Search

Deep brain stimulation (DBS) is among the most successful paradigms in both translational and reverse translational neuroscience. DBS has developed into a standard treatment for movement disorders such as Parkinson's disease (PD) in recent decades, however, specific mechanisms behind DBS's efficacy and side effects remain unrevealed. Several hypotheses have been proposed, including neuronal firing rate and pattern theories that emphasize the impact of DBS on local circuitry but detail distant electrophysiological readouts to a lesser extent. Furthermore, ample preclinical and clinical evidence indicates that DBS influences neurotransmitter dynamics in PD, particularly the effects of subthalamic nucleus (STN) DBS on striatal dopaminergic and glutamatergic systems; pallidum DBS on striatal dopaminergic and GABAergic systems; pedunculopontine nucleus DBS on cholinergic systems; and STN-DBS on locus coeruleus (LC) noradrenergic system. DBS has additionally been associated with mood-related side effects within brainstem serotoninergic systems in response to STN-DBS. Still, addressing the mechanisms of DBS on neurotransmitters' dynamics is commonly overlooked due to its practical difficulties in monitoring real-time changes in remote areas. Given that electrical stimulation alters neurotransmitter release in local and remote regions, it eventually exhibits changes in specific neuronal functions. Consequently, such changes lead to further modulation, synthesis, and release of neurotransmitters. This narrative review discusses the main neurotransmitter dynamics in PD and their role in mediating DBS effects from preclinical and clinical data.

This Practice Advisory presents a comprehensive and evidence-based set of position statements and recommendations for the use of contrast media in interventional pain procedures. The advisory was established by an international panel of experts under the auspices of 11 multinational and multispecialty organizations based on a comprehensive review of the literature up to December 31, 2019. The advisory discusses the risks of using gadolinium-based contrast agents. These include nephrogenic systemic fibrosis, gadolinium brain deposition/retention, and encephalopathy and death after an unintentional intrathecal gadolinium injection. The advisory provides recommendations on the selection of a specific gadolinium-based contrast agent in patients with renal insufficiency, those who had multiple gadolinium-enhanced magnetic resonance imaging examinations, and in cases of paraspinal injections. Additionally, recommendations are made for patients who have a history of mild, moderate, or severe hypersensitivity reactions to contrast medium.

Stereotactic lesioning of the bilateral globus pallidus (GPi) was one of the first surgical treatments for medication-refractory dystonia but has largely been abandoned in clinical practice after the introduction of deep brain stimulation (DBS). However, some patients with dystonia are not eligible for DBS. Therefore, we reviewed the efficacy, safety, and sustainability of bilateral pallidotomy by conducting a systematic review of individual patient data (IPD). Guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and IPD were followed. In May 2020, Medline, Embase, Web of Science, and Cochrane Library were searched for studies reporting on outcome of bilateral pallidotomy for dystonia. If available, IPD were collected. In this systematic review, 100 patients from 33 articles were evaluated. Adverse events were reported in 20 patients (20%), of which 8 were permanent (8%). Pre-and postoperative Burke-Fahn-Marsden Dystonia Rating Movement Scale scores were available for 53 patients. A clinically relevant improvement (>20%) of this score was found in 42 of 53 patients (79%). Twenty-five patients with status dystonicus (SD) were described. In all but 2 the SD resolved after bilateral pallidotomy. Seven patients experienced a relapse of SD. Median-reported follow-up was 12 months (n = 83; range: 2-180 months). Based on the current literature, bilateral pallidotomy is an effective and relatively safe procedure for certain types of dystonia, particularly in medication-refractory SD. Although due to publication bias the underreporting of negative outcomes is very likely, bilateral pallidotomy is a reasonable alternative to DBS in selected dystonia patients. (c) 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Stereotactic lesioning of the bilateral globus pallidus (GPi) was one of the first surgical treatments for medication‐refractory dystonia but has largely been abandoned in clinical practice after the introduction of deep brain stimulation (DBS). However, some patients with dystonia are not eligible for DBS. Therefore, we reviewed the efficacy, safety, and sustainability of bilateral pallidotomy by conducting a systematic review of individual patient data (IPD). Guidelines of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses and IPD were followed. In May 2020, Medline, Embase, Web of Science, and Cochrane Library were searched for studies reporting on outcome of bilateral pallidotomy for dystonia. If available, IPD were collected. In this systematic review, 100 patients from 33 articles were evaluated. Adverse events were reported in 20 patients (20%), of which 8 were permanent (8%). Pre‐and postoperative Burke‐Fahn‐Marsden Dystonia Rating Movement Scale scores were available for 53 patients. A clinically relevant improvement (>20%) of this score was found in 42 of 53 patients (79%). Twenty‐five patients with status dystonicus (SD) were described. In all but 2 the SD resolved after bilateral pallidotomy. Seven patients experienced a relapse of SD. Median‐reported follow‐up was 12 months (n = 83; range: 2–180 months). Based on the current literature, bilateral pallidotomy is an effective and relatively safe procedure for certain types of dystonia, particularly in medication‐refractory SD. Although due to publication bias the underreporting of negative outcomes is very likely, bilateral pallidotomy is a reasonable alternative to DBS in selected dystonia patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

