Showing papers in "Journal of Psychiatry & Neuroscience in 2020"

Consensus statement on the use of clozapine during the COVID-19 pandemic.

Abstract: With the ongoing coronavirus disease 2019 (COVID-19) pandemic, psychiatrists find themselves in the clinical situation of being asked by patients, family members and patient advocacy societies to help ensure access to clozapine as a medication critical for ongoing patient care. To provide clozapine prescribing guidance and facilitate regulatory agencies modifying laboratory monitoring and/or dispensing requirements, an expert advisory subgroup of the Treatment Response and Resistance in Psychosis working group developed the following background, recommendations and rationale as a consensus statement.

Abnormalities of intrinsic regional brain activity in first-episode and chronic schizophrenia: a meta-analysis of resting-state functional MRI

Abstract: Background: Resting-state functional MRI (fMRI) studies have provided much evidence for abnormal intrinsic brain activity in schizophrenia, but results have been inconsistent. Methods: We conducted a meta-analysis of whole-brain, resting-state fMRI studies that explored differences in amplitude of low-frequency fluctuation (ALFF) between people with schizophrenia (including first episode and chronic) and healthy controls. Results: A systematic literature search identified 24 studies comparing a total of 1249 people with schizophrenia and 1179 healthy controls. Overall, patients with schizophrenia displayed decreased ALFF in the bilateral postcentral gyrus, bilateral precuneus, left inferior parietal gyri and right occipital lobe, and increased ALFF in the right putamen, right inferior frontal gyrus, left inferior temporal gyrus and right anterior cingulate cortex. In the subgroup analysis, patients with first-episode schizophrenia demonstrated decreased ALFF in the bilateral inferior parietal gyri, right precuneus and left medial prefrontal cortex, and increased ALFF in the bilateral putamen and bilateral occipital gyrus. Patients with chronic schizophrenia showed decreased ALFF in the bilateral postcentral gyrus, left precuneus and right occipital gyrus, and increased ALFF in the bilateral inferior frontal gyri, bilateral superior frontal gyrus, left amygdala, left inferior temporal gyrus, right anterior cingulate cortex and left insula. Limitations: The small sample size of our subgroup analysis, predominantly Asian samples, processing steps and publication bias could have limited the accuracy of the results. Conclusion: Our comprehensive meta-analysis suggests that findings of aberrant regional intrinsic brain activity during the initial stages of schizophrenia, and much more widespread damage with the progression of disease, may contribute to our understanding of the progressive pathophysiology of schizophrenia.

The orbitofrontal cortex, food intake and obesity

Abstract: Obesity is a major health challenge facing many people throughout the world. Increased consumption of palatable, high-caloric foods is one of the major drivers of obesity. Both orexigenic and anorexic states have been thoroughly reviewed elsewhere; here, we focus on the cognitive control of feeding in the context of obesity, and how the orbitofrontal cortex (OFC) is implicated, based on data from preclinical and clinical research. The OFC is important in decision-making and has been heavily researched in neuropsychiatric illnesses such as addiction and obsessive–compulsive disorder. However, activity in the OFC has only recently been described in research into food intake, obesity and eating disorders. The OFC integrates sensory modalities such as taste, smell and vision, and it has dense reciprocal projections into thalamic, midbrain and striatal regions to fine-tune decision-making. Thus, the OFC may be anatomically and functionally situated to play a critical role in the etiology and maintenance of excess feeding behaviour. We propose that the OFC serves as an integrative hub for orchestrating motivated feeding behaviour and suggest how its neurobiology and functional output might be altered in the obese state.

High-frequency versus theta burst transcranial magnetic stimulation for the treatment of poststroke cognitive impairment in humans

Abstract: Background Because the reliability of repetitive transcranial magnetic stimulation (rTMS) in treating poststroke cognitive impairment has not been convincingly demonstrated, we systematically examined the effectiveness of this regimen with 2 protocols. Methods We randomly allocated 41 patients with poststroke cognitive impairment to receive 5 Hz rTMS (n = 11), intermittent theta burst stimulation (iTBS; n = 15) or sham stimulation (n = 15). Each group received 10 stimulation sessions over the left dorsolateral prefrontal cortex. We performed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Beck Depression Inventory at baseline and after the intervention. Results The 5 Hz rTMS group showed significantly greater improvement than the sham group in RBANS total score (p = 0.006), attention (p = 0.001) and delayed memory (p < 0.001). The iTBS group showed significantly greater improvement than the sham group in RBANS total score (p = 0.005) and delayed memory (p = 0.007). The 5 Hz rTMS group exhibited a superior modulating effect in attention compared to the iTBS group (p = 0.016). Patients without comorbid hypertension (p = 0.008) were predisposed to favourable therapeutic outcomes. Limitations Although we included only patients with left hemispheric stroke, heterogeneity associated with cortical and subcortical implications existed. We did not investigate the remote effects of rTMS. Conclusion Our results demonstrated that both 5 Hz rTMS and iTBS were effective for poststroke cognitive impairment in terms of global cognition, attention and memory function; the domain of attention was susceptible to 5 Hz modulation. Treatment with 5 Hz rTMS may slow cognitive decline, representing both a pivotal process in poststroke cognitive impairment and an aspect of neuroplasticity that contributes to disease-modifying strategies. Clinical trial registration NCT02006615; clinicaltrials.gov/ct2/show/NCT02006615.

Volumetric brain differences in clinical depression in association with anxiety: a systematic review with meta-analysis.

