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Sample records for pedunculopontine nucleus stimulation

  1. A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation.

    PubMed

    Thevathasan, Wesley; Cole, Michael H; Graepel, Cara L; Hyam, Jonathan A; Jenkinson, Ned; Brittain, John-Stuart; Coyne, Terry J; Silburn, Peter A; Aziz, Tipu Z; Kerr, Graham; Brown, Peter

    2012-05-01

    Gait freezing is an episodic arrest of locomotion due to an inability to take normal steps. Pedunculopontine nucleus stimulation is an emerging therapy proposed to improve gait freezing, even where refractory to medication. However, the efficacy and precise effects of pedunculopontine nucleus stimulation on Parkinsonian gait disturbance are not established. The clinical application of this new therapy is controversial and it is unknown if bilateral stimulation is more effective than unilateral. Here, in a double-blinded study using objective spatiotemporal gait analysis, we assessed the impact of unilateral and bilateral pedunculopontine nucleus stimulation on triggered episodes of gait freezing and on background deficits of unconstrained gait in Parkinson's disease. Under experimental conditions, while OFF medication, Parkinsonian patients with severe gait freezing implanted with pedunculopontine nucleus stimulators below the pontomesencephalic junction were assessed during three conditions; off stimulation, unilateral stimulation and bilateral stimulation. Results were compared to Parkinsonian patients without gait freezing matched for disease severity and healthy controls. Pedunculopontine nucleus stimulation improved objective measures of gait freezing, with bilateral stimulation more effective than unilateral. During unconstrained walking, Parkinsonian patients who experience gait freezing had reduced step length and increased step length variability compared to patients without gait freezing; however, these deficits were unchanged by pedunculopontine nucleus stimulation. Chronic pedunculopontine nucleus stimulation improved Freezing of Gait Questionnaire scores, reflecting a reduction of the freezing encountered in patients' usual environments and medication states. This study provides objective, double-blinded evidence that in a specific subgroup of Parkinsonian patients, stimulation of a caudal pedunculopontine nucleus region selectively improves gait

  2. Computational modeling of pedunculopontine nucleus deep brain stimulation

    PubMed Central

    Zitella, Laura M.; Mohsenian, Kevin; Pahwa, Mrinal; Gloeckner, Cory; Johnson, Matthew D.

    2013-01-01

    Objective Deep brain stimulation (DBS) near the pedunculopontine nucleus (PPN) has been posited to improve medication-intractable gait and balance problems in patients with Parkinson’s disease. However, clinical studies evaluating this DBS target have not demonstrated consistent therapeutic effects, with several studies reporting the emergence of paresthesia and oculomotor side effects. The spatial and pathway-specific extent to which brainstem regions are modulated during PPN-DBS is not well understood. Approach Here, we describe two computational models that estimate the direct effects of DBS in the PPN region for human and translational non-human primate (NHP) studies. The three-dimensional models were constructed from segmented histological images from each species, multi-compartment neuron models, and inhomogeneous finite element models of the voltage distribution in the brainstem during DBS. Main Results The computational models predicted that: 1) the majority of PPN neurons are activated with −3V monopolar cathodic stimulation; 2) surgical targeting errors of as little as 1 mm in both species decrement activation selectivity; 3) specifically, monopolar stimulation in caudal, medial, or anterior PPN activates a significant proportion of the superior cerebellar peduncle (up to 60% in the human model and 90% in the NHP model at -3V); 4) monopolar stimulation in rostral, lateral, or anterior PPN activates a large percentage of medial lemniscus fibers (up to 33% in the human model and 40% in the NHP model at −3V); and, 5) the current clinical cylindrical electrode design is suboptimal for isolating the modulatory effects to PPN neurons. Significance We show that a DBS lead design with radially-segmented electrodes may yield improved functional outcome for PPN-DBS. PMID:23723145

  3. Computational modeling of pedunculopontine nucleus deep brain stimulation

    NASA Astrophysics Data System (ADS)

    Zitella, Laura M.; Mohsenian, Kevin; Pahwa, Mrinal; Gloeckner, Cory; Johnson, Matthew D.

    2013-08-01

    Objective. Deep brain stimulation (DBS) near the pedunculopontine nucleus (PPN) has been posited to improve medication-intractable gait and balance problems in patients with Parkinson's disease. However, clinical studies evaluating this DBS target have not demonstrated consistent therapeutic effects, with several studies reporting the emergence of paresthesia and oculomotor side effects. The spatial and pathway-specific extent to which brainstem regions are modulated during PPN-DBS is not well understood. Approach. Here, we describe two computational models that estimate the direct effects of DBS in the PPN region for human and translational non-human primate (NHP) studies. The three-dimensional models were constructed from segmented histological images from each species, multi-compartment neuron models and inhomogeneous finite element models of the voltage distribution in the brainstem during DBS. Main Results. The computational models predicted that: (1) the majority of PPN neurons are activated with -3 V monopolar cathodic stimulation; (2) surgical targeting errors of as little as 1 mm in both species decrement activation selectivity; (3) specifically, monopolar stimulation in caudal, medial, or anterior PPN activates a significant proportion of the superior cerebellar peduncle (up to 60% in the human model and 90% in the NHP model at -3 V) (4) monopolar stimulation in rostral, lateral or anterior PPN activates a large percentage of medial lemniscus fibers (up to 33% in the human model and 40% in the NHP model at -3 V) and (5) the current clinical cylindrical electrode design is suboptimal for isolating the modulatory effects to PPN neurons. Significance. We show that a DBS lead design with radially-segmented electrodes may yield improved functional outcome for PPN-DBS.

  4. A block to pre-prepared movement in gait freezing, relieved by pedunculopontine nucleus stimulation.

    PubMed

    Thevathasan, Wesley; Pogosyan, Alek; Hyam, Jonathan A; Jenkinson, Ned; Bogdanovic, Marko; Coyne, Terry J; Silburn, Peter A; Aziz, Tipu Z; Brown, Peter

    2011-07-01

    Gait freezing and postural instability are disabling features of Parkinsonian disorders, treatable with pedunculopontine nucleus stimulation. Both features are considered deficits of proximal and axial musculature, innervated predominantly by reticulospinal pathways and tend to manifest when gait and posture require adjustment. Adjustments to gait and posture are amenable to pre-preparation and rapid triggered release. Experimentally, such accelerated release can be elicited by loud auditory stimuli--a phenomenon known as 'StartReact'. We observed StartReact in healthy and Parkinsonian controls. However, StartReact was absent in Parkinsonian patients with severe gait freezing and postural instability. Pedunculopontine nucleus stimulation restored StartReact proximally and proximal reaction times to loud stimuli correlated with gait and postural disturbance. These findings suggest a relative block to triggered, pre-prepared movement in gait freezing and postural instability, relieved by pedunculopontine nucleus stimulation.

  5. 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.

  6. The pedunculopontine nucleus area: critical evaluation of interspecies differences relevant for its use as a target for deep brain stimulation.

    PubMed

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

    2011-01-01

    Recently, the pedunculopontine nucleus has been highlighted as a target for deep brain stimulation for the treatment of freezing of postural instability and gait disorders in Parkinson's disease and progressive supranuclear palsy. There is great controversy, however, as to the exact location of the optimal site for stimulation. In this review, we give an overview of anatomy and connectivity of the pedunculopontine nucleus area in rats, cats, non-human primates and humans. Additionally, we report on the behavioural changes after chemical or electrical manipulation of the pedunculopontine nucleus. We discuss the relation to adjacent regions of the pedunculopontine nucleus, such as the cuneiform nucleus and the subcuneiform nucleus, which together with the pedunculopontine nucleus are the main areas of the mesencephalic locomotor region and play a major role in the initiation of gait. This information is discussed with respect to the experimental designs used for research purposes directed to a better understanding of the circuitry pathway of the pedunculopontine nucleus in association with basal ganglia pathology, and with respect to deep brain stimulation of the pedunculopontine nucleus area in humans.

  7. Deep brain stimulation of the pedunculopontine nucleus in Parkinson's disease. Preliminary experience at Oxford.

    PubMed

    Pereira, E A; Muthusamy, K A; De Pennington, N; Joint, C A; Aziz, T Z

    2008-01-01

    Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) is a novel neurosurgical therapy developed to address symptoms of gait freezing and postural instability in Parkinson's disease and related disorders. Here, we summarize our non-human primate and neuroimaging research of relevance to our surgical targeting of the PPN. We also describe our clinical experience of PPN DBS with greatest motor improvements achieved by stimulation at low frequencies.

  8. Regional anatomy of the pedunculopontine nucleus: relevance for deep brain stimulation.

    PubMed

    Fournier-Gosselin, Marie-Pierre; Lipsman, Nir; Saint-Cyr, Jean A; Hamani, Clement; Lozano, Andres M

    2013-09-01

    The pedunculopontine nucleus (PPN) is currently being investigated as a potential deep brain stimulation target to improve gait and posture in Parkinson's disease. This review examines the complex anatomy of the PPN region and suggests a functional mapping of the surrounding nuclei and fiber tracts that may serve as a guide to a more accurate placement of electrodes while avoiding potentially adverse effects. The relationships of the PPN were examined in different human brain atlases. Schematic representations of those structures in the vicinity of the PPN were generated and correlated with their potential stimulation effects. By providing a functional map and representative schematics of the PPN region, we hope to optimize the placement of deep brain stimulation electrodes, thereby maximizing safety and clinical efficacy.

  9. Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Anatomy and Terminology

    PubMed Central

    Hamani, Clement; Aziz, Tipu; Bloem, Bastiaan R.; Brown, Peter; Chabardes, Stephan; Coyne, Terry; Foote, Kelly; Garcia-Rill, Edgar; Hirsch, Etienne C.; Lozano, Andres M.; Mazzone, Paolo A.M.; Okun, Michael S.; Hutchison, William; Silburn, Peter; Zrinzo, Ludvic; Alam, Mesbah; Goetz, Laurent; Pereira, Erlick; Rughani, Anand; Thevathasan, Wesley; Moro, Elena; Krauss, Joachim K.

    2017-01-01

    Several lines of evidence over the last few years have been important in ascertaining that the pedunculopontine nucleus (PPN) region could be considered as a potential target for deep brain stimulation (DBS) to treat freezing and other problems as part of a spectrum of gait disorders in Parkinson disease and other akinetic movement disorders. Since the introduction of PPN DBS, a variety of clinical studies have been published. Most indicate improvements in freezing and falls in patients who are severely affected by these problems. The results across patients, however, have been variable, perhaps reflecting patient selection, heterogeneity in target selection and differences in surgical methodology and stimulation settings. Here we outline both the accumulated knowledge and the domains of uncertainty in surgical anatomy and terminology. Specific topics were assigned to groups of experts, and this work was accumulated and reviewed by the executive committee of the working group. Areas of disagreement were discussed and modified accordingly until a consensus could be reached. We demonstrate that both the anatomy and the functional role of the PPN region need further study. The borders of the PPN and of adjacent nuclei differ when different brainstem atlases and atlas slices are compared. It is difficult to delineate precisely the PPN pars dissipata from the nucleus cuneiformis, as these structures partially overlap. This lack of clarity contributes to the difficulty in targeting and determining the exact localization of the electrodes implanted in patients with akinetic gait disorders. Future clinical studies need to consider these issues. PMID:27723662

  10. Critical evaluation of the anatomical location of the Barrington nucleus: relevance for deep brain stimulation surgery of pedunculopontine tegmental nucleus.

    PubMed

    Blanco, Lisette; Yuste, Jose Enrique; Carrillo-de Sauvage, María Angeles; Gómez, Aurora; Fernández-Villalba, Emiliano; Avilés-Olmos, Itciar; Limousin, Patricia; Zrinzo, Ludvic; Herrero, María Trinidad

    2013-09-05

    Deep brain stimulation (DBS) has become the standard surgical procedure for advanced Parkinson's disease (PD). Recently, the pedunculopontine tegmental nucleus (PPN) has emerged as a potential target for DBS in patients whose quality of life is compromised by freezing of gait and falls. To date, only a few groups have published their long-term clinical experience with PPN stimulation. Bearing in mind that the Barrington (Bar) nucleus and some adjacent nuclei (also known as the micturition centre) are close to the PPN and may be affected by DBS, the aim of the present study was to review the anatomical location of this structure in human and other species. To this end, the Bar nucleus area was analysed in mouse, monkey and human tissues, paying particular attention to the anatomical position in humans, where it has been largely overlooked. Results confirm that anatomical location renders the Bar nucleus susceptible to influence by the PPN DBS lead or to diffusion of electrical current. This may have an undesirable impact on the quality of life of patients.

  11. Pedunculopontine Nucleus Region Deep Brain Stimulation in Parkinson Disease: Surgical Techniques, Side Effects, and Postoperative Imaging

    PubMed Central

    Hamani, Clement; Lozano, Andres M.; Mazzone, Paolo A.M.; Moro, Elena; Hutchison, William; Silburn, Peter A.; Zrinzo, Ludvic; Alam, Mesbah; Goetz, Laurent; Pereira, Erlick; Rughani, Anand; Thevathasan, Wesley; Aziz, Tipu; Bloem, Bastiaan R.; Brown, Peter; Chabardes, Stephan; Coyne, Terry; Foote, Kelly; Garcia-Rill, Edgar; Hirsch, Etienne C.; Okun, Michael S.; Krauss, Joachim K.

    2017-01-01

    The pedunculopontine nucleus (PPN) region has received considerable attention in clinical studies as a target for deep brain stimulation (DBS) in Parkinson disease. These studies have yielded variable results with an overall impression of improvement in falls and freezing in many but not all patients treated. We evaluated the available data on the surgical anatomy and terminology of the PPN region in a companion paper. Here we focus on issues concerning surgical technique, imaging, and early side effects of surgery. The aim of this paper was to gain more insight into the reasoning for choosing specific techniques and to discuss short-comings of available studies. Our data demonstrate the wide range in almost all fields which were investigated. There are a number of important challenges to be resolved, such as identification of the optimal target, the choice of the surgical approach to optimize electrode placement, the impact on the outcome of specific surgical techniques, the reliability of intraoperative confirmation of the target, and methodological differences in postoperative validation of the electrode position. There is considerable variability both within and across groups, the overall experience with PPN DBS is still limited, and there is a lack of controlled trials. Despite these challenges, the procedure seems to provide benefit to selected patients and appears to be relatively safe. One important limitation in comparing studies from different centers and analyzing outcomes is the great variability in targeting and surgical techniques, as shown in our paper. The challenges we identified will be of relevance when designing future studies to better address several controversial issues. We hope that the data we accumulated may facilitate the development of surgical protocols for PPN DBS. PMID:27728909

  12. c-Fos expression after deep brain stimulation of the pedunculopontine tegmental nucleus in the rat 6-hydroxydopamine Parkinson model.

    PubMed

    Saryyeva, Assel; Nakamura, Makoto; Krauss, Joachim K; Schwabe, Kerstin

    2011-11-01

    Deep brain stimulation (DBS) is used to alleviate motor dysfunction in Parkinson's disease (PD). The pedunculopontine nucleus (PPN) may be a potential target for severe freezing and postural instability with 25 Hz stimulation being considered more effective than 130 Hz stimulation. Here we evaluated the expression of c-Fos after 25 Hz and 130 Hz DBS of the pedunculopontine tegmental nucleus (PPTg, i.e., the rodent equivalent to the human PPN) in the rat 6-hydroxydopamine (6-OHDA) PD model. Anaesthetized male Sprague Dawley rats with unilateral 6-OHDA-induced nigrostriatal lesions were stimulated with 25 Hz, 130 Hz, or 0 Hz sham-stimulation for 4h by electrodes implanted into the ipsilateral PPTg. Thereafter the distribution and number of neurons expressing the immediate early gene c-Fos, a marker for acute neuronal activity, was assessed. DBS of the PPTg induced strong ipsilateral c-Fos expression at the stimulation site, with 25 Hz having a more marked impact than 130 Hz. Additionally, c-Fos was strongly expressed in the central gray. In the dorsal part expression was stronger after 25 Hz stimulation, while in the medial and ventral part there was no difference between 25 Hz and 130 Hz stimulation. Expression in the basal ganglia was negligible. In the rat 6-OHDA PD model stimulation of the PPTg did not affect c-Fos expression in the basal ganglia, but had a strong impact on other functional circuitries. PPN stimulation in humans might therefore also have an impact on other systems than the motor system.

  13. 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.

  14. 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.

  15. Pedunculopontine Nucleus Stimulation: Where are We Now and What Needs to be Done to Move the Field Forward?

    PubMed Central

    Morita, Hokuto; Hass, Chris J.; Moro, Elena; Sudhyadhom, Atchar; Kumar, Rajeev; Okun, Michael S.

    2014-01-01

    Falls and gait impairment in Parkinson’s Disease (PD) is a leading cause of morbidity and mortality, significantly impacting quality of life and contributing heavily to disability. Thus far axial symptoms, such as postural instability and gait freezing, have been refractory to current treatment approaches and remain a critical unmet need. There has been increased excitement surrounding the surgical targeting of the pedunculopontine nucleus (PPN) for addressing axial symptoms in PD. The PPN and cuneate nucleus comprise the mesencephalic locomotor region, and electrophysiologic studies in animal models and human imaging studies have revealed a key role for the PPN in gait and postural control, underscoring a potential role for DBS surgery. Previous limited studies of PPN deep brain stimulation (DBS) in treating gait symptoms have had mixed clinical outcomes, likely reflect targeting variability and the inherent challenges of targeting a small brainstem structure that is both anatomically and neurochemically heterogeneous. Diffusion tractography shows promise for more accurate targeting and standardization of results. Due to the limited experience with PPN DBS, several unresolved questions remain about targeting and programing. At present, it is unclear if there is incremental benefit with bilateral versus unilateral targeting of PPN or whether PPN targeting should be performed as an adjunct to one of the more traditional targets. The PPN also modulates non-motor functions including REM sleep, cognition, mood, attention, arousal, and these observations will require long-term monitoring to fully characterize potential side effects and benefits. Surgical targeting of the PPN is feasible and shows promise for addressing axial symptoms in PD but may require further refinements in targeting, improved imaging, and better lead design to fully realize benefits. This review summarizes the current knowledge of PPN as a DBS target and areas that need to be addressed to advance

  16. The serendipity case of the pedunculopontine nucleus low-frequency brain stimulation: chasing a gait response, finding sleep, and cognition improvement.

    PubMed

    Stefani, Alessandro; Peppe, Antonella; Galati, Salvatore; Bassi, Mario Stampanoni; D'Angelo, Vincenza; Pierantozzi, Mariangela

    2013-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficacious therapy for Parkinson's disease (PD) but its effects on non-motor facets may be detrimental. The low-frequency stimulation (LFS) of the pedunculopontine nucleus (PPN or the nucleus tegmenti pedunculopontini - PPTg-) opened new perspectives. In our hands, PPTg-LFS revealed a modest influence on gait but increased sleep quality and degree of attentiveness. At odds with potential adverse events following STN-DBS, executive functions, under PPTg-ON, ameliorated. A recent study comparing both targets found that only PPTg-LFS improved night-time sleep and daytime sleepiness. Chances are that different neurosurgical groups influence either the PPN sub-portion identified as pars dissipata (more interconnected with GPi/STN) or the caudal PPN region known as pars compacta, preferentially targeting intralaminar and associative nucleus of the thalamus. Yet, the wide electrical field delivered affects a plethora of en passant circuits, and a fine distinction on the specific pathways involved is elusive. This review explores our angle of vision, by which PPTg-LFS activates cholinergic and glutamatergic ascending fibers, influencing non-motor behaviors.

  17. The Serendipity Case of the Pedunculopontine Nucleus Low-Frequency Brain Stimulation: Chasing a Gait Response, Finding Sleep, and Cognition Improvement

    PubMed Central

    Stefani, Alessandro; Peppe, Antonella; Galati, Salvatore; Stampanoni Bassi, Mario; D’Angelo, Vincenza; Pierantozzi, Mariangela

    2013-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficacious therapy for Parkinson’s disease (PD) but its effects on non-motor facets may be detrimental. The low-frequency stimulation (LFS) of the pedunculopontine nucleus (PPN or the nucleus tegmenti pedunculopontini – PPTg-) opened new perspectives. In our hands, PPTg-LFS revealed a modest influence on gait but increased sleep quality and degree of attentiveness. At odds with potential adverse events following STN-DBS, executive functions, under PPTg-ON, ameliorated. A recent study comparing both targets found that only PPTg-LFS improved night-time sleep and daytime sleepiness. Chances are that different neurosurgical groups influence either the PPN sub-portion identified as pars dissipata (more interconnected with GPi/STN) or the caudal PPN region known as pars compacta, preferentially targeting intralaminar and associative nucleus of the thalamus. Yet, the wide electrical field delivered affects a plethora of en passant circuits, and a fine distinction on the specific pathways involved is elusive. This review explores our angle of vision, by which PPTg-LFS activates cholinergic and glutamatergic ascending fibers, influencing non-motor behaviors. PMID:23761781

  18. Connectivity of the pedunculopontine nucleus in parkinsonian freezing of gait.

    PubMed

    Schweder, Patrick M; Hansen, Peter C; Green, Alex L; Quaghebeur, Gerardine; Stein, John; Aziz, Tipu Z

    2010-10-06

    Parkinson's disease (PD) may involve sudden unintended arrests in gait or failure to initiate gait, known as gait freezing. Deep brain stimulation of the pedunculopontine nucleus (PPN) has been found to be an effective therapy for this phenomenon. In this study, we characterized the connectivity of the PPN freezing of gait (FOG) patients, compared with non-FOG PD and healthy controls using diffusion tensor imaging techniques. Differences in PPN connectivity profiles of the study groups were shown in the cerebellum and pons. The PPN showed connectivity with the cerebellum in controls and non-FOG PD. FOG patients showed absence of cerebellar connectivity, and increased visibility of the decussation of corticopontine fibres in the anterior pons. The findings suggest that corticopontine projections, which cross at the pons are increased in gait freezing, highlighting the importance and role of corticopontine-cerebellar pathways in the pathophysiology of this phenomenon.

  19. Pedunculopontine arousal system physiology - Deep brain stimulation (DBS).

    PubMed

    Garcia-Rill, Edgar; Luster, Brennon; D'Onofrio, Stasia; Mahaffey, Susan; Bisagno, Veronica; Urbano, Francisco J

    2015-11-01

    This review describes the wake/sleep symptoms present in Parkinson׳s disease, and the role of the pedunculopontine nucleus in these symptoms. The physiology of PPN cells is important not only because it is a major element of the reticular activating system, but also because it is a novel target for deep brain stimulation in the treatment of gait and postural deficits in Parkinson׳s disease. A greater understanding of the physiology of the target nuclei within the brainstem and basal ganglia, amassed over the past decades, has enabled increasingly better patient outcomes from deep brain stimulation for movement disorders.

  20. Pedunculopontine arousal system physiology – Deep brain stimulation (DBS)

    PubMed Central

    Garcia-Rill, Edgar; Luster, Brennon; D’Onofrio, Stasia; Mahaffey, Susan; Bisagno, Veronica; Urbano, Francisco J.

    2015-01-01

    This review describes the wake/sleep symptoms present in Parkinson׳s disease, and the role of the pedunculopontine nucleus in these symptoms. The physiology of PPN cells is important not only because it is a major element of the reticular activating system, but also because it is a novel target for deep brain stimulation in the treatment of gait and postural deficits in Parkinson׳s disease. A greater understanding of the physiology of the target nuclei within the brainstem and basal ganglia, amassed over the past decades, has enabled increasingly better patient outcomes from deep brain stimulation for movement disorders. PMID:26779322

  1. Glutamate and GABA modulate dopamine in the pedunculopontine tegmental nucleus.

    PubMed

    Steiniger, Björn; Kretschmer, Beate D

    2003-04-01

    The pedunculopontine tegmental nucleus (PPTg) has an important anatomical position connecting basal ganglia and limbic systems with motor execution structures in the pons and spinal cord. It receives glutamatergic and GABAergic input and has additional reciprocal connections with mesencephalic dopaminergic neurons, suggesting that the PPTg plays a key role in frontostriatal information processing. In vivo microdialysis in freely moving rats, in combination with behavioral analysis, was used in this study to investigate whether the dopaminergic input can be modulated at the level of the PPTg via N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) or GABA(B) receptors. Stimulation of the GABA(B) receptor decreased dopamine release in the PPTg while that of the AMPA and NMDA receptors increased it. A time-related comparison of the effects of NMDA (0.75 and 1 mM) and AMPA (50 and 25 microM) revealed a more long-lasting effect after AMPA stimulation than after NMDA. However, only the infusion of the GABA(B) receptor agonist baclofen (100 and 200 microM) stimulated stereotyped behavior (e.g. sniffing, digging or head movements) and contralateral circling. This study clearly demonstrates that GABAergic as well as glutamatergic terminals in the PPTg are critically involved in the modulation of the dopamine system. Moreover, a decrease in PPTg dopamine via GABA(B) receptor stimulation seems to be behaviorally relevant.

  2. Pedunculopontine nucleus microelectrode recordings in movement disorder patients.

    PubMed

    Weinberger, Moran; Hamani, Clement; Hutchison, William D; Moro, Elena; Lozano, Andres M; Dostrovsky, Jonathan O

    2008-06-01

    The pedunculopontine nucleus (PPN) lies within the brainstem reticular formation and is involved in the motor control of gait and posture. Interest has focused recently on the PPN as a target for implantation of chronic deep brain stimulation (DBS) electrodes for Parkinson's disease (PD) and progressive supranuclear palsy (PSP) therapy. The aim of this study was to examine the neurophysiology of the human PPN region and to identify neurophysiological landmarks that may aid the proper placement of DBS electrodes in the nucleus for the treatment of PD and PSP. Neuronal firing and local field potentials were recorded simultaneously from two independently driven microelectrodes during stereotactic neurosurgery for implantation of a unilateral DBS electrode in the PPN in five PD patients and two PSP patients. Within the PPN region, the majority (57%) of the neurons fired randomly while about 21% of the neurons exhibited 'bursty' firing. In addition, 21% of the neurons had a long action potential duration and significantly lower firing rate suggesting they were cholinergic neurons. A change in firing rate produced by passive and/or active contralateral limb movement was observed in 38% of the neurons that were tested in the PPN region. Interestingly, oscillatory local field potential activity in the beta frequency range ( approximately 25 Hz) was also observed in the PPN region. These electrophysiological characteristics of the PPN region provide further support for the proposed role of this region in motor control. It remains to be seen to what extent the physiological characteristics of the neurons and the stimulation-evoked effects will permit reliable identification of PPN and determination of the optimal target for DBS therapy.

  3. Effects of bilateral vestibular deafferentation in rat on hippocampal theta response to somatosensory stimulation, acetylcholine release, and cholinergic neurons in the pedunculopontine tegmental nucleus.

    PubMed

    Aitken, Phillip; Zheng, Yiwen; Smith, Paul F

    2017-03-27

    Vestibular dysfunction has been shown to cause spatial memory impairment. Neurophysiological studies indicate that bilateral vestibular loss (BVL), in particular, is associated with an impairment of the response of hippocampal place cells and theta rhythm. However, the specific neural pathways through which vestibular information reaches the hippocampus are yet to be fully elucidated. The aim of the present study was to further investigate the hypothesised 'theta-generating pathway' from the brainstem vestibular nucleus to the hippocampus. BVL, and in some cases, unilateral vestibular loss (UVL), induced by intratympanic sodium arsanilate injections in rats, were used to investigate the effects of vestibular loss on somatosensory-induced type 2 theta rhythm, acetylcholine (ACh) release in the hippocampus, and the number of cholinergic neurons in the pedunculopontine tegmental nucleus (PPTg), an important part of the theta-generating pathway. Under urethane anaesthesia, BVL was found to cause a significant increase in the maximum power of the type 2 theta (3-6 Hz) frequency band compared to UVL and sham animals. Rats with BVL generally exhibited a lower basal level of ACh release than sham rats; however, this difference was not statistically significant. The PPTg of BVL rats exhibited significantly more choline-acetyltransferase (ChAT)-positive neurons than that of sham animals, as did the contralateral PPTg of UVL animals; however, the number of ChAT-positive neurons on the ipsilateral side of UVL animals was not significantly different from sham animals. The results of these studies indicate that parts of the theta-generating pathway undergo a significant reorganisation following vestibular loss, which suggests that this pathway is important for the interaction between the vestibular system and the hippocampus.

  4. Functional Connectivity of the Pedunculopontine Nucleus and Surrounding Region in Parkinson’s Disease

    PubMed Central

    Taulu, Samu; Thevathasan, Wesley; Hyam, Jonathan A.; Foltynie, Tom; Limousin, Patricia; Bogdanovic, Marko; Zrinzo, Ludvic; Green, Alexander L.; Aziz, Tipu Z.; Friston, Karl; Brown, Peter

    2017-01-01

    Deep brain stimulation of the pedunculopontine nucleus and surrounding region (PPNR) is a novel treatment strategy for gait freezing in Parkinson’s disease (PD). However, clinical results have been variable, in part because of the paucity of functional information that might help guide selection of the optimal surgical target. In this study, we use simultaneous magnetoencephalography and local field recordings from the PPNR in seven PD patients, to characterize functional connectivity with distant brain areas at rest. The PPNR was preferentially coupled to brainstem and cingulate regions in the alpha frequency (8–12 Hz) band and to the medial motor strip and neighboring areas in the beta (18–33 Hz) band. The distribution of coupling also depended on the vertical distance of the electrode from the pontomesencephalic line: most effects being greatest in the middle PPNR, which may correspond to the caudal pars dissipata of the pedunculopontine nucleus. These observations confirm the crucial position of the PPNR as a functional node between cortical areas such as the cingulate/ medial motor strip and other brainstem nuclei, particularly in the dorsal pons. In particular they suggest a special role for the middle PPNR as this has the greatest functional connectivity with other brain regions. PMID:28316456

  5. Magnetic resonance diffusion tensor imaging for the pedunculopontine nucleus: proof of concept and histological correlation.

    PubMed

    Alho, A T D L; Hamani, C; Alho, E J L; da Silva, R E; Santos, G A B; Neves, R C; Carreira, L L; Araújo, C M M; Magalhães, G; Coelho, D B; Alegro, M C; Martin, M G M; Grinberg, L T; Pasqualucci, C A; Heinsen, H; Fonoff, E T; Amaro, E

    2017-03-10

    The pedunculopontine nucleus (PPN) has been proposed as target for deep brain stimulation (DBS) in patients with postural instability and gait disorders due to its involvement in muscle tonus adjustments and control of locomotion. However, it is a deep-seated brainstem nucleus without clear imaging or electrophysiological markers. Some studies suggested that diffusion tensor imaging (DTI) may help guiding electrode placement in the PPN by showing the surrounding fiber bundles, but none have provided a direct histological correlation. We investigated DTI fractional anisotropy (FA) maps from in vivo and in situ post-mortem magnetic resonance images (MRI) compared to histological evaluations for improving PPN targeting in humans. A post-mortem brain was scanned in a clinical 3T MR system in situ. Thereafter, the brain was processed with a special method ideally suited for cytoarchitectonic analyses. Also, nine volunteers had in vivo brain scanning using the same MRI protocol. Images from volunteers were compared to those obtained in the post-mortem study. FA values of the volunteers were obtained from PPN, inferior colliculus, cerebellar crossing fibers and medial lemniscus using histological data and atlas information. FA values in the PPN were significantly lower than in the surrounding white matter region and higher than in areas with predominantly gray matter. In Nissl-stained histologic sections, the PPN extended for more than 10 mm in the rostro-caudal axis being closely attached to the lateral parabrachial nucleus. Our DTI analyses and the spatial correlation with histological findings proposed a location for PPN that matched the position assigned to this nucleus in the literature. Coregistration of neuroimaging and cytoarchitectonic features can add value to help establishing functional architectonics of the PPN and facilitate neurosurgical targeting of this extended nucleus.

  6. The Pedunculopontine Tegmental Nucleus as a Motor and Cognitive Interface between the Cerebellum and Basal Ganglia

    PubMed Central

    Mori, Fumika; Okada, Ken-ichi; Nomura, Taishin; Kobayashi, Yasushi

    2016-01-01

    As an important component of ascending activating systems, brainstem cholinergic neurons in the pedunculopontine tegmental nucleus (PPTg) are involved in the regulation of motor control (locomotion, posture and gaze) and cognitive processes (attention, learning and memory). The PPTg is highly interconnected with several regions of the basal ganglia, and one of its key functions is to regulate and relay activity from the basal ganglia. Together, they have been implicated in the motor control system (such as voluntary movement initiation or inhibition), and modulate aspects of executive function (such as motivation). In addition to its intimate connection with the basal ganglia, projections from the PPTg to the cerebellum have been recently reported to synaptically activate the deep cerebellar nuclei. Classically, the cerebellum and basal ganglia were regarded as forming separated anatomical loops that play a distinct functional role in motor and cognitive behavioral control. Here, we suggest that the PPTg may also act as an interface device between the basal ganglia and cerebellum. As such, part of the therapeutic effect of PPTg deep brain stimulation (DBS) to relieve gait freezing and postural instability in advanced Parkinson’s disease (PD) patients might also involve modulation of the cerebellum. We review the anatomical position and role of the PPTg in the pathway of basal ganglia and cerebellum in relation to motor control, cognitive function and PD. PMID:27872585

  7. Deep brain stimulation of different pedunculopontine targets in a novel rodent model of parkinsonism.

    PubMed

    Gut, Nadine K; Winn, Philip

    2015-03-25

    The pedunculopontine tegmental nucleus (PPTg) has been proposed as a target for deep brain stimulation (DBS) in parkinsonian patients, particularly for symptoms such as gait and postural difficulties refractory to dopaminergic treatments. Several patients have had electrodes implanted aimed at the PPTg, but outcomes have been disappointing, with little evidence that gait and posture are improved. The PPTg is a heterogeneous structure. Consequently, exact target sites in PPTg, possible DBS mechanisms, and potential benefits still need systematic investigation in good animal models. We have investigated the role of PPTg in gait, developed a refined model of parkinsonism including partial loss of the PPTg with bilateral destruction of nigrostriatal dopamine neurons that mimics human pathophysiology, and investigated the effect of DBS at different PPTg locations on gait and posture using a wireless device that lets rats move freely while receiving stimulation. Neither partial nor complete lesions of PPTg caused gait deficits, underlining questions raised previously about the status of PPTg as a motor control structure. The effect of DBS in the refined and standard model of parkinsonism were very different despite minimal behavioral differences in nonstimulation control conditions. Anterior PPTg DBS caused severe episodes of freezing and worsened gait, whereas specific gait parameters were mildly improved by stimulation of posterior PPTg. These results emphasize the critical importance of intra-PPTg DBS location and highlight the need to take PPTg degeneration into consideration when modeling parkinsonian symptoms. They also further implicate a role for PPTg in the pathophysiology of parkinsonism.

  8. Recording Gamma Band Oscillations in Pedunculopontine Nucleus Neurons.

    PubMed

    Urbano, Francisco J; Luster, Brennon R; D'Onofrio, Stasia; Mahaffey, Susan; Garcia-Rill, Edgar

    2016-09-14

    Synaptic efferents from the PPN are known to modulate the neuronal activity of several intralaminar thalamic regions (e.g., the centrolateral/parafascicular; Cl/Pf nucleus). The activation of either the PPN or Cl/Pf nuclei in vivo has been described to induce the arousal of the animal and an increment in gamma band activity in the cortical electroencephalogram (EEG). The cellular mechanisms for the generation of gamma band oscillations in Reticular Activating System (RAS) neurons are the same as those found to generate gamma band oscillations in other brains nuclei. During current-clamp recordings of PPN neurons (from parasagittal slices from 9 - 25 day-old rats), the use of depolarizing square steps rapidly activated voltage-dependent potassium channels that prevented PPN neurons from being depolarized beyond -25 mV. Injecting 1 - 2 sec long depolarizing current ramps gradually depolarized PPN membrane potential resting values towards 0 mV. However, injecting depolarizing square pulses generated gamma-band oscillations of membrane potential that showed to be smaller in amplitude compared to the oscillations generated by ramps. All experiments were performed in the presence of voltage-gated sodium channels and fast synaptic receptors blockers. It has been shown that the activation of high-threshold voltage-dependent calcium channels underlie gamma-band oscillatory activity in PPN neurons. Specific methodological and pharmacological interventions are described here, providing the necessary tools to induce and sustain PPN subthreshold gamma band oscillation in vitro.

  9. Electrolytic lesions of the pedunculopontine nucleus disrupt concurrent learned aversion induced by NaCl.

    PubMed

    Mediavilla, C; Molina, F; Puerto, A

    2000-09-01

    Bilateral electrolytic lesions in the pedunculopontine nucleus (PPN) impair acquisition of short-term, or concurrent, Taste Aversion Learning (TAL) in rats. This type of TAL is characterized by the daily presentation of two different flavor stimuli at the same time, one associated with simultaneous intragastric administration of an aversive product (hypertonic NaCl) and the other with physiological saline. Sham-lesioned control animals learn this taste discrimination task, but both lesioned animals and control animals learn a long-term, or delayed, TAL task in which each gustatory stimulus is presented individually every other day and the intragastric products, LiCl (0.15 M) and physiological saline, are administered after a 15-min delay. These results are analyzed in the context of the cerebellar circuits involved in learning and in relation to the two TAL modalities described above.

  10. Mitochondrial Abnormality Associates with Type-Specific Neuronal Loss and Cell Morphology Changes in the Pedunculopontine Nucleus in Parkinson Disease

    PubMed Central

    Pienaar, Ilse S.; Elson, Joanna L.; Racca, Claudia; Nelson, Glyn; Turnbull, Douglass M.; Morris, Christopher M.

    2014-01-01

    Cholinergic neuronal loss in the pedunculopontine nucleus (PPN) associates with abnormal functions, including certain motor and nonmotor symptoms. This realization has led to low-frequency stimulation of the PPN for treating patients with Parkinson disease (PD) who are refractory to other treatment modalities. However, the molecular mechanisms underlying PPN neuronal loss and the therapeutic substrate for the clinical benefits following PPN stimulation remain poorly characterized, hampering progress toward designing more efficient therapies aimed at restoring the PPN's normal functions during progressive parkinsonism. Here, we investigated postmortem pathological changes in the PPN of PD cases. Our study detected a loss of neurons producing gamma-aminobutyric acid (GABA) as their output and glycinergic neurons, along with the pronounced loss of cholinergic neurons. These losses were accompanied by altered somatic cell size that affected the remaining neurons of all neuronal subtypes studied here. Because studies showed that mitochondrial dysfunction exists in sporadic PD and in PD animal models, we investigated whether altered mitochondrial composition exists in the PPN. A significant up-regulation of several mitochondrial proteins was seen in GABAergic and glycinergic neurons; however, cholinergic neurons indicated down-regulation of the same proteins. Our findings suggest an imbalance in the activity of key neuronal subgroups of the PPN in PD, potentially because of abnormal inhibitory activity and altered cholinergic outflow. PMID:24099985

  11. Astrocyte-Dependent Slow Inward Currents (SICs) Participate in Neuromodulatory Mechanisms in the Pedunculopontine Nucleus (PPN)

    PubMed Central

    Kovács, Adrienn; Pál, Balázs

    2017-01-01

    Slow inward currents (SICs) are known as excitatory events of neurons caused by astrocytic glutamate release and consequential activation of neuronal extrasynaptic NMDA receptors. In the present article we investigate the role of these astrocyte-dependent excitatory events on a cholinergic nucleus of the reticular activating system (RAS), the pedunculopontine nucleus (PPN). It is well known about this and other elements of the RAS, that they do not only give rise to neuromodulatory innervation of several areas, but also targets neuromodulatory actions from other members of the RAS or factors providing the homeostatic drive for sleep. Using slice electrophysiology, optogenetics and morphological reconstruction, we revealed that SICs are present in a population of PPN neurons. The frequency of SICs recorded on PPN neurons was higher when the soma of the given neuron was close to an astrocytic soma. SICs do not appear simultaneously on neighboring neurons, thus it is unlikely that they synchronize neuronal activity in this structure. Occurrence of SICs is regulated by cannabinoid, muscarinic and serotonergic neuromodulatory mechanisms. In most cases, SICs occurred independently from tonic neuronal currents. SICs were affected by different neuromodulatory agents in a rather uniform way: if control SIC activity was low, the applied drugs increased it, but if SIC activity was increased in control, the same drugs lowered it. SICs of PPN neurons possibly represent a mechanism which elicits network-independent spikes on certain PPN neurons; forming an alternative, astrocyte-dependent pathway of neuromodulatory mechanisms. PMID:28203147

  12. Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine Tegmental Nucleus Have Distinct Effects on Sleep/Wake Behavior in Mice.

    PubMed

    Kroeger, Daniel; Ferrari, Loris L; Petit, Gaetan; Mahoney, Carrie E; Fuller, Patrick M; Arrigoni, Elda; Scammell, Thomas E

    2017-02-01

    The pedunculopontine tegmental (PPT) nucleus has long been implicated in the regulation of cortical activity and behavioral states, including rapid eye-movement (REM) sleep. For example, electrical stimulation of the PPT region during sleep leads to rapid awakening, whereas lesions of the PPT in cats reduce REM sleep. Though these effects have been linked with the activity of cholinergic PPT neurons, the PPT also includes intermingled glutamatergic and GABAergic cell populations, and the precise roles of cholinergic, glutamatergic, and GABAergic PPT cell groups in regulating cortical activity and behavioral state remain unknown. Using a chemogenetic approach in three Cre-driver mouse lines, we found that selective activation of glutamatergic PPT neurons induced prolonged cortical activation and behavioral wakefulness, whereas inhibition reduced wakefulness and increased non-REM (NREM) sleep. Activation of cholinergic PPT neurons suppressed lower-frequency electroencephalogram rhythms during NREM sleep. Last, activation of GABAergic PPT neurons slightly reduced REM sleep. These findings reveal that glutamatergic, cholinergic, and GABAergic PPT neurons differentially influence cortical activity and sleep/wake states.

  13. Pedunculopontine Nucleus Gamma Band Activity-Preconscious Awareness, Waking, and REM Sleep

    PubMed Central

    Urbano, Francisco J.; D’Onofrio, Stasia M.; Luster, Brennon R.; Beck, Paige B.; Hyde, James Robert; Bisagno, Veronica; Garcia-Rill, Edgar

    2014-01-01

    The pedunculopontine nucleus (PPN) is a major component of the reticular activating system (RAS) that regulates waking and REM sleep, states of high-frequency EEG activity. Recently, we described the presence of high threshold, voltage-dependent N- and P/Q-type calcium channels in RAS nuclei that subserve gamma band oscillations in the mesopontine PPN, intralaminar parafascicular nucleus (Pf), and pontine subcoeruleus nucleus dorsalis (SubCD). Cortical gamma band activity participates in sensory perception, problem solving, and memory. Rather than participating in the temporal binding of sensory events as in the cortex, gamma band activity in the RAS may participate in the processes of preconscious awareness, and provide the essential stream of information for the formulation of many of our actions. That is, the RAS may play an early permissive role in volition. Our latest results suggest that (1) the manifestation of gamma band activity during waking may employ a separate intracellular pathway compared to that during REM sleep, (2) neuronal calcium sensor (NCS-1) protein, which is over expressed in schizophrenia and bipolar disorder, modulates gamma band oscillations in the PPN in a concentration-dependent manner, (3) leptin, which undergoes resistance in obesity resulting in sleep dysregulation, decreases sodium currents in PPN neurons, accounting for its normal attenuation of waking, and (4) following our discovery of electrical coupling in the RAS, we hypothesize that there are cell clusters within the PPN that may act in concert. These results provide novel information on the mechanisms controlling high-frequency activity related to waking and REM sleep by elements of the RAS. PMID:25368599

  14. Pedunculopontine Nucleus Gamma Band Activity-Preconscious Awareness, Waking, and REM Sleep.

    PubMed

    Urbano, Francisco J; D'Onofrio, Stasia M; Luster, Brennon R; Beck, Paige B; Hyde, James Robert; Bisagno, Veronica; Garcia-Rill, Edgar

    2014-01-01

    The pedunculopontine nucleus (PPN) is a major component of the reticular activating system (RAS) that regulates waking and REM sleep, states of high-frequency EEG activity. Recently, we described the presence of high threshold, voltage-dependent N- and P/Q-type calcium channels in RAS nuclei that subserve gamma band oscillations in the mesopontine PPN, intralaminar parafascicular nucleus (Pf), and pontine subcoeruleus nucleus dorsalis (SubCD). Cortical gamma band activity participates in sensory perception, problem solving, and memory. Rather than participating in the temporal binding of sensory events as in the cortex, gamma band activity in the RAS may participate in the processes of preconscious awareness, and provide the essential stream of information for the formulation of many of our actions. That is, the RAS may play an early permissive role in volition. Our latest results suggest that (1) the manifestation of gamma band activity during waking may employ a separate intracellular pathway compared to that during REM sleep, (2) neuronal calcium sensor (NCS-1) protein, which is over expressed in schizophrenia and bipolar disorder, modulates gamma band oscillations in the PPN in a concentration-dependent manner, (3) leptin, which undergoes resistance in obesity resulting in sleep dysregulation, decreases sodium currents in PPN neurons, accounting for its normal attenuation of waking, and (4) following our discovery of electrical coupling in the RAS, we hypothesize that there are cell clusters within the PPN that may act in concert. These results provide novel information on the mechanisms controlling high-frequency activity related to waking and REM sleep by elements of the RAS.

  15. The pedunculopontine tegmental nucleus: from basic neuroscience to neurosurgical applications: arousal from slices to humans: implications for DBS.

    PubMed

    Garcia-Rill, Edgar; Simon, Christen; Smith, Kristen; Kezunovic, Nebosja; Hyde, James

    2011-10-01

    One element of the reticular activating system (RAS) is the pedunculopontine nucleus (PPN), which projects to the thalamus to trigger thalamocortical rhythms and the brainstem to modulate muscle tone and locomotion. The PPN is a posterior midbrain site known to induce locomotion in decerebrate animals when activated at 40-60 Hz, and has become a target for DBS in disorders involving gait deficits. We developed a research program using brainstem slices containing the PPN to study the cellular and molecular organization of this region. We showed that PPN neurons preferentially fire at gamma band frequency (30-60 Hz) when maximally activated, accounting for the effects of electrical stimulation. In addition, we developed the P13 midlatency auditory evoked potential, which is generated by PPN outputs, in freely moving rats. This allows the study of PPN cellular and molecular mechanisms in the whole animal. We also study the P50 midlatency auditory evoked potential, which is the human equivalent of the rodent P13 potential, allowing us to study PPN-related processes detected in vitro, confirmed in the whole animal, and tested in humans. Previous findings on the P50 potential in PD suggest that PPN output in this disorder is overactive. This translational research program led to the discovery of a novel mechanism of sleep-wake control based on electrical coupling, pointing the way to a number of new clinical applications in the development of novel stimulants (e.g., modafinil) and anesthetics. In addition, it provides methods for monitoring therapeutic efficacy of DBS in humans and animal models.

  16. REM sleep diversity following the pedunculopontine tegmental nucleus lesion in rat.

    PubMed

    Petrovic, Jelena; Lazic, Katarina; Kalauzi, Aleksandar; Saponjic, Jasna

    2014-09-01

    The aim of this study was to demonstrate that two REM clusters, which emerge following bilateral pedunculopontine tegmental nucleus (PPT) lesions in rats, are two functionally distinct REM states. We performed the experiments in Wistar rats, chronically instrumented for sleep recording. Bilateral PPT lesions were produced by the microinfusion of 100 nl of 0.1M ibotenic acid (IBO). Following a recovery period of 2 weeks, we recorded their sleep for 6h. Bilateral PPT lesions were identified by NADPH - diaphorase histochemistry. We applied Fourier analysis to the signals acquired throughout the 6h recordings, and each 10s epoch was differentiated as a Wake, NREM or REM state. We analyzed the topography of the sleep/wake states architecture and their transition structure, their all state-related EEG microstructures, and the sensorimotor (SMCx) and motor (MCx) cortex REM related cortico-muscular coherences (CMCs). Bilateral PPT lesion in rats increased the likelihood of the emergence of two distinct REM sleep states, specifically expressed within the MCx: REM1 and REM2. Bilateral PPT lesion did not change the sleep/wake states architecture of the SMCx, but pathologically increased the duration of REM1 within the MCx, alongside increasing Wake/REM1/Wake and NREM/REM2/NREM transitions within both cortices. In addition, the augmented total REM SMCx EEG beta amplitude and REM1 MCx EEG theta amplitude was the underlying EEG microstructure pathology. PPT lesion induced REM1 and REM2 are differential states with regard to total EMG power, topographically distinct EEG microstructures, and locomotor drives to nuchal musculature.

  17. Spatiotemporal properties of high-speed calcium oscillations in the pedunculopontine nucleus

    PubMed Central

    Hyde, James; Kezunovic, Nebojsa; Urbano, Francisco J.

    2013-01-01

    The pedunculopontine nucleus (PPN) is a component of the reticular activating system (RAS), and is involved in the activated states of waking and rapid eye movement (REM) sleep. Gamma oscillations (approximately 30–80 Hz) are evident in all PPN neurons and are mediated by high-threshold voltage-dependent N- and P/Q-type calcium channels. We tested the hypothesis that high-speed calcium imaging would reveal calcium-mediated oscillations in dendritic compartments in synchrony with patch-clamp recorded oscillations during depolarizing current ramps. Patch-clamped 8- to 16-day-old rat PPN neurons (n = 67 out of 121) were filled with Fura 2, Bis Fura, or OGB1/CHR. This study also characterized a novel ratiometric technique using Oregon Green BAPTA-1 (OGB1) with coinjections of a new long-stokes-shift dye, Chromeo 494 (CHR). Fluorescent calcium transients were blocked with the nonspecific calcium channel blocker cadmium, or by the combination of ω-agatoxin-IVA, a specific P/Q-type calcium channel blocker, and ω-conotoxin-GVIA, a specific N-type calcium channel blocker. The calcium transients were evident in different dendrites (suggesting channels are present throughout the dendritic tree) along the sampled length without interruption (suggesting channels are evenly distributed), and appeared to represent a summation of oscillations present in the soma. We confirm that PPN calcium channel-mediated oscillations are due to P/Q- and N-type channels, and reveal that these channels are distributed along the dendrites of PPN cells. PMID:23990242

  18. Effects of unilateral pedunculopontine stimulation on electromyographic activation patterns during gait in individual patients with Parkinson's disease.

    PubMed

    Caliandro, Pietro; Insola, A; Scarnati, E; Padua, L; Russo, G; Granieri, E; Mazzone, P

    2011-10-01

    In Parkinson's disease (PD), the effects of deep brain stimulation of the pedunculopontine nucleus (PPTg-DBS) on gait has been object of international debate. Some evidence demonstrated that, in the late swing-early stance phase of gait cycle, a reduced surface electromyographic activation (sEMG) of tibialis anterior (TA) is linked to the striatal dopamine deficiency in PD patients. In the present study we report preliminary results on the effect of PPTg-DBS on electromyographic patterns during gait in individual PD patients. To evaluate the sEMG amplitude of TA, the root mean square (RMS) of the TA burst in late swing-early stance phase (RMS-A) was normalized as a percent of the RMS of the TA burst in late stance-early swing (RMS-B). We studied three male patients in the following conditions: on PPTg-DBS/on L: -dopa, on PPTg-DBS/off L: -dopa, off PPTg-DBS/on L: -dopa, off PPTg-DBS/off L: -dopa. For each assessment the UPDRS III was filled in. We observed no difference between on PPTg-DBS/off L: -dopa and off PPTg-DBS/off L: -dopa in UPDRS III scores. In off PPTg-DBS/off L: -dopa, patient A (right implant) showed absence of the right and left RMSA, respectively, in 80% and 83% of gait cycles. Patient B (right implant) showed absence of the right RMS-A in 86% of cycles. RMS-A of the patient C (left implant) was bilaterally normal. In on PPTg- DBS/off L: -dopa, no patient showed reduced RMS-A. Although the very low number of subjects we evaluated, our observations suggest that PPTg plays a role in modulating TA activation pattern during the steady state of gait.

  19. The anterior and posterior pedunculopontine tegmental nucleus are involved in behavior and neuronal activity of the cuneiform and entopeduncular nuclei.

    PubMed

    Jin, X; Schwabe, K; Krauss, J K; Alam, M

    2016-05-13

    Loss of cholinergic neurons in the mesencephalic locomotor region, comprising the pedunculopontine nucleus (PPN) and the cuneiform nucleus (CnF), is related to gait disturbances in late stage Parkinson's disease (PD). We investigate the effect of anterior or posterior cholinergic lesions of the PPN on gait-related motor behavior, and on neuronal network activity of the PPN area and basal ganglia (BG) motor loop in rats. Anterior PPN lesions, posterior PPN lesions or sham lesions were induced by stereotaxic microinjection of the cholinergic toxin AF64-A or vehicle in male Sprague-Dawley rats. First, locomotor activity (open field), postural disturbances (Rotarod) and gait asymmetry (treadmill test) were assessed. Thereafter, single-unit and oscillatory activities were measured in the non-lesioned area of the PPN, the CnF and the entopeduncular nucleus (EPN), the BG output region, with microelectrodes under urethane anesthesia. Additionally, ECoG was recorded in the motor cortex. Injection of AF64-A into the anterior and posterior PPN decreased cholinergic cell counts as compared to naive controls (P<0.001) but also destroyed non-cholinergic cells. Only anterior PPN lesions decreased the front limb swing time of gait in the treadmill test, while not affecting other gait-related parameters tested. Main electrophysiological findings were that anterior PPN lesions increased the firing activity in the CnF (P<0.001). Further, lesions of either PPN region decreased the coherence of alpha (8-12 Hz) band between CnF and motor cortex (MCx), and increased the beta (12-30 Hz) oscillatory synchronization between EPN and the MCx. Lesions of the PPN in rats had complex effects on oscillatory neuronal activity of the CnF and the BG network, which may contribute to the understanding of the pathophysiology of gait disturbance in PD.

  20. Modulation of gamma oscillations in the pedunculopontine nucleus by neuronal calcium sensor protein-1: relevance to schizophrenia and bipolar disorder

    PubMed Central

    D'Onofrio, Stasia; Kezunovic, Nebojsa; Hyde, James R.; Luster, Brennon; Messias, Erick; Urbano, Francisco J.

    2014-01-01

    Reduced levels of gamma-band activity are present in schizophrenia and bipolar disorder patients. In the same disorders, increased neuronal calcium sensor protein-1 (NCS-1) expression was reported in a series of postmortem studies. These disorders are also characterized by sleep dysregulation, suggesting a role for the reticular activating system (RAS). The discovery of gamma-band activity in the pedunculopontine nucleus (PPN), the cholinergic arm of the RAS, revealed that such activity was mediated by high-threshold calcium channels that are regulated by NCS-1. We hypothesized that NCS-1 normally regulates gamma-band oscillations through these calcium channels and that excessive levels of NCS-1, such as would be expected with overexpression, decrease gamma-band activity. We found that PPN neurons in rat brain slices manifested gamma-band oscillations that were increased by low levels of NCS-1 but suppressed by high levels of NCS-1. Our results suggest that NCS-1 overexpression may be responsible for the decrease in gamma-band activity present in at least some schizophrenia and bipolar disorder patients. PMID:25376789

  1. The pedunculopontine nucleus is related to visual hallucinations in Parkinson's disease: preliminary results of a voxel-based morphometry study.

    PubMed

    Janzen, J; van 't Ent, D; Lemstra, A W; Berendse, H W; Barkhof, F; Foncke, E M J

    2012-01-01

    Visual hallucinations (VH) are common in Parkinson's disease (PD) and lead to a poor quality of life. For a long time, dopaminergic therapy was considered to be the most important risk factor for the development of VH in PD. Recently, the cholinergic system, including the pedunculopontine nucleus (PPN), has been implicated in the pathophysiology of VH. The aim of the present study was to investigate grey matter density of the PPN region and one of its projection areas, the thalamus. Thirteen non-demented PD patients with VH were compared to 16 non-demented PD patients without VH, 13 demented PD patients (PDD) with VH and 11 patients with dementia with Lewy bodies (DLB). Isotropic 3-D T1-weighted MRI images (3T) were analysed using voxel-based morphometry (VBM) with the PPN region and thalamus as ROIs. PD and PDD patients with VH showed grey matter reductions of the PPN region and the thalamus compared to PD patients without VH. VH in PD(D) patients are associated with atrophy of the PPN region and its thalamic target area, suggesting that a cholinergic deficit may be involved in the development of VH in PD(D).

  2. Effect of neurotoxic lesion of pedunculopontine nucleus in nigral and striatal redox balance and motor performance in rats.

    PubMed

    Jimenez-Martin, J; Blanco-Lezcano, L; González-Fraguela, M E; Díaz-Hung, M-L; Serrano-Sánchez, T; Almenares, J L; Francis-Turner, L

    2015-03-19

    Early degeneration of pedunculopontine nucleus (PPN) is considered part of changes that characterize premotor stages of Parkinson's disease (PD). In this paper, the effects of unilateral neurotoxic lesion of the PPN in motor execution and in the development of oxidative stress events in striatal and nigral tissues in rats were evaluated. The motor performance was assessed using the beam test (BT) and the cylinder test (CT). Nigral and striatal redox balance, was studied by means of biochemical indicators such as malondialdehyde (MDA), nitric oxide (NO) and the catalase enzymatic activity (CAT EA). Lesioned rats showed fine motor dysfunction expressed both as an increase in the length (p<0.001) and deviation (p<0.001) of the traveled path and also in the time spent (p<0.01) in the circular small beam (CBS) (p<0.01) in comparison with control groups. In addition, the lesioned rats group presented a right asymmetry index greater than 0.5 which is consistent with a significant increase in the percentage of use of the right forelimb (ipsilateral to the lesion), compared with the control group (p<0.05). Biochemical studies revealed that after 48-h PPN neurotoxic injury, the CAT EA showed a significant increase in the subtantia nigra pars compacta (SNpc) (p<0.05). This significant increase of CAT EA persisted in the nigral tissue (p<0.001) and reached the striatal tissue (p<0.001) seven days after PPN injury. Also at seven days post-injury PPN, increased concentrations of MDA (p<0.01) and a tendency to decrease in the concentrations of NO in both structures (SNpc and striatum) were found. The events associated with the generation of free radicals at nigral and striatal levels, can be part of the physiological mechanisms underlying motor dysfunction in rats with unilateral PPN neurotoxic lesion.

  3. Subpopulations of cholinergic, GABAergic and glutamatergic neurons in the pedunculopontine nucleus contain calcium-binding proteins and are heterogeneously distributed.

    PubMed

    Martinez-Gonzalez, Cristina; Wang, Hui-Ling; Micklem, Benjamin R; Bolam, J Paul; Mena-Segovia, Juan

    2012-03-01

    Neurons in the pedunculopontine nucleus (PPN) are highly heterogeneous in their discharge properties, their neurochemical markers, their pattern of connectivity and the behavioural processes in which they participate. Three main transmitter phenotypes have been described, cholinergic, GABAergic and glutamatergic, and yet electrophysiological evidence suggests heterogeneity within these subtypes. To gain further insight into the molecular composition of these three populations in the rat, we investigated the pattern of expression of calcium binding proteins (CBPs) across distinct regions of the PPN and in relation to the presence of other neurochemical markers. Calbindin- and calretinin-positive neurons are as abundant as cholinergic neurons, and their expression follows a rostro-caudal gradient, whereas parvalbumin is expressed by a low number of neurons. We observed a high degree of expression of CBPs by GABAergic and glutamatergic neurons, with a large majority of calbindin- and calretinin-positive neurons expressing GAD or VGluT2 mRNA. Notably, CBP-positive neurons expressing GAD mRNA were more concentrated in the rostral PPN, whereas the caudal PPN was characterized by a higher density of CBP-positive neurons expressing VGluT2 mRNA. In contrast to these two large populations, in cholinergic neurons expression of calretinin is observed only in low numbers and expression of calbindin is virtually non-existent. These findings thus identify novel subtypes of cholinergic, GABAergic and glutamatergic neurons based on their expression of CBPs, and further contribute to the notion of the PPN as a highly heterogeneous structure, an attribute that is likely to underlie its functional complexity.

  4. Lesion of the pedunculopontine tegmental nucleus in rat augments cortical activation and disturbs sleep/wake state transitions structure.

    PubMed

    Petrovic, Jelena; Ciric, Jelena; Lazic, Katarina; Kalauzi, Aleksandar; Saponjic, Jasna

    2013-09-01

    The pedunculopontine tegmental nucleus (PPT) represents a major aggregation of cholinergic neurons in the mammalian brainstem, which is important in the generation and maintenance of REM sleep. We investigated the effects of unilateral and bilateral PPT lesions on sleep and all the conventional sleep-state related EEG frequency bands amplitudes, in an attempt to find the EEG markers for the onset and progression of PPT cholinergic neuronal degeneration. The experiments were performed on 35 adult male Wistar rats, chronically implanted for sleep recording. During the surgical procedure for EEG and EMG electrodes implantation, the unilateral or bilateral PPT lesion was produced under ketamine/diazepam anesthesia, by the stereotaxically guided microinfusion of 100 nl 0.1M ibotenic acid (IBO) into PPT. We applied Fourier analysis to signals acquired throughout 6h of recordings, and each 10s epoch was differentiated as a Wake, NREM or REM state. We also calculated the group probability density estimates (PDE) of all Wake, NREM and REM conventional EEG frequency amplitudes, and the number of all the transition states using MATLAB 6.5. Our results show that the unilateral or bilateral PPT lesions did not change the sleep/wake architecture, but did change the sleep/wake state transitions structure and the sleep/state related "EEG microstructure". Unilateral or bilateral PPT lesions sustainably increased Wake/REM and REM/Wake transitions from 14 to 35 days after lesions. This was followed by decreased NREM/REM and REM/NREM transitions from 28 days only in the case of the bilateral PPT lesion. The unilateral PPT lesion augmented both Wake theta and REM beta while it also attenuated the relative amplitude of the Wake delta frequency, with a delay of one week. Following a bilateral PPT lesion there was augmentation of the relative amplitude of the Wake, NREM, and REM beta and REM gamma frequency which occurred simultaneously to NREM and Wake delta attenuation. We have shown

  5. Reward and Behavioral Factors Contributing to the Tonic Activity of Monkey Pedunculopontine Tegmental Nucleus Neurons during Saccade Tasks

    PubMed Central

    Okada, Ken-ichi; Kobayashi, Yasushi

    2016-01-01

    The pedunculopontine tegmental nucleus (PPTg) in the brainstem plays a role in controlling reinforcement learning and executing conditioned behavior. We previously examined the activity of PPTg neurons in monkeys during a reward-conditioned, visually guided saccade task, and reported that a population of these neurons exhibited tonic responses throughout the task period. These tonic responses might depend on prediction of the upcoming reward, successful execution of the task, or both. Here, we sought to further distinguish these factors and to investigate how each contributes to the tonic neuronal activity of the PPTg. In our normal visually guided saccade task, the monkey initially fixated on the central fixation target (FT), then made saccades to the peripheral saccade target and received a juice reward after the saccade target disappeared. Most of the tonic activity terminated shortly after the reward delivery, when the monkey broke fixation. To distinguish between reward and behavioral epochs, we then changed the task sequence for a block of trials, such that the saccade target remained visible after the reward delivery. Under these visible conditions, the monkeys tended to continue fixating on the saccade target even after the reward delivery. Therefore, the prediction of the upcoming reward and the end of an individual trial were separated in time. Regardless of the task conditions, half of the tonically active PPTg neurons terminated their activity around the time of the reward delivery, consistent with the view that PPTg neurons might send reward prediction signals until the time of reward delivery, which is essential for computing reward prediction error in reinforcement learning. On the other hand, the other half of the tonically active PPTg neurons changed their activity dependent on the task condition. In the normal condition, the tonic responses terminated around the time of the reward delivery, while in the visible condition, the activity continued

  6. Excitotoxic lesions of the tegmental pedunculopontine nucleus impair copulation in naive male rats and block the rewarding effects of copulation in experienced male rats.

