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This study aimed to summarize the evidence on sleep alterations in medication-naïve children and adolescents with autism spectrum disorder (ASD).
We systematically searched PubMed/Medline, Embase and Web of Science databases from inception through March 22, 2021. This study was registered with PROSPERO (CRD42021243881). Any observational study was included that enrolled medication-naïve children and adolescents with ASD and compared objective (actigraphy and polysomnography) or subjective sleep parameters with typically developing (TD) counterparts. We extracted relevant data such as the study design and outcome measures. The methodological quality was assessed through the Newcastle-Ottawa Scale (NOS). A meta-analysis was carried out using the random-effects model by pooling effect sizes as Hedges’ g. To assess publication bias, Egger’s test and p-curve analysis were done. A priori planned meta-regression and subgroup analysis were also performed to identify potential moderators.
Out of 4277 retrieved references, 16 studies were eligible with 981 ASD patients and 1220 TD individuals. The analysis of objective measures showed that medication-naïve ASD patients had significantly longer sleep latency (Hedges’ g 0.59; 95% confidence interval [95% CI] 0.26 to 0.92), reduced sleep efficiency (Hedges’ g −0.58; 95% CI −0.87 to −0.28), time in bed (Hedges’ g −0.64; 95% CI −1.02 to −0.26) and total sleep time (Hedges’ g −0.64; 95% CI −1.01 to −0.27). The analysis of subjective measures showed that they had more problems in daytime sleepiness (Hedges’ g 0.48; 95% CI 0.26 to 0.71), sleep latency (Hedges’ g 1.15; 95% CI 0.72 to 1.58), initiating and maintaining sleep (Hedges’ g 0.86; 95% CI 0.39 to 1.33) and sleep hyperhidrosis (Hedges’ g 0.48; 95% CI 0.29 to 0.66). Potential publication bias was detected for sleep latency, sleep period time and total sleep time measured by polysomnography. Some sleep alterations were moderated by age, sex and concurrent intellectual disability. The median NOS score was 8 (interquartile range 7.25–8.75).
We found that medication-naïve children and adolescents with ASD presented significantly more subjective and objective sleep alterations compared to TD and identified possible moderators of these differences. Future research requires an analysis of how these sleep alterations are linked to core symptom severity and comorbid behavioural problems, which would provide an integrated therapeutic intervention for ASD. However, our results should be interpreted in light of the potential publication bias.
A leading theory of the negative symptoms of schizophrenia is that they reflect reduced responsiveness to rewarding stimuli. This proposal has been linked to abnormal (reduced) dopamine function in the disorder, because phasic release of dopamine is known to code for reward prediction error (RPE). Nevertheless, few functional imaging studies have examined if patients with negative symptoms show reduced RPE-associated activations.
Matched groups of DSM-5 schizophrenia patients with high negative symptom scores (HNS, N = 27) or absent negative symptoms (ANS, N = 27) and healthy controls (HC, N = 30) underwent fMRI scanning while they performed a probabilistic monetary reward task designed to generate a measure of RPE.
In the HC, whole-brain analysis revealed that RPE was positively associated with activation in the ventral striatum, the putamen, and areas of the lateral prefrontal cortex and orbitofrontal cortex, among other regions. Group comparison revealed no activation differences between the healthy controls and the ANS patients. However, compared to the ANS patients, the HNS patients showed regions of significantly reduced activation in the left ventrolateral and dorsolateral prefrontal cortex, and in the right lingual and fusiform gyrus. HNS and ANS patients showed no activation differences in ventral striatal or midbrain regions-of-interest (ROIs), but the HNS patients showed reduced activation in a left orbitofrontal cortex ROI.
The findings do not suggest that a generalized reduction of RPE signalling underlies negative symptoms. Instead, they point to a more circumscribed dysfunction in the lateral frontal and possibly the orbitofrontal cortex.
Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact.
We obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 1231 BD and 1601 control individuals from 13 countries within the ENIGMA-BD Working Group. We jointly modeled the statistical effects of BD and BMI on brain structure using mixed effects and tested for interaction and mediation. We also investigated the impact of medications on the BMI-related associations.
