Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group.

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

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.

Childhood maltreatment modifies the relationship of depression with hippocampal volume.

BACKGROUND: Childhood maltreatment (CM) may modify the relationship between major depressive disorder (MDD) and hippocampal volume reduction. To disentangle the impact of MDD and CM on hippocampal volume we investigated the association between MDD and hippocampal volume in persons with and without a history of CM in two independent cohorts. METHOD: We used data of 262 participants from the Netherlands Study of Depression and Anxiety (NESDA) (mean age 37 years, 32% male) and 636 participants from the SMART-Medea study (mean age 61 years, 81% male). In both studies a 12-month diagnosis of MDD and CM were assessed using a diagnostic interview. Hippocampal volume was measured in NESDA using FreeSurfer software on 3-T magnetic resonance (MR) images and in SMART it was manually outlined on 1.5-T MR images. With analysis of covariance adjusted for intracranial volume, age, gender and lifestyle factors we estimated the effects of MDD and CM on hippocampal volume. RESULTS: In both cohorts CM was not significantly associated with hippocampal volume. After pooling the data MDD was associated with smaller hippocampal volume (B = -138.90 mm(3), p = 0.05) and the interaction between MDD and CM reached significance (p = 0.04); in participants with CM, MDD was related to smaller hippocampal volume (NESDA: B = -316.8 mm(3), p = 0.02; SMART: B = -407.6, p = 0.046), but not in participants without CM (p > 0.05). CONCLUSIONS: Our study shows that in two independent cohorts, particularly in individuals with CM, a diagnosis of MDD is related to smaller hippocampal volume. Prospective studies are needed to further determine through which mechanism CM may amplify the relationship between MDD and hippocampal volume.

Neural substrates of impulsive decision making modulated by modafinil in alcohol-dependent patients.

BACKGROUND: Impulsive decision making is a hallmark of frequently occurring addiction disorders including alcohol dependence (AD). Therefore, ameliorating impulsive decision making is a promising target for the treatment of AD. Previous studies have shown that modafinil enhances cognitive control functions in various psychiatric disorders. However, the effects of modafinil on delay discounting and its underlying neural correlates have not been investigated as yet. The aim of the current study was to investigate the effects of modafinil on neural correlates of impulsive decision making in abstinent AD patients and healthy control (HC) subjects. METHOD: A randomized, double-blind, placebo-controlled, within-subjects cross-over study using functional magnetic resonance imaging (fMRI) was conducted in 14 AD patients and 16 HC subjects. All subjects participated in two fMRI sessions in which they either received a single dose of placebo or 200 mg of modafinil 2 h before the session. During fMRI, subjects completed a delay-discounting task to measure impulsive decision making. RESULTS: Modafinil improved impulsive decision making in AD pateints, which was accompanied by enhanced recruitment of frontoparietal regions and reduced activation of the ventromedial prefrontal cortex. Moreover, modafinil-induced enhancement of functional connectivity between the superior frontal gyrus and ventral striatum was specifically associated with improvement in impulsive decision making. CONCLUSIONS: These findings indicate that modafinil can improve impulsive decision making in AD patients through an enhanced coupling of prefrontal control regions and brain regions coding the subjective value of rewards. Therefore, the current study supports the implementation of modafinil in future clinical trials for AD.

[Impulse control in addiction: a translational perspective]. / Impulsregulatie en verslaving: een translationeel onderzoek.

BACKGROUND: Impulsivity is a hallmark of addiction and predicts treatment response and relapse. Impulsivity is, however, a complex construct. Translational cross-species research is needed to give us greater insight into the neurobiology and the role of impulsivity in addiction and to help with the development of new treatment strategies for improving patients' impulse control. AIM: To review recent evidence concerning the concept of impulsivity and the role of impulsivity in addiction. METHOD: The concept and neurobiology of impulsivity are reviewed from a translational perspective. The role of impulsivity in addiction and implications for treatment are discussed. RESULTS: Our recent translational cross-species study indicates that impulsivity is made up of several, separate independent features with partly distinct underlying neurobiological substrates. There are also indications that these features make a unique and independent contribution to separate stages of the addiction cycle. CONCLUSION: In addition, the improvement of impulse control is a promising new target area for treatments that could lead to better results. However, those involved in developing new treatment strategies will have to take into account the complexity and multidimensional character of impulsivity.

