Deep brain stimulation normalizes amygdala responsivity in treatment-resistant depression.

Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is a promising intervention for treatment-resistant depression (TRD). However, the working mechanisms of vALIC DBS in TRD remain largely unexplored. As major depressive disorder has been associated with aberrant amygdala functioning, we investigated whether vALIC DBS affects amygdala responsivity and functional connectivity. To investigate the long-term effects of DBS, eleven patients with TRD performed an implicit emotional face-viewing paradigm during functional magnetic resonance imaging (fMRI) before DBS surgery and after DBS parameter optimization. Sixteen matched healthy controls performed the fMRI paradigm at two-time points to control for test-retest effects. To investigate the short-term effects of DBS de-activation after parameter optimization, thirteen patients additionally performed the fMRI paradigm after double-blind periods of active and sham stimulation. Results showed that TRD patients had decreased right amygdala responsivity compared to healthy controls at baseline. Long-term vALIC DBS normalized right amygdala responsivity, which was associated with faster reaction times. This effect was not dependent on emotional valence. Furthermore, active compared to sham DBS increased amygdala connectivity with sensorimotor and cingulate cortices, which was not significantly different between responders and non-responders. These results suggest that vALIC DBS restores amygdala responsivity and behavioral vigilance in TRD, which may contribute to the DBS-induced antidepressant effect.

Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.

Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this causal depression network (CDN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis Principal Component Analysis (PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CDN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CDN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes (t = -2.35, p = 0.019). This evidence further supports that treatment interventions converge on a CDN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.

Changes in postictal cerebral perfusion are related to the duration of electroconvulsive therapy-induced seizures.

OBJECTIVE: Postictal symptoms may result from cerebral hypoperfusion, which is possibly a consequence of seizure-induced vasoconstriction. Longer seizures have previously been shown to cause more severe postictal hypoperfusion in rats and epilepsy patients. We studied cerebral perfusion after generalized seizures elicited by electroconvulsive therapy (ECT) and its relation to seizure duration. METHODS: Patients with a major depressive episode who underwent ECT were included. During treatment, 21-channel continuous electroencephalogram (EEG) was recorded. Arterial spin labeling magnetic resonance imaging scans were acquired before the ECT course (baseline) and approximately 1 h after an ECT-induced seizure (postictal) to quantify global and regional gray matter cerebral blood flow (CBF). Seizure duration was assessed from the period of epileptiform discharges on the EEG. Healthy controls were scanned twice to assess test-retest variability. We performed hypothesis-driven Bayesian analyses to study the relation between global and regional perfusion changes and seizure duration. RESULTS: Twenty-four patients and 27 healthy controls were included. Changes in postictal global and regional CBF were correlated with seizure duration. In patients with longer seizure durations, global decrease in CBF reached values up to 28 mL/100 g/min. Regional reductions in CBF were most prominent in the inferior frontal gyrus, cingulate gyrus, and insula (up to 35 mL/100 g/min). In patients with shorter seizures, global and regional perfusion increased (up to 20 mL/100 g/min). These perfusion changes were larger than changes observed in healthy controls, with a maximum median global CBF increase of 12 mL/100 g/min and a maximum median global CBF decrease of 20 mL/100 g/min. SIGNIFICANCE: Seizure duration is a key factor determining postictal perfusion changes. In future studies, seizure duration needs to be considered as a confounding factor due to its opposite effect on postictal perfusion.

Severe Postictal Confusion After Electroconvulsive Therapy: A Retrospective Study.

OBJECTIVES: Severe postictal confusion (sPIC) is an important but poorly investigated adverse effect of electroconvulsive therapy (ECT). In this retrospective study, prevalence of sPIC and potential risk factors were explored. METHODS: Medical charts of 295 ECT patients (mean ± SD age, 57 ± 15 years; male, 36%) were scrutinized for occurrence of sPIC, as well as demographic, clinical, and treatment characteristics. Patients showing sPIC were compared with patients who did not, using univariate statistics. Multivariate analyses with a split-sample validation procedure were used to assess whether predictive models could be developed using independent data sets. RESULTS: O 295 patients, 74 (25.1%) showed sPIC. All patients showing sPIC needed extra medication, 9% (n = 7) required physically restraints, and 5% (n = 4) had to be secluded. Univariate analyses showed several trends: patients with sPIC were more often males (P = 0.05), had more often history of cerebrovascular incident (P = 0.02), did not use concomitant selective serotonin reuptake inhibitors (P = 0.01), received higher median dosage of succinylcholine (P = 0.02), and received pretreatment with flumazenil more often (P = 0.07), but these associations did not remain significant after correction for multiple comparisons. Multiple logistic regression analysis did not result in a model that could predict sPIC in the holdout data set. CONCLUSIONS: In this retrospective naturalistic study in 295 ECT patients, the prevalence of sPIC appeared to be 25%. Patients showing sPIC were characterized by male sex, history of cerebrovascular incident, use of higher-dose succinylcholine, and pretreatment with flumazenil. However, multivariate analysis revealed no significant model to predict sPIC in independent data.