    PubMed

    Kippin, Tod E; van der Kooy, Derek

    2003-11-01

    The tegmental pedunculopontine nucleus (TPP) of the brainstem mediates food reward in food-sated animals and opiate reward in drug-naive animals. In the present study, we examine the effect of excitotoxic lesions of the TPP on sexual behaviour in naive and experienced male rats. Male, Long-Evans rats received either 0.25 micro L injections of NMDA (4.2 micro g/side) or vehicle (shams) into the TPP. In sexually naive males, complete bilateral TPP lesions decreased all measure of copulation (i.e. mounts, intromissions and ejaculations), prevented acquisition of conditioned sexual excitement, decreased approach preference for a receptive female over a non-receptive one, and decreased non-contact erections; unilateral or bilateral posterior-sparing TPP lesions did not affect any of these measures. Conversely, in sexually experienced males, lesions not only failed to disrupt copulation, but also increased conditioned sexual excitement, decreased post-ejaculatory interval and blocked the effect of prolonged copulation on conditioned sexual excitement. Following differential pairing of distinctive environments with and without copulation, sham males with sexual experience displayed a significant preference for the environment paired with copulation, whereas the lesion males with sexual experience displayed a significant aversion for the environment paired with copulation. These findings indicate that the TPP is critical for the acquisition of copulation in naive males and mediates the rewarding consequences of copulation in experienced males. Together these findings demonstrate that the TPP mediates sexual reward, but that sexual experience is not sufficient to produce a deprivation state.

  7. 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

  8. Pedunculopontine arousal system physiology—Implications for schizophrenia

    PubMed Central

    Garcia-Rill, Edgar; D’Onofrio, Stasia; Mahaffey, Susan; Bisagno, Veronica; Urbano, Francisco J.

    2015-01-01

    Schizophrenia is characterized by major sleep/wake disturbances including increased vigilance and arousal, decreased slow wave sleep, and increased REM sleep drive. Other arousal-related symptoms include sensory gating deficits as exemplified by decreased habituation of the blink reflex. There is also dysregulation of gamma band activity, suggestive of disturbances in a host of arousal-related mechanisms. This review examines the role of the reticular activating system, especially the pedunculopontine nucleus, in the symptoms of the disease. Recent discoveries on the physiology of the pedunculopontine nucleus help explain many of these disorders of arousal in, and point to novel therapeutic avenues for, schizophrenia. PMID:26483949

  9. Pedunculopontine arousal system physiology-Implications for schizophrenia.

    PubMed

    Garcia-Rill, Edgar; D'Onofrio, Stasia; Mahaffey, Susan; Bisagno, Veronica; Urbano, Francisco J

    2015-01-01

    Schizophrenia is characterized by major sleep/wake disturbances including increased vigilance and arousal, decreased slow wave sleep, and increased REM sleep drive. Other arousal-related symptoms include sensory gating deficits as exemplified by decreased habituation of the blink reflex. There is also dysregulation of gamma band activity, suggestive of disturbances in a host of arousal-related mechanisms. This review examines the role of the reticular activating system, especially the pedunculopontine nucleus, in the symptoms of the disease. Recent discoveries on the physiology of the pedunculopontine nucleus help explain many of these disorders of arousal in, and point to novel therapeutic avenues for, schizophrenia.

  10. Posterior occipitocervical instrumented fusion for dropped head syndrome after deep brain stimulation.

    PubMed

    Pereira, E A C; Wilson-MacDonald, J; Green, A L; Aziz, T Z; Cadoux-Hudson, T A D

    2010-04-01

    We describe dropped head syndrome in a patient with Parkinson's disease receiving subthalamic nucleus deep brain stimulation (DBS). Posterior occipitocervical instrumented fusion after transarticular screw fixation of an odontoid fracture is shown and its rationale explained. Pedunculopontine nucleus DBS as treatment for fall-predominant Parkinson's disease, and globus pallidus interna DBS for dystonia-predominant Parkinson's disease, are discussed.

  11. Pedunculopontine arousal system physiology - Implications for insomnia.

    PubMed

    Garcia-Rill, Edgar; Luster, Brennon; Mahaffey, Susan; Bisagno, Veronica; Urbano, Francisco J

    2015-01-01

    We consider insomnia a disorder of waking rather than a disorder of sleep. This review examines the role of the reticular activating system, especially the pedunculopontine nucleus, in the symptoms of insomnia, mainly representing an overactive waking drive. We determined that high frequency activity during waking and REM sleep is controlled by two different intracellular pathways and channel types in PPN cells. We found three different PPN cell types that have one or both channels and may be active during waking only, REM sleep only, or both. These discoveries point to a specific mechanism and novel therapeutic avenues for insomnia.

  12. 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

  13. Tractography patterns of subthalamic nucleus deep brain stimulation.

    PubMed

    Vanegas-Arroyave, Nora; Lauro, Peter M; Huang, Ling; Hallett, Mark; Horovitz, Silvina G; Zaghloul, Kareem A; Lungu, Codrin

    2016-04-01

    Deep brain stimulation therapy is an effective symptomatic treatment for Parkinson's disease, yet the precise mechanisms responsible for its therapeutic effects remain unclear. Although the targets of deep brain stimulation are grey matter structures, axonal modulation is known to play an important role in deep brain stimulation's therapeutic mechanism. Several white matter structures in proximity to the subthalamic nucleus have been implicated in the clinical benefits of deep brain stimulation for Parkinson's disease. We assessed the connectivity patterns that characterize clinically beneficial electrodes in Parkinson's disease patients, after deep brain stimulation of the subthalamic nucleus. We evaluated 22 patients with Parkinson's disease (11 females, age 57 ± 9.1 years, disease duration 13.3 ± 6.3 years) who received bilateral deep brain stimulation of the subthalamic nucleus at the National Institutes of Health. During an initial electrode screening session, one month after deep brain stimulation implantation, the clinical benefits of each contact were determined. The electrode was localized by coregistering preoperative magnetic resonance imaging and postoperative computer tomography images and the volume of tissue activated was estimated from stimulation voltage and impedance. Brain connectivity for the volume of tissue activated of deep brain stimulation contacts was assessed using probabilistic tractography with diffusion-tensor data. Areas most frequently connected to clinically effective contacts included the thalamus, substantia nigra, brainstem and superior frontal gyrus. A series of discriminant analyses demonstrated that the strength of connectivity to the superior frontal gyrus and the thalamus were positively associated with clinical effectiveness. The connectivity patterns observed in our study suggest that the modulation of white matter tracts directed to the superior frontal gyrus and the thalamus is associated with favourable clinical

  14. 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.

  15. Subthalamic nucleus stimulation and somatosensory temporal discrimination in Parkinson's disease.

    PubMed

    Conte, Antonella; Modugno, Nicola; Lena, Francesco; Dispenza, Sabrina; Gandolfi, Barbara; Iezzi, Ennio; Fabbrini, Giovanni; Berardelli, Alfredo

    2010-09-01

    Whereas numerous studies document the effects of dopamine medication and deep brain stimulation on motor function in patients with Parkinson's disease, few have investigated deep brain stimulation-induced changes in sensory functions. In this study of 13 patients with Parkinson's disease, we tested the effects of deep brain stimulation on the somatosensory temporal discrimination threshold. To investigate whether deep brain stimulation and dopaminergic medication induce similar changes in somatosensory discrimination, somatosensory temporal discrimination threshold values were acquired under four experimental conditions: (i) medication ON/deep brain stimulation on; (ii) medication ON/deep brain stimulation off; (iii) medication OFF/deep brain stimulation on; and (iv) medication OFF/deep brain stimulation off. Patients also underwent clinical and neuropsychological evaluations during each experimental session. Somatosensory temporal discrimination threshold values obtained in patients were compared with 13 age-matched healthy subjects. Somatosensory temporal discrimination threshold values were significantly higher in patients than in healthy subjects. In patients, somatosensory temporal discrimination threshold values were significantly lower when patients were studied in medication ON than in medication OFF conditions. Somatosensory temporal discrimination threshold values differed significantly between deep brain stimulation on and deep brain stimulation off conditions only when the patients were studied in the medication ON condition and were higher in the deep brain stimulation on/medication ON than in the deep brain stimulation off/medication ON condition. Dopamine but not subthalamic nucleus deep brain stimulation restores the altered somatosensory temporal discrimination in patients with Parkinson's disease. Deep brain stimulation degrades somatosensory temporal discrimination by modifying central somatosensory processing whereas dopamine restores the

  16. Cholinergic mechanisms of high-frequency stimulation in entopeduncular nucleus

    PubMed Central

    Luo, Feng

    2015-01-01

    Chronic, high-frequency (>100 Hz) electrical stimulation, known as deep brain stimulation (DBS), of the internal segment of the globus pallidus (GPi) is a highly effective therapy for Parkinson's disease (PD) and dystonia. Despite some understanding of how it works acutely in PD models, there remain questions about its mechanisms of action. Several hypotheses have been proposed, such as depolarization blockade, activation of inhibitory synapses, depletion of neurotransmitters, and/or disruption/alteration of network oscillations. In this study we investigated the cellular mechanisms of high-frequency stimulation (HFS) in entopeduncular nucleus (EP; rat equivalent of GPi) neurons using whole cell patch-clamp recordings. We found that HFS applied inside the EP nucleus induced a prolonged afterdepolarization that was dependent on stimulation frequency, pulse duration, and current amplitude. The high frequencies (>100 Hz) and pulse widths (>0.15 ms) used clinically for dystonia DBS could reliably induce these afterdepolarizations, which persisted under blockade of ionotropic glutamate (kynurenic acid, 2 mM), GABAA (picrotoxin, 50 μM), GABAB (CGP 55845, 1 μM), and acetylcholine nicotinic receptors (DHβE, 2 μM). However, this effect was blocked by atropine (2 μM; nonselective muscarinic antagonist) or tetrodotoxin (0.5 μM). Finally, the muscarinic-dependent afterdepolarizations were sensitive to Ca2+-sensitive nonspecific cationic (CAN) channel blockade. Hence, these data suggest that muscarinic receptor activation during HFS can lead to feedforward excitation through the opening of CAN channels. This study for the first time describes a cholinergic mechanism of HFS in EP neurons and provides new insight into the underlying mechanisms of DBS. PMID:26334006

  17. Activation of Pedunculopontine Glutamate Neurons Is Reinforcing.

    PubMed

    Yoo, Ji Hoon; Zell, Vivien; Wu, Johnathan; Punta, Cindy; Ramajayam, Nivedita; Shen, Xinyi; Faget, Lauren; Lilascharoen, Varoth; Lim, Byung Kook; Hnasko, Thomas S

    2017-01-04

    Dopamine transmission from midbrain ventral tegmental area (VTA) neurons underlies behavioral processes related to motivation and drug addiction. The pedunculopontine tegmental nucleus (PPTg) is a brainstem nucleus containing glutamate-, acetylcholine-, and GABA-releasing neurons with connections to basal ganglia and limbic brain regions. Here we investigated the role of PPTg glutamate neurons in reinforcement, with an emphasis on their projections to VTA dopamine neurons. We used cell-type-specific anterograde tracing and optogenetic methods to selectively label and manipulate glutamate projections from PPTg neurons in mice. We used anatomical, electrophysiological, and behavioral assays to determine their patterns of connectivity and ascribe functional roles in reinforcement. We found that photoactivation of PPTg glutamate cell bodies could serve as a direct positive reinforcer on intracranial self-photostimulation assays. Further, PPTg glutamate neurons directly innervate VTA; photostimulation of this pathway preferentially excites VTA dopamine neurons and is sufficient to induce behavioral reinforcement. These results demonstrate that ascending PPTg glutamate projections can drive motivated behavior, and PPTg to VTA synapses may represent an important target relevant to drug addiction and other mental health disorders.

  18. Selective Stimulation and Measurement in the Cochlear Nucleus With the Spike Microelectrode Array

    DTIC Science & Technology

    2007-11-02

    Selective Stimulation and Measurement in the Cochlear Nucleus with the Spike Microelectrode Array F. MASE1, H. TAKAHASHI1, T. EJIRI1, M. NAKAO1, N...aren’t always effective, because we don’t have sufficient knowledge of the auditory pathways and the Cochlear Nucleus (CN) functions to stimulate the... Cochlear Nucleus functionally. Our goals are to enhance our understanding of such functions and to develop effective stimulating strategies of the CN

  19. 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.

  20. Pedunculopontine arousal system physiology – Implications for insomnia

    PubMed Central

    Garcia-Rill, Edgar; Luster, Brennon; Mahaffey, Susan; Bisagno, Veronica; Urbano, Francisco J.

    2015-01-01

    We consider insomnia a disorder of waking rather than a disorder of sleep. This review examines the role of the reticular activating system, especially the pedunculopontine nucleus, in the symptoms of insomnia, mainly representing an overactive waking drive. We determined that high frequency activity during waking and REM sleep is controlled by two different intracellular pathways and channel types in PPN cells. We found three different PPN cell types that have one or both channels and may be active during waking only, REM sleep only, or both. These discoveries point to a specific mechanism and novel therapeutic avenues for insomnia. PMID:26483950

  1. Functional anatomy of subthalamic nucleus stimulation in Parkinson disease

    PubMed Central

    Eisenstein, Sarah A.; Koller, Jonathan M.; Black, Kathleen D.; Campbell, Meghan C.; Lugar, Heather M.; Ushe, Mwiza; Tabbal, Samer D.; Karimi, Morvarid; Hershey, Tamara; Perlmutter, Joel S.; Black, Kevin J.

    2014-01-01

    Objective We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3D brain region and to assign statistical significance after stringent Type I error correction. This method was applied to behavioral changes in Parkinson disease (PD) induced by subthalamic nucleus (STN) DBS to determine whether these responses depended on anatomical location of DBS. Method Fifty-one PD participants with STN DBS were evaluated off medication, with DBS off and during unilateral STN DBS with clinically optimized settings. Dependent variables included DBS-induced changes in Unified Parkinson Disease Rating Scale (UPDRS) subscores, kinematic measures of bradykinesia and rigidity, working memory, response inhibition, mood, anxiety, and akathisia. Weighted t-tests at each voxel produced p images showing where DBS most significantly affected each dependent variable based on outcomes of participants with nearby DBS. Finally, a permutation test computed the probability that this p image indicated significantly different responses based on stimulation site. Results Most motor variables improved with DBS anywhere in the STN region, but several motor, cognitive and affective responses significantly depended on precise location stimulated, with peak p values in superior STN/zona incerta (quantified bradykinesia), dorsal STN (mood, anxiety), and inferior STN/substantia nigra (UPDRS tremor, working memory). Interpretation Our method identified DBS-induced behavioral changes that depended significantly on DBS site. These results do not support complete functional segregation within STN, since movement improved with DBS throughout, and mood improved with dorsal STN DBS. Rather, findings support functional convergence of motor, cognitive and limbic information in STN. PMID:24953991

  2. 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

  3. 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.

  4. Opioids in the nucleus accumbens stimulate ethanol intake.

    PubMed

    Barson, Jessica R; Carr, Ambrose J; Soun, Jennifer E; Sobhani, Nasim C; Leibowitz, Sarah F; Hoebel, Bartley G

    2009-10-19

    The nucleus accumbens (NAc) participates in the control of both motivation and addiction. To test the possibility that opioids in the NAc can cause rats to select ethanol in preference to food, Sprague-Dawley rats with ethanol, food, and water available, were injected with two doses each of morphine, the mu-receptor agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-Enkephalin (DAMGO), the delta-receptor agonist D-Ala-Gly-Phe-Met-NH2 (DALA), the k-receptor agonist (+/-)-trans-U-50488 methanesulfonate (U-50,488H), or the opioid antagonist naloxone methiodide (m-naloxone). As an anatomical control for drug reflux, injections were also made 2mm above the NAc. The main result was that morphine in the NAc significantly increased ethanol and food intake, whereas m-naloxone reduced ethanol intake without affecting food or water intake. Of the selective receptor agonists, DALA in the NAc increased ethanol intake in preference to food. This is in contrast to DAMGO, which stimulated food but not ethanol intake, and the k-agonist U-50,488H, which had no effect on intake. When injected in the anatomical control site 2mm dorsal to the NAc, the opioids had no effects on ethanol intake. These results demonstrate that ethanol intake produced by morphine in the NAc is driven in large part by the delta-receptor. In light of other studies showing ethanol intake to increase enkephalin expression in the NAc, the present finding of enkephalin-induced ethanol intake suggests the existence of a positive feedback loop that fosters alcohol abuse. Naltrexone therapy for alcohol abuse may then act, in part, in the NAc by blocking this opioid-triggered cycle of alcohol intake.

  5. Intracranial self-stimulation in the parafascicular nucleus of the rat.

    PubMed

    Vale-Martínez, A; Guillazo-Blanch, G; Aldavert-Vera, L; Segura-Torres, P; Martí-Nicolovius, M

    1999-03-01

    A behavioral analysis of intracranial self-stimulation was provided for parafascicular nucleus. To evaluate whether intracranial self-stimulation in this nucleus could be site-specific and to determine if the positive sites are the same parafascicular areas that facilitate learning when stimulated, rats were tested via monopolar electrodes situated throughout the parafascicular nucleus. Animals were trained to self-stimulate by pressing a lever in a conventional Skinner box (1-5 sessions). Twenty-two of the 42 animals included in the study, had the electrode at the parafascicular nucleus. Only two of them showed intracranial self-stimulation. Histological analyses indicated that the latter rats had the electrode implanted at the anterior area of the medial parafascicular. Other two animals also showed intracranial self-stimulation but they had the electrode in a more posterior brain region, between the Dark-schewitsch nucleus and the red nucleus. The animals implanted at the parafascicular showed higher response rates than the other two rats. These results confirm that: (a) the anterior region of the medial parafascicular is a positive site for stable and regular intracranial self-stimulation behavior, and (b) these positive sites do not coincide with the parafascicular regions related to learning improvement.

  6. Induction of a physiological memory in the cerebral cortex by stimulation of the nucleus basalis.

    PubMed

    Bakin, J S; Weinberger, N M

    1996-10-01

    Auditory cortical receptive field plasticity produced during behavioral learning may be considered to constitute "physiological memory" because it has major characteristics of behavioral memory: associativity, specificity, rapid acquisition, and long-term retention. To investigate basal forebrain mechanisms in receptive field plasticity, we paired a tone with stimulation of the nucleus basalis, the main subcortical source of cortical acetylcholine, in the adult guinea pig. Nucleus basalis stimulation produced electroencephalogram desynchronization that was blocked by systemic and cortical atropine. Paired tone/nucleus basalis stimulation, but not unpaired stimulation, induced receptive field plasticity similar to that produced by behavioral learning. Thus paired activation of the nucleus basalis is sufficient to induce receptive field plasticity, possibly via cholinergic actions in the cortex.

  7. Opioids in the Hypothalamic Paraventricular Nucleus Stimulate Ethanol Intake

    PubMed Central

    Barson, Jessica R.; Carr, Ambrose J.; Soun, Jennifer E.; Sobhani, Nasim C.; Rada, Pedro; Leibowitz, Sarah F.; Hoebel, Bartley G.

    2017-01-01

    Background Specialized hypothalamic systems that increase food intake might also increase ethanol intake. To test this possibility, morphine and receptor-specific opioid agonists were microinjected in the paraventricular nucleus (PVN) of rats that had learned to drink ethanol. To cross-validate the results, naloxone methiodide (m-naloxone), an opioid antagonist, was microinjected with the expectation that it would have the opposite effect of morphine and the specific opioid agonists. Methods Sprague-Dawley rats were trained, without sugar, to drink 4% or 7% ethanol and were then implanted with chronic brain cannulas aimed at the PVN. After recovery, those drinking 7% ethanol, with food and water available, were injected with two doses each of morphine or m-naloxone. To test for receptor specificity, two doses each of the μ-receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin (DAMGO), δ-receptor agonist D-Ala-Gly-Phe-Met-NH2 (DALA), or k-receptor agonist U-50,488H were injected. DAMGO was also tested in rats drinking 4% ethanol without food or water available. As an anatomical control for drug reflux, injections were made 2 mm dorsal to the PVN. Results A main result was a significant increase in ethanol intake induced by PVN injection of morphine. The opposite effect was produced by m-naloxone. The effects of morphine and m-naloxone were exclusively on intake of ethanol, even though food and water were freely available. In the analysis with specific receptor agonists, PVN injection of the δ-agonist DALA significantly increased 7% ethanol intake without affecting food or water intake. This is in contrast to the k-agonist U-50,488H, which decreased ethanol intake, and the μ-agonist DAMGO, which had no effect on ethanol intake in the presence or absence of food and water. In the anatomical control location 2 mm dorsal to the PVN, no drug caused any significant changes in ethanol, food, or water intake, providing evidence that the active site was close to the

  8. Role of the red nucleus in suppressing the jaw-opening reflex following stimulation of the raphe magnus nucleus.

    PubMed

    Satoh, Yoshihide; Ishizuka, Ken'Ichi; Iwasaki, Shin-ichi

    2014-08-01

    In a previous study, we found that electrical and chemical stimulation of the red nucleus (RN) suppressed the high-threshold afferent-evoked jaw-opening reflex (JOR). It has been reported that the RN receives bilaterally projection fibers from the raphe magnus nucleus (RMg), and that stimulation of the RMg inhibits the tooth pulp-evoked nociceptive JOR. These facts imply that RMg-induced inhibition of the JOR could be mediated via the RN. The present study first examines whether stimulation of the RMg suppresses the high-threshold afferent-evoked JOR. The JOR was evoked by electrical stimulation of the inferior alveolar nerve (IAN), and was recorded as the electromyographic response of the anterior belly of the digastric muscle. The stimulus intensity was 4.0 (high-threshold) times the threshold. Conditioning electrical stimulation of the RMg significantly suppressed the JOR. A further study then examined whether electrically induced lesions of the RN or microinjection of muscimol into the RN affects RMg-induced suppression of the JOR. Electrically induced lesions of the bilateral RN and microinjection of muscimol into the bilateral RN both reduced the RMg-induced suppression of the JOR. These results suggest that RMg-induced suppression of the high-threshold afferent-evoked JOR is mediated by a relay in the RN.

  9. 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…

  10. Pedunculopontine arousal system physiology—Effects of psychostimulant abuse

    PubMed Central

    Urbano, Francisco J.; Bisagno, Verónica; González, Betina; Celeste Rivero-Echeto, María; Muñiz, Javier A.; Luster, Brennon; D’Onofrio, Stasia; Mahaffey, Susan; Garcia-Rill, Edgar

    2015-01-01

    This review describes the interactions between the pedunculopontine nucleus (PPN), the ventral tegmental area (VTA), and the thalamocortical system. Experiments using modulators of cholinergic receptors in the PPN clarified its role on psychostimulant-induced locomotion. PPN activation was found to be involved in the animal’s voluntary search for psychostimulants. Every PPN neuron is known to generate gamma band oscillations. Voltage-gated calcium channels are key elements in the generation and maintenance of gamma band activity of PPN neurons. Calcium channels are also key elements mediating psychostimulant-induced alterations in the thalamic targets of PPN output. Thus, the PPN is a key substrate for maintaining arousal and REM sleep, but also in modulating psychostimulant self-administration. PMID:26779323

  11. Pedunculopontine arousal system physiology-Effects of psychostimulant abuse.

    PubMed

    Urbano, Francisco J; Bisagno, Verónica; González, Betina; Celeste Rivero-Echeto, María; Muñiz, Javier A; Luster, Brennon; D'Onofrio, Stasia; Mahaffey, Susan; Garcia-Rill, Edgar

    2015-11-01

    This review describes the interactions between the pedunculopontine nucleus (PPN), the ventral tegmental area (VTA), and the thalamocortical system. Experiments using modulators of cholinergic receptors in the PPN clarified its role on psychostimulant-induced locomotion. PPN activation was found to be involved in the animal's voluntary search for psychostimulants. Every PPN neuron is known to generate gamma band oscillations. Voltage-gated calcium channels are key elements in the generation and maintenance of gamma band activity of PPN neurons. Calcium channels are also key elements mediating psychostimulant-induced alterations in the thalamic targets of PPN output. Thus, the PPN is a key substrate for maintaining arousal and REM sleep, but also in modulating psychostimulant self-administration.

  12. GABA and glycine receptors in the nucleus ambiguus mediate tachycardia elicited by chemical stimulation of the hypothalamic arcuate nucleus.

    PubMed

    Chitravanshi, Vineet C; Kawabe, Kazumi; Sapru, Hreday N

    2015-07-01

    We have previously reported that stimulation of the hypothalamic arcuate nucleus (ARCN) by microinjections of N-methyl-d-aspartic acid (NMDA) elicits tachycardia, which is partially mediated via inhibition of vagal inputs to the heart. The neuronal pools and neurotransmitters in them mediating tachycardia elicited from the ARCN have not been identified. We tested the hypothesis that the tachycardia elicited from the ARCN may be mediated by inhibitory neurotransmitters in the nucleus ambiguus (nAmb). Experiments were done in urethane-anesthetized, artificially ventilated, male Wistar rats. In separate groups of rats, unilateral and bilateral microinjections of muscimol (1 mM), gabazine (0.01 mM), and strychnine (0.5 mM) into the nAmb significantly attenuated tachycardia elicited by unilateral microinjections of NMDA (10 mM) into the ARCN. Histological examination of the brains showed that the microinjections sites were within the targeted nuclei. Retrograde anatomic tracing from the nAmb revealed direct bilateral projections from the ARCN and hypothalamic paraventricular nucleus to the nAmb. The results of the present study suggest that tachycardia elicited by stimulation of the ARCN by microinjections of NMDA is mediated via GABAA and glycine receptors located in the nAmb.

  13. [The neuronal responses of the caudate nucleus in the cat to sensory stimulation].

    PubMed

    Rodionova, E I; Pigarev, I N

    1990-01-01

    Responses of caudate neurons to a large variety of visual and other sensory stimuli were studied in alert cats. Sharp drops in the spontaneous activity of the unknown origin and differences in the activity level were revealed in adjacent parts of the caudate nucleus. The following types of neurons were recorded: neurons responding to visual stimulation; neurons responding to somatic stimulation; neurons responding to combined visual-somatic stimulation. The best response was observed to moving visual stimuli that attracted the animal's attention, alimentary objects specifically. The caudate nucleus of each hemisphere contained representation of both contra- and ipsilateral half of the animal body. Cell responses to sensory stimuli from the caudate nucleus have been compared with those from some cortical areas.

  14. Paradoxical augmented relapse in alcohol-dependent rats during deep-brain stimulation in the nucleus accumbens

    PubMed Central

    Hadar, R; Vengeliene, V; Barroeta Hlusicke, E; Canals, S; Noori, H R; Wieske, F; Rummel, J; Harnack, D; Heinz, A; Spanagel, R; Winter, C

    2016-01-01

    Case reports indicate that deep-brain stimulation in the nucleus accumbens may be beneficial to alcohol-dependent patients. The lack of clinical trials and our limited knowledge of deep-brain stimulation call for translational experiments to validate these reports. To mimic the human situation, we used a chronic-continuous brain-stimulation paradigm targeting the nucleus accumbens and other brain sites in alcohol-dependent rats. To determine the network effects of deep-brain stimulation in alcohol-dependent rats, we combined electrical stimulation of the nucleus accumbens with functional magnetic resonance imaging (fMRI), and studied neurotransmitter levels in nucleus accumbens-stimulated versus sham-stimulated rats. Surprisingly, we report here that electrical stimulation of the nucleus accumbens led to augmented relapse behavior in alcohol-dependent rats. Our associated fMRI data revealed some activated areas, including the medial prefrontal cortex and caudate putamen. However, when we applied stimulation to these areas, relapse behavior was not affected, confirming that the nucleus accumbens is critical for generating this paradoxical effect. Neurochemical analysis of the major activated brain sites of the network revealed that the effect of stimulation may depend on accumbal dopamine levels. This was supported by the finding that brain-stimulation-treated rats exhibited augmented alcohol-induced dopamine release compared with sham-stimulated animals. Our data suggest that deep-brain stimulation in the nucleus accumbens enhances alcohol-liking probably via augmented dopamine release and can thereby promote relapse. PMID:27327255

  15. Paradoxical augmented relapse in alcohol-dependent rats during deep-brain stimulation in the nucleus accumbens.

    PubMed

    Hadar, R; Vengeliene, V; Barroeta Hlusicke, E; Canals, S; Noori, H R; Wieske, F; Rummel, J; Harnack, D; Heinz, A; Spanagel, R; Winter, C

    2016-06-21

    Case reports indicate that deep-brain stimulation in the nucleus accumbens may be beneficial to alcohol-dependent patients. The lack of clinical trials and our limited knowledge of deep-brain stimulation call for translational experiments to validate these reports. To mimic the human situation, we used a chronic-continuous brain-stimulation paradigm targeting the nucleus accumbens and other brain sites in alcohol-dependent rats. To determine the network effects of deep-brain stimulation in alcohol-dependent rats, we combined electrical stimulation of the nucleus accumbens with functional magnetic resonance imaging (fMRI), and studied neurotransmitter levels in nucleus accumbens-stimulated versus sham-stimulated rats. Surprisingly, we report here that electrical stimulation of the nucleus accumbens led to augmented relapse behavior in alcohol-dependent rats. Our associated fMRI data revealed some activated areas, including the medial prefrontal cortex and caudate putamen. However, when we applied stimulation to these areas, relapse behavior was not affected, confirming that the nucleus accumbens is critical for generating this paradoxical effect. Neurochemical analysis of the major activated brain sites of the network revealed that the effect of stimulation may depend on accumbal dopamine levels. This was supported by the finding that brain-stimulation-treated rats exhibited augmented alcohol-induced dopamine release compared with sham-stimulated animals. Our data suggest that deep-brain stimulation in the nucleus accumbens enhances alcohol-liking probably via augmented dopamine release and can thereby promote relapse.

  16. Responses evoked in the cerebellar cortex by stimulation of the caudate nucleus in the cat

    PubMed Central

    Fox, Mary; Williams, T. D.

    1968-01-01

    1. Responses evoked in the cerebellar cortex following stimulation of caudate nucleus are described. 2. The evoked responses recorded from the surface of the cerebellar cortex were found to be of two types, one with a short (4-6 msec) latency and one with a longer (12-17 msec) latency. 3. The short latency response was maximal in the lobulus simplex, the longer latency response was maximal in paramedian lobule. 4. Following lesions in the inferior olive the longer latency response was absent. 5. Recordings from within the cerebellar cortex showed that the short latency response was uniformly distributed throughout the grey matter, the longer latency response was maximal in the region of the Purkinje cell bodies. 6. It was concluded that the short latency response was due to activation via the mossy fibres and the longer latency response to activation via the climbing fibres. 7. It was found that responses could be evoked in the cerebellum following stimulation of only the latero-ventral part of the caudate nucleus; stimulation of the rest of the nucleus caused no response in the cerebellum. This division of the caudate nucleus into two parts is similar to the subdivision of the caudate nucleus made by other workers using different criteria. PMID:5698279

  17. 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…

  18. Auditory Responses to Electric and Infrared Neural Stimulation of the Rat Cochlear Nucleus

    PubMed Central

    Verma, Rohit; Guex, Amelie A.; Hancock, Kenneth E.; Durakovic, Nedim; McKay, Colette M.; Slama, Michaël C. C.; Brown, M. Christian; Lee, Daniel J.

    2014-01-01

    In an effort to improve the auditory brainstem implant, a prosthesis in which user outcomes are modest, we applied electric and infrared neural stimulation (INS) to the cochlear nucleus in a rat animal model. Electric stimulation evoked regions of neural activation in the inferior colliculus and short-latency, multipeaked auditory brainstem responses (ABRs). Pulsed INS, delivered to the surface of the cochlear nucleus via an optical fiber, evoked broad neural activation in the inferior colliculus. Strongest responses were recorded when the fiber was placed at lateral positions on the cochlear nucleus, close to the temporal bone. INS-evoked ABRs were multipeaked but longer in latency than those for electric stimulation; they resembled the responses to acoustic stimulation. After deafening, responses to electric stimulation persisted, whereas those to INS disappeared, consistent with a reported “optophonic” effect, a laser-induced acoustic artifact. Thus, for deaf individuals who use the auditory brainstem implant, INS alone did not appear promising as a new approach. PMID:24508368

  19. 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

  20. 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.

  1. Stimulation of the nucleus accumbens as behavioral reward in awake behaving monkeys.

    PubMed

    Bichot, Narcisse P; Heard, Matthew T; Desimone, Robert

    2011-08-15

    It has been known that monkeys will repeatedly press a bar for electrical stimulation in several different brain structures. We explored the possibility of using electrical stimulation in one such structure, the nucleus accumbens, as a substitute for liquid reward in animals performing a complex task, namely visual search. The animals had full access to water in the cage at all times on days when stimulation was used to motivate them. Electrical stimulation was delivered bilaterally at mirror locations in and around the accumbens, and the animals' motivation to work for electrical stimulation was quantified by the number of trials they performed correctly per unit of time. Acute mapping revealed that stimulation over a large area successfully supported behavioral performance during the task. Performance improved with increasing currents until it reached an asymptotic, theoretically maximal level. Moreover, stimulation with chronically implanted electrodes showed that an animal's motivation to work for electrical stimulation was at least equivalent to, and often better than, when it worked for liquid reward while on water control. These results suggest that electrical stimulation in the accumbens is a viable method of reward in complex tasks. Because this method of reward does not necessitate control over water or food intake, it may offer an alternative to the traditional liquid or food rewards in monkeys, depending on the goals and requirements of the particular research project.

  2. Freezing and hypokinesia of gait induced by stimulation of the subthalamic region.

    PubMed

    Tommasi, Giorgio; Lopiano, Leonardo; Zibetti, Maurizio; Cinquepalmi, Annina; Fronda, Chiara; Bergamasco, Bruno; Ducati, Alessandro; Lanotte, Michele

    2007-07-15

    We report a case of a Parkinson's disease patient treated by bilateral deep brain stimulation of the subthalamic nucleus, who developed freezing and hypokinesia of gait induced by stimulation through a left-side misplaced electrode which was more antero-medial than the planned trajectory. Subsequently, correct repositioning of the left electrode afforded complete relief of gait disturbances. Freezing and hypokinesia of gait may be side effects of deep brain stimulation of the subthalamic region due to current spreading antero-medially to the subthalamic nucleus. These side effects are not subject to habituation and restrict any increase in stimulation parameters. We hypothesize that pallidal projections to the pedunculopontine nucleus could be responsible for these gait disturbances in our patient.

  3. 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.

  4. 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.

  5. Cognitive and behavioural effects of chronic stimulation of the subthalamic nucleus in patients with Parkinson's disease

    PubMed Central

    Daniele, A; Albanese, A; Contarino, M; Zinzi, P; Barbier, A; Gasparini, F; Romito, L; Bentivoglio, A; Scerrati, M

    2003-01-01

    Objective: To investigate cognitive and behavioural effects of bilateral lead implants for high frequency stimulation (HFS) of the subthalamic nucleus in patients with Parkinson's disease; and to discriminate between HFS and the effects of surgical intervention on cognitive function by carrying out postoperative cognitive assessments with the stimulators turned on or off. Methods: Motor, cognitive, behavioural, and functional assessments were undertaken in 20 patients with Parkinson's disease before implantation and then at three, six, and 12 months afterwards. Nine patients were also examined 18 months after surgery. Postoperative cognitive assessments were carried out with stimulators turned off at three and 18 months, and turned on at six and 12 months. Results: Cognitive assessment showed a significant postoperative decline in performance on tasks of letter verbal fluency (across all postoperative assessments, but more pronounced at three months) and episodic verbal memory (only at three months, with stimulators off). At three, six, and 12 months after surgery, there was a significant improvement in the mini-mental state examination and in a task of executive function (modified Wisconsin card sorting test). On all postoperative assessments, there was an improvement in parkinsonian motor symptoms, quality of life, and activities of daily living while off antiparkinsonian drugs. A significant postoperative decrease in depressive and anxiety symptoms was observed across all assessments. Similar results were seen in the subgroup of nine patients with an 18 month follow up. Following implantation, three patients developed transient manic symptoms and one showed persistent psychic akinesia. Conclusions: Bilateral HFS of the subthalamic nucleus is a relatively safe procedure with respect to long term cognitive and behavioural morbidity, although individual variability in postoperative cognitive and behavioural outcome invites caution. Stimulation of the subthalamic

  6. Hypothalamic paraventricular nucleus stimulation reduces intestinal injury in rats with ulcerative colitis

    PubMed Central

    Deng, Quan-Jun; Deng, Ding-Jing; Che, Jin; Zhao, Hai-Rong; Yu, Jun-Jie; Lu, Yong-Yu

    2016-01-01

    AIM: To investigate the effect and mechanism of stimulation of the hypothalamic paraventricular nucleus with glutamate acid in rats with ulcerative colitis (UC). METHODS: The rats were anesthetized with 10% chloral hydrate via abdominal injection and treated with an equal volume of TNBS + 50% ethanol enema, injected into the upper section of the anus with the tail facing up. Colonic damage scores were calculated after injecting a certain dose of glutamic acid into the paraventricular nucleus (PVN), and the effect of the nucleus tractus solitarius (NTS) and vagus nerve in alleviating UC injury through chemical stimulation of the PVN was observed in rats. Expression changes of C-myc, Apaf-1, caspase-3, interleukin (IL)-6, and IL-17 during the protection against UC injury through chemical stimulation of the PVN in rats were detected by Western blot. Malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in colon tissues of rats were measured by colorimetric methods. RESULTS: Chemical stimulation of the PVN significantly reduced UC in rats in a dose-dependent manner. The protective effects of the chemical stimulation of the PVN on rats with UC were eliminated after chemical damage to the PVN. After glutamate receptor antagonist kynurenic acid was injected into the PVN, the protective effects of the chemical stimulation of the PVN were eliminated in rats with UC. After AVP-Vl receptor antagonist ([Deamino-penl, val4, D-Arg8]-vasopressin) was injected into NTS or bilateral chemical damage to NTS, the protective effect of the chemical stimulation of PVN on UC was also eliminated. After chemical stimulation of the PVN, SOD activity increased, MDA content decreased, C-myc protein expression significantly increased, caspase-3 and Apaf-1 protein expression significantly decreased, and IL-6 and IL-17 expression decreased in colon tissues in rats with UC. CONCLUSION: Chemical stimulation of the hypothalamic PVN provides a protective effect against UC injury in

  7. Plasma corticosterone responses to lesions and stimulations of the limbic thalami nuclei, medial mammillary nucleus and cingulate cortex.

    PubMed

    Suárez, M; Perassi, N I

    1988-06-01

    The influence of extrahypothalamic limbic structures on adrenocortical activity was investigated in female adult rats. Bilateral lesions on the anteromedial thalami nucleus (AMTN), anteroventral thalami nucleus (AVTN) or the posterior cingulate cortex (PCC) all elicited a significant decrease on plasma corticosterone, while their electrochemical stimulation produced a significant increase with respect to animals with sham lesions or sham stimulation. In contrast, after lesions of the dorsomedial thalami nucleus (DMTN), medial mammillary nucleus (pars lateralis) (MMN) or retrosplenial cortex (RC), values of plasma corticosterone were significantly higher than those found in controls, whereas following their stimulation plasma corticosterone levels were lower than in controls. Bilateral lesions or stimulations of anterior cingulate cortex had no significant effect upon corticosterone secretion. These findings may be interpreted as indicative of the existence of excitatory (AMTN, AVTN, and PCC) and inhibitory (DMTN, MMN and RC) central nervous structures for the control of corticoadrenal secretion besides those already known.

  8. Weight gain following subthalamic nucleus deep brain stimulation: a PET study.

    PubMed

    Sauleau, Paul; Le Jeune, Florence; Drapier, Sophie; Houvenaghel, Jean-François; Dondaine, Thibaut; Haegelen, Claire; Lalys, Florent; Robert, Gabriel; Drapier, Dominique; Vérin, Marc

    2014-12-01

    Several hypotheses have been put forward to explain weight gain after deep brain stimulation (DBS), but none provides a fully satisfactory account of this adverse effect. We analyzed the correlation between changes in brain metabolism (using positron emission tomography [PET] imaging) and weight gain after bilateral subthalamic nucleus DBS in patients with Parkinson's disease. Body mass index was calculated and brain activity prospectively measured using 2-deoxy-2[18F]fluoro-D-glucose 3 months before and 4 months after the start of subthalamic nucleus deep brain stimulation in 23 patients with Parkinson's disease. Motor complications (United Parkinson's Disease Rating Scale [UPDRS]-IV scores) and dopaminergic medication were included in the analysis to control for their possible influence on brain metabolism. Mean ± standard deviation (SD) body mass index increased significantly by 0.8 ± 1.5 kg/m(2) (P = 0.03). Correlations were found between weight gain and changes in brain metabolism in limbic and associative areas, including the orbitofrontal cortex (Brodmann areas [BAs] 10 and 11), lateral and medial parts of the temporal lobe (BAs 20, 21, 22,39 and 42), anterior cingulate cortex (BA 32), and retrosplenial cortex (BA 30). However, we found no correlation between weight gain and metabolic changes in sensorimotor areas. These findings suggest that changes in associative and limbic processes contribute to weight gain after subthalamic nucleus DBS in Parkinson's disease.

  9. Deep brain stimulation of the nucleus accumbens shell attenuates cocaine reinstatement through local and antidromic activation.

    PubMed

    Vassoler, Fair M; White, Samantha L; Hopkins, Thomas J; Guercio, Leonardo A; Espallergues, Julie; Berton, Olivier; Schmidt, Heath D; Pierce, R Christopher

    2013-09-04

    Accumbal deep brain stimulation (DBS) is a promising therapeutic modality for the treatment of addiction. Here, we demonstrate that DBS in the nucleus accumbens shell, but not the core, attenuates cocaine priming-induced reinstatement of drug seeking, an animal model of relapse, in male Sprague Dawley rats. Next, we compared DBS of the shell with pharmacological inactivation. Results indicated that inactivation using reagents that influenced (lidocaine) or spared (GABA receptor agonists) fibers of passage blocked cocaine reinstatement when administered into the core but not the shell. It seems unlikely, therefore, that intrashell DBS influences cocaine reinstatement by inactivating this nucleus or the fibers coursing through it. To examine potential circuit-wide changes, c-Fos immunohistochemistry was used to examine neuronal activation following DBS of the nucleus accumbens shell. Intrashell DBS increased c-Fos induction at the site of stimulation as well as in the infralimbic cortex, but had no effect on the dorsal striatum, prelimbic cortex, or ventral pallidum. Recent evidence indicates that accumbens DBS antidromically stimulates axon terminals, which ultimately activates GABAergic interneurons in cortical areas that send afferents to the shell. To test this hypothesis, GABA receptor agonists (baclofen/muscimol) were microinjected into the anterior cingulate, and prelimbic or infralimbic cortices before cocaine reinstatement. Pharmacological inactivation of all three medial prefrontal cortical subregions attenuated the reinstatement of cocaine seeking. These results are consistent with DBS of the accumbens shell attenuating cocaine reinstatement via local activation and/or activation of GABAergic interneurons in the medial prefrontal cortex via antidromic stimulation of cortico-accumbal afferents.

  10. Optogenetic stimulation of the cochlear nucleus using channelrhodopsin-2 evokes activity in the central auditory pathway

    PubMed Central

    Darrow, Keith N.; Slama, Michaël C. C.; Owoc, Maryanna; Kozin, Elliott; Hancock, Kenneth; Kempfle, Judith; Edge, Albert; Lacour, Stephanie; Boyden, Edward; Polley, Daniel; Brown, M. Christian; Lee, Daniel J.

    2016-01-01

    Optogenetics has become an important research tool and is being considered as the basis for several neural prostheses. However, few studies have applied optogenetics to the auditory brainstem. This study explored whether optical activation of the cochlear nucleus (CN) elicited responses in neurons in higher centers of the auditory pathway, and it measured the evoked response to optical stimulation. Viral-mediated gene transfer was used to express channelrhodopsin-2 (ChR2) in the mouse CN. Blue light was delivered via an optical fiber placed near the surface of the infected CN and recordings were made in higher-level centers. Optical stimulation evoked excitatory multiunit spiking activity throughout the tonotopic axis of central nucleus of the inferior colliculus (IC) and the auditory cortex (Actx). The pattern and magnitude of IC activity elicited by optical stimulation was comparable to that obtained with a 50 dB SPL acoustic click stimulus. This broad pattern of activity was consistent with histological confirmation of GFP label of cell bodies and axons throughout the CN. Increasing pulse rates up to 320 Hz did not significantly affect threshold or bandwidth of the IC responses, but rates higher than 50 Hz resulted in desynchronized activity. Optical stimulation also evoked an auditory brainstem response, which had a simpler waveform than the response to acoustic stimulation. Control cases showed no responses to optical stimulation. These data suggest that optogenetic control of central auditory neurons is feasible, but opsins with faster channel kinetics will be necessary to convey information in rates typical of many auditory signals. PMID:25481416

  11. 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.

  12. 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

  13. Observational learning in mice can be prevented by medial prefrontal cortex stimulation and enhanced by nucleus accumbens stimulation.

    PubMed

    Jurado-Parras, M Teresa; Gruart, Agnès; Delgado-García, José M

    2012-02-21

    The neural structures involved in ongoing appetitive and/or observational learning behaviors remain largely unknown. Operant conditioning and observational learning were evoked and recorded in a modified Skinner box provided with an on-line video recording system. Mice improved their acquisition of a simple operant conditioning task by observational learning. Electrical stimulation of the observer's medial prefrontal cortex (mPFC) at a key moment of the demonstration (when the demonstrator presses a lever in order to obtain a reward) cancels out the benefits of observation. In contrast, electrical stimulation of the observer's nucleus accumbens (NAc) enhances observational learning. Ongoing cognitive processes in the demonstrator could also be driven by electrical stimulation of these two structures, preventing the proper execution of the ongoing instrumental task (mPFC) or stopping pellet intake (NAc). Long-term potentiation (LTP) evoked in these two cortical structures did not prevent the acquisition or retrieval process--namely, mPFC and/or NAc stimulation only prevented, or modified, the ongoing behavioral process. The dorsal hippocampus was not involved in either of these two behavioral processes. Thus, both ongoing observational learning and performance of an instrumental task require the active contribution of the mPFC and/or the NAc.

  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.

  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. Medial auditory thalamus is necessary for acquisition and retention of eyeblink conditioning to cochlear nucleus stimulation.

    PubMed

    Halverson, Hunter E; Poremba, Amy; Freeman, John H

    2015-05-01

    Associative learning tasks commonly involve an auditory stimulus, which must be projected through the auditory system to the sites of memory induction for learning to occur. The cochlear nucleus (CN) projection to the pontine nuclei has been posited as the necessary auditory pathway for cerebellar learning, including eyeblink conditioning. However, the medial auditory thalamic nuclei (MATN), consisting of the medial division of the medial geniculate, suprageniculate, and posterior interlaminar nucleus have also been implicated as a critical auditory relay to the pontine nuclei for cerebellum-dependent motor learning. The MATN also conveys auditory information to the amygdala necessary for avoidance and fear conditioning. The current study used CN stimulation to increase activity in the pontine nuclei, relative to a tone stimulus, and possibly provide sufficient input to the cerebellum for acquisition or retention of eyeblink conditioning during MATN inactivation. Primary and secondary effects of CN stimulation and MATN inactivation were examined using 2-deoxy-glucose autoradiography. Stimulation of CN increased activity in the pontine nuclei, however, this increase was not sufficient for cerebellar learning during MATN inactivation. Results of the current experiment provide additional evidence indicating the MATN may be the critical auditory relay for many associative learning tasks.

  17. Deep brain stimulation of the nucleus accumbens for the treatment of addiction.

    PubMed

    Müller, Ulf J; Voges, Jürgen; Steiner, Johann; Galazky, Imke; Heinze, Hans-Jochen; Möller, Michaela; Pisapia, Jared; Halpern, Casey; Caplan, Arthur; Bogerts, Bernhard; Kuhn, Jens

    2013-04-01

    Despite novel medications and other therapeutic strategies, addiction to psychotropic substances remains one of the most serious public health problems worldwide. In this review, beginning with an introduction of deep brain stimulation (DBS), we highlight the importance of the nucleus accumbens (NAc) in the context of the reward circuitry and addictive behavior. We will provide a short historic overview of other neurosurgical approaches to treat addiction and describe the experimental and preclinical data on DBS in addiction. Finally, we call attention to key ethical issues related to using DBS to treat addiction that are important for future research and the design of clinical trials.

  18. Improved sequence learning with subthalamic nucleus deep brain stimulation: evidence for treatment-specific network modulation.

    PubMed

    Mure, Hideo; Tang, Chris C; Argyelan, Miklos; Ghilardi, Maria-Felice; Kaplitt, Michael G; Dhawan, Vijay; Eidelberg, David

    2012-02-22

    We used a network approach to study the effects of anti-parkinsonian treatment on motor sequence learning in humans. Eight Parkinson's disease (PD) patients with bilateral subthalamic nucleus (STN) deep brain stimulation underwent H(2)(15)O positron emission tomography (PET) imaging to measure regional cerebral blood flow (rCBF) while they performed kinematically matched sequence learning and movement tasks at baseline and during stimulation. Network analysis revealed a significant learning-related spatial covariance pattern characterized by consistent increases in subject expression during stimulation (p = 0.008, permutation test). The network was associated with increased activity in the lateral cerebellum, dorsal premotor cortex, and parahippocampal gyrus, with covarying reductions in the supplementary motor area (SMA) and orbitofrontal cortex. Stimulation-mediated increases in network activity correlated with concurrent improvement in learning performance (p < 0.02). To determine whether similar changes occurred during dopaminergic pharmacotherapy, we studied the subjects during an intravenous levodopa infusion titrated to achieve a motor response equivalent to stimulation. Despite consistent improvement in motor ratings during infusion, levodopa did not alter learning performance or network activity. Analysis of learning-related rCBF in network regions revealed improvement in baseline abnormalities with STN stimulation but not levodopa. These effects were most pronounced in the SMA. In this region, a consistent rCBF response to stimulation was observed across subjects and trials (p = 0.01), although the levodopa response was not significant. These findings link the cognitive treatment response in PD to changes in the activity of a specific cerebello-premotor cortical network. Selective modulation of overactive SMA-STN projection pathways may underlie the improvement in learning found with stimulation.

  19. Effects of Subthalamic Nucleus Stimulation on Emotional Prosody Comprehension in Parkinson's Disease

    PubMed Central

    Kreifelts, Benjamin; Krüger, Rejko; Wächter, Tobias

    2011-01-01

    Background Although impaired decoding of emotional prosody has frequently been associated with Parkinson's disease (PD), to date only few reports have sought to explore the effect of Parkinson's treatment on disturbances of prosody decoding. In particular, little is known about how surgical treatment approaches such as high frequency deep brain stimulation (DBS) affect emotional speech perception in patients with PD. Accordingly, the objective of this study was to evaluate the effect of subthalamic nucleus (STN) stimulation on prosody processing. Methodology/Principal Findings To this end the performance of 13 PD patients on three tasks requiring the decoding of emotional speech was assessed and subsequently compared to the performance of healthy control individuals. To delineate the effect of STN-DBS, all patients were tested with stimulators turned on as well as with stimulators turned off. Results revealed that irrespective of whether assessments were made “on” or “off” stimulation, patients' performance was less accurate as compared to healthy control participants on all tasks employed in this study. However, while accuracy appeared to be unaffected by stimulator status, a facilitation of reactions specific to highly conflicting emotional stimulus material (i.e. stimulus material presenting contradicting emotional messages on a verbal and non-verbal prosodic level) was observed during “on” stimulation assessments. Conclusion In sum, presented results suggest that the processing of emotional speech is indeed modulated by STN-DBS. Observed alterations might, on the one hand, reflect a more efficient processing of highly conflicting stimulus material following DBS. However, on the other hand, given the lack of an improvement in accuracy, increased impulsivity associated with STN stimulation needs to be taken into consideration. PMID:21552518

  20. Functional Magnetic Resonance Imaging of Electrical and Optogenetic Deep Brain Stimulation at the Rat Nucleus Accumbens

    PubMed Central

    Albaugh, Daniel L.; Salzwedel, Andrew; Van Den Berge, Nathalie; Gao, Wei; Stuber, Garret D.; Shih, Yen-Yu Ian

    2016-01-01

    Deep brain stimulation of the nucleus accumbens (NAc-DBS) is an emerging therapy for diverse, refractory neuropsychiatric diseases. Although DBS therapy is broadly hypothesized to work through large-scale neural modulation, little is known regarding the neural circuits and networks affected by NAc-DBS. Using a healthy, sedated rat model of NAc-DBS, we employed both evoked- and functional connectivity (fc) MRI to examine the functional circuit and network changes achieved by electrical NAc stimulation. Optogenetic-fMRI experiments were also undertaken to evaluate the circuit modulation profile achieved by selective stimulation of NAc neurons. NAc-DBS directly modulated neural activity within prefrontal cortex and a large number of subcortical limbic areas (e.g., amygdala, lateral hypothalamus), and influenced functional connectivity among sensorimotor, executive, and limbic networks. The pattern and extent of circuit modulation measured by evoked-fMRI was relatively insensitive to DBS frequency. Optogenetic stimulation of NAc cell bodies induced a positive fMRI signal in the NAc, but no other detectable downstream responses, indicating that therapeutic NAc-DBS might exert its effect through antidromic stimulation. Our study provides a comprehensive mapping of circuit and network-level neuromodulation by NAc-DBS, which should facilitate our developing understanding of its therapeutic mechanisms of action. PMID:27601003

  1. Electrical stimulation of the parabrachial nucleus induces reanimation from isoflurane general anesthesia.

    PubMed

    Muindi, Fanuel; Kenny, Jonathan D; Taylor, Norman E; Solt, Ken; Wilson, Matthew A; Brown, Emery N; Van Dort, Christa J

    2016-06-01

    Clinically, emergence from general anesthesia is viewed as a passive process where anesthetics are discontinued at the end of surgery and anesthesiologists wait for the drugs to wear off. The mechanisms involved in emergence are not well understood and there are currently no drugs that can actively reverse the state of general anesthesia. An emerging hypothesis states that brain regions that control arousal become active during emergence and are a key part of the return to wakefulness. In this study, we tested the hypothesis that electrical activation of the glutamatergic parabrachial nucleus (PBN) in the brainstem is sufficient to induce reanimation (active emergence) during continuous isoflurane general anesthesia. Using c-Fos immunohistochemistry as a marker of neural activity, we first show a selective increase in active neurons in the PBN during passive emergence from isoflurane anesthesia. We then electrically stimulated the PBN to assess whether it is sufficient to induce reanimation from isoflurane general anesthesia. Stimulation induced behavioral arousal and restoration of the righting reflex during continuous isoflurane general anesthesia. In contrast, stimulation of the nearby central inferior colliculus (CIC) did not restore the righting reflex. Spectral analysis of the electroencephalogram (EEG) revealed that stimulation produced a significant decrease in EEG delta power during PBN stimulation. The results are consistent with the hypothesis that the PBN provides critical arousal input during emergence from isoflurane anesthesia.

  2. Bilateral deep brain stimulation of the nucleus accumbens for comorbid obsessive compulsive disorder and Tourette's syndrome.

    PubMed

    Sachdev, Perminder Singh; Cannon, Elisabeth; Coyne, Terry J; Silburn, Peter

    2012-09-12

    We present the case of a 32-year-old Caucasian woman with severe treatment-refractory obsessive compulsive disorder (OCD) and Tourette's syndrome. Both conditions were present prior to age 5 and impacted significantly on the patient's functioning. Multiple trials of evidence-based pharmacological and behavioural therapies had not achieved remission of symptoms. Bilateral deep brain stimulation of the nucleus accumbens was undertaken to treat both illnesses but with a particular focus on OCD, as the patient identified this as the more debilitating of the two disorders. Following surgery there was an immediate improvement in OCD and tic severity. At follow-up 8 months later, there was a 90% improvement in OCD symptoms and a 57% improvement in tic severity. No intraoperative or postoperative complications or adverse events occurred and there were no undesired effects of stimulation.

  3. A case of musical preference for Johnny Cash following deep brain stimulation of the nucleus accumbens

    PubMed Central

    Mantione, Mariska; Figee, Martijn; Denys, Damiaan

    2014-01-01

    Music is among all cultures an important part of the live of most people. Music has psychological benefits and may generate strong emotional and physiological responses. Recently, neuroscientists have discovered that music influences the reward circuit of the nucleus accumbens (NAcc), even when no explicit reward is present. In this clinical case study, we describe a 60-year old patient who developed a sudden and distinct musical preference for Johnny Cash following deep brain stimulation (DBS) targeted at the NAcc. This case report substantiates the assumption that the NAcc is involved in musical preference, based on the observation of direct stimulation of the accumbens with DBS. It also shows that accumbens DBS can change musical preference without habituation of its rewarding properties. PMID:24834035

  4. Effects of Nucleus Basalis Magnocellularis Stimulation on a Socially Transmitted Food Preference and c-Fos Expression

    ERIC Educational Resources Information Center

    Boix-Trelis, Nuria; Vale-Martinez, Anna; Guillazo-Blanch, Gemma; Costa-Miserachs, David; Marti-Nicolovius, Margarita

    2006-01-01

    Experiment 1 examined the effects of electrical stimulation of nucleus basalis magnocellularis (NBM) on a relational odor-association task--the social transmission of food preference (STFP). Rats were stimulated unilaterally in the NBM for 20 min (100 [mu]A, 1 Hz) immediately before the social training. They were tested on their ability to…

  5. GABA-mediated oxytocinergic inhibition in dorsal horn neurons by hypothalamic paraventricular nucleus stimulation.

    PubMed

    Rojas-Piloni, Gerardo; López-Hidalgo, Mónica; Martínez-Lorenzana, Guadalupe; Rodríguez-Jiménez, Javier; Condés-Lara, Miguel

    2007-03-16

    In anaesthetized rats, we tested whether the unit activity of dorsal horn neurons that receive nociceptive input is modulated by electrical stimulation of the hypothalamic paraventricular nucleus (PVN). An electrophysiological mapping of dorsal horn neurons at L3-L4 let us choose cells responding to a receptive field located in the toes region of the left hindpaw. Dorsal horn neurons were classified according to their response properties to peripheral stimulation. Wide Dynamic Range (WDR) cells responding to electrical stimulation of the peripheral receptive field and presenting synaptic input of Adelta, Abeta, and C-fibers were studied. Suspected interneurons that are typically silent and lack peripheral receptive field responses were also analyzed. PVN electrical stimulation inhibits Adelta (-55.0+/-10.2%), C-fiber (-73.1+/-6.7%), and post-discharge (-75.0+/-8.9%) peripheral activation in WDR cells, and silent interneurons were activated. So, this last type of interneuron was called a PVN-ON cell. In WDR cells, the inhibition of peripheral responses caused by PVN stimulation was blocked by intrathecal administration of a specific oxytocin antagonist or bicuculline. However, PVN-ON cell activation was blocked by the same specific oxytocin antagonist, but not by bicuculline. Our results suggest that PVN stimulation inhibits nociceptive peripheral-evoked responses in WDR neurons by a descending oxytocinergic pathway mediated by GABAergic PVN-ON cells. We discuss our observation that the PVN electrical stimulation selectively inhibits Adelta and C-fiber activity without affecting Abeta fibers. We conclude that Adelta and C-fibers receive a presynaptic inhibition mediated by GABA.

  6. Effects of Anterior Thalamic Nucleus Deep Brain Stimulation in Chronic Epileptic Rats

    PubMed Central

    Amorim, Beatriz; Cavarsan, Clarissa; Miranda, Maisa Ferreira; Aarão, Mayra C.; Madureira, Ana Paula; Rodrigues, Antônio M.; Nobrega, José N.; Mello, Luiz E.; Hamani, Clement

    2014-01-01

    Deep brain stimulation (DBS) has been investigated for the treatment of epilepsy. In rodents, an increase in the latency for the development of seizures and status epilepticus (SE) has been reported in different animal models but the consequences of delivering stimulation to chronic epileptic animals have not been extensively addressed. We study the effects of anterior thalamic nucleus (AN) stimulation at different current intensities in rats rendered epileptic following pilocarpine (Pilo) administration. Four months after Pilo-induced SE, chronic epileptic rats were bilaterally implanted with AN electrodes or had sham-surgery. Stimulation was delivered for 6 h/day, 5 days/week at 130 Hz, 90 µsec. and either 100 µA or 500 µA. The frequency of spontaneous recurrent seizures in animals receiving stimulation was compared to that recorded in the preoperative period and in rats given sham treatment. To investigate the effects of DBS on hippocampal excitability, brain slices from animals receiving AN DBS or sham surgery were studied with electrophysiology. We found that rats treated with AN DBS at 100 µA had a 52% non-significant reduction in the frequency of seizures as compared to sham-treated controls and 61% less seizures than at baseline. Animals given DBS at 500 µA had 5.1 times more seizures than controls and a 2.8 fold increase in seizure rate as compared to preoperative values. In non-stimulated controls, the average frequency of seizures before and after surgery remained unaltered. In vitro recordings have shown that slices from animals previously given DBS at 100 µA had a longer latency for the development of epileptiform activity, shorter and smaller DC shifts, and a smaller spike amplitude compared to non-stimulated controls. In contrast, a higher spike amplitude was recorded in slices from animals given AN DBS at 500 µA. PMID:24892420

  7. 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

  8. Subthalamic nucleus deep brain stimulation affects distractor interference in auditory working memory.

    PubMed

    Camalier, Corrie R; Wang, Alice Y; McIntosh, Lindsey G; Park, Sohee; Neimat, Joseph S

    2017-03-01

    Computational and theoretical accounts hypothesize the basal ganglia play a supramodal "gating" role in the maintenance of working memory representations, especially in preservation from distractor interference. There are currently two major limitations to this account. The first is that supporting experiments have focused exclusively on the visuospatial domain, leaving questions as to whether such "gating" is domain-specific. The second is that current evidence relies on correlational measures, as it is extremely difficult to causally and reversibly manipulate subcortical structures in humans. To address these shortcomings, we examined non-spatial, auditory working memory performance during reversible modulation of the basal ganglia, an approach afforded by deep brain stimulation of the subthalamic nucleus. We found that subthalamic nucleus stimulation impaired auditory working memory performance, specifically in the group tested in the presence of distractors, even though the distractors were predictable and completely irrelevant to the encoding of the task stimuli. This study provides key causal evidence that the basal ganglia act as a supramodal filter in working memory processes, further adding to our growing understanding of their role in cognition.

  9. Cardiovascular and phrenic nerve responses to stimulation of the amygdala central nucleus in the anaesthetized rabbit.

    PubMed Central

    Cox, G E; Jordan, D; Paton, J F; Spyer, K M; Wood, L M

    1987-01-01

    1. The cardiovascular responses to electrical stimulation of the central nucleus of the amygdala (c.n.) have been studied in chloralose-anaesthetized rabbits. A pattern of response involving bradycardia, hypotension and hind-limb vasodilatation, accompanied by an increase in the rate of phrenic nerve discharge, was evoked only in response to stimulation within the medial portion of the c.n. 2. The cardiovascular responses were not secondary to the changes in respiratory activity since they were unaffected by altering central respiratory drive by either hypo- or hyperventilation of the animal. 3. The bradycardia was attenuated by the administration of atropine sulphate and abolished by the subsequent administration of propranolol, which when given alone attenuated the bradycardia. Atropine or propranolol given alone also attenuated the hypotension evoked by medial c.n. stimulation but the concurrent hind-limb vasodilatation was unaffected. 4. Atenolol, which unlike propranolol does not cross the blood-brain barrier, had little effect on the bradycardia in response to medial c.n. stimulation, but the subsequent administration of atropine abolished it. The hypotension in response to medial c.n. stimulation was also unaffected by atenolol. 5. The vasodilatation in response to medial c.n. stimulation was abolished by administration of guanethidine even after restoration of hind-limb perfusion pressure to control values by the infusion of angiotensin II into the hind-limb perfusion circuit. 6. Electrical stimulation of areas within 0.5 mm of the medial c.n. also resulted in bradycardia but then it was accompanied by hypertension and hind-limb vasoconstriction. Stimulation of areas 1.0 mm distant to the medial c.n. resulted in small and inconsistent cardiovascular responses. 7. These results show that hind-limb vasodilatation, mediated by withdrawal of sympathetic tone, occurs in response to stimulation within the medial c.n. of the rabbit and is in part responsible for

  10. Effect of stimulation in the ventral intermediate nucleus of the thalamus on limb control in Parkinson's disease: a case study.