Coordinated cortical thickness alterations across six neurodevelopmental and psychiatric disorders.

Neuropsychiatric disorders are increasingly conceptualized as overlapping spectra sharing multi-level neurobiological alterations. However, whether transdiagnostic cortical alterations covary in a biologically meaningful way is currently unknown. Here, we studied co-alteration networks across six neurodevelopmental and psychiatric disorders, reflecting pathological structural covariance. In 12,024 patients and 18,969 controls from the ENIGMA consortium, we observed that co-alteration patterns followed normative connectome organization and were anchored to prefrontal and temporal disease epicenters. Manifold learning revealed frontal-to-temporal and sensory/limbic-to-occipitoparietal transdiagnostic gradients, differentiating shared illness effects on cortical thickness along these axes. The principal gradient aligned with a normative cortical thickness covariance gradient and established a transcriptomic link to cortico-cerebello-thalamic circuits. Moreover, transdiagnostic gradients segregated functional networks involved in basic sensory, attentional/perceptual, and domain-general cognitive processes, and distinguished between regional cytoarchitectonic profiles. Together, our findings indicate that shared illness effects occur in a synchronized fashion and along multiple levels of hierarchical cortical organization.

Emotional processing in panic disorder and its subtypes: An fMRI study using emotional faces.

BACKGROUND: Inconsistent findings regarding the pathophysiology of panic disorder (PD) could result from clinical heterogeneity. Identifying subtypes could enhance insights into the neurobiological substrates of PD. METHODS: An emotional faces fMRI paradigm was used in a group of PD patients (n = 73) and healthy controls (n = 58). The overall PD group was further divided into three previously identified subtypes: a cognitive-autonomic (n = 22), an autonomic (n = 16) and an aspecific (n = 35) subtype. Differences in brain activity levels in response to emotional facial expressions between groups were examined for six regions of interests, namely the amygdala, ventromedial prefrontal cortex, anterior cingulate, fusiform gyrus, lingual gyrus and insula. RESULTS: PD patients showed lower activity in the rostral anterior cingulate in response to angry faces than healthy controls, which was mainly driven by the autonomic subtype. No significant differences were found in other brain regions when comparing PD patients with controls or when comparing across PD subtypes. LIMITATIONS: Sample sizes in subgroups were relatively small CONCLUSIONS: The role of the rostral anterior cingulate cortex for emotional processes critical in panic disorder is highlighted by this study and provides, albeit preliminary, evidence for the use of a subtype approach to advance our neurobiological insights in PD considering its involvement in the appraisal of autonomic viscero-sensory symptoms.

[Modafinil in psychiatric disorders: the promising state reconsidered]. / Modafinil bij psychiatrische aandoeningen: de veelbelovende status opnieuw bekeken.

BACKGROUND: For more than two decades psychiatrists have known about and have promoted modafinil, a very promising stimulant that boosts wakefulness in cases of narcolepsy and also enhances cognitive functions. At present, however, we must conclude that modafinil is hardly ever used to treat illness other than narcolepsy. AIM: To review current attitudes and practice with regard to the use and efficacy of modafinil in the treatment of psychiatric disorders. METHOD: Relevant placebo-controlled studies were retrieved via PubMed (Medline) and Web of Science. RESULTS: Modafinil is used experimentally to treat ADHD, mood disorders, schizophrenia and substance-dependence. Compared to placebo, modafinil achieves positive but mainly variable results on different clinical and cognitive measures. It achieves results very rapidly, within a week, but over a period of time the results stabilise. CONCLUSION: Modafinil is particularly successful in the treatment of ADHD, depression and cocaine-dependency on measures of attention and hyperactivity, fatigue and cocaine-use respectively. There is a need for further placebo-controlled trials with longer follow-up periods and larger sample size in order to ensure the safety of the product and to refine its area of efficacy.

