Altered Functional Connectivity in Resting State Networks in Tourette’s Disorder

Introduction: Brain regions are anatomically and functionally interconnected in order to facilitate important functions like cognition and movement. It remains incompletely understood how brain connectivity contributes to the pathophysiology of Tourette’s disorder (TD). By using resting-state functional MRI, we aimed to identify alterations in the default mode network (DMN), frontal-parietal network (FPN), sensori-motor network (SMN), and salience network (SN) in TD compared with healthy control (HC) subjects.Method: In 23 adult TD patients and 22 HC, 3T-MRI resting-state scans were obtained. Independent component analysis was performed comparing TD and HC to investigate connectivity patterns within and between resting-state networks.Results: TD patients showed higher involvement of the dorsal medial prefrontal cortex in the connectivity of the DMN and less involvement of the inferior parietal cortex in the connectivity of the FPN when compared to HC. Moreover, TD patients showed a stronger coupling between DMN and left FPN than HC. Finally, in TD patients, functional connectivity within DMN correlated negatively with tic severity.Conclusion: We tentatively interpret the increased functional connectivity within DMN in TD patients as compensatory to the lower functional connectivity within left FPN. The stronger coupling between DMN and left FPN, together with the finding that higher DMN intrinsic connectivity is associated with lower tic severity would indicate that DMN is recruited to exert motor inhibition

The role of habit in compulsivity.

Compulsivity has been recently characterized as a manifestation of an imbalance between the brain׳s goal-directed and habit-learning systems. Habits are perhaps the most fundamental building block of animal learning, and it is therefore unsurprising that there are multiple ways in which the development and execution of habits can be promoted/discouraged. Delineating these neurocognitive routes may be critical to understanding if and how habits contribute to the many faces of compulsivity observed across a range of psychiatric disorders. In this review, we distinguish the contribution of excessive stimulus-response habit learning from that of deficient goal-directed control over action and response inhibition, and discuss the role of stress and anxiety as likely contributors to the transition from goal-directed action to habit. To this end, behavioural, pharmacological, neurobiological and clinical evidence are synthesised and a hypothesis is formulated to capture how habits fit into a model of compulsivity as a trans-diagnostic psychiatric trait.CM Gillan is supported by a Sir Henry Wellcome Postdoctoral Fellowship (101521/Z/12/Z).This is the final version of the article. It was first available from Elsevier via https://doi.org/10.1016/j.euroneuro.2015.12.03

Emotion Processing, Reappraisal, and Craving in Alcohol Dependence: A Functional Magnetic Resonance Imaging Study

Alcohol dependence has long been related to impaired emotion regulation—including reappraisal—but little is known about the performance and associated neural activity of alcohol-dependent patients (ADPs) on an emotion reappraisal task. This study, therefore, compares reappraisal of negative, positive, neutral, and alcohol-related images at a behavioral and neural level between ADPs and healthy controls (HCs).Thirty-nine ADPs and 39 age-, gender-, and education-matched HCs performed an emotion reappraisal task during functional magnetic resonance imaging (fMRI), and craving was measured before and after the reappraisal task. During the emotion reappraisal task, participants were instructed to either attend or reappraise positive, negative, neutral, or alcohol-related images, and to indicate their experienced emotion on a visual analogue scale (VAS).Both ADPs and HCs completed the emotion reappraisal task successfully, showing significant differences in self-reported experienced emotion after attending versus reappraising visual stimuli and in brain activity in emotion processing/reappraisal relevant areas. ADPs were not impaired in cognitive reappraisal at a behavioral or neural level relative to HCs, nor did ADPs indicate any difference in self-reported emotion while attending emotional images. However, ADPs were different from HC in emotion processing: ADPs revealed a blunted response in the (posterior) insula, precuneus, operculum, and superior temporal gyrus while attending emotional images compared neutral images compared to HCs, and in ADPs, higher baseline craving levels were associated with a less blunted response to alcohol-related images than in HCs. These results reveal that ADPs do not show impaired reappraisal abilities when instructed, although future studies should assess voluntary reappraisal abilities in alcohol-dependent patients.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT02557815

The Effect of High-Frequency Repetitive Transcranial Magnetic Stimulation on Emotion Processing, Reappraisal, and Craving in Alcohol Use Disorder Patients and Healthy Controls: A Functional Magnetic Resonance Imaging Study