Abstract: Background Structural differences associated with depression have not been confirmed in brain regions apart from the hippocampus. Comorbid anxiety has been inconsistently assessed, and may explain discrepancies in previous findings. We investigated the link between depression, comorbid anxiety and brain structure. Methods We followed Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines (PROSPERO CRD42018089286). We searched the Cochrane Library, MEDLINE, PsycInfo, PubMed and Scopus, from database inception to Sept. 13, 2018, for MRI case-control studies that reported brain volumes in healthy adults and adults with clinical depression. We summarized mean volumetric differences using meta-analyses, and we assessed demographics, depression factors and segmentation procedure as moderators using meta-regressions. Results We included 112 studies in the meta-analyses, assessing 4911 healthy participants and 5934 participants with depression (mean age 49.8 yr, 68.2% female). Volume effects were greater in late-onset depression and in multiple episodes of depression. Adults with depression and no comorbidity showed significantly lower volumes in the putamen, pallidum and thalamus, as well as significantly lower grey matter volume and intracranial volume; the largest effects were in the hippocampus (6.8%, p < 0.001). Adults with depression and comorbid anxiety showed significantly higher volumes in the amygdala (3.6%, p < 0.001). Comorbid anxiety lowered depression effects by 3% on average. Sex moderated reductions in intracranial volume. Limitations High heterogeneity in hippocampus effects could not be accounted for by any moderator. Data on symptom severity and medication were sparse, but other factors likely made significant contributions. Conclusion Depression-related differences in brain structure were modulated by comorbid anxiety, chronicity of symptoms and onset of illness. Early diagnosis of anxiety symptomatology will prove crucial to ensuring effective, tailored treatments for improving long-term mental health and mitigating cognitive problems, given the effects in the hippocampus.

Magnetic resonance imaging texture predicts progression to dementia due to Alzheimer disease earlier than hippocampal volume

Abstract: Background: Early identification of people at risk of imminent progression to dementia due to Alzheimer disease is crucial for timely intervention and treatment. We investigated whether the texture of MRI brain scans could predict the progression of mild cognitive impairment (MCI) to Alzheimer disease earlier than volume. Methods: We constructed a development data set (121 people who were cognitively normal and 145 who had mild Alzheimer disease) and a validation data set (113 patients with stable MCI who did not progress to Alzheimer disease for 3 years; 40 with early MCI who progressed to Alzheimer disease after 12–36 months; and 41 with late MCI who progressed to Alzheimer disease within 12 months) from the Alzheimer’s Disease Neuroimaging Initiative. We analyzed the texture of the hippocampus, precuneus and posterior cingulate cortex using a grey-level co-occurrence matrix. We constructed texture and volume indices from the development data set using logistic regression. Using area under the curve (AUC) of receiver operator characteristics, we compared the accuracy of hippocampal volume, hippocampal texture and the composite texture of the hippocampus, precuneus and posterior cingulate cortex in predicting conversion from MCI to Alzheimer disease in the validation data set. Results: Compared with hippocampal volume, hippocampal texture (0.790 v. 0.739, p = 0.047) and composite texture (0.811 v. 0.739, p = 0.007) showed larger AUCs for conversion to Alzheimer disease from both early and late MCI. Hippocampal texture showed a marginally larger AUC than hippocampal volume in early MCI (0.795 v. 0.726, p = 0.060). Composite texture showed a larger AUC for conversion to Alzheimer disease than hippocampal volume in both early (0.817 v. 0.726, p = 0.027) and late MCI (0.805 v. 0.753, p = 0.019). Limitations: This study was limited by the absence of histological data, and the pathology reflected by the texture measures remains to be validated. Conclusion: Textures of the hippocampus, precuneus and posterior cingulate cortex predicted conversion from MCI to Alzheimer disease at an earlier time point and with higher accuracy than hippocampal volume.

A genome-wide association study of cocaine use disorder accounting for phenotypic heterogeneity and gene–environment interaction

Abstract: Background: Phenotypic heterogeneity and complicated gene–environment interplay in etiology are among the primary factors that hinder the identification of genetic variants associated with cocaine use disorder. Methods: To detect novel genetic variants associated with cocaine use disorder, we derived disease traits with reduced phenotypic heterogeneity using cluster analysis of a study sample (n = 9965). We then used these traits in genome-wide association tests, performed separately for 2070 African Americans and 1570 European Americans, using a new mixed model that accounted for the moderating effects of 5 childhood environmental factors. We used an independent sample (918 African Americans, 1382 European Americans) for replication. Results: The cluster analysis yielded 5 cocaine use disorder subtypes, of which subtypes 4 (n = 3258) and 5 (n = 1916) comprised heavy cocaine users, had high heritability estimates (h2 = 0.66 and 0.64, respectively) and were used in association tests. Seven of the 13 identified genetic loci in the discovery phase were available in the replication sample. In African Americans, rs114492924 (discovery p = 1.23 × E−8), a single nucleotide polymorphism in LINC01411, was replicated in the replication sample (p = 3.63 × E−3). In a meta-analysis that combined the discovery and replication results, 3 loci in African Americans were significant genome-wide: rs10188036 in TRAK2 (p = 2.95 × E−8), del-1:15511771 in TMEM51 (p = 9.11 × E−10) and rs149843442 near LPHN2 (p = 3.50 × E−8). Limitations: Lack of data prevented us from replicating 6 of the 13 identified loci. Conclusion: Our results demonstrate the importance of considering phenotypic heterogeneity and gene–environment interplay in detecting genetic variations that contribute to cocaine use disorder, because new genetic loci have been identified using our novel analytic method.

Attentional bias modification is associated with fMRI response toward negative stimuli in individuals with residual depression: a randomized controlled trial

Abstract: Background: Attentional bias modification (ABM) may lead to more adaptive emotion perception and emotion regulation. Understanding the neural basis of these effects may lead to greater precision for the development of future treatments. Task-related functional MRI (fMRI) after ABM training has not been investigated in depression so far. The main aim of this randomized controlled trial was to explore differences in brain activity after ABM training, in response to emotional stimuli. Methods: A total of 134 people with previous depression, who had been treated for depression and had various degrees of residual symptoms, were randomized to 14 days of active ABM or a closely matched placebo training, followed by an fMRI emotion regulation task. The training procedure was a classical dot–probe task with emotional face stimuli. In the active ABM condition, the probes replaced the more positively valenced face of a given pair. As participants implicitly learned to predict the probe location, this would be likely to induce a more positive attentional bias. The placebo condition was identical, except for the contingency of the probe, which appeared equally behind positive and negative stimuli. We compared depression symptoms and subjective ratings of perceived negativity during fMRI between the training groups. We explored brain activation in predefined regions of interest and across the whole brain. We explored activation in areas associated with changes in attentional bias and degree of depression. Results: Compared with the placebo group, the ABM group showed reduced activation in the amygdala and the anterior cingulate cortex when passively viewing negative images. We found no group differences in predefined regions of interest associated with emotion regulation strategies. Response in the temporal cortices was associated with the degree of change in attentional bias and the degree of depressive symptoms in ABM versus placebo. Limitations: These findings should be replicated in other samples of patients with depression, and in studies using fMRI designs that allow analyses of within-group variability from baseline to follow-up. Conclusion: Attentional bias modification training has an effect on brain function in the circuitry associated with emotional appraisal and the generation of affective states. Clinicaltrials.gov identifier NCT02931487.