BMI and BD additively impacted the structure of many of the same brain regions. Both BMI and BD were negatively associated with cortical thickness, but not surface area. In most regions the number of jointly used psychiatric medication classes remained associated with lower cortical thickness when controlling for BMI. In a single region, fusiform gyrus, about a third of the negative association between number of jointly used psychiatric medications and cortical thickness was mediated by association between the number of medications and higher BMI.
We confirmed consistent associations between higher BMI and lower cortical thickness, but not surface area, across the cerebral mantle, in regions which were also associated with BD. Higher BMI in people with BD indicated more pronounced brain alterations. BMI is important for understanding the neuroanatomical changes in BD and the effects of psychiatric medications on the brain.
To date, a large number of functional magnetic resonance imaging (fMRI) studies have been conducted on psychosis. However, little is known about changes in brain functioning in psychotic patients using an emotional auditory paradigm at different stages of the disease. Such knowledge is important for advancing our understanding of the disorder and thus creating more targeted interventions. This study aimed to investigate whether individuals with first-episode psychosis (FEP) and chronic schizophrenia show abnormal brain responses to emotional auditory processing and to compare the responses between FEP and chronic schizophrenia.
Patients with FEP (n = 31) or chronic schizophrenia (n = 23) and healthy controls (HCs, n = 31) underwent an fMRI scan while presented with both emotional and nonemotional words.
Using HC as a reference, patients with FEP showed decreased right temporal activation, while patients with chronic schizophrenia showed increased bilateral temporal activation. When comparing the patient groups, individuals with FEP showed lower frontal lobe activation.
To the best of our knowledge, this is the first study with an emotional auditory paradigm used in psychotic patients at different stages of the disease. Our results suggested that the temporal lobe might be a key issue in the physiopathology of psychosis, although abnormal activation could also be derived from a connectivity problem. There is lower activation in the early stage and evolution to greater activation when patients become chronic. This study highlights the relevance of using emotional paradigms to better understand brain activation at different stages of psychosis.
Neuroimaging research has shown that patients with schizophrenia (SCZ) present brain structural and functional alterations, but the results across imaging modalities and task paradigms are difficult to reconcile. Specifically, no meta-analyses have tested whether the same brain systems that are structurally different in SCZ patients are also involved in neurocognitive and social cognitive tasks. To answer this, we conducted separate meta-analyses of voxel-based morphometry, neurocognitive functional magnetic resonance imaging (fMRI), and social cognitive fMRI studies. Next, with a multimodal approach, we identified the common alterations across meta-analyses. Further exploratory meta-analyses were performed taking into account several clinical variables (illness duration, medication status, and symptom severity). A cluster covering the dorsomedial prefrontal cortex (dmPFC) and the supplementary motor area (SMA), and the right inferior frontal gyrus (IFG), presented shared structural and neurocognitive-related activation decreases, while the right angular gyrus presented shared decreases between structural and social cognitive-related activation. The exploratory meta-analyses replicated to some extent these findings, while new regions of alterations appeared in patient subgroups with specific clinical features. In conclusion, we found task-specific correlates of brain structure and function in SCZ, which help summarize and integrate a growing literature.
Cognitive-behavior therapy (CBT) is a well-established first-line intervention for anxiety-related disorders, including specific phobia, social anxiety disorder, panic disorder/agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. Several neural predictors of CBT outcome for anxiety-related disorders have been proposed, but previous results are inconsistent.
We conducted a systematic review and meta-analysis of task-based functional magnetic resonance imaging (fMRI) studies investigating whole-brain predictors of CBT outcome in anxiety-related disorders (17 studies, n = 442).
Across different tasks, we observed that brain response in a network of regions involved in salience and interoception processing, encompassing fronto-insular (the right inferior frontal gyrus-anterior insular cortex) and fronto-limbic (the dorsomedial prefrontal cortex-dorsal anterior cingulate cortex) cortices was strongly associated with a positive CBT outcome.
Our results suggest that there are robust neural predictors of CBT outcome in anxiety-related disorders that may eventually lead (probably in combination with other data) to develop personalized approaches for the treatment of these mental disorders.