    PubMed

    Pfann, K D; Penn, R D; Shannon, K M; Shapiro, M B; Corcos, D M

    1996-05-01

    This study focuses on upper extremity strength and movement control in a patient with Parkinson's disease who had stimulating electrodes surgically implanted in the ventral intermediate nucleus (VIM) of the left thalamus. We examined torque generation and control of movement distance in single degree-of-freedom elbow movements under three different stimulation conditions: (a) no stimulation, (b) high stimulation, in which tremor was minimized but there was also tingling and perceived weakness, and (c) moderate stimulation, in which tremor was partially reduced, but there was also a subjective sense of increased strength compared with the high-stimulation condition. The patient's ability to generate both steady torque and rapid movements was poorest with no stimulation. The patient generated the largest torques with moderate stimulation and performed the fastest movements with high stimulation. However, even with tremor minimized, the patient's electromyogram (EMG) burst patterns were not typical of those of neurologically healthy subjects, although the movements were clearly improved.

  11. Effects of electrical stimulation of the dorsal raphe nucleus on local cerebral blood flow in the rat

    SciTech Connect

    Bonvento, G.; Lacombe, P.; Seylaz, J. )

    1989-06-01

    We have studied the effects of electrical stimulation of the dorsal raphe nucleus on local cerebral blood flow (LCBF), as assessed by the quantitative ({sup 14}C)-iodoantipyrine autoradiographic technique. Stimulation of the dorsal raphe nucleus in the alpha-chloralose anesthetized rat caused a significant decrease in LCBF, ranging from -13 to -26% in 24 brain structures out of 33 investigated. The most pronounced decreases (-23 to -26%) were observed in the accumbens, amygdaloid, interpeduncular nuclei and in the median raphe nucleus, limbic system relays. The decreases also concerned cortical regions and the extrapyramidal system. These results indicate that activation of ascending serotonergic system produces a vasoconstriction and that the dorsal raphe nucleus has a widespread modulatory influence on the cerebral circulation.

  12. Subthalamic nucleus stimulation modulates motor cortex oscillatory activity in Parkinson's disease.

    PubMed

    Devos, D; Labyt, E; Derambure, P; Bourriez, J L; Cassim, F; Reyns, N; Blond, S; Guieu, J D; Destée, A; Defebvre, L

    2004-02-01

    In Parkinson's disease, impaired motor preparation has been related to an increased latency in the appearance of movement-related desynchronization (MRD) throughout the contralateral primary sensorimotor (PSM) cortex. Internal globus pallidus (GPi) stimulation improved movement desynchronization over the PSM cortex during movement execution but failed to improve impaired motor preparation. PET studies indicate that subthalamic nucleus (STN) stimulation partly reverses the abnormal premotor pattern of brain activation during movement. By monitoring MRD, we aimed to assess changes in premotor and PSM cortex oscillatory activity induced by bilateral STN stimulation and to compare these changes with those induced by l-dopa. Ten Parkinson's disease patients and a group of healthy, age-matched controls performed self-paced wrist flexions in each of four conditions: without either stimulation or l-dopa (the 'off' condition), with stimulation and without l-dopa (On Stim), with l-dopa and without stimulation ('on drug'), and with both stimulation and l-dopa (On Both). Compared with the Off condition, in both the On Stim and the On Drug condition the Unified Parkinson's Disease Rating Scale (UPDRS) III score decreased by about 60% and in the On Both condition it decreased by 80%. The desynchronization latency over central regions contralateral to movement and the movement desynchronization over bilateral central regions were significantly increased by stimulation and by l-dopa, with a maximal effect when the two were associated. Furthermore, desynchronization latency significantly decreased over bilateral frontocentral regions in the three treatment conditions compared with the Off condition. In Parkinson's disease, STN stimulation may induce a change in abnormal cortical oscillatory activity patterns (similar to that produced by l-dopa) by decreasing the abnormal spreading of desynchronization over frontocentral regions and increasing PSM cortex activity during movement

  13. 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

  14. Low-frequency subthalamic nucleus deep brain stimulation for axial symptoms in advanced Parkinson's disease.

    PubMed

    Sidiropoulos, Christos; Walsh, Richard; Meaney, Christopher; Poon, Y Y; Fallis, Melanie; Moro, Elena

    2013-09-01

    Axial symptoms such as freezing of gait and falls are common manifestations of advanced Parkinson's disease (PD) and are partially responsive to medical treatment. High-frequency (≥130 Hz) deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly efficacious in ameliorating appendicular symptoms in PD. However, it is typically less effective in improving axial symptomatology, especially in the long term. We have studied the effects of low-frequency stimulation (LFS) (≤80 Hz) for improving speech, gait and balance dysfunction in the largest patient population to date. PD patients with bilateral STN-DBS and resistant axial symptoms were switched from chronic 130 Hz stimulation to LFS and followed up to 4 years. Primary outcome measures were total motor UPDRS scores, and axial and gait subscores before and after LFS. Bivariate analyses and correlation coefficients were calculated for the different conditions. Potential predictors of therapeutic response were also investigated. Forty-five advanced PD patients who had high frequency stimulation (HFS) for 39.5 ± 27.8 consecutive months were switched to LFS. LFS was kept on for a median period of 111.5 days before the assessment. There was no significant improvement in any of the primary outcomes between HFS and LFS, although a minority of patients preferred to be maintained on LFS for longer periods of time. No predictive factors of response could be identified. There was overall no improvement from LFS in axial symptoms. This could be partly due to some study limitations. Larger prospective trials are warranted to better clarify the impact of stimulation frequency on axial signs.

  15. Deep brain stimulation of the subthalamic nucleus: All that glitters isn't gold?

    PubMed

    Galati, Salvatore; Stefani, Alessandro

    2015-04-15

    With the silver anniversary of deep brain stimulation (DBS) behind us, this would seem to be a good juncture to consider its successes and unanswered questions. Bilateral subthalamic nucleus (STN) stimulation has changed the clinical perspective of several thousand Parkinson's disease (PD) patients worldwide. A recent reappraisal animates the field with strong arguments in favor of an anticipation of the stereotactic approach in patients with as little as 5 to 6 years of disease history if they manifest motor complications. From what was once a no-choice option, STN-DBS is now becoming more and more attractive to neurologists dealing with movement disorders. Despite the development of new pharmacological treatment and renewed rehabilitation programs able to modify the severity of drug-related complications, a resurgence of stimulation therapy reminiscent of an old era of medicine with an attendant blinkered mindset has emerged. Yet, the DBS-mediated effects are modest on critical aspects such as gait impairment and extremely variable depending on the clinical phenotype and individual clinical profile. Hence, the indication for DBS should become more, and not less, individually tailored. Those physicians considering deep brain stimulation (DBS) as a therapeutic option need to evaluate results beyond short-term quality of life, giving the correct weight to the direct and indirect costs over the longer term as well as to life prognosis. Unequivocal recourse to early-stimulation surgery necessitates investigations not limited to a mere comparative assessment versus drug-mediated benefits, but instead showing evidence of a clear degree of disease-modifying effect or a rescue of basal ganglia plasticity.

  16. Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release

    PubMed Central

    Melchior, James R.; Ferris, Mark J.; Stuber, Garret D.; Riddle, David R.; Jones, Sara R.

    2015-01-01

    The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse local microenvironments. Dopamine (DA) neuron terminals similarly express a heterogeneous collection of terminal receptors that modulate DA signaling. Cyclic voltammetry is often used to probe DA terminal dynamics in brain slice preparations; however, this method traditionally requires electrical stimulation to induce DA release. Electrical stimulation excites all of the neuronal processes in the stimulation field, potentially introducing simultaneous, multi-synaptic modulation of DA terminal release. We used optogenetics to selectively stimulate DA terminals and used voltammetry to compare DA responses from electrical and optical stimulation of the same area of tissue around a recording electrode. We found that with multiple pulse stimulation trains, optically stimulated DA release increasingly exceeded that of electrical stimulation. Furthermore, electrical stimulation produced inhibition of DA release across longer duration stimulations. The GABAB antagonist, CGP 55845, increased electrically stimulated DA release significantly more than light stimulated release. The nicotinic acetylcholine receptor antagonist, dihydro-β-erythroidine hydrobromide, inhibited single pulse electrically stimulated DA release while having no effect on optically stimulated DA release. Our results demonstrate that electrical stimulation introduces local multi-synaptic modulation of DA release that is absent with optogenetically targeted stimulation. PMID:26011081

  17. 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

  18. Decisional impulsivity and the associative-limbic subthalamic nucleus in obsessive-compulsive disorder: stimulation and connectivity

    PubMed Central

    Droux, Fabien; Morris, Laurel; Chabardes, Stephan; Bougerol, Thierry; David, Olivier; Krack, Paul; Polosan, Mircea

    2017-01-01

    Why do we make hasty decisions for short-term gain? Rapid decision-making with limited accumulation of evidence and delay discounting are forms of decisional impulsivity. The subthalamic nucleus is implicated in inhibitory function but its role in decisional impulsivity is less well-understood. Here we assess decisional impulsivity in subjects with obsessive compulsive disorder who have undergone deep brain stimulation of the limbic and associative subthalamic nucleus. We show that stimulation of the subthalamic nucleus is causally implicated in increasing decisional impulsivity with less accumulation of evidence during probabilistic uncertainty and in enhancing delay discounting. Subthalamic stimulation shifts evidence accumulation in subjects with obsessive-compulsive disorder towards a functional less cautious style closer to that of healthy controls emphasizing its adaptive nature. Thus, subjects with obsessive compulsive disorder on subthalamic stimulation may be less likely to check for evidence (e.g. checking that the stove is on) with no difference in subjective confidence (or doubt). In a separate study, we replicate in humans (154 healthy controls) using resting state functional connectivity, tracing studies conducted in non-human primates dissociating limbic, associative and motor frontal hyper-direct connectivity with anterior and posterior subregions of the subthalamic nucleus. We show lateralization of functional connectivity of bilateral ventral striatum to right anterior ventromedial subthalamic nucleus consistent with previous observations of lateralization of emotionally evoked activity to right ventral subthalamic nucleus. We use a multi-echo sequence with independent components analysis, which has been shown to have enhanced signal-to-noise ratio, thus optimizing visualization of small subcortical structures. These findings in healthy controls converge with the effective contacts in obsessive compulsive disorder patients localized within the

  19. Decisional impulsivity and the associative-limbic subthalamic nucleus in obsessive-compulsive disorder: stimulation and connectivity.

    PubMed

    Voon, Valerie; Droux, Fabien; Morris, Laurel; Chabardes, Stephan; Bougerol, Thierry; David, Olivier; Krack, Paul; Polosan, Mircea

    2017-02-01

    Why do we make hasty decisions for short-term gain? Rapid decision-making with limited accumulation of evidence and delay discounting are forms of decisional impulsivity. The subthalamic nucleus is implicated in inhibitory function but its role in decisional impulsivity is less well-understood. Here we assess decisional impulsivity in subjects with obsessive compulsive disorder who have undergone deep brain stimulation of the limbic and associative subthalamic nucleus. We show that stimulation of the subthalamic nucleus is causally implicated in increasing decisional impulsivity with less accumulation of evidence during probabilistic uncertainty and in enhancing delay discounting. Subthalamic stimulation shifts evidence accumulation in subjects with obsessive-compulsive disorder towards a functional less cautious style closer to that of healthy controls emphasizing its adaptive nature. Thus, subjects with obsessive compulsive disorder on subthalamic stimulation may be less likely to check for evidence (e.g. checking that the stove is on) with no difference in subjective confidence (or doubt). In a separate study, we replicate in humans (154 healthy controls) using resting state functional connectivity, tracing studies conducted in non-human primates dissociating limbic, associative and motor frontal hyper-direct connectivity with anterior and posterior subregions of the subthalamic nucleus. We show lateralization of functional connectivity of bilateral ventral striatum to right anterior ventromedial subthalamic nucleus consistent with previous observations of lateralization of emotionally evoked activity to right ventral subthalamic nucleus. We use a multi-echo sequence with independent components analysis, which has been shown to have enhanced signal-to-noise ratio, thus optimizing visualization of small subcortical structures. These findings in healthy controls converge with the effective contacts in obsessive compulsive disorder patients localized within the

  20. Modulation of cortical motor evoked potential after stroke during electrical stimulation of the lateral cerebellar nucleus

    PubMed Central

    Park, Hyun-Joo; Furmaga, Havan; Cooperrider, Jessica; Gale, John T.; Baker, Kenneth B.; Machado, Andre G.

    2015-01-01

    Background Deep brain stimulation (DBS) targeting the dentato-thalamo-cortical (DTC) pathway at its origin in the lateral cerebellar nucleus (LCN) has been shown to enhance motor recovery in a rodent model of cortical ischemia. LCN DBS also yielded frequency specific changes in motor cortex excitability in the normal brain, indexed by motor evoked potential (MEP) amplitude. Objective To investigate the effect of cortical stroke on cortical motor excitability in a rodent ischemia model and to measure the effects of LCN DBS on post-ischemia excitability as a function of stimulation parameters. Methods Adult Sprague-Dawley rats were divided into two groups: naïve and stroke, with cortical ischemia induced through multiple, unilateral endothelin-1 injections. All animals were implanted with a bipolar electrode in the LCN opposite the affected hemisphere. MEPs were elicited from the affected hemisphere using intracortical microstimulation (ICMS) techniques. Multiple LCN DBS parameters were examined, including isochronal stimulation at 20, 30, 50, and 100 Hz as well as a novel burst stimulation pattern. Results ICMS-evoked MEPs were reduced in stroke (n=10) relative to naïve (n=12) animals. However, both groups showed frequency-dependent augmentation of cortical excitability in response to LCN DBS. In the naïve group, LCN DBS increased MEPs by 22–58%, while in the stroke group, MEPs were enhanced by 9–41% compared to OFF DBS conditions. Conclusions Activation of the DTC pathway increases cortical excitability in both naïve and post-stroke animals. These effects may underlie, at least partially, functional reorganization and therapeutic benefits associated with chronic LCN DBS in post-stroke animals. PMID:26215752

  1. Dopamine efflux in the rat striatum evoked by electrical stimulation of the subthalamic nucleus: potential mechanism of action in Parkinson's disease.

    PubMed

    Lee, Kendall H; Blaha, Charles D; Harris, Brent T; Cooper, Shannon; Hitti, Frederick L; Leiter, James C; Roberts, David W; Kim, Uhnoh

    2006-02-01

    The precise mechanism whereby continuous high-frequency electrical stimulation of the subthalamic nucleus ameliorates motor symptoms of Parkinson's disease is unknown. We examined the effects of high-frequency stimulation of regions dorsal to and within the subthalamic nucleus on dopamine efflux in the striatum of urethane-anaesthetized rats using constant potential amperometry. Complementary extracellular electrophysiological studies determined the activity of subthalamic nucleus neurons in response to similar electrical stimulation of the subthalamic nucleus. High-frequency stimulation of the subthalamic nucleus increased action potential firing in the subthalamic nucleus only during the initial stimulation period and was followed by a cessation of firing over the remainder of stimulation. Electrical stimulation of the subthalamic nucleus with 15 pulses elicited stimulus-time-locked increases in striatal dopamine efflux with maximal peak effects occurring at 50 Hz frequency and 300 microA intensity. Extended subthalamic nucleus stimulation (1000 pulses at 50 Hz; 300 microA) elicited a similar peak increase in striatal dopamine efflux that was followed by a relatively lower steady-state elevation in extracellular dopamine over the course of stimulation. In contrast, extended stimulation immediately adjacent and dorsal to the subthalamic nucleus resulted in an 11-fold greater increase in dopamine efflux that remained elevated over the course of the stimulation. Immunohistochemical staining for tyrosine hydroxylase revealed catecholaminergic fibers running immediately dorsal to and through the subthalamic nucleus. Taken together, these results suggest that enhanced dopamine release within the basal ganglia may be an important mechanism whereby high-frequency stimulation of the subthalamic nucleus improves motor symptoms of Parkinson's disease.

  2. 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

  3. Effects of subthalamic nucleus stimulation on characteristics of EMG activity underlying reaction time in Parkinson's disease.

    PubMed

    Kumru, Hatice; Summerfield, Christopher; Valldeoriola, Francesc; Valls-Solé, Josep

    2004-01-01

    We examined the effects of high-frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) on characteristics of electromyographic (EMG) activity of the agonist muscle in 8 patients with Parkinson's disease (PD). Patients were examined during STN-DBS (ON), and 30 minutes after switching off both stimulators (OFF). They were asked to make a ballistic movement in paradigms of simple reaction time (SRT) and choice reaction time (CRT) tasks. Onset of movement (MOVonset) was measured as the latency of the initial displacement from baseline of the signal from an accelerometer attached to the dorsum of the hand. In the associated EMG activity, recorded from wrist extensor muscles, we measured onset latency (EMGonset), size of the first EMG burst (EMGsize), and number of EMG bursts (EMGbursts) counted between EMGonset and task execution. MOVonset and EMGonset were significantly shorter in ON than in OFF conditions in CRT. EMGsize was larger, EMGbursts were reduced, and peak of the acceleration profile was larger in ON compared with OFF conditions in both SRT and CRT. Our results indicate that STN-DBS induces a significant improvement in motor performance of reaction time tasks in PD patients. Such improvement is associated with a change in features of the EMG activity suggesting an increase in the excitability of the motor pathways engaged in ballistic movements.

  4. 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.

  5. 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…

  6. 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…

  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. Deep brain stimulation of anterior nucleus thalami disrupts sleep in epilepsy patients.

    PubMed

    Voges, Berthold R; Schmitt, Friedhelm C; Hamel, Wolfgang; House, Patrick M; Kluge, Christian; Moll, Christian K E; Stodieck, Stefan R

    2015-08-01

    In view of the regulatory function of the thalamus in the sleep-wake cycle, the impact of deep brain stimulation (DBS) of the anterior nucleus thalami (ANT) on sleep was assessed in a small consecutive cohort of epilepsy patients with standardized polysomnography (PSG). In nine patients treated with ANT-DBS (voltage 5 V, frequency 145 Hz, cyclic mode), the number of arousals during stimulation and nonstimulation periods, neuropsychiatric symptoms (npS), and seizure frequency were determined. Electroclinical arousals were triggered in 14.0 to 67.0% (mean 42.4 ± SD 16.8%) of all deep brain stimuli. Six patients reported npS. Nocturnal DBS voltages were reduced in eight patients (one patient without npS refused) and PSGs were repeated. Electroclinical arousals occurred between 1.4 and 6.7 (mean 3.3 ± 1.7) times more frequently during stimulation periods compared to nonstimulation periods; the number of arousals positively correlated with the level of DBS voltage (range 1 V to 5 V) (Spearman's rank coefficient 0.53121; p < 0.05). No patient experienced seizure deterioration and four patients reported remission of npS. This case-cohort study provides evidence that ANT-DBS interrupts sleep in a voltage-dependent manner, thus putatively resulting in an increase of npS. Reduction of nocturnal DBS voltage seems to lead to improvement of npS without hampering efficacy of ANT-DBS.

  9. 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

  10. Effects of subthalamic nucleus stimulation on motor cortex plasticity in Parkinson disease

    PubMed Central

    Kim, Sang Jin; Udupa, Kaviraja; Ni, Zhen; Moro, Elena; Gunraj, Carolyn; Mazzella, Filomena; Lozano, Andres M.; Hodaie, Mojgan; Lang, Anthony E.

    2015-01-01

    Objective: We hypothesized that subthalamic nucleus (STN) deep brain stimulation (DBS) will improve long-term potentiation (LTP)-like plasticity in motor cortex in Parkinson disease (PD). Methods: We studied 8 patients with PD treated with STN-DBS and 9 age-matched healthy controls. Patients with PD were studied in 4 sessions in medication (Med) OFF/stimulator (Stim) OFF, Med-OFF/Stim-ON, Med-ON/Stim-OFF, and Med-ON/Stim-ON states in random order. Motor evoked potential amplitude and cortical silent period duration were measured at baseline before paired associated stimulation (PAS) and at 3 different time intervals (T0, T30, T60) up to 60 minutes after PAS in the abductor pollicis brevis and abductor digiti minimi muscles. Results: Motor evoked potential size significantly increased after PAS in controls (+67.7% of baseline at T30) and in patients in the Med-ON/Stim-ON condition (+55.8% of baseline at T30), but not in patients in the Med-OFF/Stim-OFF (−0.4% of baseline at T30), Med-OFF/Stim-ON (+10.3% of baseline at T30), and Med-ON/Stim-OFF conditions (+17.3% of baseline at T30). Cortical silent period duration increased after PAS in controls but not in patients in all test conditions. Conclusions: Our findings suggest that STN-DBS together with dopaminergic medications restore LTP-like plasticity in motor cortex in PD. Restoration of cortical plasticity may be one of the mechanisms of how STN-DBS produces clinical benefit. PMID:26156511

  11. Predicting quality of life outcomes after subthalamic nucleus deep brain stimulation

    PubMed Central

    Cooper, Scott E.; Griffith, Sandra D.; Machado, Andre G.

    2014-01-01

    Objectives: To examine disease, treatment, cognitive, and psychological factors associated with quality of life (QoL) before and after surgery and assess the ability to predict QoL outcomes. Methods: We identified a retrospective, cross-sectional sample of 85 patients with Parkinson disease who underwent subthalamic deep brain stimulation (DBS). Patients' QoL was categorized as “improved” and “stable/worsened” using reliable change indices. Univariate correlational analyses identified relationships between Parkinson's Disease Questionnaire–39 ratings and disease (Unified Parkinson's Disease Rating Scale–III [UPDRS-III] motor scores on and off medications, disease duration), treatment (medication burden, unilateral vs bilateral DBS), cognitive (neuropsychological battery), and psychological (depression) variables. Step-wise multiple linear regression and logistic regression models included selected preoperative variables to predict change in QoL ratings and QoL outcome after surgery. Results: Fifty-one percent of patients reported clinically significant improvements in QoL while 47% reported stable QoL and 2% worsened. Motor scores (UPDRS-III) were not relevant to QoL changes, potentially because of the rarity of poor motor outcomes, while single-trial learning and depression scores were the most important variables in predicting QoL changes. There was a subtle additional benefit to undergoing bilateral subthalamic nucleus DBS. Conclusions: The findings provide greater insight into the nonmotor features that contribute to the success of subthalamic nucleus DBS procedures from the patient's perspective and raise questions about the treatment focus and emphasis on symptom profiles in DBS candidacy evaluations. PMID:25274851

  12. Deep brain stimulation of the subthalamic nucleus modulates sensitivity to decision outcome value in Parkinson’s disease

    PubMed Central

    Seymour, Ben; Barbe, Michael; Dayan, Peter; Shiner, Tamara; Dolan, Ray; Fink, Gereon R.

    2016-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson’s disease is known to cause a subtle but important adverse impact on behaviour, with impulsivity its most widely reported manifestation. However, precisely which computational components of the decision process are modulated is not fully understood. Here we probe a number of distinct subprocesses, including temporal discount, outcome utility, instrumental learning rate, instrumental outcome sensitivity, reward-loss trade-offs, and perseveration. We tested 22 Parkinson’s Disease patients both on and off subthalamic nucleus deep brain stimulation (STN-DBS), while they performed an instrumental learning task involving financial rewards and losses, and an inter-temporal choice task for financial rewards. We found that instrumental learning performance was significantly worse following stimulation, due to modulation of instrumental outcome sensitivity. Specifically, patients became less sensitive to decision values for both rewards and losses, but without any change to the learning rate or reward-loss trade-offs. However, we found no evidence that DBS modulated different components of temporal impulsivity. In conclusion, our results implicate the subthalamic nucleus in a modulation of outcome value in experience-based learning and decision-making in Parkinson’s disease, suggesting a more pervasive role of the subthalamic nucleus in the control of human decision-making than previously thought. PMID:27624437

  13. Deep brain stimulation of the subthalamic nucleus modulates sensitivity to decision outcome value in Parkinson’s disease

    NASA Astrophysics Data System (ADS)

    Seymour, Ben; Barbe, Michael; Dayan, Peter; Shiner, Tamara; Dolan, Ray; Fink, Gereon R.

    2016-09-01

    Deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson’s disease is known to cause a subtle but important adverse impact on behaviour, with impulsivity its most widely reported manifestation. However, precisely which computational components of the decision process are modulated is not fully understood. Here we probe a number of distinct subprocesses, including temporal discount, outcome utility, instrumental learning rate, instrumental outcome sensitivity, reward-loss trade-offs, and perseveration. We tested 22 Parkinson’s Disease patients both on and off subthalamic nucleus deep brain stimulation (STN-DBS), while they performed an instrumental learning task involving financial rewards and losses, and an inter-temporal choice task for financial rewards. We found that instrumental learning performance was significantly worse following stimulation, due to modulation of instrumental outcome sensitivity. Specifically, patients became less sensitive to decision values for both rewards and losses, but without any change to the learning rate or reward-loss trade-offs. However, we found no evidence that DBS modulated different components of temporal impulsivity. In conclusion, our results implicate the subthalamic nucleus in a modulation of outcome value in experience-based learning and decision-making in Parkinson’s disease, suggesting a more pervasive role of the subthalamic nucleus in the control of human decision-making than previously thought.

  14. 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.

  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. Change of the melanocortin system caused by bilateral subthalamic nucleus stimulation in Parkinson's disease.

    PubMed

    Escamilla-Sevilla, F; Pérez-Navarro, M J; Muñoz-Pasadas, M; Sáez-Zea, C; Jouma-Katati, M; Piédrola-Maroto, G; Ramírez-Navarro, A; Mínguez-Castellanos, A

    2011-10-01

    OBJECTIVES - Determine whether bilateral subthalamic nucleus stimulation (STN-DBS) in Parkinson's disease (PD) is associated with an increase in neuropeptide Y (NPY) and/or resistance to inhibition by leptin in relation to post-surgery weight gain. MATERIALS AND METHODS - This prospective study included 20 patients who underwent bilateral STN-DBS and 17 who refused surgery. Data were obtained at baseline, 3 and 6 months on neurological and nutritional status, including determination of body mass index (BMI) and serum NPY and leptin levels. RESULTS -  NPY and leptin levels changed over time, with a distinct pattern. The BMI increase at 6 months was greater in the surgical group (5.5 ± 6.3% vs 0.5 ± 3.5%; P = 0.035). Medical group exhibited a reduction in leptin level (-2.0 ± 4.3 ng/ml) and a consequent increase in NPY level (72.4 ± 58.7 pmol/ml). However, STN-DBS patients showed an increase in leptin (3.1 ± 5.0 ng/ml; P = 0.001 vs medical group) and also in NPY (12.1 ± 53.6 pmol/ml; P = 0.022 vs medical group) levels, which suggests resistance to inhibition by leptin. Rise in NPY level correlated with higher stimulation voltages. CONCLUSIONS -  Bilateral STN-DBS causes disruption of the melanocortin system, probably related to diffusion of the electric current to the hypothalamus. This mechanism may in part explain the weight gain of patients with PD after surgery.

  17. Fornix deep brain stimulation circuit effect is dependent on major excitatory transmission via the nucleus accumbens

    PubMed Central

    Ross, Erika K.; Kim, Joo Pyung; Settell, Megan L.; Han, Seong Rok; Blaha, Charles D.; Min, Hoon-Ki; Lee, Kendall H.

    2016-01-01

    Introduction Deep brain stimulation (DBS) is a circuit-based treatment shown to relieve symptoms from multiple neurologic and neuropsychiatric disorders. In order to treat the memory deficit associated with Alzheimer's disease (AD), several clinical trials have tested the efficacy of DBS near the fornix. Early results from these studies indicated that patients who received fornix DBS experienced an improvement in memory and quality of life, yet the mechanisms behind this effect remain controversial. It is known that transmission between the medial limbic and corticolimbic circuits plays an integral role in declarative memory, and dysfunction at the circuit level results in various forms of dementia, including AD. Here, we aimed to determine the potential underlying mechanism of fornix DBS by examining the functional circuitry and brain structures engaged by fornix DBS. Methods A multimodal approach was employed to examine global and local temporal changes that occur in an anesthetized swine model of fornix DBS. Changes in global functional activity were measured by functional MRI (fMRI), and local neurochemical changes were monitored by fast scan cyclic voltammetry (FSCV) during electrical stimulation of the fornix. Additionally, intracranial microinfusions into the nucleus accumbens (NAc) were performed to investigate the global activity changes that occur with dopamine and glutamate receptor-specific antagonism. Results Hemodynamic responses in both medial limbic and corticolimbic circuits measured by fMRI were induced by fornix DBS. Additionally, fornix DBS resulted in increases in dopamine oxidation current (corresponding to dopamine efflux) monitored by FSCV in the NAc. Finally, fornix DBS-evoked hemodynamic responses in the amygdala and hippocampus decreased following dopamine and glutamate receptor antagonism in the NAc. Conclusions The present findings suggest that fornix DBS modulates dopamine release on presynaptic dopaminergic terminals in the NAc

  18. Behavioral memory induced by stimulation of the nucleus basalis: effects of contingency reversal.

    PubMed

    Miasnikov, Alexandre A; Chen, Jemmy C; Weinberger, Norman M

    2009-03-01

    Specific behavioral associative memory induced by stimulation of the cortically-projecting cholinergic nucleus basalis (NB) is dependent on intrinsic acetylcholine and shares with natural memory such features as associativity, specificity, rapid formation, consolidation and long-term retention. Herein, we examined extinction and the effects of stimulus pre-exposure. Two groups of adult male rats (n=4 each) were first tested for behavioral responses (disruption of ongoing respiration) to tones (1-15 kHz), constituting a pre-training behavioral frequency generalization gradient (BFGG). They next received a first session of training, 200 trials of a tone (8.00 kHz, 70 dB, 2 s) either paired with electrical stimulation of the NB (100 Hz, 0.2 s, approximately 67 microA, NBstm) (group IP) or unpaired (group IU). Twenty-four hours later, they were tested for behavioral memory by obtaining post-training BFGGs. Then the contingencies were reversed yet another 24 h later; the IP group received tone and NBstm unpaired and the IU group received them paired. A final set of generalization gradients was obtained the next day. All stimuli were presented with subjects under state control indexed by regular respiration. Tested 24 h post-initial training, the IP group developed specific associative behavioral memory indicated by increased responses only to CS-band frequencies, while the IU group did not. After subsequent training with unpaired stimuli, the IP group exhibited experimental extinction. Furthermore, after initial exposure to the CS and NBstm unpaired, the IU group exhibited a tendency toward reduced conditioning to CS/NBstm pairing and a significant increase in latency of conditioned responses. The present findings provide additional support for the hypothesis that engagement of the NB is sufficient to induce natural associative memory and suggest that activation of the NB may be a normal component in the formation of natural associative memory.

  19. 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.

  20. 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.

  1. Chronic electrical stimulation of the contralesional lateral cerebellar nucleus enhances recovery of motor function after cerebral ischemia in rats

    PubMed Central

    Machado, Andre G.; Baker, Kenneth B.; Schuster, Daniel; Butler, Robert S.; Rezai, Ali

    2009-01-01

    Novel neurorehabilitative strategies are needed to improve motor outcomes following stroke. Based on the disynaptic excitatory projections of the dentatothalamocortical pathway to the motor cortex as well as anterior and posterior cortical areas, we hypothesize that chronic electrical stimulation of the contralesional dentate (lateral cerebellar) nucleus output can enhance motor recovery after ischemia via augmentation of perilesional cortical excitability. Seventy five Wistar rats were pre-trained in the Montoya staircase task and subsequently suffered left cerebral ischemia with the 3-vessel occlusion model. All survivors underwent stereotactic right lateral cerebellar nucleus (LCN) implantation of bipolar electrodes. Rats were then randomized to 4 groups: LCN stimulation at 10 pps, 20 pps, 50 pps or sham stimulation, which was delivered for a period of six weeks. Performance on the Montoya task was re-assessed over the last four weeks of the stimulation period. On the right (contralesional) side, motor performance of the groups undergoing sham, 10 pps, 20 pps and 50 pps stimulation was, respectively, 2.5± 2.7; 2.1 ± 2.5; 6.0 ± 3.9 (p<0.01) and 4.5 ± 3.5 pellets. There was no difference on the left (ipsilesional) side motor performance among the sham or stimulation groups, varying from 15.9 ± 6.7 to 17.2 ± 2.1 pellets. We conclude that contralesional chronic electrical stimulation of the lateral cerebellar nucleus at 20 pps but not at 10 or 50 pps improves motor recovery in rats following ischemic strokes. This effect is likely to be mediated by increased perilesional cortical excitability via chronic activation of the dentatothalamocortical pathway. PMID:19445910

  2. Electrical stimulation of reward sites in the ventral tegmental area increases dopamine transmission in the nucleus accumbens of the rat.

    PubMed

    Fiorino, D F; Coury, A; Fibiger, H C; Phillips, A G

    1993-06-30

    In vivo microdialysis with HPLC-ED was used to measure dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the nucleus accumbens of the rat, prior, during, and after 15-min periods of electrical brain stimulation at sites in the ventral tegmental area (VTA) that supported intracranial self-stimulation (ICSS). In the first experiment, both ICSS and yoked stimulation of the VTA evoked significant increases in extracellular concentrations of DA, its metabolites, and 5-HIAA. Comparable results from ICSS and yoked groups were interpreted as evidence that the rewarding properties of VTA stimulation were a causal factor in the elevated DA transmission in the nucleus accumbens, rather than intense operant behavior. Further evidence for this hypothesis came from a second set of data in which changes in extracellular DA levels during the measurement of rate/intensity functions for ICSS were positively correlated. 5-HIAA concentrations also increased during ICSS but these changes were not correlated with either ICSS rate or current intensity, suggesting that changes in serotonin metabolism were unlikely to subserve brain stimulation reward in the VTA. These results add to the growing body of evidence linking changes in extracellular DA in the mesolimbic DA system with both brain stimulation reward and the conditioned and unconditioned rewarding effects of biologically relevant stimuli.

  3. Hypoglycemia-activated GLUT2 neurons of the nucleus tractus solitarius stimulate vagal activity and glucagon secretion.

    PubMed

    Lamy, Christophe M; Sanno, Hitomi; Labouèbe, Gwenaël; Picard, Alexandre; Magnan, Christophe; Chatton, Jean-Yves; Thorens, Bernard

    2014-03-04

    Glucose-sensing neurons in the brainstem participate in the regulation of energy homeostasis but have been poorly characterized because of the lack of specific markers to identify them. Here we show that GLUT2-expressing neurons of the nucleus of the tractus solitarius form a distinct population of hypoglycemia-activated neurons. Their response to low glucose is mediated by reduced intracellular glucose metabolism, increased AMP-activated protein kinase activity, and closure of leak K(+) channels. These are GABAergic neurons that send projections to the vagal motor nucleus. Light-induced stimulation of channelrhodospin-expressing GLUT2 neurons in vivo led to increased parasympathetic nerve firing and glucagon secretion. Thus GLUT2 neurons of the nucleus tractus solitarius link hypoglycemia detection to counterregulatory response. These results may help identify the cause of hypoglycemia-associated autonomic failure, a major threat in the insulin treatment of diabetes.

  4. Electric stimulation of the tuberomamillary nucleus affects epileptic activity and sleep-wake cycle in a genetic absence epilepsy model.

    PubMed

    Blik, Vitaliya

    2015-01-01

    Deep brain stimulation (DBS) is a promising approach for epilepsy treatment, but the optimal targets and parameters of stimulation are yet to be investigated. Tuberomamillary nucleus (TMN) is involved in EEG desynchronization-one of the proposed mechanisms for DBS action. We studied whether TMN stimulation could interfere with epileptic spike-wave discharges (SWDs) in WAG/Rij rats with inherited absence epilepsy and whether such stimulation would affect sleep-wake cycle. EEG and video registration were used to determine SWD occurrence and stages of sleep and wake during three-hours recording sessions. Stimulation (100Hz) was applied in two modes: closed-loop (with previously determined interruption threshold intensity) or open-loop mode (with 50% or 70% threshold intensity). Closed-loop stimulation successfully interrupted SWDs but elevated their number by 148 ± 54% compared to baseline. It was accompanied by increase in number of episodes but not total duration of both active and passive wakefulness. Open-loop stimulation with amplitude 50% threshold did not change measured parameters, though 70% threshold stimulation reduced SWDs number by 40 ± 9%, significantly raised the amount of active wakefulness and decreased the amount of both slow-wave and rapid eye movement sleep. These results suggest that the TMN is unfavorable as a target for DBS as its stimulation may cause alterations in sleep-wake cycle. A careful choosing of parameters and control of sleep-wake activity is necessary when applying DBS in epilepsy.

  5. Responses of the red nucleus neurons to stimulation of the paw pads of forelimbs before and after cerebellar lesions.

    PubMed

    Tarnecki, R; Lupa, K; Niechaj, A

    2001-09-01

    Cerebellar cortex ablation releases deep cerebellar nuclei of monosynaptic inhibition from Purkinje cells. Therefore, it strengthens excitatory influence from Interpositus Nucleus (IN) upon Red Nucleus (RN), which results in much higher facilitation of the rubro-spinal neurons. This causes a big increase of spontaneous discharge rate, and eliminates brakes of discharges from responses generated by somatosensory stimuli. These two changes destroy content and timing of feedback information flowing through the spino-cerebello-rubro-spinal loop. This false bias of the feedback information, very important for fast postural adjustment and coordination of ongoing movements executed by central motor program, may at least in part be responsible for abnormal motor behavior evoked by cerebellar damage. Hemicerebellectomy resulted in dramatically reduced spontaneous activity and responses to limb stimulation because of severing a major input to the red nucleus from deep cerebellar nuclei. Due to direct somatosensory input to magnocellular Red Nucleus (mcRN) from the spinal cord that bypassed the cerebellum, the latency of response to limb stimulation was not changed and the narrower receptive fields were still present.

  6. Interleaving subthalamic nucleus deep brain stimulation to avoid side effects while achieving satisfactory motor benefits in Parkinson disease

    PubMed Central

    Zhang, Shizhen; Zhou, Peizhi; Jiang, Shu; Wang, Wei; Li, Peng

    2016-01-01

    Abstract Background: Deep brain stimulation (DBS) of the subthalamic nucleus is an effective treatment for advanced Parkinson disease (PD). However, achieving ideal outcomes by conventional programming can be difficult in some patients, resulting in suboptimal control of PD symptoms and stimulation-induced adverse effects. Interleaving stimulation (ILS) is a newer programming technique that can individually optimize the stimulation area, thereby improving control of PD symptoms while alleviating stimulation-induced side effects after conventional programming fails to achieve the desired results. Methods: We retrospectively reviewed PD patients who received DBS programming during the previous 4 years in our hospital. We collected clinical and demographic data from 12 patients who received ILS because of incomplete alleviation of PD symptoms or stimulation-induced adverse effects after conventional programming had proven ineffective or intolerable. Appropriate lead location was confirmed with postoperative reconstruction images. The rationale and clinical efficacy of ILS was analyzed. Results: We divided our patients into 4 groups based on the following symptoms: stimulation-induced dysarthria and choreoathetoid dyskinesias, gait disturbance, and incomplete control of parkinsonism. After treatment with ILS, patients showed satisfactory improvement in PD symptoms and alleviation of stimulation-induced side effects, with a mean improvement in Unified PD Rating Scale motor scores of 26.9%. Conclusions: ILS is a newer choice and effective programming strategy to maximize symptom control in PD while decreasing stimulation-induced adverse effects when conventional programming fails to achieve satisfactory outcome. However, we should keep in mind that most DBS patients are routinely treated with conventional stimulation and that not all patients benefit from ILS. ILS is not recommended as the first choice of programming, and it is recommended only when patients have

  7. Systemically administered oxytocin decreases methamphetamine activation of the subthalamic nucleus and accumbens core and stimulates oxytocinergic neurons in the hypothalamus.

    PubMed

    Carson, Dean S; Hunt, Glenn E; Guastella, Adam J; Barber, Lachlan; Cornish, Jennifer L; Arnold, Jonathon C; Boucher, Aurelie A; McGregor, Iain S

    2010-10-01

    Recent preclinical evidence indicates that the neuropeptide oxytocin may have potential in the treatment of drug dependence and drug withdrawal. Oxytocin reduces methamphetamine self-administration, conditioned place preference and hyperactivity in rodents. However, it is unclear how oxytocin acts in the brain to produce such effects. The present study examined how patterns of neural activation produced by methamphetamine were modified by co-administered oxytocin. Male Sprague-Dawley rats were pretreated with either 2 mg/kg oxytocin (IP) or saline and then injected with either 2 mg/kg methamphetamine (IP) or saline. After injection, locomotor activity was measured for 80 minutes prior to perfusion. As in previous studies, co-administered oxytocin significantly reduced methamphetamine-induced behaviors. Strikingly, oxytocin significantly reduced methamphetamine-induced Fos expression in two regions of the basal ganglia: the subthalamic nucleus and the nucleus accumbens core. The subthalamic nucleus is of particular interest given emerging evidence for this structure in compulsive, addiction-relevant behaviors. When administered alone, oxytocin increased Fos expression in several regions, most notably in the oxytocin-synthesizing neurons of the supraoptic nucleus and paraventricular nucleus of the hypothalamus. This provides new evidence for central actions of peripheral oxytocin and suggests a self-stimulation effect of exogenous oxytocin on its own hypothalamic circuitry. Overall, these results give further insight into the way in which oxytocin might moderate compulsive behaviors and demonstrate the capacity of peripherally administered oxytocin to induce widespread central effects.

  8. Deep brain stimulation of the medial septum or nucleus accumbens alleviates psychosis-relevant behavior in ketamine-treated rats.

    PubMed

    Ma, Jingyi; Leung, L Stan

    2014-06-01

    Deep brain stimulation (DBS) has been shown to be effective for relief of Parkinson's disease, depression and obsessive-compulsive disorder in humans, but the effect of DBS on psychosis is largely unknown. In previous studies, we showed that inactivation of the medial septum or nucleus accumbens normalized the hyperactive and psychosis-related behaviors induced by psychoactive drugs. We hypothesized that DBS of the medial septum or nucleus accumbens normalizes the ketamine-induced abnormal behaviors and brain activity in freely moving rats. Male Long-Evans rats were subcutaneously injected with ketamine (3 mg/kg) alone, or given ketamine and DBS, or injected with saline alone. Subcutaneous injection of ketamine resulted in loss of gating of hippocampal auditory evoked potentials (AEPs), deficit in prepulse inhibition (PPI) and hyperlocomotion, accompanied by increased hippocampal gamma oscillations of 70-100 Hz. Continuous 130-Hz stimulation of the nucleus accumbens, or 100-Hz burst stimulation of the medial septum (1s on and 5s off) significantly attenuated ketamine-induced PPI deficit and hyperlocomotion. Medial septal stimulation also prevented the loss of gating of hippocampal AEPs and the increase in hippocampal gamma waves induced by ketamine. Neither septal or accumbens DBS alone without ketamine injection affected spontaneous locomotion or PPI. The results suggest that DBS of the medial septum or nucleus accumbens may be an effective method to alleviate psychiatric symptoms of schizophrenia. The effect of medial septal DBS in suppressing both hippocampal gamma oscillations and abnormal behaviors induced by ketamine suggests that hippocampal gamma oscillations are a correlate of disrupted behaviors.

  9. Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson's disease.

    PubMed

    Saint-Cyr, J A; Trépanier, L L; Kumar, R; Lozano, A M; Lang, A E

    2000-10-01

    The aim of this study was to examine possible neuropsychological changes in patients with advanced idiopathic Parkinson's disease treated with bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). Eleven patients (age = 67 +/- 8 years, years with Parkinson's disease = 15 +/- 3, verbal IQ = 114 +/- 12) were evaluated (in their best 'on state') with tests assessing processes reliant on the functional integrity of frontal striatal circuitry, prior to the procedure (n = 11), at 3-6 months (n = 11) and at 9-12 months (n =10) post-operatively. Six of these patients were older than 69 years. Despite clinical motor benefits at 3-6 months post-operative, significant declines were noted in working memory, speed of mental processing, bimanual motor speed and co-ordination, set switching, phonemic fluency, long-term consolidation of verbal material and the encoding of visuospatial material. Declines were more consistently observed in patients who were older than 69 years, leading to a mental state comparable with progressive supranuclear palsy. 'Frontal' behavioural dyscontrol without the benefit of insight was also reported by half (three of six) of the caregivers of the elderly subgroup. At 9-12 months postoperative, only learning based on multiple trials had recovered. Tasks reliant on the integrity of frontal striatal circuitry either did not recover or gradually worsened over time. Bilateral STN DBS can have a negative impact on various aspects of frontal executive functioning, especially in patients older than 69 years. Future studies will evaluate a larger group of patients and examine the possible reversibility of these effects by turning the DBS off.

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. 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.

  15. Responses from two firing patterns in inferior colliculus neurons to stimulation of the lateral lemniscus dorsal nucleus

    PubMed Central

    Li, Xiao-ting; Wang, Ning-yu; Wang, Yan-jun; Xu, Zhi-qing; Liu, Jin-feng; Bai, Yun-fei; Dai, Jin-sheng; Zhao, Jing-yi

    2016-01-01

    The γ-aminobutyric acid neurons (GABAergic neurons) in the inferior colliculus are classified into various patterns based on their intrinsic electrical properties to a constant current injection. Although this classification is associated with physiological function, the exact role for neurons with various firing patterns in acoustic processing remains poorly understood. In the present study, we analyzed characteristics of inferior colliculus neurons in vitro, and recorded responses to stimulation of the dorsal nucleus of the lateral lemniscus using the whole-cell patch clamp technique. Seven inferior colliculus neurons were tested and were classified into two firing patterns: sustained-regular (n = 4) and sustained-adapting firing patterns (n = 3). The majority of inferior colliculus neurons exhibited slight changes in response to stimulation and bicuculline. The responses of one neuron with a sustained-adapting firing pattern were suppressed after stimulation, but recovered to normal levels following application of the γ-aminobutyric acid receptor antagonist. One neuron with a sustained-regular pattern showed suppressed stimulation responses, which were not affected by bicuculline. Results suggest that GABAergic neurons in the inferior colliculus exhibit sustained-regular or sustained-adapting firing patterns. Additionally, GABAergic projections from the dorsal nucleus of the lateral lemniscus to the inferior colliculus are associated with sound localization. The different neuronal responses of various firing patterns suggest a role in sound localization. A better understanding of these mechanisms and functions will provide better clinical treatment paradigms for hearing deficiencies. PMID:27335563

  16. Spinal direct current stimulation modulates the activity of gracile nucleus and primary somatosensory cortex in anaesthetized rats

    PubMed Central

    Aguilar, J; Pulecchi, F; Dilena, R; Oliviero, A; Priori, A; Foffani, G

    2011-01-01

    Abstract Afferent somatosensory activity from the spinal cord has a profound impact on the activity of the brain. Here we investigated the effects of spinal stimulation using direct current, delivered at the thoracic level, on the spontaneous activity and on the somatosensory evoked potentials of the gracile nucleus, which is the main entry point for hindpaw somatosensory signals reaching the brain from the dorsal columns, and of the primary somatosensory cortex in anaesthetized rats. Anodal spinal direct current stimulation (sDCS) increased the spontaneous activity and decreased the amplitude of evoked responses in the gracile nucleus, whereas cathodal sDCS produced the opposite effects. At the level of the primary somatosensory cortex, the changes in spontaneous activity induced by sDCS were consistent with the effects observed in the gracile nucleus, but the changes in cortical evoked responses were more variable and state dependent. Therefore, sDCS can modulate in a polarity-specific manner the supraspinal activity of the somatosensory system, offering a versatile bottom-up neuromodulation technique that could potentially be useful in a number of clinical applications. PMID:21825031

  17. 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.

  18. Optogenetic stimulation of cholinergic brainstem neurons during focal limbic seizures: Effects on cortical physiology.

    PubMed

    Furman, Moran; Zhan, Qiong; McCafferty, Cian; Lerner, Benjamin A; Motelow, Joshua E; Meng, Jin; Ma, Chanthia; Buchanan, Gordon F; Witten, Ilana B; Deisseroth, Karl; Cardin, Jessica A; Blumenfeld, Hal

    2015-12-01

    Focal temporal lobe seizures often cause impaired cortical function and loss of consciousness. Recent work suggests that the mechanism for depressed cortical function during focal seizures may depend on decreased subcortical cholinergic arousal, which leads to a sleep-like state of cortical slow-wave activity. To test this hypothesis, we sought to directly activate subcortical cholinergic neurons during focal limbic seizures to determine the effects on cortical function. Here we used an optogenetic approach to selectively stimulate cholinergic brainstem neurons in the pedunculopontine tegmental nucleus during focal limbic seizures induced in a lightly anesthetized rat model. We found an increase in cortical gamma activity and a decrease in delta activity in response to cholinergic stimulation. These findings support the mechanistic role of reduced subcortical cholinergic arousal in causing cortical dysfunction during seizures. Through further work, electrical or optogenetic stimulation of subcortical arousal networks may ultimately lead to new treatments aimed at preventing cortical dysfunction during seizures.

  19. Long-term high frequency deep brain stimulation of the nucleus accumbens drives time-dependent changes in functional connectivity in the rodent limbic system.

    PubMed

    Ewing, Samuel G; Grace, Anthony A

    2013-05-01

    Deep brain stimulation of the ventral striatum is an effective treatment for a variety of treatment refractory psychiatric disorders yet the mechanism of action remains elusive. We examined how five days of stimulation affected rhythmic brain activity in freely moving rats in terms of oscillatory power within, and coherence between, selected limbic regions bilaterally. Custom made bipolar stimulating/recording electrodes were implanted, bilaterally, in the nucleus accumbens core. Local field potential (LFP) recording electrodes were implanted, bilaterally in the prelimbic and orbitofrontal cortices and mediodorsal thalamic nucleus. Stimulation was delivered bilaterally with 100 μs duration constant current pulses at a frequency of 130 Hz delivered at an amplitude of 100 μA using a custom-made stimulation device. Synchronized video and LFP data were collected from animals in their home cages before, during and after stimulation. Signals were processed to remove movement and stimulation artifacts, and analyzed to determine changes in spectral power within, and coherence between regions. Five days stimulation of the nucleus accumbens core yielded temporally dynamic modulation of LFP power in multiple bandwidths across multiple brain regions. Coherence was seen to decrease in the alpha band between the mediodorsal thalamic nucleus and core of the nucleus accumbens. Coherence between each core of the nucleus accumbens bilaterally showed rich temporal dynamics throughout the five day stimulation period. Stimulation cessation revealed significant "rebound" effects in both power and coherence in multiple brain regions. Overall, the initial changes in power observed with short-term stimulation are replaced by altered coherence, which may reflect the functional action of DBS.

  20. Subthalamic nucleus stimulation does not influence basal glucose metabolism or insulin sensitivity in patients with Parkinson's disease.

    PubMed

    Lammers, Nicolette M; Sondermeijer, Brigitte M; Twickler, Th B Marcel; de Bie, Rob M; Ackermans, Mariëtte T; Fliers, Eric; Schuurman, P Richard; La Fleur, Susanne E; Serlie, Mireille J

    2014-01-01

    Animal studies have shown that central dopamine signaling influences glucose metabolism. As a first step to show this association in an experimental setting in humans, we studied whether deep brain stimulation (DBS) of the subthalamic nucleus (STN), which modulates the basal ganglia circuitry, alters basal endogenous glucose production (EGP) or insulin sensitivity in patients with Parkinson's disease (PD). We studied 8 patients with PD treated with DBS STN, in the basal state and during a hyperinsulinemic euglycemic clamp using a stable glucose isotope, in the stimulated and non-stimulated condition. We measured EGP, hepatic insulin sensitivity, peripheral insulin sensitivity (Rd), resting energy expenditure (REE), glucoregulatory hormones, and Parkinson symptoms, using the Unified Parkinson's Disease Rating Scale (UPDRS). Basal plasma glucose and EGP did not differ between the stimulated and non-stimulated condition. Hepatic insulin sensitivity was similar in both conditions and there were no significant differences in Rd and plasma glucoregulatory hormones between DBS on and DBS off. UPDRS was significantly higher in the non-stimulated condition. DBS of the STN in patients with PD does not influence basal EGP or insulin sensitivity. These results suggest that acute modulation of the motor basal ganglia circuitry does not affect glucose metabolism in humans.

  1. 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.

  2. mu-Opioid receptor stimulation in the nucleus accumbens elevates fatty tastant intake by increasing palatability and suppressing satiety signals.

    PubMed

    Katsuura, Yoshihiro; Heckmann, Jennifer A; Taha, Sharif A

    2011-07-01

    Infusion of a μ-opioid receptor (MOR) agonist into the nucleus accumbens (NAcc) drives voracious food intake, an effect hypothesized to occur through increased tastant palatability. While intake of many palatable foods is elevated by MOR stimulation, this manipulation has a preferential effect on fatty food ingestion. Consumption of high-fat foods is increased by NAcc MOR stimulation even in rats that prefer a carbohydrate-rich alternative under baseline conditions. This suggests that NAcc MOR stimulation may not simply potentiate palatability signals and raises the possibility that mechanisms mediating fat intake may be distinct from those underlying intake of other tastants. The present study was conducted to investigate the physiological mechanisms underlying the effects of NAcc MOR stimulation on fatty food intake. In experiment 1, we analyzed lick microstructure in rats ingesting Intralipid to identify the changes underlying feeding induced by infusion of a MOR-specific agonist into the NAcc. MOR stimulation in the NAcc core, but not shell, increased burst duration and first-minute licks, while simultaneously increasing the rate and duration of Intralipid ingestion. These results suggest that MOR activation in the core increases Intralipid palatability and attenuates inhibitory postingestive feedback. In experiment 2, we measured the effects of MOR stimulation in the NAcc core on consumption of nonnutritive olestra. A MOR-specific agonist dose dependently increased olestra intake, demonstrating that caloric signaling is not required for hyperphagia induced by NAcc MOR stimulation. Feeding induced by drug infusion in both experiments 1 and 2 was blocked by a MOR antagonist. In experiment 3, we determined whether MOR activation in the NAcc core could attenuate satiety-related signaling caused by infusion of the melanocortin agonist MTII into the third ventricle. Suppression of intake caused by MTII was reversed by MOR stimulation. Together, our results suggest

  3. An Evaluation of Neuroplasticity and Behavior After Deep Brain Stimulation of the Nucleus Accumbens in an Animal Model of Depression

    PubMed Central

    Falowski, Steven M.; Sharan, Ashwini; Reyes, Beverly A. S.; Sikkema, Carl; Szot, Patricia; Van Bockstaele, Elisabeth J.

    2015-01-01

    BACKGROUND Recent interest has demonstrated the nucleus accumbens (NAcc) as a potential target for the treatment of depression with deep brain stimulation (DBS). OBJECTIVE To demonstrate that DBS of the NAcc is an effective treatment modality for depression and that chemical and structural changes associated with these behavioral changes are markers of neuroplasticity. METHODS A deep brain stimulator was placed in the NAcc of male Wistar-Kyoto rats. Groups were divided into sham (no stimulation), intermittent (3 h/d for 2 weeks), or continuous (constant stimulation for 2 weeks). Exploratory and anxietylike behaviors were evaluated with the open-field test before and after stimulation. Tissue samples of the prefrontal cortex (PFC) were processed with Western blot analysis of markers of noradrenergic activity that included the noradrenergic synthesizing enzyme tyrosine hydroxylase. Analysis of tissue levels for catecholamines was achieved with high-performance liquid chromatography. Morphological properties of cortical pyramidal neurons were assessed with Golgi-Cox staining. RESULTS Subjects undergoing intermittent and continuous stimulation of the NAcc exhibited an increase in exploratory behavior and reduced anxietylike behaviors. Tyrosine hydroxylase expression levels were decreased in the PFC after intermittent and continuous DBS, and dopamine and norepinephrine levels were decreased after continuous stimulation. Golgi-Cox staining indicated that DBS increased the length of apical and basilar dendrites in pyramidal neurons of the PFC. CONCLUSION Deep brain stimulation induces behavioral improvement in and neurochemical and morphological alterations of the PFC that demonstrate changes within the circuitry of the brain different from the target area of stimulation. This observed dendritic plasticity may underlie the therapeutic efficacy of this treatment. PMID:21566538

  4. Deep brain stimulation of the nucleus accumbens shell increases impulsive behavior and tissue levels of dopamine and serotonin.

    PubMed

    Sesia, Thibaut; Bulthuis, Vincent; Tan, Sonny; Lim, Lee Wei; Vlamings, Rinske; Blokland, Arjan; Steinbusch, Harry W M; Sharp, Trevor; Visser-Vandewalle, Veerle; Temel, Yasin

    2010-10-01

    The nucleus accumbens (NAc) is gaining interest as a target for deep brain stimulation (DBS) in refractory neuropsychiatric disorders with impulsivity as core symptom. The nucleus accumbens is composed of two subterritories, core and shell, which have different anatomical connections. In animal models, it has been shown that DBS of the NAc changes impulsive action. Here, we tested the hypothesis that a change in impulsive action by DBS of the NAc is associated with changes in dopamine levels. Rats received stimulating electrodes either in the NAc core or shell, and underwent behavioral testing in a reaction time task. In addition, in a second experiment, the effect of DBS of the NAc core and shell on extracellular dopamine and serotonin levels was assessed in the NAc and medial prefrontal cortex. Control subjects received sham surgery. We have found that DBS of the NAc shell stimulation induced more impulsive action but less perseverative checking. These effects were associated with increased levels of dopamine and serotonin in the NAc, but not in the medial prefrontal cortex. DBS of the NAc core had no effect on impulsive action, but decreased perseverative responses indicative of a better impulse control. In these subjects, no effects were found on neurotransmitter levels. Our data point out that DBS of the NAc shell has negative effects on impulsive action which is accompanied by increases of dopamine and serotonin levels in the NAc, whereas DBS of the NAc core has beneficial behavioral effects.

  5. Camptocormia and deep brain stimulation: The interesting overlapping etiologies and the therapeutic role of subthalamic nucleus-deep brain stimulation in Parkinson disease with camptocormia

    PubMed Central

    Ekmekci, Hakan; Kaptan, Hulagu

    2016-01-01

    Background: Camptocormia is known as “bent spine syndrome” and defined as a forward hyperflexion. The most common etiologic factor is related with the movement disorders, mainly in Parkinson's disease (PD). Case Description: We present the case of a 51-year-old woman who has been followed with PD for the last 10 years, and also under the therapy for PD. An unappreciated correlation low back pain with camptocormia developed. She underwent deep brain stimulation (DBS) in the subthalamic nucleus bilaterally and improved her bending posture. Conclusion: The relationship between the DBS and camptocormia is discussed in this unique condition. PMID:26958425

  6. Capgras Syndrome in a Patient with Parkinson's Disease after Bilateral Subthalamic Nucleus Deep Brain Stimulation: A Case Report

    PubMed Central

    Kyrtsos, Christina Rose; Stahl, Mark C.; Eslinger, Paul; Subramanian, Thyagarajan; Lucassen, Elisabeth B.

    2015-01-01

    Capgras syndrome is a delusional misidentification syndrome (DMS) which can be seen in neurodegenerative diseases such as Lewy body dementia and, to a lesser extent, in Parkinson's disease (PD). Here, we report the case of a 78-year-old man with a history of idiopathic PD who developed Capgras syndrome following bilateral subthalamic nucleus deep brain stimulation (DBS) implantation. As the risk of DMS has been related to deficits in executive, memory, and visuospatial function preoperatively, this case highlights the importance of continuing to improve patient selection for DBS surgery. Capgras syndrome is a rare potential complication of DBS surgery in PD patients with preexisting cognitive decline. PMID:26078747

  7. Medial Auditory Thalamus Is Necessary for Acquisition and Retention of Eyeblink Conditioning to Cochlear Nucleus Stimulation

    ERIC Educational Resources Information Center

    Halverson, Hunter E.; Poremba, Amy; Freeman, John H.

    2015-01-01

    Associative learning tasks commonly involve an auditory stimulus, which must be projected through the auditory system to the sites of memory induction for learning to occur. The cochlear nucleus (CN) projection to the pontine nuclei has been posited as the necessary auditory pathway for cerebellar learning, including eyeblink conditioning.…

  8. 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.

  9. Comparison of two methods for selecting minimum stimulation levels used in programming the Nucleus 22 cochlear implant.

    PubMed

    Skinner, M W; Holden, L K; Holden, T A; Demorest, M E

    1999-08-01

    Minimum stimulation levels for active electrodes in a Nucleus 22 cochlear implant were set at threshold (clinical default value) and raised levels (M = +2.04 dB) to determine if raised levels would improve recipients' understanding of soft speech sounds with the SPEAK speech coding strategy. Eight postlinguistically deaf adults participated in a 4-phase A1B1A2B2 test design. Speech recognition was evaluated with consonant-vowel nucleus-consonant (CNC) words in quiet and sentences in noise, both presented at 50, 60, and 70 dB SPL during 2 weekly sessions at the end of each phase. Group mean scores were significantly higher with the raised level program for words and phonemes at 50 and 60 dB SPL and for sentences at 50 and 70 dB SPL. All participants chose to use the raised level program in everyday life at the end of the study. The results suggest that clinical use of a raised level program for Nucleus 22 recipients has the potential to make soft sounds louder and, therefore, more salient in everyday life. Further research is needed to determine if this approach is appropriate for other cochlear implant devices.

  10. Population synaptic potentials evoked in lumbar motoneurons following stimulation of the nucleus reticularis gigantocellularis during carbachol-induced atonia.

    PubMed

    Yamuy, J; Jiménez, I; Morales, F; Rudomin, P; Chase, M

    1994-03-14

    The effect of electrical stimulation of the medullary nucleus reticularis gigantocellularis (NRGc) on lumbar spinal cord motoneurons was studied in the decerebrate cat using sucrose-gap recordings from ventral roots. The NRGc was stimulated ipsi- and contralaterally before and during atonia elicited by the microinjection of carbachol into the pontine reticular formation. Prior to carbachol administration, the NRGc-induced response recorded from the sucrose-gap consisted of two consecutive excitatory population synaptic potentials followed by a long-lasting, small amplitude inhibitory population synaptic potential. Following carbachol injection, the same NRGc stimulus evoked a distinct, large amplitude inhibitory population synaptic potential, whereas the excitatory population synaptic potentials decreased in amplitude. In addition, after carbachol administration, the amplitude of the monosynaptic excitatory population synaptic potential, which was evoked by stimulation of group Ia afferents in hindlimb nerves, was reduced by 18 to 43%. When evoked at the peak of the NRGc-induced inhibitory response, this potential was further decreased in amplitude. Systemic strychnine administration (0.07-0.1 mg/kg, i.v.) blocked the NRGc-induced inhibitory population synaptic potential and promoted an increase in the amplitude of the excitatory population synaptic potentials induced by stimulation of the NRGc and group Ia afferents. These data indicate that during the state of carbachol-induced atonia, the NRGc effects on ipsi- and contralateral spinal cord motoneurons are predominantly inhibitory and that glycine is likely to be involved in this inhibitory process. These results support the hypothesis that the nucleus reticularis gigantocellularis is part of the system responsible for state-dependent somatomotor inhibition that occurs during active sleep.

  11. Ethanol injected into the hypothalamic arcuate nucleus induces behavioral stimulation in rats: an effect prevented by catalase inhibition and naltrexone.

    PubMed

    Pastor, Raúl; Aragon, Carlos M G

    2008-10-01

    It is suggested that some of the behavioral effects of ethanol, including its psychomotor properties, are mediated by beta-endorphin and opioid receptors. Ethanol-induced increases in the release of hypothalamic beta-endorphin depend on the catalasemic conversion of ethanol to acetaldehyde. Here, we evaluated the locomotor activity in rats microinjected with ethanol directly into the hypothalamic arcuate nucleus (ArcN), the main site of beta-endorphin synthesis in the brain and a region with high levels of catalase expression. Intra-ArcN ethanol-induced changes in motor activity were also investigated in rats pretreated with the opioid receptor antagonist, naltrexone (0-2 mg/kg) or the catalase inhibitor 3-amino-1,2,4-triazole (AT; 0-1 g/kg). We found that ethanol microinjections of 64 or 128, but not 256 microg, produced locomotor stimulation. Intra-ArcN ethanol (128 microg)-induced activation was prevented by naltrexone and AT, whereas these compounds did not affect spontaneous activity. The present results support earlier evidence indicating that the ArcN and the beta-endorphinic neurons of this nucleus are necessary for ethanol to induce stimulation. In addition, our data suggest that brain structures that, as the ArcN, are rich in catalase may support the formation of ethanol-derived pharmacologically relevant concentrations of acetaldehyde and, thus be of particular importance for the behavioral effects of ethanol.

  12. Burst-firing activity of presumed 5-HT neurones of the rat dorsal raphe nucleus: electrophysiological analysis by antidromic stimulation.