AIM: To investigate the effects of subthalamic deep brain stimulation (STN DBS) therapy on sleep quality of Parkinson\"s Disease (PD) patients and the relationship between sleep, motor symptoms, depression, and adverse effects of dopamine replacement therapies. MATERIAL and METHODS: A total of 26 PD patients have been included and assessed using various tools both 1 week before and 8 months after the STN DBS therapy. The data collection tools were the Unified Parkinson\"s Disease Rating Scale (UPDRS), Beck Depression Inventory (BDI), Montreal Cognitive Assessment (MoCA), Parkinson\"s Disease Questionnaire (PDQ-39), Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS) and Polysomnography. RESULTS: PSQI, ISI, and ESS scores were found to have significantly improved after the STN DBS therapy (p=0.002, p=0.006, p

Deep brain stimulation (DBS) is among the most successful paradigms in both translational and reverse translational neuroscience. DBS has developed into a standard treatment for movement disorders such as Parkinson’s disease (PD) in recent decades, however, specific mechanisms behind DBS’s efficacy and side effects remain unrevealed. Several hypotheses have been proposed, including neuronal firing rate and pattern theories that emphasize the impact of DBS on local circuitry but detail distant electrophysiological readouts to a lesser extent. Furthermore, ample preclinical and clinical evidence indicates that DBS influences neurotransmitter dynamics in PD, particularly the effects of subthalamic nucleus (STN) DBS on striatal dopaminergic and glutamatergic systems; pallidum DBS on striatal dopaminergic and GABAergic systems; pedunculopontine nucleus DBS on cholinergic systems; and STN-DBS on locus coeruleus (LC) noradrenergic system. DBS has additionally been associated with mood-related side effects within brainstem serotoninergic systems in response to STN-DBS. Still, addressing the mechanisms of DBS on neurotransmitters’ dynamics is commonly overlooked due to its practical difficulties in monitoring real-time changes in remote areas. Given that electrical stimulation alters neurotransmitter release in local and remote regions, it eventually exhibits changes in specific neuronal functions. Consequently, such changes lead to further modulation, synthesis, and release of neurotransmitters. This narrative review discusses the main neurotransmitter dynamics in PD and their role in mediating DBS effects from preclinical and clinical data.

Background: Deep brain stimulation (DBS) is an accepted treatment for patients with medication-resistant Tourette syndrome (TS). Sedation is commonly required during electrode implantation to attenuate anxiety, pain, and severe tics. Anesthetic agents potentially impair the quality of microelectrode recordings (MER). Little is known about the effect of these anesthetics on MER in patients with TS. We describe our experience with different sedative regimens on MER and tic severity in patients with TS. Methods: The clinical records of all TS patients who underwent DBS surgery between 2010 and 2018 were reviewed. Demographic data, stimulation targets, anesthetic agents, perioperative complications, and MER from each hemisphere were collected and analyzed. Single-unit activity was identified by filtering spiking activity from broadband MER data and principal component analysis with K-means clustering. Vocal and motor tics which caused artifacts in the MER data were manually selected using visual and auditory inspection. Results: Six patients underwent bilateral DBS electrode implantation. In all patients, the target was the anterior internal globus pallidus. Patient comfort and hemodynamic and respiratory stability were maintained with conscious sedation with one or more of the following anesthetic drugs: propofol, midazolam, remifentanil, clonidine, and dexmedetomidine. Good quality MER and clinical testing were obtained in 9 hemispheres of 6 patients. In 3 patients, MER quality was poor on one side. Conclusion: Cautiously applied sedative drugs can provide patient comfort, hemodynamic and respiratory stability, and suppress severe tics, with minimal interference with MER.