Metabolic state and value-based decision-making in acute and recovered female patients with anorexia nervosa

Abstract: Background Patients with anorexia nervosa forgo eating despite emaciation and severe health consequences. Such dysfunctional decision-making might be explained by an excessive level of self-control, alterations in homeostatic and hedonic regulation, or an interplay between these processes. We aimed to understand value-based decision-making in anorexia nervosa and its association with the gut hormone ghrelin. Besides its homeostatic function, ghrelin has been implicated in the hedonic regulation of appetite and reward via the modulation of phasic dopamine signalling. Methods In a cross-sectional design, we studied acutely underweight (n = 94) and recovered (n = 37) patients with anorexia nervosa of the restrictive subtype, as well as healthy control participants (n = 119). We assessed plasma concentrations of desacyl ghrelin and parameters of delay discounting, probability discounting for gains and losses, and loss aversion. Results Recovered patients displayed higher risk aversion for gains, but we observed no group differences for the remaining decision-making parameters. Desacyl ghrelin was higher in acutely underweight and recovered participants with anorexia nervosa relative to healthy controls. Moreover, we found a significant group × desacyl ghrelin interaction in delay discounting, indicating that in contrast to healthy controls, acutely underweight patients with anorexia nervosa who had high desacyl ghrelin concentrations preferably chose the delayed reward option. Limitations We probed decision-making using monetary rewards, but patients with anorexia nervosa may react differently to disorder-relevant stimuli. Furthermore, in contrast to acyl ghrelin, the functions of desacyl ghrelin are unclear. Therefore, the interpretation of the results is preliminary. Conclusion The propensity for risk aversion as found in recovered patients with anorexia nervosa could help them successfully complete therapy, or it could reflect sequelae of the disorder. Conversely, ghrelin findings might be related to a mechanism contributing to disease maintenance; that is, in acutely underweight anorexia nervosa, a hungry state may facilitate the ability to forgo an immediate reward to achieve a (dysfunctional) long-term goal.

Autonomic dysfunction and sudden death in patients with Rett syndrome: a systematic review

Abstract: Background: Rett syndrome (RTT), a debilitating neuropsychiatric disorder that begins in early childhood, is characterized by impairments in the autonomic nervous system that can lead to sudden unexpected death. This study explores the mechanisms of autonomic dysfunction to identify potential risk factors for sudden death in patients with RTT. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, we undertook comprehensive systematic reviews using the PubMed, Scopus, Cochrane, PsycINFO, Embase and Web of Science databases. Results: We identified and critically appraised 39 articles for autonomic dysfunction and 5 for sudden death that satisfied the eligibility criteria. Following thematic analysis, we identified 7 themes: breathing irregularities, abnormal spontaneous brainstem activations, heart rate variability metrics, QTc changes, vagal imbalance, fluctuation in peptides and serotonergic neurotransmission. We grouped these 7 themes into 3 final themes: (A) brainstem modulation of breathing, (B) electrical instability of the cardiovascular system and (C) neurochemical changes contributing to autonomic decline. We described key evidence relating to each theme and identified important areas that could improve the clinical management of patients with RTT. Limitations: The heterogeneity of the methods used to assess autonomic function increased the difficulty of making inferences from the different studies. Conclusion: This study identified the important mediators of autonomic dysfunction and sudden death in patients with RTT. We proposed brainstem mechanisms and emphasized risk factors that increase brainstem vulnerability. We discussed clinical management to reduce sudden death and future directions for this vulnerable population.

Trauma, treatment and Tetris: video gaming increases hippocampal volume in male patients with combat-related posttraumatic stress disorder.

Abstract: Background: Tetris has been proposed as a preventive intervention to reduce intrusive memories of a traumatic event. However, no neuroimaging study has assessed Tetris in patients with existing posttraumatic stress disorder (PTSD) or explored how playing Tetris may affect brain structure. Methods: We recruited patients with combat-related PTSD before psychotherapy and randomly assigned them to an experimental Tetris and therapy group (n = 20) or to a therapy-only control group (n = 20). In the control group, participants completed therapy as usual: eye movement desensitization and reprocessing (EMDR) psychotherapy. In the Tetris group, in addition to EMDR, participants also played 60 minutes of Tetris every day from onset to completion of therapy, approximately 6 weeks later. Participants completed structural MRI and psychological questionnaires before and after therapy, and we collected psychological questionnaire data at follow-up, approximately 6 months later. We hypothesized that the Tetris group would show increases in hippocampal volume and reductions in symptoms, both directly after completion of therapy and at follow-up. Results: Following therapy, hippocampal volume increased in the Tetris group, but not the control group. As well, hippocampal increases were correlated with reductions in symptoms of PTSD, depression and anxiety between completion of therapy and follow-up in the Tetris group, but not the control group. Limitations Playing Tetris may act as a cognitive interference task and as a brain-training intervention, but it was not possible to distinguish between these 2 potential mechanisms. Conclusion: Tetris may be useful as an adjunct therapeutic intervention for PTSD. Tetris-related increases in hippocampal volume may ensure that therapeutic gains are maintained after completion of therapy.