Impaired cognitive–motivational functioning is present in many psychiatric disorders, including alcohol use disorder (AUD). Emotion regulation is a key intermediate factor, relating to the (cognitive) regulation of emotional and motivational states, such as in regulation of craving or negative emotions that may lead to relapse in alcohol use. These cognitive–motivational functions, including emotion regulation, are a target in cognitive behavioral therapy and may possibly be improved by neurostimulation techniques. The present between-subjects, single-blind study assesses the effects of sham-controlled high-frequency neuronavigated repetitive transcranial magnetic stimulation (10 Hz) of the right dorsolateral prefrontal cortex (dlPFC) on several aspects relevant for emotion regulation (emotion processing and reappraisal abilities) and related brain activity, as well as self-reported craving in a sample of alcohol use disorder patients (AUD; n = 39) and healthy controls (HC; n = 36). During the emotion reappraisal task, participants were instructed to either attend or reappraise their emotions related to the negative, positive, neutral, and alcohol-related images, after which they rated their experienced emotions. We found that repetitive transcranial magnetic stimulation (rTMS) reduces self-reported experienced emotions in response to positive and negative images in AUD patients, whereas experienced emotions were increased in response to neutral and positive images in HCs. In the functional magnetic resonance imaging (fMRI) analyses, we found that rTMS reduces right dlPFC activity during appraisal of affective images relative to sham stimulation only in AUD patients. We could not confirm our hypotheses regarding the effect of rTMS craving levels, or on reappraisal related brain function, since no significant effects of rTMS on craving or reappraisal related brain function were found. These findings imply that rTMS can reduce the emotional impact of images as reflected in blood oxygenation level-dependent (BOLD) response, especially in AUD patients. Future studies should replicate and expand the current study, for instance, by assessing the effect of multiple stimulation sessions on both explicit and implicit emotion regulation paradigms and craving, and assess the effect of rTMS within subgroups with specific addiction-relevant image preferences.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02557815

Brain circuitry of compulsivity.

Compulsivity is associated with alterations in the structure and the function of parallel and interacting brain circuits involved in emotional processing (involving both the reward and the fear circuits), cognitive control, and motor functioning. These brain circuits develop during the pre-natal period and early childhood under strong genetic and environmental influences. In this review we bring together literature on cognitive, emotional, and behavioral processes in compulsivity, based mainly on studies in patients with obsessive-compulsive disorder and addiction. Disease symptoms normally change over time. Goal-directed behaviors, in response to reward or anxiety, often become more habitual over time. During the course of compulsive disorders the mental processes and repetitive behaviors themselves contribute to the neuroplastic changes in the involved circuits, mainly in case of chronicity. On the other hand, successful treatment is able to normalize altered circuit functioning or to induce compensatory mechanisms. We conclude that insight in the neurobiological characteristics of the individual symptom profile and disease course, including the potential targets for neuroplasticity is an unmet need to advance the field.Dr. Soriano-Mas is funded by a ׳Miguel Servet׳ contract from the Carlos III Health Institute (CP10/00604). Dr. Goudriaan is supported by a VIDI Innovative Research Grant (Grant no. 91713354) funded by the Dutch Scientific Research Association (NWO-ZonMW). Dr. Alonso was funded by the Instituto de Salut Carlos III-FISPI14/00413. Dr. Nakamae received Grant support from MEXT KAKENHI (Nos. 24791223 and 26461753).This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.euroneuro.2015.12.00

Stable inhibition-related inferior frontal hypoactivation and fronto-limbic hyperconnectivity in obsessive–compulsive disorder after concentrated exposure therapy

