Subcortical shape alterations in major depressive disorder: Findings from the ENIGMA major depressive disorder working group.

Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with adolescent-onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = -0.164 to -0.180). Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = -0.173 to -0.184). Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.

Social Mindfulness and Psychosis: Neural Response to Socially Mindful Behavior in First-Episode Psychosis and Patients at Clinical High-Risk.

Background: Psychosis is characterized by problems in social functioning and trust, the assumed glue to positive social relations. But what helps building trust? A prime candidate could be social mindfulness: the ability and willingness to see and consider another person's needs and wishes during social decision making. We investigated whether first-episode psychosis patients (FEP) and patients at clinical high-risk (CHR) show reduced social mindfulness, and examined the underlying neural mechanisms. Methods: Twenty FEP, 17 CHR and 46 healthy controls, aged 16-31, performed the social mindfulness task (SoMi) during fMRI scanning, spontaneously and after the instruction "to keep the other's best interest in mind." As first of two people, participants had to choose one out of four products, of which three were identical and one was unique, differing in a single aspect (e.g., color). Results: FEP tended to choose the unique item (unmindful choice) more often than controls. After instruction, all groups significantly increased the number of mindful choices compared to the spontaneous condition. FEP showed reduced activation of the caudate and medial prefrontal cortex (mPFC) during mindful, and of the anterior cingulate cortex (ACC), mPFC, and left dorsolateral prefrontal cortex (dlPFC) during unmindful decisions. CHR showed reduced activation of the ACC compared to controls. Discussion: FEP showed a trend toward more unmindful choices. A similar increase of mindful choices after instruction indicated the ability for social mindfulness when prompted. Results suggested reduced sensitivity to the rewarding aspects of social mindfulness in FEP, and reduced consideration for the other player. FEP (and CHR to a lesser extent) might perceive unmindful choices as less incongruent with the automatic mindful responses than controls. Reduced socially mindful behavior in FEP may hinder the building of trust and cooperative interactions.

Giving others the option of choice: An fMRI study on low-cost cooperation.

Successful social relationships require a consideration of a partner's thoughts and intentions. This aspect of social life is captured in the social mindfulness paradigm (SoMi task), in which participants make decisions that either limit or preserve options for their interaction partner's subsequent choice. Here we investigated the neural correlates of spontaneous socially mindful and unmindful behaviours. Functional magnetic resonance data were acquired from 47 healthy adolescents and young adults (age 16-27) as they completed the SoMi task. Being faced with socially relevant choices was associated with activity in the medial prefrontal cortex, anterior cingulate, caudate, and insula, which is consistent with prior neuroeconomical research. Importantly, socially mindful choices were associated with activity in the right parietal cortex and the caudate, whereas unmindful choices were associated with activity in the left prefrontal cortex. These neural findings were consistent with the behavioural preference for mindful choices, suggesting that socially mindful decisions are the basic inclination, whereas socially unmindful responses may require greater effort and control. Together, these results begin to uncover the neural correlates of socially mindful and unmindful choices, and illuminate the psychological processes involved in cooperative social behaviour.

Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia.

BACKGROUND: Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)-Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. METHODS: We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. RESULTS: In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen's d = -0.17, p = .00054), and smaller amygdalae (d = -0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p < .0063). CONCLUSIONS: Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain's response to trauma.

Comparing the effect of clozapine and risperidone on cue reactivity in male patients with schizophrenia and a cannabis use disorder: A randomized fMRI study.