    PubMed

    Hajós, M; Sharp, T

    1996-11-18

    We recently reported raphe neurones which frequently fired spikes in short bursts. However, the action potentials were broad and the neurones fired in a slow and regular pattern, suggesting they were an unusual type of 5-hydroxytryptamine (5-HT) neurone. In the present study, we investigated whether these putative burst-firing 5-HT neurones project to the forebrain and whether all spikes fired in bursts propagate along the axon. In anaesthetised rats, electrical stimulation of the medial forebrain bundle evoked antidromic spikes in both burst-firing neurones and in single-spiking, classical 5-HT neurones recorded in the dorsal raphe nucleus. Although the antidromic spike latency of the single-spiking and burst-firing neurones showed a clear overlap, burst-firing neurones had a significantly shorter latency than single-spiking neurones. For both burst-firing neurones and classical 5-HT neurones, antidromic spikes made collisions with spontaneously occurring spikes. Furthermore, in all burst-firing neurones tested, first, second and third order spikes in a burst could be made to collide with antidromic spike. Interestingly, in a small number of burst-firing neurones, antidromic stimulation evoked spike doublets, similar to those recorded spontaneously. From these data we conclude that burst-firing neurones in the dorsal raphe nucleus project to the forebrain, and each spike generated by the burst propagates along the axon and could thereby release transmitter (5-HT).

  13. Parafascicular thalamic nucleus deep brain stimulation decreases NMDA receptor GluN1 subunit gene expression in the prefrontal cortex.

    PubMed

    Fernández-Cabrera, Mónica R; Selvas, Abraham; Miguéns, Miguel; Higuera-Matas, Alejandro; Vale-Martínez, Anna; Ambrosio, Emilio; Martí-Nicolovius, Margarita; Guillazo-Blanch, Gemma

    2017-04-21

    The rodent parafascicular nucleus (PFn) or the centromedian-parafascicular complex of primates is a posterior intralaminar nucleus of the thalamus related to cortical activation and maintenance of states of consciousness underlying attention, learning and memory. Deep brain stimulation (DBS) of the PFn has been proved to restore arousal and consciousness in humans and to enhance performance in learning and memory tasks in rats. The primary expected effect of PFn DBS is to induce plastic changes in target neurons of brain areas associated with cognitive function. In this study, Wistar rats were stimulated for 20mins in the PFn following a DBS protocol that had previously facilitated memory in rats. NMDA and GABAB receptor binding, and gene expression of the GluN1subunit of the NMDA receptor (NMDAR) were assessed in regions related to cognitive functions, such as the prefrontal cortex and hippocampus. The results showed that PFn DBS induced a decrease in NMDAR GluN1 subunit gene expression in the cingulate and prelimbic cortices, but no significant statistical differences were found in the density of NMDA or GABAB receptors in any of the analyzed regions. Taken together, our findings suggest a possible role for the NMDAR GluN1 subunit in the prefrontal cortex in the procognitive actions of the PFn DBS.

  14. Acamprosate blocks the increase in dopamine extracellular levels in nucleus accumbens evoked by chemical stimulation of the ventral hippocampus.

    PubMed

    Cano-Cebrián, M J; Zornoza-Sabina, T; Guerri, C; Polache, A; Granero, L

    2003-10-01

    Recently, we have shown that acamprosate is able to modulate extracellular dopamine (DA) levels in the nucleus accumbens (NAc) and may act as an antagonist of N-methyl-D-aspartate (NMDA) receptors. Neurochemical studies show that chemical stimulation (using NMDA) of the ventral subiculum (vSub) of the hippocampus produces robust and sustained increases in extracellular DA levels in the NAc, an effect mediated through ionotropic glutamate (iGlu) receptors. The present study examines whether acamprosate locally infused in the NAc of rats could block or attenuate the increase in NAc extracellular DA elicited by chemical stimulation (with 5 mM NMDA) of the ventral subiculum of the hippocampus. The stimulation of the vSub during perfusion of artificial cerebrospinal fluid in NAc induced a significant and persistent increase in NAc DA levels. Reverse dialysis of 0.05 mM acamprosate in NAc blocked the increase in DA evoked by the chemical stimulation of the vSub. These data support the possibility that the antagonism at the NMDA receptors in NAc can explain, at least in part, the mechanism of action of this drug.

  15. Analysis of Gene Expression Changes in the Rat Hippocampus After Deep Brain Stimulation of the Anterior Thalamic Nucleus

    PubMed Central

    Selvakumar, Tharakeswari; Alavian, Kambiz N.; Tierney, Travis

    2015-01-01

    Deep brain stimulation (DBS) surgery, targeting various regions of the brain such as the basal ganglia, thalamus, and subthalamic regions, is an effective treatment for several movement disorders that have failed to respond to medication. Recent progress in the field of DBS surgery has begun to extend the application of this surgical technique to other conditions as diverse as morbid obesity, depression and obsessive compulsive disorder. Despite these expanding indications, little is known about the underlying physiological mechanisms that facilitate the beneficial effects of DBS surgery. One approach to this question is to perform gene expression analysis in neurons that receive the electrical stimulation. Previous studies have shown that neurogenesis in the rat dentate gyrus is elicited in DBS targeting of the anterior nucleus of the thalamus1. DBS surgery targeting the ATN is used widely for treatment refractory epilepsy. It is thus of much interest for us to explore the transcriptional changes induced by electrically stimulating the ATN. In this manuscript, we describe our methodologies for stereotactically-guided DBS surgery targeting the ATN in adult male Wistar rats. We also discuss the subsequent steps for tissue dissection, RNA isolation, cDNA preparation and quantitative RT-PCR for measuring gene expression changes. This method could be applied and modified for stimulating the basal ganglia and other regions of the brain commonly clinically targeted. The gene expression study described here assumes a candidate target gene approach for discovering molecular players that could be directing the mechanism for DBS. PMID:25867749

  16. Electrical resistance increases at the tissue-electrode interface as an early response to nucleus accumbens deep brain stimulation.

    PubMed

    Kale, Rajas P; Kouzani, Abbas Z; Berk, Julian; Walder, Ken; Berk, Michael; Tye, Susannah J

    2016-08-01

    The therapeutic actions of deep brain stimulation are not fully understood. The early inflammatory response of electrode implantation is associated with symptom relief without electrical stimulation, but is negated by anti-inflammatory drugs. Early excitotoxic necrosis and subsequent glial scarring modulate the conductivity of the tissue-electrode interface, which can provide some detail into the inflammatory response of individual patients. The feasibility of this was demonstrated by measuring resistance values across a bipolar electrode which was unilaterally implanted into the nucleus accumbens of a rat while receiving continuous deep brain stimulation with a portable back-mounted device using clinical parameters (130Hz, 200μA, 90μs) for 3 days. Daily resistance values rose significantly (p<;0.0001), while hourly resistance analysis demonstrated a plateau after an initial spike in resistance, which was then followed by a steady increase (p<;0.05; p<;0.0001). We discuss that the biphasic nature of the inflammatory response may contribute to these observations and conclude that this method may translate to a safe predictive screening for more effective clinical deep brain stimulation.

  17. Deep brain stimulation of the globus pallidus internus or ventralis intermedius nucleus of thalamus for Holmes tremor.

    PubMed

    Espinoza Martinez, Jairo Alberto; Arango, Gabriel J; Fonoff, Erich Talamoni; Reithmeier, Thomas; Escobar, Oscar Andrés; Furlanetti, Luciano; Alvarez Berastegui, G Rene; Fernandes da Silva, Fabio Eduardo; Contreras Lopez, William Omar

    2015-10-01

    Holmes tremor (HT) is a difficult-to-treat, very disabling symptomatic condition which characteristically appears weeks to years after a brain lesion. It features a unique combination of rest, action, and postural tremors. Pharmacotherapy is mostly not effective. Chronic deep brain stimulation (DBS) of ventralis intermedius nucleus (Vim) of thalamus has been described as being the best surgical approach in singular case series; various authors observe, however, cases with partial responses only; therefore, alternatives are still needed. We report ten patients with HT unresponsive to best medical therapy who underwent DBS in our center from March 2002 to June 2012. Based in our previous experience dealing with cases of unsatisfactory Vim intraoperative tremor control and in order to optimize surgical results, presurgical target planning included two Nuclei: Vim and posteroventral Globus pallidus internus (GPi) (Espinoza et al. 2010; Espinoza et al. Stereotact Funct Neurosurg 90(suppl 1):1-202, p 61, 2012). Definitive chosen target was decided after single-cell microelectrode recording, intraoperative test stimulation, thresholds for stimulation-induced adverse effects and best clinical response compared to baseline status. Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) was used to evaluate outcome. The electrode was implanted in the nucleus with the best tremor suppression achievement; on the other hand, GPi DBS was initially decided if one of the following conditions was present: (a) If Vim nucleus anatomy was grossly altered; (b) when intraoperative tremor control was unsatisfactory despite Vim high-intensity stimulation; or (c) if unaffordable side effects or even tremor worsening occurred during intraoperative macrostimulation. Seven patients received definitive Gpi DBS implantation, while three patients received Vim DBS. In all observed cases, we observed an improvement on the TRS. In two cases where Vim thalamic anatomy was altered by the pathological insult

  18. Effects of ventro-medial mesencephalic tegmentum (VMT) stimulation on the spontaneous activity of nucleus accumbens neurones: influence of the dopamine system.

    PubMed

    Le Douarin, C; Penit, J; Glowinski, J; Thierry, A M

    1986-01-22

    The effects of VMT-stimulation (100-500 microA, 0.6 ms; 1 Hz) on the spontaneous activity of neurones in the nucleus accumbens were analyzed in ketamine-anaesthetized rats. On spontaneously active cells (firing greater than 0.5 spikes/s), 3 types of responses were observed: either inhibition (36%), excitation (5%) or a composite sequence of excitation followed by inhibition (12%). Moreover, 14% of silent nucleus accumbens neurones were excited by single pulse VMT-stimulation. Finally, 3% of nucleus accumbens neurones recorded were driven antidromically by VMT-stimulation. Destruction of dopamine (DA) projections by 6-hydroxydopamine prevented the inhibitory responses to VMT stimulation in the great majority of cells studied, without affecting the excitatory responses. After systemic administration of haloperidol or sulpiride, the inhibitory responses to VMT stimulation were attenuated markedly, whilst the excitatory responses were, however, maintained. These results suggest that the inhibitory, but not the excitatory, effects of VMT-stimulation on nucleus accumbens neurones may be mediated by an activation of the mesolimbic DA system.

  19. Microinfusion of nefazodone into the basolateral nucleus of the amygdala enhances defensive behavior induced by NMDA stimulation of the inferior colliculus.

    PubMed

    Maisonnette, S; Villela, C; Carotti, A P; Landeira-Fernandez, J

    2000-01-01

    The inferior colliculus is notably associated with defensive behavior. Electrical or pharmacological stimulation of the inferior colliculus induces aversive reactions such as running and jumping. Lesion of the basolateral nucleus of the amygdala decreases the threshold of aversive reactions induced by electrical stimulation of the inferior colliculus. The present work examined the influence of microinjections of nefazodone, a serotonin (5-HT(2)) antagonist, into the basolateral nucleus of amygdala on aversive reactions induced by N-methyl-D-aspartate (NMDA) microinjected into the inferior colliculus. Rats implanted with cannulae in the inferior colliculus and in the basolateral nucleus of the amygdala were submitted to the open-field test where defensive behaviors were observed. Results indicated that microinjection of nefazodone into the basolateral nucleus of the amygdala increases aversive responses induced by NMDA injections into the inferior colliculus. This result suggests that the inferior colliculus and the basolateral nucleus of the amygdala have a functional relationship on the neural circuitry of defensive behavior. Moreover, 5-HT(2) receptors located at the basolateral nucleus of the amygdala seem to play an inhibitory role on defensive behaviors induced by inferior colliculus stimulation.

  20. Electrical stimulation of the hypothalamic nucleus paraventricularis mimics the effects of light on pineal melatonin synthesis

    SciTech Connect

    Olcese, J.; Reuss, S.; Steinlechner, S.

    1987-02-02

    In an attempt to clarify further the role of the hypothalamic paraventricular nuclei (PVN) in the control of pineal function, the effects of 2 min electrical stimulation of these nuclei were investigated in acutely blinded, adult, male Sprague-Dawley rats. Pineal serotonin-N-acetyltransferase (NAT) activity, melatonin content and catecholamine levels were measured by means of radio-enzymatic, radioimmunoassay and high-performance liquid-chromatography methods, respectively. All three pineal parameters underwent significant declines following brief PVN stimulation during the night time. These observations lend credence to the view that the neural pathways transmitting light information to the sympathetic innervation controlling pineal melatonin synthesis. 22 references, 1 figure.

  1. Deep brain stimulation of the ventral intermediate nucleus of the thalamus in medically refractory orthostatic tremor: preliminary observations.

    PubMed

    Espay, Alberto J; Duker, Andrew P; Chen, Robert; Okun, Michael S; Barrett, Edwin T; Devoto, Johnna; Zeilman, Pamela; Gartner, Maureen; Burton, Noël; Miranda, Helard A; Mandybur, George T; Zesiewicz, Theresa A; Foote, Kelly D; Revilla, Fredy J

    2008-12-15

    Orthostatic tremor (OT) is a disabling movement disorder associated with postural and gait impairment in the elderly. Medical therapy often yields insufficient benefit. We report the clinical and electrophysiological data on two patients with medication-refractory OT treated with deep brain stimulation of the ventral intermediate thalamic nucleus (Vim DBS). Patient 1 underwent bilateral deep brain stimulation (DBS) and Patient 2 unilateral Vim DBS following 28 and 30 years of disease duration, respectively. Both patients showed increased latency to symptom onset after rising from a seated position, improved tolerance for prolonged standing, and slower crescendo of tremor severity when remaining upright. Postoperative evaluation demonstrated decreased amplitude of electromyographic activity with persistence of well-defined oscillatory behavior showing strong coherence at 15 Hz between all muscles tested in the upper and lower limbs. Postural sway was unchanged. Clinical benefits have been sustained for over 18 months in Patient 1, and receded after 3 months in Patient 2. These findings support the consideration of bilateral Vim DBS implantation as a therapeutic option in patients with medically refractory OT. Further efficacy studies on chronic stimulation to disrupt the abnormal oscillatory activity in this disorder are warranted.

  2. Low-frequency stimulation of the tuberomammillary nucleus facilitates electrical amygdaloid-kindling acquisition in Sprague-Dawley rats.

    PubMed

    Wu, Deng-Chang; Zhu-Ge, Zheng-Bing; Yu, Chao-Yang; Fang, Qi; Wang, Shuang; Jin, Chun-Lei; Zhang, Shi-Hong; Chen, Zhong

    2008-10-01

    Histamine plays a suppressive role in seizure. The tuberomammillary nucleus (TM) is the only locus of histaminergic neurons in the brain. To determine whether deep brain stimulation (DBS) of the TM provides protection against seizures, we tested the effects of low-frequency stimulation (LFS, 1 Hz), high frequency stimulation (HFS, 100 Hz), and electrolytic lesions of the TM on seizures generated by amygdaloid kindling, pentylenetetrazol (PTZ) and maximal electroshock (MES) in rats. LFS of TM accelerated the progression of behavioral seizure stage and increased the mean afterdischarge duration (ADD) during acquisition of amygdaloid-kindling seizures, but had no considerable anticonvulsive effect in fully kindled animals. It augmented the MES-induced seizures as well, but had no appreciable effects on PTZ-kindled seizures. In addition, both HFS and bilateral lesions of the TM exacerbated the progression of amygdaloid-kindling seizures. These results suggest that specific negative sites for DBS exist in the brain, such as the TM. This study indicates that it is crucial to choose a suitable target for DBS in the clinical treatment of epilepsy.

  3. Improvement of Advanced Parkinson's Disease Manifestations with Deep Brain Stimulation of the Subthalamic Nucleus: A Single Institution Experience.

    PubMed

    Rabie, Ahmed; Verhagen Metman, Leo; Fakhry, Mazen; Eassa, Ayman Youssef Ezeldin; Fouad, Wael; Shakal, Ahmed; Slavin, Konstantin V

    2016-12-13

    We present our experience at the University of Illinois at Chicago (UIC) in deep brain stimulation (DBS) of the subthalamic nucleus (STN), describing our surgical technique, and reporting our clinical results, and morbidities. Twenty patients with advanced Parkinson's disease (PD) who underwent bilateral STN-DBS were studied. Patients were assessed preoperatively and followed up for one year using the Unified Parkinson's Disease Rating Scale (UPDRS) in "on" and "off" medication and "on" and "off" stimulation conditions. At one-year follow-up, we calculated significant improvement in all the motor aspects of PD (UPDRS III) and in activities of daily living (UPDRS II) in the "off" medication state. The "off" medication UPDRS improved by 49.3%, tremors improved by 81.6%, rigidity improved by 50.0%, and bradykinesia improved by 39.3%. The "off" medication UPDRS II scores improved by 73.8%. The Levodopa equivalent daily dose was reduced by 54.1%. The UPDRS IVa score (dyskinesia) was reduced by 65.1%. The UPDRS IVb score (motor fluctuation) was reduced by 48.6%. Deep brain stimulation of the STN improves the cardinal motor manifestations of the idiopathic PD. It also improves activities of daily living, and reduces medication-induced complications.

  4. Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: From history to the interaction with the monoaminergic systems.

    PubMed

    Faggiani, E; Benazzouz, A

    2017-04-01

    Parkinson's disease is the second most common neurodegenerative disorder, characterized by the manifestation of motor symptoms, which are mainly attributed to the degeneration of dopamine neurons in the pars compacta of substantia nigra. Based on advancements in the understanding of the pathophysiology of the disease, especially in animal models, the subthalamic nucleus has been pointed as a major target for deep brain stimulation in the treatment of motor symptoms, first developed in non-human primate and then successfully transfered to parkinsonian patients. Nevertheless, despite the focus on motor deficits, Parkinson's disease is also characterized by the manifestation of non-motor symptoms, which can be due to the additional degeneration of norepinephrine, serotonin and cholinergic systems. The pathophysiology of the non-motor symptoms is under studied and consequently not well treated. Furthermore, data from the literature about the impact of subthalamic deep brain stimulation on non-motor disorders are controversial and still under debate. Similarly, the risk of mood disorders post-deep brain stimulation surgery remains also controversial. Here, we review the clinical and experimental data of this neurosurgical approach on motor and non-motor behaviors and provide evidence for its interaction with the monoaminergic systems.

  5. Improvement of Advanced Parkinson’s Disease Manifestations with Deep Brain Stimulation of the Subthalamic Nucleus: A Single Institution Experience

    PubMed Central

    Rabie, Ahmed; Verhagen Metman, Leo; Fakhry, Mazen; Eassa, Ayman Youssef Ezeldin; Fouad, Wael; Shakal, Ahmed; Slavin, Konstantin V.

    2016-01-01

    We present our experience at the University of Illinois at Chicago (UIC) in deep brain stimulation (DBS) of the subthalamic nucleus (STN), describing our surgical technique, and reporting our clinical results, and morbidities. Twenty patients with advanced Parkinson’s disease (PD) who underwent bilateral STN-DBS were studied. Patients were assessed preoperatively and followed up for one year using the Unified Parkinson’s Disease Rating Scale (UPDRS) in “on” and “off” medication and “on” and “off” stimulation conditions. At one-year follow-up, we calculated significant improvement in all the motor aspects of PD (UPDRS III) and in activities of daily living (UPDRS II) in the “off” medication state. The “off” medication UPDRS improved by 49.3%, tremors improved by 81.6%, rigidity improved by 50.0%, and bradykinesia improved by 39.3%. The “off” medication UPDRS II scores improved by 73.8%. The Levodopa equivalent daily dose was reduced by 54.1%. The UPDRS IVa score (dyskinesia) was reduced by 65.1%. The UPDRS IVb score (motor fluctuation) was reduced by 48.6%. Deep brain stimulation of the STN improves the cardinal motor manifestations of the idiopathic PD. It also improves activities of daily living, and reduces medication-induced complications. PMID:27983589

  6. Subthalamic Nucleus Stimulation Modulates Motor Cortex Oscillatory Activity in Parkinson's Disease

    ERIC Educational Resources Information Center

    Devos, D.; Labyt, E.; Derambure, P.; Bourriez, J. L.; Cassim, F.; Reyns, N.; Blond, S.; Guieu, J. D.; Destee, A.; Defebvre, L.

    2004-01-01

    In Parkinson's disease, impaired motor preparation has been related to an increased latency in the appearance of movement-related desynchronization (MRD) throughout the contralateral primary sensorimotor (PSM) cortex. Internal globus pallidus (GPi) stimulation improved movement desynchronization over the PSM cortex during movement execution but…

  7. 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.

  8. Cervical Stimulation Activates A1 and Locus Coeruleus Neurons that Project to the Paraventricular Nucleus of the Hypothalamus

    PubMed Central

    Poletini, Maristela O.; McKee, De’Nise T.; Szawka, Raphael E.; Bertram, Richard; Helena, Cleyde V. V.; Freeman, Marc E.

    2012-01-01

    In female rats, stimulation of the uterine cervix during mating induces two daily surges of prolactin. Inhibition of hypothalamic dopamine release and stimulation of oxytocin neurons in the paraventricular nucleus (PVN) are required for prolactin secretion. We aim to better understand how stimulation of the uterine cervix is translated into two daily prolactin surges. We hypothesize that noradrenergic neurons in the A1, A2, and locus coeruleus (LC) are responsible for conveying the peripheral stimulus to the PVN. In order to determine whether projections from these neurons to the PVN are activated by cervical stimulation (CS), we injected a retrograde tracer, Fluoro-Gold (FG), into the PVN of ovariectomized rats. Fourteen days after injection, animals were submitted to artificial CS or handling and perfused with a fixative solution. Brains were removed and sectioned from the A1, A2, and LC for c-Fos, tyrosine hydroxylase (TH), and FG triple-labeling using immunohistochemistry. CS increased the percentage of TH/FG+ double-labeled neurons expressing c-Fos in the A1 and LC. CS also increased the percentage of TH+ neurons expressing c-Fos within the A1 and A2, independent of their projections to the PVN. Our data reinforce the significant contributions of the A1 and A2 to carry sensory information during mating, and provide evidence of a functional pathway in which CS activates A1 and LC neurons projecting to the PVN, which is potentially involved in the translation of CS into two daily prolactin surges. PMID:22732530

  9. Peripheral osmotic stimulation inhibits the brain's innate immune response to microdialysis of acidic perfusion fluid adjacent to supraoptic nucleus

    PubMed Central

    Hu, Sanmei

    2009-01-01

    During the brain's innate immune response microglia, astroglia and ependymal cells resolve/repair damaged tissue and control infection. Released interleukin-1β (IL-1β) reaching cerebroventricles stimulates circumventricular organs (CVOs; subfornical organ, SFO; organum vasculosum lamina terminalis, OVLT), the median preoptic nucleus (MePO), and magnocellular and parvocellular neurons in the supraoptic (SON) and paraventricular (PVN) nuclei. Hypertonic saline (HS) also activates these osmosensory CVOs and neuroendocrine systems, but, in contrast to IL-1β, inhibits the peripheral immune response. To examine whether the brain's innate immune response is attenuated by osmotic stimulation, sterile acidic perfusion fluid was microdialyzed (2 μl/min) in the SON area of conscious rats for 6 h with sterile HS (1.5 M NaCl) injected subcutaneously (15 ml/kg) at 5 h. Immunohistochemistry identified cytokine sources (IL-1β+; OX-42+ microglia) and targets (IL-1R+; inducible cyclooxygenase, COX-2+; c-Fos+) near the probe, in CVOs, MePO, ependymal cells, periventricular hypothalamus, SON, and PVN. Inserting the probe stimulated magnocellular neurons (c-Fos+; SON; PVN) via the MePO (c-Fos+), a response enhanced by HS. Microdialysis activated microglia (OX-42+; amoeboid/hypertrophied; IL-1β+) in the adjacent SON and bilaterally in perivascular areas of the PVN, periventricular hypothalamus and ependyma, coincident with c-Fos expression in ependymal cells and COX-2 in the vasculature. These microglial responses were attenuated by HS, coincident with activating parvocellular and magnocellular neuroendocrine systems and elevating circulating IL-1β, oxytocin, and vasopressin. Acidosis-induced cellular injury from microdialysis activated the brain's innate immune response by a mechanism inhibited by peripheral osmotic stimulation. PMID:19759333

  10. Selective serotonin receptor stimulation of the medial nucleus accumbens causes differential effects on food intake and locomotion.

    PubMed

    Pratt, Wayne E; Blackstone, Kaitlin; Connolly, Megan E; Skelly, Mary Jane

    2009-10-01

    Substantial evidence suggests that pharmacological manipulations of neural serotonin pathways influence ingestive behaviors. Despite the known role of the nucleus accumbens in directing appetitive and consummatory behavior, there has been little examination of the influences that serotonin receptors may play in modulating feeding within nucleus accumbens circuitry. In these experiments, the authors examined the effects of bilateral nucleus accumbens infusions of the 5-HT1/7 receptor agonist 5-CT (at 0.0, 0.5, 1.0, or 4.0 microg/0.5 microl/side), the 5-HT receptor agonist EMD 386088 (at 0.0, 1.0, and 4.0 microg/0.5 microl/side), or the 5-HT2C preferential agonist RO 60-0175 (at 0.0, 2.0, or 5.0 microg/0.5 microl/side) on food intake and locomotor activity in the rat. Intra-accumbens infusions of 5-CT caused a dose-dependent reduction of food intake and rearing behavior, both in food-restricted animals given 2-hr free access to Purina Protab RMH 3000 Chow, as well as in nondeprived rats offered 2-hr access to a highly palatable fat/sucrose diet. In contrast, stimulation of 5-HT receptors with EMD 386088 caused a dose-dependent increase of intake under both feeding conditions, without affecting measures of locomotion. Infusions of the moderately selective 5-HT2C receptor agonist RO 60-0175 had no effects on feeding or locomotor measures in food-restricted animals, but did reduce intake of the fat/sucrose in nonrestricted animals at the 2.0 microg, but not the 5.0 microg dose. Intra-accumbens infusions of selective antagonists for the 5-HT (SB 269970), 5-HT (SB 252585), and 5-HT2C (RS 102221) receptors did not affect locomotion, and demonstrated no lasting changes in feeding for any of the groups tested. These data are the first to suggest that the activation of different serotonin receptor subtypes within the feeding circuitry of the medial nucleus accumbens differentially influence consummatory behavior.

  11. Anatomo-clinical correlation of intraoperative stimulation-induced side-effects during HF-DBS of the subthalamic nucleus.

    PubMed

    Tamma, F; Caputo, E; Chiesa, V; Egidi, M; Locatelli, M; Rampini, P; Cinnante, C; Pesenti, A; Priori, A

    2002-09-01

    The efficacy of deep brain stimulation of the subthalamic nucleus (STN) is dependent on the accuracy of targeting. In order to reduce the number of passes and, consequently, the duration of surgery and risk of bleeding, we have set up a new method based on direct magnetic resonance imaging (MRI) localisation of the STN. This procedure allows a short duration of the neurophysiological session (one or two initial tracks). Whenever a supplementary track is needed, the stimulation-induced side effects are analysed to choose from one of the remaining holes in Ben's gun. A good knowledge of anatomical structures surrounding the STN is mandatory to relate side effects to the actual position of the track. In our series of 11 patients (22 sides, 37 tracks), the most common and reproducible side effects were those characterised by motor, sensorial, oculomotor and vegetative signs and symptoms. Moreover, the therapeutic window (distance between the current intensity needed to obtain the best clinical effect and the intensity capable to induce side effects) predicted clinical efficacy in the long-term, and contributed to the choice of which among the examined tracks had to be implanted with the chronic macroelectrode.

  12. 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.

  13. The angiotensin II-AT1 receptor stimulates reactive oxygen species within the cell nucleus

    SciTech Connect

    Pendergrass, Karl D.; Gwathmey, TanYa M.; Michalek, Ryan D.; Grayson, Jason M.; Chappell, Mark C.

    2009-06-26

    We and others have reported significant expression of the Ang II Type 1 receptor (AT1R) on renal nuclei; thus, the present study assessed the functional pathways and distribution of the intracellular AT1R on isolated nuclei. Ang II (1 nM) stimulated DCF fluorescence, an intranuclear indicator of reactive oxygen species (ROS), while the AT1R antagonist losartan or the NADPH oxidase (NOX) inhibitor DPI abolished the increase in ROS. Dual labeling of nuclei with antibodies against nucleoporin 62 (Nup62) and AT1R or the NADPH oxidase isoform NOX4 revealed complete overlap of the Nup62 and AT1R (99%) by flow cytometry, while NOX4 was present on 65% of nuclei. Treatment of nuclei with a PKC agonist increased ROS while the PKC inhibitor GF109203X or PI3 kinase inhibitor LY294002 abolished Ang II stimulation of ROS. We conclude that the Ang II-AT1R-PKC axis may directly influence nuclear function within the kidney through a redox sensitive pathway.

  14. 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…

  15. 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…

  16. Deep Brain Stimulation of Medial Dorsal and Ventral Anterior Nucleus of the Thalamus in OCD: A Retrospective Case Series

    PubMed Central

    Lenartz, Doris; Kuhn, Jens; Sturm, Volker

    2016-01-01

    Background The current notion that cortico-striato-thalamo-cortical circuits are involved in the pathophysiology of obsessive-compulsive disorder (OCD) has instigated the search for the most suitable target for deep brain stimulation (DBS). However, despite extensive research, uncertainty about the ideal target remains with many structures being underexplored. The aim of this report is to address a new target for DBS, the medial dorsal (MD) and the ventral anterior (VA) nucleus of the thalamus, which has thus far received little attention in the treatment of OCD. Methods In this retrospective trial, four patients (three female, one male) aged 31–48 years, suffering from therapy-refractory OCD underwent high-frequency DBS of the MD and VA. In two patients (de novo group) the thalamus was chosen as a primary target for DBS, whereas in two patients (rescue DBS group) lead implantation was performed in a rescue DBS attempt following unsuccessful primary stimulation. Results Continuous thalamic stimulation yielded no significant improvement in OCD symptom severity. Over the course of thalamic DBS symptoms improved in only one patient who showed “partial response” on the Yale-Brown Obsessive Compulsive (Y-BOCS) Scale. Beck Depression Inventory scores dropped by around 46% in the de novo group; anxiety symptoms improved by up to 34%. In the de novo DBS group no effect of DBS on anxiety and mood was observable. Conclusion MD/VA-DBS yielded no adequate alleviation of therapy-refractory OCD, the overall strategy in targeting MD/VA as described in this paper can thus not be recommended in DBS for OCD. The magnocellular portion of MD (MDMC), however, might prove a promising target in the treatment of mood related and anxiety disorders. PMID:27504631

  17. GLP-1 Receptor Stimulation of the Lateral Parabrachial Nucleus Reduces Food Intake: Neuroanatomical, Electrophysiological, and Behavioral Evidence

    PubMed Central

    Richard, Jennifer E.; Farkas, Imre; Anesten, Fredrik; Anderberg, Rozita H.; Dickson, Suzanne L.; Gribble, Fiona M.; Reimann, Frank; Jansson, John-Olov; Liposits, Zsolt

    2014-01-01

    The parabrachial nucleus (PBN) is a key nucleus for the regulation of feeding behavior. Inhibitory inputs from the hypothalamus to the PBN play a crucial role in the normal maintenance of feeding behavior, because their loss leads to starvation. Viscerosensory stimuli result in neuronal activation of the PBN. However, the origin and neurochemical identity of the excitatory neuronal input to the PBN remain largely unexplored. Here, we hypothesize that hindbrain glucagon-like peptide 1 (GLP-1) neurons provide excitatory inputs to the PBN, activation of which may lead to a reduction in feeding behavior. Our data, obtained from mice expressing the yellow fluorescent protein in GLP-1-producing neurons, revealed that hindbrain GLP-1-producing neurons project to the lateral PBN (lPBN). Stimulation of lPBN GLP-1 receptors (GLP-1Rs) reduced the intake of chow and palatable food and decreased body weight in rats. It also activated lPBN neurons, reflected by an increase in the number of c-Fos-positive cells in this region. Further support for an excitatory role of GLP-1 in the PBN is provided by electrophysiological studies showing a remarkable increase in firing of lPBN neurons after Exendin-4 application. We show that within the PBN, GLP-1R activation increased gene expression of 2 energy balance regulating peptides, calcitonin gene-related peptide (CGRP) and IL-6. Moreover, nearly 70% of the lPBN GLP-1 fibers innervated lPBN CGRP neurons. Direct intra-lPBN CGRP application resulted in anorexia. Collectively, our molecular, anatomical, electrophysiological, pharmacological, and behavioral data provide evidence for a functional role of the GLP-1R for feeding control in the PBN. PMID:25116706

  18. The non-peptide neurokinin-1 antagonist, RPR 100893, decreases c-fos expression in trigeminal nucleus caudalis following noxious chemical meningeal stimulation.

    PubMed

    Cutrer, F M; Moussaoui, S; Garret, C; Moskowitz, M A

    1995-02-01

    The effect of RPR 100893, a selective and specific neurokinin-1 antagonist, or its enantiomer RPR 103253 was examined on c-fos antigen expression in brain stem and upper cervical cord 2 h after intracisternal capsaicin injection (30.5 micrograms/ml) in pentobarbital-anesthetized Hartley guinea-pigs. Positive cells were counted at three levels corresponding to obex, -2.25 mm and -6.75 mm in 18 sections (50 microns). Immunoreactivity was strongly expressed within laminae I and IIo of trigeminal nucleus caudalis, area postrema and the leptomeninges. Moderate labeling was present in the nucleus of the solitary tract and the medullary lateral reticular nucleus, whereas few positive cells were found in the ventral portion of the medullary reticular nucleus and Rexed laminae III-V and X. The distribution of labeled cells was consistent with previously reported results following subarachnoid placement of the noxious agents, blood or carrageenin. Pretreatment with RPR 100893 (1, 10 and 100 micrograms/kg, i.v.) but not its enantiomer (100 micrograms/kg, i.v.) 30 min prior to capsaicin injection significantly reduced the number of positive cells in the trigeminal nucleus caudalis (P < 0.01) in a dose-dependent manner, but not within area postrema or nucleus of the solitary tract. These results indicate that (i) the instillation of capsaicin into the subarachnoid space is an effective stimulus for the induction of c-fos antigen within trigeminal nucleus caudalis, presumably through activation of trigeminovascular afferents, and (ii) the neurokinin-1 antagonist RPR 100893 reduces the number of positive cells selectively within this nucleus. The findings are significant because drugs which alleviate vascular headaches decrease the number of c-fos-positive cells within trigeminal nucleus caudalis following noxious meningeal stimulation. Hence, strategies aimed at blocking the neurokinin-1 receptor may be useful for treating migraine and cluster headache.

  19. Microelectrode targeting of the subthalamic nucleus for deep brain stimulation surgery.

    PubMed

    Montgomery, Erwin B

    2012-09-15

    Though microelectrode recordings likely increase the risks and costs of DBS, incremental improvement in accuracy may translate into improved outcomes that justify these risks and costs. Clinically based, controlled studies to resolve these issues are problematic. Until such studies are reported, physicians must rely on indirect evidence. The spatial variability of physiologically defined optimal targets, as determined by microelectrode recording (MER), necessary for targeting the STN was calculated. Study of the effectiveness of a MER algorithm was based on the number of penetrations required. The radius of the volume with a 99% chance of including the physiologically defined optimal target, based on 108 cases, was 4.5 mm. This is larger than the estimated radius of the DBS effect, which is variously estimated to be 2 to 3.9 mm. The 99% confidence radius in the plane orthogonal to the lead was 3.2 mm. In 70% of cases, the imaging-based trajectories corresponded to the physiologically defined optimal target. For the remaining 30% of cases, 70% required only a single additional MER tract. The radii of the 99% confidence volume and area may be larger than the effective radius of stimulation. Surveying within those volumes or areas is therefore necessary to assure that at least 99% of cases will cover the physiologically defined target. The MER algorithm was robust in detecting the physiologically defined optimal target. However, there are significant caveats in interpretation of the data.

  20. A long-term follow-up of weight changes in subthalamic nucleus stimulated Parkinson's disease patients.

    PubMed

    Foubert-Samier, A; Maurice, S; Hivert, S; Guelh, D; Rigalleau, V; Burbaud, P; Cuny, E; Meissner, W; Tison, F

    2012-02-01

    Deep brain stimulation of the subthalamic nucleus (STN-DBS) constitutes the mainstay treatment in advanced Parkinson's disease (PD) with motor fluctuations. Despite its efficacy on motor signs and quality of life, emergent adverse events have been recently reported. Among them, weight gain (WG) is a recognized adverse event of subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). Also, WG is poorly known at the long-term and predisposing factors have not yet been identified. We conducted a cross-sectional study of WG in 47 STN-DBS PD patients between 1999-2006. Data on disease history, motor status and dopaminergic drug treatment were retrospectively collected at surgery and 1 year post-surgery. Weight at disease diagnosis and at surgery, as well as the current weight and height were gathered by an autoquestionnaire. Moreover, the weight before surgery was obtained and verified in medical files in more than 90% of our patients. Sixty-six patients who underwent surgery between 1999-2006 were included, but six were deceased, four refused to participate and nine were lost for follow-up. So, 47 (71%) were retained in our analysis. A total of 78.7% of patients gained weight. On average 4.7 years follow up after surgery, the mean weight gain was +7.2±8.1kg compared to the preoperative assessment (p<0.001) and the mean BMI gain was +2.7±3.0kg/m(2) compared to pre-surgery values (p<0.001). The patients gained more weight after surgery than they had lost during disease evolution before surgery. Women and patients with a more severe UPDRS-III "off" drug score before surgery significantly gained more weight. Our study provides further evidence that the WG is a problem after STN-DBS and concerns a majority of patients at the long term. It may expose them to complications that should be considered for prevention and the patient's information before surgery.

  1. Modulation of nutritional state in Parkinsonian patients with bilateral subthalamic nucleus stimulation.

    PubMed

    Guimarães, Joana; Matos, Eduarda; Rosas, Maria José; Vieira-Coelho, Augusta; Borges, Nuno; Correia, Flora; Vaz, Rui; Garrett, Carolina

    2009-12-01

    Chronic bilateral subthalamic stimulation (DBS-STN) provides considerable clinical benefits in Parkinson disease patients, with improvement in primary symptoms and resolution of side effects of chronic pharmacological treatment. Apart from its therapeutic effects on PD symptoms, DBS-STN also appears to induce weight gain, which may itself induce critical metabolic disorders and limit the benefits of surgery. No data are available in literature showing the efficacy of a nutritional intervention to prevent rapid and/or excessive weight gain after DBSSTN. Fifty-seven PD patients were included in this study and were divided into two groups: Group 1 comprised 16 patients with a nutritional intervention immediately after surgery (1 week after); Group 2 comprised 41 patients with a nutritional intervention in a later period after surgery (mean time of 2.5 ± 1.6 years). Weight, body mass index (BMI), percentage of fat mass, levodopa daily dose (LDD) and part III of the Unified Parkinson's disease rating scale (UPDRS) were studied before and after an individualized and structured nutritional intervention. Three months after nutritional intervention, Group 1 had a mean BMI (24.1 ± 2.99), that was not significantly different (p = 0.114) from BMI before intervention, with stability of the weight and in percentage of fat mass. In Group 2 all the patients gained weight, reaching to 13.17 ± 10%; a total of 63% of patients became overweight (BMI 25 kg/m(2)). Three months after nutritional intervention, Group 2 had a mean BMI (24.80 ± 2.45) that was significantly (p = 0.03) different from BMI before intervention (26.75 ± 2.99), although percentage of fat mass was higher in women. With this study, we have conclude that nutritional intervention adequate to patient-age, disease characteristics, medical therapy with L-dopa and physical activity, is effective incontrolling weight after DBS-STN surgery.

  2. Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson’s Disease

    PubMed Central

    Charles, David; Konrad, Peter E.; Neimat, Joseph S.; Molinari, Anna L.; Tramontana, Michael G.; Finder, Stuart G.; Gill, Chandler E.; Bliton, Mark J.; Kao, Chris C.; Phibbs, Fenna T.; Hedera, Peter; Salomon, Ronald M.; Cannard, Kevin R.; Wang, Lily; Song, Yanna; Davis, Thomas L.

    2014-01-01

    Background Deep brain stimulation (DBS) is an effective and approved therapy for advanced Parkinson’s disease (PD), and a recent study suggests efficacy in mid-stage disease. This manuscript reports the results of a pilot trial investigating preliminary safety and tolerability of DBS in early PD. Methods Thirty subjects with idiopathic PD (Hoehn & Yahr Stage II off medication), age 50–75, on medication ≥ 6 months but < 4 years, and without motor fluctuations or dyskinesias were randomized to optimal drug therapy (ODT) (n=15) or DBS+ODT (n=15). Co-primary endpoints were the time to reach a 4-point worsening from baseline in the UPDRS-III off therapy and the change in levodopa equivalent daily dose from baseline to 24 months. Results As hypothesized, the mean UPDRS total and part III scores were not significantly different on or off therapy at 24 months. The DBS+ODT group took less medication at all time points, and this reached maximum difference at 18 months. With a few exceptions, differences in neuropsychological functioning were not significant. Two subjects in the DBS+ODT group suffered serious adverse events; remaining adverse events were mild or transient. Conclusions This study demonstrates that subjects with early stage PD will enroll in and complete trials testing invasive therapies and provides preliminary evidence that DBS is well tolerated in early PD. The results of this trial provide the data necessary to design a large, phase III, double-blind, multicenter trial investigating the safety and efficacy of DBS in early PD. PMID:24768120

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. Intensive Voice Treatment (LSVT®LOUD) for Parkinson’s disease following Deep Brain Stimulation of the Subthalamic Nucleus

    PubMed Central

    Spielman, Jennifer; Mahler, Leslie; Halpern, Angela; Gilley, Phllip; Klepitskaya, Olga; Ramig, Lorraine

    2011-01-01

    Purpose Intensive voice therapy (LSVT®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 for surgical subjects were comparable to non-surgical cohorts. Methods Eight subjects with PD (four with STN-DBS and four without) received LSVT LOUD four times a week for four weeks. Four additional subjects with PD remained untreated. Voice intensity (SPL), Vowel Articulation Index (VAI), the Voice Handicap Index (VHI), and a structured interview were evaluated before and after treatment and again six months later. Results Both treated groups showed significant increases in SPL from pre to post and six-month follow up. VAI was significantly higher for the treated groups compared to the untreated subjects at follow up. Several treated individuals had significant clinical improvement in VHI scores, particularly within the LSVT-DBS group. Treated individuals reported improvements in voice and speech in structured interviews; however, answers suggest more variable long-term maintenance within the LSVT-DBS group. The untreated group exhibited no significant changes in any measure throughout the study. Conclusions Results support LSVT LOUD for treating voice and speech in individuals with PD following STN-DBS surgery. However, modifications may be required to maintain functional improvements. PMID:21724193

  8. Deep Brain Stimulation of the Nucleus Accumbens Core Affects Trait Impulsivity in a Baseline-Dependent Manner

    PubMed Central

    Schippers, Maria C.; Bruinsma, Bastiaan; Gaastra, Mathijs; Mesman, Tanja I.; Denys, Damiaan; De Vries, Taco J.; Pattij, Tommy

    2017-01-01

    Deep brain stimulation (DBS) of the nucleus accumbens (NA) is explored as a treatment for refractory psychiatric disorders, such as obsessive-compulsive disorder (OCD), depressive disorder (MDD), and substance use disorder (SUD). A common feature of some of these disorders is pathological impulsivity. Here, the effects of NAcore DBS on impulsive choice and impulsive action, two distinct forms of impulsive behavior, were investigated in translational animal tasks, the delayed reward task (DRT) and five-choice serial reaction time task (5-CSRTT), respectively. In both tasks, the effects of NAcore DBS were negatively correlated with baseline impulsive behavior, with more pronounced effects in the 5-CSRTT. To further examine the effects of DBS on trait impulsive action, rats were screened for high (HI) and low (LI) impulsive responding in the 5-CSRTT. NAcore DBS decreased impulsive, premature responding in HI rats under conventional conditions. However, upon challenged conditions to increase impulsive responding, NAcore DBS did not alter impulsivity. These results strongly suggest a baseline-dependent effect of DBS on impulsivity, which is in line with clinical observations. PMID:28386221

  9. Distinct types of non-cholinergic pedunculopontine neurons are differentially modulated during global brain states.

    PubMed

    Ros, H; Magill, P J; Moss, J; Bolam, J P; Mena-Segovia, J

    2010-09-29

    The pedunculopontine nucleus (PPN) is critically involved in brain-state transitions that promote neocortical activation. In addition, the PPN is involved in the control of several behavioral processes including locomotion, motivation and reward, but the neuronal substrates that underlie such an array of functions remain elusive. Here we analyzed the physiological properties of non-cholinergic PPN neurons in vivo across distinct brain states, and correlated these with their morphological properties after juxtacellular labeling. We show that non-cholinergic neurons in the PPN whose firing is not strongly correlated to neocortical activity are highly heterogeneous and are composed of at least three different subtypes: (1) "quiescent" neurons, which are nearly silent during slow-wave activity (SWA) but respond robustly to neocortical activation; (2) "tonic firing" neurons, which have a stationary firing rate that is independent of neocortical activity across different brain states; and (3) "irregular firing" neurons, which exhibit a variable level of correlation with neocortical activity. The majority of non-cholinergic neurons have an ascending axonal trajectory, with the exception of some irregular firing neurons that have descending axons. Furthermore, we observed asymmetric synaptic contacts within the PPN arising from the axon collaterals of labeled neurons, suggesting that excitatory, non-cholinergic neurons can shape the activity of neighboring cells. Our results provide the first evidence of distinct firing properties associated with non-cholinergic neuronal subtypes in the PPN, suggesting a functional heterogeneity, and support the notion of a local network assembled by projection neurons, the properties of which are likely to determine the output of the PPN in diverse behavioral contexts.

  10. Potentiating effect of eszopiclone on GABA(A) receptor-mediated responses in pedunculopontine neurons.

    PubMed

    Ye, Meijun; Garcia-Rill, Edgar

    2009-07-01

    The pedunculopontine nucleus (PPN) is part of the cholinergic arm of the reticular activating system, which is mostly active during waking and REM sleep. GABAergic modulation of this area appears to regulate sleep-wake cycles. Eszopiclone (ESZ), a nonbenzodiazepine hypnotic agent, appears to modulate GABAergic receptors. However, the action site of ESZ in the brain is still unresolved. We tested the hypothesis that ESZ acts by potentiating GABA(A) receptors on PPN neurons. Wholecell voltage clamp recordings were performed on PPN neurons in 7-15 day rat brainstem slices, and the potentiating effects of ESZ on the responses to the GABA(A) receptor agonist isoguvacine (IGV), and on GABA(A) receptor-mediated inhibitory post-synaptic currents (IPSCs), were determined. In the presence of tetrodotoxin, ESZ (1) increased the amplitude of the outward current induced by IGV, (2) increased its duration, and (3) enhanced the IGV-induced decrease in input resistance (Rin). The GABA(A) receptor antagonist gabazine (GBZ) blocked these effects. ESZ alone did not induce detectable currents or change Rin at a holding potential of -60 mV, but when held at 0 mV, ESZ induced an outward current in 13/21 PPN cells, an effect blocked by GBZ. ESZ also increased the amplitude (n = 18/21), duration (n = 17/21), and frequency (n = 13/15) of IPSCs. ESZ may potentiate GABA(A) inhibition in the PPN via pre- and post-synaptic modulation, which may underlie the hypnotic effects of ESZ. The differential effects of ESZ on both pre- and post-synaptic sites may partially explain why it has less significant side effects compared to other hypnotic agents.

  11. Bar pressing for food: differential consequences of lesions to the anterior versus posterior pedunculopontine.

    PubMed

    Wilson, David I G; MacLaren, Duncan A A; Winn, Philip

    2009-08-01

    The pedunculopontine tegmental nucleus (PPTg) is in a key position to participate in operant reinforcement via its connections with the corticostriatal architecture and the medial reticular formation. Indeed, previous work has demonstrated that rats bearing lesions of the whole PPTg are impaired when learning to make two bar presses for amphetamine reinforcement. Anterior and posterior portions of the PPTg make different anatomical connections, including preferential projections by the anterior PPTg to substantia nigra pars compacta dopamine neurons and by the posterior PPTg to ventral tegmental area dopamine neurons. We wanted to assess the effects of anterior and posterior PPTg ibotenate lesions on rats learning simple and more complex schedules of natural reinforcement. We trained rats with lesions to the anterior PPTg (n = 11) and the posterior PPTg (n = 5) [and appropriate controls (n = 15)] to bar press for food on a variety of fixed-ratio and variable-ratio reinforcement schedules and then during extinction. We found that posterior PPTg-lesioned rats bar pressed at lower rates, were slower to learn to bar press, and often had deficits characteristic of impaired learning and/or motivation. In contrast, anterior PPTg-lesioned rats learned to bar press for reinforcement at normal rates. However, they made errors of perseveration and anticipation throughout many schedules, and pressed at a higher rate than controls during extinction, deficits best characterized as reflecting disorganized response control. Together, these data suggest that the anterior PPTg and posterior PPTg (and their related circuits) contribute differently to reinforcement learning, incentive motivation, and response control, processes that are considered to malfunction in drug addiction.

  12. MSG-Evoked c-Fos Activity in the Nucleus of the Solitary Tract Is Dependent upon Fluid Delivery and Stimulation Parameters

    PubMed Central

    Thompson, John A.

    2016-01-01

    The marker of neuronal activation, c-Fos, can be used to visualize spatial patterns of neural activity in response to taste stimulation. Because animals will not voluntarily consume aversive tastes, these stimuli are infused directly into the oral cavity via intraoral cannulae, whereas appetitive stimuli are given in drinking bottles. Differences in these 2 methods make comparison of taste-evoked brain activity between results that utilize these methods problematic. Surprisingly, the intraoral cannulae experimental conditions that produce a similar pattern of c-Fos activity in response to taste stimulation remain unexplored. Stimulation pattern (e.g., constant/intermittent) and hydration state (e.g., water-restricted/hydrated) are the 2 primary differences between delivering tastes via bottles versus intraoral cannulae. Thus, we quantified monosodium glutamate (MSG)-evoked brain activity, as measured by c-Fos, in the nucleus of the solitary tract (nTS; primary taste nucleus) across several conditions. The number and pattern of c-Fos neurons in the nTS of animals that were water-restricted and received a constant infusion of MSG via intraoral cannula most closely mimicked animals that consumed MSG from a bottle. Therefore, in order to compare c-Fos activity between cannulae-stimulated and bottle-stimulated animals, cannulated animals should be water restricted prior to stimulation, and receive taste stimuli at a constant flow. PMID:26762887

  13. MSG-Evoked c-Fos Activity in the Nucleus of the Solitary Tract Is Dependent upon Fluid Delivery and Stimulation Parameters.

    PubMed

    Stratford, Jennifer M; Thompson, John A

    2016-03-01

    The marker of neuronal activation, c-Fos, can be used to visualize spatial patterns of neural activity in response to taste stimulation. Because animals will not voluntarily consume aversive tastes, these stimuli are infused directly into the oral cavity via intraoral cannulae, whereas appetitive stimuli are given in drinking bottles. Differences in these 2 methods make comparison of taste-evoked brain activity between results that utilize these methods problematic. Surprisingly, the intraoral cannulae experimental conditions that produce a similar pattern of c-Fos activity in response to taste stimulation remain unexplored. Stimulation pattern (e.g., constant/intermittent) and hydration state (e.g., water-restricted/hydrated) are the 2 primary differences between delivering tastes via bottles versus intraoral cannulae. Thus, we quantified monosodium glutamate (MSG)-evoked brain activity, as measured by c-Fos, in the nucleus of the solitary tract (nTS; primary taste nucleus) across several conditions. The number and pattern of c-Fos neurons in the nTS of animals that were water-restricted and received a constant infusion of MSG via intraoral cannula most closely mimicked animals that consumed MSG from a bottle. Therefore, in order to compare c-Fos activity between cannulae-stimulated and bottle-stimulated animals, cannulated animals should be water restricted prior to stimulation, and receive taste stimuli at a constant flow.

  14. Electrical stimulation of cerebellar fastigial nucleus promotes the expression of growth arrest and DNA damage inducible gene β and motor function recovery in cerebral ischemia/reperfusion rats.

    PubMed

    Liu, Bin; Li, Jianrui; Li, Longling; Yu, Lehua; Li, Changqing

    2012-06-27

    This study focused on the effects of electrical stimulation of cerebellar fastigial nucleus on the expression of growth arrest and DNA damage inducible gene β (Gadd45β) and on motor function recovery after focal cerebral ischemia/reperfusion (I/R) in rats. Sprague-Dawley (SD) rats were randomly divided into 4 groups: sham I/R (control group), I/R (I/R group), I/R with sham stimulation and I/R with electrical stimulation at 6h, 12h, 24h, 2d and 3d after I/R. Cerebral ischemia and reperfusion was established by nylon monofilament occlusion method. Fastigial nucleus (FN) electrical stimulation was applied at 2h after ischemia for 1h. The changes in the expression of Gadd45β were analyzed by immunohistochemistry, real-time polymerase chain reaction (PCR) and Western-blot respectively. Another group of rats were divided into the same 4 groups. Montoya staircase test score was used to test the motor function of affected forelimb. The levels of Gadd45β were significantly elevated after I/R injury. FN electrical stimulation treatment elevated the expression of Gadd45β further and improved motor function recovery. These results suggest that FN electrical stimulation can promote the expression of Gadd45β and motor function recovery after focal cerebral ischemia.

  15. MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation.

    PubMed

    Raviv, Ziv; Kalie, Eyal; Seger, Rony

    2004-04-01

    The ERK5 signaling cascade acts through sequential activation of MEKK2/3, MEK5 and ERK5 and transmits signals to a variety of stress and mitogenic related targets. In this study we examined the subcellular localization of the components of the ERK5 cascade and found that in resting, as well as in EGF-stimulated HeLa and Rat-1 cells, endogenous ERK5 is localized mainly in the nucleus. This location is different from the previously described location of exogenous ERK5, in the cytosol of resting cells, which is confirmed in this study. The reason for the different localization could be a saturation of anchoring moieties by the endogenous ERK5. Indeed, in situ detergent extraction analysis using Nonidet P-40, revealed that ERK5 is bound to detergent resistant moieties in the nucleus, while the exogenous protein fails to interact with those anchors. The upstream activator MEK5 is also localized in the nucleus both before and after EGF stimulation and is resistant to NP-40 extraction in resting cells. ERK5 remains bound to these nuclear moieties even after stimulation, while MEK5 is detached from the anchors but remains localized in the nucleus. Unlike ERK5 and MEK5, their upstream activator MEKK2 is localized mainly in the cytosol of resting cells, and translocates into the nucleus upon EGF stimulation, allowing transmission of signals to the nuclear MEK5. The nuclear localization of MEK5 and ERK5 is different from that of ERK1/2 and MEK1/2 in resting cells, indicating that each MAPK cascade uses distinct mechanisms to transmit extracellular signals to their nuclear targets.

  16. Release of Norepinephrine in the Preoptic Area Activates Anteroventral Periventricular Nucleus Neurons and Stimulates the Surge of Luteinizing Hormone

    PubMed Central

    Poletini, Maristela O.; Leite, Cristiane M.; Bernuci, Marcelo P.; Kalil, Bruna; Mendonça, Leonardo B.D.; Carolino, Ruither O. G.; Helena, Cleyde V. V.; Bertram, Richard; Franci, Celso R.; Anselmo-Franci, Janete A.

    2013-01-01

    The role of norepinephrine (NE) in regulation of LH is still controversial. We investigated the role played by NE in the positive feedback of estradiol and progesterone. Ovarian-steroid control over NE release in the preoptic area (POA) was determined using microdialysis. Compared with ovariectomized (OVX) rats, estradiol-treated OVX (OVX+E) rats displayed lower release of NE in the morning but increased release coincident with the afternoon surge of LH. OVX rats treated with estradiol and progesterone (OVX+EP) exhibited markedly greater NE release than OVX+E rats, and amplification of the LH surge. The effect of NE on LH secretion was confirmed using reverse microdialysis. The LH surge and c-Fos expression in anteroventral periventricular nucleus neurons were significantly increased in OVX+E rats dialyzed with 100 nm NE in the POA. After Fluoro-Gold injection in the POA, c-Fos expression in Fluoro-Gold/tyrosine hydroxylase-immunoreactive neurons increased during the afternoon in the A2 of both OVX+E and OVX+EP rats, in the locus coeruleus (LC) of OVX+EP rats, but was unchanged in the A1. The selective lesion of LC terminals, by intracerebroventricular N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, reduced the surge of LH in OVX+EP but not in OVX+E rats. Thus, estradiol and progesterone activate A2 and LC neurons, respectively, and this is associated with the increased release of NE in the POA and the magnitude of the LH surge. NE stimulates LH secretion, at least in part, through activation of anteroventral periventricular neurons. These findings contribute to elucidation of the role played by NE during the positive feedback of ovarian steroids. PMID:23150494

  17. The integration of neural information by a passive kinetic stimulus and galvanic vestibular stimulation in the lateral vestibular nucleus.

    PubMed

    Kim, Gyutae; Kim, Kyu-Sung; Lee, Sangmin

    2017-02-07

    Despite an easy control and the direct effects on vestibular neurons, the clinical applications of galvanic vestibular stimulation (GVS) have been restricted because of its unclear activities as input. On the other hand, some critical conclusions have been made in the peripheral and the central processing of neural information by kinetic stimuli with different motion frequencies. Nevertheless, it is still elusive how the neural responses to simultaneous GVS and kinetic stimulus are modified during transmission and integration at the central vestibular area. To understand how the neural information was transmitted and integrated, we examined the neuronal responses to GVS, kinetic stimulus, and their combined stimulus in the vestibular nucleus. The neuronal response to each stimulus was recorded, and its responding features (amplitude and baseline) were extracted by applying the curve fitting based on a sinusoidal function. Twenty-five (96.2%) comparisons of the amplitudes showed that the amplitudes decreased during the combined stimulus (p < 0.001). However, the relations in the amplitudes (slope = 0.712) and the baselines (slope = 0.747) were linear. The neuronal effects by the different stimuli were separately estimated; the changes of the amplitudes were mainly caused by the kinetic stimulus and those of the baselines were largely influenced by GVS. Therefore, the slopes in the comparisons implied the neural sensitivity to the applied stimuli. Using the slopes, we found that the reduced amounts of the neural information were transmitted. Overall, the comparisons of the responding features demonstrated the linearity and the subadditivity in the neural transmission.

  18. Elastic and viscoelastic mechanical properties of brain tissues on the implanting trajectory of sub-thalamic nucleus stimulation.

    PubMed

    Li, Yan; Deng, Jianxin; Zhou, Jun; Li, Xueen

    2016-11-01

    Corresponding to pre-puncture and post-puncture insertion, elastic and viscoelastic mechanical properties of brain tissues on the implanting trajectory of sub-thalamic nucleus stimulation are investigated, respectively. Elastic mechanical properties in pre-puncture are investigated through pre-puncture needle insertion experiments using whole porcine brains. A linear polynomial and a second order polynomial are fitted to the average insertion force in pre-puncture. The Young's modulus in pre-puncture is calculated from the slope of the two fittings. Viscoelastic mechanical properties of brain tissues in post-puncture insertion are investigated through indentation stress relaxation tests for six interested regions along a planned trajectory. A linear viscoelastic model with a Prony series approximation is fitted to the average load trace of each region using Boltzmann hereditary integral. Shear relaxation moduli of each region are calculated using the parameters of the Prony series approximation. The results show that, in pre-puncture insertion, needle force almost increases linearly with needle displacement. Both fitting lines can perfectly fit the average insertion force. The Young's moduli calculated from the slope of the two fittings are worthy of trust to model linearly or nonlinearly instantaneous elastic responses of brain tissues, respectively. In post-puncture insertion, both region and time significantly affect the viscoelastic behaviors. Six tested regions can be classified into three categories in stiffness. Shear relaxation moduli decay dramatically in short time scales but equilibrium is never truly achieved. The regional and temporal viscoelastic mechanical properties in post-puncture insertion are valuable for guiding probe insertion into each region on the implanting trajectory.

  19. Movement-Related Discharge in the Macaque Globus Pallidus during High-Frequency Stimulation of the Subthalamic Nucleus

    PubMed Central

    Zimnik, Andrew J.; Nora, Gerald J.; Desmurget, Michel

    2015-01-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) has largely replaced ablative therapies for Parkinson's disease. Because of the similar efficacies of the two treatments, it has been proposed that DBS acts by creating an “informational lesion,” whereby pathologic neuronal firing patterns are replaced by low-entropy, stimulus-entrained firing patterns. The informational lesion hypothesis, in its current form, states that DBS blocks the transmission of all information from the basal ganglia, including both pathologic firing patterns and normal, task-related modulations in activity. We tested this prediction in two healthy rhesus macaques by recording single-unit spiking activity from the globus pallidus (232 neurons) while the animals completed choice reaction time reaching movements with and without STN-DBS. Despite strong effects of DBS on the activity of most pallidal cells, reach-related modulations in firing rate were equally prevalent in the DBS-on and DBS-off states. This remained true even when the analysis was restricted to cells affected significantly by DBS. In addition, the overall form and timing of perimovement modulations in firing rate were preserved between DBS-on and DBS-off states in the majority of neurons (66%). Active movement and DBS had largely additive effects on the firing rate of most neurons, indicating an orthogonal relationship in which both inputs contribute independently to the overall firing rate of pallidal neurons. These findings suggest that STN-DBS does not act as an indiscriminate informational lesion but rather as a filter that permits task-related modulations in activity while, presumably, eliminating the pathological firing associated with parkinsonism. PMID:25740526

  20. 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

  1. The effect of blockade of dopamine receptors on the inhibition of episodic luteinizing hormone release during electrical stimulation of the arcuate nucleus in ovariectomized rats.

    PubMed

    Gallo, R V

    1978-04-01

    This study examined the possible involvement of dopamine (DA) in mediating the inhibition of episodic LH release that occurs during electrical stimulation of the arcuate nucleus (ARH) in ovariectomized rats. Animals were treated before stimulation with pimozide (1.26--2.0 mg/kg) or d-butaclamol (1 mg/kg), blockers of DA receptors, or l-butaclamol. Apomorphine, which inhibits episodic LH release by activating DA receptors, was given near the end of the experiment to determine if these receptors were blocked. ARH stimulation suppressed pulsatile LH release in six rats when DA receptors were not blocked by pimozide (as well as two in which blockade was not tested). A transient increase occurred in one other animal. When DA receptors were blocked by pimozide, stimulation of the ARH inhibited episodic LH release in nine rats, suggesting that DA may have no role in mediating this inhibition. However, because increased LH release occurred in five additional animals, as well as in one with partial receptor blockade, the possibility remains that DA may perhaps have a minor role in this inhibitory response. Although ARH stimulation increased LH release after DA receptor blockade by d-butaclamol, this effect could not be ascribed to the DA antagonist property of this agent, because elevated blood LH levels also occurred during stimulation in rats treated with l-butaclamol, in which DA receptors were not blocked. d- and l-butaclamol may possess a non-stereospecific action on a non-dopaminergic event, thus reversing the response to ARH stimulation. Finally, whether DA receptors were blocked or not by pimozide, d-, or l-butaclamol, activation of the ventromedial hypothalamic and periventricular nucleus regions suppressed episodic LH release, but did not increase LH secretion. This suggests that the region through which stimulation can inhibit, but not increase, LH release may extend in the hypothalamus to these two areas.

  2. Repeated cocaine enhances ventral hippocampal-stimulated dopamine efflux in the nucleus accumbens and alters ventral hippocampal NMDA receptor subunit expression.

