Impacts of ADHD Symptomatology on the Response to Cognitive-Behavioural Therapy with Gilles de la Tourette Syndrome Patients.

(1) Background: Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. Attention deficit and hyperactivity disorder (ADHD) is a common comorbidity of TS that adds further impairment. Cognitive-behavioural therapy (CBT) has shown efficacy in treating tics, yet its effectiveness in individuals with TS and comorbid ADHD remains unclear. Also, it is suggested that ADHD characteristics like executive dysfunction and inattention could hinder the response to CBT. This study aims to compare the response to CBT for tics and its maintenance six months post-therapy among TS individuals with and without ADHD symptoms. (2) Methods: In this study, 55 TS participants who completed 14-week CBT for tics were split into high (TS+) or low (TS-) ADHD symptomatology groups. Outcomes were evaluated using the Yale Global Tic Severity Scale (YGTSS) regarding global tic severity and motor and vocal tic frequency post-CBT and at a 6-month follow-up. (3) Results: No significant group difference was found regarding improvements post-CBT (n = 55), nor the maintenance six months later (n = 45). (4) Conclusions: ADHD symptoms may not hinder the response to CBT or its maintenance, suggesting that TS individuals with ADHD symptoms may not require specialized CBT interventions.

Parkinsonian Symptoms, Not Dyskinesia, Negatively Affect Active Life Participation of Dyskinetic Patients with Parkinson's Disease.

Background: The impact of slight-to-moderate levodopa-induced dyskinesia (LID) on the level of participation in active life in patients with Parkinson's disease (PD) has never been objectively determined. Methods: Levels of LID, tremor and bradykinesia were measured during best-ON state in 121 patients diagnosed with PD and having peak-dose LID using inertial sensors positioned on each body limb. Rigidity and postural instability were assessed using clinical evaluations. Cognition and depression were assessed using the MMSE and the GDS-15. Participation in active life was assessed in patients and in 69 healthy controls using the Activity Card Sort (ACS), which measures levels of activity engagement and activities affected by the symptomatology. Outcome measures were compared between patients and controls using ANCOVA, controlling for age or Wilcoxon-Mann-Whitney tests. Spearman correlations and multivariate analyses were then performed between symptomatology and ACS scores. Results: Patients had significantly lower activity engagement than controls and had significantly affected activities. LID was neither associated with activity engagement nor affected activities. Higher levels of tremor, postural instability, cognitive decline and depression were associated with lower activity engagement and higher affected activities. Multivariate analyses revealed that only tremor, postural instability and depression accounted significantly in the variances of these variables. Discussion: Slight-to-moderate LID had little impact compared to other symptoms on the level of participation in active life, suggesting that other symptoms should remain the treatment priority to maintain the level of participation of patients in an active lifestyle.

A Focused Update on Tardive Dyskinesia.

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication following chronic exposure to centrally acting dopamine receptor antagonists, mainly of the class of antipsychotics drugs. New generations of antipsychotic drugs reduced its mean prevalence to 20%, but it continues to mar the drug experience and social integration in a significant fraction of patients. The underlying molecular cascade remains elusive, explaining in part why TD management is so often difficult. Protocol variations between experimental laboratories and inter-species differences in the biological response to antipsychotic drugs have added layers of complexity. The traditional dopamine D2 receptor supersensitivity hypothesis was revisited in an experimental nonhuman primate model. Findings in the striatum revealed a strong upregulation of D3, not D2, receptors specific to dyskinetic animals, and indirect evidence suggestive of a link between overactivation of glycogen synthase kinase-3ß signaling and TD. New effective vesicular monoamine transporter type 2 inhibitors alleviating TD have been approved in the USA. They were integrated to an emerging stepwise treatment algorithm for troublesome TD, which also includes consideration for changes in the current antipsychotic drug regimen and recognition of potentially aggravating factors such as anticholinergic co-medications. These advances may benefit TD.

Chronic Neuroleptic-Induced Parkinsonism Examined With Positron Emission Tomography.