Accumulating evidence suggests that alterations in inflammatory biomarkers are important in depression. However, previous meta-analyses disagree on these associations, and errors in data extraction may account for these discrepancies.
PubMed/MEDLINE, Embase, PsycINFO, and the Cochrane Library were searched from database inception to 14 January 2020. Meta-analyses of observational studies examining the association between depression and levels of tumor necrosis factor-α (TNF-α), interleukin 1-β (IL-1β), interleukin-6 (IL-6), and C-reactive protein (CRP) were eligible. Errors were classified as follows: incorrect sample sizes, incorrectly used standard deviation, incorrect participant inclusion, calculation error, or analysis with insufficient data. We determined their impact on the results after correction thereof.
Errors were noted in 14 of the 15 meta-analyses included. Across 521 primary studies, 118 (22.6%) showed the following errors: incorrect sample sizes (20 studies, 16.9%), incorrect use of standard deviation (35 studies, 29.7%), incorrect participant inclusion (7 studies, 5.9%), calculation errors (33 studies, 28.0%), and analysis with insufficient data (23 studies, 19.5%). After correcting these errors, 11 (29.7%) out of 37 pooled effect sizes changed by a magnitude of more than 0.1, ranging from 0.11 to 1.15. The updated meta-analyses showed that elevated levels of TNF- α, IL-6, CRP, but not IL-1β, are associated with depression.
These findings show that data extraction errors in meta-analyses can impact findings. Efforts to reduce such errors are important in studies of the association between depression and peripheral inflammatory biomarkers, for which high heterogeneity and conflicting results have been continuously reported.
Although executive impairment has been reported in mania, its brain functional correlates have been relatively little studied. This study examined goal management, believed to be more closely related to executive impairment in daily life than other executive tasks, using a novel functional magnetic resonance imaging (fMRI) paradigm in patients in this illness phase.
Twenty-one currently manic patients with bipolar disorder and 30 matched healthy controls were scanned while performing the Computerized Multiple Elements Test (CMET). This requires participants to sequentially play four simple games, with transition between games being made either voluntarily (executive condition) or automatically (control condition).
CMET performance was impaired in the manic patients compared to the healthy controls. Manic patients failed to increase activation in the lateral frontal, cingulate and inferior parietal cortex when the executive demands of the task increased, while this increase was observed in the healthy controls. Activity in these regions was associated with task performance.
Manic patients show evidence of impaired goal management, which is associated with a pattern of reduced medial and lateral frontal and parietal activity.
Individuals at clinical high risk of psychosis (CHR-P) recruited in randomized clinical trials (RCTs) and observational cohorts may display a different enrichment and hence risk of transition to psychosis. No meta-analysis has ever addressed this issue.
“Preferred Reporting Items for Systematic reviews and Meta-Analyses” (PRISMA) and “Meta-analysis Of Observational Studies in Epidemiology” (MOOSE)–compliant meta-analysis. PubMed and Web of Science were searched until November 2020 (PROSPERO:CRD42021229223). We included nonoverlapping longitudinal studies (RCTs-control condition and observational cohorts) reporting the transition to psychosis in CHR-P individuals. The primary effect size measure was the cumulative risk of transition at 0.5, 1, and 2 years follow-up in RCTs compared to observational cohorts. Random effects meta-analyses, heterogeneity assessment, quality assessment, and meta-regressions were conducted.
Ninety-four independent studies (24 RCTs, 70 observational cohorts) and 9,243 individuals (mean age = 20.1 ± 3.0 years; 43.7% females) were included. The meta-analytical risk of transitioning to psychosis from a CHR-P stage was 0.091 (95% confidence intervals [CI] = 0.068–0.121) at 0.5 years, 0.140 (95% CI = 0.101–0.191) at 1 year and 0.165 (95% CI = 0.097–0.267) at 2 years follow-up in RCTs, and 0.081 (95% CI = 0.067–0.099) at 0.5 years, 0.138 (95% CI = 0.114–0.167) at 1 year, and 0.174 (95% CI = 0.156–0.193) at 2 years follow-up in observational cohorts. There were no between-group differences in transition risks (p > 0.05). The proportion of CHR-P individuals with substance use disorders (excluding alcohol and cannabis) was higher in observational cohorts (16.8, 95% CI = 13.3–21.0%) than in RCTs (3.4, 95% CI = 0.8–12.7%; p = 0.018).
