Placebo effects in randomized trials of pharmacological and neurostimulation interventions for mental disorders: An umbrella review.

There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder (g = 0.90, 95% CI [0.70, 1.09]), depression (g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome (g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder (d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder (d = 0.32, 95% CI [0.22, 0.41]), primary insomnia (g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged 'low' quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.

An umbrella review of candidate predictors of response, remission, recovery, and relapse across mental disorders.

We aimed to identify diagnosis-specific/transdiagnostic/transoutcome multivariable candidate predictors (MCPs) of key outcomes in mental disorders. We conducted an umbrella review (protocol  link ), searching MEDLINE/Embase (19/07/2022), including systematic reviews of studies reporting on MCPs of response, remission, recovery, or relapse, in DSM/ICD-defined mental disorders. From published predictors, we filtered MCPs, validating MCP criteria. AMSTAR2/PROBAST measured quality/risk of bias of systematic reviews/individual studies. We included 117 systematic reviews, 403 studies, 299,888 individuals with mental disorders, testing 796 prediction models. Only 4.3%/1.2% of the systematic reviews/individual studies were at low risk of bias. The most frequently targeted outcome was remission (36.9%), the least frequent was recovery (2.5%). Studies mainly focused on depressive (39.4%), substance-use (17.9%), and schizophrenia-spectrum (11.9%) disorders. We identified numerous MCPs within disorders for response, remission and relapse, but none for recovery. Transdiagnostic MCPs of remission included lower disease-specific symptoms (disorders = 5), female sex/higher education (disorders = 3), and quality of life/functioning (disorders = 2). Transdiagnostic MCPs of relapse included higher disease-specific symptoms (disorders = 5), higher depressive symptoms (disorders = 3), and younger age/higher anxiety symptoms/global illness severity/ number of previous episodes/negative life events (disorders = 2). Finally, positive trans-outcome MCPs for depression included less negative life events/depressive symptoms (response, remission, less relapse), female sex (response, remission) and better functioning (response, less relapse); for schizophrenia, less positive symptoms/higher depressive symptoms (remission, less relapse); for substance use disorder, marital status/higher education (remission, less relapse). Male sex, younger age, more clinical symptoms and comorbid mental/physical symptoms/disorders were poor prognostic factors, while positive factors included social contacts and employment, absent negative life events, higher education, early access/intervention, lower disease-specific and comorbid mental and physical symptoms/conditions, across mental disorders. Current data limitations include high risk of bias of studies and extraction of single predictors from multivariable models. Identified MCPs can inform future development, validation or refinement of prediction models of key outcomes in mental disorders.

Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review.

Neurodevelopmental disorders - including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders - manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis of these disorders would be highly relevant from a clinical and public health standpoint. We conducted the first systematic review of studies on candidate diagnostic biomarkers for these disorders in children and adolescents. We searched Medline and Embase + Embase Classic with terms relating to biomarkers until April 6, 2022, and conducted additional targeted searches for genome-wide association studies (GWAS) and neuroimaging or neurophysiological studies carried out by international consortia. We considered a candidate biomarker as promising if it was reported in at least two independent studies providing evidence of sensitivity and specificity of at least 80%. After screening 10,625 references, we retained 780 studies (374 biochemical, 203 neuroimaging, 133 neurophysiological and 65 neuropsychological studies, and five GWAS), including a total of approximately 120,000 cases and 176,000 controls. While the majority of the studies focused simply on associations, we could not find any biomarker for which there was evidence - from two or more studies from independent research groups, with results going into the same direction - of specificity and sensitivity of at least 80%. Other important metrics to assess the validity of a candidate biomarker, such as positive predictive value and negative predictive value, were infrequently reported. Limitations of the currently available studies include mostly small sample size, heterogeneous approaches and candidate biomarker targets, undue focus on single instead of joint biomarker signatures, and incomplete accounting for potential confounding factors. Future multivariable and multi-level approaches may be best suited to find valid candidate biomarkers, which will then need to be validated in external, independent samples and then, importantly, tested in terms of feasibility and cost-effectiveness, before they can be implemented in daily clinical practice.

Egocentric distance perception in older adults: Results from a functional magnetic resonance imaging and driving simulator study.

The ability to appropriately perceive distances in activities of daily living, such as driving, is necessary when performing complex maneuvers. With aging, certain driving behaviors and cognitive functions change; however, it remains unknown if egocentric distance perception (EDP) performance is altered and whether its neural activity also changes as we grow older. To that end, 19 young and 17 older healthy adults drove in a driving simulator and performed an functional magnetic resonance imaging (fMRI) experiment where we presented adults with an EDP task. We discovered that (a) EDP task performance was similar between groups, with higher response times in older adults; (b) older adults showed higher prefrontal and parietal activation; and (c) higher functional connectivity within frontal and parietal-occipital-cerebellar networks; and (d) an association between EDP performance and hard braking behaviors in the driving simulator was found. In conclusion, EDP functioning remains largely intact with aging, possibly due to an extended and effective rearrangement in functional brain resources, and may play a role in braking behaviors while driving.

Associations between mental and physical conditions in children and adolescents: An umbrella review.

