulted in an increase in trials to criterion in the initial stages, but learning rate improved within the session. There was no evidence of a 'cost' of set-shifting - the ED stage was completed in fewer trials than the ID stage - and neither was there a cost of reversal learning. Strikingly, combined lesions of both regions did not resemble the effects of either lesion alone and resulted in no apparent deficits.

  19. Towards high accuracy classification of MER signals for target localization in Parkinson's disease.

    PubMed

    Pinzon-Morales, Ruben-Dario; Orozco-Gutierrez, Alvaro-Angel; Carmona-Villada, Hans; Castellanos, Cesar-German

    2010-01-01

    In recent years Microelectrode recording (MER) analysis has proved to be a powerful localization tool of basal ganglia for Parkinson disease's treatment, especially the Subthalamic Nucleus (STN). In this paper, a signal-dependent method is presented for identification of the STN and other brain zones in Parkinsonian patients. The proposed method, refereed as optimal wavelet feature extraction method (OWFE), is constructed by lifting schemes (LS), which are a flexible and fast implementation of the wavelet transform (WT). The operators in the LS are optimized by means of Genetic Algorithms and Lagrange multipliers considering information contained in MER signals. Then a basic Bayesian classifier (LDC) is used to identify STN and other types of basal ganglia nuclei. The proposed method introduced several advantages from similar works reported in literature. First, the method is signal-dependent and non a priori information is required to decompose the MER signal. Second, the classification accuracy is mostly depended on the feature selection stage because it is not enhanced by elaborated classifiers such as support vector machines or hidden Markov models. Finally, the generalization property of the OWFE has been validated with two databases and different types of classifiers such as k-NN classifier and quadratic Bayesian classifier (QDC). Results have shown that proposed method is able to identify the STN with average accuracy superior than 97%.

  20. Evidence of subthalamic PGO-like waves during REM sleep in humans: a deep brain polysomnographic study.

    PubMed

    Fernández-Mendoza, Julio; Lozano, Beatriz; Seijo, Fernando; Santamarta-Liébana, Elena; Ramos-Platón, Maria José; Vela-Bueno, Antonio; Fernández-González, Fernando

    2009-09-01

    The aim of this study was to examine whether the subthalamic nucleus (STN) plays a role in the transmission of PGO-like waves during REM sleep in humans. Simultaneous recordings from deep brain electrodes to record local field potentials (LFPs), and standard polysomnography to ascertain sleep/wake states. Main Hospital, department of clinical neurophysiology sleep laboratory. 12 individuals with Parkinson's disease, with electrodes implanted in the STN; and, as a control for localization purposes, 4 cluster headache patients with electrodes implanted in the posterior hypothalamus. All subjects underwent functional neurosurgery for implantation of deep brain stimulation electrodes. Sharp, polarity-reversed LFPs were recorded within the STN during REM sleep in humans. These subthalamic PGO-like waves (2-3 Hz, 80-200 pV, and 300-500 msec) appeared during REM epochs as singlets or in clusters of 3-13 waves. During the pre-REM period, subthalamic PGO-like waves were temporally related to drops in the submental electromyogram and/or onset of muscular atonia. Clusters of PGO-like waves occurred typically before and during the bursts of rapid eye movements and were associated with an enhancement in fast (15-35 Hz) subthalamic oscillatory activity. Subthalamic PGO-like waves can be recorded during pre-REM and REM sleep in humans. Our data suggest that the STN may play an active role in an ascending activating network implicated in the transmission of PGO waves during REM sleep in humans.

  1. Hemisphere-Specific Effects of Subthalamic Nucleus Deep Brain Stimulation on Speaking Rate and Articulatory Accuracy of Syllable Repetitions in Parkinson's Disease.

    PubMed

    Wang, Emily Q; Metman, Leo Verhagen; Bakay, Roy A E; Arzbaecher, Jean; Bernard, Bryan; Corcos, Daniel M

    2006-01-01

    This study tested the hypothesis that left versus right deep brain stimulation (DBS) of the subthalamic nucleus (STN) would have differential effects on speech. Twenty right-handed individuals with advanced Parkinson's disease (PD) underwent unilateral STN DBS. Ten were operated on the right and 10 on the left hemisphere as indicated by severity of nonspeech motor function. Speech was evaluated before surgery and 3 to 6 months after surgery with stimulator-off and with stimulator-on, with all participants off anti-parkinsonian medication for 12 hours before evaluation. Evaluators and patient speakers were blinded to the stimulator status at the postsurgery evaluations. Motor performance was assessed with UPDRS-III. Each participant produced three samples of diadochokinetic syllables. Syllable rate, syllable and vowel duration, VOT, and F0 were obtained. The diadochokinetic syllables were rated for articulatory accuracy and speaking rate. Twenty graduate clinicians served as judges. The samples were randomly presented via headphones. A mixed ANOVA with repeated measures was used to assess the significance of the changes in UPRS-III scores and speech measures. The results indicated that unilateral STN DBS produced improvement in nonspeech motor function regardless of the side of stimulation. In contrast, the changes in articulatory accuracy and syllable rate associated with the STN DBS were hemisphere specific.

  2. Lexical-semantic inhibitory mechanisms in Parkinson's disease as a function of subthalamic stimulation.

    PubMed

    Castner, Joanna E; Copland, David A; Silburn, Peter A; Coyne, Terry J; Sinclair, Felicity; Chenery, Helen J

    2007-11-05

    Inhibitory control may be affected by Parkinson's disease (PD) due to impairment within the non-motor basal ganglia-thalamocortical circuits. The present study aimed to identify the effects of chronic stimulation of the subthalamic nucleus (STN) on lexical-semantic inhibitory control. Eighteen participants with PD who had undergone surgery for deep brain stimulation (DBS) of the STN, completed a picture-word interference (PWI) task and the Hayling test in on and off stimulation conditions. The results of PD participants were compared with 21 non-neurologically impaired control participants. PD participants performed no differently from controls on the PWI task, and no significant differences between on and off stimulation conditions were revealed, therefore suggesting that PD participants are not impaired in lexical-semantic interference control. In contrast, in the off stimulation condition, PD participants had significantly delayed reaction times and increased errors on the inhibition section of the Hayling test compared with the STN stimulation condition and control participants. These results suggest that PD patients are impaired in aspects of inhibitory control that are dependent on behavioural inhibition (such as the suppression of prepotent responses) and selection from competing alternatives without the presence of external cues. Furthermore, STN stimulation acts to restore these behavioural inhibitory processes.

  3. Unilateral Subthalamic Nucleus Stimulation in the Treatment of Asymmetric Parkinson"s Disease with Early Motor Complications.

    PubMed

    Sobstyl, Michal; Zabek, Miroslaw; Zaczynski, Artur; Gorecki, Wojciech; Mossakowski, Zbigniew; Brzuszkiewicz-Kuzmicka, Grazyna

    2017-01-01

    The aim of this study was to assess the results of unilateral subthalamic nucleus (STN) stimulation for the treatment of Parkinson"s disease (PD) with marked asymmetry of parkinsonian motor symptoms and early motor complications. The clinical series consisted of 32 consecutive PD patients, in whom unilateral STN stimulation was performed. All patients were assessed according to the Unified Parkinson"s Disease Rating Scale (UPDRS), and Hoehn and Yahr staging. The patients were assessed preoperatively, and at 12, and 24 months after unilateral STN stimulation. 22 patients were followed for 2 years. Medication off/stimulation on total UPDRS motor scores were improved by 29% when compared to the baseline medication off motor scores. The contralateral motor scores improved by 49%, whereas the axial motor scores by 18% in medication off/stimulation on condition. The duration and severity of levodopa induced dyskinesia were reduced respectively by 73% and by 77%. The daily levodopa dose was decreased by only 10%. Unilateral STN stimulation is a safe and effective procedure for selected patients with marked asymmetry Parkinson"s disease motor symptoms and early motor complications.

  4. Network effects and pathways in Deep brain stimulation in Parkinson's disease.

    PubMed

    Koirala, N; Fleischer, V; Granert, O; Deuschl, G; Muthuraman, M; Groppa, S

    2016-08-01

    Deep brain stimulation of subthalamic nucleus (STN-DBS) became a standard therapeutic option in Parkinson's disease (PD), even though the underlying modulated network of STN-DBS is still poorly described. Probabilistic tractography and connectivity analysis as derived from diffusion tensor imaging (DTI) were performed together with modelling of implanted electrode positions and linked postoperative clinical outcome. Fifteen patients with idiopathic PD without dementia were selected for DBS treatment. After pre-processing, probabilistic tractography was run from cortical and subcortical seeds of the hypothesized network to targets represented by the positions of the active DBS contacts. The performed analysis showed that the projections of the stimulation site to supplementary motor area (SMA) and primary motor cortex (M1) are mainly involved in the network effects of STN-DBS. An involvement of the "hyperdirected pathway" and a clear delimitation of the cortico-spinal tract were demonstrated. This study shows the effects of STN-DBS in PD distinctly rely on the network connections of the stimulated region to M1 and SMA, motor and premotor regions.

  5. [Drug effects informational services: databases for patenting and marketing].

    PubMed

    Shkarenkova, L S; Orlovskaya, T T; Ovchinnikovaq, T V

    1997-01-01

    The review is concerned with databases (DB) for patent and commercial aspects of new drugs marketing. The DB characteristics are given and the search peculiarities in every DB and its possible access are discussed. BD accessible through the STN International are presented.

  6. Dissecting human skeletal muscle troponin proteoforms by top-down mass spectrometry.

    PubMed

    Chen, Yi-Chen; Sumandea, Marius P; Larsson, Lars; Moss, Richard L; Ge, Ying

    2015-04-01

    Skeletal muscles are the most abundant tissues in the human body. They are composed of a heterogeneous collection of muscle fibers that perform various functions. Skeletal muscle troponin (sTn) regulates skeletal muscle contraction and relaxation. sTn consists of 3 subunits, troponin I (TnI), troponin T (TnT), and troponin C (TnC). TnI inhibits the actomyosin Mg(2+)-ATPase, TnC binds Ca(2+), and TnT is the tropomyosin (Tm)-binding subunit. The cardiac and skeletal isoforms of Tn share many similarities but the roles of modifications of Tn in the two muscles may differ. The modifications of cardiac Tn are known to alter muscle contractility and have been well-characterized. However, the modification status of sTn remains unclear. Here, we have employed top-down mass spectrometry (MS) to decipher the modifications of human sTnT and sTnI. We have extensively characterized sTnT and sTnI proteoforms, including alternatively spliced isoforms and post-translationally modified forms, found in human skeletal muscle with high mass accuracy and comprehensive sequence coverage. Moreover, we have localized the phosphorylation site of slow sTnT isoform III to Ser1 by tandem MS with electron capture dissociation. This is the first study to comprehensively characterize human sTn and also the first to identify the basal phosphorylation site for human sTnT by top-down MS.

  7. Glutamate Signaling and Mitochondrial Dysfunction in Models of Parkinson’s Disease

    DTIC Science & Technology

    2014-03-01

    neurodegeneration, ion channel, optogenetics , electrophysiology 3. OVERALL PROJECT SUMMARY: Specific Aim 1: To characterize interactions between N...a collaboration with Dr. Traynelis to test the impact of these compounds on PPN and STN synaptic responses evoked with optogenetic techniques (see...neurons similar to those produced by exogenous glutamate application. Our initial strategy was to use optogenetic approaches to study the PPN input

  8. Subthalamic nucleus gamma activity increases not only during movement but also during movement inhibition

    PubMed Central

    Fischer, Petra; Pogosyan, Alek; Herz, Damian M; Cheeran, Binith; Green, Alexander L; Fitzgerald, James; Aziz, Tipu Z; Hyam, Jonathan; Little, Simon; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Brown, Peter; Tan, Huiling

    2017-01-01

    Gamma activity in the subthalamic nucleus (STN) is widely viewed as a pro-kinetic rhythm. Here we test the hypothesis that rather than being specifically linked to movement execution, gamma activity reflects dynamic processing in this nucleus. We investigated the role of gamma during fast stopping and recorded scalp electroencephalogram and local field potentials from deep brain stimulation electrodes in 9 Parkinson’s disease patients. Patients interrupted finger tapping (paced by a metronome) in response to a stop-signal sound, which was timed such that successful stopping would occur only in ~50% of all trials. STN gamma (60–90 Hz) increased most strongly when the tap was successfully stopped, whereas phase-based connectivity between the contralateral STN and motor cortex decreased. Beta or theta power seemed less directly related to stopping. In summary, STN gamma activity may support flexible motor control as it did not only increase during movement execution but also during rapid action-stopping. DOI: http://dx.doi.org/10.7554/eLife.23947.001 PMID:28742498

  9. Patient-specific models of deep brain stimulation: Influence of field model complexity on neural activation predictions

    PubMed Central

    Chaturvedi, Ashutosh; Butson, Christopher R.; Lempka, Scott F.; Cooper, Scott E.; McIntyre, Cameron C.

    2010-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become the surgical therapy of choice for medically intractable Parkinson’s disease. However, quantitative understanding of the interaction between the electric field generated by DBS and the underlying neural tissue is limited. Recently, computational models of varying levels of complexity have been used to study the neural response to DBS. The goal of this study was to evaluate the quantitative impact of incrementally incorporating increasing levels of complexity into computer models of STN DBS. Our analysis focused on the direct activation of experimentally measureable fiber pathways within the internal capsule (IC). Our model system was customized to an STN DBS patient and stimulation thresholds for activation of IC axons were calculated with electric field models that ranged from an electrostatic, homogenous, isotropic model to one that explicitly incorporated the voltage-drop and capacitance of the electrode-electrolyte interface, tissue encapsulation of the electrode, and diffusion-tensor based 3D tissue anisotropy and inhomogeneity. The model predictions were compared to experimental IC activation defined from electromyographic (EMG) recordings from eight different muscle groups in the contralateral arm and leg of the STN DBS patient. Coupled evaluation of the model and experimental data showed that the most realistic predictions of axonal thresholds were achieved with the most detailed model. Furthermore, the more simplistic neurostimulation models substantially overestimated the spatial extent of neural activation. PMID:20607090

  10. Deep Brain Stimulation of Caudal Zona Incerta and Subthalamic Nucleus in Patients with Parkinson's Disease: Effects on Diadochokinetic Rate

    PubMed Central

    Karlsson, Fredrik; Unger, Elin; Wahlgren, Sofia; Blomstedt, Patric; Linder, Jan; Nordh, Erik; Zafar, Hamayun; van Doorn, Jan

    2011-01-01

    The hypokinetic dysarthria observed in Parkinson's disease (PD) affects the range, speed, and accuracy of articulatory gestures in patients, reducing the perceived quality of speech acoustic output in continuous speech. Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) and of the caudal zona incerta (cZi-DBS) are current surgical treatment options for PD. This study aimed at investigating the outcome of STN-DBS (7 patients) and cZi-DBS (7 patients) in two articulatory diadochokinesis tasks (AMR and SMR) using measurements of articulation rate and quality of the plosive consonants (using the percent measurable VOT metric). The results indicate that patients receiving STN-DBS increased in articulation rate in the Stim-ON condition in the AMR task only, with no effect on production quality. Patients receiving cZi-DBS decreased in articulation rate in the Stim-ON condition and further showed a reduction in production quality. The data therefore suggest that cZi-DBS is more detrimental for extended articulatory movements than STN-DBS. PMID:22007342

  11. The Parkinsonian Subthalamic Network: Measures of Power, Linear, and Non-linear Synchronization and their Relationship to L-DOPA Treatment and OFF State Motor Severity

