Functional connectivity during tic suppression predicts reductions in vocal tics following behavior therapy in children with Tourette syndrome.

BACKGROUND: Comprehensive Behavioral Intervention for Tics (CBIT) is recommended as a first-line treatment for Tourette syndrome in children and adults. While there is strong evidence proving its efficacy, the mechanisms of reduction in tic severity during CBIT are still poorly understood. In a recent study, our group identified a functional brain network involved in tic suppression in children with TS. We reasoned that voluntary tic suppression and CBIT may share some mechanisms and thus we wanted to assess whether functional connectivity during tic suppression was associated with CBIT outcome. METHODS: Thirty-two children with TS, aged 8 to 13 years old, participated in a randomized controlled trial of CBIT v. a treatment-as-usual control condition. EEG was recorded during tic suppression in all participants at baseline and endpoint. We used a source-reconstructed EEG connectivity pipeline to assess functional connectivity during tic suppression. RESULTS: Functional connectivity during tic suppression did not change from baseline to endpoint. However, baseline tic suppression-related functional connectivity specifically predicted the decrease in vocal tic severity from baseline to endpoint in the CBIT group. Supplementary analyses revealed that the functional connectivity between the right superior frontal gyrus and the right angular gyrus was mainly driving this effect. CONCLUSIONS: This study revealed that functional connectivity during tic suppression at baseline predicted reduction in vocal tic severity. These results suggest probable overlap between the mechanisms of voluntary tic suppression and those of behavior therapy for tics.

Amygdala-prefrontal connectivity in children with maladaptive aggression is modulated by social impairment.

Aggressive behavior is common across childhood-onset psychiatric disorders and is associated with impairments in social cognition and communication. The present study examined whether amygdala connectivity and reactivity during face emotion processing in children with maladaptive aggression are moderated by social impairment. This cross-sectional study included a well-characterized transdiagnostic sample of 101 children of age 8-16 years old with clinically significant levels of aggressive behavior and 32 typically developing children without aggressive behavior. Children completed a face emotion perception task of fearful and calm faces during functional magnetic resonance imaging. Aggressive behavior and social functioning were measured by standardized parent ratings. Relative to controls, children with aggressive behavior showed reduced connectivity between the amygdala and the dorsolateral prefrontal cortex (PFC) during implicit emotion processing. In children with aggressive behavior, the association between reduced amygdala-ventrolateral PFC connectivity and greater severity of aggression was moderated by greater social impairment. Amygdala reactivity to fearful faces was also associated with severity of aggressive behavior for children without social deficits but not for children with social deficits. Social impairments entail difficulties in interpreting social cues and enacting socially appropriate responses to frustration or provocation, which increase the propensity for an aggressive response via diminished connectivity between the amygdala and the ventral PFC.

Parent-child physiological concordance predicts stronger observational fear learning in children with a less secure relationship with their parent.

Observational fear learning is common in children as they learn to fear by observing their parents. Although adaptive, it can also contribute to the development of fear-related psychopathologies such as anxiety disorders. Therefore, it is important to identify and study the factors that modulate children's sensitivity to observational fear learning. For instance, observational fear learning can be facilitated by the synchronization of biological systems between two people. In parent-child dyads, physiological concordance is important and varies according to the attachment relationship, among others. We investigated the joint effect of parent-child physiological concordance and attachment on observational fear learning in children. A total of 84 parent-child dyads participated in this study. Parents were filmed while exposed to a fear-conditioning protocol, where one stimulus was associated with a shock (CS+) and the other was not (CS-). This recording was then shown to the children (observational learning). Thereafter, both stimuli (CS+ and CS-) were presented to the children without any shock (direct expression test). For both the parent and child, skin conductance activity was recorded throughout the entire procedure. We measured physiological concordance between the parent's phasic skin conductance signal during conditioning and the child's signal during the observational learning stage. Children showing stronger concordance and a less secure relationship with their parent exhibited higher levels of fear to the CS+, as indicated by a heightened skin conductance response during the direct expression test. Thus, when children have an insecure relationship with their parent, strong physiological concordance may increase their sensitivity to observational fear learning.

Sex Differences in Youth with Chronic Tic Disorder and Tourette Syndrome: Evaluation of Tic Severity, Psychological Profiles, and Quality of Life.