BACKGROUND: Neuroleptic drug-induced parkinsonism (NIP) is a leading cause of parkinsonism, particularly in aging. Based on abnormal dopamine transporter scan results, individuals displaying chronic NIP are often diagnosed with Lewy-body Parkinson's disease (PD), but this assumption needs further substantiation. OBJECTIVE: To quantitate the profile of striatal dopaminergic nerve terminal density in NIP relative to PD. METHODS: We used the positron emission tomography ligand [11 C](+)-dihydrotetrabenazine targeting vesicular monoamine transporter type 2 (VMAT2) binding sites and collected various clinical parameters (motor ratings, olfaction, polysomnography to document rapid eye movement sleep muscle activity, quantitative sensory testing for pain thresholds) possibly predicting binding results in patients older than age 50 living with schizophrenia spectrum disorders under long-term stable antipsychotic drug treatment, with (N = 11) or without (N = 11) chart documention of chronic NIP, and compared them to healthy volunteers (N = 11) and others medicated for PD (N = 12). RESULTS: Striatal VMAT2 binding was dichotomous in the NIP group between those with spared (N = 5) or low (N = 6) PD-like values. Striatal binding reduction in the low VMAT2-NIP group was asymmetric without the gradient of maximal involvement in the posterior putamen typical of PD. Anosmia was the only nonmotor parameter measured matching the abnormal striatal VMAT2 binding status. CONCLUSION: These preliminary observations suggest that striatal VMAT2 binding is abnormal in a fraction of chronic NIP cases and differs in spatial distribution from PD. The possibility of a drug-induced axonopathy and resultant synaptopathy, as well as the evolution of the binding deficit, warrant further longitudinal studies in a large cohort. © 2020 International Parkinson and Movement Disorder Society.

Can We Predict the Motor Performance of Patients With Parkinson's Disease Based on Their Symptomatology?

Introduction: Parkinson's disease hinders the ability of a person to perform daily activities. However, the varying impact of specific symptoms and their interactions on a person's motor repertoire is not understood. The current study investigates the possibility to predict global motor disabilities based on the patient symptomatology and medication. Methods: A cohort of 115 patients diagnosed with Parkinson's disease (mean age = 67.0 ± 8.7 years old) participated in the study. Participants performed different tasks, including the Timed-Up & Go, eating soup and the Purdue Pegboard test. Performance on these tasks was judged using timing, number of errors committed, and count achieved. K-means method was used to cluster the overall performance and create different motor performance groups. Symptomatology was objectively assessed for each participant from a combination of wearable inertial sensors (bradykinesia, tremor, dyskinesia) and clinical assessment (rigidity, postural instability). A multinomial regression model was derived to predict the performance cluster membership based on the patients' symptomatology, socio-demographics information and medication. Results: Clustering exposed four distinct performance groups: normal behavior, slightly affected in fine motor tasks, affected only in TUG, and affected in all areas. The statistical model revealed that low to moderate level of dyskinesia increased the likelihood of being in the normal group. A rise in postural instability and rest tremor increase the chance to be affected in TUG. Finally, LEDD did not help distinguishing between groups, but the presence of Amantadine as part of the medication regimen appears to decrease the likelihood of being part of the groups affected in TUG. Conclusion: The approach allowed to demonstrate the potential of using clinical symptoms to predict the impact of Parkinson's disease on a person's mobility performance.

Remnants of Cardinal Symptoms of Parkinson's Disease, Not Dyskinesia, Are Problematic for Dyskinetic Patients Performing Activities of Daily Living.

Introduction: The impact of levodopa-induced dyskinesia (LID) on the daily lives of patients with Parkinson's disease (PD) remains to be determined. Furthermore, evidence suggests that cardinal motor symptoms of PD may coexist with LID, but their impact on activities of daily living (ADL) relative to LID is not known. This cross-sectional study aimed at determining the effect of LID and cardinal motor symptoms of PD on ADL in patients who were experiencing peak-dose choreic-type LID. Method: One hundred and twenty-one patients diagnosed with PD known to experience choreic-type LID were recruited for the study. Patients were asked to perform a set of ADL. Levels of LID, tremor, bradykinesia, and freezing of gait (FoG) were measured using 17 inertial sensors design to capture full body movements, while rigidity, and postural instability were assessed using clinical evaluations. Cognition was also assessed using the mini-mental state examination. Success criteria were set for each ADL using the time needed to perform the task and errors measured in 69 age-gender-matched healthy controls. Binary logistic regressions were used to identify symptoms influencing success or failure for each activity. Receiver operating characteristic curves were computed on each significant symptom, and Youden indexes were calculated to determine the critical level of symptomatology at which the performance significantly changed. Results: Results show that 97.7% of patients who presented with LID during the experiment also presented with at least one cardinal motor symptom. On average, patients took more time and did more errors during ADL. Multivariate analyses revealed that for the great majority of ADL, LID were not associated with worsening of performance; however, postural instability, tremor, rigidity, and cognitive decline significantly decreased the odds of success. Conclusions: Residual symptoms of PD, such as tremor, rigidity, and postural instability still present at peak-dose were more problematic than LID in the performance of ADL for patients experiencing slight-to-moderate LID. We also found that cognitive decline was associated with decreased performance in certain tasks. Therefore, a strategy using lower doses of medication to manage LID may be counterproductive since it would not address most of these symptoms already present in patients.