Response inhibition has previously been suggested as an endophenotype for obsessive–compulsive disorder (OCD), evidenced by studies showing worse task performance, and altered task-related activation and connectivity. However, it’s unclear if these measures change following treatment. In this study, 31 OCD patients and 28 healthy controls performed a stop signal task during 3 T functional magnetic resonance imaging before treatment, while 24 OCD patients and 17 healthy controls were rescanned one week and three months after concentrated exposure and response prevention over four consecutive days using Bergen 4-Day Format. To study changes over time we performed a longitudinal analysis on stop signal reaction time and task-related activation and amygdala connectivity during successful and failed inhibition. Results showed that there was no group difference in task performance. Before treatment, OCD patients compared to controls showed less inhibition-related activation in the right inferior frontal gyrus, and increased functional connectivity between the right amygdala and the right inferior frontal gyrus and pre-supplementary motor area. During error-processing, OCD patients versus controls showed less activation in the pre-SMA before treatment. These group differences did not change after treatment. Pre-treatment task performance, brain activation, and connectivity were unrelated to the degree of symptom improvement after treatment. In conclusion, inferior frontal gyrus hypoactivation and increased fronto-limbic connectivity are likely trait markers of OCD that remain after effective exposure therapy.publishedVersio

Effects of Bergen 4-Day Treatment on Resting-State Graph Features in Obsessive-Compulsive Disorder

Background Exposure and response prevention is an effective treatment for obsessive-compulsive disorder (OCD), but it is unclear how symptom reduction is related to changes in the brain. We aimed to determine the effects of a 4-day concentrated exposure and response prevention program (Bergen 4-day treatment) on the static and dynamic functional connectome in patients with OCD. Methods Thirty-four patients with OCD (25 unmedicated) underwent resting-state functional magnetic resonance imaging the day before the Bergen 4-day treatment, and 28 (21 unmedicated) were rescanned after 1 week. Twenty-eight healthy control subjects were also scanned for baseline comparisons and 19 of them were rescanned after 1 week. Static and dynamic graph measures were quantified to determine network topology at the global, subnetwork, and regional levels (including efficiency, clustering, between-subnetwork connectivity, and node flexibility in module allegiance). The Yale-Brown Obsessive Compulsive Scale was used to measure symptom severity. Results Twenty-four patients (86%) responded to treatment. We found significant group × time effects in frontoparietal-limbic connectivity (ηp2 = .19, p = .03) and flexibility of the right subgenual anterior cingulate cortex (ηp2 = .18, p = .03), where, in both cases, unmedicated patients showed significant decreases while healthy control subjects showed no significant changes. Healthy control subjects showed increases in global and subnetwork efficiency and clustering coefficient, particularly in the somatomotor subnetwork. Conclusions Concentrated exposure and response prevention in unmedicated patients with OCD leads to decreased connectivity between the frontoparietal and limbic subnetworks and less flexibility of the connectivity of the subgenual anterior cingulate cortex, suggesting a more independent and stable network topology. This may represent less limbic interference on cognitive control subnetworks after treatment.acceptedVersio

Disentangling Within- and Between-Person Effects During Response Inhibition in Obsessive-Compulsive Disorder

Background: Obsessive-compulsive disorder (OCD) has been related to worse performance, abnormal brain activity, and functional connectivity during response inhibition. Whether these findings are indications of stable traits that contribute to the development of the disorder, or whether they are a result of the state severity of obsessions and anxiety, remains unclear since previous research mainly has employed cross-sectional designs. The present study aimed to assess longitudinal between- and within-person relationships between symptoms, task performance, right inferior frontal gyrus brain activation, and connectivity between the right amygdala and the right pre-supplementary motor area in 29 OCD patients before and after concentrated exposure and response prevention treatment. Method: Patients received exposure and response prevention delivered during 4 consecutive days, following the Bergen 4-day Treatment format. Patients performed a Stop Signal Task during 3T functional Magnetic Resonance Imaging the day before treatment, as well as 1 week and 3 months after treatment completion. Multilevel models were used to analyze disaggregated within- and between-person effects over time. Independent variables were scores on the symptom severity scales for OCD, anxiety, depression, and state distress during scanning. Dependent variables were reaction time for go trials, stop signal response time, task-related brain activation and connectivity. Results: A positive between-person effect was found for obsessive-compulsive, anxiety, and depressive symptom severity on go trial reaction time, indicating that patients with higher symptom scores on average respond slower during accurate go trials. We also found no significant between- or within-person relations between symptom severity and task-related activation or fronto-limbic connectivity. Conclusions: The between-person findings may point toward a general association between slower processing speed and symptom severity in OCD. Longitudinal studies should disaggregate between- and within-person effects to better understand variation over time.publishedVersio

(HIIT-The Track) High-Intensity Interval Training for People with Parkinson's Disease: Individual Response Patterns of (Non-)Motor Symptoms and Blood-Based Biomarkers-A Crossover Single-Case Experimental Design.