OBJECTIVE: Cannabis use disorders (CUDs) are highly comorbid in patients with schizophrenia and associated with poor outcome. Clozapine has been put forward as the first choice antipsychotic in this patient group. However, little is known about the mechanisms underlying the assumed superiority of clozapine. METHODS: A total of 38 patients with DSM-IV schizophrenia (30 with and 8 without a DSM-IV CUD) and 20 healthy comparison subjects were included between April 2009 and June 2012. Patients were randomized to antipsychotic treatment with clozapine or risperidone. At baseline and after 4weeks of medication, brain response to cannabis-related, positive and neutral images was measured using functional MRI. Neural correlates of cue reactivity were assessed in the following regions of interest: amygdala, ventral striatum, insula, thalamus, orbitofrontal cortex and anterior cingulate cortex. Subjective craving was assessed using self-report questionnaires (OCDUS and MCQ). RESULTS: At baseline, patients with a comorbid CUD showed higher subjective craving and greater activation in response to cannabis-related images compared to patients without a CUD and healthy controls in most regions of interest. Clozapine treated patients reported a greater reduction in craving (F(1,28)=6.0, p=0.04) and showed a larger decrease in amygdala activation during cannabis-related images compared to risperidone treated patients (T=3.94, pFWE=0.006). In addition, significant correlations were found between subjective craving and thalamus and insula activation during cannabis-related images. CONCLUSION: These findings provide evidence that clozapine is superior to risperidone in decreasing subjective craving and cue reactivity for cannabis-related images probably due to a differential effect on dopaminergic neurotransmission. TRIAL REGISTRATION: 'Nederlands trial register' (http://www.trialregister.nl), nr NTR1761, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1761.

Abnormalities in metabolite concentrations in tourette's disorder and obsessive-compulsive disorder-A proton magnetic resonance spectroscopy study.

INTRODUCTION: Abnormal glutamatergic transmission in cortico-striato-thalamo-cortical (CSTC) circuits is thought to be involved in the pathophysiology of Tourette's disorder (TD) and obsessive-compulsive disorder (OCD). Using proton magnetic resonance spectroscopy, the current study aimed to investigate regional concentrations of glutamatergic compounds in TD and OCD patients in comparison to healthy control subjects (HC). MATERIAL AND METHODS: Twenty-three TD patients, 20 OCD patients and 22 HC were included. Short echo-time single-voxel 3T MRS was obtained from dorsal anterior cingulate cortex (dACC) and midline bilateral thalamus. RESULTS: The 3-group comparison showed a significant difference in choline concentration in the thalamus. Thalamic choline was highest in OCD patients, showing a significant difference with TD, and a trend compared to HC (post-hoc analyses). Glutamine in dACC correlated negatively with tic severity scores in TD patients, while glutamate in thalamus correlated positively with anxiety severity scores in OCD patients. CONCLUSIONS: These findings suggest subtle differences in metabolites in CSTC areas between TD and OCD. Alterations of choline concentrations seem to be both regional (only in thalamus, not in dACC) and disease specific in OCD pathology. The findings need replication in larger groups, but encourage further research into glutamatergic metabolites in TD and OCD.

Recovery of neurocognitive functions following sustained abstinence after substance dependence and implications for treatment.

BACKGROUND: Substance Use Disorders (SUDs) have been associated with impaired neurocognitive functioning, which may (partly) improve with sustained abstinence. New treatments are emerging, aimed at improving cognitive functions, and being tested. However, no integrated review is available regarding neurocognitive recovery following sustained abstinence. OBJECTIVES: In this review, results from prospective studies on neurocognitive recovery using neuropsychological assessments before and after sustained abstinence from SUDs are summarized and discussed. RESULTS: Thirty-five prospective studies were selected for this review, including twenty-two alcohol, three cannabis, four cocaine, three (meth)amphetamine, and three opioid studies. Results suggest that some cognitive functions (partially) recover after sustained abstinence, and that there are predictors of an unfavorable course such as poly-substance use and number of previous detoxifications. CONCLUSIONS: Prospective studies indicate that sustained abstinence after SUDs generally results in (partial) neurocognitive recovery. However, a final answer regarding full recovery awaits prospective studies with neurocognitive assessments before, during, and after sustained abstinence from SUDs. New interventions that might enhance neurocognitive recovery after abstinence are discussed, including neurocognitive training, medication and neuromodulation.

Opposite brain emotion-regulation patterns in identity states of dissociative identity disorder: a PET study and neurobiological model.