Peripheral serotonin transporter DNA methylation is linked to increased salience network connectivity in females with anorexia nervosa

Abstract: Background Epigenetic variation in the serotonin transporter gene (SLC6A4) has been shown to modulate the functioning of brain circuitry associated with the salience network and may heighten the risk for mental illness. This study is, to our knowledge, the first to test this epigenome–brain–behaviour pathway in patients with anorexia nervosa. Methods We obtained resting-state functional connectivity (rsFC) data and blood samples from 55 acutely underweight female patients with anorexia nervosa and 55 age-matched female healthy controls. We decomposed imaging data using independent component analysis. We used bisulfite pyrosequencing to analyze blood DNA methylation within the promoter region of SLC6A4. We then explored salience network rsFC patterns in the group × methylation interaction. Results We identified a positive relationship between SLC6A4 methylation levels and rsFC between the dorsolateral prefrontal cortex and the salience network in patients with anorexia nervosa compared to healthy controls. Increased rsFC in the salience network mediated the link between SLC6A4 methylation and eating disorder symptoms in patients with anorexia nervosa. We confirmed findings of rsFC alterations for CpG-specific methylation at a locus with evidence of methylation correspondence between brain and blood tissue. Limitations This study was cross-sectional in nature, the sample size was modest for the method and methylation levels were measured peripherally, so findings cannot be fully generalized to brain tissue. Conclusion This study sheds light on the neurobiological process of how epigenetic variation in the SLC6A4 gene may relate to rsFC in the salience network that is linked to psychopathology in anorexia nervosa.

Indirect frontocingulate structural connectivity predicts clinical response to accelerated rTMS in major depressive disorder

Abstract: Background: Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for major depressive disorder (MDD), but its clinical efficacy remains rather modest. One reason for this could be that the propagation of rTMS effects via structural connections from the stimulated area to deeper brain structures (such as the cingulate cortices) is suboptimal. Methods: We investigated whether structural connectivity — derived from diffusion MRI data — could serve as a biomarker to predict treatment response. We hypothesized that stronger structural connections between the patient-specific stimulation position in the left dorsolateral prefrontal cortex (dlPFC) and the cingulate cortices would predict better clinical outcomes. We applied accelerated intermittent theta burst stimulation (aiTBS) to the left dlPFC in 40 patients with MDD. We correlated baseline structural connectivity, quantified using various metrics (fractional anisotropy, mean diffusivity, tract density, tract volume and number of tracts), with changes in depression severity scores after aiTBS. Results: Exploratory results (p < 0.05) showed that structural connectivity between the patient-specific stimulation site and the caudal and posterior parts of the cingulate cortex had predictive potential for clinical response to aiTBS. Limitations: We used the diffusion tensor to perform tractography. A main limitation was that multiple fibre directions within voxels could not be resolved, which might have led to missing connections in some patients. Conclusion: Stronger structural frontocingular connections may be of essence to optimally benefit from left dlPFC rTMS treatment in MDD. Even though the results are promising, further investigation with larger numbers of patients, more advanced tractography algorithms and classic daily rTMS treatment paradigms is warranted. Clinical trial registration: http://clinicaltrials.gov/show/NCT01832805

Neuroanatomical predictors of response to subcallosal cingulate deep brain stimulation for treatment-resistant depression

Abstract: Background: Deep brain stimulation targeting the subcallosal cingulate gyrus (SCG DBS) improves the symptoms of treatment-resistant depression in some patients, but not in others. We hypothesized that there are pre-existing structural brain differences between responders and nonresponders to SCG DBS, detectable using structural MRI. Methods: We studied preoperative, T1-weighted MRI scans of 27 patients treated with SCG DBS from 2003 to 2011. Responders (n = 15) were patients with a > 50% improvement in Hamilton Rating Scale for Depression score following 12 months of SCG DBS. Preoperative subcallosal cingulate gyrus grey matter volume was obtained using manual segmentation by a trained observer blinded to patient identity. Volumes of hippocampus, thalamus, amygdala, whole-brain cortical grey matter and white matter volume were obtained using automated techniques. Results: Preoperative subcallosal cingulate gyrus, thalamic and amygdalar volumes were significantly larger in patients who went on to respond to SCG-DBS. Hippocampal volume did not differ between groups. Cortical grey matter volume was significantly smaller in responders, and cortical grey matter:white matter ratio distinguished between responders and nonresponders with high sensitivity and specificity. Limitations: Normalization by intracranial volume nullified some between-group differences in volumetric measures. Conclusion: There are structural brain differences between patients with treatment-resistant depression who respond to SCG DBS and those who do not. Specifically, the structural integrity of the subcallosal cingulate gyrus target region and its connected subcortical areas, and variations in cortical volume across the entire brain, appear to be important determinants of response. Structural MRI shows promise as a biomarker in deep brain stimulation for depression, and may play a role in refining patient selection for future trials.

Frontoparietal and salience network alterations in obsessive–compulsive disorder: insights from independent component and sliding time window analyses

Abstract: Background: Resting-state functional MRI (fMRI) studies commonly report alterations in 3 core networks in obsessive–compulsive disorder (OCD) — the frontoparietal network, the default mode network and the salience network — defined by functionally connected infra-slow oscillations in ongoing brain activity. However, most of these studies observed static functional connectivity in the brains of patients with OCD. Methods: To investigate dynamic functional connectivity alterations and widen the evidence base toward the triple network model in OCD, we performed group-based independent component and sliding time window analyses in 49 patients with OCD and 41 healthy controls. Results: The traditional independent component analysis showed alterations in the left frontoparietal network as well as between the left and right frontoparietal networks in patients with OCD compared with healthy controls. For dynamic functional connectivity, the sliding time window approach revealed peak dysconnectivity between the left and right frontoparietal networks and between the left frontoparietal network and the salience network. Limitations: The number of independent components, noise in the resting-state fMRI images, the heterogeneity of the OCD sample, and comorbidities and medication status in the patients could have biased the results. Conclusion: Disrupted modulation of these intrinsic brain networks may contribute to the pathophysiology of OCD.