Decreased functional connectivity of the insula within the salience network as an indicator for prospective insufficient response to antidepressants.

Insufficient response to treatment is the main cause of prolonged suffering from major depressive disorder (MDD). Early identification of insufficient response could result in faster and more targeted treatment strategies to reduce suffering. We therefore explored whether baseline alterations within and between resting state functional connectivity networks could serve as markers of insufficient response to antidepressant treatment in two years of follow-up. We selected MDD patients (N = 17) from the NEtherlands Study of Depression and Anxiety (NESDA), who received ≥ two antidepressants, indicative for insufficient response, during the two year follow-up, a group of MDD patients who received only one antidepressant (N = 32) and a healthy control group (N = 19) matched on clinical characteristics and demographics. An independent component analysis (ICA) of baseline resting-state scans was conducted after which functional connectivity within the components was compared between groups. We observed lower connectivity of the right insula within the salience network in the group with ≥ two antidepressants compared to the group with one antidepressant. No difference in connectivity was found between the patient groups and healthy control group. Given the suggested role of the right insula in switching between task-positive mode (activation during attention-demanding tasks) and task-negative mode (activation during the absence of any task), we explored whether right insula activation differed during switching between these two modes. We observed that in the ≥2 antidepressant group, the right insula was less active compared to the group with one antidepressant, when switching from task-positive to task-negative mode than the other way around. These findings imply that lower right insula connectivity within the salience network may serve as an indicator for prospective insufficient response to antidepressants. This result, supplemented by the diminished insula activation when switching between task and rest related networks, could indicate an underlying mechanism that, if not sufficiently targeted by current antidepressants, could lead to insufficient response. When replicated, these findings may contribute to the identification of biomarkers for early detection of insufficient response.

The relation between gray matter volume and the use of alcohol, tobacco, cocaine and cannabis in male polysubstance users.

BACKGROUND: Neuroimaging studies have demonstrated gray matter (GM) volume abnormalities in substance users. While the majority of substance users are polysubstance users, very little is known about the relation between GM volume abnormalities and polysubstance use. METHODS: In this study we assessed the relation between GM volume, and the use of alcohol, tobacco, cocaine and cannabis as well as the total number of substances used, in a sample of 169 males: 15 non-substance users, 89 moderate drinkers, 27 moderate drinkers who also smoke tobacco, 13 moderate drinkers who also smoke tobacco and use cocaine, 10 heavy drinkers who smoke tobacco and use cocaine and 15 heavy drinkers who smoke tobacco, cannabis and use cocaine. RESULTS: Regression analyses showed that there was a negative relation between the number of substances used and volume of the dorsal medial prefrontal cortex (mPFC) and the ventral mPFC. Without controlling for the use of other substances, the volume of the dorsal mPFC was negatively associated with the use of alcohol, tobacco, and cocaine. After controlling for the use of other substances, a negative relation was found between tobacco and cocaine and volume of the thalami and ventrolateral PFC, respectively. CONCLUSION: These findings indicate that mPFC alterations may not be substance-specific, but rather related to the number of substances used, whereas, thalamic and ventrolateral PFC pathology is specifically associated with tobacco and cocaine use, respectively. These findings are important, as the differential alterations in GM volume may underlie different cognitive deficits associated with substance use disorders.

The effect of N-acetylcysteine on brain glutamate and gamma-aminobutyric acid concentrations and on smoking cessation: A randomized, double-blind, placebo-controlled trial.