Background: Tourette syndrome (TS) and Chronic Tic Disorder (CT) are neurodevelopmental conditions involving motor and/or phonic tics. Youth with tics may encounter feelings of isolation, diminished self-esteem and quality of life, and academic difficulties. A growing body of scientific literature suggests sex differences in youth with tics, but findings have been mixed so far. Because symptom severity peaks around puberty, understanding sex differences in tic manifestations and associated symptoms during this critical period is essential. Therefore, we aimed to assess sex differences related to tic symptoms, action planning styles, quality of life, and externalizing/internalizing symptoms in youth with tics. Methods: Our sample consisted of 66 youths with tics (19 girls) aged 7-14 (mean = 10 years). Youths were assessed with clinical interviews, as well as self- and parent-reported inventories evaluating tic symptoms, psychological profiles, and quality of life. Results: While no differences in tic symptoms were found, girls exhibited lower functional inflexibility, reduced overall functional planning effectiveness, and higher impairment in the psychological well-being subscale than boys. Additionally, girls had reduced general life satisfaction and social self-esteem. Boys reported more explosive outbursts, higher levels of hyperactivity, and more difficulties with self-concept. Conclusions: Our analyses suggested differences in several manifestations associated with tics. This introduces new perspectives that refine our understanding of sex differences. A better understanding of sex differences in tic disorders may eventually improve outcomes for all individuals living with these conditions.

Increased Alpha-Band Connectivity During Tic Suppression in Children With Tourette Syndrome Revealed by Source Electroencephalography Analyses.

BACKGROUND: Tourette syndrome (TS) is a neurodevelopmental disorder involving chronic motor and phonic tics. Most individuals with TS can suppress their tics for at least a short period of time. Yet, the brain correlates of tic suppression are still poorly understood. METHODS: In the current study, high-density electroencephalography was recorded during a resting-state and a tic suppression session in 72 children with TS. Functional connectivity between cortical regions was assessed in the alpha band (8-13 Hz) using an electroencephalography source connectivity method. Graph theory and network-based statistics were used to assess the global network topology and to identify brain regions showing increased connectivity during tic suppression. RESULTS: Graph theoretical analyses revealed distinctive global network topology during tic suppression, relative to rest. Using network-based statistics, we found a subnetwork of increased connectivity during tic suppression (p < .001). That subnetwork encompassed many cortical areas, including the right superior frontal gyrus and the left precuneus, which are involved in the default mode network. We also found a condition-by-age interaction, suggesting age-mediated increases in connectivity during tic suppression. CONCLUSIONS: These results suggest that children with TS suppress their tics through a brain circuit involving distributed cortical regions, many of which are part of the default mode network. Brain connectivity during tic suppression also increases as youths with TS mature. These results highlight a mechanism by which children with TS may control their tics, which could be relevant for future treatment studies.

Evaluation of EEG biomarkers of Comprehensive Behavioral Intervention for Tics in children with Tourette syndrome.

OBJECTIVE: Comprehensive Behavioral Intervention for Tics (CBIT) is a first-line treatment of Tourette syndrome (TS). However, the brain mechanisms involved in CBIT are poorly understood. Enhanced frontomesial EEG coherence during a Go/NoGo task has been suggested as a mechanism involved in voluntary tic control. In the current study, we conducted a randomized controlled trial to assess whether EEG coherence during a Go/NoGo task was associated with CBIT outcome. METHODS: Thirty-two children with TS were randomly assigned to CBIT or to treatment-as-usual (TAU). Treatment outcome was assessed by a blinded evaluator with the Yale Global Tic Severity Scale (YGTSS) and the Clinical Global Impression - Improvement Scale (CGI-I). EEG was recorded during a Go/NoGo task at baseline and endpoint. EEG coherence was computed in the alpha frequency band between a priori selected channel pairs spanning the frontal and motor areas. RESULTS: Tic severity decreased significantly in the CBIT group. However, CBIT did not impact EEG coherence and baseline EEG coherence did not predict treatment outcome. CONCLUSIONS: Although CBIT was superior to TAU on blinded clinical outcomes, EEG coherence during the Go/NoGo task was not associated with change in tic severity. SIGNIFICANCE: The brain processes involved in the inhibition of motor responses do not appear to be involved in CBIT.

Electrophysiological signatures of inhibitory control in children with Tourette syndrome and attention-deficit/hyperactivity disorder.