Intact value-based decision-making during intertemporal choice in women with remitted anorexia nervosa? An fMRI study

Abstract: Background: Extreme restrictive food choice in anorexia nervosa is thought to reflect excessive self-control and/or abnormal reward sensitivity. Studies using intertemporal choice paradigms have suggested an increased capacity to delay reward in anorexia nervosa, and this may explain an unusual ability to resist immediate temptation and override hunger in the long-term pursuit of thinness. It remains unclear, however, whether altered delay discounting in anorexia nervosa constitutes a state effect of acute illness or a trait marker observable after recovery. Methods: We repeated the analysis from our previous fMRI investigation of intertemporal choice in acutely underweight patients with anorexia nervosa in a sample of weight-recovered women with anorexia nervosa (n = 36) and age-matched healthy controls (n = 36) who participated in the same study protocol. Follow-up analyses explored functional connectivity separately in both the weight-recovered/healthy controls sample and the acute/healthy controls sample. Results: In contrast to our previous findings in acutely underweight patients with anorexia nervosa, we found no differences between weight-recovered patients with anorexia nervosa and healthy controls at either behavioural or neural levels. New analysis of data from the acute/healthy controls sample revealed increased coupling between dorsal anterior cingulate cortex and posterior brain regions as a function of decision difficulty, supporting the hypothesis of altered neural efficiency in the underweight state. Limitations: This was a cross-sectional study, and the results may be task-specific. Conclusion: Although our results underlined previous demonstrations of divergent temporal reward discounting in acutely underweight patients with anorexia nervosa, we found no evidence of alteration in patients with weight-recovered anorexia nervosa. Together, these findings suggest that impaired valuebased decision-making may not constitute a defining trait variable or “scar” of the disorder.

Neurobiological commonalities and distinctions among 3 major psychiatric disorders: a graph theoretical analysis of the structural connectome

Abstract: Background White matter network alterations have increasingly been implicated in major depressive disorder, bipolar disorder and schizophrenia. The aim of this study was to identify shared and distinct white matter network alterations among the 3 disorders. Methods We used analysis of covariance, with age and gender as covariates, to investigate white matter network alterations in 123 patients with schizophrenia, 123 with bipolar disorder, 124 with major depressive disorder and 209 healthy controls. Results We found significant group differences in global network efficiency (F = 3.386, p = 0.018), nodal efficiency (F = 8.015, p < 0.001 corrected for false discovery rate [FDR]) and nodal degree (F = 5.971, pFDR < 0.001) in the left middle occipital gyrus, as well as nodal efficiency (F = 6.930, pFDR < 0.001) and nodal degree (F = 5.884, pFDR < 0.001) in the left postcentral gyrus. We found no significant alterations in patients with major depressive disorder. Post hoc analyses revealed that compared with healthy controls, patients in the schizophrenia and bipolar disorder groups showed decreased global network efficiency, nodal efficiency and nodal degree in the left middle occipital gyrus. Furthermore, patients in the schizophrenia group showed decreased nodal efficiency and nodal degree in the left postcentral gyrus compared with healthy controls. Limitations Our findings could have been confounded in part by treatment differences. Conclusion Our findings implicate graded white matter network alterations across the 3 disorders, enhancing our understanding of shared and distinct pathophysiological mechanisms across diagnoses and providing vital insights into neuroimaging-based methods for diagnosis and research.

Anatomic alterations across amygdala subnuclei in medication-free patients with obsessive-compulsive disorder.

Abstract: Background The amygdala has been implicated in obsessive-compulsive disorder (OCD), a common, disabling illness. However, the regional distribution of anatomic alterations in this structure and their association with the symptoms of OCD remains to be established. Methods We collected high-resolution 3D T1-weighted images from 81 untreated patients with OCD and no lifetime history of comorbid psychotic, affective or anxiety disorders, and from 95 age- and sex-matched healthy controls. We extracted the volume of the central nucleus of the amygdala (CeA) and the basolateral complex of the amygdala (BLA) and compared them across groups using FreeSurfer 6.0. In exploratory analyses, we evaluated other subnuclei, including the cortical medial nuclei, the anterior amygdaloid area, and the corticoamygdaloid transition area. Results Patients with OCD had reduced amygdala volume bilaterally compared with healthy controls (left, p = 0.034; right, p = 0.002). Volume reductions were greater in the CeA (left: -11.9%, p = 0.002; right: -13.3%, p < 0.001) than in the BLA (left lateral nucleus: -3.3%, p = 0.029; right lateral nucleus: -3.9%, p = 0.018; right basal nucleus: -4.1%, p = 0.017; left accessory basal nucleus: -6.5%, p = 0.001; right accessory basal nucleus: -9.3%, p < 0.001). Volume reductions in the CeA were associated with illness duration. Exploratory analysis revealed smaller medial (left: -15.4%, p < 0.001, η2 = 0.101) and cortical (left: -9.1%, p = 0.001, η2 = 0.058; right: -15.4%, p < 0.001, η2 = 0.175) nuclei in patients with OCD compared with healthy controls. Limitations Although the strict exclusion criteria used in the study helped us to identify OCD-specific alterations, they may have limited generalizability to the broader OCD population. Conclusion Our results provide a comprehensive anatomic profile of alterations in the amygdala subnuclei in untreated patients with OCD and highlight a distinctive pattern of volume reductions across subnuclei in OCD. Based on the functional properties of the amygdala subnuclei established from preclinical research, CeA impairment may contribute to behavioural inflexibility, and BLA disruption may be responsible for altered fear conditioning and the affective components of OCD.

Melatonin suppression by melanopsin-weighted light in patients with bipolar I disorder compared to healthy controls