    PubMed Central

    West, Timothy; Farmer, Simon; Berthouze, Luc; Jha, Ashwani; Beudel, Martijn; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Brown, Peter; Litvak, Vladimir

    2016-01-01

    In this paper we investigated the dopaminergic modulation of neuronal interactions occurring in the subthalamic nucleus (STN) during Parkinson's disease (PD). We utilized linear measures of local and long range synchrony such as power and coherence, as well as Detrended Fluctuation Analysis for Phase Synchrony (DFA-PS)- a recently developed non-linear method that computes the extent of long tailed autocorrelations present in the phase interactions between two coupled signals. Through analysis of local field potentials (LFPs) taken from the STN we seek to determine changes in the neurodynamics that may underpin the pathophysiology of PD in a group of 12 patients who had undergone surgery for deep brain stimulation. We demonstrate up modulation of alpha-theta (5–12 Hz) band power in response to L-DOPA treatment, whilst low beta band power (15–20 Hz) band-power is suppressed. We also find evidence for significant local connectivity within the region surrounding STN although there was evidence for its modulation via administration of L-DOPA. Further to this we present evidence for a positive correlation between the phase ordering of bilateral STN interactions and the severity of bradykinetic and rigidity symptoms in PD. Although, the ability of non-linear measures to predict clinical state did not exceed standard measures such as beta power, these measures may help identify the connections which play a role in pathological dynamics. PMID:27826233

  12. Articulatory Closure Proficiency in Patients with Parkinson's Disease Following Deep Brain Stimulation of the Subthalamic Nucleus and Caudal Zona Incerta

    ERIC Educational Resources Information Center

    Karlsson, Fredrik; Olofsson, Katarina; Blomstedt, Patric; Linder, Jan; Nordh, Erik; van Doorn, Jan

    2014-01-01

    Purpose: The present study aimed at comparing the effects of deep brain stimulation (DBS) treatment of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) on the proficiency in achieving oral closure and release during plosive production of people with Parkinson's disease. Method: Nineteen patients participated preoperatively and…

  13. Pitch Variability in Patients with Parkinson's Disease: Effects of Deep Brain Stimulation of Caudal Zona Incerta and Subthalamic Nucleus

    ERIC Educational Resources Information Center

    Karlsson, Fredrik; Olofsson, Katarina; Blomstedt, Patric; Linder, Jan; van Doorn, Jan

    2013-01-01

    Purpose: The purpose of the present study was to examine the effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) pitch characteristics of connected speech in patients with Parkinson's disease (PD). Method: The authors evaluated 16 patients preoperatively and 12 months after DBS surgery. Eight…

  14. Intensive Voice Treatment (LSVT[R]LOUD) for Parkinson's Disease Following Deep Brain Stimulation of the Subthalamic Nucleus

    ERIC Educational Resources Information Center

    Spielman, Jennifer; Mahler, Leslie; Halpern, Angela; Gilley, Phllip; Klepitskaya, Olga; Ramig, Lorraine

    2011-01-01

    Purpose: Intensive voice therapy (LSVT[R]LOUD) can effectively manage voice and speech symptoms associated with idiopathic Parkinson disease (PD). This small-group study evaluated voice and speech in individuals with and without deep brain stimulation of the subthalamic nucleus (STN-DBS) before and after LSVT LOUD, to determine whether outcomes…

  15. Subthalamic deep brain stimulation reduces pathological information transmission to the thalamus in a rat model of parkinsonism

    PubMed Central

    Anderson, Collin J.; Sheppard, Daylan T.; Huynh, Rachel; Anderson, Daria Nesterovich; Polar, Christian A.; Dorval, Alan D.

    2015-01-01

    The degeneration of dopaminergic neurons in the substantia nigra pars compacta leads to parkinsonian motor symptoms via changes in electrophysiological activity throughout the basal ganglia. High-frequency deep brain stimulation (DBS) partially treats these symptoms, but the mechanisms are unclear. We hypothesize that motor symptoms of Parkinson’s disease (PD) are associated with increased information transmission from basal ganglia output neurons to motor thalamus input neurons and that therapeutic DBS of the subthalamic nucleus (STN) treats these symptoms by reducing this extraneous information transmission. We tested these hypotheses in a unilateral, 6-hydroxydopamine-lesioned rodent model of hemiparkinsonism. Information transfer between basal ganglia output neurons and motor thalamus input neurons increased in both the orthodromic and antidromic directions with hemiparkinsonian (hPD) onset, and these changes were reversed by behaviorally therapeutic STN-DBS. Omnidirectional information increases in the parkinsonian state underscore the detrimental nature of that pathological information and suggest a loss of information channel independence. Therapeutic STN-DBS reduced that pathological information, suggesting an effective increase in the number of independent information channels. We interpret these data with a model in which pathological information and fewer information channels diminishes the scope of possible motor activities, driving parkinsonian symptoms. In this model, STN-DBS restores information-channel independence by eliminating or masking the parkinsonism-associated information, and thus enlarges the scope of possible motor activities, alleviating parkinsonian symptoms. PMID:26217192

  16. Effects of Stimulation of the Subthalamic Nucleus on Naming and Reading Nouns and Verbs in Parkinson's Disease

    ERIC Educational Resources Information Center

    Silveri, Maria Caterina; Ciccarelli, Nicoletta; Baldonero, Eleonora; Piano, Carla; Zinno, Massimiliano; Soleti, Francesco; Bentivoglio, Anna Rita; Albanese, Alberto; Daniele, Antonio

    2012-01-01

    An impairment for verbs has been described in patients with Parkinson's disease (PD), suggesting that a disruption of frontal-subcortical circuits may result in dysfunction of the neural systems involved in action-verb processing. A previous study suggested that deep brain stimulation (DBS) of the subthalamic nucleus (STN) during verb generation…

  17. Method to Select Metropolitan Areas of Epidemiologic Interest for Enhanced Air Quality Monitoring

    EPA Science Inventory

    The U.S. Environmental Protection Agency’s current Speciation Trends Network (STN) covers most major U.S. metropolitan areas and a wide range of particulate matter (PM) constituents and gaseous co-pollutants. However, using filter-based methods, most PM constituents are measured ...

  18. Cortical Hemiballism: A Case of Hemiballismus Associated with Parietal Lobe Infarct.

    PubMed

    Shrestha, Pragya; Adhikari, Janak; Poudel, Dilli; Pathak, Ranjan; Karmacharya, Paras

    2015-12-01

    Hemiballismus is characterized by involuntary, irregular, large amplitude, and violent flinging movements of limbs. Stroke (middle and posterior cerebral artery) remains the most common etiology with 2/3 being lacunar. Lesions outside the substantia niagra (STN) can cause hemiballism, and only a minority by STN lesions, unlike the classical belief. Compared to those arising from STN, cortical hemiballismus is usually less severe with a good prognosis. A 61-year-old man presented with sudden onset involuntary flinging movements of his right upper extremity accompanied by numbness and tingling. Past medical history was significant for stroke 2 years back with no residual deficits. Vitals signs were blood pressure of 165/84 mm Hg, and heart rate - 82 beats/min. Irregular, arrhythmic, jerky flinging movement, and decreased sensation to light touch in right upper extremity was noted. Magnetic resonance imaging of the brain revealed acute posterior left parietal lobe infarction. He was treated with aspirin and atorvastatin. Thrombolytic therapy was offered but declined. The movements resolved spontaneously over the next 2 days. No further episodes occurred at 3-month follow-up. Lesions affecting various areas outside the STN can cause hemiballism and usually carries a good prognosis with spontaneous resolution. Acute thrombolytic therapy may be considered on an individual basis. Treatment with antipsychotics can be useful for severe and recurring symptoms.

  19. Submyelin potassium accumulation may functionally block subsets of local axons during deep brain stimulation: a modeling study

    NASA Astrophysics Data System (ADS)

    Bellinger, S. C.; Miyazawa, G.; Steinmetz, P. N.

    2008-09-01

    Deep brain stimulation has been used for over a decade to relieve the symptoms of Parkinson's disease, although its mechanism of action remains poorly understood. To better understand the direct effects of DBS on central neurons, a computational model of a myelinated axon has been constructed which includes the effects of K+ accumulation within the peri-axonal space. Using best estimates of anatomic and electrogenic model parameters for in vivo STN axons, the model predicts a functional block along the axon due to K+ accumulation in the submyelin space. The functional block occurs for a range of model parameters: high stimulation frequencies (>130 Hz); high extracellular K+ concentrations (>3 × 10-3 M); low maximum Na+/K+ ATPase current densities (<0.026 A m-2); low diffusion coefficients for K+ diffusion out of the submyelin space (<2.4 × 10-9 m2 s-1); small periaxonal space widths of the myelin attachment sections (<2.7 × 10-9 m) and perinodal/internodal sections (<8.4 × 10-9 m). These results suggest that therapeutic DBS of the STN likely results in a functional block for many STN axons, although a subset of STN axons may also be activated at the stimulating frequency.

  20. Sedation with α2 Agonist Dexmedetomidine During Unilateral Subthalamic Nucleus Deep Brain Stimulation: A Preliminary Report.

    PubMed

    Morace, Roberta; De Angelis, Michelangelo; Aglialoro, Emiliano; Maucione, Gianni; Cavallo, LuigiMaria; Solari, Domenico; Modugno, Nicola; Santilli, Marco; Esposito, Vincenzo; Aloj, Fulvio

    2016-05-01

    The α2 agonist dexmedetomidine (DEX) is an anesthetic agent that can provide sedation and analgesia without respiratory depression or changes in neuronal activity during microrecordings. The aim of our study was to confirm the efficacy and safety of anesthesia with DEX for unilateral deep brain stimulation of the subthalamic nucleus (STN) in patients with Parkinson disease. In 2013 and 2014, a series of 11 consecutive patients received continuous low-dose DEX infusion during unilateral deep brain stimulation of the STN. Intraoperative microrecordings, stimulation results, and patient reaction times in executing verbal and motor tasks were retrospectively analyzed. Functional outcomes were evaluated by comparing preoperative and 1-year postoperative Unified Parkinson's Disease Rating Scale Part III scores. Typical activity of the STN was recorded in all patients, and the delay in the execution of both motor and verbal tasks was ≤2 seconds. No hemorrhagic complications occurred, and no postoperative side effects were observed. The mean percentage of Unified Parkinson's Disease Rating Scale Part III improvement at last follow-up was 39.01% (range, 23.70%-55.60%). The mean percentage of levodopa equivalent dose reduction was 45.86% (range, 21.50%-65.70%). The results of our study confirm that the use of DEX in managing patients with Parkinson disease during unilateral deep brain stimulation of the STN is safe and effective and can be considered a promising option for sedation during this type of procedure. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Effects of contact location and voltage amplitude on speech and movement in bilateral subthalamic nucleus deep brain stimulation.

    PubMed

    Tripoliti, Elina; Zrinzo, Ludvic; Martinez-Torres, Irene; Tisch, Stephen; Frost, Eleanor; Borrell, Ellie; Hariz, Marwan I; Limousin, Patricia

    2008-12-15

    Subthalamic nucleus deep brain stimulation (STN-DBS) is particularly effective in improving limb symptoms in Parkinson's disease. However, speech shows a variable response. Contact site and amplitude of stimulation have been suggested as possible factors influencing speech. In this double blind study, we assessed 14 patients post bilateral STN-DBS, without medication. Six conditions were studied in random order as follows: stimulation inside the STN at low voltage (2 V) and at high voltage (4 V); above the STN at 2 V and at 4 V, at usual clinical parameters, and off-stimulation. The site of stimulation was defined on the postoperative stereotactic MRI data. Speech protocol consisted of the assessment of intelligibility of the dysarthric speech, maximum sustained phonation, and a 1-minute monologue. Movement was assessed using the UPDRS-III. Stimulation at 4 V significantly reduced the speech intelligibility (P = 0.004) independently from the site of stimulation. Stimulation at 4 V significantly improved the motor function. Stimulation inside the nucleus was significantly more effective than outside the nucleus (P = 0.0006). The significant improvement in movement coupled with significant deterioration in speech intelligibility when patients are stimulated inside the nucleus at high voltage indicates a critical role for electrical stimulation parameters in speech motor control. (c) 2008 Movement Disorder Society.

  2. Coping with Chemical Nomenclature in the Age of Computers.

    ERIC Educational Resources Information Center

    Dess, Howard M.

    1988-01-01

    Reviews nomenclature-related problems for users of Chemical Abstracts (CA) and describes online techniques for searching with generic/trade/common names, non-CA index names, and CA index names using CAS-Online via STN (Scientific and Technical Information Network). Terms used in the online substance display format are explained. (10 references)…

  3. Chemical Substructure Searching: Comparing Three Commercially Available Databases.

    ERIC Educational Resources Information Center

    Wagner, A. Ben

    1986-01-01

    Compares the differences in coverage and utility of three substructure databases--Chemical Abstracts, Index Chemicus, and Chemical Information System's Nomenclature Search System. The differences between Chemical Abstracts with two different vendors--STN International and Questel--are described and a summary guide for choosing between databases is…

  4. Near-infrared stimulation on globus pallidus and subthalamus

    NASA Astrophysics Data System (ADS)

    Yoo, Minsu; Koo, Ho; Kim, Minsun; Kim, Hyoung-Ihl; Kim, Sohee

    2013-12-01

    Near-infrared stimulation (NIS) is an emerging technique used to evoke action potentials in nervous systems. Its efficacy of evoking action potentials has been demonstrated in different nerve tissues. However, few studies have been performed using NIS to stimulate the deep brain structures, such as globus pallidus (GP) and subthalamic nucleus (STN). Male Sprague-Dawley rats were randomly divided into GP stimulation group (n=11) and STN stimulation group (n=6). After introducing optrodes stereotaxically into the GP or STN, we stimulated neural tissue for 2 min with continuous near-infrared light of 808 nm while varying the radiant exposure from 40 to 10 mW. The effects were investigated with extracellular recordings and the temperature rises at the stimulation site were also measured. NIS was found to elicit excitatory responses in eight out of 11 cases (73%) and inhibitory responses in three cases in the GP stimulation group, whereas it predominantly evoked inhibitory responses in seven out of eight cases (87.5%) and an excitatory response in one case in STN stimulation group. Only radiation above 20 mW, accompanying temperature increases of more than 2°C, elicited a statistically significant neural response (p<0.05). The responsiveness to NIS was linearly dependent on the power of radiation exposure.

