Neurocognitive Predictors of Treatment Response to Randomized Treatment in Adults with Tic Disorders

Tourette\u27s disorder (TS) and chronic tic disorder (CTD) are neurodevelopmental disorders characterized by involuntary vocal and motor tics. Consequently, TS/CTD have been conceptualized as disorders of cognitive and motor inhibitory control. However, most neurocognitive studies have found comparable or superior inhibitory capacity among individuals with TS/CTD relative to healthy controls. These findings have led to the hypothesis that individuals with TS/CTD develop increased inhibitory control due to the constant need to inhibit tics. However, the role of cognitive control in TS/CTD is not yet understood, particularly in adults. To examine the role of inhibitory control in TS/CTD, the present study investigated this association by assessing the relationship between inhibitory control and treatment response in a large sample of adults with TS/CTD. As part of a large randomized trial comparing behavior therapy versus supportive psychotherapy for TS/CTD, a battery of tests, including tests of inhibitory control was administered to 122 adults with TS/CTD at baseline. We assessed the association between neuropsychological test performance and change in symptom severity, as well as compared the performance of treatment responders and non-responders as defined by the Clinical Global Impression Scale. Results indicated that change in symptoms, and treatment response were not associated with neuropsychological performance on tests of inhibitory control, intellectual ability, or motor function, regardless of type of treatment. The finding that significant change in symptom severity of TS/CTD patients is not associated with impairment or change in inhibitory control regardless of treatment type suggests that inhibitory control may not be a clinically relevant facet of these disorders in adults

Pilot randomized trial demonstrating reversal of obesity-related abnormalities in reward system responsivity to food cues with a behavioral intervention

Objectives: Obesity is associated with hyperactivation of the reward system for high-calorie (HC) versus low-calorie (LC) food cues, which encourages unhealthy food selection and overeating. However, the extent to which this hyperactivation can be reversed is uncertain, and to date there has been no demonstration of changes by behavioral intervention. Subjects and methods: We used functional magnetic resonance imaging to measure changes in activation of the striatum for food images at baseline and 6 months in a pilot study of 13 overweight or obese adults randomized to a control group or a novel weight-loss intervention. Results: Compared to controls, intervention participants achieved significant weight loss (−6.3±1.0 kg versus +2.1±1.1 kg, P<0.001) and had increased activation for LC food images with a composition consistent with that recommended in the behavioral intervention at 6 months versus baseline in the right ventral putamen (P=0.04), decreased activation for HC images of typically consumed foods in the left dorsal putamen (P=0.01). There was also a large significant shift in relative activation favoring LC versus HC foods in both regions (P<0.04). Conclusions: This study provides the first demonstration of a positive shift in activation of the reward system toward healthy versus unhealthy food cues in a behavioral intervention, suggesting new avenues to enhance behavioral treatments of obesity

Avoidant/Restrictive Food Intake Disorder: a Three-Dimensional Model of Neurobiology with Implications for Etiology and Treatment

Purpose of Review: DSM-5 defined avoidant/restrictive food intake disorder (ARFID) as a failure to meet nutritional needs leading to low weight, nutritional deficiency, dependence on supplemental feedings, and/or psychosocial impairment. We summarize what is known about ARFID and introduce a three-dimensional model to inform research. // Recent Findings: Because ARFID prevalence, risk factors, and maintaining mechanisms are not known, prevailing treatment approaches are based on clinical experience rather than data. Furthermore, most ARFID research has focused on children, rather than adolescents or adults. We hypothesize a three-dimensional model wherein neurobiological abnormalities in sensory perception, homeostatic appetite, and negative valence systems underlie the three primary ARFID presentations of sensory sensitivity, lack of interest in eating, and fear of aversive consequences, respectively. // Summary: Now that ARFID has been defined, studies investigating risk factors, prevalence, and pathophysiology are needed. Our model suggests testable hypotheses about etiology and highlights cognitive-behavioral therapy as one possible treatment

Do Sleep Disturbances Predict or Moderate the Response to Psychotherapy in Bipolar Disorder?

