Estimating multimodal brain variability in schizophrenia spectrum disorders: A worldwide ENIGMA study.

Objective: Schizophrenia is a multifaceted disorder associated with structural brain heterogeneity. Despite its relevance for identifying illness subtypes and informative biomarkers, structural brain heterogeneity in schizophrenia remains incompletely understood. Therefore, the objective of this study was to provide a comprehensive insight into the structural brain heterogeneity associated with schizophrenia. Methods: This meta- and mega-analysis investigated the variability of multimodal structural brain measures of white and gray matter in individuals with schizophrenia versus healthy controls. Using the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6139 individuals for a given brain measure, we examined variability in cortical thickness, surface area, folding index, subcortical volume and fractional anisotropy. Results: We found that individuals with schizophrenia are distinguished by higher heterogeneity in the frontotemporal network with regard to multimodal structural measures. Moreover, individuals with schizophrenia showed higher homogeneity of the folding index, especially in the left parahippocampal region. Conclusions: Higher multimodal heterogeneity in frontotemporal regions potentially implies different subtypes of schizophrenia that converge on impaired frontotemporal interaction as a core feature of the disorder. Conversely, more homogeneous folding patterns in the left parahippocampal region might signify a consistent characteristic of schizophrenia shared across subtypes. These findings underscore the importance of structural brain variability in advancing our neurobiological understanding of schizophrenia, and aid in identifying illness subtypes as well as informative biomarkers.

Neural Correlates of Positive and Negative Formal Thought Disorder in Individuals with Schizophrenia: An ENIGMA Schizophrenia Working Group Study.

Formal thought disorder (FTD) is a key clinical factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, relationship between FTD symptom dimensions and patterns of regional brain volume deficiencies in schizophrenia remain to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles based on a large multi-site cohort through the ENIGMA Schizophrenia Working Group (752 individuals with schizophrenia and 1256 controls), to unravel the neuroanatomy of positive, negative and total FTD in schizophrenia and their cellular bases. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks for positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD was also linked to microglial cell types. These findings relate different dimensions of FTD to distinct brain structural changes and their cellular underpinnings, improve our mechanistic understanding of these key psychotic symptoms.

Investigating Relationships Among Self-Efficacy, Mood, and Anxiety Using Digital Technologies: Randomized Controlled Trial.

BACKGROUND: Digital tools assessing momentary parameters and offering interventions in people's daily lives play an increasingly important role in mental health research and treatment. Ecological momentary assessment (EMA) makes it possible to assess transient mental health states and their parameters. Ecological momentary interventions (EMIs) offer mental health interventions that fit well into individuals' daily lives and routines. Self-efficacy is a transdiagnostic construct that is commonly associated with positive mental health outcomes. OBJECTIVE: The aim of our study assessing mood, specific self-efficacy, and other parameters using EMA was 2-fold. First, we wanted to determine the effects of daily assessed moods and dissatisfaction with social contacts as well as the effects of baseline variables, such as depression, on specific self-efficacy in the training group (TG). Second, we aimed to explore which variables influenced both groups' positive and negative moods during the 7-day study period. METHODS: In this randomized controlled trial, we applied digital self-efficacy training (EMI) to 93 university students with elevated self-reported stress levels and daily collected different parameters, such as mood, dissatisfaction with social contacts, and specific self-efficacy, using EMA. Participants were randomized to either the TG, where they completed the self-efficacy training combined with EMA, or the control group, where they completed EMA only. RESULTS: In total, 93 university students participated in the trial. Positive momentary mood was associated with higher specific self-efficacy in the evening of the same day (b=0.15, SE 0.05, P=.005). Higher self-efficacy at baseline was associated with reduced negative mood during study participation (b=-0.61, SE 0.30, P=.04), while we could not determine an effect on positive mood. Baseline depression severity was significantly associated with lower specific self-efficacy over the week of the training (b=-0.92, SE 0.35, P=.004). Associations between higher baseline anxiety with higher mean negative mood (state anxiety: b=0.78, SE 0.38, P=.04; trait anxiety: b=0.73, SE 0.33, P=.03) and lower mean positive mood (b=-0.64, SE 0.28, P=.02) during study participation were found. Emotional flexibility was significantly enhanced in the TG. Additionally, dissatisfaction with social contacts was associated with both a decreased positive mood (b=-0.56, SE 0.15, P<.001) and an increased negative mood (b=0.45, SE 0.12, P<.001). CONCLUSIONS: This study showed several significant associations between mood and self-efficacy as well as those between mood and anxiety in students with elevated stress levels, for example, suggesting that improving mood in people with low mood could enhance the effects of digital self-efficacy training. In addition, engaging in 1-week self-efficacy training was associated with increased emotional flexibility. Future work is needed to replicate and investigate the training's effects in other groups and settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05617248; https://clinicaltrials.gov/study/NCT05617248.