Parkinson's disease patients experiencing peak-dose dyskinesia redistribute involuntary movements throughout their body to improve motor control.

INTRODUCTION: In Parkinson's disease (PD), dyskinesia is considered a major side effect of dopamine replacement therapy. Nevertheless, many patients with dyskinesia function adequately. OBJECTIVE: To study objectively dyskinesia phenomenology in order to understand why or how patients with dyskinesia are still able to perform motor tasks. METHODS: Patients with and without dyskinesia, as well as healthy older adults, performed a geostationary task during which they attempted to stabilize a glass of water at eye level. Dyskinesia amplitude displayed by each body segment was extracted from accelerometers, and its distribution among the segments, analyzed. RESULTS: Patients experiencing dyskinesia initially distributed most of their dyskinesia away from the segments directly involved in the task. With time, this distribution shifts back towards the hand. CONCLUSION: Our results suggest that patients developed a strategy of involuntary movement's redistribution to attenuate their functional impact on voluntary movements. However, this strategy can only be maintained for a certain period before "re-emerging" dyskinesia occurs.

Tardive dyskinesia is associated with altered putamen Akt/GSK-3ß signaling in nonhuman primates.

BACKGROUND: Tardive dyskinesia is a delayed and potentially irreversible motor complication arising from chronic exposure to antipsychotic drugs. Interaction of antipsychotic drugs with G protein-coupled receptors triggers multiple intracellular events. Nevertheless, signaling pathways that might be associated with chronic unwanted effects of antipsychotic drugs remain elusive. In this study, we aimed to better understand kinase signaling associated with the expression of tardive dyskinesia in nonhuman primates. METHODS: We exposed capuchin monkeys to prolonged haloperidol (n = 10) or clozapine (n = 6) treatments. Untreated animals were used as controls (n = 6). Half of haloperidol-treated animals (5) developed mild tardive dyskinesia similar to that found in humans. Using Western blots and immunochemistry, we measured putamen total and phosphorylated protein kinase levels associated with canonical and noncanonical signaling cascades of G protein-coupled receptors. RESULTS: Antipsychotic drugs enhanced pDARPP-32 and pERK1/2, but no difference ws observed in phosphoprotein kinase levels between dyskinetic and nondyskinetic monkeys. On the other hand, comparison of kinase levels between haloperidol-treated dyskinetic and nondyskinetic monkeys indicated that dyskinetic animals had lower GRK6 and ß-arrestin2 levels. Levels of pAkt and pGSK-3ß were also reduced, but only haloperidol-treated monkeys that developed tardive dyskinesia had reduced pGSK-3ß levels, whereas pAkt levels in dyskinetic animals positively correlated with dyskinetic scores. Interestingly, double immunofluorescence labeling showed that putamen dopamine D3 receptor levels were upregulated and that D3/pAkt colocalization was enriched in haloperidol-treated animals displaying tardive dyskinesia. CONCLUSIONS: Our results suggest that upregulation of putamen dopamine D3 receptor and alterations along the noncanonical GRK6/ß-arrestin2/Akt/GSK-3ß molecular cascade are associated with the development of tardive dyskinesia in nonhuman primates. © 2019 International Parkinson and Movement Disorder Society.

Electrophysiological predictors of cognitive-behavioral therapy outcome in tic disorders.