Background and Purpose l-DOPA prolonged treatment leads to disabling motor complications as dyskinesia that could be decreased by drugs acting on 5-HT1A receptors. Since the internal segment of the globus pallidus, homologous to the entopeduncular nucleus in rodents, seems to be involved in the etiopathology of l-DOPA-induced dyskinesia, we investigated whether the entopeduncular nucleus is modulated by the 5-HT1A receptor partial and full agonists, buspirone, and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) in control and 6-hydroxydopamine (6-OHDA)-lesioned rats with or without long-term l-DOPA treatment. Experimental Approach Extracellular single-unit electrocorticogram and local field potential recordings under anaesthesia, immunostaining assays and optogenetic manipulation coupled to electrophysiological recordings were performed. Key Results Systemic buspirone reduced the entopeduncular nucleus firing rate in the sham animals and burst activity in the 6-OHDA-lesioned rats (with or without l-DOPA treatment), while local administration reduced entopeduncular nucleus activity in all the groups, regardless of DA integrity. Systemic 8-OH-DPAT also induced inhibitory effects only in the sham animals. Effects triggered by buspirone and 8-OH-DPAT were reversed by the 5-HT1A receptor antagonist, WAY-100635. Neither buspirone nor 8-OH-DPAT modified the low-frequency oscillatory activity in the entopeduncular nucleus or its synchronization with the motor cortex. Buspirone did not alter the response induced by subthalamic nucleus opto-stimulation in the entopeduncular nucleus. Conclusion and Implications Systemic 5-HT1A receptor activation elicits different effects on the electrophysiological properties of the entopeduncular nucleus depending on the integrity of the nigrostriatal pathway and it does not alter the relationship between subthalamic nucleus and entopeduncular nucleus neuron activity. Euskal Herriko Unibertsitatea, Grant/Award Number: GIU19/092; Basque Government, Grant/Award Numbers: PIBA 2019-38, T747-13; Spanish Ministry of Economy and Competitiveness, Grant/Award Number: SAF2016-77758-R AEI/FEDER, UE

The basal ganglia (BG) are involved in cognitive/motivational functions in addition to movement control. Thus, BG segregated circuits, the sensorimotor (SM) and medial prefrontal (mPF) circuits, process different functional domains, such as motor and cognitive/motivational behaviours, respectively. With a high presence in the BG, the CB1 cannabinoid receptor modulates BG circuits. Furthermore, dopamine (DA), one of the principal neurotransmitters in the BG, also plays a key role in circuit functionality. Taking into account the interaction between DA and the endocannabinoid system at the BG level, we investigated the functioning of BG circuits and their modulation by the CB1 receptor under DA-depleted conditions. We performed single-unit extracellular recordings of substantia nigra pars reticulata (SNr) neurons with simultaneous cortical stimulation in sham and 6-hydroxydopamine (6-OHDA)-lesioned rats, together with immunohistochemical assays. We showed that DA loss alters cortico-nigral information processing in both circuits, with a predominant transmission through the hyperdirect pathway in the SM circuit and an increased transmission through the direct pathway in the mPF circuit. Moreover, although DA denervation does not change CB1 receptor density, it impairs its functionality, leading to a lack of modulation. These data highlight an abnormal transfer of information through the associative/limbic domains after DA denervation that may be related to the non-motor symptoms manifested by Parkinson's disease patients. This study was supported by grants from the Basque Government (PIBA 2019-38), the University of the Basque Country (GIU19/092), and the MINECO fund SAF2016-77758-R (AEI/FEDER, UE). M.A, has a fellowship from the MECD.

7 Tesla (7T) magnetic resonance imaging holds great promise for improved visualization of the human brain for clinical purposes. To assess whether 7T is superior regarding localization procedures of small brain structures, we compared manual parcellations of the red nucleus, subthalamic nucleus, substantia nigra, globus pallidus interna and externa. These parcellations were created on a commonly used clinical anisotropic clinical 3T with an optimized isotropic (o)3T and standard 7T scan. The clinical 3T MRI scans did not allow delineation of an anatomically plausible structure due to its limited spatial resolution. o3T and 7T parcellations were directly compared. We found that 7T outperformed the o3T MRI as reflected by higher Dice scores, which were used as a measurement of interrater agreement for manual parcellations on quantitative susceptibility maps. This increase in agreement was associated with higher contrast to noise ratios for smaller structures, but not for the larger globus pallidus segments. Additionally, control-analyses were performed to account for potential biases in manual parcellations by assessing semi-automatic parcellations. These results showed a higher consistency for structure volumes for 7T compared to optimized 3T which illustrates the importance of the use of isotropic voxels for 3D visualization of the surgical target area. Together these results indicate that 7T outperforms c3T as well as o3T given the constraints of a clinical setting.

We investigated modulation of functional neuronal connectivity by a proprioceptive stimulus in sixteen young people with dystonia and eight controls. A robotic wrist interface delivered controlled passive wrist extension movements, the onset of which was synchronised with scalp EEG recordings. Data were segmented into epochs around the stimulus and up to 160 epochs per subject were averaged to produce a Stretch Evoked Potential (StretchEP). Event-related network dynamics were estimated using a methodology that features Wavelet Transform Coherency (WTC). Global Microscale Nodal Strength (GMNS) was introduced to estimate overall engagement of areas into short-lived networks related to the StretchEP, and Global Connectedness (GC) estimated the spatial extent of the StretchEP networks. Dynamic Connectivity Maps showed a striking difference between dystonia and controls, with particularly strong theta band event-related connectivity in dystonia. GC also showed a trend towards higher values in dystonia than controls. In summary, we demonstrate the feasibility of this method to investigate event-related neuronal connectivity in relation to a proprioceptive stimulus in a paediatric patient population. Young people with dystonia show an exaggerated network response to a proprioceptive stimulus, displaying both excessive theta-band synchronisation across the sensorimotor network and widespread engagement of cortical regions in the activated network.