  5. Spatial Localization of Sources in the Rat Subthalamic Motor Region Using an Inverse Current Source Density Method

    PubMed Central

    van Dijk, Kees J.; Janssen, Marcus L. F.; Zwartjes, Daphne G. M.; Temel, Yasin; Visser-Vandewalle, Veerle; Veltink, Peter H.; Benazzouz, Abdelhamid; Heida, Tjitske

    2016-01-01

    Objective: In this study we introduce the use of the current source density (CSD) method as a way to visualize the spatial organization of evoked responses in the rat subthalamic nucleus (STN) at fixed time stamps resulting from motor cortex stimulation. This method offers opportunities to visualize neuronal input and study the relation between the synaptic input and the neural output of neural populations. Approach: Motor cortex evoked local field potentials and unit activity were measured in the subthalamic region, with a 3D measurement grid consisting of 320 measurement points and high spatial resolution. This allowed us to visualize the evoked synaptic input by estimating the current source density (CSD) from the measured local field potentials, using the inverse CSD method. At the same time, the neuronal output of the cells within the grid is assessed by calculating post stimulus time histograms. Main results: The CSD method resulted in clear and distinguishable sources and sinks of the neuronal input activity in the STN after motor cortex stimulation. We showed that the center of the synaptic input of the STN from the motor cortex is located dorsal to the input from globus pallidus. Significance: For the first time we have performed CSD analysis on motor cortex stimulation evoked LFP responses in the rat STN as a proof of principle. Our results suggest that the CSD method can be used to gain new insights into the spatial extent of synaptic pathways in brain structures. PMID:27857684

  6. Subthalamic, not striatal, activity correlates with basal ganglia downstream activity in normal and parkinsonian monkeys

    PubMed Central

    Deffains, Marc; Iskhakova, Liliya; Katabi, Shiran; Haber, Suzanne N; Israel, Zvi; Bergman, Hagai

    2016-01-01

    The striatum and the subthalamic nucleus (STN) constitute the input stage of the basal ganglia (BG) network and together innervate BG downstream structures using GABA and glutamate, respectively. Comparison of the neuronal activity in BG input and downstream structures reveals that subthalamic, not striatal, activity fluctuations correlate with modulations in the increase/decrease discharge balance of BG downstream neurons during temporal discounting classical condition task. After induction of parkinsonism with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), abnormal low beta (8-15 Hz) spiking and local field potential (LFP) oscillations resonate across the BG network. Nevertheless, LFP beta oscillations entrain spiking activity of STN, striatal cholinergic interneurons and BG downstream structures, but do not entrain spiking activity of striatal projection neurons. Our results highlight the pivotal role of STN divergent projections in BG physiology and pathophysiology and may explain why STN is such an effective site for invasive treatment of advanced Parkinson's disease and other BG-related disorders. DOI: http://dx.doi.org/10.7554/eLife.16443.001 PMID:27552049

  7. Effects of Stimulation of the Subthalamic Nucleus on Naming and Reading Nouns and Verbs in Parkinson's Disease

    ERIC Educational Resources Information Center

    Silveri, Maria Caterina; Ciccarelli, Nicoletta; Baldonero, Eleonora; Piano, Carla; Zinno, Massimiliano; Soleti, Francesco; Bentivoglio, Anna Rita; Albanese, Alberto; Daniele, Antonio

    2012-01-01

    An impairment for verbs has been described in patients with Parkinson's disease (PD), suggesting that a disruption of frontal-subcortical circuits may result in dysfunction of the neural systems involved in action-verb processing. A previous study suggested that deep brain stimulation (DBS) of the subthalamic nucleus (STN) during verb generation…

  8. The Parkinsonian Subthalamic Network: Measures of Power, Linear, and Non-linear Synchronization and their Relationship to L-DOPA Treatment and OFF State Motor Severity.

    PubMed

    West, Timothy; Farmer, Simon; Berthouze, Luc; Jha, Ashwani; Beudel, Martijn; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Brown, Peter; Litvak, Vladimir

    2016-01-01

    In this paper we investigated the dopaminergic modulation of neuronal interactions occurring in the subthalamic nucleus (STN) during Parkinson's disease (PD). We utilized linear measures of local and long range synchrony such as power and coherence, as well as Detrended Fluctuation Analysis for Phase Synchrony (DFA-PS)- a recently developed non-linear method that computes the extent of long tailed autocorrelations present in the phase interactions between two coupled signals. Through analysis of local field potentials (LFPs) taken from the STN we seek to determine changes in the neurodynamics that may underpin the pathophysiology of PD in a group of 12 patients who had undergone surgery for deep brain stimulation. We demonstrate up modulation of alpha-theta (5-12 Hz) band power in response to L-DOPA treatment, whilst low beta band power (15-20 Hz) band-power is suppressed. We also find evidence for significant local connectivity within the region surrounding STN although there was evidence for its modulation via administration of L-DOPA. Further to this we present evidence for a positive correlation between the phase ordering of bilateral STN interactions and the severity of bradykinetic and rigidity symptoms in PD. Although, the ability of non-linear measures to predict clinical state did not exceed standard measures such as beta power, these measures may help identify the connections which play a role in pathological dynamics.

  9. Unilateral subthalamic deep brain stimulation in advanced Parkinson's disease.

    PubMed

    Linazasoro, Gurutz; Van Blercom, Nadège; Lasa, Asier

    2003-06-01

    Eight patients with advanced PD received a unilateral STN DBS. The UPDRS III off drug-on DBS was improved by a mean 44%. Dyskinesias were ameliorated. Levodopa daily dose was reduced. Three patients required the implantation of the second electrode. Unilateral DBS may be efficacious in some patients with advanced PD. Copyright 2003 Movement Disorder Society

  10. GRASS 3.0 Programmer’s Manual

    DTIC Science & Technology

    1989-09-01

    Category FIle Fomat ................................................. 28 5.5. Cell Color Table Fornut...12.9.2. Cell Category Fie 91 12.9.3. Cell Color Table .............................................................................. 94 12.9.4. Cell...119 12.17.3. stn ct Colors ................................................................................... 120 12.17.4. stnr t History

  11. Changes in Vowel Articulation with Subthalamic Nucleus Deep Brain Stimulation in Dysarthric Speakers with Parkinson's Disease

    PubMed Central

    Langlois, Mélanie; Prud'Homme, Michel; Cantin, Léo

    2014-01-01

    Purpose. To investigate changes in vowel articulation with the electrical deep brain stimulation (DBS) of the subthalamic nucleus (STN) in dysarthric speakers with Parkinson's disease (PD). Methods. Eight Quebec-French speakers diagnosed with idiopathic PD who had undergone STN DBS were evaluated ON-stimulation and OFF-stimulation (1 hour after DBS was turned off). Vowel articulation was compared ON-simulation versus OFF-stimulation using acoustic vowel space and formant centralization ratio, calculated with the first (F1) and second formant (F2) of the vowels /i/, /u/, and /a/. The impact of the preceding consonant context on articulation, which represents a measure of coarticulation, was also analyzed as a function of the stimulation state. Results. Maximum vowel articulation increased during ON-stimulation. Analyses also indicate that vowel articulation was modulated by the consonant context but this relationship did not change with STN DBS. Conclusions. Results suggest that STN DBS may improve articulation in dysarthric speakers with PD, in terms of range of movement. Optimization of the electrical parameters for each patient is important and may lead to improvement in speech fine motor control. However, the impact on overall speech intelligibility may still be small. Clinical considerations are discussed and new research avenues are suggested. PMID:25400977

  12. Probing the Role of Medication, DBS Electrode Position, and Antidromic Activation on Impulsivity Using a Computational Model of Basal Ganglia.

    PubMed

    Mandali, Alekhya; Chakravarthy, V Srinivasa

    2016-01-01

    Everyday, we encounter situations where available choices are nearly equally rewarding (high conflict) calling for some tough decision making. Experimental recordings showed that the activity of Sub Thalamic Nucleus (STN) increases during such situations providing the extra time needed to make the right decision, teasing apart the most rewarding choice from the runner up closely trailing behind. This prolonged deliberation necessary for decision making under high conflict was absent in Parkinson's disease (PD) patients who underwent Deep Brain Stimulation (DBS) surgery of STN. In an attempt to understand the underlying cause of such adverse response, we built a 2D spiking network model (50 × 50 lattice) of Basal ganglia incorporating the key nuclei. Using the model we studied the Probabilistic learning task (PLT) in untreated, treated (L-Dopa and Dopamine Agonist) and STN-DBS PD conditions. Based on the experimental observation that dopaminergic activity is analogous to temporal difference (TD) and induces cortico-striatal plasticity, we introduced learning in the cortico-striatal weights. The results show that healthy and untreated conditions of PD model were able to more or less equally select (avoid) the rewarding (punitive) choice, a behavior that was absent in treated PD condition. The time taken to select a choice in high conflict trials was high in normal condition, which is in agreement with experimental results. The treated PD (Dopamine Agonist) patients made impulsive decisions (small reaction time) which in turn led to poor performance. The underlying cause of the observed impulsivity in DBS patients was studied in the model by (1) varying the electrode position within STN, (2) causing antidromic activation of GPe neurons. The effect of electrode position on reaction time was analyzed by studying the activity of STN neurons where, a decrease in STN neural activity was observed for certain electrode positions. We also observed that a higher antidromic

  13. Abnormal Protein Glycosylation and Activated PI3K/Akt/mTOR Pathway: Role in Bladder Cancer Prognosis and Targeted Therapeutics.

    PubMed

    Costa, Céu; Pereira, Sofia; Lima, Luís; Peixoto, Andreia; Fernandes, Elisabete; Neves, Diogo; Neves, Manuel; Gaiteiro, Cristiana; Tavares, Ana; Gil da Costa, Rui M; Cruz, Ricardo; Amaro, Teresina; Oliveira, Paula A; Ferreira, José Alexandre; Santos, Lúcio L

    2015-01-01

    Muscle invasive bladder cancer (MIBC, stage ≥T2) is generally associated with poor prognosis, constituting the second most common cause of death among genitourinary tumours. Due to high molecular heterogeneity significant variations in the natural history and disease outcome have been observed. This has also delayed the introduction of personalized therapeutics, making advanced stage bladder cancer almost an orphan disease in terms of treatment. Altered protein glycosylation translated by the expression of the sialyl-Tn antigen (STn) and its precursor Tn as well as the activation of the PI3K/Akt/mTOR pathway are cancer-associated events that may hold potential for patient stratification and guided therapy. Therefore, a retrospective design, 96 bladder tumours of different stages (Ta, T1-T4) was screened for STn and phosphorylated forms of Akt (pAkt), mTOR (pmTOR), S6 (pS6) and PTEN, related with the activation of the PI3K/Akt/mTOR pathway. In our series the expression of Tn was residual and was not linked to stage or outcome, while STn was statically higher in MIBC when compared to non-muscle invasive tumours (p = 0.001) and associated decreased cancer-specific survival (log rank p = 0.024). Conversely, PI3K/Akt/mTOR pathway intermediates showed an equal distribution between non-muscle invasive bladder cancer (NMIBC) and MIBC and did not associate with cancer-specif survival (CSS) in any of these groups. However, the overexpression of pAKT, pmTOR and/or pS6 allowed discriminating STn-positive advanced stage bladder tumours facing worst CSS (p = 0.027). Furthermore, multivariate Cox regression analysis revealed that overexpression of PI3K/Akt/mTOR pathway proteins in STn+ MIBC was independently associated with approximately 6-fold risk of death by cancer (p = 0.039). Mice bearing advanced stage chemically-induced bladder tumours mimicking the histological and molecular nature of human tumours were then administrated with mTOR-pathway inhibitor sirolimus (rapamycin

  14. Probing the Role of Medication, DBS Electrode Position, and Antidromic Activation on Impulsivity Using a Computational Model of Basal Ganglia

    PubMed Central

    Mandali, Alekhya; Chakravarthy, V. Srinivasa

    2016-01-01

    Everyday, we encounter situations where available choices are nearly equally rewarding (high conflict) calling for some tough decision making. Experimental recordings showed that the activity of Sub Thalamic Nucleus (STN) increases during such situations providing the extra time needed to make the right decision, teasing apart the most rewarding choice from the runner up closely trailing behind. This prolonged deliberation necessary for decision making under high conflict was absent in Parkinson's disease (PD) patients who underwent Deep Brain Stimulation (DBS) surgery of STN. In an attempt to understand the underlying cause of such adverse response, we built a 2D spiking network model (50 × 50 lattice) of Basal ganglia incorporating the key nuclei. Using the model we studied the Probabilistic learning task (PLT) in untreated, treated (L-Dopa and Dopamine Agonist) and STN-DBS PD conditions. Based on the experimental observation that dopaminergic activity is analogous to temporal difference (TD) and induces cortico-striatal plasticity, we introduced learning in the cortico-striatal weights. The results show that healthy and untreated conditions of PD model were able to more or less equally select (avoid) the rewarding (punitive) choice, a behavior that was absent in treated PD condition. The time taken to select a choice in high conflict trials was high in normal condition, which is in agreement with experimental results. The treated PD (Dopamine Agonist) patients made impulsive decisions (small reaction time) which in turn led to poor performance. The underlying cause of the observed impulsivity in DBS patients was studied in the model by (1) varying the electrode position within STN, (2) causing antidromic activation of GPe neurons. The effect of electrode position on reaction time was analyzed by studying the activity of STN neurons where, a decrease in STN neural activity was observed for certain electrode positions. We also observed that a higher antidromic

  15. Abnormal Protein Glycosylation and Activated PI3K/Akt/mTOR Pathway: Role in Bladder Cancer Prognosis and Targeted Therapeutics

    PubMed Central

    Lima, Luís; Peixoto, Andreia; Fernandes, Elisabete; Neves, Diogo; Neves, Manuel; Gaiteiro, Cristiana; Tavares, Ana; Gil da Costa, Rui M.; Cruz, Ricardo; Amaro, Teresina; Oliveira, Paula A.; Ferreira, José Alexandre; Santos, Lúcio L.

    2015-01-01

    Muscle invasive bladder cancer (MIBC, stage ≥T2) is generally associated with poor prognosis, constituting the second most common cause of death among genitourinary tumours. Due to high molecular heterogeneity significant variations in the natural history and disease outcome have been observed. This has also delayed the introduction of personalized therapeutics, making advanced stage bladder cancer almost an orphan disease in terms of treatment. Altered protein glycosylation translated by the expression of the sialyl-Tn antigen (STn) and its precursor Tn as well as the activation of the PI3K/Akt/mTOR pathway are cancer-associated events that may hold potential for patient stratification and guided therapy. Therefore, a retrospective design, 96 bladder tumours of different stages (Ta, T1-T4) was screened for STn and phosphorylated forms of Akt (pAkt), mTOR (pmTOR), S6 (pS6) and PTEN, related with the activation of the PI3K/Akt/mTOR pathway. In our series the expression of Tn was residual and was not linked to stage or outcome, while STn was statically higher in MIBC when compared to non-muscle invasive tumours (p = 0.001) and associated decreased cancer-specific survival (log rank p = 0.024). Conversely, PI3K/Akt/mTOR pathway intermediates showed an equal distribution between non-muscle invasive bladder cancer (NMIBC) and MIBC and did not associate with cancer-specif survival (CSS) in any of these groups. However, the overexpression of pAKT, pmTOR and/or pS6 allowed discriminating STn-positive advanced stage bladder tumours facing worst CSS (p = 0.027). Furthermore, multivariate Cox regression analysis revealed that overexpression of PI3K/Akt/mTOR pathway proteins in STn+ MIBC was independently associated with approximately 6-fold risk of death by cancer (p = 0.039). Mice bearing advanced stage chemically-induced bladder tumours mimicking the histological and molecular nature of human tumours were then administrated with mTOR-pathway inhibitor sirolimus (rapamycin

  16. Meta-analysis comparing deep brain stimulation of the globus pallidus and subthalamic nucleus to treat advanced Parkinson disease.