Imaging studies in posttraumatic stress disorder (PTSD) have shown differing neural network patterns between hypo-aroused/dissociative and hyper-aroused subtypes. Since dissociative identity disorder (DID) involves different emotional states, this study tests whether DID fits aspects of the differing brain-activation patterns in PTSD. While brain activation was monitored using positron emission tomography, DID individuals (n=11) and matched DID-simulating healthy controls (n=16) underwent an autobiographic script-driven imagery paradigm in a hypo-aroused and a hyper-aroused identity state. Results were consistent with those previously found in the two PTSD subtypes for the rostral/dorsal anterior cingulate, the prefrontal cortex, and the amygdala and insula, respectively. Furthermore, the dissociative identity state uniquely activated the posterior association areas and the parahippocampal gyri, whereas the hyper-aroused identity state uniquely activated the caudate nucleus. Therefore, we proposed an extended PTSD-based neurobiological model for emotion modulation in DID: the hypo-aroused identity state activates the prefrontal cortex, cingulate, posterior association areas and parahippocampal gyri, thereby overmodulating emotion regulation; the hyper-aroused identity state activates the amygdala and insula as well as the dorsal striatum, thereby undermodulating emotion regulation. This confirms the notion that DID is related to PTSD as hypo-aroused and hyper-arousal states in DID and PTSD are similar.

The effect of clozapine and risperidone on attentional bias in patients with schizophrenia and a cannabis use disorder: An fMRI study.

Cannabis use disorders (CUDs) are highly comorbid in patients with schizophrenia and are associated with poor outcome. Clozapine has been put forward as the first choice antipsychotic in this comorbid group. However, little is known about the mechanisms underlying the assumed superiority of clozapine. We compared the effects of clozapine and risperidone on attentional bias, subjective craving and associated regional brain activity in patients with schizophrenia and CUD. Overall, 36 patients with schizophrenia and 19 healthy controls were included. Patients were randomised to antipsychotic treatment with clozapine or risperidone. At baseline and after 4 weeks of medication use, regional brain responses were measured during a classical Stroop and a cannabis word Stroop using functional magnetic resonance imaging. Clozapine-treated CUD patients showed a larger reduction in craving and in activation of the insula during the cannabis word Stroop, while risperidone-treated patients showed a larger decrease in activation of the right anterior cingulate cortex during the classical Stroop. A significant association was found between decreases in subjective craving and decreases in insula activation during the cannabis word Stroop. These findings strongly suggest that clozapine may be a better treatment choice in patients with schizophrenia and CUD than risperidone.

Effects of non-invasive neurostimulation on craving: a meta-analysis.

This meta-analysis was conducted to evaluate the available evidence regarding the effects of non-invasive neurostimulation of the dorsolateral prefrontal cortex (DLPFC), on craving in substance dependence and craving for high palatable food. Non-invasive neurostimulation techniques were restricted to repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS). A total of 17 eligible studies were identified. Random effects analysis revealed a pooled standardized effect size (Hedge's g) of 0.476 (CI: 0.316-0.636), indicating a medium effect size favouring active non-invasive neurostimulation over sham stimulation in the reduction of craving (z=5.832, p<0.001). No significant differences were found between rTMS and tDCS, between the various substances of abuse and between substances of abuse and food, or between left and right DLPFC stimulation. In conclusion, this meta-analysis provides the first clear evidence that non-invasive neurostimulation of the DLPFC decreases craving levels in substance dependence.

The effect of caffeine on working memory load-related brain activation in middle-aged males.