    PubMed

    Barr, Jeffrey L; Forster, Gina L; Unterwald, Ellen M

    2014-08-01

    Dopaminergic neurotransmission in the nucleus accumbens is important for various reward-related cognitive processes including reinforcement learning. Repeated cocaine enhances hippocampal synaptic plasticity, and phasic elevations of accumbal dopamine evoked by unconditioned stimuli are dependent on impulse flow from the ventral hippocampus. Therefore, sensitized hippocampal activity may be one mechanism by which drugs of abuse enhance limbic dopaminergic activity. In this study, in vivo microdialysis in freely moving adult male Sprague-Dawley rats was used to investigate the effect of repeated cocaine on ventral hippocampus-mediated dopaminergic transmission within the medial shell of the nucleus accumbens. Following seven daily injections of saline or cocaine (20 mg/kg, ip), unilateral infusion of N-methyl-d-aspartate (NMDA, 0.5 μg) into the ventral hippocampus transiently increased both motoric activity and ipsilateral dopamine efflux in the medial shell of the nucleus accumbens, and this effect was greater in rats that received repeated cocaine compared to controls that received repeated saline. In addition, repeated cocaine altered NMDA receptor subunit expression in the ventral hippocampus, reducing the NR2A : NR2B subunit ratio. Together, these results suggest that repeated exposure to cocaine produces maladaptive ventral hippocampal-nucleus accumbens communication, in part through changes in glutamate receptor composition. A behaviorally sensitizing regimen of cocaine (20 mg/kg, ip 7 days) also sensitized ventral hippocampus (hipp)-mediated dopaminergic transmission within the nucleus accumbens (Nac) to NMDA stimulation (bolts). This was associated with reduced ventral hippocampal NR2A:NR2B subunit ratio, suggesting that repeated exposure to cocaine produces changes in hippocampal NMDA receptor composition that lead to enhanced ventral hippocampus-nucleus accumbens communication.

  3. Effects of Thalamic Reticular Nucleus Electrical Stimulation in Rats in a T-maze Perseverative Behavior Model Induced by 8-OH-DPAT.

    PubMed

    Andrade, Pablo; Carrillo-Ruiz, José D; Ramírez, Ylián; Jiménez, Fiacro

    2010-01-01

    Objective. Evaluate the possible decrease of chemically induced perseverative behavior in rats after electrical stimulation at different frequencies in the thalamic reticular nucleus. Material and Methods. A total of 28 male rats were divided in four groups: control, sham, OFF stimulation, and ON stimulation (450 µsec, 1 V, 6 and 120 Hz) that underwent the administration of saline solution and 8-OH-DPAT. The animals were evaluated in a T-maze model in which three choices or more in the same branch are considered as perseverative. Intragroup analysis was done through paired T-student and intergroup analysis through an ANOVA test. Results. The numbers of perseverations mean for the control group were 1.3 before and 1.4 post saline solution injections. Sham group mean of 1.3 pre and 3.4 post 8-OH-DPAT administration; OFF stimulation group 1.1 pre and 3.3 post 8-OH-DPAT administration; and for ON stimulation 1.1 pre and 1.9 post 8-OH-DPAT administration for stimulation at low frequency (6 Hz) and 3.4 at high frequency (120 Hz). Evident intergroup statistical differences were shown (p < 0.01). Conclusions. Electrical stimulation with the low-frequency group was the only group that after manipulation with 8-OH-DPAT showed a decrease in perseverative behavior, even close to baseline.

  4. Single-unit analysis of the human posterior hypothalamus and red nucleus during deep brain stimulation for aggressivity.

    PubMed

    Micieli, Robert; Rios, Adriana Lucia Lopez; Aguilar, Ricardo Plata; Posada, Luis Fernando Botero; Hutchison, William D

    2017-04-01

    OBJECTIVE Deep brain stimulation (DBS) of the posterior hypothalamus (PH) has been reported to be effective for aggressive behavior in a number of isolated cases. Few of these case studies have analyzed single-unit recordings in the human PH and none have quantitatively analyzed single units in the red nucleus (RN). The authors report on the properties of ongoing neuronal discharges in bilateral trajectories targeting the PH and the effectiveness of DBS of the PH as a treatment for aggressive behavior. METHODS DBS electrodes were surgically implanted in the PH of 1 awake patient with Sotos syndrome and 3 other anesthetized patients with treatment-resistant aggressivity. Intraoperative extracellular recordings were obtained from the ventral thalamus, PH, and RN and analyzed offline to discriminate single units and measure firing rates and firing patterns. Target location was based on the stereotactic coordinates used by Sano et al. in their 1970 study and the location of the dorsal border of the RN. RESULTS A total of 138 units were analyzed from the 4 patients. Most of the PH units had a slow, irregular discharge (mean [± SD] 4.5 ± 2.7 Hz, n = 68) but some units also had a higher discharge rate (16.7 ± 4.7 Hz, n = 15). Two populations of neurons were observed in the ventral thalamic region as well, one with a high firing rate (mean 16.5 ± 6.5 Hz, n = 5) and one with a low firing rate (mean 4.6 ± 2.8 Hz, n = 6). RN units had a regular firing rate with a mean of 20.4 ± 9.9 Hz and displayed periods of oscillatory activity in the beta range. PH units displayed a prolonged period of inhibition following microstimulation compared with RN units that were not inhibited. Patients under anesthesia showed a trend for lower firing rates in the PH but not in the RN. All 4 patients displayed a reduction in their aggressive behavior after surgery. CONCLUSIONS During PH DBS, microelectrode recordings can provide an additional mechanism to help identify the PH target and

  5. 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.

  6. Responses of single units in the inferior olive to stimulation of the limb nerves, peripheral skin receptors, cerebellum, caudate nucleus and motor cortex

    PubMed Central

    Sedgwick, E. M.; Williams, T. D.

    1967-01-01

    1. Extra- and intracellular responses of single units in the inferior olive following stimulation of the cerebellum, limb nerves, skin receptors, the caudate nucleus and cerebral cortex have been described. 2. Responses following cerebellar stimulation were assumed to be antidromic spikes when they occurred after a latency of less than 4 msec and followed stimulus frequencies greater than 220/sec. Other responses with longer latencies were thought to be transynaptic. Evidence for recurrent inhibition of the Renshaw type is given. 3. Following limb nerve stimulation two types of units have been observed; units responding after a short latency and to stimulation of one limb only and units responding with a long latency following stimulation of one or more of the limbs. 4. Units responding to stimulation of the limb nerve after a short latency could often be excited by hair movement and/or light touch on the pads. Other units were excited by pinching and others could not be excited by a physiological stimulus. The receptive field of these units was small and there was no evidence of fringe inhibition. 5. Most units observed represented the contralateral forelimb but there was a significant number of units representing the ipsilateral limbs. 6. The caudato-olivary pathway has been shown to be excitatory. Short latency limb units do not receive afferents from the caudate nucleus. 7. Afferents from the motor cortex excite units in the inferior olive. A remarkable correlation of latencies of responses from both the cerebral cortex and the limbs on to individual units has been described. 8. The results suggest a complex organization of neurones within the inferior olive. A possible plan of the organization of neurones is given and discussed. PMID:5340538

  7. Posterior hypothalamic nucleus deep brain stimulation restores locomotion in rats with haloperidol-induced akinesia but not skilled forelimb use in pellet reaching and lever pressing.

    PubMed

    Young, C K; Whishaw, I Q; Bland, B H

    2011-09-29

    Recent studies have shown that electrical stimulation of the posterior hypothalamic nucleus (PH) facilitates locomotion in control rats, and rats were made akinetic by dopaminergic blockade via haloperidol or dopamine depletion by the neurotoxin 6-hydroxydopamine. These findings suggest that PH stimulation might be a promising treatment for akinesia associated with dopamine loss in Parkinson's disease. The present study further examined the positive effects of PH stimulation on behavior by characterizing its potential facilitatory effects on tasks that require skilled movements. Rats were trained to reach for food pellets with a forelimb (skilled reaching) or press a bar in an operant conditioning task for food. PH stimulation in undrugged rats not only facilitated locomotion in each of the tasks, but also impaired performance of the skilled movement components of the tasks. Haloperidol reduced locomotion and skilled movement, and PH stimulation only restored locomotion. The results are discussed in relation to the idea that PH stimulation selectively facilitates locomotor behavior and may have limited use in restoring impairments in skilled movements and consummatory behavior that results from dopaminergic depletion.

  8. Dorsal periaqueductal gray post-stimulation freezing is counteracted by neurokinin-1 receptor antagonism in the central nucleus of the amygdala in rats.

    PubMed

    Carvalho, M C; Santos, J M; Brandão, M L

    2015-05-01

    Electrical stimulation of the dorsal periaqueductal gray (dPAG) in rats generates defensive responses that are characterized by freezing and escape behaviors, followed by post-stimulation freezing that resembles symptoms of panic attacks. dPAG post-stimulation freezing involves the processing of ascending aversive information to prosencephalic centers, including the amygdala, which allows the animal to evaluate the consequences of stressful situations. The basolateral nucleus of the amygdala (BLA) is thought to act as a filter for innate and learned aversive information that is transmitted to higher structures. The central (CeA) and medial (MeA) nuclei of the amygdala constitute an output for the expression of fear reactions through projections to limbic and brainstem regions. Neurokinin (NK) receptors are abundant in the CeA, MeA, and BLA, but their role in the expression of defensive responses and processing of aversive information that is evoked by electrical stimulation of the dPAG is still unclear. In the present study, we examined the role of NK1 receptors in these amygdala nuclei in the expression of defensive responses induced by electrical stimulation of the dPAG in rats and fear memory of this aversive stimulation. Rats were implanted with an electrode into the dPAG for electrical stimulation and one cannula in the CeA, MeA, or BLA for injections of vehicle (phosphate-buffered saline) or the NK1 receptor antagonist spantide (SPA; 100 pmol/0.2 μl). Injections of SPA into the CeA but not BLA or MeA reduced the duration of post-stimulation freezing evoked by electrical stimulation of the dPAG, without changing the aversive thresholds of freezing or escape. Twenty-four hours later, exploratory behavior was evaluated in the elevated plus maze test (EPM) in the CeA group of rats. Electrical stimulation of the dPAG rats that received vehicle exhibited higher aversion to the open arms of the EPM than sham rats that did not receive any dPAG stimulation. SPA

  9. Excitatory projections from the amygdala to neurons in the nucleus pontis oralis in the rat: an intracellular study.

    PubMed

    Xi, M; Fung, S J; Sampogna, S; Chase, M H

    2011-12-01

    There is a consensus that active (REM) sleep (AS) is controlled by cholinergic projections from the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT) to neurons in the nucleus pontis oralis (NPO) that generate AS (i.e. AS-Generator neurons). The present study was designed to provide evidence that other projections to the NPO, such as those from the amygdala, are also capable of inducing AS. Accordingly, the responses of neurons, recorded intracellularly in the NPO, were examined following stimulation of the ipsilateral central nucleus of the amygdala (CNA) in urethane-anesthetized rats. Single pulse stimulation in the CNA produced an early, fast depolarizing potential (EPSP) in neurons within the NPO. The mean latency to the onset of these excitatory postsynaptic potentials (EPSPs) was 3.6±0.2 ms. A late, small-amplitude inhibitory synaptic potential (IPSP) was present following EPSPs in a portion of the NPO neurons. Following stimulation of the CNA with a train of 8-10 pulses, NPO neurons exhibited a sustained depolarization (5-10 mV) of their resting membrane potential. When single subthreshold intracellular depolarizing current pulses were delivered to NPO neurons, CNA-induced EPSPs were sufficient to promote the discharge of these cells. Stimulation of the CNA with a short train of stimuli induced potent temporal facilitation of EPSPs in NPO neurons. Two forms of synaptic plasticity were revealed by the patterns of response of NPO neurons following stimulation of the CNA: paired-pulse facilitation (PPF) and post-tetanic potentiation (PTP). Six of recorded NPO neurons were identified morphologically with neurobiotin. They were medium to large, multipolar cells with diameters >20 μM, which resemble AS-on cells in the NPO. The present results demonstrate that amygdalar projections are capable of exerting a powerful excitatory postsynaptic drive that activates NPO neurons. Therefore, we suggest that the amygdala is capable of inducing AS via direct

  10. Functional role of Barrington's nucleus in the micturition reflex: relevance in the surgical treatment of Parkinson's disease.

    PubMed

    Blanco, L; Ros, C M; Tarragón, E; Fernández-Villalba, E; Herrero, M T

    2014-04-25

    The pontine micturition center or Barrington's nucleus (BN) - besides regulating micturition - co-regulates the activity of other pelvic viscera such as the colon and genitals. At present, this issue is gaining particular importance due to: (i) recent findings of α-synuclein in BN, (ii) known urinary dysfunction in parkinsonian patients (part of the so-called non-motor symptoms), other patients with dementia and as in very old individuals; and (iii) its proximity to the pedunculopontine nucleus, a surgical target in deep brain stimulation for Parkinson's disease (PD). The structural and functional organization of the micturition reflex comprises a coordinating action of somatic motor activity with both divisions of the autonomic nervous system, modulated by trunk encephalic and cortical centers that involve the BN as locus coeruleus and periaqueductal gray matter, among other trunk encephalic structures. The involvement of dopaminergic activity (physiologic inhibition of the micturition reflex mediated by dopaminergic D1 activity) that diminishes in Parkinsonism and leads to overactivity of the micturition reflex is also well known. In this review, the integrating role of the BN in the context of vesical and gastrointestinal behavior is revisited, and the principal morpho-functional findings that associate dysfunction with the urinary disorders that appear during the pre-motor stages of PD are summarized.

  11. FGF-2 is required to prevent astrogliosis in the facial nucleus after facial nerve injury and mechanical stimulation of denervated vibrissal muscles.

    PubMed

    Hizay, Arzu; Seitz, Mark; Grosheva, Maria; Sinis, Nektarios; Kaya, Yasemin; Bendella, Habib; Sarikcioglu, Levent; Dunlop, Sarah A; Angelov, Doychin N

    2016-03-01

    Recently, we have shown that manual stimulation of paralyzed vibrissal muscles after facial-facial anastomosis reduced the poly-innervation of neuromuscular junctions and restored vibrissal whisking. Using gene knock outs, we found a differential dependence of manual stimulation effects on growth factors. Thus, insulin-like growth factor-1 and brain-derived neurotrophic factor are required to underpin manual stimulation-mediated improvements, whereas FGF-2 is not. The lack of dependence on FGF-2 in mediating these peripheral effects prompted us to look centrally, i.e. within the facial nucleus where increased astrogliosis after facial-facial anastomosis follows "synaptic stripping". We measured the intensity of Cy3-fluorescence after immunostaining for glial fibrillary acidic protein (GFAP) as an indirect indicator of synaptic coverage of axotomized neurons in the facial nucleus of mice lacking FGF-2 (FGF-2(-/-) mice). There was no difference in GFAP-Cy3-fluorescence (pixel number, gray value range 17-103) between intact wildtype mice (2.12±0.37×10(7)) and their intact FGF-2(-/-) counterparts (2.12±0.27×10(7)) nor after facial-facial anastomosis +handling (wildtype: 4.06±0.32×10(7); FGF-2(-/-): 4.39±0.17×10(7)). However, after facial-facial anastomosis, GFAP-Cy3-fluorescence remained elevated in FGF-2(-/-)-animals (4.54±0.12×10(7)), whereas manual stimulation reduced the intensity of GFAP-immunofluorescence in wild type mice to values that were not significantly different from intact mice (2.63±0.39×10). We conclude that FGF-2 is not required to underpin the beneficial effects of manual stimulation at the neuro-muscular junction, but it is required to minimize astrogliosis in the brainstem and, by implication, restore synaptic coverage of recovering facial motoneurons.

  12. Efficacy of unilateral deep brain stimulation of the thalamic ventralis intermedius nucleus in a patient with bipolar disorder associated with Klinefelter syndrome and essential tremor. Case report.

    PubMed

    Telfeian, A E; Boockvar, J A; Simuni, T; Jaggi, J; Skolnick, B; Baltuch, G H

    2000-07-01

    Deep brain stimulation (DBS) of the ventralis intermedius nucleus (Vim) is a safe and effective treatment for essential tremor. Bipolar disorder and essential tremor had each been reported to occur in association with Klinefelter syndrome but the three diseases have been reported to occur together in only one patient. The genetic basis and natural history of these disorders are not completely understood and may be related rather than coincidental. The authors report on a 23-year-old man with Klinefelter syndrome (47,XXY) and bipolar disorder who was treated successfully with unilateral DBS of the thalamic Vim for essential tremor.

  13. Selective serotonin receptor stimulation of the medial nucleus accumbens differentially affects appetitive motivation for food on a progressive ratio schedule of reinforcement

    PubMed Central

    Pratt, Wayne E.; Schall, Megan A.; Choi, Eugene

    2012-01-01

    Previously, we reported that stimulation of selective serotonin (5-HT) receptor subtypes in the nucleus accumbens shell differentially affected consumption of freely available food. Specifically, activation of 5-HT6 receptors caused a dose-dependent increase in food intake, while the stimulation of 5-HT1/7 receptor subtypes decreased feeding [34]. The current experiments tested whether similar pharmacological activation of nucleus accumbens serotonin receptors would also affect appetitive motivation, as measured by the amount of effort non-deprived rats exerted to earn sugar reinforcement. Rats were trained to lever press for sugar pellets on a progressive ratio 2 schedule of reinforcement. Across multiple treatment days, three separate groups (N = 8–10) received bilateral infusions of the 5-HT6 agonist EMD 386088 (at 0.0, 1.0 and 4.0 μg/0.5 μl/side), the 5-HT1/7 agonist 5-CT (at 0, 0.5, 1.0, or 4.0 μg/0.5 μl/side), or the 5-HT2C agonist RO 60-0175 fumarate (at 0, 2.0, or 5.0 μg/0.5 μl/side) into the anterior medial nucleus accumbens prior to a 1-hr progressive ratio session. Stimulation of 5-HT6 receptors caused a dose-dependent increase in motivation as assessed by break point, reinforcers earned, and total active lever presses. Stimulation of 5-HT1/7 receptors increased lever pressing at the 0.5 μg dose of 5-CT, but inhibited lever presses and break point at 4.0 μg/side. Injection of the 5- HT2C agonist had no effect on motivation within the task. Collectively, these experiments suggest that, in addition to their role in modulating food consumption, nucleus accumbens 5-HT6 and 5-HT1/7 receptors also differentially regulate the appetitive components of food-directed motivation. PMID:22306095

  14. Selective serotonin receptor stimulation of the medial nucleus accumbens differentially affects appetitive motivation for food on a progressive ratio schedule of reinforcement.

    PubMed

    Pratt, Wayne E; Schall, Megan A; Choi, Eugene

    2012-03-09

    Previously, we reported that stimulation of selective serotonin (5-HT) receptor subtypes in the nucleus accumbens shell differentially affected consumption of freely available food. Specifically, activation of 5-HT(6) receptors caused a dose-dependent increase in food intake, while the stimulation of 5-HT(1/7) receptor subtypes decreased feeding [34]. The current experiments tested whether similar pharmacological activation of nucleus accumbens serotonin receptors would also affect appetitive motivation, as measured by the amount of effort non-deprived rats exerted to earn sugar reinforcement. Rats were trained to lever press for sugar pellets on a progressive ratio 2 schedule of reinforcement. Across multiple treatment days, three separate groups (N=8-10) received bilateral infusions of the 5-HT(6) agonist EMD 386088 (at 0.0, 1.0 and 4.0 μg/0.5 μl/side), the 5-HT(1/7) agonist 5-CT (at 0, 0.5, 1.0, or 4.0 μg/0.5 μl/side), or the 5-HT(2C) agonist RO 60-0175 fumarate (at 0, 2.0, or 5.0 μg/0.5 μl/side) into the anterior medial nucleus accumbens prior to a 1-h progressive ratio session. Stimulation of 5-HT(6) receptors caused a dose-dependent increase in motivation as assessed by break point, reinforcers earned, and total active lever presses. Stimulation of 5-HT(1/7) receptors increased lever pressing at the 0.5 μg dose of 5-CT, but inhibited lever presses and break point at 4.0 μg/side. Injection of the 5-HT(2C) agonist had no effect on motivation within the task. Collectively, these experiments suggest that, in addition to their role in modulating food consumption, nucleus accumbens 5-HT(6) and 5-HT(1/7) receptors also differentially regulate the appetitive components of food-directed motivation.

  15. 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.

  16. 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

  17. Deep brain stimulation of the nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and sucrose seeking in rats.

    PubMed

    Guercio, Leonardo A; Schmidt, Heath D; Pierce, R Christopher

    2015-03-15

    Stimuli previously associated with drug taking can become triggers that can elicit craving and lead to relapse of drug-seeking behavior. Here, we examined the influence of deep brain stimulation (DBS) in the nucleus accumbens shell on cue-induced reinstatement of cocaine seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.254 mg, i.v.) for 2 h daily for 21 days, with each infusion of cocaine being paired with a cue light. After 21 days of self-administration, cocaine-taking behavior was extinguished by replacing cocaine with saline in the absence of the cue light. Next, during the reinstatement phase, DBS was administered bilaterally into the nucleus accumbens shell through bipolar stainless steel electrodes immediately prior to re-exposure to cues previously associated with cocaine reinforcement. DBS continued throughout the 2 h reinstatement session. Parallel studies examined the influence of accumbens shell DBS on reinstatement induced by cues previously associated with sucrose reinforcement. Results indicated that DBS of the nucleus accumbens shell significantly attenuated cue-induced reinstatement of cocaine and sucrose seeking. Together, these results indicate that DBS of the accumbens shell disrupts cue-induced reinstatement associated with both a drug and a natural reinforcer.

  18. Betting on DBS: Effects of Subthalamic Nucleus Deep Brain Stimulation on Risk-Taking and Decision-Making in Patients with Parkinson’s Disease

    PubMed Central

    Brandt, Jason; Rogerson, Mark; Al-Joudi, Haya; Reckess, Gila; Shpritz, Barnett; Umeh, Chizoba C.; Aljehani, Noha; Mills, Kelly; Mari, Zoltan

    2014-01-01

    Objective Concerns persist that deep brain stimulation (DBS) for Parkinson’s disease (PD) increases impulsivity and/or induces excessive reward-seeking. We report here the performance of PD patients with implanted subthalamic nucleus electrodes, with stimulation on and off, on three laboratory tasks of risk-taking and decision-making. They are compared to PD patients maintained on medication and normal control subjects. Methods and Results In the Game of Dice Task, a test of “risky” decision-making, PD patients with or without DBS made highest-risk bets more often, and ended up with less money, than normal controls. There was a trend for DBS stimulation to ameliorate this effect. Deal or No-Deal is an “ambiguous” decision-making task that assessed preference for risk (holding on to one’s briefcase) over a “sure thing” (accepting the banker’s offer). Here, DBS patients were more conservative with stimulation on than off. They accepted smaller offers from the banker and won less money in the DBS-on condition. Overall, the two PD groups won less money than healthy participants. The Framing Paradigm assessed willingness to gamble on a fixed (unambiguous) prize depending on whether the reward was “framed” as a loss or a gain. Nonsurgical PD patients tended to be more risk-averse than normal subjects, whereas DBS patients were more willing to gamble for gains as well as losses both on and off stimulation. Conclusions On “risky” decision-making tasks, DBS patients were more risk-taking than normal, but stimulation may temper this tendency. In contrast, in an “ambiguous risk” situation, DBS patients were more risk-averse (conservative) than normal, and this tendency was greatest with stimulation. PMID:25486385

  19. Alterations in blood glucose and plasma glucagon concentrations during deep brain stimulation in the shell region of the nucleus accumbens in rats.

    PubMed

    Diepenbroek, Charlene; van der Plasse, Geoffrey; Eggels, Leslie; Rijnsburger, Merel; Feenstra, Matthijs G P; Kalsbeek, Andries; Denys, Damiaan; Fliers, Eric; Serlie, Mireille J; la Fleur, Susanne E

    2013-01-01

    Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is an effective therapy for obsessive compulsive disorder (OCD) and is currently under investigation as a treatment for eating disorders. DBS of this area is associated with altered food intake and pharmacological treatment of OCD is associated with the risk of developing type 2 diabetes. Therefore we examined if DBS of the NAc-shell (sNAc) influences glucose metabolism. Male Wistar rats were subjected to DBS, or sham stimulation, for a period of 1 h. To assess the effects of stimulation on blood glucose and glucoregulatory hormones, blood samples were drawn before, during and after stimulation. Subsequently, all animals were used for quantitative assessment of Fos immunoreactivity in the lateral hypothalamic area (LHA) using computerized image analysis. DBS of the sNAc rapidly increased plasma concentrations of glucagon and glucose while sham stimulation and DBS outside the sNAc were ineffective. In addition, the increase in glucose was dependent on DBS intensity. In contrast, the DBS-induced increase in plasma corticosterone concentrations was independent of intensity and region, indicating that the observed DBS-induced metabolic changes were not due to corticosterone release. Stimulation of the sNAc with 200 μA increased Fos immunoreactivity in the LHA compared to sham or 100 μA stimulated animals. These data show that DBS of the sNAc alters glucose metabolism in a region- and intensity- dependent manner in association with neuronal activation in the LHA. Moreover, these data illustrate the need to monitor changes in glucose metabolism during DBS-treatment of OCD patients.

  20. Functional connectivity between the thalamus and postsubiculum: analysis of evoked responses elicited by stimulation of the laterodorsal thalamic nucleus in anesthetized rats.

    PubMed

    Shires, Kate L; Hawthorne, James P; Hope, Alexander M J; Dudchenko, Paul A; Wood, Emma R; Martin, Stephen J

    2013-07-01

    The laterodorsal nucleus (LDN) of the thalamus provides a prominent afferent projection to the postsubiculum (dorsal presubiculum). To characterize synaptic transmission in this pathway, we placed stimulating electrodes in the LDN and recorded fEPSPs elicited in the postsubiculum of urethane-anesthetized rats. LDN stimulation elicited a source-sink dipole between the deep and superficial layers of the postsubiculum, respectively, consistent with anatomical evidence for the termination of thalamic afferents in the superficial layers of the structure, and the existence of deep layer neurons with apical dendrites extending into these layers. Postsubicular fEPSPs were typically 0.5-1.0 mV in amplitude, with a peak latency of approximately 6 ms. Consistent with anatomical observations, the short onset latency of fEPSPs elicited by LDN stimulation, and their ability to follow a 60-Hz train of stimulation, indicate that the projection is monosynaptic. Paired-pulse stimulation revealed pronounced paired-pulse depression that was maximal at 100 ms, suggesting that initial release probabilities are high at LDN-postsubiculum synapses, in common with many neocortical pathways. A conventional tetanus protocol that yields LTP in hippocampal pathways had no effect on postsubicular fEPSPs, but long-term depression could be induced by 60-Hz stimulation. Drug infusion studies revealed that synaptic transmission in the LDN-postsubiculum projection is predominantly AMPA-receptor mediated. Rats were implanted with indwelling infusion cannulae targeting the postsubiculum, and, after a recovery period, were anaesthetized withurethane, and implanted with stimulating and recording electrodes. Infusion of CNQX almost completely abolished postsubicular fEPSPs, whereas D-AP5 had little effect. However, 60-Hz LTD was blocked by D-AP5 infusion, revealing that this form of synaptic plasticity is NMDA-receptor dependent.

  1. 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.

  2. Stimulation of Baroresponsive Parts of the Nucleus of the Solitary Tract Produces Nitric Oxide-mediated Choroidal Vasodilation in Rat Eye

    PubMed Central

    Li, Chunyan; Fitzgerald, Malinda E. C.; Del Mar, Nobel; Reiner, Anton

    2016-01-01

    Preganglionic parasympathetic neurons of the ventromedial part of the superior salivatory nucleus (SSN) mediate vasodilation of orbital and choroidal blood vessels, via their projection to the nitrergic pterygopalatine ganglion (PPG) neurons that innervate these vessels. We recently showed that the baroresponsive part of the nucleus of the solitary tract (NTS) innervates choroidal control parasympathetic preganglionic neurons of SSN in rats. As this projection provides a means by which blood pressure (BP) signals may modulate choroidal blood flow (ChBF), we investigated if activation of baroresponsive NTS evokes ChBF increases in rat eye, using Laser Doppler Flowmetry (LDF) to measure ChBF transclerally. We found that electrical activation of ipsilateral baroresponsive NTS and its efferent fiber pathway to choroidal SSN increased mean ChBF by about 40–80% above baseline, depending on current level. The ChBF responses obtained with stimulation of baroresponsive NTS were driven by increases in both choroidal blood volume (ChBVol; i.e., vasodilation) and choroidal blood velocity (ChBVel; possibly due to orbital vessel dilation). Stimulation of baroresponsive NTS, by contrast, yielded no significant mean increases in systemic arterial blood pressure (ABP). We further found that the increases in ChBF with NTS stimulation were significantly reduced by administration of the neuronal nitric oxide (NO) synthase inhibitor Nω-propyl-l-arginine (NPA), thus implicating nitrergic PPG terminals in the NTS-elicited ChBF increases. Our results show that the NTS neurons projecting to choroidal SSN do mediate increase in ChBF, and thus suggest a role of baroresponsive NTS in the BP-dependent regulation of ChBF. PMID:27774055

  3. Thalamotomy-Like Effects From Partial Removal of a Ventral Intermediate Nucleus Deep Brain Stimulator Lead in a Patient With Essential Tremor: Case Report

    PubMed Central

    Rolston, John D.; Ramos, Alexander D.; Heath, Susan; Englot, Dario J.; Lim, Daniel A.

    2017-01-01

    BACKGROUND AND IMPORTANCE The ventral intermediate nucleus of the thalamus is a primary target of deep brain stimulation (DBS) in patients with essential tremor. Despite reliable control of contralateral tremor, there is sometimes a need for lead revision in cases of infection, hardware malfunction, or failure to relieve symptoms. Here, we present the case of a patient undergoing revision after ventral intermediate nucleus (Vim) DBS failed to control his tremor. During the electrode removal, the distal portion of the lead was found to be tightly adherent to tissue within the deep brain. Partial removal of the electrode in turn caused weakness, paresthesias, and tremor control similar to the effects produced by thalamotomy or thalamic injury. CLINICAL PRESENTATION A 48-year-old man with essential tremor had bilateral Vim DBS leads implanted 10 years earlier but had poor control of his tremor and ultimately opted for surgical revision with lead placement in the zona incerta. During attempted removal of his right lead, the patient became somnolent with contralateral weakness and paresthesias. The procedure was aborted, and postoperative neuroimaging was immediately obtained, showing no signs of stroke or hemorrhage. The patient had almost complete control of his left arm tremor postoperatively, and his weakness soon resolved. CONCLUSION To the best of our knowledge, this is the first reported case of cerebral injury after DBS revision and offers insights into the mechanism of high-frequency electric stimulation compared with lesions. That is, although high-frequency stimulation failed to control this patient’s tremor, thalamotomy-like injury was completely effective. PMID:26200771

  4. Inhibition of the amygdala central nucleus by stimulation of cerebellar output in rats: a putative mechanism for extinction of the conditioned fear response.

    PubMed

    Magal, Ari; Mintz, Matti

    2014-11-01

    The amygdala and the cerebellum serve two distinctively different functions. The amygdala plays a role in the expression of emotional information, whereas the cerebellum is involved in the timing of discrete motor responses. Interaction between these two systems is the basis of the two-stage theory of learning, according to which an encounter with a challenging event triggers fast classical conditioning of fear-conditioned responses in the amygdala and slow conditioning of motor-conditioned responses in the cerebellum. A third stage was hypothesised when an apparent interaction between amygdala and cerebellar associative plasticity was observed: an adaptive rate of cerebellum-dependent motor-conditioned responses was associated with a decrease in amygdala-dependent fear-conditioned responses, and was interpreted as extinction of amygdala-related fear-conditioned responses by the cerebellar output. To explore this hypothesis, we mimicked some components of classical eyeblink conditioning in anesthetised rats by applying an aversive periorbital pulse as an unconditioned stimulus and a train of pulses to the cerebellar output nuclei as a cerebellar neuronal-conditioned response. The central amygdala multiple unit response to the periorbital pulse was measured with or without a preceding train to the cerebellar output nuclei. The results showed that activation of the cerebellar output nuclei prior to periorbital stimulation produced diverse patterns of inhibition of the amygdala response to the periorbital aversive stimulus, depending upon the nucleus stimulated, the laterality of the nucleus stimulated, and the stimulus interval used. These results provide a putative extinction mechanism of learned fear behavior, and could have implications for the treatment of pathologies involving abnormal fear responses by using motor training as therapy.

  5. Selective optogenetic stimulation of the retrotrapezoid nucleus in sleeping rats activates breathing without changing blood pressure or causing arousal or sighs

    PubMed Central

    Burke, Peter G. R.; Kanbar, Roy; Viar, Kenneth E.; Stornetta, Ruth L.

    2015-01-01

    Combined optogenetic activation of the retrotrapezoid nucleus (RTN; a CO2/proton-activated brainstem nucleus) with nearby catecholaminergic neurons (C1 and A5), or selective C1 neuron stimulation, increases blood pressure (BP) and breathing, causes arousal from non-rapid eye movement (non-REM) sleep, and triggers sighs. Here we wished to determine which of these physiological responses are elicited when RTN neurons are selectively activated. The left rostral RTN and nearby A5 neurons were transduced with channelrhodopsin-2 (ChR2+) using a lentiviral vector. Very few C1 cells were transduced. BP, breathing, EEG, and neck EMG were monitored. During non-REM sleep, photostimulation of ChR2+ neurons (20s, 2-20 Hz) instantly increased V̇e without changing BP (13 rats). V̇e and BP were unaffected by light in nine control (ChR2−) rats. Photostimulation produced no sighs and caused arousal (EEG desynchronization) more frequently in ChR2+ than ChR2− rats (62 ± 5% of trials vs. 25 ± 2%; P < 0.0001). Six ChR2+ rats then received spinal injections of a saporin-based toxin that spared RTN neurons but destroyed surrounding catecholaminergic neurons. Photostimulation of the ChR2+ neurons produced the same ventilatory stimulation before and after lesion, but arousal was no longer elicited. Overall (all ChR2+ rats combined), ΔV̇e correlated with the number of ChR2+ RTN neurons whereas arousal probability correlated with the number of ChR2+ catecholaminergic neurons. In conclusion, RTN neurons activate breathing powerfully and, unlike the C1 cells, have minimal effects on BP and have a weak arousal capability at best. A5 neuron stimulation produces little effect on breathing and BP but does appear to facilitate arousal. PMID:25858492

  6. Functional interaction between the orexin-1 and CB1 receptors within the nucleus accumbens in the conditioned place preference induced by the lateral hypothalamus stimulation.

    PubMed

    Fatahi, Zahra; Assar, Nasim; Mahmoudi, Dorna; Pahlevani, Pouyan; Moradi, Marzieh; Haghparast, Abbas

    2015-02-28

    Several studies have shown that chemical stimulation of the lateral hypothalamus (LH) by carbachol induces the conditioned place preference (CPP) in rats. LH is the main source of the orexinergic neurons and sends projections to some areas of the brain such as the nucleus accumbens (NAc). We tried to determine the role of intra-accumbal orexin-1 (OX1) receptors in development (acquisition) and expression of reward-related behaviors induced by LH stimulation and involvement of CB1 cannabinoid receptors in this area. Adult male Wistar rats were unilaterally implanted by two separate cannulae into the LH and NAc. The CPP paradigm was done; conditioning scores and locomotor activities were recorded. The results showed that intra-accumbal administration of SB334867 as a selective OX1 receptor antagonist (1, 3, 10 and 30nM/0.5μl DMSO) 5min before intra-LH carbachol (250nM/0.5μl saline) during 3-day conditioning phase, could dose-dependently inhibit the development of LH-induced CPP. In expression experiments, intra-NAc administration of SB334867 on the test day could decrease the expression of LH stimulation-induced CPP. Furthermore, concurrent intra-accumbal administration of effective/ineffective doses of SB334867 and AM251 (45 and 15μM) as a CB1 receptor antagonist, before carbachol during the conditioning phase, could attenuate the development of LH stimulation-induced CPP. It seems that the orexinergic projection from the LH to the NAc is involved in the LH stimulation-induced CPP and OX1 receptor in the NAc has a substantial role in this phenomenon. Our findings also suggest the existence a functional interaction between OX1 and CB1 receptors within the NAc in place preference.

  7. 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

  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

    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

  9. Effect of Bilateral Stimulation of the Subthalamic Nucleus on Different Speech Subsystems in Patients with Parkinson's Disease

    ERIC Educational Resources Information Center

    Putzer, Manfred; Barry, William J.; Moringlane, Jean Richard

    2008-01-01

    The effect of deep brain stimulation on the two speech-production subsystems, articulation and phonation, of nine Parkinsonian patients is examined. Production parameters (stop closure voicing; stop closure, VOT, vowel) in fast syllable-repetitions were defined and measured and quantitative, objective metrics of vocal fold function were obtained…

  10. Selective lesions of the cholinergic neurons within the posterior pedunculopontine do not alter operant learning or nicotine sensitization.

    PubMed

    MacLaren, Duncan A A; Wilson, David I G; Winn, Philip

    2016-04-01

    Cholinergic neurons within the pedunculopontine tegmental nucleus have been implicated in a range of functions, including behavioral state control, attention, and modulation of midbrain and basal ganglia systems. Previous experiments with excitotoxic lesions have found persistent learning impairment and altered response to nicotine following lesion of the posterior component of the PPTg (pPPTg). These effects have been attributed to disrupted input to midbrain dopamine systems, particularly the ventral tegmental area. The pPPTg contains a dense collection of cholinergic neurons and also large numbers of glutamatergic and GABAergic neurons. Because these interdigitated populations of neurons are all susceptible to excitotoxins, the effects of such lesions cannot be attributed to one neuronal population. We wished to assess whether the learning impairments and altered responses to nicotine in excitotoxic PPTg-lesioned rats were due to loss of cholinergic neurons within the pPPTg. Selective depletion of cholinergic pPPTg neurons is achievable with the fusion toxin Dtx-UII, which targets UII receptors expressed only by cholinergic neurons in this region. Rats bearing bilateral lesions of cholinergic pPPTg neurons (>90% ChAT+ neuronal loss) displayed no deficits in the learning or performance of fixed and variable ratio schedules of reinforcement for pellet reward. Separate rats with the same lesions had a normal locomotor response to nicotine and furthermore sensitized to repeated administration of nicotine at the same rate as sham controls. Previously seen changes in these behaviors following excitotoxic pPPTg lesions cannot be attributed solely to loss of cholinergic neurons. These findings indicate that non-cholinergic neurons within the pPPTg are responsible for the learning deficits and altered responses to nicotine seen after excitotoxic lesions. The functions of cholinergic neurons may be related to behavioral state control and attention rather than learning.

  11. 5-HT1A receptor-responsive pedunculopontine tegmental neurons suppress REM sleep and respiratory motor activity.

    PubMed

    Grace, Kevin P; Liu, Hattie; Horner, Richard L

    2012-02-01

    Serotonin type 1A (5-HT(1A)) receptor-responsive neurons in the pedunculopontine tegmental nucleus (PPTn) become maximally active immediately before and during rapid eye movement (REM) sleep. A prevailing model of REM sleep generation indicates that activation of such neurons contributes significantly to the generation of REM sleep, and if correct then inactivation of such neurons ought to suppress REM sleep. We test this hypothesis using bilateral microperfusion of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 10 μm) into the PPTn; this tool has been shown to selectively silence REM sleep-active PPTn neurons while the activity of wake/REM sleep-active PPTn neurons is unaffected. Contrary to the prevailing model, bilateral microperfusion of 8-OH-DPAT into the PPTn (n = 23 rats) significantly increased REM sleep both as a percentage of the total recording time and sleep time, compared with both within-animal vehicle controls and between-animal time-controls. This increased REM sleep resulted from an increased frequency of REM sleep bouts but not their duration, indicating an effect on mechanisms of REM sleep initiation but not maintenance. Furthermore, an increased proportion of the REM sleep bouts stemmed from periods of low REM sleep drive quantified electrographically. Targeted suppression of 5-HT(1A) receptor-responsive PPTn neurons also increased respiratory rate and respiratory-related genioglossus activity, and increased the frequency and amplitude of the sporadic genioglossus activations occurring during REM sleep. These data indicate that 5-HT(1A) receptor-responsive PPTn neurons normally function to restrain REM sleep by elevating the drive threshold for REM sleep induction, and restrain the expression of respiratory rate and motor activities.

  12. Differential regulation of serotonin-1A receptor-stimulated [35S]GTP gamma S binding in the dorsal raphe nucleus by citalopram and escitalopram.

    PubMed

    Rossi, Dania V; Burke, Teresa F; Hensler, Julie G

    2008-03-31

    The effect of chronic citalopram or escitalopram administration on 5-HT1A receptor function in the dorsal raphe nucleus was determined by measuring [35S]GTP gamma S binding stimulated by the 5-HT1A receptor agonist (R)-(+)-8-OH-DPAT (1nM-10 microM). Although chronic administration of citalopram or escitalopram has been shown to desensitize somatodendritic 5-HT1A autoreceptors, we found that escitalopram treatment decreased the efficacy of 5-HT1A receptors to activate G proteins, whereas citalopram treatment did not. The binding of [3H]8-OH-DPAT to the coupled, high affinity agonist state of the receptor was not altered by either treatment. Interestingly, escitalopram administration resulted in greater occupancy of serotonin transporter sites as measured by the inhibition of [3H]cyanoimipramine binding. As the binding and action of escitalopram is limited by the inactive enantiomer R-citalopram present in racemic citalopram, we propose that the regulation of 5-HT1A receptor function in the dorsal raphe nucleus at the level of receptor-G protein interaction may be a result of greater inhibition of the serotonin transporter by escitalopram.

  13. 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.

  14. 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.

  15. 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.

  16. Acute deep brain stimulation in the thalamic reticular nucleus protects against acute stress and modulates initial events of adult hippocampal neurogenesis.

    PubMed

    Magdaleno-Madrigal, Víctor Manuel; Pantoja-Jiménez, Christopher Rodrigo; Bazaldúa, Adrián; Fernández-Mas, Rodrigo; Almazán-Alvarado, Salvador; Bolaños-Alejos, Fernanda; Ortíz-López, Leonardo; Ramírez-Rodriguez, Gerardo Bernabé

    2016-11-01

    Deep brain stimulation (DBS) is used as an alternative therapeutic procedure for pharmacoresistant psychiatric disorders. Recently the thalamic reticular nucleus (TRN) gained attention due to the description of a novel pathway from the amygdala to this nucleus suggesting that may be differentially disrupted in mood disorders. The limbic system is implicated in the regulation of these disorders that are accompanied by neuroplastic changes. The hippocampus is highly plastic and shows the generation of new neurons, process affected by stress but positively regulated by antidepressant drugs. We explored the impact of applying acute DBS to the TRN (DBS-TRN) in male Wistar rats exposed to acute stress caused by the forced-swim Porsolt's test (FST) and on initial events of hippocampal neurogenesis. After the first session of forced-swim, rats were randomly subdivided in a DBS-TRN and a Sham group. Stimulated rats received 10min of DBS, thus the depressant-like behavior reflected as immobility was evaluated in the second session of forced-swim. Locomotricity was evaluated in the open field test. Cell proliferation and doublecortin-associated cells were quantified in the hippocampus of other cohorts of rats. No effects of electrode implantation were found in locomotricity. Acute DBS-TRN reduced immobility in comparison to the Sham group (p<0.001). DBS-TRN increased cell proliferation (Ki67 or BrdU-positive cells; p=0.02, p=0.02) and the number of doublecortin-cells compared to the Sham group (p<0.02). Similar effects were found in rats previously exposed to the first session of forced-swim. Our data could suggest that TRN brain region may be a promising target for DBS to treat intractable depression.

  17. Effects of deep brain stimulation on balance and gait in patients with Parkinson's disease: A systematic neurophysiological review.

    PubMed

    Collomb-Clerc, A; Welter, M-L

    2015-11-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal globus pallidus (GPi) deep brain stimulation (DBS) provides an efficient treatment for the alleviation of motor signs in patients with Parkinson's disease. The effects of DBS on gait and balance disorders are less successful and may even lead to an aggravation of freezing of gait and imbalance. The identification of a substantia nigra pars reticulata (SNr)-mesencephalic locomotor region (MLR) network in the control of locomotion and postural control and of its dysfunction/lesion in PD patients with gait and balance disorders led to suggestion that DBS should be targeting the SNr and the pedunculopontine nucleus (part of the MLR) for PD patients with these disabling axial motor signs. However, the clinical results to date have been disappointing. In this review, we discuss the effects of DBS of these basal ganglia and brainstem structures on the neurophysiological parameters of gait and balance control in PD patients. Overall, the data suggest that both STN and GPi-DBS improve gait parameters and quiet standing postural control in PD patients, but have no effect or may even aggravate dynamic postural control, in particular with STN-DBS. Conversely, DBS of the SNr and PPN has no effect on gait parameters but improves anticipatory postural adjustments and gait postural control.

  18. Encoding of the amplitude modulation of pulsatile electrical stimulation in the feline cochlear nucleus by neurons in the inferior colliculus; effects of stimulus pulse rate

    NASA Astrophysics Data System (ADS)

    McCreery, Douglas; Han, Martin; Pikov, Victor; Yadav, Kamal; Pannu, Satinderpall

    2013-10-01

    Objectives. Persons without a functional auditory nerve cannot benefit from cochlear implants, but some hearing can be restored by an auditory brainstem implant (ABI) with stimulating electrodes implanted on the surface of the cochlear nucleus (CN). Most users benefit from their ABI, but speech recognition tends to be poorer than for users of cochlear implants. Psychophysical studies suggest that poor modulation detection may contribute to the limited performance of ABI users. In a cat model, we determined how the pulse rate of the electrical stimulus applied within or on the CN affects temporal and rate encoding of amplitude modulation (AM) by neurons in the central nucleus of the inferior colliculus (ICC). Approach. Stimulating microelectrodes were implanted chronically in and on the cats' CN, and multi-site recording microelectrodes were implanted chronically into the ICC. Encoding of AM pulse trains by neurons in the ICC was characterized as vector strength (VS), the synchrony of neural activity with the AM, and as the mean rate of neuronal action potentials (neuronal spike rate (NSR)). Main results. For intranuclear microstimulation, encoding of AM as VS was up to 3 dB greater when stimulus pulse rate was increased from 250 to 500 pps, but only for neuronal units with low best acoustic frequencies, and when the electrical stimulation was modulated at low frequencies (10-20 Hz). For stimulation on the surface of the CN, VS was similar at 250 and 500 pps, and the dynamic range of the VS was reduced for pulse rates greater than 250 pps. Modulation depth was encoded strongly as VS when the maximum stimulus amplitude was held constant across a range of modulation depth. This ‘constant maximum’ protocol allows enhancement of modulation depth while preserving overall dynamic range. However, modulation depth was not encoded as strongly as NSR. Significance. The findings have implications for improved sound processors for present and future ABIs. The performance of

  19. Deep brain stimulation for movement disorders: update on recent discoveries and outlook on future developments.

    PubMed

    Mahlknecht, Philipp; Limousin, Patricia; Foltynie, Thomas

    2015-11-01

    Modern deep brain stimulation (DBS) has become a routine therapy for patients with movement disorders such as Parkinson's disease, generalized or segmental dystonia and for multiple forms of tremor. Growing numbers of publications also report beneficial effects in other movement disorders such as Tourette's syndrome, various forms of chorea and DBS is even being studied for Parkinson's-related dementia. While exerting remarkable effects on many motor symptoms, DBS does not restore normal neurophysiology and therefore may also have undesirable side effects including speech and gait deterioration. Furthermore, its efficacy might be compromised in the long term, due to progression of the underlying disease. Various programming strategies have been studied to try and address these issues, e.g., the use of low-frequency rather than high-frequency stimulation or the targeting of alternative brain structures such as the pedunculopontine nucleus. In addition, further technical developments will soon provide clinicians with an expanded choice of hardware such as segmented electrodes allowing for a steering of the current to optimize beneficial effects and reduce side effects as well as the possibility of adaptive stimulation systems based on closed-loop concepts with or without accompanying advances in programming and imaging software. In the present article, we will provide an update on the most recent achievements and discoveries relevant to the application of DBS in the treatment of movement disorder patients and give an outlook on future clinical and technical developments.

  20. Mu-Opioid Stimulation in Rat Prefrontal Cortex Engages Hypothalamic Orexin/Hypocretin-Containing Neurons, and Reveals Dissociable Roles of Nucleus Accumbens and Hypothalamus in Cortically Driven Feeding

    PubMed Central

    Mena, Jesus D.; Selleck, Ryan A.

    2013-01-01

    Mu-opioid receptor (μOR) stimulation within ventral medial prefrontal cortex (vmPFC) induces feeding and hyperactivity, resulting possibly from recruitment of glutamate signaling in multiple vmPFC projection targets. We tested this hypothesis by analyzing Fos expression in vmPFC terminal fields after intra-vmPFC μOR stimulation, and by examining of the impact of glutamate receptor blockade in two feeding-related targets of vmPFC, the lateral-perifornical hypothalamic area (LH-PeF) and nucleus accumbens shell (Acb shell), upon behavioral effects elicited by intra-vmPFC μOR stimulation in rats. Intra-vmPFC infusion of the μOR agonist, DAMGO, provoked Fos expression in the dorsomedial sector of tuberal hypothalamus (including the perifornical area) and increased the percentage of Fos-expressing hypocretin/orexin-immunoreactive neurons in these zones. NMDA receptor blockade in the LH-PeF nearly eliminated intra-vmPFC DAMGO-induced food intake without altering DAMGO-induced hyperactivity. In contrast, blocking AMPA-type glutamate receptors within the Acb shell (the feeding-relevant subtype in this structure) antagonized intra-vmPFC DAMGO-induced hyperlocomotion but enhanced food intake. Intra-vmPFC DAMGO also elevated the breakpoint for sucrose-reinforced progressive-ratio responding; this effect was significantly enhanced by concomitant AMPA blockade in the Acb shell. Conversely, intra-Acb shell AMPA stimulation reduced breakpoint and increased nonspecific responding on the inactive lever. These data indicate intra-vmPFC μOR signaling jointly modulates appetitive motivation and generalized motoric activation through functionally dissociable vmPFC projection targets. These findings may shed light on the circuitry underlying disorganized appetitive responses in psychopathology; e.g., binge eating and opiate or alcohol abuse, disorders in which μORs and aberrant cortical activation have been implicated. PMID:24259576

  1. The stereoisomer (+)-naloxone potentiates G-protein coupling and feeding associated with stimulation of mu opioid receptors in the parabrachial nucleus.

    PubMed

    Chaijale, Nayla N; Aloyo, Vincent J; Simansky, Kenny J

    2013-03-01

    Classically, opioids produce their effects by activating Gi-proteins that inhibit adenylate cyclase activity. Previous studies proposed that mu-opioid receptors can also stimulate adenylate cyclase due to an initial transient coupling to Gs-proteins. Treatment with ultra-low doses of the nonselective opioid antagonist (-)-naloxone or its inactive enantiomer (+)-naloxone blocks this excitatory effect and enhances Gi-coupling. Previously we reported that infusion of the mu-opioid receptor agonist [D-Ala2, N-Me-Phe4, Glycinol5]-Enkephalin (DAMGO) into the mu-opioid receptor expressing lateral parabrachial nucleus increases feeding. Pretreatment with (-)-naloxone blocks this effect. We used this parabrachial circuit as a model to assess cellular actions of ultra-low doses of (-)-naloxone and (+)-naloxone in modifying the effects of DAMGO. Our results showed that an ultra-low concentration of (-)-naloxone (0.001 nM) and several concentrations of (+)-naloxone (0.01-10 nM) enhanced DAMGO-stimulated guanosine-5'-0-(γ-thio)-triphosphate incorporation in parabrachial sections in vitro. Further, we analyzed the relevance of these effects in vivo. In the present study, we show that (+)-naloxone can potentiate DAMGO-induced feeding at doses at which (-)-naloxone was an antagonist. These results implicated (+)-naloxone as a novel tool for studying mu-opioid receptor functions and suggest that (+)-naloxone may have therapeutic value to enhance clinical actions of opiate drugs.

  2. 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.

  3. Deep brain stimulation reveals a dissociation of consummatory and motivated behaviour in the medial and lateral nucleus accumbens shell of the rat.

    PubMed

    van der Plasse, Geoffrey; Schrama, Regina; van Seters, Sebastiaan P; Vanderschuren, Louk J M J; Westenberg, Herman G M

    2012-01-01

    Following the successful application of deep brain stimulation (DBS) in the treatment of Parkinson's disease and promising results in clinical trials for obsessive compulsive disorder and major depression, DBS is currently being tested in small patient-populations with eating disorders and addiction. However, in spite of its potential use in a broad spectrum of disorders, the mechanisms of action of DBS remain largely unclear and optimal neural targets for stimulation in several disorders have yet to be established. Thus, there is a great need to examine site-specific effects of DBS on a behavioural level and to understand how DBS may modulate pathological behaviour. In view of the possible application of DBS in the treatment of disorders characterized by impaired processing of reward and motivation, like addiction and eating disorders, we examined the effect of DBS of the nucleus accumbens (NAcc) on food-directed behavior. Rats were implanted with bilateral stimulation electrodes in one of three anatomically and functionally distinct sub-areas of the NAcc: the core, lateral shell (lShell) and medial shell (mShell). Subsequently, we studied the effects of DBS on food consumption, and the motivational and appetitive properties of food. The data revealed a functional dissociation between the lShell and mShell. DBS of the lShell reduced motivation to respond for sucrose under a progressive ratio schedule of reinforcement, mShell DBS, however, profoundly and selectively increased the intake of chow. DBS of the NAcc core did not alter any form of food-directed behavior studied. DBS of neither structure affected sucrose preference. These data indicate that the intake of chow and the motivation to work for palatable food can independently be modulated by DBS of subregions of the NAcc shell. As such, these findings provide important leads for the possible future application of DBS as a treatment for eating disorders such as anorexia nervosa.

  4. Contrasting effects of 5-HT3 receptor stimulation of the nucleus accumbens or ventral tegmentum on food intake in the rat.

    PubMed

    Pratt, Wayne E; Lin, Peagan; Pierce-Messick, Zachary; Ilesanmi, Adeolu O; Clissold, Kara A

    2017-04-14

    Although serotonin (5-HT) signaling is known to regulate food intake and energy homeostasis, the roles of the 5-HT3 receptor in feeding processes have been elusive. 5-HT3 receptors are found throughout mesolimbic circuitry that promote feeding not only in response to hunger, but also to the palatable and rewarding properties of food. These experiments examined if stimulation or blockade of the 5-HT3 receptor of the nucleus accumbens (NAcc) or ventral tegmentum affected food intake in the rat in response to hunger or the presence of a palatable diet. Rats (N=6-9/group) received bilateral injections of the 5-HT3 agonist m-chlorophenylbiguanide hydrochloride (mCPBG; at 0.0, 10.0, or 20.0μg/0.5μl/side) or the 5-HT3 antagonist ondansetron hydrochloride (at 0.0, 1.0, 2.0, or 5.0μg/0.5μl/side) into either the NAcc or the ventral tegmentum. NAcc 5-HT3 receptor stimulation significantly increased 2-h food intake in food-deprived animals offered rat chow and in a separate group of unrestricted rats offered a sweetened fat diet. In contrast to the feeding increase seen with NAcc treatments, stimulation of 5-HT3 receptors of the ventral tegmentum significantly reduced food and water intake in food-restricted animals; reductions of intake in non-restricted rats offered the palatable diet did not approach significance. Blockade of the 5-HT3 receptor had no effect on feeding in either brain region. These data support a functional role for serotonergic signaling in the mesolimbic pathway on motivated behavior, and demonstrate that 5-HT3 receptors differentially modulate food consumption in a region-dependent manner.

  5. Low-frequency stimulation in anterior nucleus of thalamus alleviates kainate-induced chronic epilepsy and modulates the hippocampal EEG rhythm.

    PubMed

    Wang, Yi; Liang, Jiao; Xu, Cenglin; Wang, Ying; Kuang, Yifang; Xu, Zhenghao; Guo, Yi; Wang, Shuang; Gao, Feng; Chen, Zhong

    2016-02-01

    High-frequency stimulation (HFS) of the anterior nucleus of thalamus (ANT) is a new and alternative option for the treatment of intractable epilepsy. However, the responder rate is relatively low. The present study was designed to determine the effect of low-frequency stimulation (LFS) in ANT on chronic spontaneous recurrent seizures and related pathological pattern in intra-hippocampal kainate mouse model. We found that LFS (1 Hz, 100 μs, 300 μA), but not HFS (100 Hz, 100 μs, 30 μA), in bilateral ANT significantly decreased the frequency of spontaneous recurrent seizures, either non-convulsive focal seizures or tonic-clonic generalized seizures. The anti-epileptic effect persisted for one week after LFS cessation, which manifested as a long-term inhibition of the frequency of seizures with short (20-60 s) and intermediate duration (60-120 s). Meanwhile, LFS decreased the frequency of high-frequency oscillations (HFOs) and interictal spikes, two indicators of seizure severity, whereas HFS increased the HFO frequency. Furthermore, LFS decreased the power of the delta band and increased the power of the gamma band of hippocampal background EEG. In addition, LFS, but not HFS, improved the performance of chronic epileptic mice in objection-location task, novel objection recognition and freezing test. These results provide the first evidence that LFS in ANT alleviates kainate-induced chronic epilepsy and cognitive impairment, which may be related to the modulation of the hippocampal EEG rhythm. This may be of great therapeutic significance for clinical treatment of epilepsy with deep brain stimulation.

  6. Inverted-U shaped effects of D1 dopamine receptor stimulation in the medial preoptic nucleus on sexually-motivated song in male European starlings

    PubMed Central

    Riters, Lauren V.; Pawlisch, Benjamin A.; Kelm-Nelson, Cynthia A.; Stevenson, Sharon A.

    2014-01-01

    Past studies in songbirds highlight a central role for the medial preoptic nucleus (mPOA) in context-appropriate vocal communication. During the breeding season, male songbirds sing primarily to attract females (sexually-motivated song) and to repel competitors (agonistically-motivated song). Past data link dopamine and D1 dopamine receptors in the mPOA to sexually-motivated but not agonistically-motivated song; however, direct effects of dopamine receptor manipulations in the mPOA on song have not been experimentally tested. Here we tested the hypothesis that D1 receptor stimulation in the mPOA selectively influences sexually-motivated male song and the possibility that the effects of D1 agonism differ at low and high doses. In a first study, breeding condition male European starlings received infusions of saline or a single dose of the D1 receptor agonist SKF 38393 on separate test days into mPOA or hypothalamic control areas. Stimulation of D1 receptors in mPOA triggered sexually-motivated but not agonistically-motivated song. A second study showed inverted-U shaped dose-response effects of the agonist such that low levels of sexually-motivated song were observed at low and high levels of D1 receptor activation. A third study showed that effects of the D1 agonist were blocked by the D1 receptor antagonist SCH 23390. These findings suggest that an optimal level of D1 dopamine receptor stimulation in mPOA is needed to facilitate sexually-motivated vocal production. The results support a central, context-specific role for the mPOA in vocal communication and more broadly demonstrate a complex, modulatory influence of D1 receptors in mPOA on sexually-motivated behavior. PMID:24528137

  7. Response of neurons in the thalamic nucleus submedius (Sm) to noxious stimulation and electrophysiological identification of on- and off-cells in rats.

    PubMed

    Fu, Jian-Jun; Tang, Jing-Shi; Yuan, Bin; Jia, Hong

    2002-09-01

    Previous studies have indicated that thalamic nucleus submedius (Sm) is involved in nociceptive modulation and plays an important role in an endogenous analgesic system (a feedback loop) consisting of spinal cord (Sc)-Sm-ventrolateral orbital cortex-periaqueductal gray-Sc. However, the function of different types of Sm neurons in nociceptive modulation is unclear. For this reason, on the basis of further studies of properties of the Sm neurons responding to noxious stimuli, the different effects of systemic morphine on the Sm neurons were examined and two classes of nociceptive modulatory neurons, named as off- and on-cells, in this region were identified in lightly anesthetized rats. The results showed that (1) most (84%, 132/157) of the Sm neurons responded to peripheral noxious stimuli. Of these neurons, 66% (n = 87) were inhibited, 34% (n = 45) excited. All neurons had very large and bilateral, even all body receptive fields. No neuron was found to be responsive to innocuous stimulation; (2) systemic morphine increased the firing rate of neurons inhibited by noxious stimulation, but decreased that of neurons excited by the same stimulation. Furthermore, the effects of morphine could be reversed by systemic naloxone; (3) 45 of Sm neurons examined could be divided into three different classes: off-cells that decreased the firing rate from tail heating just prior to occurrence of the tail-flick (TF) reflex (3140 +/- 167 ms, n = 27), on-cells that increased the firing rate just before the TF reflex (1720 +/- 240 ms, n = 8), and neutral-cells that did not respond to any stimuli and neuronal activities were not related to the TF reflex (n = 10). Findings of this study provided electrophysiological evidence for involvement of Sm neurons, as those in the rostral ventromedial medulla, in the opioid-receptor-mediated descending nociceptive modulation.

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. Effects of GABA(B), 5-HT(1A), and 5-HT(2) receptor stimulation on activation and inhibition of the rat lateral amygdala following medial geniculate nucleus stimulation in vivo.

    PubMed

    Sokal, David M; Giarola, Alessandra S; Large, Charles H

    2005-01-07

    The input from the medial geniculate nucleus of the thalamus (MGN) to the lateral amygdala is known to be important in the regulation of fear and anxiety. Modulation of this pathway may be useful for the treatment of anxiety disorders. We set out to determine whether simple extracellular electrophysiological techniques could be used to study pharmacological modulation of this pathway in vivo. We studied the effects of GABA(B), 5-HT(1), and 5-HT(2) receptor agonists on activity in the lateral amygdala following stimulation of the MGN in isoflurane-anaesthetised rats. Electrical stimulation of the MGN evoked a characteristic biphasic field potential in the lateral amygdala. Baclofen (10 mg kg(-1), iv) inhibited the evoked potential with an effect that was most marked on the positive-going component (80+/-9% inhibition; P<0.05). Baclofen also significantly reduced paired-pulse inhibition of the negative-going component at short interpulse intervals (<200 ms). The 5-HT(1A) receptor ligands, 8-OH-DPAT (60 microg kg(-1), iv) and WAY-100635 (0.5 mg kg(-1), iv) were without effect on evoked responses or paired-pulse relationship. In contrast, the 5-HT(2) receptor agonist, DOI, caused a rapid inhibition of the field potential (to 59.33+/-11.41% of the baseline response; P<0.05). This effect was blocked by ketanserin, either following systemic (0.5 mg kg(-1), iv) or intra-amygdala administration. These results show that GABA(B) and 5-HT(2) receptor agonists can modulate activation of the lateral amygdala following MGN stimulation; furthermore, GABA(B) receptor agonists appear to have a profound effect on local circuit inhibition within the lateral amygdala. The results support the use of in vivo field potential recording within the MGN-lateral amygdala pathway to evaluate this as a possible site of action for novel anxiolytic drugs.