Abstract: Background: Multiple lines of evidence suggest that the onset and course of bipolar disorder is influenced by environmental light conditions. Increased suppression of melatonin by light (supersensitivity) in patients with bipolar disorder has been postulated as an endophenotype by several studies. However, due to methodological shortcomings, the results of these studies remain inconclusive. This study investigated melatonin suppression in euthymic patients with bipolar I disorder using evening blue light specifically targeting the melanopsin system. Methods: Melatonin suppression was assessed in euthymic patients with bipolar I disorder and healthy controls by exposure to monochromatic blue light (λmax = 475 nm; photon density = 1.6 × 10¹³ photons/cm²/s) for 30 minutes at 2300 h, administered via a ganzfeld dome for highly uniform light exposure. Serum melatonin concentrations were determined from serial blood sampling via radioimmunoassay. All participants received mydriatic eye drops and were genotyped for the PER3 VNTR polymorphism to avoid or adjust for potential confounding. As secondary outcomes, serum melatonin concentrations during dark conditions and after monochromatic red light exposure (λmax = 624 nm; photon density = 1.6 × 10¹³ photons/cm²/s) were also investigated. Changes in subjective alertness were investigated for all 3 lighting conditions. Results: A total of 90 participants (57 controls, 33 bipolar I disorder) completed the study. Melatonin suppression by monochromatic blue light did not differ between groups (F1,80 = 0.56; p = 0.46). Moreover, there were no differences in melatonin suppression by monochromatic red light (F1,82 = 1.80; p = 0.18) or differences in melatonin concentrations during dark conditions (F1,74 = 1.16; p = 0.29). Healthy controls displayed a stronger increase in subjective alertness during exposure to blue light than patients with bipolar I disorder (t85 = 2.28; p = 0.027). Limitations: Large interindividual differences in melatonin kinetics may have masked a true difference. Conclusion: Despite using a large cohort and highly controlled laboratory conditions, we found no differences in melatonin suppression between euthymic patients with bipolar I disorder and healthy controls. These findings do not support the notion that supersensitivity is a valid endophenotype in bipolar I disorder.

CACNA1C polymorphism and brain cortical structure in bipolar disorder

Abstract: Background: The CACNA1C gene encodes the 1C subunit of L-type voltage-gated calcium channels and has been associated with several psychiatric syndromes — including bipolar disorder — in many genome-wide association studies. Experimental and clinical studies have reported changes with respect to behaviour and biomarkers in risk allele carriers, corroborating the essential role of the CACNA1C gene in neurons, during development and in the mature brain. However, the association of this gene with regional cortical thickness has not been evaluated in patients with bipolar disorder. Methods: Using magnetic resonance imaging, we measured the average cortical thickness of 68 brain regions in 87 patients genotyped for the single-nucleotide polymorphism rs1006737 in CACNA1C. Results: We found associations with the mean thickness of several cortical areas: the left lateral orbitofrontal and rostral anterior cingulate cortices, as well as other parts of the frontal and parietal cortices. Limitations: This cross-sectional cohort study could not fully differentiate correlation from causation. Conclusion: The CACNA1C polymorphism rs1006737 is associated with the mean thickness of cortical brain areas that have been shown to be altered in bipolar disorder.

Effectiveness and safety of neuroablation for severe and treatment-resistant obsessive-compulsive disorder: a systematic review and meta-analysis.

Abstract: Background Several neuroablative procedures are available for severe and treatment-resistant obsessive-compulsive disorder (OCD), but limited knowledge about their relative clinical advantages and disadvantages poses obstacles for treatment decision-making. Methods We searched PubMed, Embase, Scopus, Web of Knowledge and the Cochrane Library for reports up to February 2019. We reviewed the literature on the effectiveness (assessed using the Yale-Brown Obsessive Compulsive Scale [Y-BOCS]) and safety of various neuroablative interventions for severe and treatment-resistant OCD. Results We included 23 studies involving 487 patients in the systematic review; 21 studies with 459 patients entered meta-analysis. Overall, neuroablation achieved a response rate (proportion of patients with ≥ 35% reduction in Y-BOCS) of 55%. Most of the adverse events (88.4%) were mild and transient. The top 3 adverse events were headache (14.9%), cognitive deficits (9.1%) and behaviour problems (8.1%). Severe or permanent adverse events included personality changes (2.3%) and brain edema or brain cyst (1.5%). The response rates associated with capsulotomy, limbic leucotomy and cingulotomy were 59% (95% confidence interval [CI] 54-65), 47% (95% CI 23-72) and 36% (95% CI 23-50), respectively. Interventions with different coverages of the dorsal part of the internal capsule were associated with different adverse-event profiles but were unlikely to modify clinical effectiveness. Limitations The level of evidence of most included studies was relatively low. Conclusion Ablative surgeries are safe and effective for a large proportion of patients with severe and treatment-resistant OCD. Among the available procedures, capsulotomy seemed to be the most effective. Further research is needed to improve clinical effectiveness and minimize risks.

Neural bases of the clinical and neurocognitive differences between earlyand late-onset obsessive–compulsive disorder

Abstract: Background Using biological evidence to define subtypes within the heterogeneous population with obsessive–compulsive disorder (OCD) is important for improving treatment response. Based on age at onset, OCD can be clustered into 2 groups, each of which is more homogeneous with respect to clinical and cognitive phenotype. However, the neural bases for these phenotypic differences need to be established to construct evidence-based homogeneous groups. Methods We compared brain volumes, clinical symptoms, and neurocognitive function for 49 people with early-onset OCD and 52 with late-onset OCD (participants in both groups were unmedicated or drug-naive), and 103 healthy controls. We performed regression analyses to examine group × volume interaction effects on clinical outcomes or neurocognitive function in people with OCD. Results We observed larger volumes in the precentral, orbitofrontal, middle frontal, and middle temporal gyri in people with early-onset OCD compared to those with late-onset OCD. Poorer visuospatial construction in early-onset OCD was correlated with a larger left middle frontal gyrus volume. Impaired visuospatial memory in people with early-onset OCD and cognitive inflexibility in people with late-onset OCD were correlated with increased and decreased volume in the left middle frontal gyrus, respectively. We found group × volume interactions for obsessive–compulsive symptom scores in the left middle temporal gyrus of people with OCD. Limitations Although we divided the subtypes using the commonly adopted criterion of age at onset, this criterion is still somewhat controversial. Conclusion We provided the neural bases for clinical and neurocognitive differences to demonstrate that biological evidence underlies the distinctions between early- and late-onset OCD. This study suggests that different treatment options should be considered for the OCD subtypes, because their neurobiology differs and is related to distinct phenotypic profiles.