INTRODUCTION Physical exercise is receiving increasing interest as an augmentative non-pharmacological intervention in Parkinson's disease (PD). This pilot study primarily aimed to quantify individual response patterns of motor symptoms to alternating exercise modalities, along with non-motor functioning and blood biomarkers of neuroplasticity and neurodegeneration. MATERIALS & METHODS People with PD performed high-intensity interval training (HIIT) and continuous aerobic exercise (CAE) using a crossover single-case experimental design. A repeated assessment of outcome measures was conducted. The trajectories of outcome measures were visualized in time series plots and interpreted relative to the minimal clinically important difference (MCID) and smallest detectable change (SDC) or as a change in the positive or negative direction using trend lines. RESULTS Data of three participants were analyzed and engaging in physical exercise seemed beneficial for reducing motor symptoms. Participant 1 demonstrated improvement in motor function, independent of exercise modality; while for participant 2, such a clinically relevant (positive) change in motor function was only observed in response to CAE. Participant 3 showed improved motor function after HIIT, but no comparison could be made with CAE because of drop-out. Heterogeneous responses on secondary outcome measures were found, not only between exercise modalities but also among participants. CONCLUSION Though this study underpins the positive impact of physical exercise in the management of PD, large variability in individual response patterns to the interventions among participants makes it difficult to identify clear exercise-induced adaptations in functioning and blood biomarkers. Further research is needed to overcome methodological challenges in measuring individual response patterns

Oral contraceptives, depressive and insomnia symptoms in adult women with and without depression

Background: Worldwide, oral contraceptive (OC) use is a very common form of birth control, although it has been associated with symptoms of depression and insomnia. Insomnia is a risk factor for major depressive disorder (MDD) but may also be a symptom of the disorder. Despite the large number of women who use OC, it is yet unknown whether women with previous or current diagnosis of depression are more likely to experience more severe depressive and insomnia symptoms during concurrent OC use than women without diagnosis of depression. Aim: This study examined associations between OC use and concurrent symptoms of depression (including atypical depression) and insomnia as well as between OC and prevalences of concurrent dysthymia and MDD. Participants were adult women with and without a history of MDD or dysthymia. We hypothesized that OC use is associated with concurrent increased severity of depressive symptoms and insomnia symptoms, as well as with an increased prevalence of concurrent diagnoses of dysthymia and MDD. We also hypothesized that a history of MDD or dysthymia moderates the relationship between OC use and depressive and insomnia symptoms. Methods: Measurements from premenopausal adult women from the Netherlands Study of Depression and Anxiety (NESDA) were grouped, based on whether participants were using OC or naturally cycling (NC). OC use, timing and regularity of the menstrual cycle were assessed with a structured interview, self-reported symptoms of depression (including atypical depression), insomnia with validated questionnaires, and MDD and dysthymia with structured diagnostic interviews. Results: We included a total of 1301 measurements in women who reported OC use and 1913 measurements in NC women (mean age 35.6, 49.8% and 28.9% of measurements in women with a previous depression or current depression, respectively). Linear mixed models showed that overall, OC use was neither associated with more severe depressive symptoms (including atypical depressive symptoms), nor with higher prevalence of diagnoses of MDD or dysthymia. However, by disentangling the amalgamated overall effect, within-person estimates indicated increased depressive symptoms and depressive disorder prevalence during OC use, whereas between-person estimated indicated lower depressive symptoms and prevalence of depressive disorders. OC use was consistently associated with more severe concurrent insomnia symptoms, in the overall estimates as well as in the within-person and between-person estimates. Presence of current or previous MDD or dysthymia did not mod-erate the associations between OC use and depressive or insomnia symptoms. Discussion: The study findings showed consistent associations between OC use and more severe insomnia symptoms, but no consistent associations between OC and depressive symptoms or diagnoses. Instead, post-hoc analyses showed that associations between OC and depression differed between within-and between person -estimates. This indicates that, although OC shows no associations on the overall level, some individuals might experience OC-associated mood symptoms. Our findings underscore the importance of accounting for individual differences in experiences during OC use. Furthermore, it raises new questions about mechanisms underlying associations between OC, depression and insomnia.Stress-related psychiatric disorders across the life spa