  15. Cocaine- and Amphetamine-Regulated Transcript (CART) Expression is Differentially Regulated in the Hypothalamic Para ventricular Nucleus of Lactating Rats Exposed to Suckling or Cold Stimulation

    PubMed Central

    Sánchez, Edith; Fekete, Csaba; Lechan, Ronald M.; Joseph-Bravo, Patricia

    2007-01-01

    Neural stimuli, such as suckling or cold exposure, increase TRH mRNA in the paraventricular nucleus (PVN) of the rat hypothalamus, yet only suckling induces prolactin secretion. As TRH co-localizes with cocaine-and amphetamine-regulated transcript (CART) in hypophysiotropic neurons of the PVN, and CART inhibits TRH-induced prolactin release but not TRH-induced TSH release in adenohypophyseal cell cultures, we raised the possibility that differential regulation of CART gene expression in the PVN may explain the differences in prolactin secretion following each of the two stimuli. Primiparous female rats were mated and handled daily during the pre- and postpartum periods. After delivery, the litter was adjusted to 8 pups and at mid-lactation, dams were separated from their pups for 8 hours and exposed to either 1h of cold or 30 min of suckling. Long term effects of suckling were studied by separating pups from their mothers for 24h, followed by a 12h period of continuous suckling. Serum TSH levels increased in response to cold exposure, while prolactin levels were increased by suckling and diminished by cold exposure. CART mRNA levels increased in rostral and mid parts of the medial parvocellular PVN following cold exposure but not after suckling stimulation. These data demonstrate a differential regulation of CART gene expression in hypophysiotropic neurons in response to stimuli that increase TRH mRNA levels, and suggest that CART activation in the PVN may contribute to the decrease in PRL release when the thyroid axis is activated by cold exposure. Section: Regulatory systems PMID:17174283

  16. 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

  17. Nucleus accumbens deep-brain stimulation efficacy in ACTH-pretreated rats: alterations in mitochondrial function relate to antidepressant-like effects

    PubMed Central

    Kim, Y; McGee, S; Czeczor, J K; Walker, A J; Kale, R P; Kouzani, A Z; Walder, K; Berk, M; Tye, S J

    2016-01-01

    Mitochondrial dysfunction has a critical role in the pathophysiology of mood disorders and treatment response. To investigate this, we established an animal model exhibiting a state of antidepressant treatment resistance in male Wistar rats using 21 days of adrenocorticotropic hormone (ACTH) administration (100 μg per day). First, the effect of ACTH treatment on the efficacy of imipramine (10 mg kg−1) was investigated alongside its effect on the prefrontal cortex (PFC) mitochondrial function. Second, we examined the mood-regulatory actions of chronic (7 day) high-frequency nucleus accumbens (NAc) deep-brain stimulation (DBS; 130 Hz, 100 μA, 90 μS) and concomitant PFC mitochondrial function. Antidepressant-like responses were assessed in the open field test (OFT) and forced swim test (FST) for both conditions. ACTH pretreatment prevented imipramine-mediated improvement in mobility during the FST (P<0.05). NAc DBS effectively improved FST mobility in ACTH-treated animals (P<0.05). No improvement in mobility was observed for sham control animals (P>0.05). Analyses of PFC mitochondrial function revealed that ACTH-treated animals had decreased capacity for adenosine triphosphate production compared with controls. In contrast, ACTH animals following NAc DBS demonstrated greater mitochondrial function relative to controls. Interestingly, a proportion (30%) of the ACTH-treated animals exhibited heightened locomotor activity in the OFT and exaggerated escape behaviors during the FST, together with general hyperactivity in their home-cage settings. More importantly, the induction of this mania-like phenotype was accompanied by overcompensative increased mitochondrial respiration. Manifestation of a DBS-induced mania-like phenotype in imipramine-resistant animals highlights the potential use of this model in elucidating mechanisms of mood dysregulation. PMID:27327257

  18. Effects of chemical stimulation of the lateral wings of the dorsal raphe nucleus on panic-like defensive behaviors and Fos protein expression in rats.

    PubMed

    Matthiesen, Melina; Spiacci, Ailton; Zangrossi, Hélio

    2017-03-06

    The lateral wings subnucleus of the dorsal raphe nucleus (lwDR) has been implicated in the modulation of panic-like behaviors, such as escape. Infusion of non- excitotoxic doses of the excitatory amino acid kainic acid into this subnucleus promptly evokes a vigorous escape response. In addition, rats exposed to panic-inducing situations show an increase in Fos protein expression in neurons within the lwDR. In the present study, we first investigated whether key structures associated with the mediation of escape behavior are recruited after chemical stimulation of the lwDR with kainic acid. We next investigated whether the infusion of the GABAA receptor antagonist bicuculline into the lwDR also evoked escape responses measured both in a circular arena and in the rat elevated T-maze. The effects of bicuculline in the circular arena were compared to those caused by the infusion of this antagonist into the ventrolateral periaqueductal gray (vlPAG), an area in close vicinity to the lwDR. The results showed that kainic acid infusion into the lwDR increased Fos protein immunostaining in brain structures deeply involved in panic-like defensive behaviors, such as the periaqueductal gray and hypothalamus, but not the amygdala. As observed with kainic acid, bicuculline evoked a pronounced escape response in the circular arena when microinjected in the lwDR, but not in the vlPAG. The escape-promoting effect of bicuculline in the lwDR was also evidenced in the elevated T-maze. These findings strength the view that dysfunction in mechanisms controlling escape in the lwDR is critically implicated in the pathophysiology of panic disorder.

  19. Deep brain stimulation of the nucleus accumbens shell induces anti-obesity effects in obese rats with alteration of dopamine neurotransmission.

    PubMed

    Zhang, Chao; Wei, Nai-Li; Wang, Yao; Wang, Xiu; Zhang, Jian-Guo; Zhang, Kai

    2015-03-04

    The aim of this study was to assess the anti-obesity effects of nucleus accumbens shell (NAc-sh) deep brain stimulation (DBS) in diet-induced obese (DIO) and chow-fed (chow) rats. The influence of DBS on dopamine (DA) signaling in the NAc-sh was also evaluated. DIO and chow rats were subjected to DBS for 14 consecutive days. Food intake and weight gain were measured daily. The gene expression of the dopamine D1 and D2 receptors was evaluated by qPCR. In addition, the extracellular levels of DA and its metabolite, dihydroxyphenylacetic acid (DOPAC), were determined by microdialysis. We observed that chronic DBS induced significant reductions in total energy intake (596.0±65.0kcal vs. 1161.6±22.2kcal, p<0.001) and weight gain (1.45±0.57% vs. 9.64±0.38%, p<0.001) in DIO rats compared to sham-DIO rats. Up-regulated D2 receptor gene expression (2.43±0.12 vs. 0.64±0.04, p<0.001) and increased DA levels (2.73±0.15pmol/mL vs. 0.62±0.05pmol/mL, p<0.001) were observed in DIO rats compared to sham-DIO rats. DBS had no influence on food intake, weight gain, or DA neurotransmission in chow rats. Our results support an association of the anorexigenic effects of NAc-sh DBS with mesolimbic DA signaling and indicate that the positive alteration of DA function in DIO rats may be responsible for the different effects of DBS in DIO and chow rats.

  20. 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.

  1. Motor dysfunction and alterations in glutathione concentration, cholinesterase activity, and BDNF expression in substantia nigra pars compacta in rats with pedunculopontine lesion.

    PubMed

    Blanco-Lezcano, Lisette; Jimenez-Martin, Javier; Díaz-Hung, Mei-Li; Alberti-Amador, Esteban; Wong-Guerra, Maylin; González-Fraguela, Ma Elena; Estupiñán-Díaz, Bárbara; Serrano-Sánchez, Teresa; Francis-Turner, Liliana; Delgado-Ocaña, Susana; Núñez-Figueredo, Yanier; Vega-Hurtado, Yamilé; Fernández-Jiménez, Isabel

    2017-04-21

    Pedunculopontine nucleus (PPN) has been considered a critically important region in the regulation of some of the physiological functions that fail during the progression of Parkinson's disease (PD). In this paper, the effects of unilateral neurotoxic lesion of the PPN [through the injection of N-methyl-d-aspartate (NMDA) solution (concentration: 0.1M; volume: 0.5µL)] in motor execution and gait disorders and the changes in cellular and molecular indicators in rat nigral tissue were evaluated. The motor execution was assessed using the beam test (BT) and the gait disorders by footprint test. Glutathione (GSH) concentrations, acetyl cholinesterase enzymatic activity (AChE EA), and brain-derived neurotrophic factor (BDNF) mRNA expression in nigral tissue were analyzed. NMDA-lesioned rats showed fine motor dysfunction with a significant increase in the slow (p≤0.01) and fast movement (p≤0.01) time and in path deviation (p≤0.01) on the smaller diameter beams. Moreover, NMDA-lesioned rats exhibited an imprecise path with moments of advances and setbacks, alternating with left and right deviations, suspensions, and inverted positions. Footprint test revealed slight gait disorders, which were manifested by a reduction in the left and right stride lengths, the intra-step distance, and the support area (p≤0.01). Biochemical studies showed that 48h after the PPN neurotoxic injury, the GSH concentrations and BDNF expression were significantly increased (p≤0.01). These variables returned to normal values 7days after the PPN lesion; the AChE EA showed a significant increase at this time. These functional changes in nigral tissue could be a plastic responses associated with early PD.

  2. Exposure to female pheromones stimulates a specific type of neuronal population in the male but not female magnocellular division of the medial preoptic nucleus (MPN mag) of the Syrian hamster.

    PubMed

    Swann, Jennifer M; Richendrfer, Holly A; Dawson, Lindsay; Nack, Elana; Whylings, Jack; Garelick, Tim

    2013-08-01

    The magnocellular division of the medial preoptic area (MPN mag) integrates pheromonal and hormonal signals to play a critical role in the expression of male typical sex behavior. The MPN mag contains two morphologically distinct neuronal populations; the percentage of each type within the nucleus is sex specific. Males have more neurons with a single nucleolus whereas females have more with multiple nucleoli. To determine which neuronal subtype mediates pheromonal induction of copulation, tissue from male and female hamsters exposed to female pheromones was immunolabeled for the immediate early protein (EGR-1). Subsequently the tissue was counterstained and the number of ERG-1 neurons with one or two nuclei was determined. The results indicate that pheromones stimulate neurons with single nucleoli in males but fail to stimulate either neuronal subtype in females suggesting that synaptic input to the MPN mag is sexually differentiated.

  3. Stimulation of food intake after central galanin is associated with arcuate nucleus activation and does not differ between genetically selected low and high body weight lines of chickens.

    PubMed

    Hagen, Christopher J; Newmyer, Brandon A; Webster, Rebekah I; Gilbert, Elizabeth R; Siegel, Paul B; Tachibana, Tetsuya; Cline, Mark A

    2013-08-01

    Galanin, a 29 residue peptide found in the hypothalamus, causes orexigenic effects in a variety of species. In the present study, we investigated appetite-associated effects of galanin in chicks from lines which have been selected from a common founder population for either low or high body weight. The low line consists of some anorexic individuals and there are obese individuals in the high line. Central galanin caused increased food intake in both lines with the magnitude of response similar in both lines. We also quantified the number of c-Fos immunoreactive cells in several hypothalamic nuclei that are associated with appetite. Only the arcuate nucleus had an increase in the number of reactive cells, a response that was similar for both lines. From these results we concluded that selection for body weight likely did not affect galanin function on induction of feeding in either lines, and that the effect of galanin is associated with arcuate nucleus activation in chicks.

  4. Mechanisms underlying sleep-wake disturbances in alcoholism: focus on the cholinergic pedunculopontine tegmentum

    PubMed Central

    Knapp, Clifford M.; Ciraulo, Domenic A.; Datta, Subimal

    2014-01-01

    Sleep-wake (S-W) disturbances are frequently associated with alcohol use disorders (AUD), occurring during periods of active drinking, withdrawal, and abstinence. These S-W disturbances can persist after months or even years of abstinence, suggesting that chronic alcohol consumption may have enduring negative effects on both homeostatic and circadian sleep processes. It is now generally accepted that S-W disturbances in alcohol-dependent individuals are a significant cause of relapse in drinking. Although significant progress has been made in identifying the socio-economic burden and health risks of alcohol addiction, the underlying neurobiological mechanisms that lead to S-W disorders in AUD are poorly understood. Marked progress has been made in understanding the basic neurobiological mechanisms of how different sleep stages are normally regulated. This review article in seeking to explain the neurobiological mechanisms underlying S-W disturbances associated with AUD, describes an evidence-based, easily testable, novel hypothesis that chronic alcohol consumption induces neuroadaptive changes in the cholinergic cell compartment of the pedunculopontine tegmentum (CCC-PPT). These changes include increases in N-methyl-D-aspartate (NMDA) and kainate receptor sensitivity and a decrease in gamma-aminobutyric acid (GABAB) - receptor sensitivity in the CCC-PPT. Together these changes are the primary pathophysiological mechanisms that underlie S-W disturbances in AUD. This review is targeted for both basic neuroscientists in alcohol addiction research and clinicians who are in search of new and more effective therapeutic interventions to treat and/or eliminate sleep disorders associated with AUD. PMID:25151622

  5. Dopamine D4 receptor stimulation in GABAergic projections of the globus pallidus to the reticular thalamic nucleus and the substantia nigra reticulata of the rat decreases locomotor activity.

    PubMed

    Erlij, David; Acosta-García, Jacqueline; Rojas-Márquez, Martín; González-Hernández, Brenda; Escartín-Perez, Erick; Aceves, Jorge; Florán, Benjamín

    2012-02-01

    Dopamine D4 receptors are localized in the GABAergic projections that globus pallidus (GP) neurons send to the reticular nucleus of the thalamus (RTN), the substantia nigra reticulata (SNr) and the subthalamic nucleus (STN). Deficient D4 function in this network could lead to hyperactivity and thus be important in generating some of the symptoms of ADHD (attention deficit hyperactivity disorder), a condition associated with polymorphisms of dopamine D4 receptors. It is then, unexpected that systemic injections of D4 ligands have no significant effects on the motor activity of normal rats. We further examined this issue by microinjecting D4 ligands and psychostimulant drugs in relevant structures. Interstitial dopamine overflow in the RTN was increased by reverse microdialysis of both methylphenidate and methamphetamine. Intranuclear injections in the RTN of methylphenidate, methamphetamine and the selective D4 agonist PD 168,077 reduced motor activity. Intraperitoneal injection of the D4 antagonist L 745,870 blocked the effects of these intranuclear injections. Similarly, intranuclear injections of PD 168,077 in the SNr inhibited motor activity, an effect that was also blocked by intraperitoneal L 745,870. In rats with 6-OHDA induced hemiparkinsonism, intraperitoneal PD 168,077 produced ipsilateral turning behavior that was blocked by L 745,870. Our results suggest that diminished D4 signaling in GP projections could lead to increased traffic through the relay nuclei of the thalamus and hyperactivity. Hence this basal-ganglia-thalamus network may be one of the targets of the beneficial effects that psychostimulant drugs have in disorders associated with D4 receptor abnormalities. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

  6. Activation of 5-HT1A and 5-HT7 receptors in the parafascicular nucleus suppresses the affective reaction of rats to noxious stimulation.

    PubMed

    Harte, Steven E; Kender, Robert G; Borszcz, George S

    2005-02-01

    The antinociceptive effects of the serotonin (5-HT)1A/7 receptor agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) administered into the medial thalamus were evaluated. Pain behaviors organized at spinal (spinal motor reflexes, SMRs), medullary (vocalizations during shock, VDSs), and forebrain (vocalization after discharges, VADs) levels of the neuraxis were elicited by tailshock. Administration of 8-OH-DPAT (5, 10, and 20 microg/side) into nucleus parafascicularis (nPf) produced dose-dependent increases in VDS and VAD thresholds, but failed to elevate SMR threshold. The increase in VAD threshold was significantly greater than that of VDS threshold. Similar effects were observed with administration of 8-OH-DPAT (20 microg/side) into the rostral portion of the central lateral thalamic nucleus. The bilateral or unilateral administration of 8-OH-DPAT (20 microg) into other thalamic nuclei, or into sites dorsal to nPf, did not elevate vocalization thresholds. Increases in vocalization thresholds produced by nPf-administered 8-OH-DPAT were mediated by both 5-HT1A and 5-HT7 receptors. Intra-nPf administration of the 5-HT1A receptor antagonist WAY-100635 (0.05 or 0.5 microg/side), or the 5-HT7 receptor antagonist SB-269970 (1 or 2 microg/side), but not the dopamine D2 receptor antagonist raclopride (10 microg/side), reversed 8-OH-DPAT induced elevations in vocalization thresholds. These results provide the first reported evidence of behavioral antinociception following the administration of a 5-HT agonist into the medial thalamus.

  7. Depletion of substance P, neurokinin A and calcitonin gene-related peptide from the contralateral and ipsilateral caudal trigeminal nucleus following unilateral electrical stimulation of the trigeminal ganglion; a possible neurophysiological and neuroanatomical link to generalized head pain.

    PubMed

    Samsam, M; Coveñas, R; Csillik, B; Ahangari, R; Yajeya, J; Riquelme, R; Narváez, J A; Tramu, G

    2001-03-01

    Primary trigeminal neurons of the trigeminal ganglion (TG) innervate major parts of the face and head, including the dura. Electrical stimulation of the TG at specific parameters, can activate its nociceptive neurons and may serve as an experimental pain model. Markowitz [J. Neurosci. 7 (1987) 4129] reported that electrical stimulation of the trigeminal ganglion (TG) causes extravasation of plasma proteins from venules of the trigeminally innervated domain possibly due to the release of vasoactive substances. Neurogenic inflammation (vasodilatation, plasma protein extravasation, release of vasoactive peptides) in dura may serve as one of the possible pathomechanisms underlying vascular head pain [Moskowitz, Ann. Neurol. 16 (1984) 157]. We performed a unilateral electrical stimulation (7.5 Hz, 5 ms, 0.8-1.4 mA for 5 min) of the TG in rat, to induce a neurogenic inflammation in the peripheral trigeminal domain including the dura, looking for calcitonin gene related peptide (CGRP), substance P (SP) and neurokinin A (NKA) immunoreactivity (IR) in the caudal trigeminal nucleus (CTN) into which massive central trigeminal processes terminate. Here, we show patchy depletion(s) of CGRP-, SP- and NKA-IRs in the contralateral CTN of the rat in addition to their ipsilateral depletion. Such depletion is due to the release of these neuropeptides in the CTN leading to the activation of bilateral trigeminal nociceptive pathway. These data afford the possibility that under specific frequencies (which may roughly correlate to the intensity of the painful stimulus) and/or specific intensities (may correlate to specific areas of the peripheral trigeminal domain) of stimulation, activation of one side of the TG may activate bilateral trigeminal nociceptive pathway leading to the perception of an ill localized/generalized pain or headache rather than a unilateral one.

  8. The Expression of Fos, Jun and AP-1 DNA Binding Activity in Rat Supraoptic Nucleus Neurons Following Acute Versus Repeated Osmotic Stimulation

    DTIC Science & Technology

    1995-06-22

    stimulation. This pattern has been observed previously in the hippocampus after treatment with the seizure-inducing drug , metrazole (Sonnenberg et al... fosB , and fra-1 and -2. fra refers to ~OS­ ~elated ~ntigen. Western blot experiments and employment of less stringent nucleic acid hybridization...fos, fra-l and fosB , only form heterodimeric complexes with Jun-related proteins (Nakabeppu et al., 1988; Rauscher et al., 1988b) The AP-l site of many

  9. Whole-brain mapping of afferent projections to the bed nucleus of the stria terminalis in tree shrews.

    PubMed

    Ni, Rong-Jun; Luo, Peng-Hao; Shu, Yu-Mian; Chen, Ju-Tao; Zhou, Jiang-Ning

    2016-10-01

    The bed nucleus of the stria terminalis (BST) plays an important role in integrating and relaying input information to other brain regions in response to stress. The cytoarchitecture of the BST in tree shrews (Tupaia belangeri chinensis) has been comprehensively described in our previous publications. However, the inputs to the BST have not been described in previous reports. The aim of the present study was to investigate the sources of afferent projections to the BST throughout the brain of tree shrews using the retrograde tracer Fluoro-Gold (FG). The present results provide the first detailed whole-brain mapping of BST-projecting neurons in the tree shrew brain. The BST was densely innervated by the prefrontal cortex, entorhinal cortex, ventral subiculum, amygdala, ventral tegmental area, and parabrachial nucleus. Moreover, moderate projections to the BST originated from the medial preoptic area, supramammillary nucleus, paraventricular thalamic nucleus, pedunculopontine tegmental nucleus, dorsal raphe nucleus, locus coeruleus, and nucleus of the solitary tract. Afferent projections to the BST are identified in the ventral pallidum, nucleus of the diagonal band, ventral posteromedial thalamic nucleus, posterior complex of the thalamus, interfascicular nucleus, retrorubral field, rhabdoid nucleus, intermediate reticular nucleus, and parvicellular reticular nucleus. In addition, the different densities of BST-projecting neurons in various regions were analyzed in the tree shrew brains. In summary, whole-brain mapping of direct inputs to the BST is delineated in tree shrews. These brain circuits are implicated in the regulation of numerous physiological and behavioral processes including stress, reward, food intake, and arousal.

  10. [Cascade of biochemical events triggered by stimulation of adrenergic receptors in the rat pineal gland--from cell membrane to nucleus].

    PubMed

    Zawilska, J B; Rosiak, J; Nowak, J Z

    1999-01-01

    Pineal glands of various vertebrate species synthesize melatonin in a circadian rhythm generated by an endogenous pacemaker. The levels of melatonin and activity of serotonin N-acetyltransferase (AA-NAT: a penultimate and key regulatory enzyme in melatonin biosynthesis) are low during the light phase and high during the dark phase of any natural or imposed light-dark illumination cycle. The expression of AA-NAT gene in rat pineal gland is regulated by a photoneural system that acts through the adrenergic-cAMP-related mechanisms in pinealocytes. Concomitant stimulation by noradrenaline of beta 1- and alpha 1-adrenergic receptors, in a mechanism of "AND gate" activation, results in a large, 60-100-fold increase in intrapinealocyte cAMP level. The role of cAMP-dependent transcription factors CREB, ICER and Fra-2 in turning on and off the AA-NAT gene expression is discussed.

  11. Deep brain stimulation for Parkinson disease in Australia: current scientific and clinical status.

    PubMed

    Poortvliet, P C; Silburn, P A; Coyne, T J; Chenery, H J

    2015-02-01

    There is currently no cure for Parkinson disease (PD). Disease management is directed primarily at motor symptom relief, but the impact of non-motor symptoms associated with PD should not be underestimated. Medical and surgical treatment options aim to increase functional independence and quality of life. Deep brain stimulation (DBS) has proven to be a safe, effective and cost-efficient surgical treatment option. In 2009, the Australian referral guidelines, developed to provide a synopsis of DBS therapy for PD, were introduced, and since then novel findings have been reported regarding the timing of intervention, target selection and symptom management. Our aim is to provide an update of DBS for PD in Australia. Intervention at earlier stages of the disease can potentially improve quality of life over a longer period with greater possibilities for meaningful social and professional contributions. For less responsive motor symptoms (e.g. freezing of gait, postural instability), the pedunculopontine nucleus has emerged as a promising new surgical target. Traditional PD treatment is focused on improvement of motor symptoms, but the disorder is also characterised by non-motor symptoms, often undiagnosed or undisclosed, that have the potential to impact quality of life to a greater extent than motor symptoms. It is essential to identify and routinely monitor for non-motor symptoms as they can emerge at all stages of the disease or can result from treatment. Many of these current advances require long-term monitoring of treatment outcomes to improve future clinical practice, refine patient selection and ensure best patient outcomes.

  12. Dynamic risk control by human nucleus accumbens.

    PubMed

    Nachev, Parashkev; Lopez-Sosa, Fernando; Gonzalez-Rosa, Javier Jesus; Galarza, Ana; Avecillas, Josue; Pineda-Pardo, Jose Angel; Lopez-Ibor, Juan José; Reneses, Blanca; Barcia, Juan Antonio; Strange, Bryan

    2015-12-01

    Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the nucleus accumbens dynamically altered risk behaviour, transiently shifting the psychometric function towards more risky decisions only for the duration of stimulation. A critical, on-line role of human nucleus accumbens in dynamic risk control is thereby established.

  13. Dynamic risk control by human nucleus accumbens

    PubMed Central

    Lopez-Sosa, Fernando; Gonzalez-Rosa, Javier Jesus; Galarza, Ana; Avecillas, Josue; Pineda-Pardo, Jose Angel; Lopez-Ibor, Juan José; Reneses, Blanca; Barcia, Juan Antonio

    2015-01-01

    Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the nucleus accumbens dynamically altered risk behaviour, transiently shifting the psychometric function towards more risky decisions only for the duration of stimulation. A critical, on-line role of human nucleus accumbens in dynamic risk control is thereby established. PMID:26428667

  14. The role of nucleus accumbens shell GABA receptors on ventral tegmental area intracranial self-stimulation and a potential role for the 5-HT(2C) receptor.

    PubMed

    Hayes, Dave J; Hoang, John; Greenshaw, Andrew J

    2011-12-01

    Brain γ-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT)(2C) receptors are implicated in the neuronal regulation of reward- and aversion-related behaviour. Within the mesocorticolimbic pathways of the brain, relationships between GABA containing neurons and 5-HT(2C) receptor activity may be important in this context. The primary aim of this study was to investigate the role of NAc shell GABA receptors on ventral tegmental area intracranial self-stimulation (ICSS) and to examine the systemic effects of GABAergic ligands in this context. The second aim was to investigate the relationship between GABA receptor- and 5-HT(2C) receptor-related ICSS behaviour, using systemic administration of the selective agonist WAY 161503. Locomotor activity was assessed to compare the potential motor effects of drugs; feeding behaviour and intra-NAc injections of amphetamine (1.0 µg/side) were used as positive controls. When administered systemically the GABA(A) receptor agonist muscimol and antagonist picrotoxin did not selectively change ICSS reward thresholds, although the 5-HT(2C) receptor agonist WAY 161503 (1.0 mg/kg) decreased reward measures. Intra-NAc shell administration of muscimol (225 ng/side) and picrotoxin (125 ng/side), respectively, decreased and increased measures of reward. Intra-NAc shell baclofen (0-225 ng/side; GABA(B) receptor agonist) did not affect any ICSS measures although it increased feeding. Combining picrotoxin and WAY 161503 attenuated the effects of each. These results suggest that a 5-HT(2C) and GABA(A) receptor-mediated neuronal relationship in the NAc shell may be relevant for the regulation of brain reward pathways.

  15. 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

  16. High energy nucleus-nucleus collisions

    NASA Technical Reports Server (NTRS)

    Wosiek, B.

    1986-01-01

    Experimental results on high energy nucleus-nucleus interactions are presented. The data are discussed within the framework of standard super-position models and from the point-of-view of the possible formation of new states of matter in heavy ion collisions.

  17. Role of noradrenergic and GABA-ergic inputs in pedunculopontine tegmentum for regulation of rapid eye movement sleep in rats.

    PubMed

    Pal, Dinesh; Mallick, Birendra Nath

    2006-07-01

    Rapid eye movement (REM) sleep disturbance is associated with several psycho-behavioral disorders, hence, it is important to understand its neural mechanism of regulation. Although it was known that the noradrenergic (NA-ergic) neurons from locus coeruleus (LC) project to the pedunculopontine tegmentum (PPT), the role of noradrenaline (NA) alone and in association with GABA, an inhibitory neurotransmitter, in PPT for REM sleep regulation was not known and was investigated in this study in freely moving normally behaving rats. Rats were surgically prepared for electrophysiological sleep-wake recording and simultaneous bilateral microinjections into PPT. 200nl of prazosin (alpha1-antagonist) or clonidine (alpha2-agonist) or propranolol (beta-antagonist) or combination of picrotoxin (GABA-A antagonist) and clonidine or vehicle (control) was microinjected bilaterally into PPT using a remote-controlled pump and the effects on REM sleep compared. Prazosin, clonidine and propranolol increased the total time spent in REM sleep whereas co-injection of picrotoxin and clonidine did not affect REM sleep. The results suggest that NA in PPT tonically inhibits REM sleep, possibly by acting on the cholinergic REM-ON neurons, while GABA inhibits the release of NA for REM sleep regulation. A model of neural connections explaining such regulation has been presented.

  18. The subthalamic nucleus influences visuospatial attention in humans.

    PubMed

    Schmalbach, Barbara; Günther, Veronika; Raethjen, Jan; Wailke, Stefanie; Falk, Daniela; Deuschl, Günther; Witt, Karsten

    2014-03-01

    Spatial attention is a lateralized feature of the human brain. Whereas the role of cortical areas of the nondominant hemisphere on spatial attention has been investigated in detail, the impact of the BG, and more precisely the subthalamic nucleus, on signs and symptoms of spatial attention is not well understood. Here we used unilateral deep brain stimulation of the subthalamic nucleus to reversibly, specifically, and intraindividually modify the neuronal BG outflow and its consequences on signs and symptoms of visuospatial attention in patients suffering from Parkinson disease. We tested 13 patients with Parkinson disease and chronic deep brain stimulation in three stimulation settings: unilateral right and left deep brain stimulation of the subthalamic nucleus as well as bilateral deep brain stimulation of the subthalamic nucleus. In all three stimulation settings, the patients viewed a set of pictures while an eye-tracker system recorded eye movements. During the exploration of the visual stimuli, we analyzed the time spent in each visual hemispace, as well as the number, duration, amplitude, peak velocity, acceleration peak, and speed of saccades. In the unilateral left-sided stimulation setting, patients show a shorter ipsilateral exploration time of the extrapersonal space, whereas number, duration, and speed of saccades did not differ between the different stimulation settings. These results demonstrated reduced visuospatial attention toward the side contralateral to the right subthalamic nucleus that was not being stimulated in a unilateral left-sided stimulation. Turning on the right stimulator, the reduced visuospatial attention vanished. These results support the involvement of the subthalamic nucleus in modulating spatial attention. Therefore, the subthalamic nucleus is part of the subcortical network that subserves spatial attention.

  19. REM sleep modulation by perifornical orexinergic inputs to the pedunculo-pontine tegmental neurons in rats.

    PubMed

    Khanday, M A; Mallick, B N

    2015-11-12

    Rapid eye movement sleep (REMS) is regulated by the interaction of the REM-ON and REM-OFF neurons located in the pedunculo-pontine-tegmentum (PPT) and the locus coeruleus (LC), respectively. Many other brain areas, particularly those controlling non-REMS (NREMS) and waking, modulate REMS by modulating these REMS-related neurons. Perifornical (PeF) orexin (Ox)-ergic neurons are reported to increase waking and reduce NREMS as well as REMS; dysfunction of the PeF neurons are related to REMS loss-associated disorders. Hence, we were interested in understanding the neural mechanism of PeF-induced REMS modulation. As a first step we have recently reported that PeF Ox-ergic neurons modulate REMS by influencing the LC neurons (site for REM-OFF neurons). Thereafter, in this in vivo study we have explored the role of PeF inputs on the PPT neurons (site for REM-ON neurons) for the regulation of REMS. Chronic male rats were surgically prepared with implanted bilateral cannulae in PeF and PPT and electrodes for recording sleep-waking patterns. After post-surgical recovery sleep-waking-REMS were recorded when bilateral PeF neurons were stimulated by glutamate and simultaneously bilateral PPT neurons were infused with either saline or orexin receptor1 (OX1R) antagonist. It was observed that PeF stimulation increased waking and decreased NREMS as well as REMS, which were prevented by OX1R antagonist into the PPT. We conclude that the PeF stimulation-induced reduction in REMS was likely to be due to inhibition of REM-ON neurons in the PPT. As waking and NREMS are inversely related, subject to confirmation, the reduction in NREMS could be due to increased waking or vice versa. Based on our findings from this and earlier studies we have proposed a model showing connections between PeF- and PPT-neurons for REMS regulation.

  20. The Nucleus Introduced

    PubMed Central

    Pederson, Thoru

    2011-01-01

    Now is an opportune moment to address the confluence of cell biological form and function that is the nucleus. Its arrival is especially timely because the recognition that the nucleus is extremely dynamic has now been solidly established as a paradigm shift over the past two decades, and also because we now see on the horizon numerous ways in which organization itself, including gene location and possibly self-organizing bodies, underlies nuclear functions. PMID:20660024

  1. Cholinergic Oculomotor Nucleus Activity Is Induced by REM Sleep Deprivation Negatively Impacting on Cognition.

    PubMed

    Santos, Patrícia Dos; Targa, Adriano D S; Noseda, Ana Carolina D; Rodrigues, Lais S; Fagotti, Juliane; Lima, Marcelo M S

    2016-09-22

    Several efforts have been made to understand the involvement of rapid eye movement (REM) sleep for cognitive processes. Consolidation or retention of recognition memories is severely disrupted by REM sleep deprivation (REMSD). In this regard, pedunculopontine tegmental nucleus (PPT) and other brainstem nuclei, such as pontine nucleus (Pn) and oculomotor nucleus (OCM), appear to be candidates to take part in this REM sleep circuitry with potential involvement in cognition. Therefore, the objective of this study was to investigate a possible association between the performance of Wistar rats in a declarative memory and PPT, Pn, and OCM activities after different periods of REMSD. We examined c-Fos and choline acetyltransferase (ChaT) expressions as indicators of neuronal activity as well as a familiarity-based memory test. The animals were distributed in groups: control, REMSD, and sleep rebound (REB). At the end of the different REMSD (24, 48, 72, and 96 h) and REB (24 h) time points, the rats were immediately tested in the object recognition test and then the brains were collected. Results indicated that OCM neurons presented an increased activity, due to ChaT-labeling associated with REMSD that negatively correlated (r = -0.32) with the cognitive performance. This suggests the existence of a cholinergic compensatory mechanism within the OCM during REMSD. We also showed that 24 h of REMSD impacted similarly in memory, compared to longer periods of REMSD. These data extend the notion that REM sleep is influenced by areas other than PPT, i.e., Pn and OCM, which could be key players in both sleep processes and cognition.

  2. Kaon-nucleus scattering

    NASA Technical Reports Server (NTRS)

    Hong, Byungsik; Maung, Khin Maung; Wilson, John W.; Buck, Warren W.

    1989-01-01

    The derivations of the Lippmann-Schwinger equation and Watson multiple scattering are given. A simple optical potential is found to be the first term of that series. The number density distribution models of the nucleus, harmonic well, and Woods-Saxon are used without t-matrix taken from the scattering experiments. The parameterized two-body inputs, which are kaon-nucleon total cross sections, elastic slope parameters, and the ratio of the real to the imaginary part of the forward elastic scattering amplitude, are presented. The eikonal approximation was chosen as our solution method to estimate the total and absorptive cross sections for the kaon-nucleus scattering.

  3. Kaon-nucleus scattering

    NASA Technical Reports Server (NTRS)

    Hong, Byungsik; Buck, Warren W.; Maung, Khin M.

    1989-01-01

    Two kinds of number density distributions of the nucleus, harmonic well and Woods-Saxon models, are used with the t-matrix that is taken from the scattering experiments to find a simple optical potential. The parameterized two body inputs, which are kaon-nucleon total cross sections, elastic slope parameters, and the ratio of the real to imaginary part of the forward elastic scattering amplitude, are shown. The eikonal approximation was chosen as the solution method to estimate the total and absorptive cross sections for the kaon-nucleus scattering.

  4. Onset of deconfinement in nucleus-nucleus collisions

    SciTech Connect

    Gazdzicki, M.; Gorenstein, M. I.; Seyboth, P.

    2012-05-15

    The energy dependence of hadron production in relativistic nucleus-nucleus collisions reveals anomalies-the kink, horn, and step. They were predicted as signals of the deconfinement phase transition and observed by the NA49 Collaboration in central PbPb collisions at the CERN SPS. This indicates the onset of the deconfinement in nucleus-nucleus collisions at about 30 A GeV.

  5. A descending dopamine pathway conserved from basal vertebrates to mammals

    PubMed Central

    Ryczko, Dimitri; Cone, Jackson J.; Alpert, Michael H.; Goetz, Laurent; Auclair, François; Dubé, Catherine; Parent, Martin; Roitman, Mitchell F.; Alford, Simon; Dubuc, Réjean

    2016-01-01

    Dopamine neurons are classically known to modulate locomotion indirectly through ascending projections to the basal ganglia that project down to brainstem locomotor networks. Their loss in Parkinson’s disease is devastating. In lampreys, we recently showed that brainstem networks also receive direct descending dopaminergic inputs that potentiate locomotor output. Here, we provide evidence that this descending dopaminergic pathway is conserved to higher vertebrates, including mammals. In salamanders, dopamine neurons projecting to the striatum or brainstem locomotor networks were partly intermingled. Stimulation of the dopaminergic region evoked dopamine release in brainstem locomotor networks and concurrent reticulospinal activity. In rats, some dopamine neurons projecting to the striatum also innervated the pedunculopontine nucleus, a known locomotor center, and stimulation of the dopaminergic region evoked pedunculopontine dopamine release in vivo. Finally, we found dopaminergic fibers in the human pedunculopontine nucleus. The conservation of a descending dopaminergic pathway across vertebrates warrants re-evaluating dopamine’s role in locomotion. PMID:27071118

  6. Gustatory Reward and the Nucleus Accumbens

    PubMed Central

    Norgren, R.; Hajnal, A.; Mungarndee, S.S.

    2011-01-01

    The concept of reward is central to psychology, but remains a cipher for neuroscience. Considerable evidence implicates dopamine in the process of reward and much of the data derives from the nucleus accumbens. Gustatory stimuli are widely used for animal studies of reward, but the connections between the taste and reward systems are unknown. In a series of experiments, our laboratory has addressed this issue using functional neurochemistry and neuroanatomy. First, using microdialysis probes, we demonstrated that sapid sucrose releases dopamine in the nucleus accumbens. The effect is dependent on oral stimulation and concentration. We subsequently determined that this response was independent of the thalamocortical gustatory system, but substantially blunted by damage to the parabrachial limbic taste projection. Further experiments using c-fos histochemistry confirmed that the limbic pathway was the prime carrier for the gustatory afferent activity that drives accumbens dopamine release. PMID:16822531

  7. Movement disorders induced by deep brain stimulation.

    PubMed

    Baizabal-Carvallo, José Fidel; Jankovic, Joseph

    2016-04-01

    Deep brain stimulation represents a major advance in the treatment of several types of movement disorders. However, during stimulation new movement disorders may emerge, thus limiting the positive effects of this therapy. These movement disorders may be induced by: 1) stimulation of the targeted nucleus, 2) stimulation of surrounding tracts and nuclei, and 3) as a result of dose adjustment of accompanying medications, such as reduction of dopaminergic drugs in patients with Parkinson's disease. Various dyskinesias, blepharospasm, and apraxia of eyelid opening have been described mainly with subthalamic nucleus stimulation, whereas hypokinesia and freezing of gait have been observed with stimulation of the globus pallidus internus. Other deep brain stimulation-related movement disorders include dyskinesias associated with stimulation of the globus pallidus externus and ataxic gait as a side effect of chronic bilateral stimulation of the ventral intermediate nucleus of thalamus. These movement disorders are generally reversible and usually resolved once the stimulation is reduced or turned off. This, however, typically leads to loss of benefit of the underlying movement disorder which can be re-gained by using different contacts, changing targets or stimulation parameters, and adjusting pharmacological therapy. New and innovative emerging technologies and stimulation techniques may help to prevent or overcome the various deep brain stimulation-induced movement disorders. In this review we aim to describe the clinical features, frequency, pathophysiology, and strategies for treatment of these iatrogenic movement disorders.

  8. 5-Hydroxytryptamine2A/2C receptors of nucleus raphe magnus and gigantocellularis/paragigantocellularis pars α reticular nuclei modulate the unconditioned fear-induced antinociception evoked by electrical stimulation of deep layers of the superior colliculus and dorsal periaqueductal grey matter.

    PubMed

    de Oliveira, Ricardo; de Oliveira, Rithiele Cristina; Falconi-Sobrinho, Luiz Luciano; da Silva Soares, Raimundo; Coimbra, Norberto Cysne

    2017-01-01

    The electrical stimulation of the dorsolateral columns of the periaquedutal grey matter (dlPAG) or deep layers of the superior colliculus (dlSC) evokes defensive behaviours followed by an antinociceptive response. Monoaminergic brainstem reticular nuclei are suggested to comprise the endogenous pain modulatory system. The aim of the present work was to investigate the role played by 5-HT2 subfamily of serotonergic receptors of the nucleus raphe magnus (NRM) and the gigantocellularis/paragigantocellularis pars α reticular nuclei (Gi/PGiα) in the elaboration of instinctive fear-induced antinociception elicited by electrical stimulation of dlPAG or of dlSC. The nociceptive thresholds were measured by the tail-flick test in Wistar rats. The 5-HT2A/2C-serotonergic receptors antagonist ritanserin was microinjected at different concentrations (0.05, 0.5 and 5.0μg/0.2μL) either in Gi/PGiα or in NRM. The blockade of 5-HT2 receptors in both Gi/PGiα and NRM decreased the innate fear-induced antinociception elicited by electrical stimulation of the dlSC or the dlPAG. These findings indicate that serotonin is involved in the hypo-algesia induced by unconditioned fear-induced behavioural responses and the 5-HT2A/2C-serotonergic receptor subfamily in neurons situated in the Gi/PGiα complex and NRM are critically recruited in pain modulation during the panic-like emotional behaviour.

  9. 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

  10. Neutrino-nucleus interactions

    SciTech Connect

    Gallagher, H.; Garvey, G.; Zeller, G.P.; /Fermilab

    2011-01-01

    The study of neutrino oscillations has necessitated a new generation of neutrino experiments that are exploring neutrino-nuclear scattering processes. We focus in particular on charged-current quasi-elastic scattering, a particularly important channel that has been extensively investigated both in the bubble-chamber era and by current experiments. Recent results have led to theoretical reexamination of this process. We review the standard picture of quasi-elastic scattering as developed in electron scattering, review and discuss experimental results, and discuss additional nuclear effects such as exchange currents and short-range correlations that may play a significant role in neutrino-nucleus scattering.

  11. Reality of comet nucleus.

    NASA Technical Reports Server (NTRS)

    Lyttleton, R. A.

    1972-01-01

    The prime problem of a comet mission must be to settle whether the cometary nucleus has an actual tangible material existence, or whether it arises from some optical effect present only at times within comets. The absence of any large particles in a comet seems to be demonstrated by certain meteor showers. A feature that would seem to indicate that a comet consists primarily of a swarm of particles is that the coma in general contracts as the comet approaches the sun, roughly in proportion within the distance, and then expands again as it recedes.

  12. Nucleus from string theory

    NASA Astrophysics Data System (ADS)

    Hashimoto, Koji; Morita, Takeshi

    2011-08-01

    In generic holographic QCD, we find that baryons are bound to form a nucleus, and that its radius obeys the empirically-known mass-number (A) dependence r∝A1/3 for large A. Our result is robust, since we use only a generic property of D-brane actions in string theory. We also show that nucleons are bound completely in a finite volume. Furthermore, employing a concrete holographic model (derived by Hashimoto, Iizuka, and Yi, describing a multibaryon system in the Sakai-Sugimoto model), the nuclear radius is evaluated as O(1)×A1/3[fm], which is consistent with experiments.

  13. Higgs-boson production in nucleus-nucleus collisions

    NASA Technical Reports Server (NTRS)

    Norbury, J. W.; Townsend, L. W. (Principal Investigator)

    1990-01-01

    Cross-section calculations are presented for the production of intermediate-mass Higgs bosons produced in ultrarelativistic nucleus-nucleus collisions via two-photon fusion. The calculations are performed in position space using Baur's method for folding together the Weizsacker-Williams virtual-photon spectra of the two colliding nuclei. It is found that two-photon fusion in nucleus-nucleus collisions is a plausible way of finding intermediate-mass Higgs bosons at the Superconducting Super Collider or the CERN Large Hadron Collider.

  14. Higgs-Boson Production in Nucleus-Nucleus Collisions

    NASA Technical Reports Server (NTRS)

    Norbury, John W.

    1992-01-01

    Cross section calculations are presented for the production of intermediate-mass Higgs bosons produced in ultrarelativistic nucleus-nucleus collisions via two photon fusion. The calculations are performed in position space using Baur's method for folding together the Weizsacker-Williams virtual-photon spectra of the two colliding nuclei. It is found that two photon fusion in nucleus-nucleus collisions is a plausible way of finding intermediate-mass Higgs bosons at the Superconducting Super Collider or the CERN Large Hadron Collider.

  15. Networking the nucleus

    PubMed Central

    Rajapakse, Indika; Scalzo, David; Tapscott, Stephen J; Kosak, Steven T; Groudine, Mark

    2010-01-01

    The nuclei of differentiating cells exhibit several fundamental principles of self-organization. They are composed of many dynamical units connected physically and functionally to each other—a complex network—and the different parts of the system are mutually adapted and produce a characteristic end state. A unique cell-specific signature emerges over time from complex interactions among constituent elements that delineate coordinate gene expression and chromosome topology. Each element itself consists of many interacting components, all dynamical in nature. Self-organizing systems can be simplified while retaining complex information using approaches that examine the relationship between elements, such as spatial relationships and transcriptional information. These relationships can be represented using well-defined networks. We hypothesize that during the process of differentiation, networks within the cell nucleus rewire according to simple rules, from which a higher level of order emerges. Studying the interaction within and among networks provides a useful framework for investigating the complex organization and dynamic function of the nucleus. PMID:20664641

  16. Meson multiplicity versus energy in relativistic nucleus-nucleus collisions

    NASA Technical Reports Server (NTRS)

    Atwater, T. W.; Freier, P. S.

    1986-01-01

    A systematic study of meson multiplicity as a function of energy at energies up to 100 GeV/u in nucleus-nucleus collisions has been made, using cosmic-ray data in nuclear emulsion. The data are consistent with simple nucleon-nucleon superposition models. Multiplicity per interacting nucleon in AA collisions does not appear to differ significantly from pp collisions.

  17. Momentum loss in proton-nucleus and nucleus-nucleus collisions

    NASA Technical Reports Server (NTRS)

    Khan, Ferdous; Townsend, Lawrence W.

    1993-01-01

    An optical model description, based on multiple scattering theory, of longitudinal momentum loss in proton-nucleus and nucleus-nucleus collisions is presented. The crucial role of the imaginary component of the nucleon-nucleon transition matrix in accounting for longitudinal momentum transfer is demonstrated. Results obtained with this model are compared with Intranuclear Cascade (INC) calculations, as well as with predictions from Vlasov-Uehling-Uhlenbeck (VUU) and quantum molecular dynamics (QMD) simulations. Comparisons are also made with experimental data where available. These indicate that the present model is adequate to account for longitudinal momentum transfer in both proton-nucleus and nucleus-nucleus collisions over a wide range of energies.

  18. Noradrenaline from Locus Coeruleus Neurons Acts on Pedunculo-Pontine Neurons to Prevent REM Sleep and Induces Its Loss-Associated Effects in Rats

    PubMed Central

    Khanday, Mudasir Ahmad; Somarajan, Bindu I.; Mehta, Rachna

    2016-01-01

    Normally, rapid eye movement sleep (REMS) does not appear during waking or non-REMS. Isolated, independent studies showed that elevated noradrenaline (NA) levels inhibit REMS and induce REMS loss-associated cytomolecular, cytomorphological, psychosomatic changes and associated symptoms. However, the source of NA and its target in the brain for REMS regulation and function in health and diseases remained to be confirmed in vivo. Using tyrosine hydroxylase (TH)-siRNA and virus-coated TH-shRNA in normal freely moving rats, we downregulated NA synthesis in locus coeruleus (LC) REM-OFF neurons in vivo. These TH-downregulated rats showed increased REMS, which was prevented by infusing NA into the pedunculo-pontine tegmentum (PPT), the site of REM-ON neurons, normal REMS returned after recovery. Moreover, unlike normal or control-siRNA- or shRNA-injected rats, upon REMS deprivation (REMSD) TH-downregulated rat brains did not show elevated Na-K ATPase (molecular changes) expression and activity. To the best of our knowledge, these are the first in vivo findings in an animal model confirming that NA from the LC REM-OFF neurons (1) acts on the PPT REM-ON neurons to prevent appearance of REMS, and (2) are responsible for inducing REMSD-associated molecular changes and symptoms. These observations clearly show neuro-physio-chemical mechanism of why normally REMS does not appear during waking. Also, that LC neurons are the primary source of NA, which in turn causes some, if not many, REMSD-associated symptoms and behavioral changes. The findings are proof-of-principle for the first time and hold potential to be exploited for confirmation toward treating REMS disorder and amelioration of REMS loss-associated symptoms in patients. PMID:27957531

  19. Electron microscopic localization of M2-muscarinic receptors in cholinergic and noncholinergic neurons of the laterodorsal tegmental and pedunculopontine nuclei of the rat mesopontine tegmentum.

    PubMed

    Garzón, Miguel; Pickel, Virginia M

    2016-10-15

    Muscarinic m2 receptors (M2Rs) are implicated in autoregulatory control of cholinergic output neurons located within the pedunculopontine (PPT) and laterodorsal tegmental (LTD) nuclei of the mesopontine tegmentum (MPT). However, these nuclei contain many noncholinergic neurons in which activation of M2R heteroceptors may contribute significantly to the decisive role of the LTD and PPT in sleep-wakefulness. We examined the electron microscopic dual immunolabeling of M2Rs and the vesicular acetylcholine transporter (VAchT) in the MPT of rat brain to identify the potential sites for M2R activation. M2R immunogold labeling was predominately seen in somatodendritic profiles throughout the PPT/LTD complex. In somata, M2R immunogold particles were often associated with Golgi lamellae and cytoplasmic endomembrannes, but were rarely in contact with the plasma membrane, as was commonly seen in dendrites. Approximately 36% of the M2R-labeled somata and 16% of the more numerous M2R-labeled dendrites coexpressed VAchT. M2R and M2R/VAchT-labeled dendritic profiles received synapses from inhibitory- and excitatory-type axon terminals, over 88% of which were unlabeled and others contained exclusively M2R or VAchT immunoreactivity. In axonal profiles M2R immunogold was localized to plasmalemmal and cytoplasmic regions and showed a similar distribution in many VAchT-negative glial profiles. These results provide ultrastructural evidence suggestive of somatic endomembrane trafficking of M2Rs, whose activation serves to regulate the postsynaptic excitatory and inhibitory responses in dendrites of cholinergic and noncholinergic neurons in the MPT. They also suggest the possibility that M2Rs in this brain region mediate the effects of acetylcholine on the release of other neurotransmitters and on glial signaling. J. Comp. Neurol. 524:3084-3103, 2016. © 2016 Wiley Periodicals, Inc.

  20. The intercalatus nucleus of Staderini.

    PubMed

    Cascella, Marco

    2016-01-01

    Rutilio Staderini was one of the leading Italian anatomists of the twentieth century, together with some scientists, such as Giulio Chiarugi, Giovanni Vitali, and others. He was also a member of a new generation of anatomists. They had continued the tradition of the most famous Italian scientists, which started from the Renaissance up until the nineteenth century. Although he carried out important studies of neuroanatomy and comparative anatomy, as well as embryology, his name is rarely remembered by most medical historians. His name is linked to the nucleus he discovered: the Staderini nucleus or intercalated nucleus, a collection of nerve cells in the medulla oblongata located lateral to the hypoglossal nucleus. This article focuses on the biography of the neuroanatomist as well as the nucleus that carries his name and his other research, especially on comparative anatomy and embryology.

  1. Food restriction increases NMDA receptor-mediated calcium-calmodulin kinase II and NMDA receptor/extracellular signal-regulated kinase 1/2-mediated cyclic amp response element-binding protein phosphorylation in nucleus accumbens upon D-1 dopamine receptor stimulation in rats.

    PubMed

    Haberny, S L; Carr, K D

    2005-01-01

    Biological drive states exert homeostatic control in part by increasing the reinforcing effects of environmental incentive stimuli. An apparent by-product of this adaptive response is the enhanced acquisition of drug self-administration behavior in food-restricted (FR) animals. While previous research has demonstrated increased central sensitivity to rewarding effects of abused drugs and direct dopamine (DA) receptor agonists in FR subjects, the underlying neurobiology is not well understood. Recently, it was demonstrated that intracerebroventricular (i.c.v.) injection of the D-1 DA receptor agonist, SKF-82958 produces a stronger activation of striatal extracellular signal-regulated kinase (ERK) 1/2 and cyclic AMP response element-binding protein (CREB) in FR relative to ad libitum (AL) fed rats. The main purpose of the present study was to characterize the involvement and mechanisms of interaction between NMDA receptor function and the augmented cellular responses to D-1 DA receptor stimulation in nucleus accumbens (NAc) of FR rats. In experiment 1, Western immunoblotting was used to demonstrate that i.c.v. injection of SKF-82958 (20 microg) produces greater phosphorylation of the NMDA NR1 subunit and calcium-calmodulin kinase II (CaMK II) in NAc of FR as compared with AL rats. In experiment 2, pretreatment of subjects with the NMDA antagonist, MK-801 (1.0 mg/kg, i.p.) decreased SKF-82958-induced activation of CaMK II, ERK1/2 and CREB, and reversed the augmenting effect of FR on activation of all three proteins. In experiment 3, pretreatment with the mitogen-activated protein kinase/ERK kinase inhibitor SL-327 (60 mg/kg, i.p.) suppressed SKF-82958- induced activation of ERK1/2 and reversed the augmenting effect of FR on CREB activation. These results point to specific neuroadaptations in the NAc of FR rats whereby D-1 DA receptor stimulation leads to increased NMDA NR1 subunit phosphorylation and consequent increases in NMDA receptor-dependent CaMK II and ERK1

  2. Mapping of alpha-melanocyte-stimulating hormone-like immunoreactivity in the cat brainstem.

    PubMed

    Coveñas, R; de León, M; Narváez, J A; Aguirre, J A; Tramu, G

    2000-04-01

    The distribution of alpha-melanocyte-stimulating hormone-like immunoreactive structures was studied in the brainstem of the cat using an indirect immunoperoxidase technique. Immunoreactivity was observed in several brainstem nuclei of the cat in which no immunoreactivity had been previously reported. Immunoreactive fibres were observed in the following; the inferior central nucleus; the pontine gray nuclei; the Kölliker-Fuse nucleus; the motor trigeminal nucleus, the anteroventral cochlear nucleus; the abducens nucleus; the retrofacial nucleus; the superior, lateral, inferior, and medial vestibular nuclei; the lateral nucleus of the superior olive; the external cuneate nucleus; the nucleus of the trapezoid body; the postpyramidal nucleus of the raphe; the medial accessory inferior olive; the dorsal accessory nucleus of the inferior olive; the nucleus ambiguus; the principal nucleus of the inferior olive; the preolivary nucleus; the nucleus ruber; the substantia nigra; and in the area postrema. Our results point to a more widespread distribution of alpha-melanocyte-stimulating hormone-like immunoreactive structures in the cat brainstem than that reported in previous studies carried out in the same region of the cat, rat and humans.

  3. Surface albedo of cometary nucleus

    NASA Astrophysics Data System (ADS)

    Mukai, T.; Mukai, S.

    A variation of the albedo on the illuminated disk of a comet nucleus is estimated, taking into account the multiple reflection of incident light due to small scale roughness. The dependences of the average albedo over the illuminated disk on the degree of roughness and on the complex refractive index of the surface materials are examined. The variation estimates are compared with measurements of the nucleus albedo of Comet Halley (Reitsema et al., 1987).

  4. Characterization of a folate-induced hypermotility response after bilateral injection into the rat nucleus accumbens

    SciTech Connect

    Stephens, R.L. Jr.

    1986-01-01

    The objective of these studies was to pharmacologically characterize the mechanism responsible for a folate-induced stimulation of locomotor activity in rats after bilateral injection into the nucleus accumbens region of the brain. Folic acid (FA) and 5-formyltetrahydrofolic acid (FTHF) produced this hypermotility response after intra-accumbens injection, while other reduced folic acid derivatives dihydrofolic acid, tetrahydrofolic acid, and 5-methyltetrahydrofolic acid were ineffective. Studies were designed to determine the role of catecholamines in the nucleus accumbens in the folate-induced hypermotility response. The findings suggest that the folate-induced response is dependent on intact neuronal dopamine stores, and is mediated by stimulation of dopamine receptors of the nucleus accumbens. However the folates do not appear to enhance dopaminergic neutransmission. Thus, FA and FTHF were inefficient at 1 mM concentrations in stimulating /sup 3/H-dopamine release from /sup 3/H-dopamine preloaded nucleus accumbens slices or dopamine from endogenous stores. Pteroic acid, the chemical precursor of folic acid which lacks the glutamate moiety, was ineffective in producing a stimulation of locomotor activity after intra-accumbens injection. Since glutamate is an excitatory amino acid (EAA), compounds characterized as EAA receptor antagonists were utilized to determine if the folate-induced hypermotility response is mediated by activation of EAA receptors in the nucleus accumbens. These results suggest that activation of quisqualate receptors of the nucleus accumbens may mediate the folate-induced hypermotility response.

  5. Sensitivity of cross sections for elastic nucleus-nucleus scattering to halo nucleus density distributions

    SciTech Connect

    Alkhazov, G. D.; Sarantsev, V. V.

    2012-12-15

    In order to clear up the sensitivity of the nucleus-nucleus scattering to the nuclear matter distributions in exotic halo nuclei, we have calculated differential cross sections for elastic scattering of the {sup 6}He and {sup 11}Li nuclei on several nuclear targets at the energy of 0.8 GeV/nucleon with different assumed nuclear density distributions in {sup 6}He and {sup 11}Li.

  6. Interactions between Brainstem Noradrenergic Neurons and the Nucleus Accumbens Shell in Modulating Memory for Emotionally Arousing Events

    ERIC Educational Resources Information Center

    Kerfoot, Erin C.; Williams, Cedric L.

    2011-01-01

    The nucleus accumbens shell (NAC) receives axons containing dopamine-[beta]-hydroxylase that originate from brainstem neurons in the nucleus of the solitary tract (NTS). Recent findings show that memory enhancement produced by stimulating NTS neurons after learning may involve interactions with the NAC. However, it is unclear whether these…

  7. Epidermal growth factor receptors destined for the nucleus are internalized via a clathrin-dependent pathway

    SciTech Connect

    De Angelis Campos, Ana Carolina; Rodrigues, Michele Angela; Andrade, Carolina de; Miranda de Goes, Alfredo; Nathanson, Michael H.; Gomes, Dawidson A.

    2011-08-26

    Highlights: {yields} EGF and its receptor translocates to the nucleus in liver cells. {yields} Real time imaging shows that EGF moves to the nucleus. {yields} EGF moves with its receptor to the nucleus. {yields} Dynamin and clathrin are necessary for EGFR nuclear translocation. -- Abstract: The epidermal growth factor (EGF) transduces its actions via the EGF receptor (EGFR), which can traffic from the plasma membrane to either the cytoplasm or the nucleus. However, the mechanism by which EGFR reaches the nucleus is unclear. To investigate these questions, liver cells were analyzed by immunoblot of cell fractions, confocal immunofluorescence and real time confocal imaging. Cell fractionation studies showed that EGFR was detectable in the nucleus after EGF stimulation with a peak in nuclear receptor after 10 min. Movement of EGFR to the nucleus was confirmed by confocal immunofluorescence and labeled EGF moved with the receptor to the nucleus. Small interference RNA (siRNA) was used to knockdown clathrin in order to assess the first endocytic steps of EGFR nuclear translocation in liver cells. A mutant dynamin (dynamin K44A) was also used to determine the pathways for this traffic. Movement of labeled EGF or EGFR to the nucleus depended upon dynamin and clathrin. This identifies the pathway that mediates the first steps for EGFR nuclear translocation in liver cells.

  8. Eyelid apraxia associated with deep brain stimulation of the periaqueductal gray area.

    PubMed

    Langevin, Jean-Philippe; Srikandarajah, Nisaharan; Krahl, Scott E; Gorgulho, Alessandra; Behnke, Eric; Malkasian, Dennis; DeSalles, Antonio A F

    2014-09-01

    We report a patient with eyelid apraxia following deep brain stimulation of the periaqueductal gray area. Based on the position of our electrode, we argue that the phenomenon is linked to inhibition of the nearby central caudal nucleus of the oculomotor nucleus by high frequency stimulation.

  9. Electrophysiological and morphological properties of neurons in the prepositus hypoglossi nucleus that express both ChAT and VGAT in a double-transgenic rat model.

    PubMed

    Saito, Yasuhiko; Zhang, Yue; Yanagawa, Yuchio

    2015-04-01

    Although it has been proposed that neurons that contain both acetylcholine (ACh) and γ-aminobutyric acid (GABA) are present in the prepositus hypoglossi nucleus (PHN), these neurons have not been characterized because of the difficulty in identifying them. In the present study, PHN neurons that express both choline acetyltransferase and the vesicular GABA transporter (VGAT) were identified using double-transgenic rats, in which the cholinergic and inhibitory neurons express the fluorescent proteins tdTomato and Venus, respectively. To characterize the neurons that express both tdTomato and Venus (D+ neurons), the afterhyperpolarization (AHP) profiles and firing patterns of these neurons were investigated via whole-cell recordings of brainstem slice preparations. Regarding the three AHP profiles and four firing patterns that the D+ neurons exhibited, an AHP with an afterdepolarization and a firing pattern that exhibited a delay in the generation of the first spike were the preferential properties of these neurons. In the three morphological types classified, the multipolar type that exhibited radiating dendrites was predominant among the D+ neurons. Immunocytochemical analysis revealed that the VGAT-immunopositive axonal boutons that expressed tdTomato were primarily located in the dorsal cap of inferior olive (IO) and the PHN. Although the PHN receives cholinergic inputs from the pedunculopontine tegmental nucleus and laterodorsal tegmental nucleus, D+ neurons were absent from these brain areas. Together, these results suggest that PHN neurons that co-express ACh and GABA exhibit specific electrophysiological and morphological properties, and innervate the dorsal cap of the IO and the PHN.

  10. Tickling increases dopamine release in the nucleus accumbens and 50 kHz ultrasonic vocalizations in adolescent rats.

    PubMed

    Hori, Miyo; Shimoju, Rie; Tokunaga, Ryota; Ohkubo, Masato; Miyabe, Shigeki; Ohnishi, Junji; Murakami, Kazuo; Kurosawa, Mieko

    2013-03-27

    Adolescent rats emit 50 kHz ultrasonic vocalizations, a marker of positive emotion, during rough-and-tumble play or on tickling stimulation. The emission of 50 kHz ultrasonic vocalizations in response to tickling is suggested to be mediated by dopamine release in the nucleus accumbens; however, there is no direct evidence supporting this hypothesis. The present study aimed to elucidate whether play behavior (tickling) in adolescent rats can trigger dopamine release in the nucleus accumbens with hedonic 50 kHz ultrasonic vocalizations. The effect of tickling stimulation was compared with light-touch stimulation, as a discernible stimulus. We examined 35-40-day-old rats, which corresponds to the period of midadolescence. Tickling stimulation for 5 min significantly increased dopamine release in the nucleus accumbens (118±7% of the prestimulus control value). Conversely, light-touch stimulation for 5 min did not significantly change dopamine release. In addition, 50 kHz ultrasonic vocalizations were emitted during tickling stimulation but not during light-touch stimulation. Further, tickling-induced 50 kHz ultrasonic vocalizations were significantly blocked by the direct application of SCH23390 (D1 receptor antagonist) and raclopride (D2/D3 receptor antagonist) into the nucleus accumbens. Our study demonstrates that tickling stimulation in adolescent rats increases dopamine release in the nucleus accumbens, leading to the generation of 50 kHz ultrasonic vocalizations.

  11. Formin' actin in the nucleus.

    PubMed

    Baarlink, Christian; Grosse, Robert

    2014-01-01

    Many if not most proteins can, under certain conditions, change cellular compartments, such as, for example, shuttling from the cytoplasm to the nucleus. Thus, many proteins may exert functions in various and very different subcellular locations, depending on the signaling context. A large amount of actin regulatory proteins has been detected in the mammalian cell nucleus, although their potential roles are much debated and are just beginning to emerge. Recently, members of the formin family of actin nucleators were also reported to dynamically localize to the nuclear environment. Here we discuss our findings that specific diaphanous-related formins can promote nuclear actin assembly in a signal-dependent manner.

  12. Functionalized active-nucleus complex sensor

    DOEpatents

    Pines, Alexander; Wemmer, David E.; Spence, Megan; Rubin, Seth

    2003-11-25

    A functionalized active-nucleus complex sensor that selectively associates with one or more target species, and a method for assaying and screening for one or a plurality of target species utilizing one or a plurality of functionalized active-nucleus complexes with at least two of the functionalized active-nucleus complexes having an attraction affinity to different corresponding target species. The functionalized active-nucleus complex has an active-nucleus and a targeting carrier. The method involves functionalizing an active-nucleus, for each functionalized active-nucleus complex, by incorporating the active-nucleus into a macromolucular or molecular complex that is capable of binding one of the target species and then bringing the macromolecular or molecular complexes into contact with the target species and detecting the occurrence of or change in a nuclear magnetic resonance signal from each of the active-nuclei in each of the functionalized active-nucleus complexes.

  13. The serotonin 5-HT7 receptor agonist LP-44 microinjected into the dorsal raphe nucleus suppresses REM sleep in the rat.

    PubMed

    Monti, Jaime M; Leopoldo, Marcello; Jantos, Héctor

    2008-08-22

    The effects of LP-44, a selective 5-HT7 receptor agonist, and of SB-269970, a selective 5-HT7 receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The 5-HT7 receptor ligands were microinjected directly into the dorsal raphe nucleus (DRN) during the light period of the 12-h light/12-h dark cycle. Infusion of LP-44 (1.25-5.0 mM) into the DRN induced a significant reduction of rapid-eye-movement sleep (REMS) and of the number of REM periods. Similar effects were observed after the direct administration into the DRN of SB-269970 (0.5-1.0 mM). Pretreatment with a dose of SB-269970 (0.5 mM) that significantly affects sleep variables antagonized the LP-44 (2.5 mM)-induced suppression of REMS and of the number of REM periods. It is proposed that the suppression of REMS after microinjection of LP-44 into the DRN is related, at least in part, to the activation of GABAergic neurons in the DRN that contribute to long projections that reach, among others, the laterodorsal and pedunculopontine tegmental nuclei involved in the promotion of REMS.