    PubMed

    Liu, Yi; Li, Weina; Tan, Changhong; Liu, Xi; Wang, Xin; Gui, Yuejiang; Qin, Lu; Deng, Fen; Hu, Changlin; Chen, Lifen

    2014-09-01

    Deep brain stimulation (DBS) is the surgical procedure of choice for patients with advanced Parkinson disease (PD). The globus pallidus internus (GPi) and the subthalamic nucleus (STN) are commonly targeted by this procedure. The purpose of this meta-analysis was to compare the efficacy of DBS in each region. MEDLINE/PubMed, EMBASE, Web of Knowledge, and the Cochrane Library were searched for English-language studies published before April 2013. of studies investigating the efficacy and clinical outcomes of DBS of the GPi and STN for PD were analyzed. Six eligible trials containing a total of 563 patients were included in the analysis. Deep brain stimulation of the GPi or STN equally improved motor function, measured by the Unified Parkinson's Disease Rating Scale Section III (UPDRSIII) (motor section, for patients in on- and off-medication phases), within 1 year postsurgery. The change score for the on-medication phase was 0.68 (95% CI - 2.12 to 3.47, p > 0.05; 5 studies, 518 patients) and for the off-medication phase was 1.83 (95% CI - 3.12 to 6.77, p > 0.05; 5 studies, 518 patients). The UPDRS Section II (activities of daily living) scores for patients on medication improved equally in both DBS groups (p = 0.97). STN DBS allowed medication dosages to be reduced more than GPi DBS (95% CI 129.27-316.64, p < 0.00001; 5 studies, 540 patients). Psychiatric symptoms, measured by Beck Depression Inventory, 2nd edition scores, showed greater improvement from baseline after GPi DBS than after STN DBS (standardized mean difference -2.28, 95% CI -3.73 to -0.84, p = 0.002; 3 studies, 382 patients). GPi and STN DBS improve motor function and activities of daily living for PD patients. Differences in therapeutic efficacy for PD were not observed between the 2 procedures. STN DBS allowed greater reduction in medication for patients, whereas GPi DBS provided greater relief from psychiatric symptoms. An understanding of other symptomatic aspects of targeting each region and long

  17. Subthalamic nucleus stimulation-induced regional blood flow responses correlate with improvement of motor signs in Parkinson disease.

    PubMed

    Karimi, M; Golchin, N; Tabbal, S D; Hershey, T; Videen, T O; Wu, J; Usche, J W M; Revilla, F J; Hartlein, J M; Wernle, A R; Mink, J W; Perlmutter, J S

    2008-10-01

    Deep brain stimulation of the subthalamic nucleus (STN DBS) improves motor symptoms in idiopathic Parkinson's disease, yet the mechanism of action remains unclear. Previous studies indicate that STN DBS increases regional cerebral blood flow (rCBF) in immediate downstream targets but does not reveal which brain regions may have functional changes associated with improved motor manifestations. We studied 48 patients with STN DBS who withheld medication overnight and underwent PET scans to measure rCBF responses to bilateral STN DBS. PET scans were performed with bilateral DBS OFF and ON in a counterbalanced order followed by clinical ratings of motor manifestations using Unified Parkinson Disease Rating Scale 3 (UPDRS 3). We investigated whether improvement in UPDRS 3 scores in rigidity, bradykinesia, postural stability and gait correlate with rCBF responses in a priori determined regions. These regions were selected based on a previous study showing significant STN DBS-induced rCBF change in the thalamus, midbrain and supplementary motor area (SMA). We also chose the pedunculopontine nucleus region (PPN) due to mounting evidence of its involvement in locomotion. In the current study, bilateral STN DBS improved rigidity (62%), bradykinesia (44%), gait (49%) and postural stability (56%) (paired t-tests: P < 0.001). As expected, bilateral STN DBS also increased rCBF in the bilateral thalami, right midbrain, and decreased rCBF in the right premotor cortex (P < 0.05, corrected). There were significant correlations between improvement of rigidity and decreased rCBF in the SMA (r(s) = -0.4, P < 0.02) and between improvement in bradykinesia and increased rCBF in the thalamus (r(s) = 0.31, P < 0.05). In addition, improved postural reflexes correlated with decreased rCBF in the PPN (r(s) = -0.38, P < 0.03). These modest correlations between selective motor manifestations and rCBF in specific regions suggest possible regional selectivity for improvement of different motor

  18. Separation of Two Distinct O-Glycoforms of Human IgA1 by Serial Lectin Chromatography Followed by Mass Spectrometry O-Glycan Analysis.

    PubMed

    Lehoux, S; Ju, T

    2017-01-01

    Human immunoglobulin A1 (IgA1), which carries four to six mucin-type O-glycans (O-glycans) on its hinge region (HR), is the most abundant O-glycoprotein in plasma or serum. While normal O-glycans from hematopoietic-originated cells are core 1-based complex structures, many reports showed that the IgA1 from patients with IgA nephropathy (IgAN) carries undergalactosylated or truncated O-glycans such as the Tn antigen and its sialylated version the SialylTn (STn) antigen on the HR. Yet, there is still a debate whether Tn/STn on the HR of IgA1 is specific to the IgA1 from patients with IgAN since these antigens have also been seen in serum IgA1 of healthy individuals. An additional question is whether the O-glycans at all sites on the two HRs of one IgA1 molecule are homogeneous (either all normal or all Tn/STn) or heterogeneous (both normal and Tn/STn O-glycans). To address these questions, we conducted a systematic study on the O-glycans of plasma IgA1 from both IgAN patients and healthy controls using serial HPA and PNA lectin chromatography followed by western blotting and further analysis of O-glycans from HPA-bound and PNA-bound IgA1 fractions by mass spectrometry. Unexpectedly, we found that a variable minor fraction of IgA1 from both IgAN patients and healthy controls had Tn/STn antigens, and that the O-glycoprotein IgA1 molecules from most samples had only two distinct O-glycoforms: one major glycoform with homogeneous normal core 1-based O-glycans and one minor glycoform with homogeneous Tn/STn antigens. These results raised a serious question about the role of Tn/STn antigens on IgA1 in pathogenesis of IgAN, and there is a demand for a practical methodology that any laboratory can utilize to analyze the O-glycans of IgA1. Herein, we describe the methodology we developed in more detail. The method could also be applied to the analysis of any other O-glycosylated proteins.

  19. High-frequency stimulation of the subthalamic nucleus inhibits the firing of juxtacellular labelled 5-HT-containing neurones.

    PubMed

    Hartung, H; Tan, S K H; Steinbusch, H M W; Temel, Y; Sharp, T

    2011-07-14

    High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is an established neurosurgical therapy for movement disability in advanced Parkinson's disease (PD), but some patients experience psychiatric side-effects like depression. In a previous electrophysiological study, we observed that HFS of the STN inhibited a population of neurones in the rat dorsal raphe nucleus (DRN), with firing properties characteristic of 5-HT neurones. The present study extended these findings to a second population of neurones, and combined extracellular recording with juxtacellular-labelling to investigate the chemical identity of the neurones affected by HFS. Bilateral HFS (130 Hz, 100-200 μA, 5 min) of the STN inhibited (26.0±2.9%) the firing of 37/74 DRN neurones displaying a slow, regular firing pattern. Slower firing neurones were more strongly inhibited than those firing faster. Importantly, 10 inhibited DRN neurones were juxtacellular-labelled with neurobiotin, and all neurones contained 5-HT as shown by post-mortem 5-HT immunocytochemistry. A minority of slow firing DRN neurones (18/74) were activated by STN HFS (37.9±8.3%) which was not observed previously. Of these neurones, three were juxtacellular-labelled and one was 5-HT immunopositive. Also a small number of DRN neurones (19/74) did not respond to HFS, four of which were juxtacellular-labelled and all contained 5-HT. These data show that individual chemically-identified 5-HT-containing neurones in the DRN were modulated by STN HFS, and that the majority were inhibited but some were activated and some failed to respond. These data extend previous findings of modulation of the 5-HT system by STN HFS but suggest a destabilisation of the 5-HT system rather than simple inhibition as indicated previously. Although the mechanism is not yet known, such changes may contribute to the psychiatric side-effects of STN stimulation in some PD patients. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Association of Deep Brain Stimulation Washout Effects With Parkinson Disease Duration

    PubMed Central

    Cooper, Scott E.; McIntyre, Cameron C.; Fernandez, Hubert H.; Vitek, Jerrold L.

    2016-01-01

    Background Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves symptoms of Parkinson disease (PD), including bradykinesia. When stimulation ceases abruptly, bradykinesia returns gradually. The duration of the gradual, slow washout varies across patients, and although the origin of this variability is unclear, it is hypothesized to be related to 1 or more clinical characteristics of patients. Objective To determine if a correlation exists between clinical characteristics of patients with Parkinson disease (age, age at disease onset, disease severity, disease duration, medication dose, or time since surgery) and the washout rate for bradykinesia when STN DBS is discontinued. Design Serial quantitative assessments of bradykinesia were performed during a defined period following cessation of STN DBS. Setting Academic research. Patients Twenty-four patients with Parkinson disease who underwent STN DBS were enrolled in the study. Patients were assessed while off medication (medication had been discontinued 10½ to 16½ hours before testing), and stimulator settings were unchanged for a mean (median) of 20 (14) months. Main Outcome Measures We measured bradykinesia in the dominant hand by assessing finger tapping (item 23 on the Unified Parkinson Disease Rating Scale), which was quantified using an angular velocity transducer strapped on the index finger. Finger tapping was assessed every 2 minutes for 20 seconds at a time. This was performed during a 20-minute period with DBS on (baseline period), during a 50-minute period following discontinuation of STN DBS for the dominant hand, and again during a 20-minute period after turning on the device. Results When STN DBS was turned off, an initial fast but partial loss of benefit was observed, which was followed by a further slow washout of the residual therapeutic effect. The half-life of the slow washout phase varied significantly across patients, and this variation was strongly related to disease

  1. Design and application of two oligonucleotide probes for the identification of Geodermatophilaceae strains using fluorescence in situ hybridization (FISH).

    PubMed

    Urzì, Clara; La Cono, Violetta; Stackebrandt, Erko

    2004-07-01

    Bacteria of the family of Geodermatophilaceae are actively involved in the decay processes [Urzì, C. and Realini, M. (1998) Int Biodeterior Biodegrad 42: 45-54; Urzì, C., Salamone, P., Schumann, P., and Stackebrandt, E. (2000) Int J Syst Evol Microbiol 50: 529-536] of stone monuments. Characterization of isolates includes phenotypic, chemotaxonomic and genetic analysis often requiring long-term procedures. The use of specific probes for members of Geodermatophilaceae family could be useful for the easy detection of those strains colonizing rock surfaces and involved in the biodeterioration. Two 16S rRNA-targeted oligonucleotide probes were designed for the specific detection of members of the family Geodermatophilaceae using fluorescence in situ hybridization (FISH); one probe specific for members of the two genera Geodermatophilus/Blastococcus and the second for members of the genus Modestobacter.

  2. [National Health and Nutrition Survey 2012: design and coverage].

    PubMed

    Romero-Martínez, Martín; Shamah-Levy, Teresa; Franco-Núñez, Aurora; Villalpando, Salvador; Cuevas-Nasu, Lucía; Gutiérrez, Juan Pablo; Rivera-Dommarco, Juan Ángel

    2013-01-01

    To describe the design and population coverage of the National Health and Nutrition Survey 2012 (NHNS 2012). The design of the NHNS 2012 is reported, as a probabilistic population based survey with a multi-stage and stratified sampling, as well as the sample inferential properties, the logistical procedures, and the obtained coverage. Household response rate for the NHNS 2012 was 87%, completing data from 50,528 households, where 96 031 individual interviews selected by age and 14,104 of ambulatory health services users were also obtained. The probabilistic design of the NHNS 2012 as well as its coverage allowed to generate inferences about health and nutrition conditions, health programs coverage, and access to health services. Because of their complex designs, all estimations from the NHNS 2012 must use the survey design: weights, primary sampling units, and stratus variables.

  3. Subthalamic nucleus deep brain stimulation impacts language in early Parkinson's disease.

    PubMed

    Phillips, Lara; Litcofsky, Kaitlyn A; Pelster, Michael; Gelfand, Matthew; Ullman, Michael T; Charles, P David

    2012-01-01

    Although deep brain stimulation (DBS) of the basal ganglia improves motor outcomes in Parkinson's disease (PD), its effects on cognition, including language, remain unclear. This study examined the impact of subthalamic nucleus (STN) DBS on two fundamental capacities of language, grammatical and lexical functions. These functions were tested with the production of regular and irregular past-tenses, which contrast aspects of grammatical (regulars) and lexical (irregulars) processing while controlling for multiple potentially confounding factors. Aspects of the motor system were tested by contrasting the naming of manipulated (motor) and non-manipulated (non-motor) objects. Performance was compared between healthy controls and early-stage PD patients treated with either DBS/medications or medications alone. Patients were assessed on and off treatment, with controls following a parallel testing schedule. STN-DBS improved naming of manipulated (motor) but not non-manipulated (non-motor) objects, as compared to both controls and patients with just medications, who did not differ from each other across assessment sessions. In contrast, STN-DBS led to worse performance at regulars (grammar) but not irregulars (lexicon), as compared to the other two subject groups, who again did not differ. The results suggest that STN-DBS negatively impacts language in early PD, but may be specific in depressing aspects of grammatical and not lexical processing. The finding that STN-DBS affects both motor and grammar (but not lexical) functions strengthens the view that both depend on basal ganglia circuitry, although the mechanisms for its differential impact on the two (improved motor, impaired grammar) remain to be elucidated.

  4. Striatal Molecular Signature of Subchronic Subthalamic Nucleus High Frequency Stimulation in Parkinsonian Rat

    PubMed Central

    Lortet, Sylviane; Lacombe, Emilie; Boulanger, Nicolas; Rihet, Pascal; Nguyen, Catherine; Goff, Lydia Kerkerian-Le; Salin, Pascal

    2013-01-01

    This study addresses the molecular mechanisms underlying the action of subthalamic nucleus high frequency stimulation (STN-HFS) in the treatment of Parkinson's disease and its interaction with levodopa (L-DOPA), focusing on the striatum. Striatal gene expression profile was assessed in rats with nigral dopamine neuron lesion, either treated or not, using agilent microarrays and qPCR verification. The treatments consisted in anti-akinetic STN-HFS (5 days), chronic L-DOPA treatment inducing dyskinesia (LIDs) or the combination of the two treatments that exacerbated LIDs. STN-HFS modulated 71 striatal genes. The main biological processes associated with the differentially expressed gene products include regulation of growth, of apoptosis and of synaptic transmission, and extracellular region is a major cellular component implicated. In particular, several of these genes have been shown to support survival or differentiation of striatal or of dopaminergic neurons. These results indicate that STN HFS may induce widespread anatomo-functional rearrangements in the striatum and create a molecular environment favorable for neuroprotection and neuroplasticity. STN-HFS and L-DOPA treatment share very few common gene regulation features indicating that the molecular substrates underlying their striatal action are mostly different; among the common effects is the down-regulation of Adrb1, which encodes the adrenergic beta-1- receptor, supporting a major role of this receptor in Parkinson's disease. In addition to genes already reported to be associated with LIDs (preprodynorphin, thyrotropin-releasing hormone, metabotropic glutamate receptor 4, cannabinoid receptor 1), the comparison between DOPA and DOPA/HFS identifies immunity-related genes as potential players in L-DOPA side effects. PMID:23593219

  5. Subthalamic Nucleus Deep Brain Stimulation Impacts Language in Early Parkinson's Disease

    PubMed Central

    Phillips, Lara; Litcofsky, Kaitlyn A.; Pelster, Michael; Gelfand, Matthew

    2012-01-01

    Although deep brain stimulation (DBS) of the basal ganglia improves motor outcomes in Parkinson's disease (PD), its effects on cognition, including language, remain unclear. This study examined the impact of subthalamic nucleus (STN) DBS on two fundamental capacities of language, grammatical and lexical functions. These functions were tested with the production of regular and irregular past-tenses, which contrast aspects of grammatical (regulars) and lexical (irregulars) processing while controlling for multiple potentially confounding factors. Aspects of the motor system were tested by contrasting the naming of manipulated (motor) and non-manipulated (non-motor) objects. Performance was compared between healthy controls and early-stage PD patients treated with either DBS/medications or medications alone. Patients were assessed on and off treatment, with controls following a parallel testing schedule. STN-DBS improved naming of manipulated (motor) but not non-manipulated (non-motor) objects, as compared to both controls and patients with just medications, who did not differ from each other across assessment sessions. In contrast, STN-DBS led to worse performance at regulars (grammar) but not irregulars (lexicon), as compared to the other two subject groups, who again did not differ. The results suggest that STN-DBS negatively impacts language in early PD, but may be specific in depressing aspects of grammatical and not lexical processing. The finding that STN-DBS affects both motor and grammar (but not lexical) functions strengthens the view that both depend on basal ganglia circuitry, although the mechanisms for its differential impact on the two (improved motor, impaired grammar) remain to be elucidated. PMID:22880117

  6. Impact of Combined Subthalamic Nucleus and Substantia Nigra Stimulation on Neuropsychiatric Symptoms in Parkinson's Disease Patients

    PubMed Central

    Horn, A.; Hamel, W.; Koeppen, J. A.; Westphal, M.; Engel, A. K.; Gerloff, C.; Moll, C. K. E.

