Stella J. de Wit

Presupplementary Motor Area Hyperactivity During Response Inhibition: A Candidate Endophenotype of Obsessive-Compulsive Disorder

OBJECTIVE Endophenotype studies of obsessive-compulsive disorder (OCD) may uncover heritable traits that are related to genetic susceptibility to OCD. Deficient response inhibition is a promising endophenotype of OCD, although its functional neural correlates have not been extensively studied. The authors sought to determine the functional neural correlates of response inhibition in a large sample of medication-free OCD patients and their unaffected siblings. METHOD Forty-one OCD patients, 17 of their siblings, and 37 matched healthy comparison subjects performed a stop-signal task during 3-T functional MRI. The stop-signal reaction time provided a behavioral measure of response inhibition. The neural correlates of response inhibition were assessed in a region-of-interest analysis that included the presupplementary motor area, inferior frontal gyrus, subthalamic nucleus, and inferior parietal cortex. RESULTS Patients with OCD had greater stop-signal reaction times relative to healthy comparison subjects. The numerical stop-signal reaction time difference between siblings and comparison subjects failed to reach significance. Both patients with OCD and their siblings showed greater activity in the left presupplementary motor area during successful inhibition relative to comparison subjects. Relative to both the comparison subjects and the siblings, patients with OCD showed decreased activity in the right inferior parietal cortex and inferior frontal gyrus. In patients and siblings, presupplementary motor area activity correlated negatively with stop-signal reaction time. CONCLUSIONS These findings suggest that presupplementary motor area hyperactivity is a neurocognitive endophenotype of OCD that is possibly related to inefficient neural processing within the presupplementary motor area itself. Patients with OCD further showed a state-dependent deficit in recruiting right inferior parietal cortex and inferior frontal gyrus, which may contribute to their inhibition deficit.

Multicenter Voxel-Based Morphometry Mega-Analysis of Structural Brain Scans in Obsessive-Compulsive Disorder

OBJECTIVE Results from structural neuroimaging studies of obsessive-compulsive disorder (OCD) have been only partially consistent. The authors sought to assess regional gray and white matter volume differences between large samples of OCD patients and healthy comparison subjects and their relation with demographic and clinical variables. METHOD A multicenter voxel-based morphometry mega-analysis was performed on 1.5-T structural T1-weighted MRI scans derived from the International OCD Brain Imaging Consortium. Regional gray and white matter brain volumes were compared between 412 adult OCD patients and 368 healthy subjects. RESULTS Relative to healthy comparison subjects, OCD patients had significantly smaller volumes of frontal gray and white matter bilaterally, including the dorsomedial prefrontal cortex, the anterior cingulate cortex, and the inferior frontal gyrus extending to the anterior insula. Patients also showed greater cerebellar gray matter volume bilaterally compared with healthy subjects. Group differences in frontal gray and white matter volume were significant after correction for multiple comparisons. Additionally, group-by-age interactions were observed in the putamen, insula, and orbitofrontal cortex (indicating relative preservation of volume in patients compared with healthy subjects with increasing age) and in the temporal cortex bilaterally (indicating a relative loss of volume in patients compared with healthy subjects with increasing age). CONCLUSIONS These findings partially support the prevailing fronto-striatal models of OCD and offer additional insights into the neuroanatomy of the disorder that were not apparent from previous smaller studies. The group-by-age interaction effects in orbitofrontal-striatal and (para)limbic brain regions may be the result of altered neuroplasticity associated with chronic compulsive behaviors, anxiety, or compensatory processes related to cognitive dysfunction.

Frontal–striatal abnormalities underlying behaviours in the compulsive–impulsive spectrum

In this paper, we tentatively bring together the psychiatric, neurological and addiction perspectives on the impulsive-compulsive spectrum of neuropsychiatric disorders, in order to understand the pathophysiology of impulse control disorders (ICDs) in Parkinsons disease. In an attempt to try to pool the various levels of information we will therefore focus on three disorders within the impulse-compulsive spectrum, i.e., obsessive-compulsive disorder (OCD), ICDs in Parkinsons disease, and cocaine seeking behaviour. Whereas there are large differences between these three domains, each with their own nomenclature, hypotheses and study results, they share the focus on an imbalance within and between the frontal-striatal circuits as underlying substrate for the behaviours. For each disorder, we summarize the results from recent studies in order to describe in which way alterations in the frontal-striatal circuits contribute to the phenotype. The phenomenological overlap between ICDs in Parkinsons disease, addiction and OCD needs further investigation, since better understanding of the overlapping and differentiating characteristics will contribute to our understanding of the pathophysiology of the disturbances and treatment alternatives.

Compensatory Frontoparietal Activity During Working Memory: An Endophenotype of Obsessive- Compulsive Disorder

BACKGROUND Subtle deficits in executive functioning are present in patients with obsessive-compulsive disorder (OCD) and their first-degree relatives, suggesting involvement of the frontoparietal circuits. The neural correlates of working memory may be a neurocognitive endophenotype of OCD. METHODS Forty-three unmedicated OCD patients, 17 unaffected siblings, and 37 matched comparison subjects performed a visuospatial n-back task, with a baseline condition (N0) and three working memory load levels (N1, N2, N3) during functional magnetic resonance imaging. Task-related brain activity was compared between groups in frontoparietal regions of interest. Generalized psychophysiological interaction analyses were used to study task-related changes in functional connectivity. RESULTS Obsessive-compulsive disorder patients, compared with comparison subjects and siblings, showed increased error rates at N3. Compared with comparison subjects, OCD patients showed task-related hyperactivation in left dorsal frontal areas and left precuneus associated with better task performance. Siblings exhibited hyperactivation in a bilateral frontoparietal network. Increased task load was associated with increased task-related brain activity, but in OCD patients and siblings this increase was smaller from load N2 to N3 than in comparison subjects. Obsessive-compulsive disorder patients, compared with siblings and comparison subjects, showed increased task-related functional connectivity between frontal regions and bilateral amygdala. CONCLUSIONS These findings indicate that compensatory frontoparietal brain activity in OCD patients and their unaffected relatives preserves task performance at low task loads but is insufficient to maintain performance at high task loads. Frontoparietal dysfunction may constitute a neurocognitive endophenotype for OCD, possibly reflecting limbic interference with and neural inefficiency within the frontoparietal network.

Response Inhibition and Interference Control in Obsessive–Compulsive Spectrum Disorders

Over the past 20 years, motor response inhibition and interference control have received considerable scientific effort and attention, due to their important role in behavior and the development of neuropsychiatric disorders. Results of neuroimaging studies indicate that motor response inhibition and interference control are dependent on cortical–striatal–thalamic–cortical (CSTC) circuits. Structural and functional abnormalities within the CSTC circuits have been reported for many neuropsychiatric disorders, including obsessive–compulsive disorder (OCD) and related disorders, such as attention-deficit hyperactivity disorder, Tourette’s syndrome, and trichotillomania. These disorders also share impairments in motor response inhibition and interference control, which may underlie some of their behavioral and cognitive symptoms. Results of task-related neuroimaging studies on inhibitory functions in these disorders show that impaired task performance is related to altered recruitment of the CSTC circuits. Previous research has shown that inhibitory performance is dependent upon dopamine, noradrenaline, and serotonin signaling, neurotransmitters that have been implicated in the pathophysiology of these disorders. In this narrative review, we discuss the common and disorder-specific pathophysiological mechanisms of inhibition-related dysfunction in OCD and related disorders.

HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter

The hypothalamus–pituitary–adrenal (HPA) axis is activated in most, but not all multiple sclerosis (MS) patients and is implicated in disease progression and comorbid mood disorders. In this post-mortem study, we investigated how HPA axis activity in MS is related to disease severity, neurodegeneration, depression, lesion pathology and gene expression in normal-appearing white matter (NAWM). In 42 MS patients, HPA axis activity was determined by measuring cortisol in cerebrospinal fluid (CSF) and counting hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons. Degree of neurodegeneration was based on levels of glutamate, tau and neurofilament in CSF. Duration of MS and time to EDSS 6 served as indicators of disease severity. Glutamate levels correlated with numbers of CRH-expressing neurons, most prominently in primary progressive MS patients, suggesting that neurodegeneration is a strong determinant of HPA axis activity. High cortisol levels were associated with slower disease progression, especially in females with secondary progressive MS. Patients with low cortisol levels had greater numbers of active lesions and tended towards having less remyelinated plaques than patients with high cortisol levels. Interestingly, NAWM of patients with high cortisol levels displayed elevated expression of glucocorticoid-responsive genes, such as CD163, and decreased expression of pro-inflammatory genes, such as tumor necrosis factor-α. Thus, HPA axis hyperactivity in MS coincides with low inflammation and/or high neurodegeneration, and may impact on lesion pathology and molecular mechanisms in NAWM and thereby be of great importance for suppression of disease activity.

State-Dependent Differences in Emotion Regulation Between Unmedicated Bipolar Disorder and Major Depressive Disorder

IMPORTANCE Major depressive disorder (MDD) and bipolar disorder (BD) are difficult to distinguish clinically during the depressed or remitted states. Both mood disorders are characterized by emotion regulation disturbances; however, little is known about emotion regulation differences between MDD and BD. Better insight into these differences would be helpful for differentiation based on disorder-specific underlying pathophysiological mechanisms. Previous studies comparing these disorders often allowed medication use, limiting generalizability and validity. Moreover, patients with MDD and BD were mostly compared during the depressed, but not the remitted, state, while state might potentially modulate differences between MDD and BD. OBJECTIVE To investigate positive and negative emotion regulation in medication-free patients with MDD and BD in 2 mood states: depressed or remitted. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study conducted from May 2009 to August 2013 comparing behavioral and functional magnetic resonance imaging emotion regulation data of 42 patients with MDD, 35 with BD, and 36 healthy control (HC) participants free of psychotropic medication recruited from several psychiatric institutions across the Netherlands. INTERVENTION A voluntary emotion regulation functional magnetic resonance imaging task using positive and negative pictures. MAIN OUTCOMES AND MEASURES Behavioral and functional magnetic resonance imaging blood oxygen level-dependent responses during emotion regulation. RESULTS In the remitted state, only patients with BD showed impaired emotion regulation (t = 3.39; P < .001; Cohen d = 0.70), irrespective of emotion type and associated with increased dorsolateral prefrontal cortex activity compared with those with MDD and healthy control participants (P = .008). In the depressed state, patients with MDD and BD differed with regard to happy vs sad emotion regulation (t = 4.19; P < .001; Cohen d = 1.66) associated with differences in rostral anterior cingulate activity (P < .001). Patients with MDD regulated sad and happy emotions poorly compared with those with BD and healthy control participants, while they demonstrated no rostral anterior cingulate difference between happy and sad emotion regulation. In contrast, patients with BD performed worse than those with MDD on sad emotion regulation but normal on happy emotion regulation, and they demonstrated significantly less rostral anterior cingulate activity while regulating happy compared with sad emotions. CONCLUSIONS AND RELEVANCE Medication-free patients with MDD vs BD appear to differ in brain activations during emotion regulation, both while depressed and in remission. These different neuropathophysiological mechanisms between MDD and BD may be useful for further development of additional diagnostic tools.

Cortical thickness in obsessive-compulsive disorder: multisite mega-analysis of 780 brain scans from six centres.

BACKGROUND There is accumulating evidence for the role of fronto-striatal and associated circuits in obsessive-compulsive disorder (OCD) but limited and conflicting data on alterations in cortical thickness. AIMS To investigate alterations in cortical thickness and subcortical volume in OCD. METHOD In total, 412 patients with OCD and 368 healthy adults underwent magnetic resonance imaging scans. Between-group analysis of covariance of cortical thickness and subcortical volumes was performed and regression analyses undertaken. RESULTS Significantly decreased cortical thickness was found in the OCD group compared with controls in the superior and inferior frontal, precentral, posterior cingulate, middle temporal, inferior parietal and precuneus gyri. There was also a group × age interaction in the parietal cortex, with increased thinning with age in the OCD group relative to controls. CONCLUSIONS Our findings are partially consistent with earlier work, suggesting that group differences in grey matter volume and cortical thickness could relate to the same underlying pathology of OCD. They partially support a frontostriatal model of OCD, but also suggest that limbic, temporal and parietal regions play a role in the pathophysiology of the disorder. The group × age interaction effects may be the result of altered neuroplasticity.

Switch the itch: A naturalistic follow-up study on the neural correlates of cognitive flexibility in obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a relatively common psychiatric disorder characterized by intrusive thoughts and behaviors that dominate daily living, like an itch patients cannot ignore. Deficits in executive functioning are common in OCD and are thought to be related to dysfunctional frontal-striatal systems. One of those executive functions is cognitive flexibility, defined as the ability to rapidly switch response strategies following changes in task-relevant information. The temporal stability of cognitive flexibility impairments in OCD has been incompletely investigated since previous studies have suggested both state and trait dependency. In this study, 16 OCD patients performed a functional magnetic resonance imaging version of a task-switching paradigm twice, intervened by a follow-up period of on average 6 months. Results show that functional abnormalities in the dorsal frontal-striatal circuit and anterior cingulate cortex at baseline normalized at follow-up. This change in the recruitment of task-related brain circuits correlated with change in disease severity. These results support the view that the imbalance between the dorsal and ventral frontal-striatal circuits is at least partly state-dependent, and is associated with a reduction in symptom severity.

Altered inhibition-related frontolimbic connectivity in obsessive-compulsive disorder

Recent studies have shown that response inhibition is impaired in patients with obsessive–compulsive disorder and their unaffected siblings, suggesting that these deficits may be considered a cognitive endophenotype of obsessive–compulsive disorder. Structural and functional neural correlates of altered response inhibition have been identified in patients and siblings. This study aims to examine the functional integrity of the response inhibition network in patients with obsessive–compulsive disorder and their unaffected siblings.