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DBS has been shown to be an effective intervention for neurological disorders. However, the intervention is complex and many aspects have not been understood. Various clinical situations have no solution and follow trial and error approaches. Dystonia is a movement disorder characterized by involuntary muscle contractions, which gives rise to abnormal movements and postures. Status dystonicus (SD) represents a life-threatening condition that requires urgent assessment and management. Electrophysiological markers for risk of symptom worsening and SD related patterns of evolution in patients treated with long-term deep brain stimulation (DBS), and specially under the effect of withdrawal and renewals of simulation are needed. To this end, we study the variability of neural synchronization as a mechanism for symptom generation under successive perturbations to a system, i.e. withdrawals and renewals of neuromodulation, through computational simulation of clinical profiles under different plasticity conditions. The simulation shows that the neuroplasticity makeup influences the variability of oscillation synchronization patterns in virtual "patients". The difference between the effect of different electrophysiological signatures is remarkable and under a certain condition (equal medium long term potentiation and long term depression) the situation resembles that of a stable equilibrium, putatively making the sudden worsening or change less likely. Stability of variability can only be observed in this condition and is clearly distinct from other scenarios. CONCLUSION: Our results demonstrate that the neuroplasticity makeup affects the variability of the oscillatory synchrony. This i) informs the shaping of the electrophysiological makeup and ii) might serve as a marker for clinical behavior., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Introduction: MRI-guided focused ultrasound (MRgFUS) thalamotomy provides an exciting development in the field of minimally invasive stereotactic neurosurgery. Current treatment options for focal hand dystonia are limited, with potentially more effective invasive stereotactic interventions, such as deep brain stimulation or lesional therapies, rarely used. The advent of minimally invasive brain lesioning provides a potentially safe and effective treatment approach with a recent pilot study establishing MRgFUS Vo-complex thalamotomy as an effective treatment option for focal hand dystonia. In this study, we undertake an open-label clinical trial to further establish MRgFUS Vo-complex thalamotomy as an effective treatment for focal hand dystonia with greater attention paid to potential motor costs associated with this treatment. To elucidate pathophysiology of dystonia and treatment mechanisms, neurophysiological and MRI analysis will be performed longitudinally to explore the hypothesis that neuroplastic and structural changes that may underlie this treatment benefit., Methods and Analysis: A total of 10 participants will be recruited into this open-label clinical trial. All participants will undergo clinical, kinemetric, neurophysiological and radiological testing at baseline, followed by repeated measures at predesignated time points post MRgFUS Vo-complex thalamotomy. Further, to identify any underlying structural or neurophysiological abnormalities present in individuals with focal hand dystonia, 10 age and gender matched control participants will be recruited to undergo comparative investigation. These results will be compared with the intervention participants both at baseline and at 12 months to assess for normalisation of these abnormalities, if present., Ethics and Dissemination: This trial was reviewed and approved by the St Vincent's Health Network Sydney Human Research Ethics Committee (2022/ETH00778). Study results will be published in peer-reviewed journals and presented at both national and international conferences., Trial Registration Number: CTRN12622000775718., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Among neurodevelopmental disorders, attention deficit hyperactivity disorder (ADHD) is the main cause of school failure in children. Notably, visuospatial dysfunction has also been emphasized as a leading cause of low cognitive performance in children with ADHD. Consequently, the present study aimed to identify ADHD-related changes in electroencephalography (EEG) characteristics, associated with visual object processing in school-aged children. We performed Multichannel EEG recordings in 16-year-old children undergoing Navon's visual object processing paradigm. We mapped global coherence during the processing of local and global visual stimuli that were consistent, inconsistent, or neutral. We found that Children with ADHD showed significant differences in global weighted coherence during the processing of local and global inconsistent visual stimuli and longer response times in comparison to the control group. Delta and theta EEG bands highlighted important features for classification in both groups. Thus, we advocate EEG coherence and low-frequency EEG spectral power as prospective markers of visual processing deficit in ADHD. Our results have implications for the development of diagnostic interventions in ADHD and provide a deeper understanding of the factors leading to low performance in school-aged children.

Deep brain stimulation (DBS) serves as a treatment for neurological and psychiatric disorders, such as Parkinson's disease (PD), essential tremor, dystonia, Tourette Syndrome (GTS), Huntington's disease, and obsessive-compulsive disorder (OCD). There is broad experience with the short-term effects of DBS in individual diseases and their signs/symptoms. However, even in acute treatment and for the same disorder or a given disorder, a prediction of effect is not perfect. Even further, the factors that influence the long-term effect of DBS and its withdrawal are hardly characterized. In this work, we aim to shed light on an important topic, the question of "DBS dependency." To address this, we make use of the Kuramoto model of phase synchronization (oscillation feature) endowed with neuroplasticity to study the effects of DBS under successive withdrawals and renewals of neuromodulation as well as influence of treatment duration in de novo DBS "patients." The results of our simulation show that the characteristics of neuroplasticity have a profound effect on the stability and mutability of oscillation synchronization patterns across successive withdrawal and renewal of DBS in chronic "patients" and also in de novo DBS "patients" with varying duration of treatment (here referred to as the "number of iterations"). Importantly, the results demonstrate the strong effect of the individual neuroplasticity makeup on the behavior of synchrony of oscillatory activity that promotes certain disorder/disease states or symptoms. The effect of DBS-mediated neuromodulation and withdrawal is highly dependent on the makeup of the neuroplastic signature of a disorder or an individual., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Trenado, Cif, Pedroarena-Leal and Ruge.)

Motor adaptation tasks investigate our ability to adjust motor behaviors to an ever-changing and unpredictable world. Previous work has shown that punishment-based feedback delivered during a visuomotor adaptation task enhances error-reduction, whereas reward increases memory retention. While the neural underpinnings of the influence of punishment on the adaptation phase remain unclear, reward has been hypothesized to increase retention through dopaminergic mechanisms. We directly tested this hypothesis through pharmacological manipulation of the dopaminergic system. A total of 96 young healthy human participants were tested in a placebo-controlled double-blind between-subjects design in which they adapted to a 40° visuomotor rotation under reward or punishment conditions. We confirmed previous evidence that reward enhances retention, but the dopamine (DA) precursor levodopa (LD) or the DA antagonist haloperidol failed to influence performance. We reason that such a negative result could be due to experimental limitations or it may suggest that the effect of reward on motor memory retention is not driven by dopaminergic processes. This provides further insight regarding the role of motivational feedback in optimizing motor learning, and the basis for further decomposing the effect of reward on the subprocesses known to underlie motor adaptation paradigms.

Background: Status dystonicus (SD) is a life-threatening condition., Objective and Methods: In a dystonia cohort who developed status dystonicus, we analyzed demographics, background dystonia phenomenology and complexity, trajectory previous to-, via status dystonicus episodes, and evolution following them., Results: Over 20 years, 40 of 328 dystonia patients who were receiving DBS developed 58 status dystonicus episodes. Dystonia was of pediatric onset (95%), frequently complex, and had additional cognitive and pyramidal impairment (62%) and MRI alterations (82.5%); 40% of episodes occured in adults. Mean disease duration preceding status dystonicus was 10.3 ± 8 years. Evolution time to status dystonicus varied from days to weeks; however, 37.5% of patients exhibited progressive worsening over years. Overall, DBS was efficient in resolving 90% of episodes., Conclusion: Status dystonicus is potentially reversible and a result of heterogeneous conditions with nonuniform underlying physiology. Recognition of the complex phenomenology, morphological alterations, and distinct patterns of evolution, before and after status dystonicus, will help our understanding of these conditions. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Depotentiation (DP) is a crucial mechanism for the tuning of memory traces once LTP (Long Term Potentiation) has been induced via learning, artificial procedures, or other activities. Putative unuseful LTP might be abolished via this process. Its deficiency is thought to play a role in pathologies, such as drug induced dyskinesia. However, since it is thought that it represents a mechanism that is linked to the susceptibility to interference during consolidation of a memory trace, it is an important process to consider when therapeutic interventions, such as psychotherapy, are administered. Perhaps a person with an abnormal depotentiation is prone to lose learned effects very easily or on the other end of the spectrum is prone to overload with previously generated unuseful LTP. Perhaps this process partly explains why some disorders and patients are extremely resistant to therapy. The present study seeks to quantify the relationship between LTP and depotentiation in the human brain by using transcranial magnetic stimulation (TMS) over the cortex of healthy participants. The results provide further evidence that depotentiation can be quantified in humans by use of noninvasive brain stimulation techniques. They provide evidence that a nonfocal rhythmic on its own inefficient stimulation, such as a modified thetaburst stimulation, can depotentiate an associative, focal spike timing-dependent PAS (paired associative stimulation)-induced LTP. Therefore, the depotentiation-like process does not seem to be restricted to specific subgroups of synapses that have undergone LTP before. Most importantly, the induced LTP seems highly correlated with the amount of generated depotentiation in healthy individuals. This might be a phenomenon typical of health and might be distorted in brain pathologies, such as dystonia, or dyskinesias. The ratio of LTP/DP might be a valuable marker for potential distortions of persistence versus deletion of memory traces represented by LTP-like plasticity.

The extinction of conditioned-fear represents a hallmark of current exposure therapies as it has been found to be impaired in people suffering from post-traumatic stress disorder (PTSD) and anxiety. A large body of knowledge focusing on psychophysiological animal and human studies suggests the involvement of key brain structures that interact via neural oscillations during the acquisition and extinction of fear. Consequently, neural oscillatory correlates of such mechanisms appear relevant regarding the development of novel therapeutic approaches to counterbalance abnormal activity in fear-related brain circuits, which, in turn, could alleviate fear and anxiety symptoms. Here, we provide an account of state-of-the-art neural oscillatory correlates for the conditioning and extinction of fear, and also deal with recent translational efforts aimed at fear extinction by neural oscillatory modulation.

Dystonia can be seen in a number of different phenotypes that may arise from different etiologies. The pathophysiological substrate of dystonia is related to three lines of research. The first postulate a loss of inhibition which may account for the excess of movement and for the overflow phenomena. A second abnormality is sensory dysfunction which is related to the mild sensory complaints in patients with focal dystonias and may be responsible for some of the motor dysfunction. Finally, there are strong pieces of evidence from animal and human studies suggesting that alterations of synaptic plasticity characterized by a disruption of homeostatic plasticity, with a prevailing facilitation of synaptic potentiation may play a pivotal role in primary dystonia. These working hypotheses have been generalized in all form of dystonia. On the other hand, several pieces of evidence now suggest that the pathophysiology may be slightly different in the different types of dystonia. Therefore, in the present review, we would like to discuss the neural mechanisms underlying the different forms of dystonia to disentangle the different weight and role of environmental and predisposing factors.

Therapy resistance of approximately one-third of patients with Gilles de la Tourette syndrome (GTS) requires consideration of alternative therapeutic interventions. The article demonstrates the role of the cerebellum in neuropsychiatric disorders and GTS in particular, specifically its role in functions relating to motor and cognitive symptoms. Certain circuits in the cerebellum have been shown to undergo learning-induced changes during conditioning, with cells in the cortex of the cerebellum appearing to decrease their activity whilst those in deep nuclei seem to do the inverse. Evidence exists showing that abnormal excitability of the motor cortex via the cerebellum could be expected to participate in motor tics in GTS possibly due to aberrations in certain structures of involved circuits. The role of the cerebellum in learning and plasticity processes renders it a strategic and valuable structure to consider for brain stimulation when investigating potential treatment options for neuropsychiatric disorders such as GTS. This article puts forth the concept of using non-invasive and invasive brain stimulation techniques as a novel platform for non-pharmacological neuromodulation of GTS symptoms., (© 2015 The British Psychological Society.)

Objective: Idiopathic adult onset cervical dystonia (IAOCD) is considered to be a partially penetrant autosomal dominant genetic condition. Dystonia may result from genetic and environmental factors. In this view, part of the physiology should be an endophenotype stemming from the genetic background. We assessed the most discriminative test to separate patients with IAOCD and healthy controls for further endophenotyping in non-affected 1st degree relatives., Methods: We included patients with IAOCD, their 1st degree relatives and healthy controls. Tests performed: (1) Sensory temporal discrimination (visual, tactile, visuo-tactile), (2) Paired pulse paradigms using transcranial magnetic stimulation (TMS), (3) Mental rotation paradigms., Results: 45 patients with IAOCD, 23 healthy controls and 14 non-affected 1st degree relatives were recruited. Visuo-tactile temporal discrimination separated best between controls and patients as well as between controls and 1st degree relatives. 36% of the latter had an abnormal visuo-tactile temporal discrimination. No difference between patients and healthy controls was found for the other paradigms., Conclusions: Visuo-tactile temporal discrimination separates controls from patients with IAOCD and its 1st degree relatives. 36% of the latter had abnormal visuo-tactile thresholds supporting the role of visuo-tactile temporal discrimination as an endophenotype for IAOCD., Significance: Even though the study was of exploratory design, our findings expand the understanding of endophenotypes in IAOCD., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Therapy resistance of approximately one-third of patients with Gilles de la Tourette syndrome (GTS) requires consideration of alternative therapeutic interventions. This article provides a condensed review of the invasive and non-invasive stimulation techniques that have been applied, to date, for treatment and investigation of GTS. Through this perspective and short review, the article discusses potential novel applications for neurostimulation techniques based on a symptom-guided approach. The concept of considering the physiological basis of specific symptoms when using stimulation techniques will provide a platform for more effective non-pharmacological neuromodulation of symptoms in GTS.

Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine, and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic, and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses., Competing Interests: The authors have declared that no competing interests exist.

The temporal preparation of motor responses to external events (temporal preparation) relies on internal representations of the accumulated elapsed time (temporal representations) before an event occurs and on estimates about its most likely time of occurrence (temporal expectations). The precision (inverse of uncertainty) of temporal preparation, however, is limited by two sources of uncertainty. One is intrinsic to the nervous system and scales with the length of elapsed time such that temporal representations are least precise for longest time durations. The other is external and arises from temporal variability of events in the outside world. The precision of temporal expectations thus decreases if events become more variable in time. It has long been recognized that the processing of time durations within the range of hundreds of milliseconds (interval timing) strongly depends on dopaminergic (DA) transmission. The role of DA for the precision of temporal preparation in humans, however, remains unclear. This study therefore directly assesses the role of DA in the precision of temporal preparation of motor responses in healthy humans. In a placebo-controlled double-blind design using a selective D2-receptor antagonist (sulpiride) and D1/D2 receptor antagonist (haloperidol), participants performed a variable foreperiod reaching task, under different conditions of internal and external temporal uncertainty. DA blockade produced a striking impairment in the ability of extracting temporal expectations across trials and on the precision of temporal representations within a trial. Large Weber fractions for interval timing, estimated by fitting subjective hazard functions, confirmed that this effect was driven by an increased uncertainty in the way participants were experiencing time. This provides novel evidence that DA regulates the precision with which we process time when preparing for an action.

The major link between the visual and motor systems is via the dorsal stream pathways from visual to parietal and frontal areas of the cortex. Although the pathway appears to be indirect, there is evidence that visual input can reach the motor cortex at relatively short latency. To shed some light on its neural basis, we studied the visuomotor interaction using paired transcranial magnetic stimulation (TMS). Motor-evoked potentials (MEPs) were recorded from the right first dorsal interosseous in sixteen healthy volunteers. A conditioning stimulus (CS) was applied over the phosphene hotspot of the visual cortex, followed by a test stimulus over the left primary motor cortex (M1) with a random interstimulus interval (ISI) in range 12-40 ms. The effects of paired stimulation were retested during visual and auditory reaction-time tasks (RT). Finally, we measured the effects of a CS on short-interval intracortical inhibition (SICI). At rest, a CS over the occiput significantly (P < 0.001) suppressed test MEPs with an ISI in the range 18-40 ms. In the visual RT, inhibition with an ISI of 40 ms (but not 18 ms) was replaced by a time-specific facilitation (P < 0.001), whereas, in the auditory RT, the CS no longer had any effect on MEPs. Finally, an occipital CS facilitated SICI with an ISI of 40 ms (P < 0.01). We conclude that it is possible to study separate functional connections from visual to motor cortices using paired-TMS with an ISI in the range 18-40 ms. The connections are inhibitory at rest and possibly mediated by inhibitory interneurones in the motor cortex. The effect with an ISI of 40 ms reverses into facilitation during a visuomotor RT but not an audiomotor RT. This suggests that it plays a role in visuomotor integration., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

To investigate whether a period of continuous theta burst stimulation (cTBS) over the supplementary motor area (SMA) induces cortical plasticity and thus improves bradykinesia in Parkinson's disease (PD) in the medication ON and OFF state. In total, 26 patients with Parkinson's disease were tested with both real and sham stimulation. The group was divided into an OFF-medication (4 females, mean age 65 years, disease duration 6 years) and an ON-medication group (7 females, mean age 61 years, disease duration 7 years) with each containing 13 individuals. Both groups were evaluated in terms of electrophysiological (motor-evoked potentials) and behavioural [Purdue Pegboard test (PPT), UPDRS motor subscore] parameters before (baseline condition) and after a 40-second period of real or sham continuous theta burst stimulation over the SMA ON and OFF dopaminergic drugs. Patients in the OFF group demonstrated an improved UPDRS III score (p < 0.05) and a better performance in the PPT for the less affected side (p < 0.025) compared to baseline after real stimulation. However, electrophysiological parameters did not change in either the ON or the OFF state. cTBS over the SMA has a mild effect on motor symptoms of the upper limb in the OFF state of PD patients. In contrast, stimulation did not change cortico-spinal excitability. A lack of change (i.e. no plasticity) to brain stimulation protocols is a known finding in PD. A clinical improvement in the OFF state, however, contrasts with this and the mechanism of these induced changes is worth further exploration.

Humans carry out many daily tasks in a seemingly automatic fashion. However, when unexpected changes in the environment occur, we have the capacity to inhibit prepotent behavior and replace it with an alternative one. Such behavioral flexibility is a hallmark of executive functions. The neurotransmitter dopamine is known to be crucial for fast, efficient, and accurate cognitive flexibility. Despite the perceived similarities between cognitive and motor flexibility, less is known regarding the role of dopamine within the motor domain. Therefore, the aim of this study was to determine the role of dopamine in motor flexibility. In a double-blind, five-session, within-subject pharmacological experiment, human participants performed an RT task within a probabilistic context that was either predictable or unpredictable. The probabilistic nature of the predictable context resulted in prediction errors. This required participants to replace the prepotent or prepared action with an unprepared action (motor flexibility). The task was overlearned, and changes in context were explicitly instructed, thus controlling for contributions from other dopamine-related processes such as probabilistic or reversal learning and interactions with other types of uncertainty. We found that dopamine receptor blockade by high-dose haloperidol (D1/D2 dopamine receptors) impaired participants' ability to react to unexpected events occurring in a predictable context, which elicit large prediction errors and necessitate motor flexibility. This effect was not observed with selective D2 receptor blockade (sulpiride), with a general increase in tonic dopamine levels (levodopa), or during an unpredictable context, which evoked minimal prediction error. We propose that dopamine is vital in responding to low-level prediction errors about stimulus outcome that requires motor flexibility.

Periodic lateralized epileptiform discharges (PLEDs) on electroencephlography (EEG) usually indicate an acute, diffuse, and severe cerebral insult. Although hyperglycemic hemichorea-hemiballisum (HCHB) and striatal hyperintensity on T1-weighted magnetic resonance (MR) images is an accepted clinical entity, PLEDs have not previously been reported. Herein, we report a 74-year-old man with hyperglycemic HCHB, hyperintense putamen on T1-MR images and PLEDs on EEG. Aggressive sugar control with neuroleptic treatment only slightly improved the severity of HCHB. We also tried titrated oral and intravenous haloperidol, clonazepam, and propranolol sequentially and in combination; however, the effects were poor. Unlike the generally reversibility of hyperglycemic HCHB, the condition was still present 6 months later. Hyperglycemia can cause HCHB and produce subcortical type-PLEDs, which may explain the findings in our patient. In conclusion, PLEDs can be found in patients with hyperglycemic HCHB and striatal hyperintensity on T1-weighted MR images, and the appearance of PLEDs may indicate an irreversible outcome. EEG should be considered in such circumstances., (© EEG and Clinical Neuroscience Society (ECNS) 2014.)

The link between basic physiology and its modulation by cognitive states, such as attention, is poorly understood. A significant association becomes apparent when patients with movement disorders describe experiences with changing their attention focus and the fundamental effect that this has on their motor symptoms. Moreover, frequently used mental strategies for treating such patients, e.g. with task-specific dystonia, widely lack laboratory-based knowledge about physiological mechanisms. In this largely unexplored field, we looked at how the locus of attention, when it changed between internal (locus hand) and external (visual target), influenced excitability in the primary motor cortex (M1) in healthy humans. Intriguingly, both internal and external attention had the capacity to change M1 excitability. Both led to a reduced stimulation-induced GABA-related inhibition and a change in motor evoked potential size, i.e. an overall increased M1 excitability. These previously unreported findings indicated: (i) that cognitive state differentially interacted with M1 physiology, (ii) that our view of distraction (attention locus shifted towards external or distant location), which is used as a prevention or management strategy for use-dependent motor disorders, is too simple and currently unsupported for clinical application, and (iii) the physiological state reached through attention modulation represents an alternative explanation for frequently reported electrophysiology findings in neuropsychiatric disorders, such as an aberrant inhibition., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Deep brain stimulation (DBS) is a powerful treatment option for movement disorders, including severe generalised dystonia. After several years of treatment, cases have been reported in which DBS has been stopped without any deterioration in clinical benefit. This might indicate that DBS can restore function in some cases. The mechanism of DBS induced clinical retention effects has been addressed before. Here, the question we asked was if such clinical stability is reflected at the underlying physiology level or whether there is indication to believe that a stand-still of symptoms might be at risk because of neurophysiological instability. We recorded patients with pre-intervention life-threatening or severe genetic dystonia with long lasting clinical benefit when turned off DBS. Despite clinical stability, our physiological studies revealed large changes in the excitability of excitatory and inhibitory motor circuits in the cortex, which exceed normal fluctuation. This discrepancy between instability in the motor network physiology caused by removal of DBS and clinical stability alerts as it potentially indicates a risk to fail and cause symptoms to return., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Diagnosis of aphasic status epilepticus is sometimes not easy because of its rarity and electroclinical dissociation. Although most cases are associated with organic brain lesions, nonketotic hyperglycemia (NKH)-related aphasic status epilepticus is rare, especially if it is isolated (without other clinical seizure activity). On the other hand, unlike other metabolic disorders, or hypoglycemia-related generalized seizures, focal motor seizure and epilepsia partialis continua can occur in 25% of NKH, with seizures being the initial manifestation in up to 50% of patients. However, the presentation of epileptic aphasia is rare in NKH patients. We report a rare case of NKH presenting initially as persistent and isolated aphasic status epilepticus. Brain magnetic resonance imaging did not reveal any focal lesion, but ictal electroencephalography (EEG) disclosed left frontotemporal continuous theta to delta waves, intermingled with epileptiform discharges. Correcting the hyperglycemia failed to improve the language disorder, and the seizure was controlled only by the addition of carbamazepine. Patients with NKH may initially present with isolated aphasic status epilepticus. Unlike stroke-related aphasia, accurate diagnosis is difficult if based solely on neurologic examination and brain neuroimaging. Use of EEG and blood sugar determination should be helpful in this special condition.

Although the central autonomic network (CAN) has been well researched in animal models, the CAN in humans is still unclear, especially for cardiovascular control. This study aimed to investigate which areas of the cerebral cortices are associated with the peripheral cardiac autonomic control involved in the CAN in uremic patients with autonomic dysfunction and normal controls. The central and peripheral autonomic network in 19 uremic patients with significant autonomic dysfunction and 24 age- and sex-matched controls [mean age ± standard deviation (SD), 55.16 ± 10.45 years and 55.42 ± 5.42 years, respectively] were evaluated by simultaneous spectral analysis of electroencephalography (EEG) and electrocardiography recording (ECG), along with serial autonomic tests [autonomic questionnaire and orthostatic blood pressure (BP) change]. Only frequency-domain heart rate variability (f-HRV) during the deep-breathing stage could differentiate the two groups. Although there is no significant difference in f-HRV during the quiet-breathing stage, different patterns of central oscillation and their correlation with peripheral cardiac autonomic indices could be found for the two groups. Although the power of specific EEG bands under electrode T3 and T6 correlated significantly with the power of peripheral HRV indices in the control group, those under electrodes P3 and Pz had significant correlations in the uremic group suggesting a role of functional connectivity between them. In addition, sympathetic activity is correlated with slow wave EEG (theta/delta) power whereas parasympathetic activity is correlated with fast wave EEG (beta) power. In conclusion, there is functional connectivity between the parietal cortex and the peripheral cardiac autonomic system (PAN) in uremics and the pattern of central autonomic connectivity differs between uremic patients with autonomic dysfunction and normal controls., (Copyright © 2013. Published by Elsevier B.V.)

We investigated the effect of pallidal deep brain stimulation (GPi-DBS) in dystonia on cognition, mood, and quality of life and also assessed if DYT1 gene status influenced cognitive outcome following GPi-DBS. Fourteen patients with primary generalized dystonia (PGD) were assessed, measuring their estimated premorbid and current IQ, memory for words and faces, and working memory, language, executive function, and sustained attention, one month before and one year or more after surgery. Changes in mood and behaviour and quality of life were also assessed. There was a significant improvement of dystonia with GPi-DBS (69 % improvement in Burke-Fahn-Marsden score, p < 0.0001). Performance on five cognitive tests either improved or declined at post-surgical follow-up. Calculation of a reliable change index suggested that deterioration in sustained attention on the PASAT was the only reliable change (worse after surgery) in cognition with GPi-DBS. DYT1 gene status did not influence cognitive outcome following GPi-DBS. Depression, anxiety and apathy were not significantly altered, and ratings of health status on the EQ5D remained unchanged. In our sample, GPi-DBS was only associated with an isolated deficit on a test of sustained attention, confirming that GPi-DBS in PGD is clinically effective and safe, without adverse effects on the main domains of cognitive function. The dissociation between GPi-DBS improving dystonia, but not having a significant positive impact on the patients' QoL, warrants further investigation.

Background: We investigated whether clinical improvement observed after deep brain stimulation (DBS) of the globus pallidus internus (GPi) in cervical dystonia (CD) is paralleled by the normalisation of temporal discrimination thresholds (TDTs), a marker of abnormal sensory processing in CD., Methods: TDT was tested in 11 patients with CD after they received DBS and was compared with TDT scores from 24 patients with CD and a group of 61 controls., Results: A clear clinical response to GPi-DBS was demonstrated (total Toronto Western Spasmodic Torticollis Rating Scale scores fell from 50 to 18; P < 0.001). In contrast, TDT remained abnormal in the CD-DBS group (P < 0.001) and was not significantly different from the abnormal TDT range observed in CD., Conclusions: Underlying sensory abnormalities in temporal discrimination observed in dystonia do not seem to be corrected by successful GPi-DBS. This adds further data to the ongoing debate regarding which pathophysiological abnormalities observed in dystonia are likely to be causal in the genesis of the disease rather than epiphenomena observed secondary to abnormal motor activity., (© 2013 International Parkinson and Movement Disorder Society.)

Background: Deep brain stimulation (DBS) of the internal globus pallidus (GPi) is an established therapy for primary generalized dystonia. However, the evolution of dystonia symptoms after DBS discontinuation after years of therapy has only rarely been reported. We therefore longitudinally studied the main physiological measurements known to be impaired in dystonia, with DBS ON and then again after termination of DBS, after at least five years of continuous DBS., Objective: We studied whether dystonia evolution after DBS discontinuation in patients benefiting from long-term GPi DBS is different from that observed in earlier stages of the therapy., Methods: In eleven DYT1 patients treated with bilateral GPi DBS for at least 5 years, dystonia was assessed ON-DBS, immediately after switch-off (OFF-DBS1) and 48 h after DBS termination (OFF-DBS2). We studied the influence of DBS intensity on dystonia when DBS was discontinued., Results: On average a significant difference in symptoms was measured only between ON-DBS and OFF-DBS1 conditions. Importantly, none of the patients returned to their preoperative dystonia severity, even 48 h after discontinuation. The amount of clinical deterioration in the OFF conditions positively correlated with higher stimulation current in the chronic ON-DBS condition., Conclusions: The duration of DBS application influences symptom evolution after DBS termination. DBS intensity seems to have a prominent role on evolution of dystonic symptoms when DBS is discontinued. In conclusion, DBS induces changing modulation of the motor network with less worsening of symptoms after long term stimulation, when DBS is stopped., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This study aimed to investigate which cerebral cortices are involved in the central autonomic network and how they are linked to the peripheral (cardiac) autonomic network in Parkinson's disease (PD) patients and normal controls. 26 PD patients with autonomic dysfunction and 23 age- and sex-matched controls were evaluated by simultaneous spectral analysis of electroencephalography (EEG) and electrocardiography (ECG) recording along with autonomic questionnaires. Although the PD group has significantly more symptoms of autonomic dysfunction, frequency-domain HRV can not differentiate these two groups. However, different patterns of central oscillation and their correlation with peripheral autonomic indices could be found for the two groups. While the power of specific EEG bands under electrodes F4, F7, Cz and Pz (parietal-lateral premotor cortex, which is considered as a compensatory area for the relative deficiency of mesial frontal-striatal circuits in PD) correlated significantly with the power of peripheral heart rate variability (HRV) indices in the PD group, those under electrodes C3, P3, P4 and F8 had significant correlation in the control group. In conclusion, functional connectivity between areas of cerebral cortex and peripheral autonomic system can be measured and differs between PD patients with autonomic dysfunction and healthy controls. The central autonomic network may play a role in brain re-organization in PD patients with autonomic dysfunction., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A characteristic feature of primary cervical dystonia is the presence of "sensory tricks" as well as the impairment of temporal and spatial sensory discrimination on formal testing. The aim of the present study was to test whether the amount of improvement of abnormal head deviation due to a sensory trick is associated with different performance of temporal sensory discrimination in patients with cervical dystonia. We recruited 32 patients with cervical dystonia. Dystonia severity was assessed using the Toronto Western Spasmodic Torticollis Rating Scale. Patients were rated according to clinical improvement to a sensory trick and assigned to 1 of the following groups: (1) no improvement (n = 6), (2) partial improvement (n = 17), (3) complete improvement (n = 9). Temporal discrimination thresholds were assessed for visual, tactile, and visuotactile modalities. Disease duration was shorter (P = .026) and dystonia severity lower (P = .033) in the group with complete improvement to sensory tricks compared with the group with partial improvement to sensory tricks. A significant effect for group and modality and a significant interaction between group × modality were found, with lower visuotactile discrimination thresholds in the group with complete improvement to sensory tricks compared with the other groups. In primary cervical dystonia, a complete resolution of dystonia during a sensory trick is associated with better visuotactile discrimination and shorter disease duration compared with patients with less effective sensory tricks, which may reflect progressive loss of adaptive mechanisms to basal ganglia dysfunction., (Copyright © 2012 Movement Disorders Society.)

Action selection describes the high-level process that selects between competing movements. In animals, behavioral variability is critical for the motor exploration required to select the action that optimizes reward and minimizes cost/punishment and is guided by dopamine (DA). The aim of this study was to test in humans whether low-level movement parameters are affected by punishment and reward in ways similar to high-level action selection. Moreover, we addressed the proposed dependence of behavioral and neurophysiological variability on DA and whether this may underpin the exploration of kinematic parameters. Participants performed an out-and-back index finger movement and were instructed that monetary reward and punishment were based on its maximal acceleration (MA). In fact, the feedback was not contingent on the participant's behavior but predetermined. Blocks highly biased toward punishment were associated with increased MA variability relative to blocks either with reward or without feedback. This increase in behavioral variability was positively correlated with neurophysiological variability, as measured by changes in corticospinal excitability with transcranial magnetic stimulation over the primary motor cortex. Following the administration of a DA antagonist, the variability associated with punishment diminished and the correlation between behavioral and neurophysiological variability no longer existed. Similar changes in variability were not observed when participants executed a predetermined MA, nor did DA influence resting neurophysiological variability. Thus, under conditions of punishment, DA-dependent processes influence the selection of low-level movement parameters. We propose that the enhanced behavioral variability reflects the exploration of kinematic parameters for less punishing, or conversely more rewarding, outcomes.

Background: First-episode schizophrenia (FE-SZ) and attention deficit hyperactivity disorder (ADHD) are both neuropsychiatric disorders associated with an impaired dopaminergic transmission. Though displaying different clinical phenotypes, a common pathophysiological pathway is discussed controversially. Several studies using transcranial magnetic stimulation (TMS) revealed abnormalities in human motor cortex excitability in both schizophrenia and ADHD patients. Studies on cortical excitability comparing these two diseases directly are lacking., Method: In this study, a total of 94 subjects were analyzed. Twenty-five FE-SZ patients were directly compared with 28 ADHD patients and 41 healthy controls (HC). We investigated cortical excitability (inhibitory and facilitatory networks) with single- and paired-pulse TMS to the left and right motor cortex., Results: Compared to HC, FE-SZ/ADHD patients displayed an impaired cortical inhibition over the left hemisphere. Apart from an enhanced intracortical facilitation, FE-SZ patients did not differ compared to ADHD patients in the main outcome measures. Both patient groups presented a dysfunctional hemispheric pattern of cortical inhibition and facilitation in comparison with HC., Conclusion: The results of this study indicate a pattern of cortical disinhibition and abnormal hemispheric balance of intracortical excitability networks in two different psychiatric diseases. These effects might be associated with an imbalance in GABAergic and dopaminergic transmission and might provide evidence for a common pathophysiological pathway of both diseases., (Copyright © 2013 S. Karger AG, Basel.)

Animal studies using polarising currents have shown that induction of synaptic long-term potentiation (LTP) and long-term depression (LTD) by bursts of patterned stimulation is affected by the membrane potential of the postsynaptic neurone. The aim of the present experiments was to test whether it is possible to observe similar phenomena in humans with the aim of improving present protocols of inducing synaptic plasticity for therapeutic purposes. We tested whether the LTP/LTD-like after effects of transcranial theta-burst stimulation (TBS) of human motor cortex, an analogue of patterned electrical stimulation in animals, were affected by simultaneous transcranial direct-current stimulation (tDCS), a non-invasive method of polarising cortical neurones in humans. Nine healthy volunteers were investigated in a single-blind, balanced cross-over study; continuous TBS (cTBS) was used to introduce LTD-like after effects, whereas intermittent TBS (iTBS) produced LTP-like effects. Each pattern was coupled with concurrent application of tDCS (<200 s, anodal, cathodal, sham). Cathodal tDCS increased the response to iTBS and abolished the effects of cTBS. Anodal tDCS changed the effects of cTBS towards facilitation, but had no impact on iTBS. Cortical motor thresholds and intracortical inhibitory/facilitatory networks were not altered by any of the stimulation protocols. We conclude that the after effects of TBS can be modulated by concurrent tDCS. We hypothesise that tDCS changes the membrane potential of the apical dendrites of cortical pyramidal neurones and that this changes the response to patterned synaptic input evoked by TBS. The data show that it may be possible to enhance LTP-like plasticity after TBS in the human cortex.

Deep brain stimulation of the subthalamic nucleus (STN DBS) has become an accepted treatment for patients experiencing the motor complications of Parkinson's disease (PD). While its successes are becoming increasingly apparent, the mechanisms underlying its action remain unclear. Multiple studies using radiotracer-based imaging have investigated DBS-induced regional changes in neural activity. However, little is known about the effect of DBS on connectivity within neural networks; in other words, whether DBS impacts upon functional integration of specialized regions of cortex. In this work, we report the first findings of fMRI in 10 subjects with PD and fully implanted DBS hardware receiving efficacious stimulation. Despite the technical demands associated with the safe acquisition of fMRI data from patients with implanted hardware, robust activation changes were identified in the insula cortex and thalamus in response to therapeutic STN DBS. We then quantified the neuromodulatory effects of DBS and compared sixteen dynamic causal models of effective connectivity between the two identified nodes. Using Bayesian model comparison, we found unequivocal evidence for the modulation of extrinsic (between region), i.e. cortico-thalamic and thalamo-cortical connections. Using Bayesian model parameter averaging we found that during voluntary movements, DBS reversed the effective connectivity between regions of the cortex and thalamus. This casts the therapeutic effects of DBS in a fundamentally new light, emphasising a role in changing distributed cortico-subcortical interactions. We conclude that STN DBS does impact upon the effective connectivity between the cortex and thalamus by changing their sensitivities to extrinsic afferents. Furthermore, we confirm that fMRI is both feasible and is tolerated well by these patients provided strict safety measures are adhered to.

Dopamine (DA) is a neurotransmitter with an important influence on learning and memory, which is thought to be due to its modulatory effect on plasticity at central synapses, which in turn depends on activation of D1 and D2 receptors. Methods of brain stimulation (transcranial direct current stimulation, tDCS; paired associative stimulation, PAS) lead to after-effects on cortical excitability that are thought to resemble long-term potentization (LTP)/long-term depression (LTD) in reduced preparations. In a previous study we found that block of D2 receptors abolished plasticity induced by tDCS but had no effect on the facilitatory plasticity induced by PAS. We postulated that the different effect of D2 receptor block on tDCS- and PAS-induced plasticity may be due to the different focality and associativity of the stimulation techniques. However, alternative explanations for this difference could not be ruled out. tDCS also differs from PAS in other aspects, as tDCS induces plasticity by subthreshold neuronal activation, modulating spontaneous activity, whereas PAS induces plasticity via phasic suprathreshold stimulation. The present study in 12 volunteers examined effects of D2 receptor blockade (sulpiride (SULP) 400 mg), on the LTP/LTD-like effects of theta burst transcranial magnetic stimulation (TBS), which has less restricted effects on cortical synapses than that of PAS, and does not induce associative plasticity, similar to tDCS, but on the other hand induces cortical excitability shifts by suprathreshold (rhythmic) activation of cortical neurons similarly to PAS. Administration of SULP blocked both the excitatory and inhibitory effects of intermittent (iTBS) and continuous TBS (cTBS), respectively. As the reduced response to TBS following SULP resembles its effect on tDCS, the results support an effect of DA on plasticity, which might be related to the focality and associativity of the plasticity induced.

Deep brain stimulation to the internal globus pallidus is an effective treatment for primary dystonia. The optimal clinical effect often occurs only weeks to months after starting stimulation. To better understand the underlying electrophysiological changes in this period, we assessed longitudinally 2 pathophysiological markers of dystonia in patients prior to and in the early treatment period (1, 3, 6 months) after deep brain stimulation surgery. Transcranial magnetic stimulation was used to track changes in short-latency intracortical inhibition, a measure of excitability of GABA(A) -ergic corticocortical connections and long-term potentiation-like synaptic plasticity (as a response to paired associative stimulation). Deep brain stimulation remained on for the duration of the study. Prior to surgery, inhibition was reduced and plasticity increased in patients compared with healthy controls. Following surgery and commencement of deep brain stimulation, short-latency intracortical inhibition increased toward normal levels over the following months with the same monotonic time course as the patients' clinical benefit. In contrast, synaptic plasticity changed rapidly, following a nonmonotonic time course: it was absent early (1 month) after surgery, and then over the following months increased toward levels observed in healthy individuals. We postulate that before surgery preexisting high levels of plasticity form strong memories of dystonic movement patterns. When deep brain stimulation is turned on, it disrupts abnormal basal ganglia signals, resulting in the absent response to paired associative stimulation at 1 month. Clinical benefit is delayed because engrams of abnormal movement persist and take time to normalize. Our observations suggest that plasticity may be a driver of long-term therapeutic effects of deep brain stimulation in dystonia., (Copyright © 2011 Movement Disorder Society.)

Long-term results show that benefits from chronic deep brain stimulation in dystonia are maintained for many years. Despite this, the neurophysiological long-term consequences of treatment and their relationship to clinical effects are not well understood. Previous studies have shown that transcranial magnetic stimulation measures of abnormal long-term potentiation-like plasticity (paired associative stimulation) and GABAa-ergic inhibition (short-interval intracortical inhibition), which are seen in dystonia, normalize after several months of deep brain stimulation. In the present study, we examine the same measures in a homogenous group of 10 DYT1 gene-positive patients after long-term deep brain stimulation treatment for at least 4.5 years. Recordings were made 'on' deep brain stimulation and after stopping deep brain stimulation for 2 days. The results show that: (i) on average, prior to discontinuing deep brain stimulation, the paired associative stimulation response was almost absent and short-interval intracortical inhibition was reduced compared with normal. This pattern differs from that in both healthy volunteers and from the typical pattern of enhanced plasticity and reduced inhibition seen in deep brain stimulation-naïve dystonia. It is similar to that seen in untreated Parkinson's disease and may relate to thus far unexplained clinical phenomena like parkinsonian symptoms that have sometimes been observed in patients treated with deep brain stimulation. (ii) Overall, there was no change in average physiological or clinical status when deep brain stimulation was turned off for 2 days, suggesting that deep brain stimulation had produced long-term neural reorganization in the motor system. (iii) However, there was considerable variation between patients. Those who had higher levels of plasticity when deep brain stimulation was 'on', had the best retention of clinical benefit when deep brain stimulation was stopped and vice versa. This may indicate that better plasticity is required for longer term retention of normal movement when deep brain stimulation is off. (iv) Patients with the highest plasticity 'on' deep brain stimulation were those who had been receiving stimulation with the least current drain. This suggests that it might be possible to 'shape' deep brain stimulation of an individual patient to maximize beneficial neurophysiological patterns that have an impact on clinical status. The results are relevant for understanding long-term consequences and management of deep brain stimulation in dystonia.

The feeling of controlling events through one's actions is fundamental to human experience, but its neural basis remains unclear. This 'sense of agency' (SoA) can be measured quantitatively as a temporal linkage between voluntary actions and their external effects. We investigated the brain areas underlying this aspect of action awareness by using theta-burst stimulation to locally and reversibly disrupt human brain function. Disruption of the pre-supplementary motor area (pre-SMA), a key structure for preparation and initiation of a voluntary action, was shown to reduce the temporal linkage between a voluntary key-press action and a subsequent electrocutaneous stimulus. In contrast, disruption of the sensorimotor cortex, which processes signals more directly related to action execution and sensory feedback, had no significant effect. Our results provide the first direct evidence of a pre-SMA contribution to SoA.

Approximately 10% of patients diagnosed clinically with early Parkinson's disease (PD) have normal dopaminergic functional imaging (Scans Without Evidence of Dopaminergic Deficit [SWEDDs]). An important subgroup of SWEDDs are those with asymmetric rest tremor resembling parkinsonian tremor. Clinical and pathophysiological features which could help to distinguish SWEDDs from PD have not been explored. We therefore studied clinical details including non-motor symptoms in 25 tremulous SWEDDs patients in comparison to 25 tremor-dominant PD patients. Blinded video rating was used to compare examination findings. Electrophysiological tremor parameters and also response to a cortical plasticity protocol using paired associative stimulation (PAS) was studied in 9 patients with SWEDDs, 9 with tremor-dominant PD (with abnormal dopamine transporter single photon emission computed tomography findings), 8 with segmental dystonia, and 8 with essential tremor (ET). Despite clinical overlap, lack of true bradykinesia, presence of dystonia, and head tremor favored a diagnosis of SWEDDs, whereas re-emergent tremor, true fatiguing or decrement, good response to dopaminergic drugs, and presence of non-motor symptoms favored PD. A single tremor parameter could not differentiate between groups, but the combination of re-emergent tremor and highest tremor amplitude at rest was characteristic of PD tremor. SWEDDs and segmental dystonia patients exhibited an abnormal exaggerated response to the PAS protocol, in contrast to a subnormal response in PD and a normal response in ET. We conclude that despite clinical overlap, there are features that can help to distinguish between PD and SWEDDs which may be useful in clinical practice. The underlying pathophysiology of SWEDDs differs from PD but has similarities with primary dystonia., ((c) 2010 Movement Disorder Society.)

This study explores the possibility of noninvasively inducing long-term changes in human corticomotor excitability by means of a brain-computer interface, which enables users to exert internal control over the cortical rhythms recorded from the scalp. We demonstrate that self-regulation of electroencephalogram rhythms in quietly sitting, naive humans significantly affects the subsequent corticomotor response to transcranial magnetic stimulation, producing durable and correlated changes in neurotransmission. Specifically, we show that the intrinsic suppression of alpha cortical rhythms can in itself produce robust increases in corticospinal excitability and decreases in intracortical inhibition of up to 150%, which last for at least 20 min. Our observations may have important implications for therapies of brain disorders associated with abnormal cortical rhythms, and support the use of electroencephalogram-based neurofeedback as a noninvasive tool for establishing a causal link between rhythmic cortical activities and their functions.

Using a twin coil transcranial magnetic stimulation (tc-TMS) approach we have previously demonstrated that facilitation may be detected in the primary motor cortex (M1) following stimulation over the ipsilateral caudal intraparietal sulcus (cIPS). Here we tested the interhemispheric interactions between the IPS and the contralateral motor cortex (M1). We found that conditioning the right cIPS facilitated contralateral M1 when the conditioning stimulus had an intensity of 90% resting motor threshold (RMT) but not at 70% or 110% RMT. Facilitation was maximal when the interstimulus interval (ISI) between cIPS and M1 was 6 or 12 ms. These facilitatory effects were mediated by interactions with specific groups of interneurons in the contralateral M1. In fact, short intracortical inhibition (SICI) was reduced following cIPS stimulation. Moreover, additional comparison of facilitation of responses evoked by anterior-posterior versus posterior-anterior stimulation of M1 suggested that facilitation was more effective on early I1/I2 circuits than on I3 circuits. In contrast to these effects, stimulation of anterior IPS (aIPS) at 90% RMT induced inhibition, instead of facilitation, of contralateral M1 at ISIs of 10-12 ms. Finally, we found similar facilitation between left cIPS and right M1 although the conditioning stimuli had to have a higher intensity compared with stimulation of right cIPS (110% instead of 90% RMT). These findings demonstrate that different subregions of the posterior parietal cortex (PPC) in humans exert both facilitatory and inhibitory effects towards the contralateral primary motor cortex. These corticocortical projections could contribute to a variety of motor tasks such as bilateral manual coordination, movement planning in space and grasping.

Objective: To test whether inhibitory continuous Theta Burst (cTBS) transcranial magnetic stimulation (TMS) can alter neural activity involved in planning and execution of a self-paced movement., Methods: In seven subjects, cTBS was applied over either the left or right primary motor cortex (left M1 and right M1) and the left dorsal premotor cortex (left PMd) in different experimental sessions. Motor evoked potentials (MEP) at rest were measured as well as the two main components of the movement related cortical potential (MRCP), the Bereitschaftspotential (BP) and the negative slope (NS'), prior to self-paced right thumb opposition., Results: cTBS suppressed contralateral MEPs when it was applied over left M1, right M1 and left PMd. In addition, cTBS over left M1, but not at any other location, reduced the amplitude of the NS' and tended to shorten the BP onset without changing EMG activity associated with voluntary muscular output. There was a significant correlation between the percent suppression of the MEP and the reduction in amplitude of the total MRCP (BP+NS')., Conclusions: cTBS can produce long-lasting effects on brain activity involved in the preparation and execution of a volitional movement., Significance: The fact that movement was not compromised while brain activity changed suggests that the motor system of healthy subjects operates with a safety factor that can adjust patterns of activation to compensate for the partial disruption caused by cTBS.

Hemispatial neglect is common after unilateral brain damage, particularly to perisylvian structures in the right-hemisphere (RH). In this disabling syndrome, behaviour and awareness are biased away from the contralesional side of space towards the ipsilesional side. Theoretical accounts of this in terms of hemispheric rivalry have speculated that the intact left-hemisphere (LH) may become hyper-excitable after a RH lesion, due to release of inhibition from the damaged hemisphere. We tested this directly using a novel twin-coil transcranial magnetic stimulation (TMS) approach to measure excitability within the intact LH of neglect patients. This involved applying a conditioning TMS pulse over left posterior parietal cortex (PPC), in order to test its effect on the amplitude of motor evoked potentials (MEPs) produced by a subsequent test pulse over left motor cortex (M1). Twelve RH stroke patients with neglect, an age-matched group of eight RH stroke patients without neglect, and 10 healthy controls were examined. We found that excitability of left PPC-M1 circuits was higher in neglect patients than the other groups, and related to the degree of neglect on clinical cancellation tests. A follow-up found that 1 Hz repetitive TMS over left PPC normalized this over-excitability, and also ameliorated visual neglect on an experimental measure with chimeric objects. Our results provide 'direct' evidence for pathological over-excitability of the LH in the neglect syndrome, as quantified by left PPC influences on left M1, with implications for possible treatment.