Cognitive-behavioral therapy (CBT) constitutes an empirically based treatment for tic disorders (TD), but much remains to be learned about its impact at the neural level. Therefore, we examined the electrophysiological correlates of CBT in TD patients, and we evaluated the utility of event-related potentials (ERP) as predictors of CBT outcome. ERPs were recorded during a stimulus-response compatibility (SRC) task in 26 TD patients and 26 healthy controls. Recordings were performed twice, before and after CBT in TD patients, and with a similar time interval in healthy controls. The stimulus- and response-locked lateralized readiness potentials (sLRP & rLRP) were assessed, as well as the N200 and the P300. The results revealed that before CBT, TD patients showed a delayed sLRP onset and larger amplitude of both the sLRP and rLRP peaks, in comparison with healthy controls. The CBT induced an acceleration of the sLRP onset and a reduction of the rLRP peak amplitude. Compared to healthy controls, TD patients showed a more frontal distribution of the No-Go P300, which was however not affected by CBT. Finally, a multiple linear regression analysis including the N200 and the incompatible sLRP onset corroborated a predictive model of therapeutic outcome, which explained 43% of the variance in tic reduction following CBT. The current study provided evidence that CBT can selectively normalize motor processes relative to stimulus-response compatibility in TD patients. Also, ERPs can predict the amount of tic symptoms improvement induced by the CBT and might therefore improve treatment modality allocation among TD patients.

Cardinal Motor Features of Parkinson's Disease Coexist with Peak-Dose Choreic-Type Drug-Induced Dyskinesia.

BACKGROUND: Clinical and anecdotal observations propose that patients with Parkinson's disease (PD) may show drug-induced dyskinesia (DID) concomitantly with cardinal motor features. However, the extent of the concomitant presence of DID and cardinal features remains to be determined. OBJECTIVES: This cross-sectional study measured peak-dose choreic-type DID in a quantitative manner in patients diagnosed with PD, and determined whether symptoms such as tremor, bradykinesia, rigidity, postural instability or freezing of gait (FoG) were still detectable in these patients. METHODS: 89 patients diagnosed with PD were recruited and assessed using a combination of quantitative measures using inertial measurement units to capture DID, tremor, bradykinesia, and FoG. Clinical evaluations were also used to assess rigidity and postural instability. Motor symptoms of PD were assessed 3 times during the testing period, and a series of activities of daily living were repeated twice, in between clinical tests, during which the level of DID was quantified. Peak-dose was identified as the period during which patients had the highest levels of DID. Levels of tremor, rigidity, bradykinesia, postural instability, and FoG were used to determine the percentage of patients showing these motor symptoms simultaneously with DID. RESULTS: 72.4% of patients tested presented with measurable DID during the experiment. Rest, postural and kinetic tremor (12.7% , 38.1% , and 15.9% respectively), bradykinesia (28.6% ), rigidity (55.6% ), postural instability (71.4% ) and FoG (9.5% ) were detected simultaneously with DID. CONCLUSIONS: PD symptomatology remains present in patients showing peak-dose choreic-type DID, illustrating the challenge facing physicians when trying to avoid dyskinesia while attempting to alleviate motor symptoms.

Chronic pain and pain processing in Parkinson's disease.

Pain is experienced by the vast majority of patients living with Parkinson's disease. It is most often of nociceptive origin, but may also be ascribed to neuropathic (radicular or central) or miscellaneous sources. The recently validated King's Parkinson's Disease Pain Scale is based on 7 domains including musculoskeletal pain, chronic body pain (central or visceral), fluctuation-related pain, nocturnal pain, oro-facial pain, pain with discolouration/oedema/swelling, and radicular pain. The basal ganglia integrate incoming nociceptive information and contribute to coordinated motor responses in pain avoidance and nocifensive behaviors. In Parkinson's disease, nigral and extra-nigral pathology, involving cortical areas, brainstem nuclei, and spinal cord, may contribute to abnormal central nociceptive processing in patients experiencing pain or not. The dopamine deficit lowers multimodal pain thresholds that are amenable to correction following levodopa dosing. Functional brain imaging with positron emission tomography following administration of H215O revealed abnormalities in the sensory discriminative processing of pain (insula/SII), as well as in the affective motivational processing of pain (anterior cingulate cortex, prefrontal cortex). Pain management is dependent on efforts invested in diagnostic accuracy to distinguish nociceptive from neuropathic pain. Treatment requires an integrated approach including strategies to lessen levodopa-related response fluctuations, in addition to other pharmacological and non-pharmacological options such as deep brain stimulation and rehabilitation.