Altered response to risky decisions and reward in patients with obsessive–compulsive disorder

Abstract: Background: Patients with obsessive–compulsive disorder (OCD) employ ritualistic behaviours to reduce or even neutralize the anxiety provoked by their obsessions. The presence of excessive rumination and indecision has motivated the view of OCD as a disorder of decision-making. Most studies have focused on the “cold,” cognitive aspects of decision-making. This study expands current understanding of OCD by characterizing the abnormalities associated with affective, or “hot” decision-making. Methods: We performed a functional MRI study in a sample of 34 patients with OCD and 33 sex- and age-matched healthy controls, during which participants made 2-choice gambles taking varying levels of risk. Results: During risky decisions, patients showed significantly reduced task-related activation in the posterior cingulum, lingual gyrus and anterior cingulate cortex. We identified significant group × risk interactions in the calcarine cortex, precuneus, amygdala and anterior cingulate cortex. During the outcome phase, patients with OCD showed stronger activation of the orbitofrontal cortex, anterior cingulate cortex and putamen in response to unexpected losses. Limitations: The group of patients not receiving medication was very small (n = 5), which precluded us from assessing the effect of medication on risk-taking behaviour in these patients. Conclusion: Obsessive–compulsive disorder is associated with abnormal brain activity patterns during risky decision-making in a set of brain regions that have been consistently implicated in the processing of reward prediction errors. Alterations in affective “hot” processes implicated in decision-making may contribute to increased indecisiveness and intolerance to uncertainty in patients with OCD.

We need an operational framework for heterogeneity in psychiatric research

Abstract: Despite advancements in research methods and the growth of large international data sharing initiatives,[1][1] our understanding of the biological underpinnings of psychiatric disorders remains limited. An often cited reason for this stagnation is the presence of “heterogeneity,” whether

Quantitative tractography reveals changes in the corticospinal tract in drug-naïve children with attention-deficit/hyperactivity disorder

Abstract: Background: The specific role of the corticospinal tract with respect to inattention and impulsive symptoms in children with attentiondeficit/hyperactivity disorder (ADHD) has been explored in the past. However, to our knowledge, no study has identified the exact regions of the corticospinal tract that are affected in ADHD. We aimed to determine comprehensive alterations in the white matter microstructure of the corticospinal tract and underlying neuropsychological substrates in ADHD. Methods: We recruited 38 drug-naive children with ADHD and 34 typically developing controls. We employed a tract-based quantitative approach to measure diffusion parameters along the trajectory of the corticospinal tract, and we further correlated alterations with attention and response inhibition measures. Results: Compared with controls, children with ADHD demonstrated significantly lower fractional anisotropy and higher radial diffusivity at the level of cerebral peduncle, and higher fractional anisotropy at the level of the posterior limb of the internal capsule in the right corticospinal tract only. As well, increased fractional anisotropy in the posterior limb of the internal capsule was negatively correlated with continuous performance test attention quotients and positively correlated with reaction time on the Stroop Colour–Word Test; increased radial diffusivity in the right peduncle region was positively correlated with omissions in the Stroop test. Limitations: The sample size was relatively small. Moreover, we did not consider the different subtypes of ADHD and lacked sufficient power to analyze subgroup differences. Higher-order diffusion modelling is needed in future white matter studies. Conclusion: We demonstrated specific changes in the right corticospinal tract in children with ADHD. Correlations with measures of attention and response inhibition underscored the functional importance of corticospinal tract disturbance in ADHD.

Genetic and environmental influences on corticostriatal circuits in twins with autism

Abstract: Background: Corticostriatal circuits (CSC) have been implicated in the presentation of some restricted and repetitive behaviours (RRBs) in children with autism-spectrum disorder (ASD), and preliminary evidence suggests that disruptions in these pathways may be associated with differences in genetic and environmental influences on brain development. The objective of this investigation was to examine the impact of genetic and environmental factors on CSC regions in twins with and without ASD and to evaluate their relationship with the severity of RRBs. Methods: We obtained T1-weighted MRIs from same-sex monozygotic and dizygotic twin pairs, aged 6–15 years. Good-quality data were available from 48 ASD pairs (n = 96 twins; 30 pairs concordant for ASD, 15 monozygotic and 15 dizygotic; 18 pairs discordant for ASD, 4 monozygotic and 14 dizygotic) and 34 typically developing control pairs (n = 68 twins; 20 monozygotic and 14 dizygotic pairs). We generated structural measures of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, putamen, pallidum and thalamus using FreeSurfer. Twin pair comparisons included intraclass correlation analyses and ACE modelling (a2 = additive genetics; c2 = common or shared environment; e2 = unique or nonshared environment). We also assessed correlations with RRB severity. Results: Structural variation in CSC regions was predominantly genetically mediated in typically developing twins (a2 = 0.56 to 0.87), except for ACC white matter volume (a2 = 0.42, 95% confidence interval [CI] 0.08 to 0.77). We also observed similar magnitudes of genetic influence in twins with ASD (a2 = 0.65 to 0.97), but the cortical thickness of the ACC (c2 = 0.44, 95% CI 0.22 to 0.66) and OFC (c2 = 0.60, 95% CI 0.25 to 0.95) was primarily associated with environmental factors in only twins with ASD. Twin pair differences in OFC grey matter volume were also correlated with RRB severity and were predominantly environmentally mediated. Limitations: We obtained MRIs on 2 scanners, and analytical approaches could not identify specific genetic and environmental factors. Conclusion: Genetic factors primarily contribute to structural variation in subcortical CSC regions, regardless of ASD, but environmental factors may exert a greater influence on the development of grey matter thickness in the OFC and ACC in children with ASD. The increased vulnerability of OFC grey matter to environmental influences may also mediate some heterogeneity in RRB severity in children with ASD.

Transcranial magnetic stimulation over the right temporoparietal junction influences the sense of agency in healthy humans.