Caffeine is commonly consumed in an effort to enhance cognitive performance. However, little is known about the usefulness of caffeine with regard to memory enhancement, with previous studies showing inconsistent effects on memory performance. We aimed to determine the effect of caffeine on working memory (WM) load-related activation during encoding, maintenance and retrieval phases of a WM maintenance task using functional magnetic resonance imaging (fMRI). 20 healthy, male, habitual caffeine consumers aged 40-61 years were administered 100 mg of caffeine in a double-blind placebo-controlled crossover design. Participants were scanned in a non-withdrawn state following a workday during which caffeinated products were consumed according to individual normal use (range = 145-595 mg). Acute caffeine administration was associated with increased load-related activation compared to placebo in the left and right dorsolateral prefrontal cortex during WM encoding, but decreased load-related activation in the left thalamus during WM maintenance. These findings are indicative of an effect of caffeine on the fronto-parietal network involved in the top-down cognitive control of WM processes during encoding and an effect on the prefrontal cortico-thalamic loop involved in the interaction between arousal and the top-down control of attention during maintenance. Therefore, the effects of caffeine on WM may be attributed to both a direct effect of caffeine on WM processes, as well as an indirect effect on WM via arousal modulation. Behavioural and fMRI results were more consistent with a detrimental effect of caffeine on WM at higher levels of WM load, than caffeine-related WM enhancement. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Heterosexual men and women both show a hypothalamic response to the chemo-signal androstadienone.

The odorous steroid compound 4,16-androstadien-3-one (androstadienone), found in axillary sweat, was previously reported to evoke hypothalamic activation in heterosexual women, but not in heterosexual men. However, subjects were exposed to the pure crystalline form of androstadienone, which raised the question whether the observed hypothalamic response is physiologically relevant. Therefore, in the present study, we asked whether sexually dimorphic hypothalamic responses could be measured when subjects were exposed to lower, more physiologically relevant concentrations of androstadienone. A total of 21 women and 16 men, all heterosexual, participated in our functional magnetic resonance imaging study (fMRI). Three different concentrations of androstadienone diluted in propylene glycol (10 mM "high," 0.1 mM "medium" and 0.001 mM "low") were delivered to the subjects' nostrils using a computer-controlled stimulator. When exposed to the "high" androstadienone concentration, women showed stronger hypothalamic activation than men. By contrast, men showed more hypothalamic activation when exposed to the "medium" androstadienone concentrations in comparison to women. Thus, we replicated that smelling the chemo-signal androstadienone elicits a hypothalamic activation. However, this effect does not seem to be gender-specific, because androstadienone activated the hypothalamus in both men and women, suggesting that androstadienone exerts specific effects in heterosexual individuals of both sexes.

Functional magnetic resonance imaging during planning before and after cognitive-behavioral therapy in pediatric obsessive-compulsive disorder.

OBJECTIVE: Pediatric obsessive compulsive disorder (OCD) has been associated with cognitive abnormalities, in particular executive impairments, and dysfunction of frontal-striatal-thalamic circuitry. The aim of this study was to investigate if planning as an executive function is compromised in pediatric OCD and is associated with frontal-striatal-thalamic dysfunction, and if this dysfunction would normalize after successful treatment. METHOD: Twenty-five medication-free pediatric patients (mean ± SD 13.95 ± 2.52 years old, range 9 to 19 years) with OCD and 25 healthy controls, matched by age and gender, were scanned twice using a self-paced pseudo-randomized event-related functional magnetic resonance imaging version of the Tower of London. Patients were rescanned after 16 sessions of protocol-based cognitive behavioral therapy; healthy controls were rescanned after a similar interval. RESULTS: Patients performed the task significantly slower but with similar accuracy compared with controls. Neuroimaging results showed less recruitment of frontal and parietal regions in patients with OCD compared with controls during the planning versus control task. With increasing task load patients compared with controls showed more recruitment of ventrolateral and medial prefrontal cortex and insula and anterior cingulate cortex. After treatment, these differences ceased to be significant, with time by group by task load interaction analyses showing a significant decrease in right posterior prefrontal activity in patients with OCD compared with healthy controls. CONCLUSION: Pediatric patients with OCD showed subtle planning impairments and decreased dorsolateral prefrontal and parietal recruitment that normalized after cognitive behavioral treatment. Planning dysfunction is likely to be a state rather than a trait feature of pediatric OCD.

Bright light in elderly subjects with nonseasonal major depressive disorder: a double blind randomised clinical trial using early morning bright blue light comparing dim red light treatment.