Deep brain stimulation (DBS) of the subthalamic nucleus is a neurosurgical intervention for Parkinson’s disease patients who no longer appropriately respond to drug treatments. A small fraction of patients will fail to respond to DBS, develop psychiatric and cognitive side-effects, or incur surgery-related complications such as infections and hemorrhagic events. In these cases, DBS may require recalibration, reimplantation, or removal. These negative responses to treatment can partly be attributed to suboptimal pre-operative planning procedures via direct targeting through low-field and low-resolution magnetic resonance imaging (MRI). One solution for increasing the success and efficacy of DBS is to optimize preoperative planning procedures via sophisticated neuroimaging techniques such as high-resolution MRI and higher field strengths to improve visualization of DBS targets and vasculature. We discuss targeting approaches, MRI acquisition, parameters, and post-acquisition analyses. Additionally, we highlight a number of approaches including the use of ultra-high field (UHF) MRI to overcome limitations of standard settings. There is a trade-off between spatial resolution, motion artifacts, and acquisition time, which could potentially be dissolved through the use of UHF-MRI. Image registration, correction, and post-processing techniques may require combined expertise of traditional radiologists, clinicians, and fundamental researchers. The optimization of pre-operative planning with MRI can therefore be best achieved through direct collaboration between researchers and clinicians.

Summary Early studies posited a relationship between sleep and the basal ganglia, but this relationship has received little attention recently. It is timely to revisit this relationship, given new insights into the functional anatomy of the basal ganglia and the physiology of sleep, which has been made possible by modern techniques such as chemogenetic and optogenetic mapping of neural circuits in rodents and intracranial recording, functional imaging, and a better understanding of human sleep disorders. We discuss the functional anatomy of the basal ganglia, and review evidence implicating their role in sleep. Whilst these studies are in their infancy, we suggest that the basal ganglia may play an integral role in the sleep-wake cycle, specifically by contributing to a thalamo-cortical-basal ganglia oscillatory network in slow-wave sleep which facilitates neural plasticity, and an active state during REM sleep which enables the enactment of cognitive and emotional networks. A better understanding of sleep mechanisms may pave the way for more effective neuromodulation strategies for sleep and basal ganglia disorders.

Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD) patients with motor fluctuations and dyskinesias. The key DBS efficacy studies were performed in PD patients with unknown genotypes; however, given the estimated monogenic mutation prevalence of approximately 5-10%, most commonly LRRK2, PRKN, PINK1 and SNCA, and risk-increasing genetic factors such as GBA, proper characterization is becoming increasingly relevant. We performed a systematic review of 46 studies that reported DBS effects in 221 genetic PD patients. The results suggest that monogenic PD patients have variable DBS benefit depending on the mutated gene. Outcome appears excellent in patients with the most common LRRK2 mutation, p.G2019S, and good in patients with PRKN mutations but poor in patients with the more rare LRRK2 p.R1441G mutation. The overall benefit of DBS in SNCA, GBA and LRRK2 p.T2031S mutations may be compromised due to rapid progression of cognitive and neuropsychiatric symptoms. In the presence of other mutations, the motor changes in DBS-treated monogenic PD patients appear comparable to those of the general PD population.

Background Although deep brain stimulation of the globus pallidus internus (GPi-DBS) is an established treatment for many forms of dystonia, including generalized as well as focal forms, its effects on brain (dys-)function remain to be elucidated, particularly for focal and segmental dystonia. Clinical response to GPi-DBS typically comes with some delay and lasts up to several days, sometimes even weeks, once stimulation is discontinued. Objective This study investigated how neural activity during rest and motor activation is affected by GPi-DBS while excluding the potential confound of altered feedback as a result of therapy-induced differences in dystonic muscle contractions. Methods Two groups of patients with focal or segmental dystonia were included in the study: 6 patients with GPi-DBS and 8 without DBS (control group). All 14 patients had cervical dystonia. Using (H2O)-O-15 PET, regional cerebral blood flow was measured at rest and during a motor task performed with a nondystonic hand. Results In patients with GPi-DBS (stimulation ON and OFF), activity at rest was reduced in a prefrontal network, and during the motor task, sensorimotor cortex activity was lower than in patients without DBS. Within-group contrasts (tapping > rest) showed less extensive task-induced motor network activation in GPi-DBS patients than in non-DBS controls. Reduced sensorimotor activation amounted to a significant group-by-task interaction only in the stimulation ON state. Conclusions These findings support previous observations in generalized dystonia that suggested that GPi-DBS normalizes dystonia-associated sensorimotor and prefrontal hyperactivity, indicating similar mechanisms in generalized and focal or segmental dystonia. Evidence is provided that these effects extend into the OFF state, which was not previously demonstrated by neuroimaging. (c) 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Objective Thalamic deep brain stimulation (DBS) is effective in reducing tics in patients with refractory Tourette syndrome at the short-term. Here, we report on the long-term outcome. Materials and Methods Seven patients underwent bilateral DBS between 2001 and 2008. The target was the centromedian nucleus, substantia periventricularis and nucleus ventro-oralis internus cross point of the thalamus. The effect on tics and side effects were evaluated with a variable follow-up duration of 12 to 78 months. Results Patient 1 and 2 showed good tic improvements of 81.6% (60 months) and 50% (36 months), respectively. However, side effects like reducing levels of energy and visual disturbances increased. In patient 1, the target was changed to the anterior part of the internal pallidum and patient 2 switched the stimulator permanently off. Patient 3 experiences still satisfying results with a tic improvement of 88.9% (78 months). Patient 4 and 7 showed minor tic improvements of 34% (16 months) and 9% (60 months), respectively. In both patients side effects became more severe and the target was changed to the anterior part of the internal pallidum. Patient 5 showed a tic improvement of 27.5% (12 months) and went abroad for stimulation of the external globus pallidus. Patient 6 developed cerebellar atrophy. He experienced several nonstimulation related side effects and turned the stimulator off. Conclusions There seems to be an increasing disbalance of therapeutic effects and side effects at long-term follow-up, often leading to either switching the stimulator off or new surgery with a different neuro-anatomic target.