Tourette syndrome (TS) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur, especially in children. Reduced inhibitory control abilities have been suggested as a shared phenotype across both conditions but its neural underpinnings remain unclear. Here, we tested the behavioral and electrophysiological correlates of inhibitory control in children with TS, ADHD, TS+ADHD, and typically developing controls (TDC). One hundred and thirty-eight children, aged 7-14 years, performed a Go/NoGo task during dense-array EEG recording. The sample included four groups: children with TS only (n = 47), TS+ADHD (n = 32), ADHD only (n = 22), and matched TDC (n = 35). Brain activity was assessed with the means of frontal midline theta oscillations, as well as the N200 and P300 components of the event-related potentials. Our analyses revealed that both groups with TS did not differ from other groups in terms of behavioral performance, frontal midline theta oscillations, and event-related potentials. Children with ADHD-only had worse Go/NoGo task performance, decreased NoGo frontal midline theta power, and delayed N200 and P300 latencies, compared to typically developing controls. In the current study, we found that children with TS or TS+ADHD do not show differences in EEG during a Go/NoGo task compared to typically developing children. Our findings however suggest that children with ADHD-only have a distinct electrophysiological profile during the Go/NoGo task as indexed by reduced frontal midline theta power and delayed N200 and P300 latencies.

Lateralized readiness potentials and sensorimotor activity in adults with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) patients are known to have various functional abnormalities in prefrontal and motor areas. Given the presence of compulsions in many OCD patients, impaired response preparation processes could be a core feature of OCD. Yet, these processes remain understudied from a neurophysiological standpoint. Nineteen OCD patients were matched on age and sex to 19 healthy controls. Continuous EEG was recorded in all participants during a stimulus-response compatibility task. EEG from electrodes C3 and C4 was then averaged into stimulus- and response-locked LRPs. We compared both groups on various LRP measures, such as the LRP onset, the Gratton dip, and the maximum LRP peak. OCD patients showed significantly larger LRP peak than healthy controls, as well as larger Gratton dip. However, there was no group difference regarding LRP onset. Among OCD patients, it seems that motor regions are overactive during response preparation. Such overactivity was found for both incorrect responses that are aborted before execution and responses that are truly executed. These results suggest that regulation of sensorimotor activity should be addressed in the treatment of OCD.

A review on how stress modulates fear conditioning: Let's not forget the role of sex and sex hormones.

Stress and fear are two fields of research that have evolved simultaneously. It was not until the eighties that these domains converged in order to better characterize the impact of stress on fear memory formation. Here, we reviewed the effects of stress occurring before fear acquisition on the main phases of fear conditioning protocols (acquisition training, extinction training, extinction retention test), with a specific focus on sex and sex hormones. We also paid close attention to methodological aspects in order to better understand and characterize discrepant findings across studies. In men, stress appears to potentiate fear acquisition at a physiological level but induces lower activations of fear-related brain regions. In women, results are inconsistent. Although some studies have shown that stress lowers physiological fear responses and heightens brain activations in women during fear acquisition, many studies report no significant effects. Irrespective of sex, pre-acquisition stress seems to induce fear extinction learning resistance. Overall, few studies have taken into account sex hormones, despite their impact on both the fear and stress brain networks. As methodological variability makes it complex to draw strong conclusions, several methodological aspects are discussed with the aim of orienting future research.

Anxiety Sensitivity Moderates the Association Between Father-Child Relationship Security and Fear Transmission.

Observational fear learning can contribute to the development of fear-related psychopathologies, such as anxiety disorders and post-traumatic stress disorder. Observational fear learning is especially relevant during childhood. Parent-child attachment and anxiety sensitivity modulate fear reactions and fear learning but their impact on observational fear learning has not been investigated. This study investigated how these factors contribute to observational fear learning in children. We examined this question among 55 healthy parent-child dyads. Children (8-12 years old) watched a video of their parent undergoing a direct fear conditioning protocol, where one stimulus (CS+Parent) was paired with a shock and one was not (CS-), and a video of a stranger for whom a different stimulus was reinforced (CS+Stranger). Subsequently, all stimuli were presented to children (without shocks) while skin conductance responses were recorded to evaluate fear levels. Our results showed that children more sensitive to anxiety and who had lower father-child relationship security levels exhibited higher skin conductance responses to the CS+Parent. Our data suggest that the father-child relationship security influences vicarious fear transmission in children who are more sensitive to anxiety. This highlights the importance of the father-child relationship security as a potential modulator of children's vulnerability to fear-related psychopathologies.