BACKGROUND: Depression frequently occurs in the elderly. Its cause is largely unknown, but several studies point to disturbances of biological rhythmicity. In both normal aging, and depression, the functioning of the suprachiasmatic nucleus (SCN) is impaired, as evidenced by an increased prevalence of day-night rhythm perturbations, such as sleeping disorders. Moreover, the inhibitory SCN neurons on the hypothalamus-pituitary adrenocortical axis (HPA-axis) have decreased activity and HPA-activity is enhanced, when compared to non-depressed elderly. Using bright light therapy (BLT) the SCN can be stimulated. In addition, the beneficial effects of BLT on seasonal depression are well accepted. BLT is a potentially safe, nonexpensive and well accepted treatment option. But the current literature on BLT for depression is inconclusive. METHODS/DESIGN: This study aims to show whether BLT can reduce non-seasonal major depression in elderly patients. Randomized double blind placebo controlled trial in 126 subjects of 60 years and older with a diagnosis of major depressive disorder (MDD, DSM-IV/SCID-I). Subjects are recruited through referrals of psychiatric outpatient clinics and from case finding from databases of general practitioners and old-people homes in the Amsterdam region. After inclusion subjects are randomly allocated to the active (bright blue light) vs. placebo (dim red light) condition using two Philips Bright Light Energy boxes type HF 3304 per subject, from which the light bulbs have been covered with bright blue- or dim red light- permitting filters. Patients will be stratified by use of antidepressants. Prior to treatment a one-week period without light treatment will be used. At three time points several endocrinological, psychophysiological, psychometrically, neuropsychological measures are performed: just before the start of light therapy, after completion of three weeks therapy period, and three weeks thereafter. DISCUSSION: If BLT reduces nonseasonal depression in elderly patients, then additional lighting may easily be implemented in the homes of patients to serve as add-on treatment to antidepressants or as a stand-alone treatment in elderly depressed patients. In addition, if our data support the role of a dysfunctional biological clock in depressed elderly subjects, such a finding may guide further development of novel chronobiological oriented treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00332670.

Different brain effects during chronic and acute sacral neuromodulation in urge incontinent patients with implanted neurostimulators.

OBJECTIVE: To compare changes in regional cerebral blood flow (rCBF), using positron emission tomography (PET), during chronic and acute sacral neuromodulation (SN). SN is an effective long-term treatment for chronic urge incontinence due to urinary bladder hyperactivity, as sensory nerves, spinal and supraspinal structures are probably responsible for the action of SN. It is not known which brain areas are involved, and the optimum benefit of SN is not immediate, suggesting that induced plasticity of the brain is necessary. PATIENTS AND METHODS: Brain activity was measured in two groups: 12 urge incontinent patients (11 women and one man; mean age 52 years) in whom an implanted unilateral S3 nerve neurostimulator had been effective for >6 months (mean time after implantation 4.5 years); and eight urge incontinent patients (seven women and one man; mean age 49 years) in whom the neurostimulator was activated for the first time in the PET scanner. RESULTS: During SN in chronically implanted patients, there were significant decreases in rCBF in the middle part of the cingulate gyrus, the ventromedial orbitofrontal cortex, midbrain and adjacent midline thalamus, and rCBF increases in the dorsolateral prefrontal cortex. During acute SN in newly implanted patients, there were significant decreases in rCBF the medial cerebellum, and increases in the right postcentral gyrus cortex, the right insular cortex and the ventromedial orbitofrontal cortex. Group analysis between chronic and newly implanted patients showed significant differences in the associative sensory cortex, premotor cortex and the cerebellum, all three involved in learning behaviour. CONCLUSIONS: These findings suggests that chronic SN influences, presumably via the spinal cord, brain areas previously implicated in detrusor hyperactivity, awareness of bladder filling, the urge to void and the timing of micturition. Furthermore, SN affects areas involved in alertness and awareness. Acute SN modulates predominantly areas involved in sensorimotor learning, which might become less active during the course of chronic SN.