    2017-01-01

    The goal of the study was to compare the tolerability and the effects of conventional subthalamic nucleus (STN) and combined subthalamic nucleus and substantia nigra (STN+SNr) high-frequency stimulation in regard to neuropsychiatric symptoms in Parkinson's disease patients. In this single center, randomized, double-blind, cross-over clinical trial, twelve patients with advanced Parkinson's disease (1 female; age: 61.3 ± 7.3 years; disease duration: 12.3 ± 5.4 years; Hoehn and Yahr stage: 2.2 ± 0.39) were included. Apathy, fatigue, depression, and impulse control disorder were assessed using a comprehensive set of standardized rating scales and questionnaires such as the Lille Apathy Rating Scale (LARS), Modified Fatigue Impact Scale (MFIS), Becks Depression Inventory (BDI-I), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS), and Parkinson's Disease Questionnaire (PDQ-39). Three patients that were initially assigned to the STN+SNr stimulation mode withdrew from the study within the first week due to discomfort. Statistical comparison of data retrieved from patients who completed the study revealed no significant differences between both stimulation conditions in terms of mean scores of scales measuring apathy, fatigue, depression, impulse control disorder, and quality of life. Individual cases showed an improvement of apathy under combined STN+SNr stimulation. In general, combined STN+SNr stimulation seems to be safe in terms of neuropsychiatric side effects, although careful patient selection and monitoring in the short-term period after changing stimulation settings are recommended. PMID:28246572

  7. Central Role of Protein Kinase A in Promoting Trigeminal Nociception in an In Vivo Model of Temporomandibular Disorders.

    PubMed

    Koop, Lindsey K; Hawkins, Jordan L; Cornelison, Lauren E; Durham, Paul L

    2017-01-01

    To investigate cellular changes in the spinal trigeminal nucleus (STN) and trigeminal ganglion (TG) associated with trigeminal nociception mediated by inflammation in the temporomandibular joint (TMJ). Male Sprague-Dawley rats (n = 86) were utilized to investigate cellular and behavioral responses to prolonged TMJ inflammation caused by bilateral injection of Complete Freund's Adjuvant (CFA) in the TMJ capsules. To investigate the cellular effects of protein kinase A (PKA) in the STN, rats were injected intrathecally with the selective PKA inhibitor KT5720 prior to injection of CFA into both TMJ capsules. Levels of calcitonin gene-related peptide (CGRP), active PKA, and ionized calcium-binding adapter molecule 1 (Iba1) in the STN and expression of phosphorylated extracellular regulated kinases (p-ERK) in the TG were determined with immunohistochemistry (n ≥ 3 experiments per test condition). Nocifensive head withdrawal responses to mechanical stimulation of the cutaneous tissue over the TMJ were monitored following CFA injection in the absence or presence of KT5720 (n = 7). Statistical analysis was performed using parametric analysis of variance (ANOVA) tests. Intrathecal injection of KT5720 significantly inhibited the stimulatory effect of CFA on levels of CGRP, PKA, and Iba1 in the STN. In addition, administration of KT5720 decreased the average number of CFA-induced nocifensive withdrawal responses to mechanical stimulation and the CFA-mediated increase in p-ERK expression in the ganglion. These findings provide evidence that elevated PKA activity in the STN promotes cellular events temporally associated with trigeminal nociception caused by prolonged TMJ inflammation.

  8. Parkinson subtype-specific Granger-causal coupling and coherence frequency in the subthalamic area.

    PubMed

    Florin, Esther; Pfeifer, Johannes; Visser-Vandewalle, Veerle; Schnitzler, Alfons; Timmermann, Lars

    2016-09-22

    Previous work on Parkinson's disease (PD) has indicated a predominantly afferent coupling between affected arm muscle activity and electrophysiological activity within the subthalamic nucleus (STN). So far, no information is available indicating which frequency components drive the afferent information flow in PD patients. Non-directional coupling e.g. by measuring coherence is primarily established in the beta band as well as at tremor frequency. Based on previous evidence it is likely that different subtypes of the disease are associated with different connectivity patterns. Therefore, we determined coherence and causality between local field potentials (LFPs) in the STN and surface electromyograms (EMGs) from the contralateral arm in 18 akinetic-rigid (AR) PD patients and 8 tremor-dominant (TD) PD patients. During the intraoperative recording, patients were asked to lift their forearm contralateral to the recording side. Significantly more afferent connections were detected for the TD patients for tremor-periods and non-tremor-periods combined as well as for only tremor periods. Within the STN 74% and 63% of the afferent connections are associated with coherence from 4-8Hz and 8-12Hz, respectively. However, when considering only tremor-periods significantly more afferent than efferent connections were associated with coherence from 12 to 20Hz across all recording heights. No difference between efferent and afferent connections is seen in the frequency range from 4 to 12Hz for all recording heights. For the AR patients, no significant difference in afferent and efferent connections within the STN was found for the different frequency bands. Still, for the AR patients dorsal of the STN significantly more afferent than efferent connections were associated with coherence in the frequency range from 12 to 16Hz. These results provide further evidence for the differential pathological oscillations and pathways present in AR and TD Parkinson patients. Copyright © 2016

  9. A Network Analysis of 15O-H2O PET Reveals Deep Brain Stimulation Effects on Brain Network of Parkinson's Disease

    PubMed Central

    Park, Hae-Jeong; Park, Bumhee; Kim, Hae Yu; Oh, Maeng-Keun; Kim, Joong Il; Yoon, Misun; Lee, Jong Doo

    2015-01-01

    Purpose As Parkinson's disease (PD) can be considered a network abnormality, the effects of deep brain stimulation (DBS) need to be investigated in the aspect of networks. This study aimed to examine how DBS of the bilateral subthalamic nucleus (STN) affects the motor networks of patients with idiopathic PD during motor performance and to show the feasibility of the network analysis using cross-sectional positron emission tomography (PET) images in DBS studies. Materials and Methods We obtained [15O]H2O PET images from ten patients with PD during a sequential finger-to-thumb opposition task and during the resting state, with DBS-On and DBS-Off at STN. To identify the alteration of motor networks in PD and their changes due to STN-DBS, we applied independent component analysis (ICA) to all the cross-sectional PET images. We analysed the strength of each component according to DBS effects, task effects and interaction effects. Results ICA blindly decomposed components of functionally associated distributed clusters, which were comparable to the results of univariate statistical parametric mapping. ICA further revealed that STN-DBS modifies usage-strengths of components corresponding to the basal ganglia-thalamo-cortical circuits in PD patients by increasing the hypoactive basal ganglia and by suppressing the hyperactive cortical motor areas, ventrolateral thalamus and cerebellum. Conclusion Our results suggest that STN-DBS may affect not only the abnormal local activity, but also alter brain networks in patients with PD. This study also demonstrated the usefulness of ICA for cross-sectional PET data to reveal network modifications due to DBS, which was not observable using the subtraction method. PMID:25837179

  10. Releasing metal catalysts via phase transition: (NiO)0.05-(SrTi0.8Nb0.2O3)0.95 as a redox stable anode material for solid oxide fuel cells.

    PubMed

    Xiao, Guoliang; Wang, Siwei; Lin, Ye; Zhang, Yanxiang; An, Ke; Chen, Fanglin

    2014-11-26

    Donor-doped perovskite-type SrTiO3 experiences stoichiometric changes at high temperatures in different Po2 involving the formation of Sr or Ti-rich impurities. NiO is incorporated into the stoichiometric strontium titanate, SrTi0.8Nb0.2O3-δ (STN), to form an A-site deficient perovskite material, (NiO)0.05-(SrTi0.8Nb0.2O3)0.95 (Ni-STN), for balancing the phase transition. Metallic Ni nanoparticles can be released upon reduction instead of forming undesired secondary phases. This material design introduces a simple catalytic modification method with good compositional control of the ceramic backbones, by which transport property and durability of solid oxide fuel cell anodes are largely determined. Using Ni-STN as anodes for solid oxide fuel cells, enhanced catalytic activity and remarkable stability in redox cycling have been achieved. Electrolyte-supported cells with the cell configuration of Ni-STN-SDC anode, La0.8Sr0.2Ga0.87Mg0.13O3 (LSGM) electrolyte, and La0.6Sr0.4Co0.2Fe0.8O3 (LSCF) cathode produce peak power densities of 612, 794, and 922 mW cm(-2) at 800, 850, and 900 °C, respectively, using H2 as the fuel and air as the oxidant. Minor degradation in fuel cell performance resulted from redox cycling can be recovered upon operating the fuel cells in H2. Such property makes Ni-STN a promising regenerative anode candidate for solid oxide fuel cells.

  11. Midline Frontal Cortex Low-Frequency Activity Drives Subthalamic Nucleus Oscillations during Conflict

    PubMed Central

    Zavala, Baltazar A.; Tan, Huiling; Little, Simon; Ashkan, Keyoumars; Hariz, Marwan; Foltynie, Thomas; Zrinzo, Ludvic; Zaghloul, Kareem A.

    2014-01-01

    Making the right decision from conflicting information takes time. Recent computational, electrophysiological, and clinical studies have implicated two brain areas as being crucial in assuring sufficient time is taken for decision-making under conditions of conflict: the medial prefrontal cortex and the subthalamic nucleus (STN). Both structures exhibit an elevation of activity at low frequencies (<10 Hz) during conflict that correlates with the amount of time taken to respond. This suggests that the two sites could become functionally coupled during conflict. To establish the nature of this interaction we recorded from deep-brain stimulation electrodes implanted bilaterally in the STN of 13 Parkinson's disease patients while they performed a sensory integration task involving randomly moving dots. By gradually increasing the number of dots moving coherently in one direction, we were able to determine changes in the STN associated with response execution. Furthermore, by occasionally having 10% of the dots move in the opposite direction as the majority, we were able to identify an independent increase in STN theta-delta activity triggered by conflict. Crucially, simultaneous midline frontal electroencephalographic recordings revealed an increase in the theta-delta band coherence between the two structures that was specific to high-conflict trials. Activity over the midline frontal cortex was Granger causal to that in STN. These results establish the cortico-subcortical circuit enabling successful choices to be made under conditions of conflict and provide support for the hypothesis that the brain uses frequency-specific channels of communication to convey behaviorally relevant information. PMID:24849364

  12. D2 dopamine receptors modulate neuronal resonance in subthalamic nucleus and cortical high-voltage spindles through HCN channels.

    PubMed

    Yang, Chen; Yan, Zhiqiang; Zhao, Bo; Wang, Julei; Gao, Guodong; Zhu, Junling; Wang, Wenting

    2016-06-01

    The high-voltage spindles (HVSs), one of the characteristic oscillations that include theta frequencies in the basal ganglia (BG)-cortical system, are involved in immobile behavior and show increasing power in Parkinson's disease (PD). Our previous results suggested that the D2 dopamine receptor might be involved in HVSs modulations in a rat model of PD. Membrane resonance is one of the cellular mechanisms of network oscillation; therefore, we investigated how dopamine modulates the theta frequency membrane resonance of neurons in the subthalamic nucleus (STN), a central pacemaker of BG, and whether such changes in STN neurons subsequently alter HVSs in the BG-cortical system. In particular, we tested whether dopamine modulates HVSs through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels-dependent membrane resonance in STN neurons. We found that an antagonist of D2 receptors, but not of D1 receptors, inhibited membrane resonance and HCN currents of STN neurons through a G-protein activity in acute brain slices. Our further in vivo experiments using local injection of a D2 receptor antagonist or an HCN blocker in STNs of free-moving rats showed an increase in HVSs power and correlation in the BG-cortical system. Local injection of lamotrigine, an HCN agonist, counteracted the effect induced by the D2 antagonist. Taken together, our results revealed a potential cellular mechanism underlying HVSs activity modulation in the BG-cortical system, i.e. tuning HCN activities in STN neurons through dopamine D2 receptors. Our findings might lead to a new direction in PD treatment by providing promising new drug targets for HVSs activity modulation.

  13. Subthalamic nucleus gamma oscillations mediate a switch from automatic to controlled processing: a study of random number generation in Parkinson's disease.

    PubMed

    Anzak, Anam; Gaynor, Louise; Beigi, Mazda; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Brown, Peter; Jahanshahi, Marjan

    2013-01-01

    In paced random number generation (RNG) participants are asked to generate numbers between 1 and 9 in a random fashion, in synchrony with a pacing stimulus. Successful task performance can be achieved through control of the main biases known to exist in human RNG compared to a computer generated series: seriation, cycling through a set of available numbers, and repetition avoidance. A role in response inhibition and switching from automatic to controlled processing has previously been ascribed to the subthalamic nucleus (STN). We sought evidence of frequency-specific changes in STN oscillatory activity which could be directly related to use of such strategies during RNG. Local field potentials (LFPs) were recorded from depth electrodes implanted in the STN of 7 patients (14 sides) with Parkinson's disease (PD), when patients were on dopaminergic medication. Patients were instructed to (1) generate a series of 100 numbers between 1 and 9 in a random fashion, and (2) undertake a control serial counting task, both in synchrony with a 0.5 Hz pacing stimulus. Significant increases in LFP power (p ≤ 0.05) across a narrow gamma frequency band (45-60 Hz) during RNG, compared to the control counting task, were observed. Further, the number of 'repeated pairs' (a decline in which reflects repetition avoidance bias in human RNG) was positively correlated with these gamma increases. We therefore suggest that STN gamma activity is relevant for controlled processing, in particular the active selection and repetition of the same number on successive trials. These results are consistent with a frequency-specific role of the STN in executive processes such as suppression of habitual responses and 'switching-on' of more controlled processing strategies. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Relative contributions of local cell and passing fiber activation and silencing to changes in thalamic fidelity during deep brain stimulation and lesioning: a computational modeling study.

    PubMed

    So, Rosa Q; Kent, Alexander R; Grill, Warren M

    2012-06-01

    Deep brain stimulation (DBS) and lesioning are two surgical techniques used in the treatment of advanced Parkinson's disease (PD) in patients whose symptoms are not well controlled by drugs, or who experience dyskinesias as a side effect of medications. Although these treatments have been widely practiced, the mechanisms behind DBS and lesioning are still not well understood. The subthalamic nucleus (STN) and globus pallidus pars interna (GPi) are two common targets for both DBS and lesioning. Previous studies have indicated that DBS not only affects local cells within the target, but also passing axons within neighboring regions. Using a computational model of the basal ganglia-thalamic network, we studied the relative contributions of activation and silencing of local cells (LCs) and fibers of passage (FOPs) to changes in the accuracy of information transmission through the thalamus (thalamic fidelity), which is correlated with the effectiveness of DBS. Activation of both LCs and FOPs during STN and GPi-DBS were beneficial to the outcome of stimulation. During STN and GPi lesioning, effects of silencing LCs and FOPs were different between the two types of lesioning. For STN lesioning, silencing GPi FOPs mainly contributed to its effectiveness, while silencing only STN LCs did not improve thalamic fidelity. In contrast, silencing both GPi LCs and GPe FOPs during GPi lesioning contributed to improvements in thalamic fidelity. Thus, two distinct mechanisms produced comparable improvements in thalamic function: driving the output of the basal ganglia to produce tonic inhibition and silencing the output of the basal ganglia to produce tonic disinhibition. These results show the importance of considering effects of activating or silencing fibers passing close to the nucleus when deciding upon a target location for DBS or lesioning.