There is no meta-analytic evidence supporting sampling biases in RCTs of CHR-P individuals. Further RCTs are needed to detect effective interventions to prevent psychosis in this at-risk group.
People with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have abnormalities in frontal, temporal, parietal and striato-thalamic networks. It is unclear to what extent these abnormalities are distinctive or shared. This comparative meta-analysis aimed to identify the most consistent disorder-differentiating and shared structural and functional abnormalities.
Systematic literature search was conducted for whole-brain voxel-based morphometry (VBM) and functional magnetic resonance imaging (fMRI) studies of cognitive control comparing people with ASD or ADHD with typically developing controls. Regional gray matter volume (GMV) and fMRI abnormalities during cognitive control were compared in the overall sample and in age-, sex- and IQ-matched subgroups with seed-based d mapping meta-analytic methods.
Eighty-six independent VBM (1533 ADHD and 1295 controls; 1445 ASD and 1477 controls) and 60 fMRI datasets (1001 ADHD and 1004 controls; 335 ASD and 353 controls) were identified. The VBM meta-analyses revealed ADHD-differentiating decreased ventromedial orbitofrontal (z = 2.22, p < 0.0001) but ASD-differentiating increased bilateral temporal and right dorsolateral prefrontal GMV (zs ⩾ 1.64, ps ⩽ 0.002). The fMRI meta-analyses of cognitive control revealed ASD-differentiating medial prefrontal underactivation but overactivation in bilateral ventrolateral prefrontal cortices and precuneus (zs ⩾ 1.04, ps ⩽ 0.003). During motor response inhibition specifically, ADHD relative to ASD showed right inferior fronto-striatal underactivation (zs ⩾ 1.14, ps ⩽ 0.003) but shared right anterior insula underactivation.
People with ADHD and ASD have mostly distinct structural abnormalities, with enlarged fronto-temporal GMV in ASD and reduced orbitofrontal GMV in ADHD; and mostly distinct functional abnormalities, which were more pronounced in ASD.
Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample.
To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls.
The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression.
These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.
Establishing neurobiological markers of posttraumatic stress disorder (PTSD) is essential to aid in diagnosis and treatment development. Fear processing deficits are central to PTSD, and their neural signatures may be used as such markers.
Here, we conducted a meta-analysis of seven Pavlovian fear conditioning fMRI studies comparing 156 patients with PTSD and 148 trauma-exposed healthy controls (TEHC) using seed-based d-mapping, to contrast neural correlates of experimental phases, namely conditioning, extinction learning, and extinction recall.
Patients with PTSD, as compared to TEHCs, exhibited increased activation in the anterior hippocampus (extending to the amygdala) and medial prefrontal cortex during conditioning; in the anterior hippocampus-amygdala regions during extinction learning; and in the anterior hippocampus-amygdala and medial prefrontal areas during extinction recall. Yet, patients with PTSD have shown an overall decreased activation in the thalamus during all phases in this meta-analysis.
Findings from this metanalysis suggest that PTSD is characterized by increased activation in areas related to salience and threat, and lower activation in the thalamus, a key relay hub between subcortical areas. If replicated, these fear network alterations may serve as objective diagnostic markers for PTSD, and potential targets for novel treatment development, including pharmacological and brain stimulation interventions. Future longitudinal studies are needed to examine whether these observed network alteration in PTSD are the cause or the consequence of PTSD.
A multitude of risk/protective factors for anxiety and obsessive-compulsive disorders have been proposed. We conducted an umbrella review to summarize the evidence of the associations between risk/protective factors and each of the following disorders: specific phobia, social anxiety disorder, generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder, and to assess the strength of this evidence whilst controlling for several biases.
