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Wilhelm, Sabine

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Wilhelm

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Sabine

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Wilhelm, Sabine
Author's Publications: search.filters.isAuthorOfPublication.9dc7b969-ae18-4695-a616-6faa0c153980

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    Dissociable Genetic Contributions to Error Processing: A Multimodal Neuroimaging Study
    (Public Library of Science, 2014) Agam, Yigal; Vangel, Mark; Roffman, Joshua; Gallagher, Patience J.; Chaponis, Jonathan; Haddad, Stephen; Goff, Donald C.; Greenberg, Jennifer; Wilhelm, Sabine; Smoller, Jordan; Manoach, Dara
    Background: Neuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation. Methods: We measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response. Results: We replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant. Conclusions: DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation.
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    Aberrant error processing in relation to symptom severity in obsessive–compulsive disorder: A multimodal neuroimaging study
    (Elsevier, 2014) Agam, Yigal; Greenberg, Jennifer; Isom, Marlisa; Falkenstein, Martha J.; Jenike, Eric; Wilhelm, Sabine; Manoach, Dara
    Background: Obsessive–compulsive disorder (OCD) is characterized by maladaptive repetitive behaviors that persist despite feedback. Using multimodal neuroimaging, we tested the hypothesis that this behavioral rigidity reflects impaired use of behavioral outcomes (here, errors) to adaptively adjust responses. We measured both neural responses to errors and adjustments in the subsequent trial to determine whether abnormalities correlate with symptom severity. Since error processing depends on communication between the anterior and the posterior cingulate cortex, we also examined the integrity of the cingulum bundle with diffusion tensor imaging. Methods: Participants performed the same antisaccade task during functional MRI and electroencephalography sessions. We measured error-related activation of the anterior cingulate cortex (ACC) and the error-related negativity (ERN). We also examined post-error adjustments, indexed by changes in activation of the default network in trials surrounding errors. Results: OCD patients showed intact error-related ACC activation and ERN, but abnormal adjustments in the post- vs. pre-error trial. Relative to controls, who responded to errors by deactivating the default network, OCD patients showed increased default network activation including in the rostral ACC (rACC). Greater rACC activation in the post-error trial correlated with more severe compulsions. Patients also showed increased fractional anisotropy (FA) in the white matter underlying rACC. Conclusions: Impaired use of behavioral outcomes to adaptively adjust neural responses may contribute to symptoms in OCD. The rACC locus of abnormal adjustment and relations with symptoms suggests difficulty suppressing emotional responses to aversive, unexpected events (e.g., errors). Increased structural connectivity of this paralimbic default network region may contribute to this impairment.
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    Brain white matter integrity and association with age at onset in pediatric obsessive-compulsive disorder
    (BioMed Central, 2014) Rosso, Isabelle; Olson, Elizabeth; Britton, Jennifer C; Stewart, S Evelyn; Papadimitriou, George; Killgore, William DS; Makris, Nikos; Wilhelm, Sabine; Jenike, Michael; Rauch, Scott
    Background: Obsessive-compulsive disorder (OCD) is a common and debilitating neuropsychiatric illness thought to involve abnormal connectivity of widespread brain networks, including frontal-striatal-thalamic circuits. At least half of OCD cases arise in childhood and their underlying neuropathology may differ at least in part from that of adult-onset OCD. Yet, only a few studies have examined brain white matter (WM) integrity in childhood-onset OCD using diffusion tensor imaging (DTI), and none have examined potential associations with age at onset. Results: In this study, 17 youth with OCD and 19 healthy control subjects, ages 10 to 19 years, underwent DTI on a 3T Siemens scanner. DSM-IV diagnoses were established with standardized interviews, and OCD symptom severity was evaluated using the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Voxel-wise analyses were conducted on data processed with tract-based spatial statistics (TBSS) to derive measures of fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). OCD patients had significantly lower FA in seven WM clusters, with over 80% of significant voxels in bilateral frontal cortex and corpus callosum (CC). There were no regions of significantly higher FA in patients compared with controls. Patients also had significantly higher RD in right frontal cortex and right body of the CC. Earlier age at onset of OCD correlated significantly with lower FA in the right thalamus and with higher RD in the right CC. FA and RD were not significantly associated with symptom severity. Conclusions: These findings point to compromised WM integrity and reduced myelination in some brain regions of children with OCD, particularly the CC and fiber tracts that connect the frontal lobes to widespread cortical and subcortical targets. They also suggest that age at onset may be a moderator of some of the WM changes in pediatric OCD.
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    Comorbidity Between Attention Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder Across the Lifespan: A Systematic and Critical Review
    (Lippincott Williams & Wilkins, 2015) Abramovitch, Amitai; Dar, Reuven; Mittelman, Andrew; Wilhelm, Sabine
    Abstract The concept of comorbidity between attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) has been discussed for two decades. No review, however, has examined this question in light of the stark contrast in disorder-specific phenomenology and neurobiology. We review reported prevalence rates and the methodological, phenomenological, and theoretical issues concerning concomitant ADHD-OCD. Reported co-occurrence rates are highly inconsistent in the literature. Studies aimed at examining the potential for comorbidity have suffered from various methodological problems, including the existence of very few community samples, highly variable exclusionary criteria, and possible clinical misinterpretation of symptoms. Despite numerous studies suggesting an ADHD-OCD comorbidity, thus far etiological (i.e., genetic) backing has been provided only for a pediatric comorbidity. Additionally, inflated rates of ADHD-OCD co-occurrence may be mediated by the presence of tic disorders, and evidence of impaired neuronal maturational processes in pediatric OCD may lead to possibly transient phenotypical expressions that resemble ADHD symptomatology. Thus, clinicians are encouraged to consider the possibility that ADHD-like symptoms resulting from OCD-specific symptomatology may be misdiagnosed as ADHD. This suggestion may account for the lower co-occurrence rates reported in adolescents and adults and for the lack of a theoretical account for comorbidity in these age groups. Existing literature is summarized and critically reviewed, and recommendations are made for future research.