Non-intervention-related effects have long been recognized in an array of medical interventions, to which surgical procedures like deep-brain stimulation are no exception. While the existence of placebo and micro-lesion effects has been convincingly demonstrated in DBS for major depression and Parkinson's disease, systematic investigations for obsessive-compulsive disorder (OCD) are currently lacking. We therefore undertook an individual patient data meta-analysis with the aim of quantifying the effect of DBS for severe, treatment-resistant OCD that is not due to the electrical stimulation of brain tissue. The MEDLINE/PubMed database was searched for double-blind, sham-controlled randomized clinical trials published in English between 1998 and 2018. Individual patient data was obtained from the original authors and combined in a meta-analysis. We assessed differences from baseline in obsessive-compulsive symptoms following sham treatment, as measured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Four studies met the inclusion criteria, randomizing 49 patients to two periods of active or sham stimulation. To preclude confounding by period effects, our estimate was based only on data from those patients who underwent sham stimulation first (n = 24). We found that sham stimulation induced a significant change in the Y-BOCS score (t = -3.15, P

Is motor response inhibition supported by a specialised neuronal inhibitory control mechanism, or by a more general system of action updating? This pre-registered study employed a context-cueing paradigm requiring both inhibitory and non-inhibitory action updating in combination with functional magnetic resonance imaging to test the specificity of responses under different updating conditions, including the cancellation of actions. Cortical regions of activity were found to be common to multiple forms of action updating. However, functional specificity during response inhibition was observed in the anterior right inferior frontal gyrus. In addition, fronto-subcortical activity was explored using a novel contrast method. These exploratory results indicate that the specificity for response inhibition observed in right prefrontal cortex continued downstream and was observed in right hemisphere subcortical activity, while left hemisphere activity was associated with right-hand response execution. Overall, our findings reveal both common and distinct correlates of response inhibition in prefrontal cortex, with exploratory analyses supporting putative models of subcortical pathways and extending them through the demonstration of lateralisation., Highlights • Anterior specificity in cortical activity to response inhibition was identified. • Methodological development of a compound contrast methodology optimising data usage. • Exploratory demonstration of lateralised subcortical action control pathways.

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. (C) 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd.

Exaggerated activity in the beta band (13-35 Hz) is a hallmark of basal ganglia signals in patients with Parkinson's disease (PD). Beta activity however is not constantly elevated, but comes in bursts. In previous work we showed that the longer beta bursts are maintained, the more the oscillatory synchronisation within the subthalamic nucleus (STN) increases, which is posited to limit the information coding capacity of local circuits. Accordingly, a higher incidence of longer bursts correlates positively with clinical impairment, while the opposite is true for short, more physiological bursts. Here, we test the hypothesis that beta bursts not only indicate local synchronisation within the STN, but also phasic coupling across the motor network and hence entail an even greater restriction of information coding capacity in patients with PD. Local field potentials from the subthalamic nucleus and EEG over the motor cortex area were recorded in nine PD patients after temporary lead externalization after surgery for deep brain stimulation and overnight withdrawal of levodopa. Beta bursts were defined as periods exceeding the 75th percentile of signal amplitude and the coupling between bursts was considered using two distinct measurements, first the % overlapping (%OVL) as a feature of the amplitude coupling and secondly the phase synchrony index (PSI) to measure the phase coupling between regions. %OVL between STN and cortex and between the left and the right STN was higher than expected between the regions than if they had been independent. Similarly, PSI was higher during bursts as opposed to non-bursts periods. In addition, %OVL was greater for long compared to short bursts. Our results support the hypothesis that beta bursts involve long-range coupling between structures in the basal ganglia-cortical network. The impact of this is greater during long as opposed to short duration beta bursts. Accordingly, we posit that episodes of simultaneously elevated coupling across multiple structures in the basal ganglia-cortical circuit further limit information coding capacity and may have further impact upon motor impairment. ispartof: NEUROBIOLOGY OF DISEASE vol:117 pages:217-225 ispartof: location:United States status: published