Neural Correlates of Positive and Negative Formal Thought Disorder in Individuals with Schizophrenia: An ENIGMA Schizophrenia Working Group Study.

Formal thought disorder (FTD) is a key clinical factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, relationship between FTD symptom dimensions and patterns of regional brain volume deficiencies in schizophrenia remain to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles based on a large multi-site cohort through the ENIGMA Schizophrenia Working Group (752 individuals with schizophrenia and 1256 controls), to unravel the neuroanatomy of positive, negative and total FTD in schizophrenia and their cellular bases. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks for positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD was also linked to microglial cell types. These findings relate different dimensions of FTD to distinct brain structural changes and their cellular underpinnings, improve our mechanistic understanding of these key psychotic symptoms.

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium.

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Linguistic features of suicidal thoughts and behaviors: A systematic review.

Language is a potential source of predictors for suicidal thoughts and behaviors (STBs), as changes in speech characteristics, communication habits, and word choice may be indicative of increased suicide risk. We reviewed the current literature on STBs that investigated linguistic features of spoken and written language. Specifically, we performed a search in linguistic, medical, engineering, and general databases for studies that investigated linguistic features as potential predictors of STBs published in peer-reviewed journals until the end of November 2021.We included 75 studies that investigated 279,032 individuals with STBs (age = 29.53 ± 10.29, 35% females). Of those, 34 (45%) focused on lexicon, 20 (27%) on prosody, 15 (20%) on lexicon and first-person singular, four (5%) on (morpho)syntax, and two (3%) were unspecified. Suicidal thoughts were predicted by more intensifiers and superlatives, while suicidal behaviors were predicted by greater usage of pronouns, changes in the amount of verb usage, more prepend and multifunctional words, more nouns and prepositions, and fewer modifiers and numerals. A diverse field of research currently investigates linguistic predictors of STBs, and more focus is needed on their specificity for either suicidal thoughts or behaviors.

Examining Side Effect Variability of Antipsychotic Treatment in Schizophrenia Spectrum Disorders: A Meta-analysis of Variance.

Side effects of antipsychotic drugs play a key role in nonadherence of treatment in schizophrenia spectrum disorders (SSD). While clinical observations suggest that side effect variability between patients may be considerable, statistical evidence is required to confirm this. Here, we hypothesized to find larger side effect variability under treatment compared with control. We included double-blind, placebo-controlled, randomized controlled trials (RCTs) of adults with a diagnosis of SSD treated with 1 out of 14 antipsychotics. Standard deviations of the pre-post treatment differences of weight gain, prolactin levels, and corrected QT (QTc) times were extracted. The outcome measure was the variability ratio of treatment to control for individual antipsychotic drugs and the overall variability ratio of treatment to control across RCTs. Individual variability ratios were weighted by the inverse-variance method and entered into a random-effects model. We included N = 16 578 patients for weight gain, N = 16 633 patients for prolactin levels, and N = 10 384 patients for QTc time. Variability ratios (VR) were significantly increased for weight gain (VR = 1.08; 95% CI: 1.02-1.14; P = .004) and prolactin levels (VR = 1.38; 95% CI: 1.17-1.62; P < .001) but did not reach significance for QTc time (VR = 1.05; 95% CI: 0.98-1.12; P = 0.135). We found marked differences between individual antipsychotics and increased variability in side effects in patients under treatment with antipsychotics suggesting that subgroups of patients or individual patients may benefit from treatment allocation through stratified or personalized medicine.

SIMON: A Digital Protocol to Monitor and Predict Suicidal Ideation.