This study examined whether sleep disturbance predicted or moderated responses to psychotherapy in participants who participated in STEP-BD, a national, multi-site study that examined the effectiveness of different treatment combinations for bipolar disorder. Participants received either a brief psychosocial intervention called collaborative care (CC; n=130), or intensive psychotherapy (IP; n=163), with study-based pharmacotherapy. Participants (N=243) were defined as current (past week) short sleepers (<6 hours/night), normal sleepers (6.5-8.5 hours/night), and long sleepers (≥9 hours/night), according to reported average nightly sleep duration the week before randomization. Sleep disturbances did not predict the likelihood of recovery nor time until recovery from a depressive episode. There was no difference in recovery rates between IP versus CC for normal sleepers, and medium effect sizes were observed for differences in short and long sleepers. In this study, sleep did not play a major role in predicting or moderating response to psychotherapy in bipolar disorder

Age at onset, course of illness and response to psychotherapy in bipolar disorder: Results from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)

Background. The course of bipolar disorder progressively worsens in some patients. Although responses to pharmacotherapy appear to diminish with greater chronicity, less is known about whether patients\u27 prior courses of illness are related to responses to psychotherapy

Accounting for dynamic fluctuations across time when examining fMRI test-retest reliability: Analysis of a reward paradigm in the EMBARC study

Longitudinal investigation of the neural correlates of reward processing in depression may represent an important step in defining effective biomarkers for antidepressant treatment outcome prediction, but the reliability of reward-related activation is not well understood. Thirty-seven healthy control participants were scanned using fMRI while performing a reward-related guessing task on two occasions, approximately one week apart. Two main contrasts were examined: right ventral striatum (VS) activation fMRI BOLD signal related to signed prediction errors (PE) and reward expectancy (RE). We also examined bilateral visual cortex activation coupled to outcome anticipation. Significant VS PE-related activity was observed at the first testing session, but at the second testing session, VS PE-related activation was significantly reduced. Conversely, significant VS RE-related activity was observed at time 2 but not time 1. Increases in VS RE-related activity from time 1 to time 2 were significantly associated with decreases in VS PE-related activity from time 1 to time 2 across participants. Intraclass correlations (ICCs) in VS were very low. By contrast, visual cortex activation had much larger ICCs, particularly in individuals with high quality data. Dynamic changes in brain activation are widely predicted, and failure to account for these changes could lead to inaccurate evaluations of the reliability of functional MRI signals. Conventional measures of reliability cannot distinguish between changes specified by algorithmic models of neural function and noisy signal. Here, we provide evidence for the former possibility: reward-related VS activations follow the pattern predicted by temporal difference models of reward learning but have low ICCs

A Comprehensive Examination Of White Matter Tracts And Connectometry In Major Depressive Disorder

Background Major depressive disorder (MDD) is a debilitating disorder characterized by widespread brain abnormalities. The literature is mixed as to whether or not white matter abnormalities are associated with MDD. This study sought to examine fractional anisotropy (FA) in white matter tracts in individuals with MDD using diffusion tensor imaging (DTI). Methods 139 participants with MDD and 39 healthy controls (HC) in a multisite study were included. DTI scans were acquired in 64 directions and FA was determined in the brain using four methods: region of interest (ROI), tract-based spatial statistics (TBSS), and diffusion tractography. Diffusion connectometry was used to identify white matter pathways associated with MDD. Results There were no significant differences when comparing FA in MDD and HC groups using any method. In the MDD group, there was a significant relationship between depression severity and FA in the right medial orbitofrontal cortex, and between age of onset of MDD and FA in the right caudal anterior cingulate cortex using the ROI method. There was a significant relationship between age of onset and connectivity in the thalamocortical radiation, inferior longitudinal fasciculus, and cerebellar tracts using diffusion connectometry. Conclusions The lack of group differences in FA and connectometry analysis may result from the clinically heterogenous nature of MDD. However, the relationship between FA and depression severity may suggest a state biomarker of depression that should be investigated as a potential indicator of response. Age of onset may also be a significant clinical feature to pursue when studying white matter tracts

A Comparison Of Structural Connectivity In Anxious Depression Versus Non-anxious Depression

