Odile A. van den Heuvel

Meta-analytical Comparison of Voxel-Based Morphometry Studies in Obsessive-Compulsive Disorder vs Other Anxiety Disorders

CONTEXT Whether obsessive-compulsive disorder (OCD) is adequately classified as an anxiety disorder is a matter of considerable debate. OBJECTIVES To quantitatively compare structural brain changes in OCD and other anxiety disorders using novel voxel-based meta-analytical methods and to generate an online database to facilitate replication and further analyses by other researchers. DATA SOURCES The PubMed, ScienceDirect, and Scopus databases were searched between 2001 (the date of the first voxel-based morphometry study in any anxiety disorder) and 2009. All voxel-based morphometry studies comparing patients with any anxiety disorder and healthy controls were retrieved. Manual searches were also conducted. Authors were contacted soliciting additional data. STUDY SELECTION Thirty-seven data sets were identified, of which 26 (including 639 patients with anxiety disorders and 737 healthy controls) met inclusion criteria. DATA EXTRACTION Coordinates were extracted from clusters of significant gray matter difference between patients and controls. Demographic, clinical, and methodological variables were extracted from each study or obtained from the authors. DATA SYNTHESIS Patients with anxiety disorders (including OCD) showed decreased bilateral gray matter volumes in the dorsomedial frontal/anterior cingulate gyri. Individuals with OCD had increased bilateral gray matter volumes (vs healthy controls and vs individuals with other anxiety disorders) in the lenticular/caudate nuclei, while patients with other anxiety disorders (mainly panic and posttraumatic stress disorders) had decreased gray matter volumes in the left lenticular nucleus. The findings remained largely unchanged in quartile and jackknife sensitivity analyses. Controlling for potential confounders such as age or antidepressant medication had little impact on the results. CONCLUSIONS The meta-analysis consistently revealed common as well as distinct neural substrates in OCD and other anxiety disorders. These results have implications for the current debate surrounding the classification of OCD in the DSM-V.

Regional brain volume in depression and anxiety disorders

CONTEXT Major depressive disorder (MDD), panic disorder, and social anxiety disorder are among the most prevalent and frequently co-occurring psychiatric disorders in adults and may have, at least in part, a common etiology. OBJECTIVE To identify the unique and shared neuroanatomical profile of depression and anxiety, controlling for illness severity, medication use, sex, age of onset, and recurrence. DESIGN Cross-sectional study. SETTING Netherlands Study of Depression and Anxiety. PARTICIPANTS Outpatients with MDD (n = 68), comorbid MDD and anxiety (n = 88), panic disorder, and/or social anxiety disorder without comorbid MDD (n = 68) and healthy controls (n = 65). MAIN OUTCOME MEASURES Volumetric magnetic resonance imaging was conducted for voxel-based morphometry analyses. We tested voxelwise for the effects of diagnosis, age at onset, and recurrence on gray matter density. Post hoc, we studied the effects of use of medication, illness severity, and sex. RESULTS We demonstrated lower gray matter volumes of the rostral anterior cingulate gyrus extending into the dorsal anterior cingulate gyrus in MDD, comorbid MDD and anxiety, and anxiety disorders without comorbid MDD, independent of illness severity, sex, and medication use. Furthermore, we demonstrated reduced right lateral inferior frontal volumes in MDD and reduced left middle/superior temporal volume in anxiety disorders without comorbid MDD. Also, patients with onset of depression before 18 years of age showed lower volumes of the subgenual prefrontal cortex. CONCLUSIONS Our findings indicate that reduced volume of the rostral-dorsal anterior cingulate gyrus is a generic effect in depression and anxiety disorders, independent of illness severity, medication use, and sex. This generic effect supports the notion of a shared etiology and may reflect a common symptom dimension related to altered emotion processing. Specific involvement of the inferior frontal cortex in MDD and lateral temporal cortex in anxiety disorders without comorbid MDD, on the other hand, may reflect disorder-specific symptom clusters. Early onset of depression is associated with a distinct neuroanatomical profile that may represent a vulnerability marker of depressive disorder.

Frontostriatal system in planning complexity: a parametric functional magnetic resonance version of tower of london task

In the present study, we sought to investigate which brain structures are recruited in planning tasks of increasing complexity. For this purpose, a parametric self-paced pseudo-randomized event-related functional MRI version of the Tower of London task was designed. We tested 22 healthy subjects, enabling assessment of imaging results at a second (random effects) level of analysis. Compared with baseline, planning activity was correlated with increased blood oxygenation level-dependent (BOLD) signal in the dorsolateral prefrontal cortex, striatum, premotor cortex, supplementary motor area, and visuospatial system (precuneus and inferior parietal cortex). Task load was associated with increased activity in these same regions. In addition, increasing task complexity was correlated with activity in the left anterior prefrontal cortex, a region supposed to be specifically involved in third-order higher cognitive functioning.

Reduced Orbitofrontal and Parietal Gray Matter in Chronic Insomnia: A Voxel-Based Morphometric Study

BACKGROUND Brain mechanisms of chronic insomnia, a highly prevalent condition, have barely been investigated. We demonstrate here a decrease in orbitofrontal gray matter (GM) volume that strongly correlates with the severity of complaints. METHODS In a case-control study, optimized voxel-based morphometry was used to compare the regional brain volumes of 24 medication-free chronic primary insomnia patients (age range 52-74 years, 17 women), carefully selected to exclude psychiatric comorbidity, with those of 13 matched control subjects without sleep problems (age range 50-76 years, 9 women). Additionally, the correlation of regional volumes with insomnia severity was investigated. RESULTS Patients had a smaller volume of GM in the left orbitofrontal cortex, strongly correlating (r = -.71) with the subjective severity of insomnia. Furthermore, reduced GM volume was found in the anterior and posterior precuneus. Patients did not show increased GM volume in any area. No group differences were found for white matter volume. CONCLUSIONS This is the first voxel-based morphometry study showing structural brain correlates of insomnia and their relation with insomnia severity. Functional roles of the affected areas in decision-making and stimulus processing might better guide future research into the poorly understood condition of insomnia.

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.

Amygdala activity in obsessive-compulsive disorder with contamination fear: a study with oxygen-15 water positron emission tomography

Previous imaging studies of obsessive-compulsive symptom states have implicated frontal-striatal and limbic regions in the pathophysiology of obsessive-compulsive disorder (OCD). Functional imaging studies, however, have yielded inconsistent results, presumably due to methodological differences (patient inclusion criteria, stimulus paradigm, imaging technique, and absence of control groups). In the present study, randomized presentation of contamination-related and neutral visual stimuli was used to investigate the neurophysiological correlates of contamination fear in a group of medication-free OCD patients with washing behaviors and healthy controls. A total of 21 subjects (11 OCD patients and 10 healthy controls) were scanned using H(2)(15)O positron emission tomography (PET). Subjects were presented with pictures of clean and dirty surroundings and were requested to make indoor/outdoor decisions to control for attention differences. State anxiety and obsessionality were rated after each scan using visual analogue scales. Main effects of stimulus type (contamination vs. neutral) were found in bilateral occipital cortex in both groups. A significant group interaction effect was observed in the left amygdala reflecting enhanced activity in response to contamination stimuli in OCD patients. Sensitization effects were observed in the right amygdala in the OCD group; these paralleled an increase in levels of distress and obsessionality as well as a decrease in dorsolateral prefrontal activity. The findings of the present study are consistent with the hypothesis of decreased frontal-striatal control of limbic structures, specifically the amygdala, resulting in an inadequate fear response in OCD patients with contamination fear.

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.

Parkinson's disease-related disorders in the impulsive-compulsive spectrum.

In Parkinson’s disease (PD), there is increasing evidence for disorders in the impulsive-compulsive spectrum, related to the disease itself, to the pharmacological management of this disease or to both. These disorders comprise dopamine deficiency syndrome (with immediate reward seeking behaviour), dopamine dependency syndrome (with addictive behaviour), dopamine dysregulation syndrome (with both addictive behaviour and stereotyped behaviour) and impulse control disorders (such as pathological gambling, compulsive shopping, binge eating and hypersexuality). These disorders are especially seen in PD patients with young age of onset, higher doses of antiparkinsonian drugs, pre-existent or current depression, pre-existing recreational drug or alcohol use, and high novelty seeking personality traits.Dopamine is not only implicated in voluntary movement control but also plays a significant role in the brain’s reward system and the modulation of behaviours. Therefore, most if not all drugnaïve PD patients will suffer dysphoria, leading to mild immediate reward seeking behaviour as a consequence of the striatal dopaminergic denervation. In some of these patients, during treatment, this may even lead to the intake of increasing quantities of levodopa, above those required to adequately treat motor parkinsonism, with all characteristics of a dopamine dependence syndrome. These patients may develop plastic changes in the striatal matrix leading to hyperkinesia, caused by extracellular striatal dopaminergic fluctuations due to pulsatile dopamine replacement therapy. As soon as these changes are also seen in the striatal striosomes, in the framework of a dopamine dysregulation syndrome, stereotyped behaviours (punding) may occur (supposedly due to dorsal versus ventral striatal overactivity). Finally, impulse control disorders are suggested as being pure adverse side-effects of dopamine replacement therapy. Obsessive-compulsive behaviour (caused by ventral to dorsal overactivity) so far has not been described in PD patients.Treatment of impulse control disorders is related to the underlying pathology. In the case of an intrinsic dopamine deficiency syndrome, treatment with dopamine replacement therapy, especially levodopa, will help. In the multifactorial (intrinsic and extrinsic) dopamine dependency and dysregulation syndromes, addictive behaviour might best be helped by psychosocial strategies, and punding by continuous dopaminergic receptor stimulation (or amantadine), hypothesized to reduce the plastic changes-induced hypersensitization. The extrinsic impulse control disorders might be best treated by reducing or replacing dopamine receptor agonists.

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.