  15. Deep brain stimulation and cognitive decline in Parkinson's disease: The predictive value of electroencephalography.

    PubMed

    Markser, A; Maier, Franziska; Lewis, C J; Dembek, T A; Pedrosa, D; Eggers, C; Timmermann, L; Kalbe, E; Fink, G R; Burghaus, Lothar

    2015-10-01

    Some Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS) develop new-onset cognitive decline. We examined whether clinical EEG recordings can be used to predict cognitive deterioration in PD patients undergoing STN-DBS. In this retrospective study, we used the Grand Total EEG (GTE)-score (short and total) to evaluate pre- and postoperative EEGs. In PD patients undergoing STN-DBS (N = 30), cognitive functioning was measured using Mini-Mental State Test and DemTect before and after surgery. Severity of motor impairment was assessed using the Unified Parkinson's Disease Rating Scale-III. Patients were classified into patients with or without cognitive decline after STN-DBS surgery. Epidemiological data, pre- and postoperative EEG recordings as well as neuropsychological and neurological data, electrode positions and the third ventricle width were compared. A logistic regression model was used to identify predictors of cognitive decline. Motor deficits significantly improved from pre- to post-surgery, while the mean GTE-scores increased significantly. Six patients developed cognitive deterioration 4-12 months postoperatively. These patients had significantly higher preoperative GTE-scores than patients without cognitive deterioration, although preoperative cognitive functioning was comparable. Electrode positions, brain atrophy and neurological data did not differ between groups. Logistic regression analysis identified the GTE-score as a significant predictor of postoperative cognitive deterioration. Data suggest that the preoperative GTE-score can be used to identify PD patients that are at high risk for developing cognitive deterioration after STN-DBS surgery even though their preoperative cognitive state was normal.

  16. Processing of emotional information in the human subthalamic nucleus.

    PubMed

    Buot, Anne; Welter, Marie-Laure; Karachi, Carine; Pochon, Jean-Baptiste; Bardinet, Eric; Yelnik, Jérôme; Mallet, Luc

    2013-12-01

    The subthalamic nucleus (STN) is an efficient target for treating patients with Parkinson's disease as well as patients with obsessive-compulsive disorder (OCD) using high frequency stimulation (HFS). In both Parkinson's disease and OCD patients, STN-HFS can trigger abnormal behaviours, such as hypomania and impulsivity. To investigate if this structure processes emotional information, and whether it depends on motor demands, we recorded subthalamic local field potentials in 16 patients with Parkinson's disease using deep brain stimulation electrodes. Recordings were made with and without dopaminergic treatment while patients performed an emotional categorisation paradigm in which the response varied according to stimulus valence (pleasant, unpleasant and neutral) and to the instruction given (motor, non-motor and passive). Pleasant, unpleasant and neutral stimuli evoked an event related potential (ERP). Without dopamine medication, ERP amplitudes were significantly larger for unpleasant compared with neutral pictures, whatever the response triggered by the stimuli; and the magnitude of this effect was maximal in the ventral part of the STN. No significant difference in ERP amplitude was observed for pleasant pictures. With dopamine medication, ERP amplitudes were significantly increased for pleasant compared with neutral pictures whatever the response triggered by the stimuli, while ERP amplitudes to unpleasant pictures were not modified. These results demonstrate that the ventral part of the STN processes the emotional valence of stimuli independently of the motor context and that dopamine enhances processing of pleasant information. These findings confirm the specific involvement of the STN in emotional processes in human, which may underlie the behavioural changes observed in patients with deep brain stimulation.

  17. Spatio-spectral characterization of local field potentials in the subthalamic nucleus via multitrack microelectrode recordings.

    PubMed

    Telkes, I; Ince, N F; Onaran, I; Abosch, A

    2015-08-01

    Deep brain stimulation of the subthalamic nucleus (STN) is a highly effective treatment for motor symptoms of Parkinson's disease. However, precise intraoperative localization of STN remains a procedural challenge. In the present study, local field potentials (LFPs) were recorded from three tracks during microelectrode recording-based (MER) targeting of STN, in five patients. The raw LFP data were preprocessed in original recording setup and then data quality was compared to data with common average derivation. The depth-frequency maps were generated according to preprocessing results for each patient and spectral characteristics of LFPs were explored at each depth across different tracks and different subjects. Spatio-spectral analysis of LFP was investigated to see whether LFP activity can be used for optimal track selection and STN border identification. Analysis show that monopolar derivation suffer from various artifacts and/or power line noise which makes the interpretation of target localization very difficult in most of the subjects. Unlikely, bipolar derivation helps to recover the neurological signals and investigation of signal characteristics. The frequency-vs-depth maps using a modified Welch periodogram with robust statistics, demonstrated that a median-based spectrum estimation approach eliminates outliers pretty well by preserving band-specific LFP activity. The results indicate that there is a clear oscillatory beta activity around 20 Hz in all subjects. 1/f normalization reveals the high frequency oscillations (HFOs) between 200-to-350 Hz in two subjects. It's noted that the optimal track selection is not consistent with the track having highest beta band oscillations in two out of five subjects. In conclusion, microelectrode-derived LFP recordings may provide an alternative approach to single unit activity (SUA)-based MER, for localizing the target STN borders during DBS surgery. Despite the small number of subjects, the present study adds to

  18. Impact of Combined Subthalamic Nucleus and Substantia Nigra Stimulation on Neuropsychiatric Symptoms in Parkinson's Disease Patients.

    PubMed

    Hidding, U; Gulberti, A; Horn, A; Buhmann, C; Hamel, W; Koeppen, J A; Westphal, M; Engel, A K; Gerloff, C; Weiss, D; Moll, C K E; Pötter-Nerger, M

    2017-01-01

    The goal of the study was to compare the tolerability and the effects of conventional subthalamic nucleus (STN) and combined subthalamic nucleus and substantia nigra (STN+SNr) high-frequency stimulation in regard to neuropsychiatric symptoms in Parkinson's disease patients. In this single center, randomized, double-blind, cross-over clinical trial, twelve patients with advanced Parkinson's disease (1 female; age: 61.3 ± 7.3 years; disease duration: 12.3 ± 5.4 years; Hoehn and Yahr stage: 2.2 ± 0.39) were included. Apathy, fatigue, depression, and impulse control disorder were assessed using a comprehensive set of standardized rating scales and questionnaires such as the Lille Apathy Rating Scale (LARS), Modified Fatigue Impact Scale (MFIS), Becks Depression Inventory (BDI-I), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS), and Parkinson's Disease Questionnaire (PDQ-39). Three patients that were initially assigned to the STN+SNr stimulation mode withdrew from the study within the first week due to discomfort. Statistical comparison of data retrieved from patients who completed the study revealed no significant differences between both stimulation conditions in terms of mean scores of scales measuring apathy, fatigue, depression, impulse control disorder, and quality of life. Individual cases showed an improvement of apathy under combined STN+SNr stimulation. In general, combined STN+SNr stimulation seems to be safe in terms of neuropsychiatric side effects, although careful patient selection and monitoring in the short-term period after changing stimulation settings are recommended.

  19. MRI directed bilateral stimulation of the subthalamic nucleus in patients with Parkinson's disease

    PubMed Central

    Patel, N; Plaha, P; O'Sullivan, K; McCarter, R; Heywood, P; Gill, S

    2003-01-01

    Objective: Bilateral chronic high frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) has emerged as an appropriate therapy for patients with advanced Parkinson's disease refractory to medical therapy. Advances in neuroimaging and neurophysiology have led to the development of varied targeting methods for the delivery of this treatment. Intraoperative neurophysiological and clinical monitoring is regarded by many to be mandatory for accurate STN localisation. We have examined efficacy of bilateral STN stimulation using a predominantly magnetic resonance imaging (MRI)-directed technique. Methods: DBS leads were stereotactically implanted into the STN using an MRI directed method, with intraoperative macrostimulation used purely for adjustment. The effects of DBS were evaluated in 16 patients followed up to 12 months, and compared with baseline assessments. Assessments were performed in both off and on medication states, and were based on the Unified Parkinson's Disease Rating Scale (UPDRS) and timed motor tests. Functional status outcomes were examined using the PDQ-39 quality of life questionnaire. A battery of psychometric tests was used to assess cognition. Results: After 12 months, stimulation in the off medication state resulted in significant improvements in Activities of Daily Living and Motor scores (UPDRS parts II and III) by 62% and 61% respectively. Timed motor tests were significantly improved in the off medication state. Motor scores (UPDRS part III) were significantly improved by 40% in the on medication state. Dyskinesias and off duration were significantly reduced and the mean dose of L-dopa equivalents was reduced by half. Psychometric test scores were mostly unchanged or improved. Adverse events were few. Conclusions: An MRI directed targeting method for implantation of DBS leads into the STN can be used safely and effectively, and results are comparable with studies using intraoperative microelectrode neurophysiological

  20. Predictive timing functions of cortical beta oscillations are impaired in Parkinson's disease and influenced by L-DOPA and deep brain stimulation of the subthalamic nucleus

    PubMed Central

    Gulberti, A.; Moll, C.K.E.; Hamel, W.; Buhmann, C.; Koeppen, J.A.; Boelmans, K.; Zittel, S.; Gerloff, C.; Westphal, M.; Schneider, T.R.; Engel, A.K.

    2015-01-01

    Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory–motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing. PMID:26594626

  1. Expression of sialyl-Tn sugar antigen in bladder cancer cells affects response to Bacillus Calmette Guérin (BCG) and to oxidative damage.

    PubMed

    Severino, Paulo F; Silva, Mariana; Carrascal, Mylene; Malagolini, Nadia; Chiricolo, Mariella; Venturi, Giulia; Astolfi, Annalisa; Catera, Mariangela; Videira, Paula A; Dall'Olio, Fabio

    2017-08-15

    The sialyl-Tn (sTn) antigen is an O-linked carbohydrate chain aberrantly expressed in bladder cancer (BC), whose biosynthesis is mainly controlled by the sialyltransferase ST6GALNAC1. Treatment with Bacillus Calmette-Guérin (BCG) is the most effective adjuvant immunotherapy for superficial BC but one third of the patients fail to respond. A poorly understood correlation between the expression of sTn and BC patient's response to BCG was previously observed. By analyzing tumor tissues, we showed that patients with high ST6GALNAC1 and IL-6 mRNA expression were BCG responders. To investigate the role of sTn in BC cell biology and BCG response, we established the cell lines MCRsTn and MCRNc by retroviral transduction of the BC cell line MCR with the ST6GALNAC1 cDNA or with an empty vector, respectively. Compared with MCRNc, BCG-stimulated MCRsTn secreted higher levels of IL-6 and IL-8 and their secretome induced a stronger IL-6, IL-1β, and TNFα secretion by macrophages, suggesting the induction of a stronger inflammatory response. Transcriptomic analysis of MCRNc and MCRsTn revealed that ST6GALNAC1/sTn expression modulates hundreds of genes towards a putative more malignant phenotype and down-regulates several genes maintaining genomic stability. Consistently, MCRsTn cells displayed higher H2O2 sensitivity. In MCRsTn,, BCG challenge induced an increased expression of several regulatory non coding RNA genes. These results indicate that the expression of ST6GALNAC1/sTn improves the response to BCG therapy by inducing a stronger macrophage response and alters gene expression towards malignancy and genomic instability, increasing the sensitivity of BC cells to the oxidizing agents released by BCG.

  2. Identification of a novel cancer-specific immunodominant glycopeptide epitope in the MUC1 tandem repeat.

    PubMed

    Tarp, Mads A; Sørensen, Anne Louise; Mandel, Ulla; Paulsen, Hans; Burchell, Joy; Taylor-Papadimitriou, Joyce; Clausen, Henrik

    2007-02-01

    The cell membrane mucin MUC1 is over-expressed and aberrantly glycosylated in many cancers, and cancer-associated MUC1 glycoforms represent potential targets for immunodiagnostic and therapeutic measures. We have recently shown that MUC1 with GalNAcalpha1-O-Ser/Thr (Tn) and NeuAcalpha2-6GalNAcalpha1-O-Ser/Thr (STn) O-glycosylation is a cancer-specific glycoform, and that Tn/STn-MUC1 glycopeptide-based vaccines can override tolerance in human MUC1 transgenic mice and induce humoral immunity with high specificity for MUC1 cancer-specific glycoforms (Sorensen AL, Reis CA, Tarp MA, Mandel U, Ramachandran K, Sankaranarayanan V, Schwientek T, Graham R, Taylor-Papadimitriou J, Hollingsworth MA, et al. 2006. Chemoenzymatically synthesized multimeric Tn/STn MUC1 glycopeptides elicit cancer-specific anti-MUC1 antibody responses and override tolerance. Glycobiology. 16:96-107). In order to further characterize the immune response to Tn/STn-MUC1 glycoforms, we generated monoclonal antibodies with specificity similar to the polyclonal antibody response found in transgenic mice. In the present study, we define the immunodominant epitope on Tn/STn-MUC1 glycopeptides to the region including the amino acids GSTA of the MUC1 20-amino acid tandem repeat (HGVTSAPDTRPAPGSTAPPA). Most other MUC1 antibodies are directed to the PDTR region, although patients with antibodies to the GSTA region have been identified. A panel of other MUC1 glycoform-specific monoclonal antibodies was included for comparison. The study demonstrates that the GSTA region of the MUC1 tandem repeat contains a highly immunodominant epitope when presented with immature short O-glycans. The cancer-specific expression of this glycopeptide epitope makes it a prime candidate for immunodiagnostic and therapeutic measures.

  3. [Effect of soil moisture on prediction of soil total nitrogen using NIR spectroscopy].

    PubMed

    An, Xiao-Fei; Li, Min-Zan; Zheng, Li-Hua; Liu, Yu-Meng; Sun, Hong

    2013-03-01

    As one of the most important components of soil liutrient, it is necessary to obtain the soil total nitrogen(STN)content in precision agriculture. It is a feasible method to predict soil total nitrogen content based on NIRS. However, the effect of soil moisture content (SMC) on the prediction of STN is very serious. In the present research, the effect of SMC was discussed from qualitative analysis and quantitative analysis by the Fourier spectrum analyzer MATRIX_I. Firstly, sixty soil samples with different STN and SMC were scanned by the MATRIX_I. It was found that the reflectince of soil samples in near infrared region decreased with the increase in SMC. Subsequently, Moisture absorbance index (MAI) was proposed by the diffuse of absorbance at the wavelengths of 1 450 and 1 940 nm to classify soil properties and then correction factor was present Finally, the STN forecasting model with BP NN method was established by the revised absorbance data at the six wavelengths of 940, 1 050, 1,100, 1,200, 1,300 and 1,550 nm. The model was evaluated by correlation coefficient of Rc, correlation coefficient of Rv, root mean square error of calibration (RMSEC), root mean square error of validation (RMSEP) and residual prediction deviation (RPD). Compared with the model obtained from original spectral data, both the accuracy and the stability were improved. The new model was with Rc of 0.86, Rv of 0.81, RMSEC of 0.06, RMSEP of 0.05, and RPD of 2.75. With the first derivative of the revised absorbance, the RPD became 2.90. The experiments indicated that the method could eliminate the effect of SMC on the prediction of STN efficiently.