  14. Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson's disease.

    PubMed

    Oswal, Ashwini; Beudel, Martijn; Zrinzo, Ludvic; Limousin, Patricia; Hariz, Marwan; Foltynie, Tom; Litvak, Vladimir; Brown, Peter

    2016-05-01

    Chronic dopamine depletion in Parkinson's disease leads to progressive motor and cognitive impairment, which is associated with the emergence of characteristic patterns of synchronous oscillatory activity within cortico-basal-ganglia circuits. Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson's disease, but its influence on synchronous activity in cortico-basal-ganglia loops remains to be fully characterized. Here, we demonstrate that deep brain stimulation selectively suppresses certain spatially and spectrally segregated resting state subthalamic nucleus-cortical networks. To this end we used a validated and novel approach for performing simultaneous recordings of the subthalamic nucleus and cortex using magnetoencephalography (during concurrent subthalamic nucleus deep brain stimulation). Our results highlight that clinically effective subthalamic nucleus deep brain stimulation suppresses synchrony locally within the subthalamic nucleus in the low beta oscillatory range and furthermore that the degree of this suppression correlates with clinical motor improvement. Moreover, deep brain stimulation relatively selectively suppressed synchronization of activity between the subthalamic nucleus and mesial premotor regions, including the supplementary motor areas. These mesial premotor regions were predominantly coupled to the subthalamic nucleus in the high beta frequency range, but the degree of deep brain stimulation-associated suppression in their coupling to the subthalamic nucleus was not found to correlate with motor improvement. Beta band coupling between the subthalamic nucleus and lateral motor areas was not influenced by deep brain stimulation. Motor cortical coupling with subthalamic nucleus predominantly involved driving of the subthalamic nucleus, with those drives in the higher beta frequency band having much shorter net delays to subthalamic nucleus than those in the lower beta band. These observations raise the

  15. Closing the loop of deep brain stimulation

    PubMed Central

    Carron, Romain; Chaillet, Antoine; Filipchuk, Anton; Pasillas-Lépine, William; Hammond, Constance

    2013-01-01

    High-frequency deep brain stimulation is used to treat a wide range of brain disorders, like Parkinson's disease. The stimulated networks usually share common electrophysiological signatures, including hyperactivity and/or dysrhythmia. From a clinical perspective, HFS is expected to alleviate clinical signs without generating adverse effects. Here, we consider whether the classical open-loop HFS fulfills these criteria and outline current experimental or theoretical research on the different types of closed-loop DBS that could provide better clinical outcomes. In the first part of the review, the two routes followed by HFS-evoked axonal spikes are explored. In one direction, orthodromic spikes functionally de-afferent the stimulated nucleus from its downstream target networks. In the opposite direction, antidromic spikes prevent this nucleus from being influenced by its afferent networks. As a result, the pathological synchronized activity no longer propagates from the cortical networks to the stimulated nucleus. The overall result can be described as a reversible functional de-afferentation of the stimulated nucleus from its upstream and downstream nuclei. In the second part of the review, the latest advances in closed-loop DBS are considered. Some of the proposed approaches are based on mathematical models, which emphasize different aspects of the parkinsonian basal ganglia: excessive synchronization, abnormal firing-rate rhythms, and a deficient thalamo-cortical relay. The stimulation strategies are classified depending on the control-theory techniques on which they are based: adaptive and on-demand stimulation schemes, delayed and multi-site approaches, stimulations based on proportional and/or derivative control actions, optimal control strategies. Some of these strategies have been validated experimentally, but there is still a large reservoir of theoretical work that may point to ways of improving practical treatment. PMID:24391555

  16. Higgs and Particle Production in Nucleus-Nucleus Collisions

    NASA Astrophysics Data System (ADS)

    Liu, Zhe

    We apply a diagrammatic approach to study Higgs boson, a color-neutral heavy particle, pro- duction in nucleus-nucleus collisions in the saturation framework without quantum evolution. We assume the strong coupling constant much smaller than one. Due to the heavy mass and colorless nature of Higgs particle, final state interactions are absent in our calculation. In order to treat the two nuclei dynamically symmetric, we use the Coulomb gauge which gives the appropriate light cone gauge for each nucleus. To further eliminate initial state interactions we choose specific prescriptions in the light cone propagators. We start the calculation from only two nucleons in each nucleus and then demonstrate how to generalize the calculation to higher orders diagrammatically. We simplify the diagrams by the Slavnov-Taylor-Ward identities. The resulting cross section is factorized into a product of two Weizsacker-Williams gluon distributions of the two nuclei when the transverse momentum of the produced scalar particle is around the saturation momentum. To our knowledge this is the first process where an exact analytic formula has been formed for a physical process, involving momenta on the order of the saturation momentum, in nucleus-nucleus collisions in the quasi-classical approximation. Since we have performed the calculation in an unconventional gauge choice, we further confirm our results in Feynman gauge where the Weizsacker-Williams gluon distribution is interpreted as a transverse momentum broadening of a hard gluons traversing a nuclear medium. The transverse momentum factorization manifests itself in light cone gauge but not so clearly in Feynman gauge. In saturation physics there are two different unintegrated gluon distributions usually encountered in the literature: the Weizsacker-Williams gluon distribution and the dipole gluon distribution. The first gluon distribution is constructed by solving classical Yang-Mills equation of motion in the Mc

  17. Deep brain stimulation for refractory epilepsy

    PubMed Central

    Mandat, Tomasz; Kornakiewicz, Anna; Koziara, Henryk; Nauman, Paweł

    2012-01-01

    Deep brain stimulation (DBS) is a method of treatment utilized to control medically refractory epilepsy (RE). Patients with medically refractory epilepsy who do not achieve satisfactory control of seizures with pharmacological treatment or surgical resection of the epileptic focus and those who do not qualify for surgery could benefit from DBS. The most frequently used stereotactic targets for DBS are the anterior thalamic nucleus, subthalamic nucleus, central-medial thalamic nucleus, hippocampus, amygdala and cerebellum. The DBS is believed to be an effective method of treatment for various types of epilepsy among adults and adolescents. Side effects may be associated with implantation of electrodes and with the stimulation itself. An increasing number of publications and growing interest in DBS application for RE may result in standardization of the qualification and treatment protocol for RE with DBS. PMID:23185188

  18. Nigral stimulation for resistant axial motor impairment in Parkinson’s disease? A randomized controlled trial

    PubMed Central

    Walach, Margarete; Meisner, Christoph; Fritz, Melanie; Scholten, Marlieke; Breit, Sorin; Plewnia, Christian; Bender, Benjamin; Gharabaghi, Alireza; Wächter, Tobias

    2013-01-01

    Gait and balance disturbances typically emerge in advanced Parkinson’s disease with generally limited response to dopaminergic medication and subthalamic nucleus deep brain stimulation. Therefore, advanced programming with interleaved pulses was put forward to introduce concomittant nigral stimulation on caudal contacts of a subthalamic lead. Here, we hypothesized that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata improves axial symptoms compared with standard subthalamic nucleus stimulation. Twelve patients were enrolled in this 2 × 2 cross-over double-blind randomized controlled clinical trial and both the safety and efficacy of combined subthalamic nucleus and substantia nigra pars reticulata stimulation were evaluated compared with standard subthalamic nucleus stimulation. The primary outcome measure was the change of a broad-scaled cumulative axial Unified Parkinson’s Disease Rating Scale score (Scale II items 13–15, Scale III items 27–31) at ‘3-week follow-up’. Secondary outcome measures specifically addressed freezing of gait, balance, quality of life, non-motor symptoms and neuropsychiatric symptoms. For the primary outcome measure no statistically significant improvement was observed for combined subthalamic nucleus and substantia nigra pars reticulata stimulation at the ‘3-week follow-up’. The secondary endpoints, however, revealed that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata might specifically improve freezing of gait, whereas balance impairment remained unchanged. The combined stimulation of subthalamic nucleus and substantia nigra pars reticulata was safe, and of note, no clinically relevant neuropsychiatric adverse effect was observed. Patients treated with subthalamic nucleus and substantia nigra pars reticulata stimulation revealed no ‘global’ effect on axial motor domains. However, this study opens the perspective that concomittant stimulation

  19. Single nucleon emission in relativistic nucleus-nucleus reactions

    NASA Technical Reports Server (NTRS)

    Norbury, John W.; Townsend, Lawrence W.

    1992-01-01

    Significant discrepancies between theory and experiment have previously been noted for nucleon emission via electromagnetic processes in relativistic nucleus-nucleus collisions. The present work investigates the hypothesis that these discrepancies have arisen due to uncertainties about how to deduce the experimental electromagnetic cross section from the total measured cross section. An optical-model calculation of single neutron removal is added to electromagnetic cross sections and compared to the total experimental cross sections. Good agreement is found thereby resolving some of the earlier noted discrepancies. A detailed comparison to the recent work of Benesh, Cook, and Vary is made for both the impact parameter and the nuclear cross section. Good agreement is obtained giving an independent confirmation of the parameterized formulas developed by those authors.

  20. Analysis of relativistic nucleus-nucleus interactions in emulsion chambers

    NASA Technical Reports Server (NTRS)

    Mcguire, Stephen C.

    1987-01-01

    The development of a computer-assisted method is reported for the determination of the angular distribution data for secondary particles produced in relativistic nucleus-nucleus collisions in emulsions. The method is applied to emulsion detectors that were placed in a constant, uniform magnetic field and exposed to beams of 60 and 200 GeV/nucleon O-16 ions at the Super Proton Synchrotron (SPS) of the European Center for Nuclear Research (CERN). Linear regression analysis is used to determine the azimuthal and polar emission angles from measured track coordinate data. The software, written in BASIC, is designed to be machine independent, and adaptable to an automated system for acquiring the track coordinates. The fitting algorithm is deterministic, and takes into account the experimental uncertainty in the measured points. Further, a procedure for using the track data to estimate the linear momenta of the charged particles observed in the detectors is included.

  1. Dynamical nucleus-nucleus potential at short distances

    SciTech Connect

    Jiang Yongying; Wang Ning; Li Zhuxia; Scheid, Werner

    2010-04-15

    The dynamical nucleus-nucleus potentials for fusion reactions {sup 40}Ca+{sup 40}Ca, {sup 48}Ca+{sup 208}Pb, and {sup 126}Sn+{sup 130}Te are studied with the improved quantum molecular dynamics model together with the extended Thomas-Fermi approximation for the kinetic energies of nuclei. The obtained fusion barrier for {sup 40}Ca+{sup 40}Ca is in good agreement with the extracted fusion barrier from the measured fusion excitation function, and the depths of the fusion pockets are close to the results of time-dependent Hartree-Fock calculations. The energy dependence of the fusion barrier is also investigated. The fusion pocket becomes shallow for a heavy fusion system and almost disappears for heavy nearly symmetric systems, and the obtained potential at short distances is higher than the adiabatic potential.

  2. Azimuthal correlation and collective behavior in nucleus-nucleus collisions

    SciTech Connect

    Mali, P.; Mukhopadhyay, A. Sarkar, S.; Singh, G.

    2015-03-15

    Various flow effects of nuclear and hadronic origin are investigated in nucleus-nucleus collisions. Nuclear emulsion data collected from {sup 84}Kr + Ag/Br interaction at an incident energy of 1.52 GeV per nucleon and from {sup 28}Si + Ag/Br interaction at an incident energy of 14.5 GeV per nucleon are used in the investigation. The transverse momentum distribution and the flow angle analysis show that collective behavior, like a bounce-off effect of the projectile spectators and a sidesplash effect of the target spectators, are present in our event samples. From an azimuthal angle analysis of the data we also see a direct flow of the projectile fragments and of the produced charged particles. On the other hand, for both data samples the target fragments exhibit a reverse flow, while the projectile fragments exhibit an elliptic flow. Relevant flow parameters are measured.

  3. The cellular mastermind(?) – Mechanotransduction and the nucleus

    PubMed Central

    Kaminski, Ashley; Fedorchak, Gregory R.; Lammerding, Jan

    2015-01-01

    Cells respond to mechanical stimulation by activation of specific signaling pathways and genes that allow the cell to adapt to its dynamic physical environment. How cells sense the various mechanical inputs and translate them into biochemical signals remains an area of active investigation. Recent reports suggest that the cell nucleus may be directly implicated in this cellular mechanotransduction process. In this chapter, we discuss how forces applied to the cell surface and cytoplasm induce changes in nuclear structure and organization, which could directly affect gene expression, while also highlighting the complex interplay between nuclear structural proteins and transcriptional regulators that may further modulate mechanotransduction signaling. Taken together, these findings paint a picture of the nucleus as a central hub in cellular mechanotransduction—both structurally and biochemically—with important implications in physiology and disease. PMID:25081618

  4. Hummingbird Comet Nucleus Analysis Mission

    NASA Technical Reports Server (NTRS)

    Kojiro, Daniel; Carle, Glenn C.; Lasher, Larry E.

    2000-01-01

    Hummingbird is a highly focused scientific mission, proposed to NASA s Discovery Program, designed to address the highest priority questions in cometary science-that of the chemical composition of the cometary nucleus. After rendezvous with the comet, Hummingbird would first methodically image and map the comet, then collect and analyze dust, ice and gases from the cometary atmosphere to enrich characterization of the comet and support landing site selection. Then, like its namesake, Hummingbird would carefully descend to a pre-selected surface site obtaining a high-resolution image, gather a surface material sample, acquire surface temperature and then immediately return to orbit for detailed chemical and elemental analyses followed by a high resolution post-sampling image of the site. Hummingbird s analytical laboratory contains instrumentation for a comprehensive molecular and elemental analysis of the cometary nucleus as well as an innovative surface sample acquisition device.

  5. Checkerboard Theory of the Nucleus.

    NASA Astrophysics Data System (ADS)

    Lach, Theodore

    2006-04-01

    The Checker Board Model (CBM) is a 2D model of the nucleus that proposes that the synchronization of the 2 outer rotating quarks in the nucleons accounts for magnetic moment of the nucleons and that the magnetic flux from the nucleons couples (weaves) into the 2D checker board array structures and this magnetic coupling in addition to electrostatic forces of the rotating and stationary quarks accounts for the apparent strong nuclear force. The symmetry of the He nucleus helps explain why this 2D structure is so stable. This model explain the mass of the proton and neutron, along with their magnetic moments and their absolute and relative sizes in terms of the above structure and predict the masses of two newly proposed quarks ^(1): the ``up'' and the ``dn'' quarks. Since the masses of the ``up'' and ``dn'' quark determined by the CBM (237.31 MeV and 42.392 MeV respectively) did not fit within the standard model as candidates for u and d, a new model (New Physics) had to be invented. This new particle physics model predicts that nature has 5 generations not 3. (1). T.M. Lach, Checkerboard Structure of the Nucleus, Infinite Energy, Vol. 5, issue 30, (2000). (2). T.M. Lach, Masses of the Sub-Nuclear Particles, nucl-th/0008026, @http://xxx.lanl.gov/

  6. Convergence of limb, visceral, and vertical semicircular canal or otolith inputs onto vestibular nucleus neurons

    NASA Technical Reports Server (NTRS)

    Jian, B. J.; Shintani, T.; Emanuel, B. A.; Yates, B. J.

    2002-01-01

    The major goal of this study was to determine the patterns of convergence of non-labyrinthine inputs from the limbs and viscera onto vestibular nucleus neurons receiving signals from vertical semicircular canals or otolith organs. A secondary aim was to ascertain whether the effects of non-labyrinthine inputs on the activity of vestibular nucleus neurons is affected by bilateral peripheral vestibular lesions. The majority (72%) of vestibular nucleus neurons in labyrinth-intact animals whose firing was modulated by vertical rotations responded to electrical stimulation of limb and/or visceral nerves. The activity of even more vestibular nucleus neurons (93%) was affected by limb or visceral nerve stimulation in chronically labyrinthectomized preparations. Some neurons received non-labyrinthine inputs from a variety of peripheral sources, including antagonist muscles acting at the same joint, whereas others received inputs from more limited sources. There was no apparent relationship between the spatial and dynamic properties of a neuron's responses to tilts in vertical planes and the non-labyrinthine inputs that it received. These data suggest that non-labyrinthine inputs elicited during movement will modulate the processing of information by the central vestibular system, and may contribute to the recovery of spontaneous activity of vestibular nucleus neurons following peripheral vestibular lesions. Furthermore, some vestibular nucleus neurons with non-labyrinthine inputs may be activated only during particular behaviors that elicit a specific combination of limb and visceral inputs.

  7. Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo

    PubMed Central

    Chen, Deheng; Xia, Dongdong; Pan, Zongyou; Xu, Daoliang; Zhou, Yifei; Wu, Yaosen; Cai, Ningyu; Tang, Qian; Wang, Chenggui; Yan, Meijun; Zhang, Jing Jie; Zhou, Kailiang; Wang, Quan; Feng, Yongzeng; Wang, Xiangyang; Xu, Huazi; Zhang, Xiaolei; Tian, Naifeng

    2016-01-01

    Intervertebral disc degeneration (IDD) is a complicated process that involves both cellular apoptosis and senescence. Metformin has been reported to stimulate autophagy, whereas autophagy is shown to protect against apoptosis and senescence. Therefore, we hypothesize that metformin may have therapeutic effect on IDD through autophagy stimulation. The effect of metformin on IDD was investigated both in vitro and in vivo. Our study showed that metformin attenuated cellular apoptosis and senescence induced by tert-butyl hydroperoxide in nucleus pulposus cells. Autophagy, as well as its upstream regulator AMPK, was activated by metformin in nucleus pulposus cells in a dose- and time-dependent manner. Inhibition of autophagy by 3-MA partially abolished the protective effect of metformin against nucleus pulposus cells' apoptosis and senescence, indicating that autophagy was involved in the protective effect of metformin on IDD. In addition, metformin was shown to promote the expression of anabolic genes such as Col2a1 and Acan expression while inhibiting the expression of catabolic genes such as Mmp3 and Adamts5 in nucleus pulposus cells. In vivo study illustrated that metformin treatment could ameliorate IDD in a puncture-induced rat model. Thus, our study showed that metformin could protect nucleus pulposus cells against apoptosis and senescence via autophagy stimulation and ameliorate disc degeneration in vivo, revealing its potential to be a therapeutic agent for IDD. PMID:27787519

  8. Classifiers for centrality determination in proton-nucleus and nucleus-nucleus collisions

    NASA Astrophysics Data System (ADS)

    Altsybeev, Igor; Kovalenko, Vladimir

    2017-03-01

    Centrality, as a geometrical property of the collision, is crucial for the physical interpretation of nucleus-nucleus and proton-nucleus experimental data. However, it cannot be directly accessed in event-by-event data analysis. Common methods for centrality estimation in A-A and p-A collisions usually rely on a single detector (either on the signal in zero-degree calorimeters or on the multiplicity in some semi-central rapidity range). In the present work, we made an attempt to develop an approach for centrality determination that is based on machine-learning techniques and utilizes information from several detector subsystems simultaneously. Different event classifiers are suggested and evaluated for their selectivity power in terms of the number of nucleons-participants and the impact parameter of the collision. Finer centrality resolution may allow to reduce impact from so-called volume fluctuations on physical observables being studied in heavy-ion experiments like ALICE at the LHC and fixed target experiment NA61/SHINE on SPS.

  9. Comparing Realistic Subthalamic Nucleus Neuron Models

    NASA Astrophysics Data System (ADS)

    Njap, Felix; Claussen, Jens C.; Moser, Andreas; Hofmann, Ulrich G.

    2011-06-01

    The mechanism of action of clinically effective electrical high frequency stimulation is still under debate. However, recent evidence points at the specific activation of GABA-ergic ion channels. Using a computational approach, we analyze temporal properties of the spike trains emitted by biologically realistic neurons of the subthalamic nucleus (STN) as a function of GABA-ergic synaptic input conductances. Our contribution is based on a model proposed by Rubin and Terman and exhibits a wide variety of different firing patterns, silent, low spiking, moderate spiking and intense spiking activity. We observed that most of the cells in our network turn to silent mode when we increase the GABAA input conductance above the threshold of 3.75 mS/cm2. On the other hand, insignificant changes in firing activity are observed when the input conductance is low or close to zero. We thus reproduce Rubin's model with vanishing synaptic conductances. To quantitatively compare spike trains from the original model with the modified model at different conductance levels, we apply four different (dis)similarity measures between them. We observe that Mahalanobis distance, Victor-Purpura metric, and Interspike Interval distribution are sensitive to different firing regimes, whereas Mutual Information seems undiscriminative for these functional changes.

  10. Photoproduction of lepton pairs in proton-nucleus and nucleus-nucleus collisions at RHIC and LHC energies

    SciTech Connect

    Moreira, B. D.; Goncalves, V. P.; De Santana Amaral, J. T.

    2013-03-25

    In this contribution we study coherent interactions as a probe of the nonlinear effects in the Quantum Electrodynamics (QED). In particular, we study the multiphoton effects in the production of leptons pairs for proton-nucleus and nucleus-nucleus collisions for heavy nuclei. In the proton-nucleus we assume the ultrarelativistic proton as a source of photons and estimate the photoproduction of lepton pairs on nuclei at RHIC and LHC energies considering the multiphoton effects associated to multiple rescattering of the projectile photon on the proton of the nucleus. In nucleus - nucleus colllisions we consider the two nuclei as a source of photons. As each scattering contributes with a factor {alpha}Z to the cross section, this contribution must be taken into account for heavy nuclei. We consider the Coulomb corrections to calculate themultiple scatterings and estimate the total cross section for muon and tau pair production in proton-nucleus and nucleus-nucleus collisions at RHIC and LHC energies.

  11. Target neurons of floccular middle zone inhibition in medial vestibular nucleus.

    PubMed

    Sato, Y; Kanda, K; Kawasaki, T

    1988-04-19

    Unitary activities of 288 neurons were recorded extracellularly in the medial vestibular nucleus (MV) in anesthetized cats. In 19 neurons, located in the rostral part of the MV adjacent to the stria acustica, floccular middle zone stimulation resulted in cessation of spontaneous discharges. Systematic microstimulation in the brainstem during recording of 16 of 19 target neurons of floccular middle zone inhibition revealed that the target neurons projected to the ipsilateral abducens nucleus (ABN), and not to the contralateral ABN nor the oculomotor nucleus. The conjugate ipsilateral horizontal eye movement elicited by middle zone stimulation may be mediated by this pathway to motoneurons and internuclear neurons in the ipsilateral ABN. In additional experiments, the MV neurons responding antidromically to ipsilateral ABN stimulation and orthodromically to ipsilateral 8 nerve stimulation were recorded extracellularly. In only 7 of 36 recorded neurons, middle zone stimulation depressed the orthodromic and spontaneous activities. Many neurons were free of floccular inhibition. As to the route of floccular inhibitory control over the vestibulo-ocular reflex (VOR) during visual-vestibular stimulation, we propose that the interaction of target and VOR relay neurons takes place at the ipsilateral ABN and modulates the VOR, in addition to well known Ito's proposal that the interaction of the floccular output and the VOR takes place at secondary vestibular neurons and modulates the VOR.

  12. The origin of nucleus: rebuild from the prokaryotic ancestors of ribosome export factors.

    PubMed

    Ohyanagi, Hajime; Ikeo, Kazuho; Gojobori, Takashi

    2008-11-01

    Various hypotheses have been proposed on the evolutionary origin of eukaryotic nucleus. Because one of the major cargoes in the nucleocytoplasmic export in the eukaryotic cell is the ribosome, its stimulating proteins called Ribosome Export Factors (REFs) might have an evolutionary history of inscribing the origin of eukaryotic nucleus. With the aim of understanding the evolutionary origin of the nucleus, here we employed the yeast REFs and searched for their evolutionary origin in more than 500 genomes of archaea and eubacteria by the PSI-BLAST search. Our results showed that the non-membranous REFs (non-mREFs) originated exclusively from eubacterial proteins, whereas the membranous REFs (mREFs) are from both archaeal and eubacterial proteins. Since the non-mREFs just work inside the nucleus while the mREFs shuttle between the nucleus and the cytoplasm, these results suggest that the extant REFs working inside the nucleus have derived exclusively from eubacterial proteins, implying that the nucleus arose in a cell that contained chromosomes possessing a substantial fraction of eubacterial genes, in line with the predictions of several models entailing endosymbiosis at eukaryote origins.

  13. Exceptionally bright, compact starburst nucleus

    SciTech Connect

    Margon, B.; Anderson, S.F.; Mateo, M.; Fich, M.; Massey, P.

    1988-11-01

    Observations are reported of a remarkably bright (V about 13) starburst nucleus, 0833 + 652, which has been detected at radio, infrared, optical, ultraviolet, and X-ray wavelengths. Despite an observed flux at each of these wavelengths which is comparable to that of NGC 7714, often considered the 'prototypical' example of the starburst phenomenon, 0833 + 652 appears to be a previously uncataloged object. Its ease of detectability throughout the electromagnetic spectrum should make it useful for a variety of problems in the study of compact emission-line galaxies. 30 references.

  14. Nucleus morphology of Comet Halley

    NASA Technical Reports Server (NTRS)

    Reitsema, H. J.; Delamere, W. A.; Huebner, W. F.; Keller, H. U.; Schmidt, W. K. H.; Wilhelm, K.; Schmidt, H. U.; Whipple, Fred L.

    1986-01-01

    Images obtained by the Halley multicolor camera were used to determine the projected size and shape of the nucleus. The location of the terminator and numerous surface features were determined. There is good correlation between the brightest surface features and the dust jets; however, many bright features are seen which are not associated with jets. Most of the observed features are circular and appear to be related to surface elevation. The angularity of the terminator gives an indication of the three-dimensional structure of the face which was observed.

  15. Deep brain light stimulation effects on glutamate and dopamine concentration.

    PubMed

    Kuo, Jinn-Rung; Lin, Shih-Shian; Liu, Janelle; Chen, Shih-How; Chio, Chung-Chin; Wang, Jhi-Joung; Liu, Jia-Ming

    2015-01-01

    Compared to deep brain electrical stimulation, which has been applied to treating pathological brain diseases, little work has been done on the effect of deep brain light stimulation. A fiber-coupled laser stimulator at 840 nm wavelength and 130 Hz pulse repetition rate is developed in this work for deep brain light stimulation in a rat model. Concentration changes in glutamate and dopamine in the striatum are observed using a microdialysis probe when the subthalamic nucleus (STN) is stimulated at various optical power levels. Experimental results show that light stimulation causes the concentration of glutamate to decrease while that of dopamine is increased. This suggests that deep brain light stimulation of the STN is a promising therapeutic strategy for dopamine-related diseases such as Parkinson's disease. The stimulator developed for this work is useful for deep brain light stimulation in biomedical research.

  16. The Nuclear Option: Evidence Implicating the Cell Nucleus in Mechanotransduction.

    PubMed

    Szczesny, Spencer E; Mauck, Robert L

    2017-02-01

    Biophysical stimuli presented to cells via microenvironmental properties (e.g., alignment and stiffness) or external forces have a significant impact on cell function and behavior. Recently, the cell nucleus has been identified as a mechanosensitive organelle that contributes to the perception and response to mechanical stimuli. However, the specific mechanotransduction mechanisms that mediate these effects have not been clearly established. Here, we offer a comprehensive review of the evidence supporting (and refuting) three hypothetical nuclear mechanotransduction mechanisms: physical reorganization of chromatin, signaling at the nuclear envelope, and altered cytoskeletal structure/tension due to nuclear remodeling. Our goal is to provide a reference detailing the progress that has been made and the areas that still require investigation regarding the role of nuclear mechanotransduction in cell biology. Additionally, we will briefly discuss the role that mathematical models of cell mechanics can play in testing these hypotheses and in elucidating how biophysical stimulation of the nucleus drives changes in cell behavior. While force-induced alterations in signaling pathways involving lamina-associated polypeptides (LAPs) (e.g., emerin and histone deacetylase 3 (HDAC3)) and transcription factors (TFs) located at the nuclear envelope currently appear to be the most clearly supported mechanism of nuclear mechanotransduction, additional work is required to examine this process in detail and to more fully test alternative mechanisms. The combination of sophisticated experimental techniques and advanced mathematical models is necessary to enhance our understanding of the role of the nucleus in the mechanotransduction processes driving numerous critical cell functions.

  17. Synaptic interactions between perifornical lateral hypothalamic area, locus coeruleus nucleus and the oral pontine reticular nucleus are implicated in the stage succession during sleep-wakefulness cycle.

    PubMed

    Tortorella, Silvia; Rodrigo-Angulo, Margarita L; Núñez, Angel; Garzón, Miguel

    2013-01-01

    The perifornical area in the posterior lateral hypothalamus (PeFLH) has been implicated in several physiological functions including the sleep-wakefulness regulation. The PeFLH area contains several cell types including those expressing orexins (Orx; also known as hypocretins), mainly located in the PeF nucleus. The aim of the present study was to elucidate the synaptic interactions between Orx neurons located in the PeFLH area and different brainstem neurons involved in the generation of wakefulness and sleep stages such as the locus coeruleus (LC) nucleus (contributing to wakefulness) and the oral pontine reticular nucleus (PnO) nucleus (contributing to REM sleep). Anatomical data demonstrated the existence of a neuronal network involving the PeFLH area, LC, and the PnO nuclei that would control the sleep-wake cycle. Electrophysiological experiments indicated that PeFLH area had an excitatory effect on LC neurons. PeFLH stimulation increased the firing rate of LC neurons and induced an activation of the EEG. The excitatory effect evoked by PeFLH stimulation in LC neurons was blocked by the injection of the Orx-1 receptor antagonist SB-334867 into the LC. Similar electrical stimulation of the PeFLH area evoked an inhibition of PnO neurons by activation of GABAergic receptors because the effect was blocked by bicuculline application into the PnO. Our data also revealed that the LC and PnO nuclei exerted a feedback control on neuronal activity of PeFLH area. Electrical stimulation of LC facilitated firing activity of PeFLH neurons by activation of catecholaminergic receptors whereas PnO stimulation inhibited PeFLH neurons by activation of GABAergic receptors. In conclusion, Orx neurons of the PeFLH area seem to be an important organizer of the wakefulness and sleep stages in order to maintain a normal succession of stages during the sleep-wakefulness cycle.

  18. Synaptic interactions between perifornical lateral hypothalamic area, locus coeruleus nucleus and the oral pontine reticular nucleus are implicated in the stage succession during sleep-wakefulness cycle

    PubMed Central

    Tortorella, Silvia; Rodrigo-Angulo, Margarita L.; Núñez, Angel; Garzón, Miguel

    2013-01-01

    The perifornical area in the posterior lateral hypothalamus (PeFLH) has been implicated in several physiological functions including the sleep-wakefulness regulation. The PeFLH area contains several cell types including those expressing orexins (Orx; also known as hypocretins), mainly located in the PeF nucleus. The aim of the present study was to elucidate the synaptic interactions between Orx neurons located in the PeFLH area and different brainstem neurons involved in the generation of wakefulness and sleep stages such as the locus coeruleus (LC) nucleus (contributing to wakefulness) and the oral pontine reticular nucleus (PnO) nucleus (contributing to REM sleep). Anatomical data demonstrated the existence of a neuronal network involving the PeFLH area, LC, and the PnO nuclei that would control the sleep-wake cycle. Electrophysiological experiments indicated that PeFLH area had an excitatory effect on LC neurons. PeFLH stimulation increased the firing rate of LC neurons and induced an activation of the EEG. The excitatory effect evoked by PeFLH stimulation in LC neurons was blocked by the injection of the Orx-1 receptor antagonist SB-334867 into the LC. Similar electrical stimulation of the PeFLH area evoked an inhibition of PnO neurons by activation of GABAergic receptors because the effect was blocked by bicuculline application into the PnO. Our data also revealed that the LC and PnO nuclei exerted a feedback control on neuronal activity of PeFLH area. Electrical stimulation of LC facilitated firing activity of PeFLH neurons by activation of catecholaminergic receptors whereas PnO stimulation inhibited PeFLH neurons by activation of GABAergic receptors. In conclusion, Orx neurons of the PeFLH area seem to be an important organizer of the wakefulness and sleep stages in order to maintain a normal succession of stages during the sleep-wakefulness cycle. PMID:24311996

  19. Neuromodulatory action of dopamine in the nucleus accumbens: an in vivo intracellular study.

    PubMed

    Yim, C Y; Mogenson, G J

    1988-08-01

    Intracellular recordings were made from neurons in the nucleus accumbens in situ to determine how dopamine produces the selective neuromodulatory action in the accumbens observed in previous studies. Electrical stimulation of the basolateral nucleus of the amygdala was found to produce monosynaptically evoked depolarizing and hyperpolarizing postsynaptic potential sequences in a large proportion of the accumbens neurons sampled. Dopamine applied iontophoretically or released endogenously by stimulation of the ventral tegmental area produced consistent membrane depolarization and an increase in membrane conductance but not an increase in spontaneous activity of the accumbens neurons. Stimulation of the ventral tegmental area with trains of 10 pulses at 10 Hz prior to stimulation of the amygdala produced 8-58% reduction in the amplitude of the depolarizing postsynaptic potential but no change in the late hyperpolarizing postsynaptic potential. Although attenuation of the depolarizing postsynaptic potential amplitude from ventral tegmental area stimulation was often accompanied by membrane depolarization, it appeared that the two responses were not causally related. The effect of ventral tegmental area stimulation on the evoked depolarizing postsynaptic potential and the membrane potential were blocked by haloperidol indicating the involvement of dopamine. Iontophoretically applied dopamine produced responses similar to ventral tegmental area stimulation with two exceptions: (i) iontophoretically applied dopamine produced consistently stronger maximal attenuation of the depolarizing postsynaptic potential than did ventral tegmental area stimulation; and (ii) iontophoretically applied dopamine always attenuated both the depolarizing postsynaptic potential and hyperpolarizing postsynaptic potential whereas ventral tegmental area stimulation produced selective attenuation of the depolarizing postsynaptic potential only. These electrophysiological results are

  20. Brain Stimulation Therapies

    MedlinePlus

    ... Magnetic Seizure Therapy Deep Brain Stimulation Additional Resources Brain Stimulation Therapies Overview Brain stimulation therapies can play ... for a shorter recovery time than ECT Deep Brain Stimulation Deep brain stimulation (DBS) was first developed ...

  1. Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson’s disease

    PubMed Central

    Oswal, Ashwini; Beudel, Martijn; Zrinzo, Ludvic; Limousin, Patricia; Hariz, Marwan; Foltynie, Tom; Litvak, Vladimir

    2016-01-01

    Chronic dopamine depletion in Parkinson’s disease leads to progressive motor and cognitive impairment, which is associated with the emergence of characteristic patterns of synchronous oscillatory activity within cortico-basal-ganglia circuits. Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson’s disease, but its influence on synchronous activity in cortico-basal-ganglia loops remains to be fully characterized. Here, we demonstrate that deep brain stimulation selectively suppresses certain spatially and spectrally segregated resting state subthalamic nucleus–cortical networks. To this end we used a validated and novel approach for performing simultaneous recordings of the subthalamic nucleus and cortex using magnetoencephalography (during concurrent subthalamic nucleus deep brain stimulation). Our results highlight that clinically effective subthalamic nucleus deep brain stimulation suppresses synchrony locally within the subthalamic nucleus in the low beta oscillatory range and furthermore that the degree of this suppression correlates with clinical motor improvement. Moreover, deep brain stimulation relatively selectively suppressed synchronization of activity between the subthalamic nucleus and mesial premotor regions, including the supplementary motor areas. These mesial premotor regions were predominantly coupled to the subthalamic nucleus in the high beta frequency range, but the degree of deep brain stimulation-associated suppression in their coupling to the subthalamic nucleus was not found to correlate with motor improvement. Beta band coupling between the subthalamic nucleus and lateral motor areas was not influenced by deep brain stimulation. Motor cortical coupling with subthalamic nucleus predominantly involved driving of the subthalamic nucleus, with those drives in the higher beta frequency band having much shorter net delays to subthalamic nucleus than those in the lower beta band. These observations raise

  2. Subthalamic nucleus, sensorimotor cortex and muscle interrelationships in Parkinson's disease.

    PubMed

    Marsden, J F; Limousin-Dowsey, P; Ashby, P; Pollak, P; Brown, P

    2001-02-01

    Ten patients with Parkinson's disease were seen following bilateral or unilateral implantation of macroelectrodes into the subthalamic nucleus. Local field potentials (LFPs) were recorded from adjacent subthalamic nucleus macroelectrode (STNME) contacts simultaneously with EEG activity over the supplementary motor (Cz-FCz) and sensorimotor (C3/4-FC3/4) areas and EMG activity from the contralateral wrist extensors during isometric and phasic wrist movements. Significant coherence was seen between STNME LFPs and Cz-FCz, STNME LFPs and C3/4-FC3/4, and STNME LFPs and EMG over the range 7-45 Hz. EEG phase-led STNME LFPs by 24.4 ms (95% confidence interval 19.8 to 29.0 ms). EMG also led STNME LFPs, but time differences tended to cluster around one of two values: 6.3 ms (-0.7 to 13.3 ms) and 46.5 ms (26.2 to 66.8 ms). Recordings from the STNME contact that demonstrated the most consistent coherence with Cz-FCz in the 15-30 Hz band coincided with the contact which, when electrically stimulated at high frequencies, produced the most effective clinical response in eight out of nine (89%) subjects (P < 0.01). Oscillatory activity at 15-30 Hz may therefore prove of use in localizing the subthalamic nucleus target that provides the best clinical effect on stimulation. These results extend the hypothesis that coherent activity may be useful in binding together related activities in simultaneously active motor centres. The presence of coherence between EEG and STNME LFPs in both the beta and the gamma band (as opposed to only the beta band between EEG and cerebellar thalamus) suggests that there may be some relative frequency selectivity in the communication between different motor structures.

  3. Projections from the central amygdaloid nucleus to the precuneiform nucleus in the mouse.

    PubMed

    Liang, Huazheng; Watson, Charles; Paxinos, George

    2015-01-01

    The mouse precuneiform nucleus has been proposed as the midbrain locomotion center, a function ascribed to its caudal neighbor, cuneiform nucleus, in the rat, cat and other species. The present study investigated the projections from the central amygdaloid nucleus to the precuneiform nucleus in the mouse using retrograde tracer injections (fluoro-gold) into the precuneiform nucleus and anterograde tracer injections (biotinylated dextran amine) into the central amygdaloid nucleus. The entire central amygdaloid nucleus except the rostral pole had retrogradely labeled neurons, especially in the middle portion where labeled neurons were densely packed. Anterogradely labeled amygdaloid fibers approached the precuneiform nucleus from the area ventrolateral to it and terminated in the entire precuneiform nucleus. Labeled fibers were also found in laminae 5 and 6 in the upper cervical cord on the ipsilateral side. The present study is the first demonstration of projections from the central amygdaloid nucleus to the precuneiform nucleus. This projection may underpin the role of the precuneiform nucleus in the modulation of the cardiovascular activity.

  4. Distribution of the neuronal inputs to the ventral premammillary nucleus of male and female rats☆

    PubMed Central

    Cavalcante, Judney Cley; Bittencourt, Jackson Cioni; Elias, Carol Fuzeti

    2014-01-01

    The ventral premammillary nucleus (PMV) expresses dense collections of sex steroid receptors and receptors for metabolic cues, including leptin, insulin and ghrelin. The PMV responds to opposite sex odor stimulation and projects to areas involved in reproductive control, including direct innervation of gonadotropin releasing hormone neurons. Thus, the PMV is well positioned to integrate metabolic and reproductive cues, and control downstream targets that mediate reproductive function. In fact, lesions of PMV neurons blunt female reproductive function and maternal aggression. However, although the projections of PMV neurons have been well documented, little is known about the neuronal inputs received by PMV neurons. To fill this gap, we performed a systematic evaluation of the brain sites innervating the PMV neurons of male and female rats using the retrograde tracer subunit B of the cholera toxin (CTb). In general, we observed that males and females show a similar pattern of afferents. We also noticed that the PMV is preferentially innervated by neurons located in the forebrain, with very few projections coming from brainstem nuclei. The majority of inputs originated from the medial nucleus of the amygdala, the bed nucleus of the stria terminalis and the medial preoptic nucleus. A moderate to high density of afferents was also observed in the ventral subiculum, the arcuate nucleus and the ventrolateral subdivision of the ventromedial nucleus of the hypothalamus. Our findings strengthen the concept that the PMV is part of the vomeronasal system and integrates the brain circuitry controlling reproductive functions. PMID:25084037

  5. Noninvasive cortical stimulation with transcranial direct current stimulation in Parkinson's disease.

    PubMed

    Fregni, Felipe; Boggio, Paulo S; Santos, Marcelo C; Lima, Moises; Vieira, Adriana L; Rigonatti, Sergio P; Silva, M Teresa A; Barbosa, Egberto R; Nitsche, Michael A; Pascual-Leone, Alvaro

    2006-10-01

    Electrical stimulation of deep brain structures, such as globus pallidus and subthalamic nucleus, is widely accepted as a therapeutic tool for patients with Parkinson's disease (PD). Cortical stimulation either with epidural implanted electrodes or repetitive transcranial magnetic stimulation can be associated with motor function enhancement in PD. We aimed to study the effects of another noninvasive technique of cortical brain stimulation, transcranial direct current stimulation (tDCS), on motor function and motor-evoked potential (MEP) characteristics of PD patients. We tested tDCS using different electrode montages [anodal stimulation of primary motor cortex (M1), cathodal stimulation of M1, anodal stimulation of dorsolateral prefrontal cortex (DLPFC), and sham-stimulation] and evaluated the effects on motor function--as indexed by Unified Parkinson's Disease Rating Scale (UPDRS), simple reaction time (sRT) and Purdue Pegboard test--and on corticospinal motor excitability (MEP characteristics). All experiments were performed in a double-blinded manner. Anodal stimulation of M1 was associated with a significant improvement of motor function compared to sham-stimulation in the UPDRS (P < 0.001) and sRT (P = 0.019). This effect was not observed for cathodal stimulation of M1 or anodal stimulation of DLPFC. Furthermore, whereas anodal stimulation of M1 significantly increased MEP amplitude and area, cathodal stimulation of M1 significantly decreased them. There was a trend toward a significant correlation between motor function improvement after M1 anodal-tDCS and MEP area increase. These results confirm and extend the notion that cortical brain stimulation might improve motor function in patients with PD.

  6. Actomyosin contractility rotates the cell nucleus.

    PubMed

    Kumar, Abhishek; Maitra, Ananyo; Sumit, Madhuresh; Ramaswamy, Sriram; Shivashankar, G V

    2014-01-21

    The cell nucleus functions amidst active cytoskeletal filaments, but its response to their contractile stresses is largely unexplored. We study the dynamics of the nuclei of single fibroblasts, with cell migration suppressed by plating onto micro-fabricated patterns. We find the nucleus undergoes noisy but coherent rotational motion. We account for this observation through a hydrodynamic approach, treating the nucleus as a highly viscous inclusion residing in a less viscous fluid of orientable filaments endowed with active stresses. Lowering actin contractility selectively by introducing blebbistatin at low concentrations drastically reduced the speed and coherence of the angular motion of the nucleus. Time-lapse imaging of actin revealed a correlated hydrodynamic flow around the nucleus, with profile and magnitude consistent with the results of our theoretical approach. Coherent intracellular flows and consequent nuclear rotation thus appear to be an intrinsic property of cells.

  7. Music and the nucleus accumbens.

    PubMed

    Mavridis, Ioannis N

    2015-03-01

    Music is a universal feature of human societies over time, mainly because it allows expression and regulation of strong emotions, thus influencing moods and evoking pleasure. The nucleus accumbens (NA), the most important pleasure center of the human brain (dominates the reward system), is the 'king of neurosciences' and dopamine (DA) can be rightfully considered as its 'crown' due to the fundamental role that this neurotransmitter plays in the brain's reward system. Purpose of this article was to review the existing literature regarding the relation between music and the NA. Studies have shown that reward value for music can be coded by activity levels in the NA, whose functional connectivity with auditory and frontal areas increases as a function of increasing musical reward. Listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the NA. The functional connectivity between brain regions mediating reward, autonomic and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. Musical stimuli can significantly increase extracellular DA levels in the NA. NA DA and serotonin were found significantly higher in animals exposed to music. Finally, passive listening to unfamiliar although liked music showed activations in the NA.

  8. In vivo histamine voltammetry in the mouse premammillary nucleus.

    PubMed

    Samaranayake, Srimal; Abdalla, Aya; Robke, Rhiannon; Wood, Kevin M; Zeqja, Anisa; Hashemi, Parastoo

    2015-06-07

    Histamine plays a major role in the mediation of allergic reactions such as peripheral inflammation. This classical monoamine is also a neurotransmitter involved in the central nervous system but its role in this context is poorly understood. Studying histamine neurotransmission is important due to its implications in many neurological disorders. The sensitivity, selectivity and high temporal resolution of fast scan cyclic voltammetry (FSCV) offer many advantages for studying electroactive neurotransmitters. Histamine has previously been studied with FSCV; however, the lack of a robust Faradaic electrochemical signal makes it difficult to selectively identify histamine in complex media, as found in vivo. In this work, we optimize an electrochemical waveform that provides a stimulation-locked and unique electrochemical signal towards histamine. We describe in vitro waveform optimization and a novel in vivo physiological model for stimulating histamine release in the mouse premammillary nucleus via stimulation of the medial forebrain bundle. We demonstrate that a robust signal can be used to effectively identify histamine and characterize its in vivo kinetics.

  9. Microtubules move the nucleus to quiescence.

    PubMed

    Laporte, Damien; Sagot, Isabelle

    2014-01-01

    The nucleus is a cellular compartment that hosts several macro-molecular machines displaying a highly complex spatial organization. This tight architectural orchestration determines not only DNA replication and repair but also regulates gene expression. In budding yeast microtubules play a key role in structuring the nucleus since they condition the Rabl arrangement in G1 and chromosome partitioning during mitosis through their attachment to centromeres via the kinetochore proteins. Recently, we have shown that upon quiescence entry, intranuclear microtubules emanating from the spindle pole body elongate to form a highly stable bundle that spans the entire nucleus. Here, we examine some molecular mechanisms that may underlie the formation of this structure. As the intranuclear microtubule bundle causes a profound re-organization of the yeast nucleus and is required for cell survival during quiescence, we discuss the possibility that the assembly of such a structure participates in quiescence establishment.

  10. Distinct roles of dopamine and subthalamic nucleus in learning and probabilistic decision making

    PubMed Central

    Bogacz, Rafal; Javed, Shazia; Mooney, Lucy K.; Murphy, Gillian; Keeley, Sophie; Whone, Alan L.

    2012-01-01

    Even simple behaviour requires us to make decisions based on combining multiple pieces of learned and new information. Making such decisions requires both learning the optimal response to each given stimulus as well as combining probabilistic information from multiple stimuli before selecting a response. Computational theories of decision making predict that learning individual stimulus–response associations and rapid combination of information from multiple stimuli are dependent on different components of basal ganglia circuitry. In particular, learning and retention of memory, required for optimal response choice, are significantly reliant on dopamine, whereas integrating information probabilistically is critically dependent upon functioning of the glutamatergic subthalamic nucleus (computing the ‘normalization term’ in Bayes’ theorem). Here, we test these theories by investigating 22 patients with Parkinson’s disease either treated with deep brain stimulation to the subthalamic nucleus and dopaminergic therapy or managed with dopaminergic therapy alone. We use computerized tasks that probe three cognitive functions—information acquisition (learning), memory over a delay and information integration when multiple pieces of sequentially presented information have to be combined. Patients performed the tasks ON or OFF deep brain stimulation and/or ON or OFF dopaminergic therapy. Consistent with the computational theories, we show that stopping dopaminergic therapy impairs memory for probabilistic information over a delay, whereas deep brain stimulation to the region of the subthalamic nucleus disrupts decision making when multiple pieces of acquired information must be combined. Furthermore, we found that when participants needed to update their decision on the basis of the last piece of information presented in the decision-making task, patients with deep brain stimulation of the subthalamic nucleus region did not slow down appropriately to revise their

  11. Distinct roles of dopamine and subthalamic nucleus in learning and probabilistic decision making.

    PubMed

    Coulthard, Elizabeth J; Bogacz, Rafal; Javed, Shazia; Mooney, Lucy K; Murphy, Gillian; Keeley, Sophie; Whone, Alan L

    2012-12-01

    Even simple behaviour requires us to make decisions based on combining multiple pieces of learned and new information. Making such decisions requires both learning the optimal response to each given stimulus as well as combining probabilistic information from multiple stimuli before selecting a response. Computational theories of decision making predict that learning individual stimulus-response associations and rapid combination of information from multiple stimuli are dependent on different components of basal ganglia circuitry. In particular, learning and retention of memory, required for optimal response choice, are significantly reliant on dopamine, whereas integrating information probabilistically is critically dependent upon functioning of the glutamatergic subthalamic nucleus (computing the 'normalization term' in Bayes' theorem). Here, we test these theories by investigating 22 patients with Parkinson's disease either treated with deep brain stimulation to the subthalamic nucleus and dopaminergic therapy or managed with dopaminergic therapy alone. We use computerized tasks that probe three cognitive functions-information acquisition (learning), memory over a delay and information integration when multiple pieces of sequentially presented information have to be combined. Patients performed the tasks ON or OFF deep brain stimulation and/or ON or OFF dopaminergic therapy. Consistent with the computational theories, we show that stopping dopaminergic therapy impairs memory for probabilistic information over a delay, whereas deep brain stimulation to the region of the subthalamic nucleus disrupts decision making when multiple pieces of acquired information must be combined. Furthermore, we found that when participants needed to update their decision on the basis of the last piece of information presented in the decision-making task, patients with deep brain stimulation of the subthalamic nucleus region did not slow down appropriately to revise their plan, a

  12. Improved Cloud Condensation Nucleus Spectrometer

    NASA Technical Reports Server (NTRS)

    Leu, Ming-Taun

    2010-01-01

    An improved thermal-gradient cloud condensation nucleus spectrometer (CCNS) has been designed to provide several enhancements over prior thermal- gradient counters, including fast response and high-sensitivity detection covering a wide range of supersaturations. CCNSs are used in laboratory research on the relationships among aerosols, supersaturation of air, and the formation of clouds. The operational characteristics of prior counters are such that it takes long times to determine aerosol critical supersaturations. Hence, there is a need for a CCNS capable of rapid scanning through a wide range of supersaturations. The present improved CCNS satisfies this need. The improved thermal-gradient CCNS (see Figure 1) incorporates the following notable features: a) The main chamber is bounded on the top and bottom by parallel thick copper plates, which are joined by a thermally conductive vertical wall on one side and a thermally nonconductive wall on the opposite side. b) To establish a temperature gradient needed to establish a supersaturation gradient, water at two different regulated temperatures is pumped through tubes along the edges of the copper plates at the thermally-nonconductive-wall side. Figure 2 presents an example of temperature and supersaturation gradients for one combination of regulated temperatures at the thermally-nonconductive-wall edges of the copper plates. c) To enable measurement of the temperature gradient, ten thermocouples are cemented to the external surfaces of the copper plates (five on the top plate and five on the bottom plate), spaced at equal intervals along the width axis of the main chamber near the outlet end. d) Pieces of filter paper or cotton felt are cemented onto the interior surfaces of the copper plates and, prior to each experimental run, are saturated with water to establish a supersaturation field inside the main chamber. e) A flow of monodisperse aerosol and a dilution flow of humid air are introduced into the main

  13. BFKL Pomeron calculus: solution to equations for nucleus-nucleus scattering in the saturation domain

    NASA Astrophysics Data System (ADS)

    Contreras, Carlos; Levin, Eugene; Meneses, Rodrigo

    2013-04-01

    In this paper we solve the equation for nucleus-nucleus scattering in the BFKL Pomeron calculus, suggested by Braun [1-3]. We find these solutions analytically at high energies as well as numerically in the entire region of energies inside the saturation region. The semi-classical approximation is used to select out the infinite set of the parasite solutions. The nucleus-nucleus cross sections at high energy are estimated and compared with the Glauber-Gribov approach. It turns out that the exact formula gives the estimates that are very close to the ones based on Glauber-Gribov formula which is important for the practical applications.

  14. Extinction of a classically conditioned response: red nucleus and interpositus.

    PubMed

    Robleto, Karla; Thompson, Richard F

    2008-03-05

    It is well established that the cerebellum and its associated circuitry are essential for classical conditioning of the eyeblink response and other discrete motor responses (e.g., limb flexion, head turn, etc.) learned with an aversive unconditioned stimulus. However, brain mechanisms underlying extinction of these responses are still relatively unclear. Behavioral studies have demonstrated extinction to be an active learning process distinct from acquisition. Accordingly, this current understanding of extinction has guided neural studies that have tried to identify possible brain structures that could support this new learning. However, whether extinction engages the same brain sites necessary for acquisition is not yet clear. This poses an overriding problem for understanding brain mechanisms necessary for extinction because such analysis cannot be done without first identifying brain sites and pathways involved in this phenomenon. Equally elusive is the validity of a behavioral theory of extinction that can account for the properties of extinction. In this study, we looked at the involvement of the interpositus and the red nucleus in extinction. Results show that, although inactivation of both nuclei blocks response expression, only inactivation of the interpositus has a detrimental effect on extinction. Moreover, this detrimental effect was completely removed when inactivation of the interpositus was paired with electrical stimulation of the red nucleus. These findings speak to the important role of cerebellar structures in the extinction of discrete motor responses and provide important insight as to the validity of a particular theory of extinction.

  15. In Vivo Voltammetric Monitoring of Norepinephrine Release in the Rat Ventral Bed Nucleus of the Stria Terminalis and Anteroventral Thalamic Nucleus

    PubMed Central

    Park, Jinwoo; Kile, Brian M.; Wightman, R. Mark

    2010-01-01

    The role and contribution of the dense noradrenergic innervation in the ventral bed nucleus of the stria terminalis (vBNST) and anteroventral thalamic nucleus (AV) to biological function and animal behaviors is poorly understood due to the small size of these nuclei. The aim of this study was to compare norepinephrine release and uptake in the vBNST with that in the AV of anesthetized rats. Measurements were made in vivo with fast-scan cyclic voltammetry following electrical stimulation of noradrenergic projection pathways, either the dorsal noradrenergic bundle (DNB) or the ventral noradrenergic bundle (VNB). The substance detected was identified as norepinephrine based upon voltammetric, anatomical, neurochemical, and pharmacological evidence. Fast-scan cyclic voltammetry enables the selective monitoring of local norepinephrine overflow in the vBNST evoked by the stimulation of either the DNB or VNB while norepinephrine in the AV was only evoked by DNB stimulation. The α2-adrenoceptor antagonist, yohimbine, and the norepinephrine uptake inhibitor, desipramine, increased norepinephrine overflow and slowed its disappearance in both regions. However, control of extracellular norepinephrine by both autoreceptors and uptake was greater in the AV. The greater control exerted by autoreceptors and uptake in the AV resulted in reduced extracellular concentration compared to the vBNST when large numbers of stimulation pulses were employed. The differences in noradrenergic transmission observed in the terminal fields of the vBNST and the AV may differentially regulate activity in these two regions that both contain high densities of norepinephrine terminals. PMID:20128849

  16. Chaotic Desynchronization as the Therapeutic Mechanism of Deep Brain Stimulation

    PubMed Central

    Wilson, Charles J.; Beverlin, Bryce; Netoff, Theoden

    2011-01-01

    High frequency deep-brain stimulation of the subthalamic nucleus (deep brain stimulation, DBS) relieves many of the symptoms of Parkinson's disease in humans and animal models. Although the treatment has seen widespread use, its therapeutic mechanism remains paradoxical. The subthalamic nucleus is excitatory, so its stimulation at rates higher than its normal firing rate should worsen the disease by increasing subthalamic excitation of the globus pallidus. The therapeutic effectiveness of DBS is also frequency and intensity sensitive, and the stimulation must be periodic; aperiodic stimulation at the same mean rate is ineffective. These requirements are not adequately explained by existing models, whether based on firing rate changes or on reduced bursting. Here we report modeling studies suggesting that high frequency periodic excitation of the subthalamic nucleus may act by desynchronizing the firing of neurons in the globus pallidus, rather than by changing the firing rate or pattern of individual cells. Globus pallidus neurons are normally desynchronized, but their activity becomes correlated in Parkinson's disease. Periodic stimulation may induce chaotic desynchronization by interacting with the intrinsic oscillatory mechanism of globus pallidus neurons. Our modeling results suggest a mechanism of action of DBS and a pathophysiology of Parkinsonism in which synchrony, rather than firing rate, is the critical pathological feature. PMID:21734868

  17. Isoperiodic neuronal activity in suprachiasmatic nucleus of the rat

    NASA Technical Reports Server (NTRS)

    Miller, J. D.; Fuller, C. A.

    1992-01-01

    A subpopulation of neurons in the suprachiasmatic nucleus (SCN) is shown here to exhibit isoperiodic bursting activity. The period of discharge in these cells may be lengthened or the periodicity may be transiently disrupted by photic stimulation. It is suggested that many, if not all, of these cells are vasoactive intestinal polypeptide (VIP) neurons. It is shown that the ultradian periodicity of these cells, estimates of the VIP neuron population size in the SCN, effects of partial lesions on tau (period), and estimates of the phase stability of SCN-driven circadian rhythms are consistent with a strongly coupled, multioscillator model of circadian rhythmicity, in which the oscillator population constitutes a restricted subset of the SCN neuronal population.

  18. Attention modulates responses in the human lateral geniculate nucleus.

    PubMed

    O'Connor, Daniel H; Fukui, Miki M; Pinsk, Mark A; Kastner, Sabine

    2002-11-01

    Attentional mechanisms are important for selecting relevant information and filtering out irrelevant information from cluttered visual scenes. Selective attention has previously been shown to affect neural activity in both extrastriate and striate visual cortex. Here, evidence from functional brain imaging shows that attentional response modulation is not confined to cortical processing, but can occur as early as the thalamic level. We found that attention modulated neural activity in the human lateral geniculate nucleus (LGN) in several ways: it enhanced neural responses to attended stimuli, attenuated responses to ignored stimuli and increased baseline activity in the absence of visual stimulation. The LGN, traditionally viewed as the gateway to visual cortex, may also serve as a 'gatekeeper' in controlling attentional response gain.

  19. Input/output properties of the lateral vestibular nucleus

    NASA Technical Reports Server (NTRS)

    Boyle, R.; Bush, G.; Ehsanian, R.

    2004-01-01

    This article is a review of work in three species, squirrel monkey, cat, and rat studying the inputs and outputs from the lateral vestibular nucleus (LVN). Different electrophysiological shock paradigms were used to determine the synaptic inputs derived from thick to thin diameter vestibular nerve afferents. Angular and linear mechanical stimulations were used to activate and study the combined and individual contribution of inner ear organs and neck afferents. The spatio-temporal properties of LVN neurons in the decerebrated rat were studied in response to dynamic acceleration inputs using sinusoidal linear translation in the horizontal head plane. Outputs were evaluated using antidromic identification techniques and identified LVN neurons were intracellularly injected with biocytin and their morphology studied.

  20. Highlight on the dynamic organization of the nucleus

    PubMed Central

    2017-01-01

    ABSTRACT The last decade has seen rapid advances in our understanding of the proteins of the nuclear envelope, which have multiple roles including positioning the nucleus, maintaining its structural organization, and in events ranging from mitosis and meiosis to chromatin positioning and gene expression. Diverse new and stimulating results relating to nuclear organization and genome function from across kingdoms were presented in a session stream entitled “Dynamic Organization of the Nucleus” at this year's Society of Experimental Biology (SEB) meeting in Brighton, UK (July 2016). This was the first session stream run by the Nuclear Dynamics Special Interest Group, which was organized by David Evans, Katja Graumann (both Oxford Brookes University, UK) and Iris Meier (Ohio State University, USA). The session featured presentations on areas relating to nuclear organization across kingdoms including the nuclear envelope, chromatin organization, and genome function. PMID:27715428

  1. Baroreflex failure in a patient with central nervous system lesions involving the nucleus tractus solitarii

    NASA Technical Reports Server (NTRS)

    Biaggioni, I.; Whetsell, W. O.; Jobe, J.; Nadeau, J. H.

    1994-01-01

    Animal studies have shown the importance of the nucleus tractus solitarii, a collection of neurons in the brain stem, in the acute regulation of blood pressure. Impulses arising from the carotid and aortic baroreceptors converge in this center, where the first synapse of the baroreflex is located. Stimulation of the nucleus tractus solitarii provides an inhibitory signal to other brain stem structures, particularly the rostral ventrolateral medulla, resulting in a reduction in sympathetic outflow and a decrease in blood pressure. Conversely, experimental lesions of the nucleus tractus solitarii lead to loss of baroreflex control of blood pressure, sympathetic activation, and severe hypertension in animals. In humans, baroreflex failure due to deafferentation of baroreceptors has been previously reported and is characterized by episodes of severe hypertension and tachycardia. We present a patient with an undetermined process of the central nervous system characterized pathologically by ubiquitous infarctions that were particularly prominent in the nucleus tractus solitarii bilaterally but spared the rostral ventrolateral medulla. Absence of a functioning baroreflex was evidenced by the lack of reflex tachycardia to the hypotensive effects of sodium nitroprusside, exaggerated pressor responses to handgrip and cold pressor test, and exaggerated depressor responses to meals and centrally acting alpha 2-agonists. This clinicopathological correlate suggests that the patient's baroreflex failure can be explained by the unique combination of the destruction of sympathetic inhibitory centers (ie, the nucleus tractus solitarii) and preservation of centers that exert a positive modulation on sympathetic tone (ie, the rostral ventrolateral medulla).

  2. Brain regions influenced by the lateral parabrachial nucleus in angiotensin II-induced water intake.

    PubMed

    Davern, P J; McKinley, M J

    2013-11-12

    This study examined which brain regions are influenced by an inhibitory lateral parabrachial nucleus (LPBN) mechanism that affects water intake. Controls and rats with bilateral LPBN lesions were administered angiotensin II (AngII) (0.5mg/kg subcutaneous - SC), drinking responses measured, and brains processed for Fos-immunohistochemistry. A separate group of LPBN-lesioned and non-lesioned animals were denied water for 90 min prior to perfusion to remove any confounding factor of water intake. LPBN-lesioned rats drank a cumulative volume of 9 mL compared with <4 mL by controls (p<0.01). Compared with sham-lesioned animals, Fos expression was attenuated in overdrinking LPBN-lesioned rats in the median preoptic nucleus (MnPO), paraventricular nucleus of the hypothalamus (PVN), supraoptic nucleus (SON) (p<0.001), bed nucleus of the stria terminalis and central nucleus of the amygdala (p<0.01). In LPBN-lesioned rats that did not drink, greater numbers of activated neurons were detected in the PVN (p<0.001), SON (p<0.01), MnPO, nucleus of the solitary tract (NTS) and area postrema (p<0.05) in response to SC AngII, compared with non-lesioned rats. These data suggest that the direct effects of LPBN lesions caused an increase in AngII-induced water intake and in rats that did not drink an increase in Fos expression, while indirect secondary effects of LPBN lesions caused a reduction in Fos expression possibly related to excessive ingestion of water. An inhibitory mechanism, likely related to arterial baroreceptor stimulation, relayed by neurons located in the LPBN influences the responses of the MnPO, PVN and SON to increases in peripheral AngII.

  3. Effects of Intralaminar Thalamic Stimulation on Language Functions

    ERIC Educational Resources Information Center

    Bhatnagar, Subhash C.; Mandybur, George T.

    2005-01-01

    Fifteen neurosurgical subjects, who were undergoing thalamic chronic electrode implants as a treatment for dyskinesia and chronic pain, were evaluated on a series of neurolinguistic functions to determine if the stimulation of the centromedianum nucleus of the thalamus affected language and cognitive processing. Analysis of the data revealed that…

  4. PI3K in the ventromedial hypothalamic nucleus mediates estrogenic actions on energy expenditure in female mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Estrogens act in the ventromedial hypothalamic nucleus (VMH) to regulate body weight homeostasis. However, the molecular mechanisms underlying these estrogenic effects are unknown. We show that activation of estrogen receptor-a (ERa) stimulates neural firing of VMH neurons expressing ERa, and these ...

  5. 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.

