Sustained attention induces altered effective connectivity of the ascending thalamo-cortical relay in obsessive-compulsive disorder.

Abnormal function of the thalamo-cortical relay is considered a hallmark of obsessive-compulsive disorder (OCD) and aberrant network interactions may underpin many of the clinical and cognitive symptoms that characterize the disorder. Several statistical approaches have been applied to in vivo fMRI data to support the general loss of thalamo-cortical connectivity in OCD. However, (a) few studies have assessed the contextual constraints under which abnormal network interactions arise or (b) have used methods of effective connectivity to understand abnormal network interactions. Effective connectivity is a particularly valuable method as it describes the putative causal influences that brain regions exert over each other, as opposed to the largely statistical consistencies captured in functional connectivity techniques. Here, using dynamic causal modeling (DCM), we evaluated how attention demand induced inter-group differences (HC ≠ OCD) in effective connectivity within a motivated thalamo-cortical network. Of interest was whether these effects were observed on the ascending thalamo-cortical relay, essential for the sensory innervation of the cortex. fMRI time series data from sixty-two participants (OCD, 30; HC, 32) collected using an established sustained attention task were submitted to a space of 162 competing models. Across the space, models distinguished between competing hypotheses of thalamo-cortical interactions. Bayesian model selection (BMS) identified marginally differing likely generative model architectures in OCD and HC groups. Bayesian model averaging (BMA), was used to weight connectivity parameter estimates across all models, with each parameter weighted by each model's posterior probability, thus providing more stable estimates of effective connectivity. Inferential statistical analyses of estimated parameters revealed two principal results: (1) Significantly reduced intrinsic connectivity of the V1 → SPC pathway in OCD, suggested connective weakness in the early constituents of the dorsal visual pathway; (2) More pertinent with the discovery possibilities afforded by DCM, sustained attention in OCD patients induced significantly reduced contextual modulation of the ascending relay from the thalamus to the prefrontal cortex. These results form an important complement to our understanding of the contextual bases of thalamo-cortical network deficits in OCD, emphasizing vulnerability of the ascending relay.

Evoking network profiles of the dorsal anterior cingulate in youth with Obsessive-Compulsive Disorder during motor control and working memory.

Interest in the pathology of Obsessive-Compulsive Disorder\has focused on brain network profiles of the dorsal Anterior Cingulate Cortex (dACC), given its role as a principal control region. Both motor control and working memory tasks induce dysfunctional dACC profiles in OCD. H H We contrasted dACC network profiles in OCD and age-comparable controls during both tasks (from data collected in the same participants). The motor task required participants to tap their right forefinger in response to a flashing white probe; the memory task was a standard n-back (2-Back) requiring participants to identify if a current stimulus was identical to the one presented two items before it in the sequence. Network interactions were modeled using Psychophysiological Interactions (PPI), a model of directional functional connectivity. Inter-group analyses indicated a) that the motor control task evoked greater dACC modulation than the working memory task, and b) that the modulatory effect was significantly greater in the OCD group. We also investigated the relationship between OCD symptom dimensions (lifetime obsession and lifetime compulsion measured using the CY-BOCS) and dACC network profiles in OCD. This analysis revealed a dichotomy between Obsessive-Compulsive symptom dimensions and the degree of dACC modulation: primarily increased obsessions predicted increased modulation during the motor control task, but primarily increased compulsions predicted increased modulation during the working memory task. These results re-emphasize the salience of the dACC in OCD, and the primacy of tasks of motor control in evoking dACC pathology in the disorder.

Glutamate system genes and brain volume alterations in pediatric obsessive-compulsive disorder: a preliminary study.

Obsessive-compulsive disorder (OCD) has been associated with regional volumetric brain abnormalities, which provide promising intermediate phenotypes of the disorder. In this study, volumes of brain regions selected for a priori evidence of association with OCD (orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), thalamus, caudate, putamen, globus pallidus and pituitary) were measured using structural magnetic resonance imaging (MRI) in 20 psychotropic-naïve pediatric OCD patients. We examined the association between these regional brain volumes and a total of 519 single nucleotide polymorphisms (SNPs) from nine glutamatergic candidate genes (DLGAP1, DLGAP2, DLGAP3, GRIN2B, SLC1A1, GRIK2, GRIK3, SLITRK1 and SLITRK5). These genes were selected based on either previous reported association with OCD in humans or evidence from animal models of OCD. After correcting for multiple comparisons by permutation testing, no SNP remained significantly associated with volumetric changes. The strongest trend toward association was identified between two SNPs in DLGAP2 (rs6558484 and rs7014992) and OFC white matter volume. Our other top ranked association findings were with ACC, OFC and thalamus. These preliminary results suggest that sequence variants in glutamate candidate genes may be associated with structural neuroimaging phenotypes of OCD.

Orbitofrontal cortex volumes in medication naïve children with major depressive disorder: a magnetic resonance imaging study.

OBJECTIVES: Adults with major depressive disorder (MDD) are reported to have reduced orbitofrontal cortex (OFC) volumes, which could be related to decreased neuronal density. We conducted a study on medication naïve children with MDD to determine whether abnormalities of OFC are present early in the illness course. METHODS: Twenty seven medication naïve pediatric Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) MDD patients (mean age +/- SD = 14.4 +/- 2.2 years; 10 males) and 26 healthy controls (mean age +/- SD = 14.4 +/- 2.4 years; 12 males) underwent a 1.5T magnetic resonance imaging (MRI) with 3D spoiled gradient recalled acquisition. The OFC volumes were compared using analysis of covariance with age, gender, and total brain volume as covariates. RESULTS: There was no significant difference in either total OFC volume or total gray matter OFC volume between MDD patients and healthy controls. Exploratory analysis revealed that patients had unexpectedly larger total right lateral (F = 4.2, df = 1, 48, p = 0.05) and right lateral gray matter (F = 4.6, df = 1, 48, p = 0.04) OFC volumes compared to healthy controls, but this finding was not significant following statistical correction for multiple comparisons. No other OFC subregions showed a significant difference. CONCLUSIONS: The lack of OFC volume abnormalities in pediatric MDD patients suggests the abnormalities previously reported for adults may develop later in life as a result of neural cell loss.

Striatal volume abnormalities in treatment-naïve patients diagnosed with pediatric major depressive disorder.

OBJECTIVE: The striatum, including the putamen and caudate, plays an important role in executive and emotional processing and may be involved in the pathophysiology of mood disorders. Few studies have examined structural abnormalities of the striatum in pediatric major depressive disorder (MDD) patients. We report striatal volume abnormalities in medication-naïve pediatric MDD compared to healthy comparison subjects. METHOD: Twenty seven medication-naïve pediatric Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) MDD and 26 healthy comparison subjects underwent volumetric magnetic resonance imaging (MRI). The putamen and caudate volumes were traced manually by a blinded rater, and the patient and control groups were compared using analysis of covariance adjusting for age, sex, intelligence quotient, and total brain volumes. RESULTS: MDD patients had significantly smaller right striatum (6.0% smaller) and right caudate volumes (7.4% smaller) compared to the healthy subjects. Left caudate volumes were inversely correlated with severity of depression in MDD subjects. Age was inversely correlated with left and right putamen volumes in MDD patients but not in the healthy subjects. CONCLUSIONS: These findings provide fresh evidence for abnormalities in the striatum of medication-naïve pediatric MDD patients and suggest the possible involvement of the striatum in the pathophysiology of MDD.