Nenad Vasic

Neural Hyporesponsiveness and Hyperresponsiveness During Immediate and Delayed Reward Processing in Adult Attention-Deficit/Hyperactivity Disorder

BACKGROUND Dysfunctional reward processing, accompanied by a limited ability to tolerate reward delays, has been proposed as an important feature in attention-deficit/hyperactivity disorder (ADHD). METHODS Using functional magnetic resonance imaging (fMRI), brain activation in adult patients with ADHD (n=14) and healthy control subjects (n=12) was examined during a series of choices between two monetary reward options that varied by delay to delivery. RESULTS Compared with healthy control subjects, hyporesponsiveness of the ventral-striatal reward system was replicated in patients with ADHD and was evident for both immediate and delayed rewards. In contrast, delayed rewards evoked hyperactivation in dorsal caudate nucleus and amygdala of ADHD patients. In both structures, neural activity toward delayed rewards was significantly correlated with self-rated ADHD symptom severity. CONCLUSIONS The finding of ventral-striatal hyporesponsiveness during immediate and delayed reward processing in patients with ADHD further strengthens the concept of a diminished neural processing of rewards in ADHD. Hyperactivation during delayed reward processing, gradually increasing along the ventral-to-dorsal extension of the caudate nucleus, and especially the concomitant hyperactivation of the amygdala are in accordance with predictions of the delay aversion hypothesis.

Gray matter reduction associated with psychopathology and cognitive dysfunction in unipolar depression: A voxel-based morphometry study

BACKGROUND Functional neuroimaging studies on both cognitive processing and psychopathology in patients with major depression have reported several functionally aberrant brain areas within limbic-cortical circuits. However, less is known about the relationship between psychopathology, cognitive deficits and regional volume alterations in this patient population. METHODS By means of voxel-based morphometry (VBM) and a standardized neuropsychological test battery, we examined 15 patients meeting DSM-IV criteria for major depression disorder and 14 healthy controls in order to investigate the relationship between affective symptoms, cognitive deficits and structural abnormalities. RESULTS Patients with depression showed reduced gray matter concentration (GMC) in the left inferior temporal cortex (BA 20), the right orbitofrontal (BA 11) and the dorsolateral prefrontal cortex (BA 46). Reduced gray matter volume (GMV) was found in the left hippocampal gyrus, the cingulate gyrus (BA 24/32) and the thalamus. Structure-cognition correlation analyses revealed that decreased GMC of the right medial and inferior frontal gyrus was associated with both depressive psychopathology and worse executive performance as measured by the Wisconsin Card Sorting Test (WCST). Furthermore, depressive psychopathology and worse performance during the WCST were associated with decreased GMV of the hippocampus. Decreased GMV of the cingulate cortex was associated with worse executive performance. LIMITATIONS Moderate illness severity, medication effects, and the relatively small patient sample size should be taken into consideration when reviewing the implications of these results. CONCLUSIONS The volumetric results indicate that regional abnormalities in gray matter volume and concentration may be associated with both psychopathological changes and cognitive deficits in depression.

Aberrant functional connectivity of dorsolateral prefrontal and cingulate networks in patients with major depression during working memory processing.

BACKGROUND In patients with major depressive disorder (MDD), functional neuroimaging studies have reported an increased activation of the dorsolateral prefrontal cortex (DLPFC) during executive performance and working memory (WM) processing, and also an increased activation of the anterior cingulate cortex (ACC) during baseline conditions. However, the functional coupling of these cortical networks during WM processing is less clear. METHOD In this study, we used a verbal WM paradigm, event-related functional magnetic resonance imaging (fMRI) and multivariate statistical techniques to explore patterns of functional coupling of temporally dissociable dorsolateral prefrontal and cingulate networks. By means of independent component analyses (ICAs), two components of interest were identified that showed either a positive or a negative temporal correlation with the delay period of the cognitive activation task in both healthy controls and MDD patients. RESULTS In a prefronto-parietal network, a decreased functional connectivity pattern was identified in depressed patients comprising inferior parietal, superior prefrontal and frontopolar regions. Within this cortical network, MDD patients additionally revealed a pattern of increased functional connectivity in the left DLPFC and the cerebellum compared to healthy controls. In a second, temporally anti-correlated network, healthy controls exhibited higher connectivity in the ACC, the ventrolateral and the superior prefrontal cortex compared to MDD patients. CONCLUSIONS These results complement and expand previous functional neuroimaging findings by demonstrating a dysconnectivity of dissociable prefrontal and cingulate regions in MDD patients. A disturbance of these dynamic networks is characterized by a simultaneously increased connectivity of the DLPFC during task-induced activation and increased connectivity of the ACC during task-induced deactivation.