Deficient striatal adaptation in aminergic and glutamatergic neurotransmission is associated with tardive dyskinesia in non-human primates exposed to antipsychotic drugs.

Tardive dyskinesia (TD) is a potentially disabling condition encompassing all delayed, persistent, and often irreversible abnormal involuntary movements arising in a fraction of subjects during long-term exposure to centrally acting dopamine receptor-blocking agents such as antipsychotic drugs and metoclopramide. However, the pathogenesis of TD has proved complex and remains elusive. To investigate the mechanism underlying the development of TD, we have chronically exposed 17 Cebus apella monkeys to typical (11) or atypical (6) antipsychotic drugs. Six additional monkeys were used as controls. Using autoradiography, Western blot and in situ hybridization techniques, we compared neurochemical components of the dopamine, serotonin, and glutamate neurotransmitter systems modulating striatal activity in monkeys chronically exposed to haloperidol and clozapine. Five (5) out of 11 monkeys treated with haloperidol develop TD, whereas none of the monkeys treated with clozapine develop TD. Haloperidol treatment significantly upregulated the levels of serotonin 5-HT2A receptor, NR2A-containing NMDA receptors, and tyrosine hydroxylase contents in the monkey putamen, whereas clozapine regulated putamen NMDA receptor levels and tyrosine hydroxylase contents, and 5-HT2A and dopamine transporter outside the putamen. Comparisons of neurochemical alterations between dyskinetic and non dyskinetic animals within the haloperidol-treated group indicate that modulations of 5-HT2A, metabotropic glutamate type 5, NR2A- and NR2B-containing NMDA receptors, and vesicular monoamine transporter type 2 levels were restricted to the non dyskinetic group. The foregoing results suggest that TD is associated with complex deficient adaptation in aminergic and glutamatergic neurotransmission in the striatum of non-human primates chronically exposed to antipsychotic drugs.

P300 Source Localization Contrasts in Body-Focused Repetitive Behaviors and Tic Disorders.

Tic disorders (TD) and body-focused repetitive behaviors (BFRB) have similar phenotypes that can be challenging to distinguish in clinical settings. Both disorders show high rates of comorbid psychiatric conditions, dysfunctional basal ganglia activity, atypical cortical functioning in the prefrontal and motor cortical regions, and cognitive deficits. Clinicians frequently confound the two disorders and it is important to find reliable objective methods to discriminate TD and BFRB. Neuropsychological tests and event-related potential (ERP) studies have yielded inconsistent results regarding a possible context updating deficit in TD and BFRB patients. However, most previous studies did not control for the presence of comorbid psychiatric condition and medication status, which might have confounded the findings reported to date. Hence, we aimed to investigate the psychophysiology of working memory using ERP in carefully screened TD and BFRB patients excluding those with psychiatric comorbidity and those taking psychoactive medication. The current study compared 12 TD patients, 12 BRFB patients, and 15 healthy control participants using a motor oddball task (button press). The P300 component was analyzed as an index of working memory functioning. Results showed that BFRB patients had decreased P300 oddball effect amplitudes over the right hemisphere compared to the TD and control groups. Clinical groups presented different scalp distributions compared to controls, which could represent a potential endophenotype candidate of BFRB and TD.

Characterization of Burning Mouth Syndrome in Patients with Parkinson's Disease.

AIMS: To determine the prevalence and characteristics of burning mouth syndrome (BMS) in a Parkinson's disease (PD) population through a self-administered, custom-made survey. METHODS: A total of 218 surveys were collected during regular outpatient visits at two Movement Disorders Clinics in Montreal (Canada) and Toulouse (France) to gather information about pain experience, PD-related symptoms, and oral and general health. A neurologist confirmed the diagnosis of PD, drug treatment, Hoehn-Yahr stage, and Schwab & England Activity of Daily Living score. Data between groups were compared using the independent samples Mann-Whitney U test and two-sided exact Fisher test. RESULTS: Data from 203 surveys were analyzed. BMS was reported by eight subjects (seven females and one male), resulting in a prevalence of 4.0% (95% confidence interval [CI] = 2.1-7.8). Five participants with chronic nonburning oral pain were excluded. PD severity and levodopa equivalent daily dose did not differ between non-BMS and BMS participants. Mean poor oral health index was higher in BMS compared to non-BMS subjects (49.0 vs 32.2 points, P < .05). BMS manifested after PD onset in seven patients, did not occur on a daily basis in four, and always coexisted with restless legs syndrome. CONCLUSION: This survey yielded a low prevalence of BMS in PD patients, indicating no strong link between the two conditions. An augmenting effect such as that resulting from drug treatment in restless legs syndrome or sensory neuropathy cannot be excluded.

