Dick J. Veltman

Whole brain resting-state analysis reveals decreased functional connectivity in major depression.

Recently, both increases and decreases in resting-state functional connectivity have been found in major depression. However, these studies only assessed functional connectivity within a specific network or between a few regions of interest, while comorbidity and use of medication was not always controlled for. Therefore, the aim of the current study was to investigate whole-brain functional connectivity, unbiased by a priori definition of regions or networks of interest, in medication-free depressive patients without comorbidity. We analyzed resting-state fMRI data of 19 medication-free patients with a recent diagnosis of major depression (within 6 months before inclusion) and no comorbidity, and 19 age- and gender-matched controls. Independent component analysis was employed on the concatenated data sets of all participants. Thirteen functionally relevant networks were identified, describing the entire study sample. Next, individual representations of the networks were created using a dual regression method. Statistical inference was subsequently done on these spatial maps using voxel-wise permutation tests. Abnormal functional connectivity was found within three resting-state networks in depression: (1) decreased bilateral amygdala and left anterior insula connectivity in an affective network, (2) reduced connectivity of the left frontal pole in a network associated with attention and working memory, and (3) decreased bilateral lingual gyrus connectivity within ventromedial visual regions. None of these effects were associated with symptom severity or gray matter density. We found abnormal resting-state functional connectivity not previously associated with major depression, which might relate to abnormal affect regulation and mild cognitive deficits, both associated with the symptomatology of the disorder.

Why gamblers fail to win: A review of cognitive and neuroimaging findings in pathological gambling

The purpose of this review is to gain more insight in the neuropathology of pathological gambling (PG) and problem gambling, and to discuss challenges in this research area. Results from the reviewed PG studies show that PG is more than just an impulse control disorder. PG seems to fit very well with recent theoretical models of addiction, which stress the involvement of the ventral tegmental-orbito frontal cortex. Differentiating types of PG on game preferences (slot machines vs. casino games) seems to be useful because different PG groups show divergent results, suggesting different neurobiological pathways to PG. A framework for future studies is suggested, indicating the need for hypothesis driven pharmacological and functional imaging studies in PG and integration of knowledge from different research areas to further elucidate the neurobiological underpinnings of this disorder.

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 Medial Prefrontal Cortex Volume in Adults Reporting Childhood Emotional Maltreatment

BACKGROUND Childhood emotional maltreatment (CEM) has been associated with a profound and enduring negative impact on behavioral and emotional functioning. Animal models have shown that adverse rearing conditions, such as maternal separation, can induce a cascade of long-term structural alterations in the brain, particularly in the hippocampus, amygdala, and prefrontal cortex. However, in humans, the neurobiological correlates of CEM are unknown. METHODS Using high-resolution T1-weighted 3T magnetic resonance imaging, anatomical scans and a whole-brain optimized voxel-based morphometry approach, we examined whether healthy control subjects and unmedicated patients with depression and/or anxiety disorders reporting CEM before age 16 (n = 84; age: mean = 38.7) displayed structural brain changes compared with control subjects and patients who reported no childhood abuse (n = 97; age: mean = 36.6). RESULTS We found that self-reported CEM is associated with a significant reduction in predominantly left dorsal medial prefrontal cortex volume, even in the absence of physical or sexual abuse during childhood. In addition, reduced medial prefrontal cortex in individuals reporting CEM is present in males and females, independent of concomitant psychopathology. CONCLUSIONS In this study, we show that CEM is associated with profound reductions of medial prefrontal cortex volume, suggesting that sustained inhibition of growth or structural damage can occur after exposure to CEM. Given the important role of the medial prefrontal cortex in the regulation of emotional behavior, our finding might provide an important link in understanding the increased emotional sensitivity in individuals reporting CEM.