Regional Brain Activation Changes and Abnormal Functional Connectivity of the Ventrolateral Prefrontal Cortex During Working Memory Processing in Adults With Attention-Deficit/ Hyperactivity Disorder

Previous studies on working memory (WM) function in adults with attention‐deficit/hyperactivity disorder (ADHD) suggested aberrant activation of the prefrontal cortex and the cerebellum. Although it has been hypothesized that activation differences in these regions most likely reflect aberrant frontocerebellar circuits, the functional coupling of these brain networks during cognitive performance has not been investigated so far. In this study, functional magnetic resonance imaging (fMRI) and both univariate and multivariate analytic techniques were used to investigate regional activation changes and functional connectivity differences during cognitive processing in healthy controls (n = 12) and ADHD adults (n = 12). Behavioral performance during a parametric verbal WM paradigm did not significantly differ between adults with ADHD and healthy controls. During the delay period of the activation task, however, ADHD patients showed significantly less activation in the left ventrolateral prefrontal cortex (VLPFC), as well as in cerebellar and occipital regions compared with healthy control subjects. In both groups, independent component analyses revealed a functional network comprising bilateral lateral prefrontal, striatal, and cingulate regions. ADHD adults had significantly lower connectivity in the bilateral VLPFC, the anterior cingulate cortex, the superior parietal lobule, and the cerebellum compared with healthy controls. Increased connectivity in ADHD adults was found in right prefrontal regions, the left dorsal cingulate cortex and the left cuneus. These findings suggest both regional brain activation deficits and functional connectivity changes of the VLPFC and the cerebellum as well as functional connectivity abnormalities of the anterior cingulate and the parietal cortex in ADHD adults during WM processing. Hum Brain Mapp, 2009.

Aberrant connectivity of lateral prefrontal networks in presymptomatic Huntington's disease

In clinically presymptomatic individuals with the Huntingtons disease (HD) gene mutation, functional neuroimaging data have suggested a dysfunction of multiple cortical and subcortical regions including the prefrontal and parietal cortex, as well as the striatum. Although it has been hypothesized that these activation differences most likely reflect aberrant corticostriatal circuits, the functional coupling of neural networks associated with cognitive performance has not been investigated so far. In this study, we used functional magnetic resonance imaging (fMRI) and multivariate analytic techniques to investigate memory-related patterns of functional connectivity in healthy controls (n=16) and pre-HD individuals (n=16). Independent component analyses (ICA) revealed distinct bilateral frontostriatal and frontoparietal networks that were activated during a verbal working memory paradigm in both healthy controls and pre-HD subjects. Compared with healthy controls, pre-HD individuals exhibited lower functional connectivity in left lateral prefrontal and parietal regions as well as in the bilateral putamen. Functional connectivity indices in the left putamen were negatively correlated with the CAG repeat size and the UHDRS behavioral score, and positively correlated with the predicted years to manifest symptom onset. The connectivity of the right putamen was negatively correlated with the UHDRS motor score. In pre-HD individuals, these results suggest an early frontostriatal and frontoparietal deficit of dissociable functional networks associated with executive processing.

Working memory dysfunction in schizophrenia compared to healthy controls and patients with depression: evidence from event-related fMRI.

Studies on working memory (WM) dysfunction in schizophrenia have reported several functionally aberrant brain areas including the lateral prefrontal cortex, superior temporal areas and the striatum. However, less is known about the relationship of WM-dysfunction, cerebral activation, task-accuracy and diagnostic specificity. Using a novel WM-task and event-related functional magnetic resonance imaging (fMRI), we studied healthy control subjects (n=17) and partially remitted, medicated inpatients meeting DSM-IV criteria for schizophrenia (n=19) and major depressive disorder (n=12). Due to the event-related technique, we excluded incorrectly performed trials, thus controlling for accuracy-related activation confounds. Compared with controls, patients with schizophrenia showed less activation in frontoparietal and subcortical regions at high cognitive load levels. Compared with patients with depression, schizophrenic patients showed less prefrontal activation in left inferior frontal cortex and right cerebellum. In patients with schizophrenia, a lack of deactivation of the superior temporal cortex was found compared to both healthy controls and patients with depression. Thus, we could not confirm previous findings of impaired lateral prefrontal activation during WM performance in schizophrenic patients after the exclusion of incorrectly performed or omitted trials in our functional analysis. However, superior temporal cortex dysfunction in patients with schizophrenia may be regarded as schizophrenia-specific finding in terms of psychiatric diagnosis specificity.