An overview of the first 5 years of the ENIGMA obsessive-compulsive disorder working group: The power of worldwide collaboration.

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive-compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.

Predicting the naturalistic course in anxiety disorders using clinical and biological markers: a machine learning approach.

BACKGROUND: Disease trajectories of patients with anxiety disorders are highly diverse and approximately 60% remain chronically ill. The ability to predict disease course in individual patients would enable personalized management of these patients. This study aimed to predict recovery from anxiety disorders within 2 years applying a machine learning approach. METHODS: In total, 887 patients with anxiety disorders (panic disorder, generalized anxiety disorder, agoraphobia, or social phobia) were selected from a naturalistic cohort study. A wide array of baseline predictors (N = 569) from five domains (clinical, psychological, sociodemographic, biological, lifestyle) were used to predict recovery from anxiety disorders and recovery from all common mental disorders (CMDs: anxiety disorders, major depressive disorder, dysthymia, or alcohol dependency) at 2-year follow-up using random forest classifiers (RFCs). RESULTS: At follow-up, 484 patients (54.6%) had recovered from anxiety disorders. RFCs achieved a cross-validated area-under-the-receiving-operator-characteristic-curve (AUC) of 0.67 when using the combination of all predictor domains (sensitivity: 62.0%, specificity 62.8%) for predicting recovery from anxiety disorders. Classification of recovery from CMDs yielded an AUC of 0.70 (sensitivity: 64.6%, specificity: 62.3%) when using all domains. In both cases, the clinical domain alone provided comparable performances. Feature analysis showed that prediction of recovery from anxiety disorders was primarily driven by anxiety features, whereas recovery from CMDs was primarily driven by depression features. CONCLUSIONS: The current study showed moderate performance in predicting recovery from anxiety disorders over a 2-year follow-up for individual patients and indicates that anxiety features are most indicative for anxiety improvement and depression features for improvement in general.

Demographic and Clinical Characteristics of Regular GHB-Users with and without GHB-Induced Comas.

BACKGROUND: Gamma hydroxybutyric acid (GHB) has been used recreationally for nearly three decades and its chronic use is frequently associated with serious adverse events including GHB-intoxication with GHB-induced comas. Moreover, despite its low prevalence, the number of individuals with GHB-use disorders is steadily increasing. However, the risk-factors associated with chronic GHB-use or the development of a GHB-use disorders remain poorly understood. Purpose: This study aims to profile two types of GHB-users, those with and those without GHB-induced comas. Methods: We included 27 GHB users with ≥4 GHB-induced comas (GHB-Coma), 27 GHB users without a coma (GHB-NoComa), and 27 polydrug users who never used GHB (No-GHB). Participants completed self-reported questionnaires in order to assess their demographic and clinical features, and their use profile of GHB and other drugs. Results: The typical GHB user in our sample was young, single, living alone, well-educated, and a student. The GHB-Coma group had lower self-control and reported higher negative affect than the GHB-NoComa group. GHB-Coma participants were heavier GHB users and mostly used GHB alone at home, whereas the GHB-NoComa group mostly used GHB with friends and in nightclubs. Remarkably, the majority of participants were not concerned about potential neurocognitive impairments induced by GHB-intoxication and/or GHB-induced comas. Conclusion: In this assessment, different profiles for recreational users with and without GHB-induced comas were well expressed. Their description contributes to a better understanding of the risk factors associated with recreational GHB-use, GHB-induced coma, and the development of GHB-use disorders.

Recreational use of GHB is associated with alterations of resting state functional connectivity of the central executive and default mode networks.