The Impact of a Cognitive-Behavioral Therapy on Event-Related Potentials in Patients with Tic Disorders or Body-Focused Repetitive Behaviors.

CONTEXT: Tic disorders (TD) are characterized by the presence of non-voluntary contractions of functionally related groups of skeletal muscles in one or multiple body parts. Patients with body-focused repetitive behaviors (BFRB) present frequent and repetitive behaviors, such as nail biting or hair pulling. TD and BFRB can be treated with a cognitive-behavioral therapy (CBT) that regulates the excessive amount of sensorimotor activation and muscular tension. Our CBT, which is called the cognitive-psychophysiological (CoPs) model, targets motor execution and inhibition, and it was reported to modify brain activity in TD. However, psychophysiological effects of therapy are still poorly understood in TD and BFRB patients. Our goals were to compare the event-related potentials (ERP) of TD and BFRB patients to control participants and to investigate the effects of the CoPs therapy on the P200, N200, and P300 components during a motor and a non-motor oddball task. METHOD: Event-related potential components were compared in 26 TD patients, 27 BFRB patients, and 27 control participants. ERP were obtained from 63 EEG electrodes during two oddball tasks. In the non-motor task, participants had to count rare stimuli. In the motor task, participants had to respond with a left and right button press for rare and frequent stimuli, respectively. ERP measures were recorded before and after therapy in both patient groups. RESULTS: CoPs therapy improved symptoms similarly in both clinical groups. Before therapy, TD and BFRB patients had reduced P300 oddball effect during the non-motor task, in comparison with controls participants. An increase in the P300 oddball effect was observed posttherapy. This increase was distributed over the whole cortex in BFRB patients, but localized in the parietal area in TD patients. DISCUSSION: These results suggest a modification of neural processes following CoPs therapy in TD and BFRB patients. CoPs therapy seems to impact patients' attentional processes and context updating capacities in working memory (i.e., P300 component). Our results are consistent with a possible role of the prefrontal cortex and corpus callosum in mediating interhemispheric interference in TD.

Cognitive-behavioral therapy induces sensorimotor and specific electrocortical changes in chronic tic and Tourette's disorder.

BACKGROUND: Tic disorders, such as the Gilles de la Tourette syndrome and persistent tic disorder, are neurodevelopmental movement disorders involving impaired motor control. Hence, patients show repetitive unwanted muscular contractions in one or more parts of the body. A cognitive-behavioral therapy, with a particular emphasis on the psychophysiology of tic expression and sensorimotor activation, can reduce the frequency and intensity of tics. However, its impact on motor activation and inhibition is not fully understood. METHODS: To study the effects of a cognitive-behavioral therapy on electrocortical activation, we recorded the event-related potentials (ERP) and lateralized readiness potentials (LRP), before and after treatment, of 20 patients with tic disorders and 20 healthy control participants (matched on age, sex and intelligence), during a stimulus-response compatibility inhibition task. The cognitive-behavioral therapy included informational, awareness training, relaxation, muscle discrimination, cognitive restructuration and relapse prevention strategies. RESULTS: Our results revealed that prior to treatment; tic patients had delayed stimulus-locked LRP onset latency, larger response-locked LRP peak amplitude, and a frontal overactivation during stimulus inhibition processing. Both stimulus-locked LRP onset latency and response-locked LRP peak amplitude normalized after the cognitive behavioral therapy completion. However, the frontal overactivation related to inhibition remained unchanged following therapy. CONCLUSIONS: Our results showed that P300 and reaction times are sensitive to stimulus-response compatibility, but are not related to tic symptoms. Secondly, overactivity of the frontal LPC and impulsivity in TD patients were not affected by treatment. Finally, CBT had normalizing effects on the activation of the pre-motor and motor cortex in TD patients. These results imply specific modifications of motor processes following therapy, while inhibition processes remained unchanged. Given that LRPs are partially generated within the sensorimotor and supplementary motor area, the reported reduction in tic frequency and improvements of LRPs components suggest that CBT induced a physiological change in patients' motor area.