Objective: Three patients with intractable Tourette syndrome (TS) underwent thalamic deep brain stimulation (DBS). To investigate the role of thalamic electrical activity in tic generation, local field potentials (LFP), EEG and EMG simultaneously were recorded.Methods: Event related potentials and event related spectral perturbations of EEG and LFP, event related cross-coherences between EEG/LFP and LFP/LFP were analyzed. As time locking events, the tic onsets were used. Spontaneous tics were compared to voluntary tic mimicking. The effect of tic suppression and DBS on thalamic LFPs was evaluated.Results: All three patients showed time-locked and prior to onset of spontaneous motor tics thalamic synchronization and thalamo-cortical cross-coherence. Also in three patients, not time-locked to motor tics, increased intra-thalamic coherences in the 1-8 Hz frequency band were found. In one patient it was demonstrated that voluntary mimicked tics were preceded by premotor cortical and thalamic potentials. In this patient unilateral thalamic DBS contralaterally decreased the background thalamic activity.Conclusions: The present study in three cases with TS shows that spontaneous tics in TS are preceded by repetitive coherent thalamo-cortical discharges, indicating that preceding a tic the basal ganglia circuits are "charged up", ultimately leading to a motor tic.Significance: Thalamic LFP recording may lead to more insight in underlying pathophysiological mechanisms in TS. (c) 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Cervical dystonia is a movement disorder which affects daily living of many patients. In clinical practice several unmet treatment needs remain open. This article focusses on the four main aspects of treatment. We describe existing and emerging treatment approaches for cervical dystonia, including botulinum toxin injections, surgical therapy, management of non-motor symptoms and rehabilitation strategies. The unsolved issues regarding each of these treatments are identified and discussed, and possible future approaches and research lines are proposed.

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 300Hz. 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 magneto-encephalography to look at functional interactions between the subthalamic nucleus and ipsilateral motor cortex. Results 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 magneto-encephalography to look at functional interactions between the subthalamic nucleus and ipsilateral motor cortex. 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.

We aimed to test the hypothesis that the cerebral selection of movement includes active suppression of unwanted movements. To that end, a cerebral activation paradigm was used in which index finger flexion was compared with similar movement, made together with fingers 3, 4, 5. Cerebral activations were assessed by positron emission tomography (PET) measurements of cerebral perfusion in 10 healthy subjects, during the two motor tasks and rest. Statistical parametric mapping (SPM) revealed significant increase of (antero)medial prefrontal activity and subtle changes in pallidum and thalamus in the condition of less movement, i.e. isolated index finger flexion contrasted to full-hand flexion. These increases indicated a mechanism of selection mediated by active suppression of unwanted movements. Suppression of all motor responses was inferred from anterolateral prefrontal activation related to rest (with only auditory cues), contrasted to both motor conditions. This segregation of inhibitory functions specifies the complementary character of response selection and inhibitory control, in such a way, that towards the medial prefrontal surface, a transition from general to increasingly selective inhibition allows the internal ordering of action. (c) 2006 Elsevier B.V. All rights reserved.

The subthalamic nucleus (STN) is currently the preferred target for chronic electrical high-frequency stimulation in Parkinson's disease. Anatomical determination of the exact position of the STN in the. individual patient, using magnetic resonance imaging, remains cumbersome, whereas calculation of the target using a stereotactic atlas bypasses patient interindividual variations in the exact delineation of the STN. The aim Of this Study was to demonstrate variations in shape and position of the STN during life. In this anatomopathological study, a method was applied to localize the STN in reference to the anterior commissure-posterior commissure line (AC-PC line) in 12 postmortem brains of patients who died of non-neurological diseases. Their age varied from 29 to 84 years. Centers and borders of the STN were macroscopically measured in three spatial orthogonal planes in relation to the AC-PC line, and verified by light microscopy. The AC-PC distance remains almost constant during life (24.4 mm; SD 3.58). With increasing age, the center of the STN tends to move 3.9 mm cranially, 2.6 mm laterally, and 0.2 mm anteriorly. This last result also differs from the position mentioned in the stereotactic brain atlases. The form of the STN also changes. During life, the STN becomes wider in the mediolateral direction and smaller in the superior-inferior and anterior-posterior direction. The shape and spatial position of the STN also change during life. These changes should be taken into account during target determination in deep brain stimulation procedures in Parkinson's disease. (c) 2005 Movement Disorder Society.