  4. Dopamine Release in the Nonhuman Primate Caudate and Putamen Depends upon Site of Stimulation in the Subthalamic Nucleus.

    PubMed

    Min, Hoon-Ki; Ross, Erika K; Jo, Hang Joon; Cho, Shinho; Settell, Megan L; Jeong, Ju Ho; Duffy, Penelope S; Chang, Su-Youne; Bennet, Kevin E; Blaha, Charles D; Lee, Kendall H

    2016-06-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for medically refractory Parkinson's disease. Although DBS has recognized clinical utility, its biologic mechanisms are not fully understood, and whether dopamine release is a potential factor in those mechanisms is in dispute. We tested the hypothesis that STN DBS-evoked dopamine release depends on the precise location of the stimulation site in the STN and the site of recording in the caudate and putamen. We conducted DBS with miniature, scaled-to-animal size, multicontact electrodes and used functional magnetic resonance imaging to identify the best dopamine recording site in the brains of nonhuman primates (rhesus macaques), which are highly representative of human brain anatomy and circuitry. Real-time stimulation-evoked dopamine release was monitored using in vivo fast-scan cyclic voltammetry. This study demonstrates that STN DBS-evoked dopamine release can be reduced or increased by redirecting STN stimulation to a slightly different site. Electrical stimulation of deep structures of the brain, or deep brain stimulation (DBS), is used to modulate pathological brain activity. However, technological limitations and incomplete understanding of the therapeutic mechanisms of DBS prevent personalization of this therapy and may contribute to less-than-optimal outcomes. We have demonstrated that DBS coincides with changes in dopamine neurotransmitter release in the basal ganglia. Here we mapped relationships between DBS and changes in neurochemical activity. Importantly, this study shows that DBS-evoked dopamine release can be reduced or increased by refocusing the DBS on a slightly different stimulation site. Copyright © 2016 Min, Ross et al.

  5. Inhibitory effect of high-frequency greater occipital nerve electrical stimulation on trigeminovascular nociceptive processing in rats.

    PubMed

    Lyubashina, Olga A; Panteleev, Sergey S; Sokolov, Alexey Y

    2017-02-01

    Electrical stimulation of the greater occipital nerve (GON) has recently shown promise as an effective non-pharmacological prophylactic therapy for drug-resistant chronic primary headaches, but the neurobiological mechanisms underlying its anticephalgic action are not elucidated. Considering that the spinal trigeminal nucleus (STN) is a key segmental structure playing a prominent role in pathophysiology of headaches, in the present study we evaluated the effects of GON electrical stimulation on ongoing and evoked firing of the dura-sensitive STN neurons. The experiments were carried out on urethane/chloralose-anesthetized, paralyzed and artificially ventilated male Wistar rats. Extracellular recordings were made from 11 neurons within the caudal part of the STN that received convergent input from the ipsilateral facial cutaneous receptive fields, dura mater and GON. In each experiment, five various combinations of the GON stimulation frequency (50, 75, 100 Hz) and intensity (1, 3, 6 V) were tested successively in 10 min interval. At all parameter sets, preconditioning GON stimulation (250 ms train of pulses applied before each recording) produced suppression of both the ongoing activity of the STN neurons and their responses to electrical stimulation of the dura mater. The inhibitory effect depended mostly on the GON stimulation intensity, being maximally pronounced when a stimulus of 6 V was applied. Thus, the GON stimulation-induced inhibition of trigeminovascular nociceptive processing at the level of STN has been demonstrated for the first time. The data obtained can contribute to a deeper understanding of neurophysiological mechanisms underlying the therapeutic efficacy of GON stimulation in primary headaches.

  6. Altered functional connectivity of the subthalamus and the bed nucleus of the stria terminalis in obsessive-compulsive disorder.

    PubMed

    Cano, M; Alonso, P; Martínez-Zalacaín, I; Subirà, M; Real, E; Segalàs, C; Pujol, J; Cardoner, N; Menchón, J M; Soriano-Mas, C

    2017-08-22

    The assessment of inter-regional functional connectivity (FC) has allowed for the description of the putative mechanism of action of treatments such as deep brain stimulation (DBS) of the nucleus accumbens in patients with obsessive-compulsive disorder (OCD). Nevertheless, the possible FC alterations of other clinically-effective DBS targets have not been explored. Here we evaluated the FC patterns of the subthalamic nucleus (STN) and the bed nucleus of the stria terminalis (BNST) in patients with OCD, as well as their association with symptom severity. Eighty-six patients with OCD and 104 healthy participants were recruited. A resting-state image was acquired for each participant and a seed-based analysis focused on our two regions of interest was performed using statistical parametric mapping software (SPM8). Between-group differences in FC patterns were assessed with two-sample t test models, while the association between symptom severity and FC patterns was assessed with multiple regression analyses. In comparison with controls, patients with OCD showed: (1) increased FC between the left STN and the right pre-motor cortex, (2) decreased FC between the right STN and the lenticular nuclei, and (3) increased FC between the left BNST and the right frontopolar cortex. Multiple regression analyses revealed a negative association between clinical severity and FC between the right STN and lenticular nucleus. This study provides a neurobiological framework to understand the mechanism of action of DBS on the STN and the BNST, which seems to involve brain circuits related with motor response inhibition and anxiety control, respectively.

  7. Midline frontal cortex low-frequency activity drives subthalamic nucleus oscillations during conflict.

    PubMed

    Zavala, Baltazar A; Tan, Huiling; Little, Simon; Ashkan, Keyoumars; Hariz, Marwan; Foltynie, Thomas; Zrinzo, Ludvic; Zaghloul, Kareem A; Brown, Peter

    2014-05-21

    Making the right decision from conflicting information takes time. Recent computational, electrophysiological, and clinical studies have implicated two brain areas as being crucial in assuring sufficient time is taken for decision-making under conditions of conflict: the medial prefrontal cortex and the subthalamic nucleus (STN). Both structures exhibit an elevation of activity at low frequencies (<10 Hz) during conflict that correlates with the amount of time taken to respond. This suggests that the two sites could become functionally coupled during conflict. To establish the nature of this interaction we recorded from deep-brain stimulation electrodes implanted bilaterally in the STN of 13 Parkinson's disease patients while they performed a sensory integration task involving randomly moving dots. By gradually increasing the number of dots moving coherently in one direction, we were able to determine changes in the STN associated with response execution. Furthermore, by occasionally having 10% of the dots move in the opposite direction as the majority, we were able to identify an independent increase in STN theta-delta activity triggered by conflict. Crucially, simultaneous midline frontal electroencephalographic recordings revealed an increase in the theta-delta band coherence between the two structures that was specific to high-conflict trials. Activity over the midline frontal cortex was Granger causal to that in STN. These results establish the cortico-subcortical circuit enabling successful choices to be made under conditions of conflict and provide support for the hypothesis that the brain uses frequency-specific channels of communication to convey behaviorally relevant information. Copyright © 2014 Zavala et al.

  8. Raclopride or high-frequency stimulation of the subthalamic nucleus stops cocaine-induced motor stereotypy and restores related alterations in prefrontal basal ganglia circuits.

    PubMed

    Aliane, Verena; Pérez, Sylvie; Deniau, Jean-Michel; Kemel, Marie-Louise

    2012-11-01

    Motor stereotypy is a key symptom of various neurological or neuropsychiatric disorders. Neuroleptics or the promising treatment using deep brain stimulation stops stereotypies but the mechanisms underlying their actions are unclear. In rat, motor stereotypies are linked to an imbalance between prefrontal and sensorimotor cortico-basal ganglia circuits. Indeed, cortico-nigral transmission was reduced in the prefrontal but not sensorimotor basal ganglia circuits and dopamine and acetylcholine release was altered in the prefrontal but not sensorimotor territory of the dorsal striatum. Furthermore, cholinergic transmission in the prefrontal territory of the dorsal striatum plays a crucial role in the arrest of motor stereotypy. Here we found that, as previously observed for raclopride, high-frequency stimulation of the subthalamic nucleus (HFS STN) rapidly stopped cocaine-induced motor stereotypies in rat. Importantly, raclopride and HFS STN exerted a strong effect on cocaine-induced alterations in prefrontal basal ganglia circuits. Raclopride restored the cholinergic transmission in the prefrontal territory of the dorsal striatum and the cortico-nigral information transmissions in the prefrontal basal ganglia circuits. HFS STN also restored the N-methyl-d-aspartic-acid-evoked release of acetylcholine and dopamine in the prefrontal territory of the dorsal striatum. However, in contrast to raclopride, HFS STN did not restore the cortico-substantia nigra pars reticulata transmissions but exerted strong inhibitory and excitatory effects on neuronal activity in the prefrontal subdivision of the substantia nigra pars reticulata. Thus, both raclopride and HFS STN stop cocaine-induced motor stereotypy, but exert different effects on the related alterations in the prefrontal basal ganglia circuits. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  9. Clinical and economic results of bilateral subthalamic nucleus stimulation in Parkinson's disease

    PubMed Central

    Fraix, V; Houeto, J‐L; Lagrange, C; Pen, C Le; Krystkowiak, P; Guehl, D; Ardouin, C; Welter, M‐L; Maurel, F; Defebvre, L; Rougier, A; Benabid, A‐L; Mesnage, V; Ligier, M; Blond, S; Burbaud, P; Bioulac, B; Destée, A; Cornu, P; Pollak, P

    2006-01-01

    Background High frequency stimulation of the subthalamic nucleus (STN) is an alternative but expensive neurosurgical treatment for parkinsonian patients with levodopa induced motor complications. Objective To assess the safety, clinical effects, quality of life, and economic cost of STN stimulation. Methods We conducted a prospective multicentre study in 95 consecutive Parkinson's disease (PD) patients receiving bilateral STN stimulation and assessed its effects over 12 months. A double blind randomised motor evaluation was carried out at 3 month follow up, and quality of life, self care ability, and predictive factors of outcome following surgery were assessed. The cost of PD was estimated over 6 months before and after surgery. Results The Unified Parkinson's Disease Rating Scale (UPDRS) motor score improved by 57% (p<0.0001) and activities of daily living improved by 48% (p<0.0001) at 12 month follow up. Double blind motor scoring improved by 51% at 3 month follow up (p<0.0001). The total PD Quality of Life Questionnaire (PDQL‐37) score improved by 28% (p<0.001). The better the preoperative motor score after a levodopa challenge, the better the outcome after STN stimulation. Five patients developed an intracerebral haematoma during electrode implantation with permanent after effects in two. The 6 month costs of PD decreased from €10 087 before surgery to €1673 after surgery (p<0.0001) mainly because of the decrease in medication. These savings allowed a return on the procedure investment, estimated at €36 904 over 2.2 years. Conclusions STN stimulation has good outcomes with relatively low risk and little cost burden in PD patients with levodopa induced motor complications. PMID:16543519

  10. Deep brain stimulation of the subthalamic nucleus alters the cortical profile of response inhibition in the beta frequency band: a scalp EEG study in Parkinson's disease

    PubMed Central

    Swann, Nicole; Poizner, Howard; Houser, Melissa; Gould, Sherrie; Greenhouse, Ian; Cai, Weidong; Strunk, Jon; George, Jobi; Aron, Adam R

    2011-01-01

    Stopping an initiated response could be implemented by a fronto-basal-ganglia circuit, including the right inferior frontal cortex (rIFC) and the subthalamic nucleus (STN). Intracranial recording studies in humans reveal an increase in beta-band power (~16-20 Hz) within the rIFC and STN when a response is stopped. This suggests that the beta-band could be important for communication in this network. If this is the case, then altering one region should affect the electrophysiological response at the other. We addressed this hypothesis by recording scalp EEG during a stop task while modulating STN activity with deep brain stimulation. We studied 15 human patients with Parkinson's Disease and 15 matched healthy control subjects. Behaviorally, patients OFF stimulation were slower than controls to stop their response. Moreover, stopping speed was improved for ON compared to OFF stimulation. For scalp EEG, there was greater beta power, around the time of stopping, for patients ON compared to OFF stimulation. This effect was stronger over the right compared to left frontal cortex, consistent with the putative right-lateralization of the stopping network. Thus, deep brain stimulation of the STN improved behavioral stopping performance and increased the beta-band response over the right frontal cortex. These results complement other evidence for a structurally-connected, functional, circuit between right frontal cortex and the basal ganglia. The results also suggest that deep brain stimulation of the STN may improve task performance by increasing the fidelity of information transfer within a fronto-basal ganglia circuit. PMID:21490213

  11. Seasonal changes in nutrients, chlorophyll a and the phytoplankton assemblage of the western subarctic gyre in the Pacific Ocean

    NASA Astrophysics Data System (ADS)

    Mochizuki, Mamiko; Shiga, Naonobu; Saito, Masaru; Imai, Keiri; Nojiri, Yukihiro

    The standing stock and species composition of phytoplankton (>10 μm) were studied using monthly water samples collected at Stn KNOT (Kyodo North Pacific Ocean Time Series; 44°N, 155°E) in the western subarctic gyre in the Pacific Ocean through June 1998 to June 1999 (except for January-April 1999) and January-February 2000. One-liter water samples were preserved in 1% neutrally buffered formalin. Identification and enumeration of phytoplankton were made with an inverted microscope. Nutrients did not appear to be depleted for phytoplakton growth during any season. The vertical distribution of phytoplankton was primarily restricted by the pycnocline, and the bulk of phytoplankton assemblage existed within the surface mixed layer. In July, however, some senescent cells were observed at 200 m. Phytoplankton abundance clearly showed a spring maximum (i.e. spring bloom) in May. The seasonal change in cell numbers, however, did not coincide closely with the change in chlorophyll a concentration. Centric diatoms, which were composed of Thalassiosira, Chaetoceros, and Coscinodiscus, dominated all year round, and showed temporal succession. Pennate diatoms (mostly Neodenticula seminae and Fragilariopsis) increased only during the spring bloom. Dinoflagellates (mostly Gymnodinium and Prorocentrum) were low in abundance, although they increased in summer when the phytoplankton standing stock was low. Silicoflagellate abundance was extremely low. Comparing the annual species composition of phytoplankton between Stn KNOT and Stn P (50°N, 145°W) in the Alaskan Gyre, there was a remarkable difference between the two sites. The phytoplankton assemblage at Stn P is characterized by a high abundance of Rhizosolenia alata and low abundance of Thalassiosira. In contrast, Thalassiosira dominates at Stn KNOT during most seasons.

  12. Influences of membrane properties on phase response curve and synchronization stability in a model globus pallidus neuron.