Abstract: Background The sense of agency is an important aspect of motor control. Impaired sense of agency has been linked to several medical conditions, including schizophrenia and functional neurological disorders. A complex brain network subserves the sense of agency, and the right temporoparietal junction is one of its main nodes. In this paper, we tested whether transcranial magnetic stimulation over the right temporoparietal junction elicited behavioural changes in the sense of agency. Methods In experiment 1, 15 healthy participants performed a behavioural task during functional MRI, with the goal of localizing the area relevant for the sense of agency in the right temporoparietal junction. In the task, the movement of a cursor (controlled by the participants) was artificially manipulated, and the sense of agency was either diminished (turbulence) or enhanced (magic). In experiment 2, we applied transcranial magnetic stimulation in 20 healthy participants in a sham-controlled, crossover trial with excitatory, inhibitory or sham (vertex) stimulation. We measured the summary agency score, an indicator of the sense of agency (lower values correspond to diminished sense of agency). Results Experiment 1 revealed a peak of activation during agency manipulation in the right temporoparietal junction (Montreal Neurological Institute coordinates x, y, z: 68, -26, 34). Experiment 2 showed that inhibition of the right temporoparietal junction significantly reduced the summary agency score in both turbulence (from -14.4 ± 11.4% to -22.5 ± 8.9%), and magic (from -0.7 ± 5.8% to -4.4 ± 4.4%). Limitations We found no excitatory effects, possibly because of a ceiling effect (because healthy participants have a normal sense of agency) or noneffectiveness of the excitatory protocol. Conclusion Our experiments showed that the network subserving the sense of agency was amenable to neuromodulation in healthy participants. This sets the ground for further research in patients with impaired sense of agency. Clinical trial identification: DRKS00012992 (German clinical trials registry).

Deficits of entropy modulation of the EEG: A biomarker for altered function in schizophrenia and bipolar disorder?

Abstract: Background: The synchronized activity of distributed neural assemblies — reflected in the electroencephalogram (EEG) — underpins mental function. In schizophrenia, modulation deficits of EEG spectral content during a P300 task have been replicated. The effects of treatment, chronicity and specificity in these deficits and their possible relationship with anatomic connectivity remain to be explored. Methods: We assessed spectral entropy modulation of the EEG during a P300 task in 79 patients with schizophrenia (of those, 31 were in their first episode), 29 patients with bipolar disorder and 48 healthy controls. Spectral entropy values summarize EEG characteristics by quantifying the irregularity of spectral content. In a subsample, we calculated the network architecture of structural connectivity using diffusion tensor imaging and graph-theory parameters. Results: We found significant spectral entropy modulation deficits with task performance in patients with chronic or first-episode schizophrenia and in patients with bipolar disorder, without significant pre-stimulus spectral entropy differences. The deficits were unrelated to treatment doses, and spectral entropy modulation did not differ between patients taking or not taking antipsychotics, lithium, benzodiazepines or antidepressants. Structural connectivity values were unrelated to spectral entropy modulation. In patients with schizophrenia, spectral entropy modulation was inversely related to negative symptoms and directly related to verbal memory. Limitations: All patients were taking medication. Patients with bipolar disorder were euthymic and chronic. The cross-sectional nature of this study prevented a more thorough analysis of state versus trait criteria for spectral entropy changes. Conclusion: Spectral entropy modulation with task performance is decreased in patients with schizophrenia and bipolar disorder. This deficit was not an effect of psychopharmacological treatment or structural connectivity and might reflect a deficit in the synchron ization of the neural assemblies that underlie cognitive activity.

Association between functional and structural connectivity of the corticostriatal network in people with schizophrenia and unaffected first-degree relatives

Abstract: Background: Dysfunction of the corticostriatal network has been implicated in the pathophysiology of schizophrenia, but findings are inconsistent within and across imaging modalities. We used multimodal neuroimaging to analyze functional and structural connectivity in the corticostriatal network in people with schizophrenia and unaffected first-degree relatives. Methods: We collected resting-state functional magnetic resonance imaging and diffusion tensor imaging scans from people with schizophrenia (n = 47), relatives (n = 30) and controls (n = 49). We compared seed-based functional and structural connectivity across groups within striatal subdivisions defined a priori. Results: Compared with controls, people with schizophrenia had altered connectivity between the subdivisions and brain regions in the frontal and temporal cortices and thalamus; relatives showed different connectivity between the subdivisions and the right anterior cingulate cortex (ACC) and the left precuneus. Post-hoc t tests revealed that people with schizophrenia had decreased functional connectivity in the ventral loop (ventral striatum–right ACC) and dorsal loop (executive striatum–right ACC and sensorimotor striatum–right ACC), accompanied by decreased structural connectivity; relatives had reduced functional connectivity in the ventral loop and the dorsal loop (right executive striatum–right ACC) and no significant difference in structural connectivity compared with the other groups. Functional connectivity among people with schizophrenia in the bilateral ventral striatum–right ACC was correlated with positive symptom severity. Limitations: The number of relatives included was moderate. Striatal subdivisions were defined based on a relatively low threshold, and structural connectivity was measured based on fractional anisotropy alone. Conclusion: Our findings provide insight into the role of hypoconnectivity of the ventral corticostriatal system in people with schizophrenia.

Psychotic symptoms are associated with lower cortical folding in youth at risk for mental illness

Abstract: Background: Cortical folding is essential for healthy brain development. Previous studies have found regional reductions in cortical folding in adult patients with psychotic illness. It is unknown whether these neuroanatomical markers are present in youth with subclinical psychotic symptoms. Methods: We collected MRIs and examined the local gyrification index in a sample of 110 youth (mean age ± standard deviation 14.0 ± 3.7 yr; range 9–25 yr) with a family history of severe mental illness: 48 with psychotic symptoms and 62 without. Images were processed using the Human Connectome Pipeline and FreeSurfer. We tested for group differences in local gyrification index using mixed-effects generalized linear models controlling for age, sex and familial clustering. Sensitivity analysis further controlled for intracranial volume, IQ, and stimulant and cannabis use. Results: Youth with psychotic symptoms displayed an overall trend toward lower cortical folding across all brain regions. After adjusting for multiple comparisons and confounders, regional reductions were localized to the frontal and occipital lobes. Specifically, the medial (B = −0.42, pFDR = 0.04) and lateral (B = −0.39, pFDR = 0.04) orbitofrontal cortices as well as the cuneus (B = −0.47, pFDR = 0.03) and the pericalcarine (B = −0.45, pFDR = 0.03) and lingual (B = −0.38, pFDR = 0.04) gyri. Limitations: Inference about developmental trajectories was limited by the cross-sectional data. Conclusion: Psychotic symptoms in youth are associated with cortical folding deficits, even in the absence of psychotic illness. The current study helps clarify the neurodevelopmental basis of psychosis at an early stage, before medication, drug use and other confounds have had a persistent effect on the brain.