Background: Major depressive disorder (MDD) and anxiety disorders are highly co-morbid. Research has shown conflicting evidence for white matter alteration and amygdala volume reduction in mood and anxiety disorders. To date, no studies have examined differences in structural connectivity between anxious depressed and non-anxious depressed individuals. This study compared fractional anisotropy (FA) and density of selected white matter tracts and amygdala volume between anxious depressed and non-anxious depressed individuals. Methods: 64- direction DTI and T1 scans were collected from 110 unmedicated subjects with MDD, 39 of whom had a co-morbid anxiety disorder diagnosis. Region of interest (ROI) and tractography methods were performed to calculate amygdala volume and FA in the uncinate fasciculus, respectively. Diffusion connectometry was performed to identify whole brain group differences in white matter health. Correlations were computed between biological and clinical measures. Results: Tractography and ROI analyses showed no significant differences between bilateral FA values or bilateral amygdala volumes when comparing the anxious depressed and non-anxious depressed groups. The diffusion connectometry analysis showed no significant differences in anisotropy between the groups. Furthermore, there were no significant relationships between MRI-based and clinical measures. Conclusion: The lack of group differences could indicate that structural connectivity and amygdalae volumes of those with anxious-depression are not significantly altered by a co-morbid anxiety disorder. Improving understanding of anxiety co-morbid with MDD would facilitate development of treatments that more accurately target the underlying networks

Rumination in bipolar disorder: evidence for an unquiet mind

Depression in bipolar disorder has long been thought to be a state characterized by mental inactivity. However, recent research demonstrates that patients with bipolar disorder engage in rumination, a form of self-focused repetitive cognitive activity, in depressed as well as in manic states. While rumination has long been associated with depressed states in major depressive disorder, the finding that patients with bipolar disorder ruminate in manic states is unique to bipolar disorder and challenges explanations put forward for why people ruminate. We review the research on rumination in bipolar disorder and propose that rumination in bipolar disorder, in both manic and depressed states, reflects executive dysfunction. We also review the neurobiology of bipolar disorder and recent neuroimaging studies of rumination, which is consistent with our hypothesis that the tendency to ruminate reflects executive dysfunction in bipolar disorder. Finally, we relate the neurobiology of rumination to the neurobiology of emotion regulation, which is disrupted in bipolar disorder

Cerebral Blood Perfusion Predicts Response To Sertraline Versus Placebo For Major Depressive Disorder In The Embarc Trial

Background: Major Depressive Disorder (MDD) has been associated with brain-related changes. However, biomarkers have yet to be defined that could “accurately” identify antidepressant-responsive patterns and reduce the trial-and-error process in treatment selection. Cerebral blood perfusion, as measured by Arterial Spin Labeling (ASL), has been used to understand resting-state brain function, detect abnormalities in MDD, and could serve as a marker for treatment selection. As part of a larger trial to identify predictors of treatment outcome, the current investigation aimed to identify perfusion predictors of treatment response in MDD. Methods: For this secondary analysis, participants include 231 individuals with MDD from the EMBARC study, a randomized, placebo-controlled trial investigating clincal, behavioral, and biological predictors of antidepressant response. Participants received sertraline (n=114) or placebo (n=117) and response was monitored for 8 weeks. Pre-treatment neuroimaging was completed, including ASL. A whole-brain, voxel-wise linear mixed-effects model was conducted to identify brain regions in which perfusion levels differentially predict (moderate) treatment response. Clinical effectiveness of perfusion moderators was investigated by composite moderator analysis and remission rates. Composite moderator analysis combined the effect of individual perfusion moderators and identified which contribute to sertraline or placebo as the “preferred” treatment. Remission rates were calculated for participants “accurately” treated based on the composite moderator (lucky) versus “inaccurately” treated (unlucky). Findings: Perfusion levels in multiple brain regions differentially predicted improvement with sertraline over placebo. Of these regions, perfusion in the putamen and anterior insula, inferior temporal gyrus, fusiform, parahippocampus, inferior parietal lobule, and orbital frontal gyrus contributed to sertraline response. Remission rates increased from 37% for all those who received sertraline to 53% for those who were lucky to have received it and sertraline was their perfusion-preferred treatment. Interpretation: This large study showed that perfusion patterns in brain regions involved with reward, salience, affective, and default mode processing moderate treatment response favoring sertraline over placebo. Accurately matching patients with defined perfusion patterns could significantly increase remission rates. Funding: National Institute of Mental Health, the Hersh Foundation, and the Center for Depression Research and Clinical Care, Peter O’Donnell Brain Institute at UT Southwestern Medical Cente