Dystonia of the limbs may be due to a wide range of aetiologies and may cause major functional limitation. We investigated whether the previously described pathological 4 to 7 Hz drive to muscles in cervical dystonia is present in patients with aetiologically different types of dystonia of the upper and lower limbs. To this end, we studied 12 symptomatic and 4 asymptomatic carriers of the DYT l gene, 6 patients with symptomatic dystonia due to focal basal ganglia lesions, and 11 patients with fixed dystonia, a condition assumed to be mostly psychogenic in aetiology. We evaluated EMG-EMG coherence in the tibialis anterior (TA) of these and 15 healthy control subjects. Ten of 12 (83%) of symptomatic DYT1 patients had an excessive 4 to 7 Hz common drive to TA, evident as an inflated coherence in this band. This drive also involved the gastrocnemius, leading to co-contracting electromyographic bursts. In contrast, asymptomatic DYT1 carriers, patients with symptomatic dystonia, patients with fixed dystonia, and healthy subjects showed no evidence of such a drive or any other distinguishing electrophysiological feature. Moreover, the pathological 4 to 7 Hz drive in symptomatic DYT1 patients was much less common in the upper limb, where it was only present in 2 of 6 (33%) patients with clinical involvement of the arms. We conclude that the nature of the abnormal drive to dystonic muscles may vary according to the, muscles under consideration and, particularly, with aetiology. (C) 2004 Movement Disorder Society.

Objective: To compare the efficacy of unilateral pallidotomy and bilateral subthalamic nucleus (STN) stimulation in patients with advanced Parkinson disease (PD) in a randomized, observer-blind, multicenter trial. Methods: Thirty-four patients with advanced PD were randomly assigned to have unilateral pallidotomy or bilateral STN stimulation. The primary outcome was the change from baseline to 6 months in the motor part of the Unified PD Rating Scale (motor UPDRS) in the off phase. Secondary outcomes were parkinsonian symptoms in the on phase (motor UPDRS), dyskinesias (Clinical Dyskinesia Rating Scale and dyskinesias UPDRS), functional status (activities of daily living UPDRS and Schwab and England scale), PD Quality of Life questionnaire, changes in drug treatment, and adverse effects. Results: The off phase motor UPDRS score improved from 46.5 to 37 points in the group of pallidotomy patients and from 51.5 to 26.5 in the STN stimulation patients (p=0.002). Of the secondary outcome measures, on phase motor UPDRS and dyskinesias UPDRS improved significantly in favor of the STN stimulation patients. Reduction of antiparkinsonian drugs was greater after STN stimulation than after pallidotomy. One patient in each group had a major adverse effect. Conclusions: Bilateral STN stimulation is more effective than unilateral pallidotomy in reducing parkinsonian symptoms in patients with advanced PD.

Deep brain stimulation is a treatment for Parkinson's disease and other related disorders, involving the surgical placement of electrodes in the deeply situated basal ganglia or thalamic structures. Good clinical outcome requires accurate targeting. However, due to limited visibility of the target structures on routine clinical MR images, direct targeting of structures can be challenging. Non-clinical MR scanners with ultra-high magnetic field (7T or higher) have the potential to improve the quality of these images. This technology report provides an overview of the current possibilities of visualizing deep brain stimulation targets and their related structures with the aid of ultra-high field MRI. Reviewed studies showed improved resolution, contrast- and signal-to-noise ratios at ultra-high field. Sequences sensitive to magnetic susceptibility such as T2(*) and susceptibility weighted imaging and their maps in general showed the best visualization of target structures, including a separation between the subthalamic nucleus and the substantia nigra, the lamina pallidi medialis and lamina pallidi incompleta within the globus pallidus and substructures of the thalamus, including the ventral intermediate nucleus (Vim). This shows that the visibility, identification, and even subdivision of the small deep brain stimulation targets benefit from increased field strength. Although ultra-high field MR imaging is associated with increased risk of geometrical distortions, it has been shown that these distortions can be avoided or corrected to the extent where the effects are limited. The availability of ultra-high field MR scanners for humans seems to provide opportunities for a more accurate targeting for deep brain stimulation in patients with Parkinson's disease and related disorders.