Cortical dysfunction in patients with Huntington's disease during working memory performance

Previous functional neuroimaging studies on executive function suggested multiple functionally aberrant cortical regions in patients with Huntingtons disease (HD). However, little is known about the neural mechanisms of working memory (WM) function in this patient population. The objective of this study was to investigate the functional neuroanatomy of WM in HD patients. We used event‐related functional magnetic resonance imaging and a parametric verbal WM task to investigate cerebral function during WM performance in 16 healthy control subjects and 12 mild to moderate stage HD patients. We excluded incorrectly performed trials to control for potential accuracy‐related activation confounds. Voxel‐based morphometry (VBM) was used to control for confounding cortical and subcortical atrophy. We found that HD patients were slower and less accurate than healthy controls across all WM load levels. In addition, HD patients showed lower activation in the left dorso‐ and ventrolateral prefrontal cortex, the left inferior parietal cortex, the left putamen, and the right cerebellum at high WM load levels only. VBM revealed gray matter differences in the bilateral caudate nucleus and the thalamus, as well as in inferior parietal and right lateral prefrontal regions. However, volumetric abnormalities in the patient group did not affect the activation differences obtained during WM task performance. These findings demonstrate that WM‐related functional abnormalities in HD patients involve distinct WM network nodes associated with cognitive control and subvocal rehearsal. Moreover, aberrant cortical function in HD patients may occur in brain regions, which are relatively well preserved in terms of brain atrophy. Hum Brain Mapp, 2009.

Volumetric abnormalities associated with cognitive deficits in patients with schizophrenia

While functional neuroimaging studies on attention and executive function in schizophrenia have reported several functionally aberrant cortical regions, less is known about the relationship of cognitive impairment and regional volume alterations. In order to investigate the relationship between cognitive impairment and structural alterations, we studied healthy control subjects and partially remitted, medicated inpatients with DSM-IV schizophrenia using voxel-based morphometry (VBM) and a standardised neuropsychological test battery. Schizophrenic patients showed reduced grey matter (GM) density in the bilateral temporal cortex, the left inferior parietal lobule, the cingulate gyrus and the left middle frontal gyrus. Reduced GM volume was additionally found in the left hippocampal gyrus and the right superior frontal cortex. Reduced white matter density was found in the posterior corpus callosum. Structure-cognition regression analyses revealed that decreased GM density of the left inferior parietal and the right middle temporal cortex was associated with worse performance during divided attention. Worse performance during the spatial span was associated with volumetric abnormalities of the hippocampal gyrus. These results indicate that regional abnormalities in brain structure may offer an account for some impaired cognitive domains in patients with schizophrenia, while other cognitive domains may remain relatively less affected by volumetric alterations.

Altered frontostriatal coupling in pre-manifest Huntington’s disease: effects of increasing cognitive load

Background and purpose:  Functional neuroimaging studies have suggested a dysfunction of prefrontal regions in clinically pre‐symptomatic individuals with the Huntington’s disease (HD) gene mutation (pre‐HD) during cognitive processing. The objective of this study was to test the impact of cognitive demand on prefrontal connectivity in pre‐HD individuals.

Default-mode network changes in preclinical Huntington's disease

The default-mode network (DMN) refers to as a set of brain regions which are active when the brain does not engage in a cognitive task and which are deactivated with task-related cognitive effort. Altered function of the DMN has been associated with a decline of cognition in several neurodegenerative diseases and related at-risk conditions. In Huntingtons disease, an autosomal dominant inherited neurodegenerative disorder, several studies so far have shown abnormal task-related brain activation patterns even in preclinical carriers of the Huntingtons disease gene mutation (preHD). To date, however, the functional integrity of the DMN has not been addressed in this population. The aim of this study was to study the functional connectivity of the DMN in 18 preHD and 18 healthy controls who underwent functional magnetic resonance imaging during an attention task. A group independent component analysis identified spatiotemporally distinct patterns of two DMN subsystems. The spatial distribution of these components in preHD was similar to controls. However, preHD showed lower subsystem-specific connectivity in the anterior medial prefrontal cortex, the left inferior parietal and the posterior cingulate cortex (p<0.05, cluster-corrected). Connectivity between the two DMN subsystems was increased in preHD compared to controls. In preHD individuals lower functional connectivity of the left inferior parietal cortex was associated with shorter reaction times in the attention task. This suggests that some functionally critical regions of the DMN may have to remain active to maintain or optimise cognitive performance in preHD.