Vicarious conditioned fear acquisition and extinction in child-parent dyads.

The biological mechanisms involved in fear transmission within families have been scarcely investigated in humans. Here we studied (1) how children acquired conditioned fear from observing their parent, or a stranger, being exposed to a fear conditioning paradigm, and (2) the subsequent fear extinction process in these children. Eighty-three child-parent dyads were recruited. The parent was filmed while undergoing a conditioning procedure where one cue was paired with a shock (CS + Parent) and one was not (CS -). Children (8 to 12 years old) watched this video and a video of an adult stranger who underwent conditioning with a different cue reinforced (CS + Stranger). Children were then exposed to all cues (no shocks were delivered) while skin conductance responses (SCR) were recorded. Children exhibited higher SCR to the CS + Parent and CS + Stranger relative to the CS -. Physiological synchronization between the child's SCR during observational learning and the parent's SCR during the actual process of fear conditioning predicted higher SCR for the child to the CS + Parent. Our data suggest that children acquire fear vicariously and this can be measured physiologically. These data lay the foundation to examine observational fear learning mechanisms that might contribute to fear and anxiety disorders transmission in clinically affected families.

Cognitive and motor event-related potentials in Tourette syndrome and tic disorders: A systematic review.

OBJECTIVES: Tourette syndrome (TS) patients face various cognitive and motor impairments. Event-related potentials (ERP) constitute an effective way to investigate the neural correlates of those functional impairments. Various components have been assessed among TS patients, with a wide variety of paradigms. This systematic review aimed to evaluate the portrait of ERP components in TS patients, and to understand the factors leading to discrepancies across studies. METHODS: A literature search was performed in Embase, PsycINFO, Pubmed, and Web of Science, to identify studies that conducted ERP experiments among TS patients. Of the 372 unique records identified, 47 met inclusion criteria and were included in our systematic review. RESULTS: Various ERP particularities were reported among included studies. Many discrepancies exist, but impairments in motor-related potentials and contingent negative variation seem constant across studies. Divergent findings point toward a possibly reduced P3b during oddball tasks. CONCLUSIONS: ERPs offer an insightful investigation into the cognitive and motor functions of TS patients. Future studies should always control for confounding factors such as comorbidity, age, or medication status. SIGNIFICANCE: This is the first systematic review of ERP in TS patients. Motor-related and slow cortical potentials could constitute electrophysiological markers of TS.

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.

A Review of the Neuropsychological Dimensions of Tourette Syndrome.

Neurocognitive functioning in Tourette syndrome (TS) has been the subject of intensive research in the past 30 years. A variety of impairments, presumably related to frontal and frontostriatal dysfunctions, have been observed. These impairments were found in various domains, such as attention, memory, executive functions, language, motor and visuomotor functions, among others. In line with contemporary research, other neurocognitive domains have recently been explored in TS, bringing evidence of altered social reasoning, for instance. Therefore, the aims of this review are to give an overview of the neuropsychological dimensions of TS, to report how neuropsychological functions evolve from childhood to adulthood, and to explain how various confounding factors can affect TS patients' performance in neuropsychological tasks. Finally, an important contribution of this review is to show how recent research has confirmed or changed our beliefs about neuropsychological functioning in TS.

The puzzling question of inhibitory control in Tourette syndrome: A meta-analysis.

Tourette syndrome (TS) is a neuropsychiatric disorder involving motor and phonic tics. Inhibitory control is a key issue in TS, and many disruptive or impulsive behaviors might arise from inhibitory deficits. However, conflicting findings regarding TS patients' inhibitory performance in neuropsychological tasks have been reported throughout the literature. Therefore, this meta-analysis aimed to evaluate inhibitory control through neuropsychological tasks, and to analyze the factors modulating inhibitory deficits. To this end, a literature search was performed through MEDLINE and PsycINFO, to retrieve studies including neuropsychological tasks that assessed inhibitory control in TS patients. Of the 4020 studies identified, 61 were included in the meta-analysis, for a total of 1717 TS patients. Our analyses revealed a small to medium effect in favor of inhibitory deficits in TS patients. This effect was larger in TS+ADHD patients, but pure TS patients also showed some inhibitory deficits. Therefore, deficits in inhibitory control seem to be an inherent component of TS, and are exacerbated when ADHD is concomitant.

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.

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.