Publication databases were searched for systematic reviews and meta-analyses examining associations between potential risk/protective factors and each of the disorders investigated. The evidence of the association between each factor and disorder was graded into convincing, highly suggestive, suggestive, weak, or non-significant according to a standardized classification based on: number of cases (>1000), random-effects p-values, 95% prediction intervals, confidence interval of the largest study, heterogeneity between studies, study effects, and excess of significance.
Nineteen systematic reviews and meta-analyses were included, corresponding to 216 individual studies covering 427 potential risk/protective factors. Only one factor association (early physical trauma as a risk factor for social anxiety disorder, OR 2.59, 95% CI 2.17–3.1) met all the criteria for convincing evidence. When excluding the requirement for more than 1000 cases, five factor associations met the other criteria for convincing evidence and 22 met the remaining criteria for highly suggestive evidence.
Although the amount and quality of the evidence for most risk/protective factors for anxiety and obsessive-compulsive disorders is limited, a number of factors significantly increase the risk for these disorders, may have potential prognostic ability and inform prevention.
Delusional disorder has been the subject of very little investigation
using brain imaging.
To examine potential structural and/or functional brain abnormalities in
We used structural imaging (voxel-based morphometry, VBM) and functional
imaging (during performance of the n-back task and
whole-brain resting connectivity analysis) to examine 22 patients meeting
DSM-IV criteria for delusional disorder and 44 matched healthy
The patients showed grey matter reductions in the medial frontal/anterior
cingulate cortex and bilateral insula on unmodulated (but not on
modulated) VBM analysis, failure of de-activation in the medial
frontal/anterior cingulate cortex during performance of the
n-back task, and decreased resting-state connectivity
in the bilateral insula.
The findings provide evidence of brain abnormality in the medial
frontal/anterior cingulate cortex and insula in delusional disorder. A
role for the former region in the pathogenesis of delusions is consistent
with several other lines of evidence.
Obsessive–compulsive disorder (OCD) has similar prevalence rates across
ethnic groups. However, ethnic minorities are underrepresented in
clinical trials of OCD. It is unclear whether this is also the case in
To explore whether ethnic minorities with OCD are underrepresented in
secondary and tertiary mental health services in the South London and
Maudsley (SLaM) NHS Foundation Trust.
The ethnic distribution of patients with OCD seen between 1999 and 2013
in SLaM (n = 1528) was compared with that of the general
population in the catchment area using census data. A cohort of patients
with depression (n = 22 716) was used for comparative
Ethnic minorities with OCD were severely underrepresented across services
(–57%, 95% CI –62% to –52%). The magnitude of the observed inequalities
was significantly more pronounced than in depression (–29%, 95% CI–31%
There is a clear need to understand the reasons behind such ethnic
inequalities and implement measures to reduce them.
Specific cortico-striato-thalamic circuits are hypothesised to mediate the symptoms of obsessive–compulsive disorder (OCD), but structural neuroimaging studies have been inconsistent.
To conduct a meta-analysis of published and unpublished voxel-based morphometry studies in OCD.
Twelve data-sets comprising 401 people with OCD and 376 healthy controls met inclusion criteria. A new improved voxel-based meta-analytic method, signed differential mapping (SDM), was developed to examine regions of increased and decreased grey matter volume in the OCD group v. control group.
No between-group differences were found in global grey matter volumes. People with OCD had increased regional grey matter volumes in bilateral lenticular nuclei, extending to the caudate nuclei, as well as decreased volumes in bilateral dorsal medial frontal/anterior cingulate gyri. A descriptive analysis of quartiles, a sensitivity analysis as well as analyses of subgroups further confirmed these findings. Meta-regression analyses showed that studies that included individuals with more severe OCD were significantly more likely to report increased grey matter volumes in the basal ganglia. No effect of current antidepressant treatment was observed.
The results support a dorsal prefrontal–striatal model of the disorder and raise the question of whether functional alterations in other brain regions commonly associated with OCD, such as the orbitofrontal cortex, may reflect secondary compensatory strategies. Whether the reported differences between participants with OCD and controls precede the onset of the symptoms and whether they are specific to OCD remains to be established.
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