    PubMed

    Fujita, Tomohiro; Fukai, Tomoki; Kitano, Katsunori

    2012-06-01

    The activity patterns of the globus pallidus (GPe) and subthalamic nucleus (STN) are closely associated with motor function and dysfunction in the basal ganglia. In the pathological state caused by dopamine depletion, the STN-GPe network exhibits rhythmic synchronous activity accompanied by rebound bursts in the STN. Therefore, the mechanism of activity transition is a key to understand basal ganglia functions. As synchronization in GPe neurons could induce pathological STN rebound bursts, it is important to study how synchrony is generated in the GPe. To clarify this issue, we applied the phase-reduction technique to a conductance-based GPe neuronal model in order to derive the phase response curve (PRC) and interaction function between coupled GPe neurons. Using the PRC and interaction function, we studied how the steady-state activity of the GPe network depends on intrinsic membrane properties, varying ionic conductances on the membrane. We noted that a change in persistent sodium current, fast delayed rectifier Kv3 potassium current, M-type potassium current and small conductance calcium-dependent potassium current influenced the PRC shape and the steady state. The effect of those currents on the PRC shape could be attributed to extension of the firing period and reduction of the phase response immediately after an action potential. In particular, the slow potassium current arising from the M-type potassium and the SK current was responsible for the reduction of the phase response. These results suggest that the membrane property modulation controls synchronization/asynchronization in the GPe and the pathological pattern of STN-GPe activity.

  13. Early gene mapping after deep brain stimulation in a rat model of tardive dyskinesia: comparison with transient local inactivation.

    PubMed

    Creed, Meaghan C; Hamani, Clement; Nobrega, José N

    2012-07-01

    Deep brain stimulation (DBS) has been extensively used in Parkinson's disease and is also currently being investigated in tardive dyskinesia (TD), a movement disorder induced by chronic treatment with antipsychotic drugs such as haloperidol (HAL). In rodents, vacuous chewing movements (VCMs) following chronic HAL administration are suggested to model orofacial dyskinesias in TD. We show that 60 min of DBS (100 μA, 90 μs, 130 Hz) applied to the entopeduncular (EPN) or subthalamic (STN) nuclei significantly decreases HAL-induced VCMs. Using zif268 as a neural activity marker, we found that in HAL-treated animals EPN stimulation increased zif268 mRNA levels in the globus pallidus (+65%) and substantia nigra compacta (+62%) and reticulata (+76%), while decreasing levels in the motor cortex and throughout the thalamus. In contrast, after STN DBS zif268 levels in HAL-treated animals decreased in all basal ganglia structures, thalamus and motor cortex (range: 29% in the ventrolateral caudate-putamen to 100% in the EPN). Local tissue inactivation by muscimol injections into the STN or EPN also reduced VCMs, but to a lesser degree than DBS. When applied to the EPN muscimol decreased zif268 levels in substantia nigra (-29%), whereas STN infusions did not result in significant zif268 changes in any brain area. These results confirm the effectiveness of DBS in reducing VCMs and suggest that tissue inactivation does not fully account for DBS effects in this preparation. The divergent effects of STN vs. EPN manipulations on HAL-induced zif268 changes suggest that similar behavioral outcomes of DBS in these two areas may involve different neuroanatomical mechanisms. Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.

  14. Deep brain stimulation for Parkinson's disease: meta-analysis of results of randomized trials at varying lengths of follow-up.

    PubMed

    Mansouri, Alireza; Taslimi, Shervin; Badhiwala, Jetan H; Witiw, Christopher D; Nassiri, Farshad; Odekerken, Vincent J J; De Bie, Rob M A; Kalia, Suneil K; Hodaie, Mojgan; Munhoz, Renato P; Fasano, Alfonso; Lozano, Andres M

    2017-06-30

    OBJECTIVE Deep brain stimulation (DBS) is effective in the management of patients with advanced Parkinson's disease (PD). While both the globus pallidus pars interna (GPi) and the subthalamic nucleus (STN) are accepted targets, their relative efficacy in randomized controlled trials (RCTs) has not been established beyond 12 months. The objective of this study was to conduct a meta-analysis of RCTs to compare outcomes among adults with PD undergoing DBS of GPi or STN at various time points, including 36 months of follow-up. METHODS The MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases were searched. Registries for clinical trials, selected conference proceedings, and the table of contents for selected journals were also searched. Screens were conducted independently and in duplicate. Among the 623 studies initially identified (615 through database search, 7 through manual review of bibliographies, and 1 through a repeat screen of literature prior to submission), 19 underwent full-text review; 13 of these were included in the quantitative meta-analysis. Data were extracted independently and in duplicate. The Cochrane Collaboration tool was used to assess the risk of bias. The GRADE evidence profile tool was used to assess the quality of the evidence. Motor scores, medication dosage reduction, activities of daily living, depression, dyskinesias, and adverse events were compared. The influence of disease duration (a priori) and the proportion of male patients within a study (post hoc) were explored as potential subgroups. RESULTS Thirteen studies (6 original cohorts) were identified. No difference in motor scores or activities of daily living was identified at 36 months. Medications were significantly reduced with STN stimulation (5 studies, weighted mean difference [WMD] -365.46, 95% CI -599.48 to -131.44, p = 0.002). Beck Depression Inventory scores were significantly better with GPi stimulation (3 studies; WMD 2.53, 95% CI 0.99-4.06 p = 0.001). The

  15. Probabilistic versus deterministic tractography for delineation of the cortico-subthalamic hyperdirect pathway in patients with Parkinson disease selected for deep brain stimulation.

    PubMed

    Petersen, Mikkel V; Lund, Torben E; Sunde, Niels; Frandsen, Jesper; Rosendal, Frederikke; Juul, Niels; Østergaard, Karen

    2017-05-01

    OBJECTIVE Diffusion-weighted MRI (DWI) and tractography allows noninvasive mapping of the structural connections of the brain, and may provide important information for neurosurgical planning. The hyperdirect pathway, connecting the subthalamic nucleus (STN) with the motor cortex, is assumed to play a key role in mediating the effects of deep brain stimulation (DBS), which is an effective but poorly understood treatment for Parkinson disease. This study aimed to apply recent methodological advances in DWI acquisition and analysis to the delineation of the hyperdirect pathway in patients with Parkinson disease selected for surgery. METHODS High spatial and angular resolution DWI data were acquired preoperatively from 5 patients with Parkinson disease undergoing DBS. The authors compared the delineated hyperdirect pathways and associated STN target maps generated by 2 different tractography methods: a tensor-based deterministic method, typically available in clinical settings, and an advanced probabilistic method based on constrained spherical deconvolution. In addition, 10 high-resolution data sets with the same scanning parameters were acquired from a healthy control participant to assess the robustness of the tractography results. RESULTS Both tractography approaches identified connections between the ipsilateral motor cortex and the STN. However, the 2 methods provided substantially different target regions in the STN, with the target center of gravity differing by > 1.4 mm on average. The probabilistic method (based on constrained spherical deconvolution) plausibly reconstructed a continuous set of connections from the motor cortex, terminating in the dorsolateral region of the STN. In contrast, the tensor-based method reconstructed a comparatively sparser and more variable subset of connections. Furthermore, across the control scans, the probabilistic method identified considerably more consistent targeting regions within the STN compared with the deterministic

  16. Prospective comparative study on cost-effectiveness of subthalamic stimulation and best medical treatment in advanced Parkinson's disease.

    PubMed

    Valldeoriola, Francesc; Morsi, Ossama; Tolosa, Eduardo; Rumià, Jordi; Martí, Maria José; Martínez-Martín, Pablo

    2007-11-15

    This is an open, prospective, longitudinal study designed to compare two cohorts of patients with advanced Parkinson's disease during 1 year, one undergoing bilateral subthalamic stimulation (STN-DBS) and the other receiving the best medical treatment (BMT), with respect to the clinical effects observed and the medical expenses produced. Assessments were done by using clinical measures and a generic health related quality of life scale. A questionnaire was used to collect direct healthcare resources. As a measure of cost-effectiveness, we calculated life years gained adjusted by health-related quality of life (QALY) and the incremental cost-effectiveness ratio (ICER). Clinical and demographic variables of both groups were comparable at baseline. Total UPDRS scores improved from 50.5 +/- 3.6 to 28.5 +/- 3.8 in STN-DBS patients and worsened from 44.3 +/- 3.3 to 54.2 +/- 4 in the control group. Pharmacological costs in the operated patients were 3,799 +/- 940 euro, while in the BMT group the costs were 13,208 +/- 4,966 euro. Other medical costs were 1,280 +/- 720 euro in the STN-DBS group and 4,017 +/- 2,962 euro in BMT patients. Nondirect medical costs were 4,079 +/- 1,289 in operated patients and 2,787 +/- 1,209 euro in the BMT group. Mean QALYs were 0.7611 +/- 0.03 in STN-DBS and 0.5401 +/- 0.06 in BMT patients. In STN-DBS patients, the ICER needed to obtain an improvement of one point in the total UPDRS score was of 239.8 euro and the ICER/QALY was of 34,389 euro. Cost-effectiveness parameters were mostly related to the degree of clinical improvement and the reduction of pharmacological costs after STN-DBS. An ICER of 34,389 euro/QALY is within appropriate limits to consider subthalamic stimulation as an efficient therapy.

  17. Effects of deep brain stimulation and medication on bradykinesia and muscle activation in Parkinson's disease.

    PubMed

    Vaillancourt, David E; Prodoehl, Janey; Verhagen Metman, Leo; Bakay, Roy A; Corcos, Daniel M

    2004-03-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and antiparkinsonian medication (Meds) have proved to be effective therapies for treating bradykinesia in Parkinson's disease. However, it is not currently known how or to what extent STN stimulation alters the control signals to agonist and antagonist muscles to change movement speed. Our objective was to investigate movement speed along with the amplitude and temporal features of EMG activity to determine how and to what extent these parameters are changed by DBS and medication. Nine patients with Parkinson's disease were studied following neurosurgery that implanted high-frequency stimulating electrodes in the STN. The experiments for the patients were performed in each of four treatment conditions: (i) OFF treatment; (ii) STN DBS; (iii) Meds; and (iv) Meds plus STN DBS. Also, a group of age- and gender-matched control subjects were examined. Medication and DBS had similar effects in that both treatments increased movement speed, increased the amplitude of the first agonist burst, increased burst duration, reduced the number of agonist bursts, reduced cocontraction, increased the size of the antagonist EMG, and reduced the centroid time of the antagonist EMG. When DBS and medication were combined, only temporal measures of burst duration and the number of agonist bursts were different from the medication alone condition. There was a positive association between the level of bradykinesia OFF treatment and the level of bradykinesia following DBS and medication. The movement speed of neurologically normal control subjects' was over 40% higher during both flexion and extension movements when compared with the patients during Meds plus STN DBS. The changes in the muscle activation patterns provide a mechanism of action for the pharmacological and surgical interventions used to treat bradykinesia in Parkinson's disease. However, despite the success of medication and DBS at improving bradykinesia in patients

  18. Study of Immunohistochemical Markers (CK-19, CD-56, Ki-67, p53) in Differentiating Benign and Malignant Solitary Thyroid Nodules with special Reference to Papillary Thyroid Carcinomas

    PubMed Central

    Dwivedi, Smriti Sudhanshu; Joshi, Avinash R; Kulkarni, Maithili Mandar; Bhayekar, Pallavi; Jadhav, Amruta; Nayar, Musphera; Kambale, Neelam S

    2016-01-01

    Introduction Solitary Thyroid Nodule (STN) has provoked increased concern owing to higher incidence of malignancy. The inter and intra observer variation in the histomorphological diagnosis of Papillary Thyroid Carcinomas (PTC) may sometimes pose a diagnostic difficulty. Aim This study was undertaken to analyse immunohistochemical (IHC) markers (CK-19, CD-56, p53, Ki-67) to differentiate between benign and malignant surgically resected STN along with their utility in the identification of PTC. Materials and Methods The present cross sectional study was conducted over a period of 4 years. A technique of manual tissue array was employed for cases subjected to IHC. The primary antibodies used were CK-19, CD-56, p53 and Ki-67. Analysis of the expression of IHC markers (p53, Ki-67) to distinguish between benign and malignant STN was done. Evaluation and correlation of expression of IHC markers (CK-19, CD-56) to determine its utility in reaching definitive diagnosis and assessing prognosis of PTC was tried. Results were subjected to statistical analysis. The results were considered to be significant when the p-value <0.05. Results Out of the 160 cases of surgically resected STN specimens, 68 cases were non-neoplastic, 24 cases were benign and 68 cases were of malignant tumours (7 cases of follicular carcinoma (FCa), 61 cases of PTC). CK-19 was found to be a sensitive (83.61%) and a highly specific positive marker (100%) for the diagnosis of PTC. The difference in CD-56 expression between PTC and non-PTC group was found to be highly statistically significant. CD-56 was found to be a sensitive (85.86%) and specific (82.25%) negative marker in differentiating PTC from follicular lesions/neoplasms. The difference in p53 expression between the malignant and non-malignant STN cases was found to be highly statistically significant with a sensitivity and specificity 85.29% and 70.65% respectively. The statistical difference in mean Ki-67 Labeling Index (LI) was found to be

  19. L-Carnitine supplementation during suckling intensifies the early postnatal skeletal myofiber formation in piglets of low birth weight.

    PubMed

    Lösel, D; Kalbe, C; Rehfeldt, C

    2009-07-01

    Piglets of low birth weight exhibit a reduced total number of skeletal myofibers at birth and throughout life compared with piglets of middle and heavy birth weight, which is associated with impaired (lean) growth and quality of carcass and meat at market weight. We investigated the effect of L-carnitine supplementation to suckling piglets of different birth weights on early postnatal myofiber formation, muscle growth, and body composition. A total of 48 piglets of low (LW) and middle (MDW) birth weight from 9 German Landrace gilts received 400 mg of L-carnitine (carnitine, n = 25) or a placebo (control, n = 23) once daily from d 7 to 27 of age and were slaughtered on d 28 of age (weaning). Carnitine-supplemented piglets deposited less fat as indicated by a reduced proportion of perirenal (P = 0.1) and intramuscular fat (P = 0.05). Circulating glucose concentrations tended to be greater in supplemented LW piglets (P = 0.13). The concentration of carnitine in semitendinosus (STN) muscle was approximately doubled (P < 0.001) by supplementation, with emphasis on the proportion of esterified carnitine. The ratio of lactate dehydrogenase to isocitrate dehydrogenase tended (P = 0.12) to be smaller in STN muscle of supplemented piglets, indicating a more oxidative muscle metabolism. The total number of STN myofibers was increased by 13% (P = 0.02) in supplemented LW piglets, thereby reaching the unchanged level of MDW littermates. In addition, supplemented LW piglets displayed a 2.4-fold mRNA expression of the gene encoding the embryonic isoform of the myosin heavy chain in STN muscle than control piglets (P = 0.05), but there were no differences in the proportion of fibers positively staining for the embryonic myosin isoform. L-carnitine-supplemented piglets exhibited a greater DNA:protein ratio (P = 0.02) in STN muscle, which resulted from a greater DNA concentration (P = 0.04). However, the STN muscle of L-carnitine-supplemented piglets was not less mature as indicated

  20. Motor responses of muscles supplied by cranial nerves to subthalamic nucleus deep brain stimuli.

    PubMed

    Costa, João; Valls-Solé, Josep; Valldeoriola, Francesc; Rumià, Jordi; Tolosa, Eduardo

    2007-01-01

    The distribution of human corticobulbar motor excitatory and inhibitory output is not fully understood. In particular, it is unclear whether the pattern of innervation is the same for upper and lower facial muscles, and what is the motor cortical area giving rise to such innervation. We used electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinson's disease to activate motor tracts at a subcortical level. We examined the excitatory and inhibitory effects of unilateral single STN deep brain stimulation (sSTN-DBS) in 14 patients by taking recordings from facial, cervical and upper limb muscles on both sides. We measured the latency and amplitude of the motor-evoked potentials (MEPs), and the latency and duration of the silent periods, and compared ipsilateral with contralateral responses and responses obtained in different muscles. Unilateral sSTN-DBS induced strictly contralateral MEPs in the trapezius, deltoid, biceps and thenar muscles. The same sti