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen’s d=−0.46), amygdala (d=−0.31), thalamus (d=−0.31), accumbens (d=−0.25) and intracranial volumes (d=−0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen’s d=−0.14, % difference=−1.24). This effect was driven by patients with recurrent MDD (Cohen’s d=−0.17, % difference=−1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen’s d=−0.20, % difference=−1.85) and a trend toward smaller amygdala (Cohen’s d=−0.11, % difference=−1.23) and larger lateral ventricles (Cohen’s d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Response Perseveration and Ventral Prefrontal Sensitivity to Reward and Punishment in Male Problem Gamblers and Smokers

Pathological gambling (PG) is associated with maladaptive perseverative behavior, but the underlying mechanism and neural circuitry is not completely clear. Here, the hypothesis was tested that PG is characterized by response perseveration and abnormalities in reward and/or punishment sensitivity in the ventral frontostriatal circuit. Executive functioning was assessed to verify if these effects are independent of the dorsal frontostriatal circuit. A group of smokers was also included to examine whether impairments in PG generalize to substance use disorders. Response perseveration and reward/punishment sensitivity were measured with a probabilistic reversal-learning task, in which subjects could win and lose money. Executive functioning was measured with a planning task, the Tower of London. Performance and fMRI data were acquired in 19 problem gamblers, 19 smokers, and 19 healthy controls. Problem gamblers showed severe response perseveration, associated with reduced activation of right ventrolateral prefrontal cortex in response to both monetary gain and loss. Results did not fully generalize to smokers. Planning performance and related activation of the dorsal frontostriatal circuit were intact in both problem gamblers and smokers. PG is related to response perseveration and diminished reward and punishment sensitivity as indicated by hypoactivation of the ventrolateral prefrontal cortex when money is gained and lost. Moreover, intact planning abilities and normal dorsal frontostriatal responsiveness indicate that this deficit is not due to impaired executive functioning. Response perseveration and ventral prefrontal hyporesponsiveness to monetary loss may be markers for maladaptive behavior seen in chemical and nonchemical addictions.

Cerebral Hyporesponsiveness and Cognitive Impairment 10 Years After Chemotherapy for Breast Cancer

Chemotherapy is associated with cognitive impairment in a subgroup of breast cancer survivors, but the neural circuitry underlying this side effect is largely unknown. Moreover, long‐term impairment has not been studied well. In the present study, functional magnetic resonance imaging (fMRI) and neuropsychological testing were performed in breast cancer survivors almost 10 years after high‐dose adjuvant chemotherapy (chemo group, n = 19) and in breast cancer survivors for whom chemotherapy had not been indicated (control group, n = 15). BOLD activation and performance were measured during an executive function task involving planning abilities (Tower of London) and a paired associates task for assessment of episodic memory. For the chemo group versus the control group, we found hyporesponsiveness of dorsolateral prefrontal cortex in the Tower of London, and of parahippocampal gyrus in the paired associates task. Also, the chemo group showed significantly impaired planning performance and borderline significantly impaired recognition memory as compared to findings in the control group. Whole‐brain analyses demonstrated hyporesponsiveness of the chemo versus the control group in very similar regions of bilateral posterior parietal cortex during both the Tower of London and the paired associates task. Neuropsychological testing showed a relatively stable pattern of cognitive impairment in the chemo group over time. These results indicate that high‐dose adjuvant chemotherapy is associated with long‐term cognitive impairments. These impairments are underpinned by (a) task‐specific hyporesponsiveness of dorsolateral prefrontal cortex and parahippocampal gyrus, and (b) a generalized hyporesponsiveness of lateral posterior parietal cortex encompassing attentional processing. Hum Brain Mapp, 2011.

Neural correlates of dysfunctional emotion regulation in major depressive disorder. A systematic review of neuroimaging studies

Abnormal emotion processing is a core feature of major depressive disorder (MDD). Since the emergence of functional neuroimaging techniques, many studies have been conducted in MDD subjects to elucidate the underlying abnormalities in the neural systems involved in emotion regulation. In this systematic review, we discuss this research in the context of the neural model of emotion regulation previously described by Phillips et al. (2008). This model differentiates between automatic and voluntary emotion regulation subprocesses. Automatic regulation subprocesses were shown to involve predominantly medial prefrontal cortical structures, in addition to the hippocampus and parahippocampus, while voluntary regulation processes additionally recruited lateral prefrontal cortical regions. In conclusion, although the available data is limited, findings suggest that MDD subjects demonstrate abnormally reduced activity in lateral prefrontal cortices during explicit voluntary control of emotional experience. During early, automatic stages of emotion regulation, on the other hand, MDD subjects appear to achieve successful emotion regulation by recruiting additional lateral prefrontal neural regions, that may be mediated by medial prefrontal, especially rostral/dorsal anterior cingulate gyrus (ACG) functioning. Dysfunctional automatic regulation may impair successful voluntary emotion regulation, and may present a target for novel therapeutic approaches in MDD.