We mapped the evidence on the type and strength of associations between a broad range of mental and physical conditions in children and adolescents, by carrying out an umbrella review, i.e., a quantitative synthesis of previous systematic reviews and meta-analyses. We also assessed to which extent the links between mental and physical conditions vary across disorders or, by contrast, are transdiagnostic. Based on a pre-established protocol, we retained 45 systematic reviews/meta-analyses, encompassing around 12.5 million of participants. In analyses limited to the most rigorous estimates, we found evidence for the following associations: ADHD-asthma, ADHD-obesity, and depression-asthma. A transdiagnostic association was confirmed between asthma and anxiety/ASD/depression/bipolar disorder, between obesity and ADHD/ASD/depression, and between dermatitis and ASD/ADHD. We conclude that obesity and allergic conditions are likely to be associated with mental disorders in children and adolescents. Our results can help clinicians explore potential links between mental and physical conditions in children/adolescent and provide a road map for future studies aimed at shading light on the underlying factors.

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 12 May 2020. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.c.4878591.v1.

Brain Activity and Functional Connectivity Patterns Associated With Fast and Slow Motor Sequence Learning in Late Middle Adulthood.

The human brain undergoes structural and functional changes across the lifespan. The study of motor sequence learning in elderly subjects is of particularly interest since previous findings in young adults might not replicate during later stages of adulthood. The present functional magnetic resonance imaging (fMRI) study assessed the performance, brain activity and functional connectivity patterns associated with motor sequence learning in late middle adulthood. For this purpose, a total of 25 subjects were evaluated during early stages of learning [i.e., fast learning (FL)]. A subset of these subjects (n = 11) was evaluated after extensive practice of a motor sequence [i.e., slow learning (SL) phase]. As expected, late middle adults improved motor performance from FL to SL. Learning-related brain activity patterns replicated most of the findings reported previously in young subjects except for the lack of hippocampal activity during FL and the involvement of cerebellum during SL. Regarding functional connectivity, precuneus and sensorimotor lobule VI of the cerebellum showed a central role during improvement of novel motor performance. In the sample of subjects evaluated, connectivity between the posterior putamen and parietal and frontal regions was significantly decreased with aging during SL. This age-related connectivity pattern may reflect losses in network efficiency when approaching late adulthood. Altogether, these results may have important applications, for instance, in motor rehabilitation programs.

Default-mode network dynamics are restricted during high speed discrimination in healthy aging: Associations with neurocognitive status and simulated driving behavior.

Numerous daily tasks, including car driving, require fine visuospatial tuning. One such visuospatial ability, speed discrimination, declines with aging but its neural underpinnings remain unknown. In this study, we use fMRI to explore the effect of aging during a high speed discrimination task and its neural underpinnings, along with a complete neuropsychological assessment and a simulated driving evaluation in order to examine how they interact with each other through a multivariate regression approach. Beyond confirming that high speed discrimination performance is diminished in the elderly, we found that this deficit might be partly due to a lack of modulation in the activity and connectivity of the default mode network (DMN) in this age group, as well as an over-recruitment of frontoparietal and cerebellar regions, possibly as a compensatory mechanism. In addition, younger adults tended to drive at faster speeds, a behavior that was associated to adequate DMN dynamics and executive functioning, an effect that seems to be lost in the elderly. In summary, these results reveal how age-related declines in fine visuospatial abilities, such as high speed discrimination, were distinctly mediated by DMN functioning, a mechanism also associated to speeding behavior in a driving simulator.

Motor sequence learning in the elderly: differential activity patterns as a function of hand modality.

Previous research on motor sequence learning (MSL) in the elderly has focused mainly on unilateral tasks, even though bilateral coordination might be impaired in this age group. In this fMRI study, 28 right-handed elderly subjects were recruited. The paradigm consisted of a Novel and a simple Control sequence executed with the right (R), left (L) and both hands (B). Behavioral performance (Accuracy[AC], Inter-tap Interval[ITI]) and associated brain activity were assessed during early learning. Behavioral performance in the Novel task was similar between unilateral conditions whereas in the bimanual condition more errors and slower motor execution were observed. Brain activity increases during learning showed differences between Conditions: R showed increased activity in pre-SMA, basal ganglia and left hippocampus while B showed activity increments mainly in posterior parietal cortex and cerebellum. L did not show any activity modulation during learning. Performance correlates for AC (related to spatial success) and ITI (related to accurate timing) shared a cortico-basal-cerebellar network. However, it was found that the ITI regressor presented additional significant correlations with activity in SMA and basal ganglia in R. The AC regressor showed additional significant correlations with activity in more extended thalamic and cerebellar areas in B. The present findings suggest that, behaviorally, the spatial and temporal components of MSL are impaired in elderly subjects when using both hands. Additionally, differential brain activity patterns were found across hand modalities. The results obtained reveal the existence of a highly specialized network in the dominant hand and identify areas specifically involved in bimanual coordination.

Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1), among other genes. Rare SQSTM1 gene mutations have been associated with Paget's disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD). OBJECTIVE: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction. METHODS: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD; n = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n = 20). The groups were matched according to current age, disease duration, and gender. RESULTS: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres. CONCLUSIONS: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern.