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Abstract Distinguishing Parkinson’s disease (PD) subgroups may be achieved by observing network responses to external stimuli. We compared TMS-evoked potential (TEP) measures from stimulation of bilateral motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), and visual cortex (V1) between 62 PD patients (age: 69.9 ± 7.5) and 76 healthy controls (age: 69.2 ± 4.3) using a TMS–EEG protocol. TEP measures were analyzed using two-way ANCOVA adjusted for MOCA. PD patients were divided into tremor dominant (TD), non-tremor dominant (NTD) and rapid disease progression (RDP) subgroups. PD patients showed lower wide-waveform adherence (wWFA) (p = 0.025) and interhemispheric connectivity (IHCCONN) (p

Non-invasive ultrasound neuromodulation has experienced exponential growth in the neuroscientific literature, recently also including clinical studies and applications. However, clinical recommendations for the secure and effective application of ultrasound neuromodulation in pathological brains are currently lacking. Here, clinical experts with neuroscientific expertise in clinical brain stimulation and ultrasound neuromodulation present initial clinical recommendations for ultrasound neuromodulation with relevance for all ultrasound neuromodulation techniques. The recommendations start with methodological safety issues focusing on technical issues to avoid harm to the brain. This is followed by clinical safety issues focusing on important factors concerning pathological situations.

Objectives: To investigate the plastic effects of parieto-motor (PAR-MOT) cortico-cortical paired associative paired stimulation (cc-PAS) in patients with two forms of focal dystonia, writer's cramp and cervical dystonia, compared to healthy volunteers (HVs). Methods: We used cc-PAS to induce associative plasticity using repeated time-locked paired transcranial magnetic stimulation (TMS) pulses over the parietal and motor cortices in 16 patients with writer's cramp (WC), 13 patients with cervical dystonia (CD), and 23 healthy volunteers. We measured parieto-motor corticocortical connectivity using posterior parietal cortex (PPC) to primary motor cortex (M1) facilitation and input-output curves (IOC) of the motor-evoked potential (MEP) before and after PAR-MOT cc-PAS. The PAR-MOT cc-PAS consisted of 100 pairs of TMS pulses every 5 s, with the conditioning pulse applied to the left angular gyrus in the intraparietal sulcus and the test pulse applied to the M1 hotspot of the first dorsal interosseous muscle. Results: The cc-PAS increased the area under the IOC by increasing its maximum level in patients with WC but not in patients with CD or healthy volunteers. The cc-PAS had no significant effect on other IOC parameters. There were no significant differences in PPC to M1 facilitation changes after PAR-MOT cc-PAS among all groups. Conclusions: This study suggests that PAR-MOT cc-PAS abnormally increases M1 excitability in patients with WC but not in those with CD. Additionally, this increased plastic response in patients with WC does not appear to be directly linked to PPC to M1 corticocortical connectivity.

Abstract Background A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson’s disease (PD). Objective Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG). Methods A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson’s Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity. Results A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups. Conclusions An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease. Trial Registration Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 – Sept 13, 2022.

We report a case of a new-onset, persistent tremor that developed during a clinical trial (NCT02927236) of intermittent theta burst stimulation [iTBS, a form of repetitive magnetic transcranial magnetic stimulation (rTMS)] for cocaine use disorder. Although the participant exhibited an exceptionally strong clinical response, subsequent unblinding revealed that they received sham iTBS. This case highlights the potential for strong functional neurological placebo responses in rTMS trials, and functional disorders might be a marker of a placebo response. Additionally, we note the possibility that the weak e-fields produced by some sham rTMS systems may induce clinically relevant effects.

Abstract Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.

Abstract Background and Objectives Ethanol has been reported to improve tremor severity in approximately two thirds of patients with essential tremor (ET), but the accuracy of that proportion is not certain and the mechanism of action is unknown. The goal of this study was to investigate alcohol response on tremor by applying an a priori objective response definition and subsequently to describe the responder rate to a standardized ethanol dose in a cohort of 85 ET patients. A secondary analysis evaluated other tremor and nontremor features, including demographics, tremor intensity, breath alcohol concentration, nontremor effects of alcohol, self‐reported responder status to ethanol, and prior ethanol exposure. Methods This was a prospective, open‐label, single‐dose challenge of oral ethanol during which motor and nonmotor measurements were obtained starting immediately prior to ethanol administration and subsequently every 20 min for 120 min. We defined tremor reduction as a 35% decline in power in the patient's tremor frequency recorded during spiral drawing 60 min after ethanol administration. Results In total, 80% of patients were considered alcohol responsive using our objective definition. Responder status and change in the objective tremor metrics were significantly correlated with the change in breath alcohol concentration levels after ethanol administration, but no other relationships to nontremor metrics were found. Discussion A high percentage of patients actually respond to acute ethanol. However, their self‐reported response does not correlate well with their objective response. Objective response correlates with breath alcohol level but not with sedation, indicating a specific effect of ethanol on tremor.

Abstract Background Deep brain stimulation (DBS) is a well-established treatment option for select patients with Parkinson’s Disease (PD). However, response to DBS varies, therefore, the ability to predict who will have better outcomes can aid patient selection. Some PD-related monogenic mutations have been reported among factors that influence response to DBS. However, monogenic disease accounts for only a minority of patients with PD. The polygenic risk score (PRS) is an indication of cumulative genetic risk for disease. The PRS in PD has also been correlated with age of onset and symptom progression, but it is unknown whether correlations exist between PRS and DBS response. Here, we performed a pilot study to look for any such correlation. Methods We performed a retrospective analysis of 33 PD patients from the NIH PD Clinic and 13 patients from the Parkinson’s Progression Markers Initiative database who had genetic testing and underwent bilateral subthalamic nucleus DBS surgery and clinical follow-up. A PD-specific PRS was calculated for all 46 patients based on the 90 susceptibility variants identified in the latest PD genome-wide association study. We tested associations between PRS and pre- and post-surgery motor and cognitive measures using multiple regression analysis for up to two years after surgery. Results Changes in scores on the Beck Depression Inventory (BDI) were not correlated with PRS when derived from all susceptibility variants, however, when removing pathogenic and high-risk carriers from the calculation, higher PRS was significantly associated with greater reduction in BDI score at 3 months and with similar trend 24 months after DBS. PRS was not a significant predictor of Unified Parkinson’s Disease Rating Scale, Dementia Rating Scale, or phenomic and semantic fluency outcomes at 3- and 24-months after DBS surgery. Conclusions This exploratory study suggests that PRS may predict degree of improvement in depressive symptoms after DBS, though was not predictive of motor and other cognitive outcomes after DBS. Additionally, PRS may be most relevant in predicting DBS outcomes in patients lacking pathogenic or high-risk PD variants. However, this was a small preliminary study and response to DBS treatment is multifactorial, therefore, more standardized high-powered studies are needed.

Abstract Sensory trick is a characteristic feature of cervical dystonia (CD), where a light touch on the area adjacent to the dystonia temporarily improves symptoms. Clinical benefit from sensory tricks can be observed before tactile contact is made or even by imagination. The supplementary motor area (SMA) may dynamically interact with the sensorimotor network and other brain regions during sensory tricks in patients with CD. In this study, we examined the functional connectivity of the SMA at rest and during sensory trick performance and imagination in CD patients compared to healthy controls using functional magnetic resonance imaging. The functional connectivity between the SMA and left intraparietal sulcus (IPS) region was lower in CD patients at rest and it increased with sensory trick imagination and performance. SMA-right cerebellum connectivity also increased with sensory trick imagination in CD patients, while it decreased in healthy controls. In CD patients, SMA connectivity increased in the brain regions involved in sensorimotor integration during sensory trick performance and imagination. Our study results showed a crucial role of SMA in sensorimotor processing during sensory trick performance and imagination and suggest the IPS as a novel potential therapeutic target for brain modulation.

BackgroundIt is well known that motor features of Parkinson’s disease (PD) commonly begin on one side of the body and extend to the other side with disease progression. The onset side generally remains more severely affected over the course of the disease. However, the pathophysiology underlying the asymmetry of motor manifestations remains unclear. The purpose of the present study is to examine whether alterations in neuronal activity in the subthalamic nucleus (STN) associate with PD severity.MethodsMicroelectrode recording was performed in the STN during targeting for 30 patients in the treatment of deep brain stimulation. The mean spontaneous firing rate (MSFR), power density spectral analysis, and correlations were calculated. Characteristics of subthalamic oscillatory activity were compared between two hemispheres. UPDRS III scores during “Off” and “On” states were obtained for the body side of initial symptoms (BSIS) and the body side of extended symptoms (BSES).ResultsThere were significant differences of MSFR (41.3 ± 11.0 Hz vs 35.2 ± 10.0 Hz) and percentage of ß frequency oscillatory neurons (51.3% vs 34.9%) between BSIS and BSES. The percentage of ß frequency oscillatory neurons correlated with the bradykinesia/rigidity scores for both sides (p < 0.05). In contrast, the percentage of tremor frequency oscillatory neurons was significantly higher in the BSES than that in the BSIS. In particular, these neurons only correlated with the tremor scores of the BSES (p < 0.05).ConclusionThe results suggest that increased neuronal firing rate and ß frequency oscillatory neurons in the STN are associated with contralateral side motor severity and its progression. Tremor frequency oscillatory neurons are less observed in the STN of the BSIS suggesting that ß oscillatory activity dominates and tremor frequency oscillatory activity reciprocally declines.

Background: Blepharospasm (BSP) is a focal dystonia. There is a lack of standardization in the length of time necessary to get a measure of BSP severity for rating scales.Objectives: 1) Determine the difference between evaluating the number of eye closures in patients with blepharospasm in 1 vs. 2 min. 2) Characterize the prevalence, phenomenology and concordance of sensory trick in subjects with only blepharospasm compared to those with blepharospasm associated with other dystonias of the head.Methods: Thirty-eight, 2-min-long standardized videos of subjects with BSP without any other dystonias were reviewed (group1). Eye closure rate was measured in 0–60 s vs. 60–120 s. Wilcoxon signed-rank test and Spearman correlation coefficient were used to compare the eye closure rate between these two intervals. An additional 68 standardized videos of subjects with blepharospasm associated with dystonia of the head were reviewed (group2). Presence, phenomenology and concordance between what subjects verbally reported as their sensory trick and what they demonstrated was classified for both groups then qualitatively compared.Results/conclusion: Eye closure rates between 0–60 s and 0–120 s were not statistically different. There is no added benefit of counting the number of eye closures in 2 min, compared to 1 min, in patients with BSP. Sensory trick was reported by 57% of subjects with BSP and 80% of subjects who have blepharospasm and other dystonias of the head. With 100% and 97% concordance, patients’ self-reported sensory trick accurately describes the movements that alleviate their dystonic movements.

Abstract Within the last decade, ultrasound has been “rediscovered” as a technique for brain therapies. Modern technologies allow focusing ultrasound through the human skull for highly focal tissue ablation, clinical neuromodulatory brain stimulation, and targeted focal blood‐brain‐barrier opening. This article gives an overview on the state‐of‐the‐art of the most recent application: ultrasound neuromodulation as a new brain therapy. Although research centers have existed for decades, the first treatment centers were not established until 2020, and clinical applications are spreading rapidly.

Abstract There has been a growing appreciation for freezing of gait as a disabling symptom that causes a significant burden in Parkinson’s disease. Previous research has highlighted some of the key components that underlie the phenomenon, but these reductionist approaches have yet to lead to a paradigm shift resulting in the development of novel treatment strategies. Addressing this issue will require greater integration of multi-modal data with complex computational modeling, but there are a number of critical aspects that need to be considered before embarking on such an approach. This paper highlights where the field needs to address current gaps and shortcomings including the standardization of definitions and measurement, phenomenology and pathophysiology, as well as considering what available data exist and how future studies should be constructed to achieve the greatest potential to better understand and treat this devastating symptom.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by both motor and nonmotor symptoms. Although the basal ganglia is traditionally the primary brain region implicated in this disease process, this limited view ignores the roles of the cortex and cerebellum that are networked with the basal ganglia to support motor and cognitive functions. In particular, recent research has highlighted dysfunction in the supplementary motor complex (SMC) in patients with PD. Using the PubMed and Google Scholar search engines, we identified research articles using keywords pertaining to the involvement of the SMC in action sequencing impairments, temporal processing disturbances, and gait impairment in patients with PD. A review of abstracts and full-text articles was used to identify relevant articles. In this review of 63 articles, we focus on the role of the SMC in PD, highlighting anatomical and functional data to create new perspectives in understanding clinical symptoms and, potentially, new therapeutic targets. The SMC has a nuanced role in the pathophysiology of PD, with both hypo- and hyperactivation associated with various symptoms. Further studies using more standardized patient populations and functional tasks are needed to more clearly elucidate the role of this region in the pathophysiology and treatment of PD.

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans.Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject’s age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be “safe” where they are applying stimulation beyond that examined in published studies that also investigated potential side effects.Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs.

Objective: Sialidosis is an inborn error of metabolism. There is evidence that the myoclonic movements observed in this disorder have a cortical origin, but this mechanism does not fully explain the bilaterally synchronous myoclonus activity frequently observed in many patients. We present evidence of a subcortical basis for synchronous myoclonic phenomena. Methods: Electromyographic investigations were undertaken in two molecularly and biochemically confirmed patients with sialidosis type-1. Results: The EMG recordings showed clear episodes of bilaterally synchronous myoclonic activity in contralateral homologous muscles. We also observed a high muscular-muscular coherence with near-zero time-lag between these muscles. Conclusion: The absence of coherence phase lag between the right-and-left homologous muscles during synchronous events indicates that a unilateral cortical source cannot fully explain the myoclonic activity. There must exist a subcortical mechanism for bilateral synchronization accounting for this phenomenon. Significance: Understanding this mechanism may illuminate cortical-subcortical relationships in myoclonus.

Abstract Background There is rare reports about opinions and clinical practice of functional movement disorders (FMD) in China. The present survey aimed to investigate the views of FMD in Chinese clinicians. Methods The Chinese version survey of FMD were conducted in nationwide practitioners by means of an online questionnaire. Results Four hundred and thirty-four Chinese clinicians completed a 21-item questionnaire probing diagnostic and management issues in FMD. More than 80% of respondents considered that atypical movement disorder, multiple somatizations, and emotional disturbance were essential or absolutely necessary for clinically definite diagnosis of FMD. About three quarters of respondents requested standard neurological investigations to rule out organic causes. Over half believed that prior diagnosis of an organic disorder (59.9%), lack of associated non-physiologic deficits (51.8%), and evidence of physical injury (50.0%) were ‘very influential’ or ‘extremely influential’ for a non-FMD diagnosis. The majority (77.4%) of the respondents may refer patients to a neuropsychiatrist or psychiatrist experienced in FMD, followed by psychologist or psychotherapist experienced in FMD (53.2%). However, lack of guidelines, physician knowledge, and training often limited clinicians’ ability in managing patients with FMD. Early diagnosis of FMD, identification and management of concurrent psychiatric disorder, and acceptance of the diagnosis by the patient were considered most important for predicting a favorable prognosis. Conclusions Opinions and clinical practice of Chinese practitioners not only varied among Chinese neurologists, but also differed from international peers. Combined efforts are needed to promote related research and establish practice guidelines in China in the future.

The problem of whether we can execute free acts or not is central in philosophical thought, and it has been studied by numerous scholars throughout the centuries. Recently, neurosciences have entered this topic contributing new data and insights into the neuroanatomical basis of cognitive processes. With the advent of connectomics, a more refined landscape of brain connectivity can be analysed at an unprecedented level of detail. Here, we identify the connectivity network involved in the movement process from a connectomics point of view, from its motivation through its execution until the sense of agency develops. We constructed a “volitional network” using data derived from the Brainnetome Atlas database considering areas involved in volitional processes as known in the literature. We divided this process into eight processes and used Graph Theory to measure several structural properties of the network. Our results show that the volitional network is small-world and that it contains four communities. Nodes of the right hemisphere are contained in three of these communities whereas nodes of the left hemisphere only in two. Centrality measures indicate the nucleus accumbens is one of the most connected nodes in the network. Extensive connectivity is observed in all processes except in Decision (to move) and modulation of Agency, which might correlate with a mismatch mechanism for perception of Agency.

Background Assessment of essential tremor is often done by a trained clinician who observes the limbs during different postures and actions and subsequently rates the tremor. While this method has been shown to be reliable, the inter- and intra-rater reliability and need for training can make the use of this method for symptom progression difficult. Many limitations of clinical rating scales can potentially be overcome by using inertial sensors, but to date many algorithms designed to quantify tremor have key limitations. Methods We propose a novel algorithm to characterize tremor using inertial sensors. It uses a two-stage approach that 1) estimates the tremor frequency of a subject and only quantifies tremor near that range; 2) estimates the tremor amplitude as the portion of signal power above baseline activity during recording, allowing tremor estimation even in the presence of other activity; and 3) estimates tremor amplitude in physical units of translation (cm) and rotation (°), consistent with current tremor rating scales. We validated the algorithm technically using a robotic arm and clinically by comparing algorithm output with data reported by a trained clinician administering a tremor rating scale to a cohort of essential tremor patients. Results Technical validation demonstrated rotational amplitude accuracy better than ±0.2 degrees and position amplitude accuracy better than ±0.1 cm. Clinical validation revealed that both rotation and position components were significantly correlated with tremor rating scale scores. Conclusion We demonstrate that our algorithm can quantify tremor accurately even in the presence of other activities, perhaps providing a step forward for at-home monitoring.

Abstract Background Diagnosis of functional movement disorders and specifically functional tremor (FT) (representing 50% of them) remains demanding. Additionally, due to heterogeneity of the disorders, structured concepts and guidelines for diagnosis and therapy are difficult to establish. Ascertaining the state of knowledge to derive instructions for operating procedures is the aim of this review. Main text Based on a standardized systematic literature research using the term “psychogenic tremor” in the MEDLINE database dating back ten years, 76 studies were evaluated. Conventional features of FT are variability of frequency and amplitude. Further, response to distraction by motor and cognitive tasks is a key diagnostic feature in differentiation between organic and functional origin. A variety of electrophysiological tests have been evaluated including surface electromyography and accelerometry to establish laboratory-supported criteria for diagnosing tremor. Also, finger tapping tests have been used to identify FT, showing positive potential as supplementary evidence. Imaging studies in general are mostly underpowered and imaging cannot be used on an individual basis. Therapeutic studies in FT often have a diagnostic component. Cognitive behavioral therapy should be the preferred psychological treatment independent of additional psychiatric symptoms. Other psychotherapeutic methods show lack of evidence concerning FT. Relaxation techniques and physiotherapy are an important additional feature, especially in children and adolescents. In regard to drug therapy, randomized and blinded trials are not available. A significant decrease in rating scales could be detected after active, not sham repetitive transcranial magnetic stimulation with a long-lasting effect. Also root magnetic stimulation seems to be effective. The clinical feature of tremor entrainment in FT can be used in combination with biofeedback as so-called tremor retrainment, using self-modulation of frequency and severity, to bring the movements under volitional control. Conclusion Diagnosis and treatment of FT is challenging and should include a combination of intensive clinical examination and targeted addition of standardized testing, especially electrophysiological methods. Often therapeutic effects have a diagnostic component. A multimodal strategy, considering psychological factors as a potential origin as well as maintaining effects seems to be most effective.

Background: Neuroimaging technology is being developed to enable non-invasive mapping of the latency distribution of cortical projection pathways in white matter, and correlative clinical neurophysiological techniques would be valuable for mutual verification. Interhemispheric interaction through the corpus callosum can be measured with interhemispheric facilitation and inhibition using transcranial magnetic stimulation. Objective: To develop a method for determining the latency distribution of the transcallosal fibers with transcranial magnetic stimulation. Methods: We measured the precise time courses of interhemispheric facilitation and inhibition with a conditioning-test paired-pulse magnetic stimulation paradigm. The conditioning stimulus was applied to the right primary motor cortex and the test stimulus was applied to the left primary motor cortex. The interstimulus interval was set at 0.1 ms resolution. The proportions of transcallosal fibers with different conduction velocities were calculated by measuring the changes in magnitudes of interhemispheric facilitation and inhibition with interstimulus interval. Results: Both interhemispheric facilitation and inhibition increased with increment in interstimulus interval. The magnitude of interhemispheric facilitation was correlated with that of interhemispheric inhibition. The latency distribution of transcallosal fibers measured with interhemispheric facilitation was also correlated with that measured with interhemispheric inhibition. Conclusions: The data can be interpreted as latency distribution of transcallosal fibers. Interhemispheric interaction measured with transcranial magnetic stimulation is a promising technique to determine the latency distribution of the transcallosal fibers. Similar techniques could be developed for other cortical pathways.

Objective: The electrophysiological classification of tremors can be a key element in the diagnosis and can facilitate treatment of a patient with tremor; however, the ability to conduct electrophysiological studies of tremor is not widely available. The purpose of this study was to develop and validate a free online platform for tremor analysis. Methods: An online platform for tremor analysis was developed using “R” language; called “Tremoroton”. For validation, we compared the frequency estimation of the tremor obtained with Tremoroton compared with a commercially available software in a cohort of 20 patients (10 with essential tremor and 10 with Parkinson diagnosis), comparing the activity recorded on the accelerometer, extensor carpi radialis and flexor carpi radialis EMG. An intraclass correlation coefficient was used for the comparison. Results: The final version of tremoroton is now online. It allows reading up to 6 channels, and will do time, frequency, time-frequency analysis and calculate coherence. We demonstrated a high correlation in frequency measurements (0.97 (0.945–0.984, 95% IC) for the accelerometers, 0.98 (0.977–0.994, 95% IC) for the extensor carpi radialis EMG, and 0.99 (0.987–0.997, 95% IC) for the flexor carpi radialis EMG) when compared to a commercial software. Conclusion: We were able to develop and validate a free online platform for tremor analysis. Significance: Making this tool available should help expanding tremor analysis techniques from research to the clinical setting.

Objective: The back-average technique is very useful to study the relation between the activity in the cortex and the muscles. It has two main clinical applications, Bereitschaftspotential (BP) recording and myoclonus studies. The BP is a slow wave negativity originating in the supplementary motor cortex and premotor cortex that precedes voluntary movements. This wave also precedes involuntary movements in functional movement disorders (FMD), and it can be used as a helpful diagnostic tool. For the myoclonus studies, the back-average technique is very important to help localizing the source of the myoclonus. The hardware needed to do BP or myoclonus studies is standard and available in any electrophysiology lab, but there are not many software solutions to do the analysis. In this article together with describing the methodology that we use for recording clinical BPs and myoclonus, we present BacAv, an online free application that we developed for the purpose of doing back-average analysis. Methods: BacAv was developed in “R” language using Rstudio, a free integrated development environment. The recommended parameters for the data acquisition for BP recording and myoclonus studies are given in this section. Results: The platform was successfully developed, is able to read txt files, look for muscle bursts, segment the data, and plot the average. The parameters of the algorithm that look for the muscle bursts can be adapted according to the characteristics of the dataset. Conclusion: We have developed software for clinicians who do not have sophisticated equipment to do back-averaging. Significance: This tool will make this useful analysis method more available in a clinical environment.

Despite recent advances in tremor and dystonia classification, it remains difficult to discriminate essential tremor from dystonic tremor as they are similar in appearance and no biomarker exists. Further, tremor can appear in the same or a different body part than the dystonia. The aim of the current study was to better understand the differential pathophysiology of these tremors.We designed a cross-sectional case-control study and recruited 16 patients with essential tremor, 16 patients with dystonic tremor, and 17 age-matched healthy volunteers. We used multi-modal imaging combining resting-state functional MRI, diffusion tensor imaging, and magnetic resonance spectroscopy. We measured functional connectivity of resting-state fMRI to assess connectivity in the tremor network, fractional anisotropy and mean diffusivity with diffusion tensor imaging, and GABA+, Glutamate/Glutamine, Choline, and N-Acetylaspartate with spectroscopy (adjusted to Creatine).Our results showed reduced functional connectivity of resting-state fMRI between the cerebellum and dentate nucleus bilaterally for the essential tremor group, but not the dystonic tremor group, compared to healthy volunteers. There was higher fractional anisotropy in the middle cerebellar peduncle bilaterally for the dystonic tremor group compared to the essential tremor group as well as for essential tremor group compared to healthy volunteers. There was also higher fractional anisotropy in the red nucleus and corticospinal tract for essential tremor and dystonic tremor groups compared to healthy volunteers. We also showed reduced mean diffusivity in the cerebellum of both essential tremor and dystonic tremor groups compared to healthy volunteers. Finally, we found elevated GABA+/Cr in the cerebellum of the essential tremor and dystonic tremor groups compared to healthy volunteers, but no difference emerged between essential tremor and dystonic tremor groups. We did not find group differences in the other metabolites.Our results indicate cerebellar alterations in essential tremor and dystonic tremor patients compared to healthy volunteers, and further changes in the cerebellum network for the dystonic tremor patients. suggesting that the cerebellum is affected differently in both tremors.

Working memory (WM) impairment is one of the most frequent cognitive deficits in Parkinson's disease (PD). However, it is not known how neural activity is altered and compensatory responses eventually fail during progression. We aimed to elucidate neural correlates of WM and compensatory mechanisms in PD. Eighteen cognitively normal PD patients (PD-CogNL), 16 with PD with mild cognitive impairment (PD-MCI), 11 with PD with dementia (PDD), and 17 healthy controls (HCs) were evaluated. Subjects performed an n-back task. Functional MRI data were analyzed by event-related analysis for correct responses. Brain activations were evaluated by comparing them to fixation cross or 0-back task, and correlated with n-back task performance. When compared to fixation cross, PD-CogNL patients had more activation in WM areas than HCs for both the 2- and 3-back tasks. PD-MCI and PDD patients had more activation in WM areas than HCs for the 0- and 1-back task. 2-back task performance was correlated with brain activations (vs. 0-back task) in the bilateral dorsolateral prefrontal cortex and frontal eye field (FEF) and left rostral prefrontal cortex, caudate nucleus, inferior/superior parietal lobule (IPL/SPL), and anterior insular cortex as well as anterior cingulate cortex. 3-back task performance was correlated with brain activations (vs. 0-back task) in the left FEF, right caudate nucleus, and bilateral IPL/SPL. Additional activations on top of the 0-back task, rather than fixation cross, are the neural correlates of WM. Our results suggest PD patients have two types of compensatory mechanisms: (1) Hyperactivation for different WM load tasks depending on their cognitive status. PD-CogNL have hyperactivation for moderate and heavy working memory load tasks while maintaining normal working memory performance. In contrast, PD-MCI and PDD have hyperactivation for control task and light working memory load task, leaving less neural resources to further activate for more demanding tasks and resulting in impaired working memory performance. (2) Bilateral recruitment of WM-related areas, in particular the DLPFC, FEF, IPL/SPL and caudate nucleus, to improve WM performance.

Functional integration between two hemispheres is crucial for perceptual binding to occur when visual stimuli are presented in the midline of the visual field. Mima and colleagues (2001) showed using EEG that midline object recognition was associated with task-related decrease in alpha band power (alpha desynchronisation) and a transient increase in interhemispheric coherence. Our objective in the current study was to replicate the results of Mima et al. and to further evaluate interhemispheric effective connectivity during midline object recognition in source space. We recruited 11 healthy adult volunteers and recorded EEG from 64 channels while they performed a midline object recognition task. Task-related power and coherence were estimated in sensor and source spaces. Further, effective connectivity was evaluated using Granger causality. While we were able to replicate the alpha desynchronisation associated with midline object recognition, we could not replicate the coherence results of Mima et al. The data-driven approach that we employed in our study localised the source of alpha desynchronisation over the left occipito-temporal region. In the alpha band, we further observed significant increase in imaginary part of coherency between bilateral occipito-temporal regions during object recognition. Finally, Granger causality analysis between the left and right occipito-temporal regions provided an insight that even though there is bidirectional interaction, the left occipito-temporal region may be crucial for integrating the information necessary for object recognition. The significance of the current study lies in using high-density EEG and applying more appropriate and robust measures of connectivity as well as statistical analysis to validate and enhance our current knowledge on the neural basis of midline object recognition.

One of the great mysteries in dystonia pathophysiology is the role of environmental factors in disease onset and development. Progress has been made in defining the genetic components of dystonic syndromes, still the mechanisms behind the discrepant relationship between dystonic genotype and phenotype remain largely unclear. Within this review, the preclinical and clinical evidence for environmental stressors as disease modifiers in dystonia pathogenesis are summarized and critically evaluated. The potential role of extragenetic factors is discussed in monogenic as well as adult-onset isolated dystonia. The available clinical evidence for a “second hit” is analyzed in light of the reduced penetrance of monogenic dystonic syndromes and put into context with evidence from animal and cellular models. The contradictory studies on adult-onset dystonia are discussed in detail and backed up by evidence from animal models. Taken together, there is clear evidence of a gene-environment interaction in dystonia, which should be considered in the continued quest to unravel dystonia pathophysiology.

Variability in the response of individuals to various non-invasive brain stimulation protocols is a major problem that limits their potential for clinical applications. Baseline motor-evoked potential (MEP) amplitude is the key predictor of an individual’s response to transcranial magnetic stimulation protocols. However, the factors that predict MEP amplitude and its variability remain unclear. In this study, we aimed to identify the input–output curve (IOC) parameters that best predict MEP amplitude and its variability. We analysed IOC data from 75 subjects and built a general linear model (GLM) using the IOC parameters as regressors and MEP amplitude at 120% resting motor threshold (RMT) as the response variable. We bootstrapped the data to estimate variability of IOC parameters and included them in a GLM to identify the significant predictors of MEP amplitude variability. Peak slope, motor threshold, and maximum MEP amplitude of the IOC were significant predictors of MEP amplitude at 120% RMT and its variability was primarily driven by the variability of peak slope and maximum MEP amplitude. Recruitment gain and maximum corticospinal excitability are the key predictors of MEP amplitude and its variability. Inter-individual variability in motor output may be reduced by achieving a uniform IOC slope.

Background: Motor surround inhibition (mSI) is a phenomenon supportive for executing selective finger movements, wherein synergist muscles are selectively facilitated while surround muscles are inhibited. Previous studies of conditioning inputs to several intracortical and cortico-cortical inhibitory networks did not show an influence on mSI. The inhibitory posterior parietal-motor network, which is crucial for executing fine movements, however, has not been studied. Objective/hypothesis: To investigate the role of inhibitory posterior parietal-motor network in mSI. We hypothesized that conditioning this inhibitory network would enhance mSI. Methods: 11 healthy adults completed study. mSI was elicited by applying a TMS pulse over the motor cortex coupled with or without a conditioning input to an inhibitory spot in the posterior parietal cortex at 2 or 4 ms interval. Results: Conditioning input to the posterior parietal cortex increased mSI by ∼20% Conclusion: The inhibitory posterior parietal-motor network appears to contribute to the genesis of mSI.

Functional movement disorders (FMDs), known over time as “hysteria”, “dissociative”, “conversion”, “somatoform”, “non-organic” and “psychogenic” disorders, are characterized by having a voluntary quality, being modifiable by attention and distraction but perceived by the patient as involuntary. Although a high prevalence of depression and anxiety is observed in these patients, a definitive role of psychiatric disorders in FMDs has not been proven, and many patients do not endorse such manifestations. Stressful events, social influences and minor trauma may precede the onset of FMDs, but their pathogenic mechanisms are unclear. Patients with FMDs have several abnormalities in their neurobiology including strengthened connectivity between the limbic and motor networks. Additionally, there is altered top-down regulation of motor activities and increased activation of areas implicated in self-awareness, self-monitoring, and active motor inhibition such as the cingulate and insular cortex. Decreased activation of the supplementary motor area (SMA) and pre-SMA, implicated in motor control and preparation, is another finding. The sense of agency defined as the feeling of controlling external events through one's own action also seems to be impaired in individuals with FMDs. Correlating with this is a loss of intentional binding, a subjective time compression between intentional action and its sensory consequences. Organic and functional dystonia may be difficult to differentiate since they share diverse neurophysiological features including decreased cortical inhibition, and similar local field potentials in the globus pallidus and thalamus; although increased cortical plasticity is observed only in patients with organic dystonia. Advances in the pathogenesis and pathophysiology of FMDs may be helpful to understand the nature of these disorders and plan further treatment strategies.

Objective: We report on two patients that presented to our clinic with the differential diagnosis of functional movement disorder vs tic disorder. Case reports: The first patient is a 23-year-old woman with a 3-year history of repetitive involuntary neck flexion movements. The second patient is a 59-year-old man with a 10-month history of involuntary trunk jerks. In both cases, the polyelectromyographic study and the observation of Bereitschaftspotential helped us in making the final diagnosis. Significance: The use of electrophysiological tools can be helpful in making the distinction between functional movement disorders and tic disorders. Keywords: Functional movement, Psychogenic movement, Tic, Bereitschaftspotential

The electrophysiological characterization of hand tremors is a useful method to complement the history and physical exam of tremor patients. Our article describes the methodology (recording, processing and interpretation) used in a diagnostic/phenotypic hand tremor study conducted in our lab at the Human Motor Control Section of the National Institute of Neurological Disorders and Stroke (NINDS), at the National Institutes of Health. The necessary equipment includes two one-axis accelerometers and four-channel electromyography (EMG). The hand tremor is recorded at rest, posture with and without weight loading, and during movement (kinetic). The recorded signals are analyzed in the time and frequency domains. The characterization of the dominant frequencies in the accelerometers and their relationship with the EMG frequencies are essential for the differential diagnosis of different tremor syndromes. We describe the electrophysiological characteristics of several tremor syndromes such as enhanced physiological tremor, essential tremor, Parkinson tremor, pharmacological-induced tremor, orthostatic tremor, and functional (psychogenic) tremor. Simplified guidance for adoption of tremor studies as a clinical tool in a movement disorders subspecialty clinic is provided. Keywords: Tremor, Electrophysiology, EMG, Accelerometry

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal postures, repetitive movements, or both. Research in dystonia has been challenged by several factors. First, dystonia is uncommon. Dystonia is not a single disorder but a family of heterogenous disorders with varied clinical manifestations and different causes. The different subtypes may be seen by providers in different clinical specialties including neurology, ophthalmology, otolaryngology, and others. These issues have made it difficult for any single center to recruit large numbers of subjects with specific types of dystonia for research studies in a timely manner. The Dystonia Coalition is a consortium of investigators that was established to address these challenges. Since 2009, the Dystonia Coalition has encouraged collaboration by engaging 56 sites across North America, Europe, Asia, and Australia. Its emphasis on collaboration has facilitated establishment of international consensus for the definition and classification of all dystonias, diagnostic criteria for specific subtypes of dystonia, standardized evaluation strategies, development of clinimetrically sound measurement tools, and large multicenter studies that document the phenotypic heterogeneity and evolution of specific types of dystonia.

Spinocerebellar Ataxia type 7 (SCA7) is a neurodegenerative disease characterized by progressive cerebellar ataxia and retinal degeneration. Increasing loss of visual function complicates the use of clinical scales to track the progression of motor symptoms, hampering our ability to develop accurate biomarkers of disease progression, and thus test the efficacy of potential treatments. We aimed to identify imaging measures of neurodegeneration, which may more accurately reflect SCA7 severity and progression. While common structural MRI techniques have been previously used for this purpose, they can be biased by neurodegeneration-driven increases in extracellular CSF-like water. In a cross-sectional study, we analyzed diffusion tensor imaging (DTI) data collected from a cohort of 13 SCA7 patients and 14 healthy volunteers using: 1) a diffusion tensor-based image registration technique, and 2) a dual-compartment DTI model to control for the potential increase in extracellular CSF-like water. These methodologies allowed us to assess both volumetric and microstructural abnormalities in both white and gray matter brain-wide in SCA7 patients for the first time. To measure tissue volume, we performed diffusion tensor-based morphometry (DTBM) using the tensor-based registration. To assess tissue microstructure, we computed the parenchymal mean diffusivity (pMD) and parenchymal fractional anisotropy (pFA) using the dual compartment model. This model also enabled us to estimate the parenchymal volume fraction (pVF), a measure of parenchymal tissue volume within a given voxel. While DTBM and pVF revealed tissue loss primarily in the brainstem, cerebellum, thalamus, and major motor white matter tracts in patients (p 1), pMD and pFA detected microstructural abnormalities in virtually all tissues brain-wide (p 1). The Scale for the Assessment and Rating of Ataxia trended towards correlation with cerebellar pVF (r = −0.66, p = 0.104, FDR corrected) and global white matter pFA (r = −0.64, p = 0.104, FDR corrected). These results advance our understanding of neurodegeneration in living SCA7 patients by providing the first voxel-wise characterization of white matter volume loss and gray matter microstructural abnormalities. Moving forward, this comprehensive approach could be applied to characterize the full spatiotemporal pattern of neurodegeneration in SCA7, and potentially develop an accurate imaging biomarker of disease progression.

Functional neurological disorder (FND) was of great interest to early clinical neuroscience leaders. During the 20th century, neurology and psychiatry grew apart – leaving FND a borderland condition. Fortunately, a renaissance has occurred in the last two decades, fostered by increased recognition that FND is prevalent and diagnosed using “rule-in” examination signs. The parallel use of scientific tools to bridge brain structure - function relationships has helped refine an integrated biopsychosocial framework through which to conceptualize FND. In particular, a growing number of quality neuroimaging studies using a variety of methodologies have shed light on the emerging pathophysiology of FND. This renewed scientific interest has occurred in parallel with enhanced interdisciplinary collaborations, as illustrated by new care models combining psychological and physical therapies and the creation of a new multidisciplinary FND society supporting knowledge dissemination in the field. Within this context, this article summarizes the output of the first International FND Neuroimaging Workgroup meeting, held virtually, on June 17th, 2020 to appraise the state of neuroimaging research in the field and to catalyze large-scale collaborations. We first briefly summarize neural circuit models of FND, and then detail the research approaches used to date in FND within core content areas: cohort characterization; control group considerations; task-based functional neuroimaging; resting-state networks; structural neuroimaging; biomarkers of symptom severity and risk of illness; and predictors of treatment response and prognosis. Lastly, we outline a neuroimaging-focused research agenda to elucidate the pathophysiology of FND and aid the development of novel biologically and psychologically-informed treatments.

Schizophrenic patients often do not have the sense that they direct their own movements or author their own thoughts (passivity phenomena). As willing must precede movement to be causal and thus generate the sense of agency, it is possible that the timing between the senses of willing and movement is shortened in schizophrenia. We tested the subjective perception of this time interval in patients with schizophrenia using a method based on Libet’s paradigm, in which subjects specify a time W – the time of willing a movement – and a time M – the time that movement occurred. Patients with schizophrenia and healthy volunteers made voluntary movements at times of their own choice while looking at a fast-rotating clock on a computer screen and reported when their movements were willed and made. We recorded surface electromyography to determine the time of actual movement, and electroencephalography to record brain potentials associated with movement. Results showed a significantly reduced interval between the reported M and W in patients with respect to the healthy volunteers (p < 0.05). Specifically, patients did not report a significant difference in the timing of W at 19 ms prior to movement onset and M at 7.4 ms prior to movement onset (p > 0.05), while the control group experienced a time W at 100 ms prior to movement onset and this differed significantly from their time M at 19 ms prior to movement onset (p < 0.01). These results suggest that patients with schizophrenia do have an altered timing of awareness of action – or an impaired judgment of the sequence of events – and that this might be etiologic in the development of the abnormal sense of agency.

Abstract Ultrasound‐based brain stimulation techniques may become a powerful new technique to modulate the human brain in a focal and targeted manner. However, for clinical brain stimulation no certified systems exist and the current techniques have to be further developed. Here, a clinical sonication technique is introduced, based on single ultrashort ultrasound pulses (transcranial pulse stimulation, TPS) which markedly differs from existing focused ultrasound techniques. In addition, a first clinical study using ultrasound brain stimulation and first observations of long term effects are presented. Comprehensive feasibility, safety, and efficacy data are provided. They consist of simulation data, laboratory measurements with rat and human skulls and brains, in vivo modulations of somatosensory evoked potentials (SEP) in healthy subjects (sham controlled) and clinical pilot data in 35 patients with Alzheimer's disease acquired in a multicenter setting (including neuropsychological scores and functional magnetic resonance imaging (fMRI)). Preclinical results show large safety margins and dose dependent neuromodulation. Patient investigations reveal high treatment tolerability and no major side effects. Neuropsychological scores improve significantly after TPS treatment and improvement lasts up to three months and correlates with an upregulation of the memory network (fMRI data). The results encourage broad neuroscientific application and translation of the method to clinical therapy and randomized sham‐controlled clinical studies.

Human locomotion involves a complex interplay among multiple brain regions and depends on constant feedback from the visual system. We summarize here the current understanding of the relationship among fixations, saccades, and gait as observed in studies sampling eye movements during locomotion, through a review of the literature and a synthesis of the relevant knowledge on the topic. A significant overlap in locomotor and saccadic neural circuitry exists that may support this relationship. Several animal studies have identified potential integration nodes between these overlapping circuitries. Behavioral studies that explored the relationship of saccadic and gait-related impairments in normal conditions and in various disease states are also discussed. Eye movements and locomotion share many underlying neural circuits, and further studies can leverage this interplay for diagnostic and therapeutic purposes.

Objective: To investigate GABA-ergic receptor density and associated brain functional and grey matter changes in focal hand dystonia (FHD). Methods: 18 patients with FHD of the right hand and 18 age and gender matched healthy volunteers (HV) participated in this study. We measured the density of GABA-A receptors using [11C] Flumazenil and perfusion using [15O] H2O. Anatomical images were also used to measure grey matter volume with voxel-based morphometry (VBM). Results: In FHD patients compared to HV, the vermis VI of the right cerebellum and the left sensorimotor cortex had a decrease of Flumazenil binding potential (FMZ-BP), whereas the striatum and the lateral cerebellum did not show significant change. Bilateral inferior prefrontal cortex had increased FMZ-BP and an increase of perfusion, which correlated negatively with disease duration. Only the left sensorimotor cortex showed a decrease of grey matter volume. Interpretation: Impairments of GABAergic neurotransmission in the cerebellum and the sensorimotor cortical areas could explain different aspects of loss of inhibitory control in FHD, the former being involved in maladaptive plasticity, the latter in surround inhibition. Reorganization of the inferior prefrontal cortices, part of the associative network, might be compensatory for the loss of inhibitory control in sensorimotor circuits. These findings suggest that cerebellar and cerebral GABAergic abnormalities could play a role in the functional imbalance of striato-cerebello-cortical loops in dystonia. Keywords: Cerebellum, Motor cortex, Focal dystonia, Inhibition, Movement disorder

Neuroimaging studies suggest that corticolimbic dysfunctions, including increased amygdala reactivity to emotional stimuli and heightened fronto-amygdala coupling, play a central role in the pathophysiology of functional movement disorders (FMD). Transcranial magnetic stimulation (TMS) has the potential to probe and modulate brain networks implicated in neuropsychiatric disorders, including FMD. Therefore, the objective of this proof-of-concept study was to investigate the safety, tolerability and preliminary efficacy of fronto-amygdala neuromodulation via targeted left prefrontal intermittent theta burst stimulation (iTBS) on brain and behavioral manifestations of FMD. Six subjects with a clinically defined diagnosis of FMD received three open-label iTBS sessions per day for two consecutive study visits. Safety and tolerability were assessed throughout the trial. Amygdala reactivity to emotionally valenced stimuli presented during an fMRI task and fronto-amygdala connectivity at rest were evaluated at baseline and after each stimulation visit, together with subjective levels of arousal and valence in response to affective stimuli. The FMD symptom severity was assessed at baseline, during treatment and 24 h after the last iTBS session. Multiple doses of iTBS were well-tolerated by all participants. Intermittent TBS significantly decreased fronto-amygdala connectivity and influenced amygdala reactivity to emotional stimuli. These neurocircuitry changes were associated to a marked reduction in FMD symptom severity. Corticolimbic modulation via iTBS represents a promising treatment for FMD that warrants additional research.

Abstract Photophobia is a common symptom seen in many neurologic disorders, however, its pathophysiology remains unclear. Even the term is ambiguous. In this paper, we review the epidemiology and clinical manifestations of photophobia in neurological disorders, including primary headache, blepharospasm, progressive supranuclear palsy, and traumatic brain injury, discuss the definition, etiology and pathogenesis, and summarize practical methods of diagnosis and treatment.

BackgroundShort-latency intracortical inhibition (SICI) and motor surround inhibition (mSI) are cortical phenomena that have been investigated with transcranial magnetic stimulation (TMS). mSI is believed to be necessary for the execution of fine finger movements, SICI may participate in mSI genesis, and however, the mechanisms underlying both mSI and SICI are not entirely clear.ObjectiveWe explored the cortical physiology of SICI and mSI in healthy subjects by TMS-evoked cortical potentials (TEPs).Methods:Single (sp) and paired-pulse (pp) TMS were delivered on the ADM muscle cortical hotspot while recording EEG and EMG. Three conditions were tested: spTMS and ppTMS at rest, and spTMS at the onset of an index finger movement. SICI and mSI were calculated on the ADM motor evoked potential (MEP) and two groups were defined based on the presence of mSI. Average TEPs were calculated for each condition and for five regions of interest.ResultsAt movement onset we observed a widespread reduction of the inhibitory late component N100 suggesting cortical facilitation associated with motor performance. At motor cortex level, SICI and mSI are associated with similar modulation of TEPs consisting in a reduction of P30 and an increase of N45 amplitude.ConclusionOur findings suggest that SICI and mSI modulate cortical excitability with shared inhibitory mechanisms.

Background: The mesial prefrontal cortex, cingulate cortex, and the ventral striatum are key nodes of the human mesial fronto-striatal circuit involved in decision-making and executive function and pathological disorders. Here we ask whether deep wide-field repetitive transcranial magnetic stimulation (rTMS) targeting the mesial prefrontal cortex (MPFC) influences resting state functional connectivity.Methods: In Study 1, we examined functional connectivity using resting state multi-echo and independent components analysis in 154 healthy subjects to characterize default connectivity in the MPFC and mid-cingulate cortex (MCC). In Study 2, we used inhibitory, 1 Hz deep rTMS with the H7-coil targeting MPFC and dorsal anterior cingulate (dACC) in a separate group of 20 healthy volunteers and examined pre- and post-TMS functional connectivity using seed-based and independent components analysis.Results: In Study 1, we show that MPFC and MCC have distinct patterns of functional connectivity with MPFC–ventral striatum showing negative, whereas MCC–ventral striatum showing positive functional connectivity. Low-frequency rTMS decreased functional connectivity of MPFC and dACC with the ventral striatum. We further showed enhanced connectivity between MCC and ventral striatum.Conclusions: These findings emphasize how deep inhibitory rTMS using the H7-coil can influence underlying network functional connectivity by decreasing connectivity of the targeted MPFC regions, thus potentially enhancing response inhibition and decreasing drug-cue reactivity processes relevant to addictions. The unexpected finding of enhanced default connectivity between MCC and ventral striatum may be related to the decreased influence and connectivity between the MPFC and MCC. These findings are highly relevant to the treatment of disorders relying on the mesio-prefrontal-cingulo-striatal circuit.

Volition and sense of agency are two primary components of a voluntary or internally generated movement. It has been shown that movement selection cannot be altered without interfering with the sense of volition using single pulse transcranial magnetic stimulation over the primary motor cortex. In the current study, we aimed at examining whether modulating the cortical excitability of the final effector in the voluntary motor pathway-the primary motor cortex, using transcranial direct current stimulation (tDCS) would alter movement selection. Our hypothesis was that anodal tDCS would increase motor cortical excitability and thereby decrease the threshold for movement execution, which could favor selection of the contralateral hand. We recruited 13 healthy adults to perform a movement selection task involving free-choice and externally-cued trials while applying real/sham tDCS in a C3-C4 dual-hemispheric electrode montage. Contrary to our hypothesis, we did not observe any effect of tDCS on movement selection either at the individual or group level. However, our data confirms the strong preference of right-handed individuals for the dominant right hand. We also found higher reaction time for internally generated movement compared to externally triggered movement. We therefore conclude that movement selection cannot be influenced at the level of primary motor cortex and that brain areas upstream of the primary motor cortex in the voluntary motor pathway may be possible targets for influencing movement selection.

10.17658/issn.2058-5462/issue-10/intro

In the above article [1], the following disclosures should have appeared. Dietrich Haubenberger is now employed by Neurocrine Biosciences, Inc., San Diego, CA 92130, USA. James McNames is an employee of APDM, Portland, OR 97201, USA, a company that may have a commercial interest in the results of this research and technology. This potential conflict of interest has been reviewed and managed by OHSU.