14 p. L-DOPA is the most effective treatment for Parkinson's disease (PD), but prolonged use leads to disabling motor complications including dyskinesia. Strong evidence supports a role of the subthalamic nucleus (STN) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy. Here, we investigated the involvement of STN in dyskinesia, using single-unit extracellular recording, behavioural and molecular approaches in hemi-parkinsonian rats rendered dyskinetic by chronic L-DOPA administration. Our results show that chronic L-DOPA treatment does not modify the abnormal STN activity induced by the 6-hydroxydopamine lesion of the nigrostriatal pathway in this model. Likewise, we observed a loss of STN responsiveness to a single L-DOPA dose both in lesioned and sham animals that received daily L-DOPA treatment. We did not find any correlation between the abnormal involuntary movement (AIM) scores and the electrophysiological parameters of STN neurons recorded 24 h or 20–120 min after the last L-DOPA injection, except for the axial subscores. Nonetheless, unilateral chemical ablation of the STN with ibotenic acid resulted in a reduction in global AIM scores and peak-severity of dyskinesia. In addition, STN lesion decreased the anti-dyskinetogenic effect of buspirone in a reciprocal manner. Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB, phosphoDARPP-32, dopamine receptor (DR) D3 and DRD2/DRD1 ratio. The STN lesion attenuated the striatal molecular changes and normalized the DRD2/DRD1 ratio. Taken together, our results show that the STN plays a role, if modest, in the physiopathology of dyskinesias. This study was supported by grants from the Spanish Ministry of Science SAF 2009-08664 (LU), the department of Industry of the Basque Government S-PE10UN24 (LU and RSP) and Kutxa Obra social (RSP). AA and AS have a fellowship from the University of the Basque Country. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of manuscript.

Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale-Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale-Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2-6 and 9-15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2-6 months and 25.7% at 9-15 months. At 9-15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9-15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2-6 months; this failed to reach significance at 9-15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

Dystonia of the limbs may be due to a wide range of aetiologies and may cause major functional limitation. We investigated whether the previously described pathological 4 to 7 Hz drive to muscles in cervical dystonia is present in patients with aetiologically different types of dystonia of the upper and lower limbs. To this end, we studied 12 symptomatic and 4 asymptomatic carriers of the DYT l gene, 6 patients with symptomatic dystonia due to focal basal ganglia lesions, and 11 patients with fixed dystonia, a condition assumed to be mostly psychogenic in aetiology. We evaluated EMG-EMG coherence in the tibialis anterior (TA) of these and 15 healthy control subjects. Ten of 12 (83%) of symptomatic DYT1 patients had an excessive 4 to 7 Hz common drive to TA, evident as an inflated coherence in this band. This drive also involved the gastrocnemius, leading to co-contracting electromyographic bursts. In contrast, asymptomatic DYT1 carriers, patients with symptomatic dystonia, patients with fixed dystonia, and healthy subjects showed no evidence of such a drive or any other distinguishing electrophysiological feature. Moreover, the pathological 4 to 7 Hz drive in symptomatic DYT1 patients was much less common in the upper limb, where it was only present in 2 of 6 (33%) patients with clinical involvement of the arms. We conclude that the nature of the abnormal drive to dystonic muscles may vary according to the, muscles under consideration and, particularly, with aetiology. (C) 2004 Movement Disorder Society.

Objective: To compare the efficacy of unilateral pallidotomy and bilateral subthalamic nucleus (STN) stimulation in patients with advanced Parkinson disease (PD) in a randomized, observer-blind, multicenter trial. Methods: Thirty-four patients with advanced PD were randomly assigned to have unilateral pallidotomy or bilateral STN stimulation. The primary outcome was the change from baseline to 6 months in the motor part of the Unified PD Rating Scale (motor UPDRS) in the off phase. Secondary outcomes were parkinsonian symptoms in the on phase (motor UPDRS), dyskinesias (Clinical Dyskinesia Rating Scale and dyskinesias UPDRS), functional status (activities of daily living UPDRS and Schwab and England scale), PD Quality of Life questionnaire, changes in drug treatment, and adverse effects. Results: The off phase motor UPDRS score improved from 46.5 to 37 points in the group of pallidotomy patients and from 51.5 to 26.5 in the STN stimulation patients (p=0.002). Of the secondary outcome measures, on phase motor UPDRS and dyskinesias UPDRS improved significantly in favor of the STN stimulation patients. Reduction of antiparkinsonian drugs was greater after STN stimulation than after pallidotomy. One patient in each group had a major adverse effect. Conclusions: Bilateral STN stimulation is more effective than unilateral pallidotomy in reducing parkinsonian symptoms in patients with advanced PD.

In the last decades, clinical neuroscience found a novel ally in neurotechnologies, devices able to record and stimulate electrical activity in the nervous system. These technologies improved the ability to diagnose and treat neural disorders. Neurotechnologies are concurrently enabling a deeper understanding of healthy and pathological dynamics of the nervous system through stimulation and record-ings during brain implants. On the other hand, clinical neurosciences are not only driving neuroengineering toward the most relevant clinical issues, but are also shaping the neurotechnologies thanks to clinical advancements. For instance, un-derstanding the etiology of a disease informs the location of a therapeutic stim-ulation, but also the way stimulation patterns should be designed to be more effective/naturalistic. Here, we describe cases of fruitful integration such as Deep Brain Stimulation and cortical interfaces to highlight how this symbiosis be-tween clinical neuroscience and neurotechnology is closer to a novel integrated framework than to a simple interdisciplinary interaction.