  6. Dynamical evolution of comet nucleus rotation

    NASA Astrophysics Data System (ADS)

    Scheeres, D. J.; Sidorenko, V. V.; Neishtadt, A. I.; Vasiliev, A. A.

    2001-11-01

    The rotational dynamics of outgassing cometary nuclei are investigated analytically using dynamical systems theory. We develop a general theory for the averaged evolution of a comet nucleus rotation state assuming that the nucleus is a spheroid (either prolate or oblate) and that the outgassing torques are a function of solar insolation and heliocentric distance. The resulting solutions are a function of the comet outgassing properties, its heliocentric orbit, and the assumed distribution of active regions on its surface. We find that the long-term evolution of the comet nucleus rotation is a strong function of the distribution of active regions over its surface. Specifically, we find that a comet nucleus with a uniformly active surface will tend towards a rotation state with a nutation angle of ~ 55 degrees and an angular momentum perpendicular to the sun-perihelion direction. Conversely, a comet nucleus with an isolated active region will tend towards a zero nutation angle with its symmetry axis and angular momentum aligned parallel to the sun-perihelion direction. For active surface regions between these extremes we find 4 qualitatively different dynamical outcomes. In all cases, the theory predicts that the comet nucleus angular momentum will have a secular increase, a phenomenon that could contribute to nucleus splitting of active comets. These results can be used to discriminate between competing theories of comet outgassing based on a nucelus' rotation state. They also allow for a range of plausible a priori constraints to be placed on a comet's rotation state to aid in the interpretation of its outgassing structure. This work was supported by the NASA JURRISS program under Grant NAG5-8715. AIN, AAV and VVS acknowledge support from Russian Foundation for Basic research via Grants 00-01-00538 and 00-01-0174 respectively. DJS acknowledges support from the PG&G program via Grant NAG5-9017.

  7. Descending projections from the nucleus accumbens shell excite activity of taste-responsive neurons in the nucleus of the solitary tract in the hamster.

    PubMed

    Li, Cheng-Shu; Lu, Da-Peng; Cho, Young K

    2015-06-01

    The nucleus of the solitary tract (NST) and the parabrachial nuclei (PbN) are the first and second relays in the rodent central taste pathway. A series of electrophysiological experiments revealed that spontaneous and taste-evoked activities of brain stem gustatory neurons are altered by descending input from multiple forebrain nuclei in the central taste pathway. The nucleus accumbens shell (NAcSh) is a key neural substrate of reward circuitry, but it has not been verified as a classical gustatory nucleus. A recent in vivo electrophysiological study demonstrated that the NAcSh modulates the spontaneous and gustatory activities of hamster pontine taste neurons. In the present study, we investigated whether activation of the NAcSh modulates gustatory responses of the NST neurons. Extracellular single-unit activity was recorded from medullary neurons in urethane-anesthetized hamsters. After taste response was confirmed by delivery of sucrose, NaCl, citric acid, and quinine hydrochloride to the anterior tongue, the NAcSh was stimulated bilaterally with concentric bipolar stimulating electrodes. Stimulation of the ipsilateral and contralateral NAcSh induced firings from 54 and 37 of 90 medullary taste neurons, respectively. Thirty cells were affected bilaterally. No inhibitory responses or antidromic invasion was observed after NAcSh activation. In the subset of taste cells tested, high-frequency electrical stimulation of the NAcSh during taste delivery enhanced taste-evoked neuronal firing. These results demonstrate that two-thirds of the medullary gustatory neurons are under excitatory descending influence from the NAcSh, which is a strong indication of communication between the gustatory pathway and the mesolimbic reward pathway.

  8. Activation of SC during electrical stimulation of LGN: retinal antidromic stimulation or corticocollicular activation?

    PubMed

    Murayama, Yusuke; Augath, Mark; Logothetis, Nikos K

    2011-12-01

    We have recently used combined electrostimulation, neurophysiology, microinjection and functional magnetic resonance imaging (fMRI) to study the cortical activity patterns elicited during stimulation of cortical afferents in monkeys. We found that stimulation of a site in lateral geniculate nucleus (LGN) increases the fMRI signal in the regions of primary visual cortex receiving input from that site, but suppresses it in the retinotopically matched regions of extrastriate cortex. Intracortical injection experiments showed that such suppression is due to synaptic inhibition. During these experiments, we have consistently observed activation of superior colliculus (SC) following LGN stimulation. Since LGN does not directly project to SC, the current study investigated the origin of SC activation. By examining experimental manipulations inactivating the primary visual cortex, we present here evidence that the robust SC activation, which follows the stimulation of LGN, is due to the activation of corticocollicular pathway.

  9. The Effect of Deep Brain Stimulation on the Speech Motor System

    ERIC Educational Resources Information Center

    Mücke, Doris; Becker, Johannes; Barbe, Michael T.; Meister, Ingo; Liebhart, Lena; Roettger, Timo B.; Dembek, Till; Timmermann, Lars; Grice, Martine

    2014-01-01

    Purpose: Chronic deep brain stimulation of the nucleus ventralis intermedius is an effective treatment for individuals with medication-resistant essential tremor. However, these individuals report that stimulation has a deleterious effect on their speech. The present study investigates one important factor leading to these effects: the…

  10. State-dependent control of breathing by the retrotrapezoid nucleus

    PubMed Central

    Burke, Peter GR; Kanbar, Roy; Basting, Tyler M; Hodges, Walter M; Viar, Kenneth E; Stornetta, Ruth L; Guyenet, Patrice G

    2015-01-01

    Key points This study explores the state dependence of the hypercapnic ventilatory reflex (HCVR). We simulated an instantaneous increase or decrease of central chemoreceptor activity by activating or inhibiting the retrotrapezoid nucleus (RTN) by optogenetics in conscious rats. During quiet wake or non-REM sleep, hypercapnia increased both breathing frequency (fR) and tidal volume (VT) whereas, in REM sleep, hypercapnia increased VT exclusively. Optogenetic inhibition of RTN reduced VT in all sleep–wake states, but reduced fR only during quiet wake and non-REM sleep. RTN stimulation always increased VT but raised fR only in quiet wake and non-REM sleep. Phasic RTN stimulation produced active expiration and reduced early expiratory airflow (i.e. increased upper airway resistance) only during wake. We conclude that the HCVR is highly state-dependent. The HCVR is reduced during REM sleep because fR is no longer under chemoreceptor control and thus could explain why central sleep apnoea is less frequent in REM sleep. Abstract Breathing has different characteristics during quiet wake, non-REM or REM sleep, including variable dependence on . We investigated whether the retrotrapezoid nucleus (RTN), a proton-sensitive structure that mediates a large portion of the hypercapnic ventilatory reflex, regulates breathing differently during sleep vs. wake. Electroencephalogram, neck electromyogram, blood pressure, respiratory frequency (fR) and tidal volume (VT) were recorded in 28 conscious adult male Sprague–Dawley rats. Optogenetic stimulation of RTN with channelrhodopsin-2, or inhibition with archaerhodopsin, simulated an instantaneous increase or decrease of central chemoreceptor activity. Both opsins were delivered with PRSX8-promoter-containing lentiviral vectors. RTN and catecholaminergic neurons were transduced. During quiet wake or non-REM sleep, hypercapnia (3 or 6% ) increased both fR and VT whereas, in REM sleep, hypercapnia increased VT exclusively. RTN

  11. 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.

  12. The dynamic landscape of the cell nucleus.

    PubMed

    Austin, Christopher M; Bellini, Michel

    2010-01-01

    While the cell nucleus was described for the first time almost two centuries ago, our modern view of the nuclear architecture is primarily based on studies from the last two decades. This surprising late start coincides with the development of new, powerful strategies to probe for the spatial organization of nuclear activities in both fixed and live cells. As a result, three major principles have emerged: first, the nucleus is not just a bag filled with nucleic acids and proteins. Rather, many distinct functional domains, including the chromosomes, resides within the confines of the nuclear envelope. Second, all these nuclear domains are highly dynamic, with molecules exchanging rapidly between them and the surrounding nucleoplasm. Finally, the motion of molecules within the nucleoplasm appears to be mostly driven by random diffusion. Here, the emerging roles of several subnuclear domains are discussed in the context of the dynamic functions of the cell nucleus.

  13. Organisation of the human dorsomedial hypothalamic nucleus.

    PubMed

    Koutcherov, Yuri; Mai, Juergen K; Ashwell, Ken W; Paxinos, George

    2004-01-19

    This study used acetylcholinesterase (AChE) histochemistry to reveal the organization of the dorsomedial hypothalamic nucleus (DM) in the human. Topographically, the human DM is similar to DM in the monkey and rat. It is wedged between the paraventricular nucleus, dorsally, and the ventromedial nucleus, ventrally. Laterally, DM borders the lateral hypothalamic area while medially it approaches the 3rd ventricle. The AChE staining distinguished two subcompartments of the human DM: the larger diffuse and the smaller compact DM. The subcompartmental organization of the human DM appears homologous to that found in the monkey and less complex than that reported in rats. Understanding of the organization of DM creates meaningful anatomical reference for physiological and pharmacological studies in the human hypothalamus.

  14. [Effect of the intermittent hypoxic training on the functioning of peptidergic neurons of the paraventricular hypothalamic nucleus and brain stem neurons in rats].

    PubMed

    Abramov, A V

    1998-03-01

    Internittent hypoxic training (IHT) increased the quantity and secretory activity of peptidergic neurons of the paraventricular hypothalamic nucleus (PHN) and activated neurons of the dorsal motor nucleus of n.vagus. These structures seem to take part in realisation of the IHT activating effect on condition of the pancreatic delta-cells. The effect involves insulin-stimulating and insuloprotective effects realised via hypothalamic and neuro-conducting ways of regulation of the endocrine pancreas with a direct participation of hypothalamic neuropeptides.

  15. Vagus Nerve Stimulation

    MedlinePlus

    Vagus nerve stimulation Overview By Mayo Clinic Staff Vagus nerve stimulation is a procedure that involves implantation of a device that stimulates the vagus nerve with electrical impulses. There's one vagus nerve on ...

  16. Nucleus model for periodic Comet Tempel 2

    NASA Technical Reports Server (NTRS)

    Sekanina, Zdenek

    1991-01-01

    Observational data obtained primarily during 1988 are analyzed and synthesized to develop a comprehensive physical model for the nucleus of Periodic Comet Tempel 2, one of the best studied members of Jupiter's family of short-period comets. It is confirmed that a previous investigation provided reliable information on the comet's spin-axis orientation, which implies and obliquity of 54 degrees of the orbit plane to the equatorial plane and which appears to have varied little - if at all - with time. This conclusion is critical for fitting a triaxial ellipsoid to approximate the figure of the nucleus.

  17. UNCOVERING THE NUCLEUS CANDIDATE FOR NGC 253

    SciTech Connect

    Günthardt, G. I.; Camperi, J. A.; Agüero, M. P.; Díaz, R. J.; Gomez, P. L.; Schirmer, M.; Bosch, G. E-mail: camperi@oac.uncor.edu E-mail: rdiaz@gemini.edu E-mail: mschirmer@gemini.edu

    2015-11-15

    NGC 253 is the nearest spiral galaxy with a nuclear starburst that becomes the best candidate for studying the relationship between starburst and active galactic nucleus activity. However, this central region is veiled by large amounts of dust, and it has been so far unclear which is the true dynamical nucleus to the point that there is no strong evidence that the galaxy harbors a supermassive black hole co-evolving with the starburst as was supposed earlier. Near-infrared (NIR) spectroscopy, especially NIR emission line analysis, could be advantageous in shedding light on the true nucleus identity. Using Flamingos-2 at Gemini South we have taken deep K-band spectra along the major axis of the central structure and through the brightest infrared source. In this work, we present evidence showing that the brightest NIR and mid-infrared source in the central region, already known as radio source TH7 and so far considered just a large stellar supercluster, in fact presents various symptoms of a genuine galactic nucleus. Therefore, it should be considered a valid nucleus candidate. Mentioning some distinctive aspects, it is the most massive compact infrared object in the central region, located at 2.″0 of the symmetry center of the galactic bar, as measured in the K-band emission. Moreover, our data indicate that this object is surrounded by a large circumnuclear stellar disk and it is also located at the rotation center of the large molecular gas disk of NGC 253. Furthermore, a kinematic residual appears in the H{sub 2} rotation curve with a sinusoidal shape consistent with an outflow centered in the candidate nucleus position. The maximum outflow velocity is located about 14 pc from TH7, which is consistent with the radius of a shell detected around the nucleus candidate, observed at 18.3 μm (Qa) and 12.8 μm ([Ne ii]) with T-ReCS. Also, the Brγ emission line profile shows a pronounced blueshift and this emission line also has the highest equivalent width at this

  18. Uncovering the Nucleus Candidate for NGC 253

    NASA Astrophysics Data System (ADS)

    Günthardt, G. I.; Agüero, M. P.; Camperi, J. A.; Díaz, R. J.; Gomez, P. L.; Bosch, G.; Schirmer, M.

    2015-11-01

    NGC 253 is the nearest spiral galaxy with a nuclear starburst that becomes the best candidate for studying the relationship between starburst and active galactic nucleus activity. However, this central region is veiled by large amounts of dust, and it has been so far unclear which is the true dynamical nucleus to the point that there is no strong evidence that the galaxy harbors a supermassive black hole co-evolving with the starburst as was supposed earlier. Near-infrared (NIR) spectroscopy, especially NIR emission line analysis, could be advantageous in shedding light on the true nucleus identity. Using Flamingos-2 at Gemini South we have taken deep K-band spectra along the major axis of the central structure and through the brightest infrared source. In this work, we present evidence showing that the brightest NIR and mid-infrared source in the central region, already known as radio source TH7 and so far considered just a large stellar supercluster, in fact presents various symptoms of a genuine galactic nucleus. Therefore, it should be considered a valid nucleus candidate. Mentioning some distinctive aspects, it is the most massive compact infrared object in the central region, located at 2.″0 of the symmetry center of the galactic bar, as measured in the K-band emission. Moreover, our data indicate that this object is surrounded by a large circumnuclear stellar disk and it is also located at the rotation center of the large molecular gas disk of NGC 253. Furthermore, a kinematic residual appears in the H2 rotation curve with a sinusoidal shape consistent with an outflow centered in the candidate nucleus position. The maximum outflow velocity is located about 14 pc from TH7, which is consistent with the radius of a shell detected around the nucleus candidate, observed at 18.3 μm (Qa) and 12.8 μm ([Ne ii]) with T-ReCS. Also, the Brγ emission line profile shows a pronounced blueshift and this emission line also has the highest equivalent width at this

  19. On Parallel Streams through the Mouse Dorsal Lateral Geniculate Nucleus.

    PubMed

    Denman, Daniel J; Contreras, Diego

    2016-01-01

    The mouse visual system is an emerging model for the study of cortical and thalamic circuit function. To maximize the usefulness of this model system, it is important to analyze the similarities and differences between the organization of all levels of the murid visual system with other, better studied systems (e.g., non-human primates and the domestic cat). While the understanding of mouse retina and cortex has expanded rapidly, less is known about mouse dorsal lateral geniculate nucleus (dLGN). Here, we study whether parallel processing streams exist in mouse dLGN. We use a battery of stimuli that have been previously shown to successfully distinguish parallel streams in other species: electrical stimulation of the optic chiasm, contrast-reversing stationary gratings at varying spatial phase, drifting sinusoidal gratings, dense noise for receptive field reconstruction, and frozen contrast-modulating noise. As in the optic nerves of domestic cats and non-human primates, we find evidence for multiple conduction velocity groups after optic chiasm stimulation. As in so-called "visual mammals", we find a subpopulation of mouse dLGN cells showing non-linear spatial summation. However, differences in stimulus selectivity and sensitivity do not provide sufficient basis for identification of clearly distinct classes of relay cells. Nevertheless, consistent with presumptively homologous status of dLGNs of all mammals, there are substantial similarities between response properties of mouse dLGN neurons and those of cats and primates.

  20. On Parallel Streams through the Mouse Dorsal Lateral Geniculate Nucleus

    PubMed Central

    Denman, Daniel J.; Contreras, Diego

    2016-01-01

    The mouse visual system is an emerging model for the study of cortical and thalamic circuit function. To maximize the usefulness of this model system, it is important to analyze the similarities and differences between the organization of all levels of the murid visual system with other, better studied systems (e.g., non-human primates and the domestic cat). While the understanding of mouse retina and cortex has expanded rapidly, less is known about mouse dorsal lateral geniculate nucleus (dLGN). Here, we study whether parallel processing streams exist in mouse dLGN. We use a battery of stimuli that have been previously shown to successfully distinguish parallel streams in other species: electrical stimulation of the optic chiasm, contrast-reversing stationary gratings at varying spatial phase, drifting sinusoidal gratings, dense noise for receptive field reconstruction, and frozen contrast-modulating noise. As in the optic nerves of domestic cats and non-human primates, we find evidence for multiple conduction velocity groups after optic chiasm stimulation. As in so-called “visual mammals”, we find a subpopulation of mouse dLGN cells showing non-linear spatial summation. However, differences in stimulus selectivity and sensitivity do not provide sufficient basis for identification of clearly distinct classes of relay cells. Nevertheless, consistent with presumptively homologous status of dLGNs of all mammals, there are substantial similarities between response properties of mouse dLGN neurons and those of cats and primates. PMID:27065811

  1. Cortico-muscular coherence increases with tremor improvement after deep brain stimulation in Parkinson's disease.

    PubMed

    Park, Hame; Kim, June Sic; Paek, Sun Ha; Jeon, Beom Seok; Lee, Jee Young; Chung, Chun Kee

    2009-10-28

    Deep brain stimulation on the subthalamic nucleus has been used to relieve Parkinsonian motor symptoms. However, the underlying physiological mechanism has not been fully understood. Beta-band cortico-muscular coherence increases when healthy humans perform isometric contraction. We hypothesized that this might be a measure of symptomatic improvement in motor performance after subthalamic nucleus deep brain stimulation. Here, we measured the beta-band cortico-muscular coherence with magnetoencephalography from three Parkinson's disease patients. We then compared the coherence values for stimulator on-state and off-state. We found that when the stimulator is on, the beta cortico-muscular coherence elevates significantly for the tremorous hand compared with that when the stimulator is off. This suggests that deep brain stimulation resulted in better cortico-muscular coordination.

  2. Signaling from the Secretory Granule to the Nucleus: Uhmk1 and PAM

    PubMed Central

    Francone, Victor P.; Ifrim, Marius F.; Rajagopal, Chitra; Leddy, Christopher J.; Wang, Yanping; Carson, John H.; Mains, Richard E.; Eipper, Betty A.

    2010-01-01

    Neurons and endocrine cells package peptides in secretory granules (large dense-core vesicles) for storage and stimulated release. Studies of peptidylglycine α-amidating monooxygenase (PAM), an essential secretory granule membrane enzyme, revealed a pathway that can relay information from secretory granules to the nucleus, resulting in alterations in gene expression. The cytosolic domain (CD) of PAM, a type 1 membrane enzyme essential for the production of amidated peptides, is basally phosphorylated by U2AF homology motif kinase 1 (Uhmk1) and other Ser/Thr kinases. Proopiomelanocortin processing in AtT-20 corticotrope tumor cells was increased when Uhmk1 expression was reduced. Uhmk1 was concentrated in the nucleus, but cycled rapidly between nucleus and cytosol. Endoproteolytic cleavage of PAM releases a soluble CD fragment that localizes to the nucleus. Localization of PAM-CD to the nucleus was decreased when PAM-CD with phosphomimetic mutations was examined and when active Uhmk1 was simultaneously overexpressed. Membrane-tethering Uhmk1 did not eliminate its ability to exclude PAM-CD from the nucleus, suggesting that cytosolic Uhmk1 could cause this response. Microarray analysis demonstrated the ability of PAM to increase expression of a small subset of genes, including aquaporin 1 (Aqp1) in AtT-20 cells. Aqp1 mRNA levels were higher in wild-type mice than in mice heterozygous for PAM, indicating that a similar relationship occurs in vivo. Expression of PAM-CD also increased Aqp1 levels whereas expression of Uhmk1 diminished Aqp1 expression. The outlines of a pathway that ties secretory granule metabolism to the transcriptome are thus apparent. PMID:20573687

  3. Fermi-motion effect on the intermediate energy nucleus-nucleus collision

    NASA Astrophysics Data System (ADS)

    Fan, G. W.; Kong, W. Y.; Han, T. F.; Li, X. C.; Ma, J. B.; Sheng, Z. Q.; Shi, G. Z.; Tian, F.; Wang, J.; Zhang, C.

    2016-11-01

    The Glauber model is modified with the Fermi-motion effect in the calculation of elastic differential cross-sections and momentum distributions of a fragment from mother nucleus. Different reaction systems at low energies are calculated with the modified Glauber model. It is found that calculations including the Fermi-motion provide a better prescription relating the model to a proper nuclear density distribution by comparing with the experimental data. On the basis of the studies, the influence of the correction on the extracted nuclear radius is quantified. The results further confirm the importance of the Fermi-motion in the nucleus-nucleus collision reactions at low energies.

  4. [Selective stimulations and lesions of the rat brain nuclei as the models for research of the human sleep pathology mechanisms].

    PubMed

    Šaponjić, Jasna

    2011-01-01

    Many complex behavioral phenomena such as sleep can not be explained without multidisciplinary experimental approach, and complementay approaches in the animal models "in vivo" and human studies. Electrophysiological, pharmacological, anatomical and immunohistochemical techniques, and particularly stereotaxically guided local nanovolume microinjection technique, enable us to selectively stimulate and lesion the brain nuclei or their specific neuronal subpopulation, and to reslove the mechanisms of certain brain structure regulatory role, and its afferent-efferent connectivity within the brain. Local stereotaxically guided nanovolume microinjection technique enable us to investigate in animals the brain nulcei functional topography with a resolution of < or = 10 microM, and at a level of 300 microM of effective radius within the brain tissue "in vivo". The advantage of local glutamate or DL- homocysteic acid microinjection stimulation or local excitotoxic (glutamate, ibotenic acid, IgG saporin) microinjection lesion over electrical stimulation/lesion of the same neuronal population are that they reduces the likelihood of activation/lesion of fibers of passage. Much of our knowledge of the sleep neuronal substrates is based on animal studies primarly in cat and rat. Selective pharmacological stimulation of the pedunculopontine tegmentum (PPT) in freely moving rat, using glutamate microinjection, proved that excitation of its cholinergic part is necessary for induction of wakefulness or REM (Datta S, 2001). Local nanovolume glutamate microinjection into PPT of anesthetized rats (Saponjić et al, 2003a) additionally evidenced P-wave and respiratory regulating neuronal subpopulation within the cholinergic compartment of PPT (apneogenic neuronal zone). Local microinjection of serotonin and noradrenaline into cholinergic PPT apneogenic zone evidenced their opposed impact through PPT on breathing, in contrast to their convergent regulatory role in behavioral state control

  5. Oxytocin in Brattleboro rats: increased synthesis is contrasted by blunted intrahypothalamic release from supraoptic nucleus neurones.

    PubMed

    Zelena, D; Pintér, O; Langnaese, K; Richter, K; Landgraf, R; Makara, G B; Engelmann, M

    2013-08-01

    Adult male Brattleboro rats were used to investigate the impact of the congenital absence of vasopressin on the release pattern of oxytocin (OXT) within the hypothalamic supraoptic nucleus (SON) in response to a 10-min forced swimming session and osmotic stimulation. Both immunohistochemical and in situ hybridisation data suggest that vasopressin-deficient animals have more oxytocin-synthesising neurones in the SON than homozygous wild-type controls. Unexpectedly, both forced swimming and peripheral osmotic stimulation resulted in a blunted release profile of oxytocin within the SON of vasopressin-deficient rats compared to controls. A similar intranuclear OXT response to direct osmotic stimulation of the SON by retrodialysis with hypertonic Ringer's solution in both genotypes confirmed the capability of SON neurones to locally release oxytocin in vasopressin-deficient rats, indicating an altered processing of information originating from multisynaptic inputs rather than a deficit in release capacity. Taken together with data obtained in previous studies, the present findings provide evidence suggesting that autocrine and paracrine signalling of magnocellular neurones differs within the paraventricular nucleus and the SON. Thus, significant alterations in intra-SON oxytocin mRNA levels cannot easily be extrapolated to intranuclear release profiles and the local signal intensity of this neuropeptide after physiological stimulation.

  6. The Checkerboard Model of the Nucleus

    NASA Astrophysics Data System (ADS)

    Lach, Theodore

    2015-04-01

    The Checker Board Model (CBM) of the nucleus and the associated extended standard model predicts that nature has 5 generations of quarks not 3 and that Nucleus is 2 dimensional. The CBM theory began with an insight into the structure of the He nucleus around the year 1989. Details of how this theory evolved which took many years, and is found on my web site (http://checkerboard.dnsalias.net) or in the following references One independent check of this model is that the wavelength of the ``up'' quark orbiting inside the proton at 84.8123% the speed of light (around the ``dn'' quark in the center of the proton) turns out to be exactly one de Broglie wavelength something determined after the mass and speed of the up quark were determined by other means. This theory explains the mass of the proton and neutron and their magnetic moments and this along with the beautiful symmetric 2D structure of the He nucleus led to the evolution of this theory. When this theory was first presented at Argonne in 1996, it was the first time that anyone had predicted the quarks orbited inside the proton at relativistic speeds and it was met with skepticism.

  7. New developments in nucleus pulposus replacement technology.

    PubMed

    Carl, Allen; Ledet, Eric; Yuan, Hansen; Sharan, Alok

    2004-01-01

    Attempts to alleviate the pain attributed to degeneration of the nucleus pulposus using replacement or reinforcement techniques dating back to the 1950s are reviewed. The various materials and their insertion techniques are discussed as are results available from early clinical experiences. These techniques are in evolution and clinical outcomes will be necessary to establish the efficacy of these approaches.

  8. Nucleus-associated actin in Amoeba proteus.

    PubMed

    Berdieva, Mariia; Bogolyubov, Dmitry; Podlipaeva, Yuliya; Goodkov, Andrew

    2016-10-01

    The presence, spatial distribution and forms of intranuclear and nucleus-associated cytoplasmic actin were studied in Amoeba proteus with immunocytochemical approaches. Labeling with different anti-actin antibodies and staining with TRITC-phalloidin and fluorescent deoxyribonuclease I were used. We showed that actin is abundant within the nucleus as well as in the cytoplasm of A. proteus cells. According to DNase I experiments, the predominant form of intranuclear actin is G-actin which is associated with chromatin strands. Besides, unpolymerized actin was shown to participate in organization of a prominent actin layer adjacent to the outer surface of nuclear envelope. No significant amount of F-actin was found in the nucleus. At the same time, the amoeba nucleus is enclosed in a basket-like structure formed by circumnuclear actin filaments and bundles connected with global cytoplasmic actin cytoskeleton. A supposed architectural function of actin filaments was studied by treatment with actin-depolymerizing agent latrunculin A. It disassembled the circumnuclear actin system, but did not affect the intranuclear chromatin structure. The results obtained for amoeba cells support the modern concept that actin is involved in fundamental nuclear processes that have evolved in the cells of multicellular organisms.

  9. Nucleon-nucleus interactions from JACEE

    NASA Technical Reports Server (NTRS)

    Burnett, T. H.; Dake, S.; Fuki, M.; Gregory, J. C.; Hayashi, T.; Holynski, R.; Iwai, J.; Jones, W. V.; Jurak, A.; Lord, J. J.

    1985-01-01

    Results on hadron-nucleus interactions from the Japanese-American Cooperation Emulsion Experiment experiment are presented. Angular distributions for charged particles, and angular and transverse momentum spectra for photons have been measured for a sample of events with sigma epsilon sub gamma. Results on central rapidity density and transverse energy flow are discussed.

  10. Suppression and facilitation of auditory neurons through coordinated acoustic and midbrain stimulation: investigating a deep brain stimulator for tinnitus

    NASA Astrophysics Data System (ADS)

    Offutt, Sarah J.; Ryan, Kellie J.; Konop, Alexander E.; Lim, Hubert H.

    2014-12-01

    Objective. The inferior colliculus (IC) is the primary processing center of auditory information in the midbrain and is one site of tinnitus-related activity. One potential option for suppressing the tinnitus percept is through deep brain stimulation via the auditory midbrain implant (AMI), which is designed for hearing restoration and is already being implanted in deaf patients who also have tinnitus. However, to assess the feasibility of AMI stimulation for tinnitus treatment we first need to characterize the functional connectivity within the IC. Previous studies have suggested modulatory projections from the dorsal cortex of the IC (ICD) to the central nucleus of the IC (ICC), though the functional properties of these projections need to be determined. Approach. In this study, we investigated the effects of electrical stimulation of the ICD on acoustic-driven activity within the ICC in ketamine-anesthetized guinea pigs. Main Results. We observed ICD stimulation induces both suppressive and facilitatory changes across ICC that can occur immediately during stimulation and remain after stimulation. Additionally, ICD stimulation paired with broadband noise stimulation at a specific delay can induce greater suppressive than facilitatory effects, especially when stimulating in more rostral and medial ICD locations. Significance. These findings demonstrate that ICD stimulation can induce specific types of plastic changes in ICC activity, which may be relevant for treating tinnitus. By using the AMI with electrode sites positioned with the ICD and the ICC, the modulatory effects of ICD stimulation can be tested directly in tinnitus patients.

  11. [Postsynaptic reactions of cerebral cortex neurons, activated by nociceptive afferents during stimulation of the Raphe nuclei].

    PubMed

    Labakhua, T Sh; Dzhanashiia, T K; Gedevanishvili, G I; Dzhokhadze, L D; Tkemaladze, T T; Abzianidze, I V

    2012-01-01

    On cats, we studied the influence of stimulation of the Raphe nuclei (RN) on postsynaptic processes evoked in neurons of the somatosensory cortex by stimulation of nociceptive (intensive stimulation of the tooth pulp) and non-nociceptive (moderate stimulation of the ventroposteromedial--VPN--nucleus of the thalamus) afferent inputs. 6 cells, selectively excited by stimulation of nocciceptors and 9 cells, activated by both the above nociceptive and non-nociceptive influences (nociceptive and convergent neurons, respectively) were recorded intracellular. In neurons of both groups, responses to nociceptive stimulation (of sufficient intensity) looked like an EPSP-spike-IPSP (the letter of significant duration, up to 200-300 ms) compleх. Conditioning stimulation of the RN which preceded test stimulus applied to the tooth pulp or VPM nucleus by 100 to 800 ms, induced 40-60 % decrease of the IPSP amplitude only, while maхimal effect of influence, in both cases, was noted within intervals of 300-800 ms between conditioning and test stimulus. During stimulation of the RN, serotonin released via receptor and second messengers, provides postsynaptic modulation of GABAergic system, decreasing the IPSP amplitude which occurs after stimulation of both the tooth pulp and VPM thalamic nucleus. This process may be realized trough either pre- or postsynaptic mechanisms.

  12. Dendritic geometry shapes neuronal cAMP signalling to the nucleus.

    PubMed

    Li, Lu; Gervasi, Nicolas; Girault, Jean-Antoine

    2015-02-18

    Neurons have complex dendritic trees, receiving numerous inputs at various distances from the cell body. Yet the rules of molecular signal propagation from dendrites to nuclei are unknown. DARPP-32 is a phosphorylation-regulated signalling hub in striatal output neurons. We combine diffusion-reaction modelling and live imaging to investigate cAMP-activated DARPP-32 signalling to the nucleus. The model predicts maximal effects on the nucleus of cAMP production in secondary dendrites, due to segmental decrease of dendrite diameter. Variations in branching, perikaryon size or spines have less pronounced effects. Biosensor kinase activity measurement following cAMP or dopamine uncaging confirms these predictions. Histone 3 phosphorylation, regulated by this pathway, is best stimulated by cAMP released in secondary-like dendrites. Thus, unexpectedly, the efficacy of diffusion-based signalling from dendrites to nucleus is not inversely proportional to the distance. We suggest a general mechanism by which dendritic geometry counterbalances the effect of dendritic distance for signalling to the nucleus.

  13. Subthalamic nucleus phase–amplitude coupling correlates with motor impairment in Parkinson’s disease

    PubMed Central

    van Wijk, Bernadette C.M.; Beudel, Martijn; Jha, Ashwani; Oswal, Ashwini; Foltynie, Tom; Hariz, Marwan I.; Limousin, Patricia; Zrinzo, Ludvic; Aziz, Tipu Z.; Green, Alexander L.; Brown, Peter; Litvak, Vladimir

    2016-01-01

    Objective High-amplitude beta band oscillations within the subthalamic nucleus are frequently associated with Parkinson’s disease but it is unclear how they might lead to motor impairments. Here we investigate a likely pathological coupling between the phase of beta band oscillations and the amplitude of high-frequency oscillations around 300 Hz. Methods We analysed an extensive data set comprising resting-state recordings obtained from deep brain stimulation electrodes in 33 patients before and/or after taking dopaminergic medication. We correlated mean values of spectral power and phase–amplitude coupling with severity of hemibody bradykinesia/rigidity. In addition, we used simultaneously recorded magnetoencephalography to look at functional interactions between the subthalamic nucleus and ipsilateral motor cortex. Results Beta band power and phase–amplitude coupling within the subthalamic nucleus correlated positively with severity of motor impairment. This effect was more pronounced within the low-beta range, whilst coherence between subthalamic nucleus and motor cortex was dominant in the high-beta range. Conclusions We speculate that the beta band might impede pro-kinetic high-frequency activity patterns when phase–amplitude coupling is prominent. Furthermore, results provide evidence for a functional subdivision of the beta band into low and high frequencies. Significance Our findings contribute to the interpretation of oscillatory activity within the cortico-basal ganglia circuit. PMID:26971483

  14. Perimovement decrease of alpha/beta oscillations in the human nucleus accumbens

    PubMed Central

    Dürschmid, Stefan; Rutledge, Robb B.; Zaehle, Tino; Schmitt, Friedhelm C.; Kaufmann, Jörn; Voges, Jürgen; Heinze, Hans-Jochen; Dolan, Raymond J.; Schoenfeld, Mircea Ariel

    2016-01-01

    The human nucleus accumbens is thought to play an important role in guiding future action selection via an evaluation of current action outcomes. Here we provide electrophysiological evidence for a more direct, i.e., online, role during action preparation. We recorded local field potentials from the nucleus accumbens in patients with epilepsy undergoing surgery for deep brain stimulation. We found a consistent decrease in the power of alpha/beta oscillations (10–30 Hz) before and around the time of movements. This perimovement alpha/beta desynchronization was observed in seven of eight patients and was present both before instructed movements in a serial reaction time task as well as before self-paced, deliberate choices in a decision making task. A similar beta decrease over sensorimotor cortex and in the subthalamic nucleus has been directly related to movement preparation and execution. Our results support the idea of a direct role of the human nucleus accumbens in action preparation and execution. PMID:27486103

  15. Analgesia induced by morphine microinjected into the nucleus raphe magnus: effects on tonic pain.

    PubMed

    Dualé, Christian; Sierralta, Fernando; Dallel, Radhouane

    2007-07-01

    One of the possible sites of action of the analgesic effect of morphine is the Nucleus Raphe Magnus, as morphine injected into this structure induces analgesia in transient pain models. In order to test if morphine in the Nucleus Raphe Magnus is also analgesic in a tonic pain model, 5 microg of morphine or saline (control) were microinjected into the Nucleus Raphe Magnus of the rat. Analgesic effects were assessed following nociceptive stimulation using transient heating of the tail (phasic pain) and subcutaneous orofacial injection of 1.5 % formalin (tonic pain). While morphine was strongly analgesic for the tail-flick response (p <0.0001 compared to control), analgesia on the response to formalin was also observed for both early (p = 0.007) and late responses (p = 0.02). However, the response to formalin was not completely blunted. These results suggest that the Nucleus Raphe Magnus is not the exclusive site of action of morphine-induced analgesia in clinical conditions.

  16. 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.

  17. Osmotic modulation of stimulus-evoked responses in the rat supraoptic nucleus.

    PubMed

    Bhumbra, G S; Orlans, H O; Dyball, R E J

    2008-04-01

    Neural information is conveyed by action potentials along axons to downstream synaptic targets. Synapses permit functionally relevant modulation of the information transmitted by converging inputs. Previous studies have measured the amount of information associated with a given stimulus based either on spike counts or on the relative frequencies of spike sequences represented as binary strings. Here we apply information theory to the phase-interval stimulus histogram (PhISH) to measure the extent of the stimulus-evoked response using the statistical relationship between each interspike interval and its phase within the stimulus cycle. We used the PhISH as a novel approach to investigate how different osmotic states affect the flow of information through the osmoreceptor complex of the hypothalamus. The amount of information conveyed from one (afferent) element of the complex, the anteroventral region of the third ventricle (AV3V), to another (an efferent element), the supraoptic nucleus, was increased by hypertonic stimulation (intravenous mannitol, z = 4.39, P < 0.001) and decreased by hypotonic stimulation (intragastric water, z = -3.37, P < 0.001). Supraoptic responses to AV3V stimulation differed from those that follow stimulation of a hypothalamic element outside the osmoreceptor complex, the suprachiasmatic nucleus (SCN), which also projects to the supraoptic nucleus. Thus osmosensitive gain control mechanisms differentially modulate osmotically dependent and osmotically independent inputs, and enhance the osmoresponsiveness of supraoptic cells within a physiological range. The value of the novel approach is that its use is not limited to the osmoreceptor ensemble but it can be used to investigate the flow of information throughout the central nervous system.

  18. Average transverse momentum and energy density in high-energy nucleus-nucleus collisions

    NASA Technical Reports Server (NTRS)

    Burnett, T. H.; Dake, S.; Fuki, M.; Gregory, J. C.; Hayashi, T.; Holynski, R.; Iwai, J.; Jones, W. V.; Jurak, A.; Lord, J. J.

    1986-01-01

    Emulsion chambers were used to measure the transverse momenta of photons or pi(0) mesons produced in high-energy cosmic-ray nucleus-nucleus collisions. A group of events having large average transverse momenta has been found which apparently exceeds the expected limiting values. Analysis of the events at early interaction times, of the order of 1 fm/c, indicates that the observed transverse momentum increases with both rapidity density and energy density.

  19. Deep brain stimulation modulates effects of motivation in Parkinson's disease.

    PubMed

    Sauleau, Paul; Eusebio, Alexandre; Vandenberghe, Wim; Nuttin, Bart; Brown, Peter

    2009-04-22

    It is unclear how motivation leads to improved motor performance. Here we test the hypothesis that motivation interacts with behavioural performance in the basal ganglia. We recorded trial-to-trial performance in a bimanual motor task in 10 patients with Parkinson's disease with electrodes chronically implanted in the subthalamic nucleus for deep brain stimulation. Motivation-associated improvements in trial-to-trial performance were contrasted with and without stimulation at high frequency. Motivation and stimulation improved trial-to-trial performance, but the effect of motivation was halved during stimulation. We conclude that the subthalamic area is mechanistically important in those processes linking motivation to improvement in motor performance. This finding may be relevant to some of the cognitive and emotional changes associated with bilateral subthalamic stimulation.

  20. Theory of feedback controlled brain stimulations for Parkinson's disease

    NASA Astrophysics Data System (ADS)

    Sanzeni, A.; Celani, A.; Tiana, G.; Vergassola, M.

    2016-01-01

    Limb tremor and other debilitating symptoms caused by the neurodegenerative Parkinson's disease are currently treated by administering drugs and by fixed-frequency deep brain stimulation. The latter interferes directly with the brain dynamics by delivering electrical impulses to neurons in the subthalamic nucleus. While deep brain stimulation has shown therapeutic benefits in many instances, its mechanism is still unclear. Since its understanding could lead to improved protocols of stimulation and feedback control, we have studied a mathematical model of the many-body neural network dynamics controlling the dynamics of the basal ganglia. On the basis of the results obtained from the model, we propose a new procedure of active stimulation, that depends on the feedback of the network and that respects the constraints imposed by existing technology. We show by numerical simulations that the new protocol outperforms the standard ones for deep brain stimulation and we suggest future experiments that could further improve the feedback procedure.

  1. Infrared neural stimulation: beam path in the guinea pig cochlea

    PubMed Central

    Moreno, Laura E; Rajguru, Suhrud M; Matic, Agnella Izzo; Yerram, Nitin; Robinson, Alan M; Hwang, Margaret; Stock, Stuart; Richter, Claus-Peter

    2011-01-01

    It has been demonstrated INS can be utilized to stimulate spiral ganglion cells in the cochlea. Although neural stimulation can be achieved without direct contact of the radiation source and the tissue, the presence of fluids or bone between the target structure and the radiation source may lead to absorption or scattering of the radiation, which may limit the efficacy of INS. The present study demonstrates the neural structures in the radiation beam path that can be stimulated. Histological reconstructions and microCT of guinea pig cochleae stimulated with an infrared laser suggest that the orientation of the beam from the optical fiber determined the site of stimulation in the cochlea. Best frequencies of the INS-evoked neural responses obtained from the central nucleus of the inferior colliculus matched the histological sites in the spiral ganglion. PMID:21763410

  2. Hyperventilation evoked by activation of the vicinity of the caudal inferior olivary nucleus depends on the fastigial nucleus in anesthetized rats.

    PubMed

    Zhuang, Jianguo; Xu, Fadi; Frazier, Donald T

    2008-05-01

    Several studies have demonstrated that cerebellar deep nuclei, particularly the rostral fastigial nucleus (FNr), are involved in respiratory modulation. These nuclei receive inputs from the contralateral caudal inferior olivary nuclei of the medulla. The objectives of this study were to determine whether electrical and chemical activation of the vicinity of the caudal inferior olivary nuclei (vIOc) affected respiration and, if true, whether the FNr was involved in the vIOc stimulation-evoked ventilatory responses. Experiments were conducted in 30 anesthetized and spontaneously breathing rats. Our results showed that 1) electrical (25 or 100 microA at 10 or 20 Hz for 10 s) and chemical (1 or 100 mM, 25-50 nl N-methyl-D-aspartate) stimulation of the vIOc augmented ventilation predominantly via increasing tidal volume; 2) the responses to the electrical stimulation were almost eliminated by lesion of the contralateral FNr via microinjection of ibotenic acid; and 3) the respiratory responses to electrical stimulation in the vicinity of the rostral IO were 65-70% smaller compared with that evoked by vIOc stimulation. These findings strongly suggest that vIOc neurons play a significant role in modulation of respiratory activity, largely depending on their projections to the FNr.

  3. Reversing cognitive-motor impairments in Parkinson's disease patients using a computational modelling approach to deep brain stimulation programming.

    PubMed

    Frankemolle, Anneke M M; Wu, Jennifer; Noecker, Angela M; Voelcker-Rehage, Claudia; Ho, Jason C; Vitek, Jerrold L; McIntyre, Cameron C; Alberts, Jay L

    2010-03-01

    Deep brain stimulation in the subthalamic nucleus is an effective and safe surgical procedure that has been shown to reduce the motor dysfunction of patients with advanced Parkinson's disease. Bilateral subthalamic nucleus deep brain stimulation, however, has been associated with declines in cognitive and cognitive-motor functioning. It has been hypothesized that spread of current to nonmotor areas of the subthalamic nucleus may be responsible for declines in cognitive and cognitive-motor functioning. The aim of this study was to assess the cognitive-motor performance in advanced Parkinson's disease patients with subthalamic nucleus deep brain stimulation parameters determined clinically (Clinical) to settings derived from a patient-specific computational model (Model). Data were collected from 10 patients with advanced Parkinson's disease bilaterally implanted with subthalamic nucleus deep brain stimulation systems. These patients were assessed off medication and under three deep brain stimulation conditions: Off, Clinical or Model based stimulation. Clinical stimulation parameters had been determined based on clinical evaluations and were stable for at least 6 months prior to study participation. Model-based parameters were selected to minimize the spread of current to nonmotor portions of the subthalamic nucleus using Cicerone Deep Brain Stimulation software. For each stimulation condition, participants performed a working memory (n-back task) and motor task (force tracking) under single- and dual-task settings. During the dual-task, participants performed the n-back and force-tracking tasks simultaneously. Clinical and Model parameters were equally effective in improving the Unified Parkinson's disease Rating Scale III scores relative to Off deep brain stimulation scores. Single-task working memory declines, in the 2-back condition, were significantly less under Model compared with Clinical deep brain stimulation settings. Under dual-task conditions, force

  4. Radiant energy required for infrared neural stimulation

    PubMed Central

    Tan, Xiaodong; Rajguru, Suhrud; Young, Hunter; Xia, Nan; Stock, Stuart R.; Xiao, Xianghui; Richter, Claus-Peter

    2015-01-01

    Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography was used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm2, respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS. PMID:26305106

  5. Radiant energy required for infrared neural stimulation

    DOE PAGES

    Tan, Xiaodong; Rajguru, Suhrud; Young, Hunter; ...

    2015-08-25

    Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography wasmore » used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm2, respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS.« less

  6. Radiant energy required for infrared neural stimulation.

    PubMed

    Tan, Xiaodong; Rajguru, Suhrud; Young, Hunter; Xia, Nan; Stock, Stuart R; Xiao, Xianghui; Richter, Claus-Peter

    2015-08-25

    Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography was used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm(2), respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS.

  7. Radiant energy required for infrared neural stimulation

    SciTech Connect

    Tan, Xiaodong; Rajguru, Suhrud; Young, Hunter; Xia, Nan; Stock, Stuart R.; Xiao, Xianghui; Richter, Claus-Peter

    2015-08-25

    Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography was used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm2, respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS.

  8. The Neutrophil Nucleus and Its Role in Neutrophilic Function.

    PubMed

    Carvalho, Leonardo Olivieri; Aquino, Elaine Nascimento; Neves, Anne Caroline Dias; Fontes, Wagner

    2015-09-01

    The cell nucleus plays a key role in differentiation processes in eukaryotic cells. It is not the nucleus in particular, but the organization of the genes and their remodeling that provides the data for the adjustments to be made according to the medium. The neutrophil nucleus has a different morphology. It is a multi-lobed nucleus where some researchers argue no longer function. However, studies indicate that it is very probable the occurrence of chromatin remodeling during activation steps. It may be that the human neutrophil nucleus also contributes to the mobility of neutrophils through thin tissue spaces. Questions like these will be discussed in this small review. The topics include morphology of human neutrophil nucleus, maturation process and modifications of the neutrophil nucleus, neutrophil activation and chromatin modifications, causes and consequences of multi-lobulated segmented morphology, and importance of the nucleus in the formation of neutrophil extracellular traps (NETs).

  9. Why do we have a caudate nucleus?

    PubMed

    Villablanca, Jaime R

    2010-01-01

    In order to understand the physiological role of the caudate nucleus, we combine here our laboratory data on cats with reports of patients with selective damage to this nucleus. Cats with bilateral removal of the caudate nuclei showed a stereotyped behavior consisting of persistently approaching and then following a person, another cat, or any object, and attempting to contact the target. Simultaneously, the animals exhibited a friendly disposition and persistent docility together with purring and forelimbs treading/kneading. The magnitude and duration of this behavior was proportional to the extent of the removal reaching a maximum after ablations of 65% or more of the caudate tissue. These cats were hyperactive but they had lost the feline elegance of movements. Additional features of acaudate cats were: (1) postural and accuracy deficits (plus perseveration) in paw usage tasks including bar pressing for food reward; (2) cognitive and perceptual impairments on a T-maze battery of tasks and on the bar pressing tasks; (3) blockage or blunting of the species-specific behavioral response to a single injection of morphine; Unilateral caudate nucleus removal did not produce global behavioral effects, but only deficit in the contralateral paw contact placing reaction and paw usage/bar pressing. Moreover and surprisingly, we found hypertrophy of the ipsilateral caudate nucleus following prenatal focal neocortical removal. The findings in human were also behavioral (not neurological) and also occurred with unilateral caudate damage. The main manifestations consisted of loss of drive (apathy), obsessive-compulsive behavior, cognitive deficits, stimulus-bound perseverative behavior, and hyperactivity. Based on all of the above data we propose that the specific function of the caudate nucleus is to control approach-attachment behavior, ranging from plain approach to a target, to romantic love. This putative function would account well for the caudate involvement in the

  10. Collateral projections from the lateral parabrachial nucleus to the paraventricular thalamic nucleus and the central amygdaloid nucleus in the rat.

    PubMed

    Liang, Shao-Hua; Yin, Jun-Bin; Sun, Yi; Bai, Yang; Zhou, Kai-Xiang; Zhao, Wen-Jun; Wang, Wei; Dong, Yu-Lin; Li, Yun-Qing

    2016-08-26

    Combined the retrograde double tracing with immunofluorescence histochemical staining, we examined the neurons in the lateral parabrachial nucleus (LPB) sent collateral projections to the paraventricular thalamic nucleus (PVT) and central amygdaloid nucleus (CeA) and their roles in the nociceptive transmission in the rat. After the injection of Fluoro-gold (FG) into the PVT and tetramethylrhodamine-dextran (TMR) into the CeA, respectively, FG/TMR double-labeled neurons were observed in the LPB. The percentages of FG/TMR double-labeled neurons to the total number of FG- or TMR-labeled neurons were 6.18% and 9.09%, respectively. Almost all of the FG/TMR double-labeled neurons (95%) exhibited calcitonin gene-related peptide (CGRP) immunoreactivity. In the condition of neuropathic pain, 94% of these neurons showed FOS immunoreactivity. The present data indicates that some of CGRP-expressing neurons in the LPB may transmit nociceptive information toward the PVT and CeA by way of axon collaterals.

  11. Characteristics of rostral solitary tract nucleus neurons with identified afferent connections that project to the parabrachial nucleus in rats.

    PubMed

    Suwabe, Takeshi; Bradley, Robert M

    2009-07-01

    Afferent information derived from oral chemoreceptors is transmitted to second-order neurons in the rostral solitary tract nucleus (rNST) and then relayed to other CNS locations responsible for complex sensory and motor behaviors. Here we investigate the characteristics of rNST neurons sending information rostrally to the parabrachial nucleus (PBN). Afferent connections to these rNST-PBN projection neurons were identified by anterograde labeling of the chorda tympani (CT), glossopharyngeal (IX), and lingual (LV) nerves. We used voltage- and current-clamp recordings in brain slices to characterize the expression of both the transient A-type potassium current, IKA and the hyperpolarization-activated inward current, Ih, important determinants of neuronal repetitive discharge characteristics. The majority of rNST-PBN neurons express IKA, and these IKA-expressing neurons predominate in CT and IX terminal fields but were expressed in approximately half of the neurons in the LV field. rNST-PBN neurons expressing Ih were evenly distributed among CT, IX and LV terminal fields. However, expression patterns of IKA and Ih differed among CT, IX, and LV fields. IKA-expressing neurons frequently coexpress Ih in CT and IX terminal fields, whereas neurons in LV terminal field often express only Ih. After GABAA receptor block all rNST-PBN neurons responded to afferent stimulation with all-or-none excitatory synaptic responses. rNST-PBN neurons had either multipolar or elongate morphologies and were distributed throughout the rNST, but multipolar neurons were more often encountered in CT and IX terminal fields. No correlation was found between the biophysical and morphological characteristics of the rNST-PBN projection neurons in each terminal field.

  12. Activation of c-fos expression in the rat inferior olivary nucleus by ghrelin.

    PubMed

    Zhang, Weizhen; Lin, Theodore R; Hu, Yuexian; Fan, Yongyi; Zhao, Lili; Mulholland, Michael W

    2003-12-26

    Ghrelin, a novel 28-amino-acid hormone secreted by gastric oxyntic glands, stimulates food intake and induces adiposity. We examined whether ghrelin activates the inferior olivary nucleus. Systemic administration of ghrelin (37 nmol/kg) induced the expression of c-fos immunoreactivity in inferior olive neurons (n=6 rats). The number of neurons containing c-fos staining was significantly increased in the ghrelin-treated rats (65+/-14 vs.11+/-6 positive neurons, n=5). No significant difference in c-fos-positive neurons was observed between left (32+/-5) and right (33+/-6) inferior olivary nuclei. The number of c-fos-positive neurons in rats with bilateral vagotomy was not significantly different from those with intact vagal nerves. The present study demonstrates that ghrelin induces c-fos expression in inferior olivary nucleus via a central mechanism.

  13. Cell Nucleus-Targeting Zwitterionic Carbon Dots

    PubMed Central

    Jung, Yun Kyung; Shin, Eeseul; Kim, Byeong-Su

    2015-01-01

    An innovative nucleus-targeting zwitterionic carbon dot (CD) vehicle has been developed for anticancer drug delivery and optical monitoring. The zwitterionic functional groups of the CDs introduced by a simple one-step synthesis using β-alanine as a passivating and zwitterionic ligand allow cytoplasmic uptake and subsequent nuclear translocation of the CDs. Moreover, multicolor fluorescence improves the accuracy of the CDs as an optical code. The CD-based drug delivery system constructed by non-covalent grafting of doxorubicin, exhibits superior antitumor efficacy owing to enhanced nuclear delivery in vitro and tumor accumulation in vivo, resulting in highly effective tumor growth inhibition. Since the zwitterionic CDs are highly biocompatible and effectively translocated into the nucleus, it provides a compelling solution to a multifunctional nanoparticle for substantially enhanced nuclear uptake of drugs and optical monitoring of translocation. PMID:26689549

  14. Cell Nucleus-Targeting Zwitterionic Carbon Dots.

    PubMed

    Jung, Yun Kyung; Shin, Eeseul; Kim, Byeong-Su

    2015-12-22

    An innovative nucleus-targeting zwitterionic carbon dot (CD) vehicle has been developed for anticancer drug delivery and optical monitoring. The zwitterionic functional groups of the CDs introduced by a simple one-step synthesis using β-alanine as a passivating and zwitterionic ligand allow cytoplasmic uptake and subsequent nuclear translocation of the CDs. Moreover, multicolor fluorescence improves the accuracy of the CDs as an optical code. The CD-based drug delivery system constructed by non-covalent grafting of doxorubicin, exhibits superior antitumor efficacy owing to enhanced nuclear delivery in vitro and tumor accumulation in vivo, resulting in highly effective tumor growth inhibition. Since the zwitterionic CDs are highly biocompatible and effectively translocated into the nucleus, it provides a compelling solution to a multifunctional nanoparticle for substantially enhanced nuclear uptake of drugs and optical monitoring of translocation.

  15. Core-nucleus distortation in hypernuclei

    SciTech Connect

    Bodmer, A.R.; Usmani, Q.N.

    1995-08-01

    We are completing a study of the effects of the spherical distortion of the {open_quotes}core{close_quotes} nucleus by the {Lambda} in a hypernucleus. The response of the core was determined by an appropriately chosen energy-density functional which depends, in particular, on the nuclear compressibility. The forcing action of the A is determined by the nuclear density dependence of the {Lambda} binding in nuclear matter which is obtained from our work on the {Lambda} single-particle energies. Because of the strongly repulsive {Lambda}NN forces, this {Lambda} binding {open_quotes}saturates{close_quotes} at a density close to the central density of nuclei, and results in a reduced core-nucleus distortion much less than would otherwise be obtained. The effects of the core distortion then turn out to be very small even for quite light hypernuclei. This result justifies the assumption that spherical core nuclei are effectively undistorted in a hypernucleus.

  16. Finite nucleus effects on relativistic energy corrections

    NASA Technical Reports Server (NTRS)

    Dyall, Kenneth G.; Faegri, Knut, Jr.

    1993-01-01

    The effect of using a finite nucleus model in quantum-chemical calculations is examined. Relativistic corrections from the first order Foldy-Wouthuysen terms are affected indirectly by the change in wavefunction, but also directly as a result of revised expressions for the Darwin and spin-orbit terms due to the change in nuclear potential. A calculation for the Rn atom indicates that the mass-velocity and Darwin corrections are much more sensitive to the finite nucleus than the non-relativistic total energy, but that the total contribution for these two terms is quite stable provided the revised form of the Darwin term is used. The spin-orbit interaction is not greatly affected by the choice of nuclear model.

  17. 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.

  18. 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.

  19. Physical Properties of Cometary Nucleus Candidates

    NASA Technical Reports Server (NTRS)

    Jewitt, David; Hillman, John (Technical Monitor)

    2003-01-01

    In this proposal we aim to study the physical properties of the Centaurs and the dead comets, these being the precursors to, and the remnants from, the active cometary nuclei. The nuclei themselves are very difficult to study, because of the contaminating effects of near-nucleus coma. Systematic investigation of the nuclei both before they enter the zone of strong sublimation and after they have depleted their near-surface volatiles should neatly bracket the properties of these objects, revealing evolutionary effects.

  20. Pygmy dipole response in 238U nucleus

    NASA Astrophysics Data System (ADS)

    Guliyev, Ekber; Kuliev, Ali Akbar; Quliyev, Huseynqulu

    2017-02-01

    The presence of the El pygmy dipole resonance (PDR) in the actinide nucleus 238U was shown via QRPA. Below the particle threshold energy, 24 excitation states were calculated. The calculations, is demonstrating the presence of a PDR with evidence for K splitting. The calculations further suggest that the PDR in 238U is predominantly K=0. The obtained results show universality of the PDR in atomic nuclei.

  1. Absolute cross sections of compound nucleus reactions

    NASA Astrophysics Data System (ADS)

    Capurro, O. A.

    1993-11-01

    The program SEEF is a Fortran IV computer code for the extraction of absolute cross sections of compound nucleus reactions. When the evaporation residue is fed by its parents, only cumulative cross sections will be obtained from off-line gamma ray measurements. But, if one has the parent excitation function (experimental or calculated), this code will make it possible to determine absolute cross sections of any exit channel.

  2. Development of a Mobile Ice Nucleus Counter

    SciTech Connect

    Kok, Gregory; Kulkarni, Gourihar

    2014-07-10

    An ice nucleus counter has been constructed. The instrument uses built-in refrigeration systems for wall cooling. A cascade refrigeration system will allow the cold wall to operate as low as -70°C, and a single stage system can operate the warm wall at -45C. A unique optical particle counter has been constructed using polarization detection of the scattered light. This allows differentiation of the particles exiting the chamber to determine if they are ice or liquid.

  3. How to build a yeast nucleus.

    PubMed

    Wong, Hua; Arbona, Jean-Michel; Zimmer, Christophe

    2013-01-01

    Biological functions including gene expression and DNA repair are affected by the 3D architecture of the genome, but the underlying mechanisms are still unknown. Notably, it remains unclear to what extent nuclear architecture is driven by generic physical properties of polymers or by specific factors such as proteins binding particular DNA sequences. The budding yeast nucleus has been intensely studied by imaging and biochemical techniques, resulting in a large quantitative data set on locus positions and DNA contact frequencies. We recently described a quantitative model of the interphase yeast nucleus in which chromosomes are represented as passively moving polymer chains. This model ignores the DNA sequence information except for specific constraints at the centromeres, telomeres, and the ribosomal DNA (rDNA). Despite its simplicity, the model accounts for a large majority of experimental data, including absolute and relative locus positions and contact frequency patterns at chromosomal and subchromosomal scales. Here, we also illustrate the model's ability to reproduce observed features of chromatin movements. Our results strongly suggest that the dynamic large-scale architecture of the yeast nucleus is dominated by statistical properties of randomly moving polymers with a few sequence-specific constraints, rather than by a large number of DNA-specific factors or epigenetic modifications. In addition, we show that our model accounts for recently measured variations in homologous recombination efficiency, illustrating its potential for quantitatively understanding functional consequences of nuclear architecture.

  4. Comet nucleus and asteroid sample return missions

    NASA Astrophysics Data System (ADS)

    1992-06-01

    Three Advanced Design Projects have been completed this academic year at Penn State. At the beginning of the fall semester the students were organized into eight groups and given their choice of either a comet nucleus or an asteroid sample return mission. Once a mission had been chosen, the students developed conceptual designs. These were evaluated at the end of the fall semester and combined into three separate mission plans, including a comet nucleus same return (CNSR), a single asteroid sample return (SASR), and a multiple asteroid sample return (MASR). To facilitate the work required for each mission, the class was reorganized in the spring semester by combining groups to form three mission teams. An integration team consisting of two members from each group was formed for each mission so that communication and information exchange would be easier among the groups. The types of projects designed by the students evolved from numerous discussions with Penn State faculty and mission planners at the Johnson Space Center Human/Robotic Spacecraft Office. Robotic sample return missions are widely considered valuable precursors to manned missions in that they can provide details about a site's environment and scientific value. For example, a sample return from an asteroid might reveal valuable resources that, once mined, could be utilized for propulsion. These missions are also more adaptable when considering the risk to humans visiting unknown and potentially dangerous locations, such as a comet nucleus.

  5. Theoretical predictions for the nucleus 296118

    NASA Astrophysics Data System (ADS)

    Sobiczewski, A.

    2016-11-01

    Theoretical predictions for the α -decay chain of the nucleus 296118 are performed. The synthesis of this nucleus is being attempted in experiments running in Dubna. The α -decay energies Qα, and the α -decay and spontaneous-fission half-lives, Tα and Tsf, are studied. The analysis of the α decay is based on a phenomenological model using only three parameters. The calculations are performed in nine variants using masses obtained within nine nuclear-mass models describing masses of the heaviest nuclei. The experimental Qα energies, known from earlier experiments for the potential daughter, 292Lv, and grand-daughter, 288Fl, nuclei are reproduced with an average of the absolute values of the discrepancies: from 0.13 to 1.52 MeV within the considered variants. Measured half-lives Tα are reconstructed within average ratios: from 1.7 to 1054. Within all variants considered, the half-life Tα of the nucleus 296118 is obtained larger than needed (around 1 μ s ) for its observation.

  6. Comet nucleus and asteroid sample return missions

    NASA Technical Reports Server (NTRS)

    1992-01-01

    Three Advanced Design Projects have been completed this academic year at Penn State. At the beginning of the fall semester the students were organized into eight groups and given their choice of either a comet nucleus or an asteroid sample return mission. Once a mission had been chosen, the students developed conceptual designs. These were evaluated at the end of the fall semester and combined into three separate mission plans, including a comet nucleus same return (CNSR), a single asteroid sample return (SASR), and a multiple asteroid sample return (MASR). To facilitate the work required for each mission, the class was reorganized in the spring semester by combining groups to form three mission teams. An integration team consisting of two members from each group was formed for each mission so that communication and information exchange would be easier among the groups. The types of projects designed by the students evolved from numerous discussions with Penn State faculty and mission planners at the Johnson Space Center Human/Robotic Spacecraft Office. Robotic sample return missions are widely considered valuable precursors to manned missions in that they can provide details about a site's environment and scientific value. For example, a sample return from an asteroid might reveal valuable resources that, once mined, could be utilized for propulsion. These missions are also more adaptable when considering the risk to humans visiting unknown and potentially dangerous locations, such as a comet nucleus.

  7. Resting state functional MRI in Parkinson's disease: the impact of deep brain stimulation on 'effective' connectivity.

    PubMed

    Kahan, Joshua; Urner, Maren; Moran, Rosalyn; Flandin, Guillaume; Marreiros, Andre; Mancini, Laura; White, Mark; Thornton, John; Yousry, Tarek; Zrinzo, Ludvic; Hariz, Marwan; Limousin, Patricia; Friston, Karl; Foltynie, Tom

    2014-04-01

    Depleted of dopamine, the dynamics of the parkinsonian brain impact on both 'action' and 'resting' motor behaviour. Deep brain stimulation has become an established means of managing these symptoms, although its mechanisms of action remain unclear. Non-invasive characterizations of induced brain responses, and the effective connectivity underlying them, generally appeals to dynamic causal modelling of neuroimaging data. When the brain is at rest, however, this sort of characterization has been limited to correlations (functional connectivity). In this work, we model the 'effective' connectivity underlying low frequency blood oxygen level-dependent fluctuations in the resting Parkinsonian motor network-disclosing the distributed effects of deep brain stimulation on cortico-subcortical connections. Specifically, we show that subthalamic nucleus deep brain stimulation modulates all the major components of the motor cortico-striato-thalamo-cortical loop, including the cortico-striatal, thalamo-cortical, direct and indirect basal ganglia pathways, and the hyperdirect subthalamic nucleus projections. The strength of effective subthalamic nucleus afferents and efferents were reduced by stimulation, whereas cortico-striatal, thalamo-cortical and direct pathways were strengthened. Remarkably, regression analysis revealed that the hyperdirect, direct, and basal ganglia afferents to the subthalamic nucleus predicted clinical status and therapeutic response to deep brain stimulation; however, suppression of the sensitivity of the subthalamic nucleus to its hyperdirect afferents by deep brain stimulation may subvert the clinical efficacy of deep brain stimulat