Gamma-hydroxybutyrate acid (GHB) is a recreational drug with a high addictive potential. Severe side effects such as GHB-induced coma are common and linked to increased emergency room attendances. Task-based functional-imaging studies have revealed an association between the regular use of GHB and multiple GHB-induced comas, and altered neurocognitive function. However the effects of multiple GHB-induced comas and regular GHB-use on intrinsic brain connectivity during rest remain unknown. The study population consisted of 23 GHB-users with ≥4 GHB-induced comas (GHB-Coma), 22 GHB-users who never experienced a GHB-induced coma (GHB-NoComa) and 24 polydrug users who never used GHB (No-GHB). Resting-state scans were collected to assess resting-state functional-connectivity within and between the default mode network (DMN), the bilateral central executive network (CEN) and the salience network (SN). The GHB-NoComa group showed decreased rsFC of the right CEN with a region in the anterior cingulate cortex (pFWE = 0.048) and decreased rsFC between the right CEN and the DMN (pFWE = 0.048) when compared with the No-GHB group. These results suggest that regular GHB-use is associated with decreased rsFC within the right CEN and between the right CEN and the DMN. The presence of multiple GHB-induced comas is not associated with (additional) alterations in rsFC.

Influence of Gamma-Hydroxybutyric Acid-Use and Gamma-Hydroxybutyric Acid-Induced Coma on Affect and the Affective Network.

BACKGROUND: Gamma-hydroxybutyric acid (GHB) is a drug of abuse associated with increased emergency room attendances, due to GHB-induced comas. Withdrawal from GHB often increases social anxiety and is linked to alterations in emotion processing. However, little is known about the effects of GHB-use and GHB-induced comas on affect regulation in humans. OBJECTIVES: We aimed to assess the effect of GHB-use and GHB-induced comas on the affective network. METHOD: We recruited 27 GHB users with ≥4 GHB-induced comas (GHB-Coma), 27 GHB users without a GHB-induced coma (GHB-NoComa), and 27 polydrug users who never used GHB (No-GHB). Participants completed self-report questionnaires assessing negative affect (depression, anxiety and stress) and performed an emotional face matching task during functional magnetic resonance imaging to probe activity of the amygdala and the hippocampus. RESULTS: The GHB-Coma group reported higher levels of depression, anxiety, and stress; showed decreased activity of the hippocampus; and increased functional connectivity of the left hippocampus with the left fusiform gyrus and a cluster on the left temporal-parietal-occipital junction, when compared with the 2 other groups. The GHB-NoComa group showed decreased functional connectivity of the left hippocampus with the amygdala in comparison with the No-GHB group. CONCLUSIONS: GHB-use but in particular GHB-induced comas, are associated with altered emotion identification and hippocampal functioning. Awareness campaigns are required to raise consciousness about the adverse effects of GHB-induced comas on affect regulation, despite the absence of subjective side effects.

Divergent influences of anterior cingulate cortex GABA concentrations on the emotion circuitry.

Neuroimaging research has revealed that emotion processing recruits a widespread neural network including the dorsal anterior cingulate cortex (dACC), hippocampus, and amygdala. Recent studies have started to investigate the role of the primary inhibitory neurotransmitter γ-aminobutyric acid (GABA) on brain function, but little is known about the influences of GABA on this emotion circuitry. Using magnetic resonance spectroscopy, we investigated the role of GABA levels in the dACC on emotion processing by presenting emotional and neutral pictures to 68 healthy male participants during functional magnetic resonance imaging. Results revealed opposing associations of dACC GABA levels and neural activity. GABA levels were positively correlated with blood oxygen level dependent (BOLD) responses to emotional stimuli in the amygdala and to emotional and neutral stimuli in the hippocampus. In contrast, GABA levels were negatively correlated with BOLD responses for the comparison between positive and negative stimuli in the dACC. Our results suggest positive influences of dACC GABA on BOLD responses in the hippocampus and amygdala, and negative influences on BOLD responses in the dACC that are dependent on emotional valence.

White matter alterations in cocaine users are negatively related to the number of additionally (ab)used substances.

Diffusion tensor imaging studies have provided evidence for white matter (WM) alterations in cocaine users. While polysubstance use is a widespread phenomenon among cocaine users, its role in WM alterations in cocaine users is currently unknown. This study examined the relation between the number of substances that are used(cocaine, alcohol and marijuana) and WM alterations in 67 male non-drug users and 67 male regular cocaine users, who were classified into five groups based on the number of used substances. Diffusion-weighted images were acquired on a 3.0 T magnetic resonance imaging scanner. Using tract-based spatial statistics we demonstrated that there was a negative relation between the number of used substances and fractional anisotropy, a global measure of WM integrity. Also, we demonstrated a positive relation between the number of used substance and radial diffusivity within the prefrontal lobe, suggesting an increase in demyelination with the number of used substances. We did not find a dose-effect between the level of substance use and WM alterations. The results of the current study may reflect the presence of a pre-existing vulnerability to polysubstance use resulting from prefrontal WM abnormalities and related impaired cognitive control although WM alterations because of polysubstance use cannot be fully excluded. This study is an important first step in understanding the problems related to polysubstance use among cocaine users.

Persistent and reversible consequences of combat stress on the mesofrontal circuit and cognition.

Prolonged stress can have long-lasting effects on cognition. Animal models suggest that deficits in executive functioning could result from alterations within the mesofrontal circuit. We investigated this hypothesis in soldiers before and after deployment to Afghanistan and a control group using functional and diffusion tensor imaging. Combat stress reduced midbrain activity and integrity, which was associated to compromised sustained attention. Long-term follow-up showed that the functional and structural changes had normalized within 1.5 y. In contrast, combat stress induced a persistent reduction in functional connectivity between the midbrain and prefrontal cortex. These results demonstrate that combat stress has adverse effects on the human mesofrontal circuit and suggests that these alterations are partially reversible.

Food can lift mood by affecting mood-regulating neurocircuits via a serotonergic mechanism.

It is commonly assumed that food can affect mood. One prevalent notion is that food containing tryptophan increases serotonin levels in the brain and alters neural processing in mood-regulating neurocircuits. However, tryptophan competes with other long-neutral-amino-acids (LNAA) for transport across the blood-brain-barrier, a limitation that can be mitigated by increasing the tryptophan/LNAA ratio. We therefore tested in a double-blind, placebo-controlled crossover study (N=32) whether a drink with a favourable tryptophan/LNAA ratio improves mood and modulates specific brain processes as assessed by functional magnetic resonance imaging (fMRI). We show that one serving of this drink increases the tryptophan/LNAA ratio in blood plasma, lifts mood in healthy young women and alters task-specific and resting-state processing in brain regions implicated in mood regulation. Specifically, Test-drink consumption reduced neural responses of the dorsal caudate nucleus during reward anticipation, increased neural responses in the dorsal cingulate cortex during fear processing, and increased ventromedial prefrontal-lateral prefrontal connectivity under resting-state conditions. Our results suggest that increasing tryptophan/LNAA ratios can lift mood by affecting mood-regulating neurocircuits.

Short-term antidepressant administration reduces default mode and task-positive network connectivity in healthy individuals during rest.

Resting-state studies in depressed patients have revealed increased connectivity within the default mode network (DMN) and task-positive network (TPN). This has been associated with heightened rumination, which is the tendency to repetitively think about symptoms of distress. Here, we performed a pharmacological neuroimaging study in healthy volunteers to investigate whether short-term antidepressant administration could reduce DMN connectivity. We recorded resting-state functional magnetic resonance imaging (fMRI) scans in twenty-three healthy volunteers after two week intake of the combined serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine in a double-blind, placebo-controlled, crossover study. Duloxetine improved mood in part as a result of increased resilience to the mood-worsening effects of scanning and reduced DMN and TPN connectivity. Within the DMN, duloxetine reduced connectivity between the medial prefrontal cortex (MPFC) and the lateral parietal cortex (LPC) and uncoupled the MPFC from the dorsolateral prefrontal cortex (DLPFC). Within the TPN, duloxetine uncoupled the intraparietal sulcus (IPS) from the inferior occipital gyrus. These results show that two-week antidepressant administration reduces DMN and TPN connectivity in healthy volunteers, which may contribute to their antidepressant effects in depression.

Time-dependent corticosteroid modulation of prefrontal working memory processing.

Corticosteroids are potent modulators of human higher cognitive function. They are released in response to stress, and are thought to be involved in the modulation of cognitive function by inducing distinct rapid nongenomic, and slow genomic changes, affecting neural plasticity throughout the brain. However, their exact effects on the neural correlates of higher-order cognitive function as performed by the prefrontal cortex at the human brain system level remain to be elucidated. Here, we targeted these time-dependent effects of corticosteroids on prefrontal cortex processing in humans using a working memory (WM) paradigm during functional MRI scanning. Implementing a randomized, double-blind, placebo-controlled design, 72 young, healthy men received 10 mg hydrocortisone either 30 min (rapid corticosteroid effects) or 240 min (slow corticosteroid effects), or placebo before a numerical n-back task with differential load (0- to 3-back). Corticosteroids' slow effects appeared to improve working memory performance and increased neuronal activity during WM performance in the dorsolateral prefrontal cortex depending on WM load, whereas no effects of corticosteroids' rapid actions were observed. Thereby, the slow actions of corticosteroids seem to facilitate adequate higher-order cognitive functioning, which may support recovery in the aftermath of stress exposure.

Menstrual cycle-related changes in amygdala morphology are associated with changes in stress sensitivity.

Premenstrual increases in negative mood are thought to arise from changes in gonadal hormone levels, presumably by influencing mood regulation and stress sensitivity. The amygdala plays a major role in this context, and animal studies suggest that gonadal hormones influence its morphology. Here, we investigated whether amygdala morphology changes over the menstrual cycle and whether this change explains differences in stress sensitivity. Twenty-eight young healthy women were investigated once during the premenstrual phase and once during the late follicular phase. T1-weighted anatomical images of the brain were acquired using magnetic resonance imaging and analyzed with optimized voxel-based morphometry. To measure mood regulation and stress sensitivity, negative affect was assessed after viewing strongly aversive as well as neutral movie clips. Our results show increased gray matter volume in the dorsal part of the left amygdala during the premenstrual phase when compared with the late follicular phase. This volume increase was positively correlated with the premenstrual increase in stress-induced negative affect. This is the first study showing structural plasticity of the amygdala in humans at the macroscopic level that is associated with both endogenous gonadal hormone fluctuations and stress sensitivity. These results correspond with animal findings of gonadal hormone-mediated neural plasticity in the amygdala and have implications for understanding the pathogenesis of specific mood disorders associated with hormonal fluctuations.

Corticosteroid induced decoupling of the amygdala in men.

The amygdala is a key regulator of vigilance and heightens attention toward threat. Its activity is boosted upon threat exposure and contributes to a neuroendocrine stress response via the hypothalamic-pituitary-adrenal (HPA) axis. Corticosteroids are known to control brain activity as well as HPA activity by providing negative feedback to the brain. However, it is unknown how corticosteroids affect the neural circuitry connected to the amygdala. Implementing a randomized, double-blind, placebo-controlled design, we here investigated the effects of 10-mg hydrocortisone on amygdala-centered functional connectivity patterns in men using resting state functional magnetic resonance imaging. Results showed generally decreased functional connectivity of the amygdala by corticosteroids. Hydrocortisone reduced "positive" functional coupling of the amygdala to brain regions involved in the initiation and maintenance of the stress response; the locus coeruleus, hypothalamus, and hippocampus. Furthermore, hydrocortisone reduced "negative" functional coupling of the amygdala to the middle frontal and temporal gyrus; brain regions known to be involved in executive control. A control analysis did not show significant corticosteroid modulation of visual cortex coupling, indicating that the amygdala decoupling was not reflecting a general reduction of network connectivity. These results suggest that corticosteroids may reduce amygdala's impact on brain processing in the aftermath of stress in men.

Gene Expression has Distinct Associations with Brain Structure and Function in Major Depressive Disorder.

Major depressive disorder (MDD) is associated with structural and functional brain abnormalities. MDD as well as brain anatomy and function are influenced by genetic factors, but the role of gene expression remains unclear. Here, this work investigates how cortical gene expression contributes to structural and functional brain abnormalities in MDD. This work compares the gray matter volume and resting-state functional measures in a Chinese sample of 848 MDD patients and 749 healthy controls, and these case-control differences are then associated with cortical variation of gene expression. While whole gene expression is positively associated with structural abnormalities, it is negatively associated with functional abnormalities. This work observes the relationships of expression levels with brain abnormalities for individual genes, and found that transcriptional correlates of brain structure and function show opposite relations with gene dysregulation in postmortem cortical tissue from MDD patients. This work further identifies genes that are positively or negatively related to structural abnormalities as well as functional abnormalities. The MDD-related genes are enriched for brain tissue, cortical cells, and biological pathways. These findings suggest that distinct genetic mechanisms underlie structural and functional brain abnormalities in MDD, and highlight the importance of cortical gene expression for the development of cortical abnormalities.

Replicable brain-phenotype associations require large-scale neuroimaging data.

Numerous neuroimaging studies have investigated the neural basis of interindividual differences but the replicability of brain-phenotype associations remains largely unknown. We used the UK Biobank neuroimaging dataset (N = 37,447) to examine associations with six variables related to physical and mental health: age, body mass index, intelligence, memory, neuroticism and alcohol consumption, and assessed the improvement of replicability for brain-phenotype associations with increasing sampling sizes. Age may require only 300 individuals to provide highly replicable associations but other phenotypes required 1,500 to 3,900 individuals. The required sample size showed a negative power law relation with the estimated effect size. When only comparing the upper and lower quarters, the minimally required sample sizes for imaging decreased by 15-75%. Our findings demonstrate that large-scale neuroimaging data are required for replicable brain-phenotype associations, that this can be mitigated by preselection of individuals and that small-scale studies may have reported false positive findings.