Paired-pulse transcranial magnetic stimulation (TMS) has been applied as a probe to test functional connectivity within distinct cortical areas of the human motor system. Here, we tested the interaction between the posterior parietal cortex (PPC) and ipsilateral motor cortex (M1). A conditioning TMS pulse over the right PPC potentiates motor evoked-potentials evoked by a test TMS pulse over the ipsilateral motor cortex, with a time course characterized by two phases: an early peak at 4 ms interstimulus interval (ISI) and a late peak at 15 ms ISI. Activation of this facilitatory pathway depends on the intensity of stimulation, because the effects are induced with a conditioning stimulus of 90% resting motor threshold but not at lower or higher intensities. Similar results were obtained testing the ipsilateral interaction in the left hemisphere with a slightly different time course. In control experiments, we found that activation of this facilitatory pathway depends on the direction of induced current in the brain and is specific for stimulation of the caudal part of the inferior parietal sulcus (cIPS) site, because it is not observed for stimulation of adjacent scalp sites. Finally, we found that by using poststimulus time histogram analysis of single motor unit firing, the PPC conditioning increases the excitability of ipsilateral M1, enhancing the relative amount of late I wave input recruited by the test stimulus over M1, suggesting that such interaction is mediated by specific interneurons in the motor cortex. The described facilitatory connections between cIPS and M1 may be important in a variety of motor tasks and neuropsychiatric disorders.

Patients with writer's cramp (WC) show abnormalities of sensorimotor integration possibly contributing to their motor deficit. We studied sensorimotor integration by determining short-latency afferent inhibition (SAI) in 12 WC patients and 10 age-matched healthy controls. A conditioning electrical median nerve stimulus was followed 14 to 36 msec later by transcranial magnetic stimulation of the contralateral primary motor cortex, and motor evoked potentials (MEP) were recorded from the relaxed or contracting abductor pollicis brevis muscle (APB). SAI was normal in WC but during APB relaxation SAI was followed by abnormal MEP facilitation, which was absent during APB contraction and in the controls. These findings suggest that somatosensory short-latency inhibitory input into the primary motor cortex is normal in WC, whereas a later excitatory input, which very likely reflects the long-latency reflex II, is exaggerated., (Copyright 2004 Movement Disorder Society.)

Learning may alter rapidly the output organization of adult motor cortex. It is a long-held hypothesis that modification of synaptic strength along cortical horizontal connections through long-term potentiation (LTP) and long-term depression (LTD) forms one important mechanism for learning-induced cortical plasticity. Strong evidence in favor of this hypothesis was provided for rat primary motor cortex (M1) by showing that motor learning reduced subsequent LTP but increased LTD. Whether a similar relationship exists in humans is unknown. Here, we induced LTP-like and LTD-like plasticity in the intact human M1 by an established paired associative stimulation (PAS) protocol. PAS consisted of 200 pairs of electrical stimulation of the right median nerve, followed by focal transcranial magnetic stimulation of the hand area of the left M1 at an interval equaling the individual N20 latency of the median nerve somatosensory-evoked cortical potential (PAS(N20)) or N20-5 msec (PAS(N20-5)). PAS(N20) induced reproducibly a LTP-like long-lasting (>30 min) increase in motor-evoked potentials from the left M1 to a thumb abductor muscle of the right hand, whereas PAS(N20-5) induced a LTD-like decrease. Repeated fastest possible thumb abduction movements resulted in learning, defined by an increase in maximum peak acceleration of the practiced movements, and prevented subsequent PAS(N20)-induced LTP-like plasticity but enhanced subsequent PAS(N20-5)-induced LTD-like plasticity. The same number of repeated slow thumb abduction movements did not result in learning and had no effects on PAS-induced plasticity. Findings support the view that learning in human M1 occurs through LTP-like mechanisms.

Paired transcranial magnetic stimulation has greatly advanced our understanding of the mechanisms which control excitability in human motor cortex. While it is clear that paired-pulse excitability depends on the exact interstimulus interval (ISI) between the first (S1) and second stimulus (S2), relatively little is known about the effects of the intensities of S1 and S2, and the effects of manipulating neurotransmission through the GABA(A) receptor. When recording the motor evoked potential (MEP) from the resting abductor digiti minimi (ADM) muscle, using a fixed ISI of 1.5 ms, and expressing the interaction between S1 and S2 as MEP(S1+S2)/(MEP(S1) + MEP(S2)), then a systematic variation of the intensities of S1 and S2 revealed short-interval intracortical facilitation (SICF) if S1 and S2 were approximately equal to MEP threshold (RMT), or if S1 > RMT and S2 < RMT. In contrast, short-interval intracortical inhibition (SICI) occurred if S1 < RMT and S2 > RMT. Contraction of the ADM left SICI unchanged but reduced SICF. The GABA(A) receptor agonist diazepam increased SICI and reduced SICF in the resting ADM while diazepam had no effect during ADM contraction. Surface EMG and single motor unit recordings revealed that during ADM contraction SICI onset was at the I3-wave latency of S2, whereas SICF typically "jumped up" by one I-wave and started with the I2-wave latency of S2. Findings suggest that SICI is mediated through a low-threshold GABA(A) receptor-dependent inhibitory pathway and summation of IPSP from S1 and EPSP from S2 at the corticospinal neurone. In contrast, SICF originates through non-synaptic facilitation at the initial axon segment of interneurones along a high-threshold excitatory pathway.

We sought to determine the activity of inhibiting and facilitating cortical circuits in areas surrounding a hand muscle motor representation in focal dystonia and in controls. In 15 patients with hand dystonia, 16 patients with blepharospasm, and age-matched controls, we applied suprathreshold transcranial magnetic stimuli with a figure-eight coil over the optimal representation of the relaxed abductor digiti minimi muscle of the dominant hand. Additional conditioning stimuli were given through a second figure-eight coil that was held either above the test coil or 2 cm or 4 cm apart in the anterior, posterior, lateral, or medial direction. We measured intracortical excitability in each of the nine positions of the conditioning coil. Intracortical inhibition was reduced in both patient groups at all conditioning coil positions. With both coils centered, the intracortical facilitation did not differ between patients and controls. After shifting the conditioning coil, the intracortical facilitation tended to be less diminished in patients than in controls, this difference between patients and controls was significant for the anterior, posterior, and medial 4-cm conditioning coil shift. Our results demonstrate decreased intracortical inhibition in the cortical hand muscle representation not only in patients with hand dystonia, but also in patients with blepharospasm. In addition, our findings in both patient groups show a trend toward a relatively increased intracortical facilitation in surrounding motor areas., (Copyright 2002 Movement Disorder Society)