Using data form a 14-day double-blind trial with 48 smokers randomized to either N-acetylcysteine (2400 mg) or placebo, we tested the effect of N-acetylcysteine on glutamate and gamma-aminobutyric acid concentrations in the dorsal anterior cingulate cortex and on smoking cessation. Smoking related behaviors and neurotransmitter concentrations in the dorsal anterior cingulate cortex were assessed before and after treatment. Forty-seven non-smoking males served as baseline controls. Smokers showed higher baseline glutamate but similar gamma-aminobutyric acid concentrations than non-smokers. There were no treatment effects on dorsal anterior cingulate cortex neurotransmitter concentrations, smoking cessation, craving, or withdrawal symptoms. These results confirm glutamate disbalance in smokers, but not efficacy of N-acetylcysteine.

Subcortical brain structure and suicidal behaviour in major depressive disorder: a meta-analysis from the ENIGMA-MDD working group.

The aetiology of suicidal behaviour is complex, and knowledge about its neurobiological mechanisms is limited. Neuroimaging methods provide a noninvasive approach to explore the neural correlates of suicide vulnerability in vivo. The ENIGMA-MDD Working Group is an international collaboration evaluating neuroimaging and clinical data from thousands of individuals collected by research groups from around the world. Here we present analyses in a subset sample (n=3097) for whom suicidality data were available. Prevalence of suicidal symptoms among major depressive disorder (MDD) cases ranged between 29 and 69% across cohorts. We compared mean subcortical grey matter volumes, lateral ventricle volumes and total intracranial volume (ICV) in MDD patients with suicidal symptoms (N=451) vs healthy controls (N=1996) or MDD patients with no suicidal symptoms (N=650). MDD patients reporting suicidal plans or attempts showed a smaller ICV (P=4.12 × 10-3) or a 2.87% smaller volume compared with controls (Cohen's d=-0.284). In addition, we observed a nonsignificant trend in which MDD cases with suicidal symptoms had smaller subcortical volumes and larger ventricular volumes compared with controls. Finally, no significant differences (P=0.28-0.97) were found between MDD patients with and those without suicidal symptoms for any of the brain volume measures. This is by far the largest neuroimaging meta-analysis of suicidal behaviour in MDD to date. Our results did not replicate previous reports of association between subcortical brain structure and suicidality and highlight the need for collecting better-powered imaging samples and using improved suicidality assessment instruments.

The relationship between impulsivity and craving in alcohol dependent patients.

RATIONALE: Impulsivity and craving are both associated with higher relapse rates and a worse prognosis in patients with a substance use disorder, but the relationship between these two phenomena has been largely ignored in the field of alcohol use disorders. OBJECTIVES: The primary aim of this study was to investigate the relationship between different dimensions of impulsivity and different forms of self-reported craving. Additionally, the influence of the severity of alcohol dependence on impulsivity, craving, and on their relationship was exploed. METHODS: Impulsivity and craving levels were investigated in 87 abstinent alcohol-dependent (AD) patients using a broad range of self-report questionnaires and behavioral impulsivity measures. Alcohol use was measured by means of the timeline followback method. RESULTS: Higher scores of emotional craving (Alcohol Urge Questionnaire-AUQ) were significantly related to higher self-reported impulsivity (Barratt Impulsiveness Scale, version 11) and to higher cognitive impulsivity (information sampling task). Additionally, exploratory analyses suggest that these relationships are more pronounced in severe AD patients compared to less severe AD patients. No significant relationships were found between emotional craving (AUQ) and motor impulsivity (stop signal task) or delay discounting and between obsessive-compulsive craving (Obsessive Compulsive Drinking Scale) and measures of impulsivity. CONCLUSIONS: Emotional craving is related to self-reported impulsivity and to cognitive impulsivity. These relationships seem to be more pronounced in AD patients with severe alcohol dependence. Further research is needed to explore the effect of this relationship on treatment outcome and relapse.