Each year, more than 800,000 persons die by suicide, making it a leading cause of death worldwide. Recent innovations in information and communication technology may offer new opportunities in suicide prevention in individuals, hereby potentially reducing this number. In our project, we design digital indices based on both self-reports and passive mobile sensing and test their ability to predict suicidal ideation, a major predictor for suicide, and psychiatric hospital readmission in high-risk individuals: psychiatric patients after discharge who were admitted in the context of suicidal ideation or a suicidal attempt, or expressed suicidal ideations during their intake. Specifically, two smartphone applications -one for self-reports (SIMON-SELF) and one for passive mobile sensing (SIMON-SENSE)- are installed on participants' smartphones. SIMON-SELF uses a text-based chatbot, called Simon, to guide participants along the study protocol and to ask participants questions about suicidal ideation and relevant other psychological variables five times a day. These self-report data are collected for four consecutive weeks after study participants are discharged from the hospital. SIMON-SENSE collects behavioral variables -such as physical activity, location, and social connectedness- parallel to the first application. We aim to include 100 patients over 12 months to test whether (1) implementation of the digital protocol in such a high-risk population is feasible, and (2) if suicidal ideation and psychiatric hospital readmission can be predicted using a combination of psychological indices and passive sensor information. To this end, a predictive algorithm for suicidal ideation and psychiatric hospital readmission using various learning algorithms (e.g., random forest and support vector machines) and multilevel models will be constructed. Data collected on the basis of psychological theory and digital phenotyping may, in the future and based on our results, help reach vulnerable individuals early and provide links to just-in-time and cost-effective interventions or establish prompt mental health service contact. The current effort may thus lead to saving lives and significantly reduce economic impact by decreasing inpatient treatment and days lost to inability.

Validation of Visual and Auditory Digital Markers of Suicidality in Acutely Suicidal Psychiatric Inpatients: Proof-of-Concept Study.

BACKGROUND: Multiple symptoms of suicide risk have been assessed based on visual and auditory information, including flattened affect, reduced movement, and slowed speech. Objective quantification of such symptomatology from novel data sources can increase the sensitivity, scalability, and timeliness of suicide risk assessment. OBJECTIVE: We aimed to examine measurements extracted from video interviews using open-source deep learning algorithms to quantify facial, vocal, and movement behaviors in relation to suicide risk severity in recently admitted patients following a suicide attempt. METHODS: We utilized video to quantify facial, vocal, and movement markers associated with mood, emotion, and motor functioning from a structured clinical conversation in 20 patients admitted to a psychiatric hospital following a suicide risk attempt. Measures were calculated using open-source deep learning algorithms for processing facial expressivity, head movement, and vocal characteristics. Derived digital measures of flattened affect, reduced movement, and slowed speech were compared to suicide risk with the Beck Scale for Suicide Ideation controlling for age and sex, using multiple linear regression. RESULTS: Suicide severity was associated with multiple visual and auditory markers, including speech prevalence (ß=-0.68, P=.02, r2=0.40), overall expressivity (ß=-0.46, P=.10, r2=0.27), and head movement measured as head pitch variability (ß=-1.24, P=.006, r2=0.48) and head yaw variability (ß=-0.54, P=.06, r2=0.32). CONCLUSIONS: Digital measurements of facial affect, movement, and speech prevalence demonstrated strong effect sizes and linear associations with the severity of suicidal ideation.

Bi-Temporal Anodal Transcranial Direct Current Stimulation during Slow-Wave Sleep Boosts Slow-Wave Density but Not Memory Consolidation.

Slow-wave sleep (SWS) has been shown to promote long-term consolidation of episodic memories in hippocampo-neocortical networks. Previous research has aimed to modulate cortical sleep slow-waves and spindles to facilitate episodic memory consolidation. Here, we instead aimed to modulate hippocampal activity during slow-wave sleep using transcranial direct current stimulation in 18 healthy humans. A pair-associate episodic memory task was used to evaluate sleep-dependent memory consolidation with face-occupation stimuli. Pre- and post-nap retrieval was assessed as a measure of memory performance. Anodal stimulation with 2 mA was applied bilaterally over the lateral temporal cortex, motivated by its particularly extensive connections to the hippocampus. The participants slept in a magnetic resonance (MR)-simulator during the recordings to test the feasibility for a future MR-study. We used a sham-controlled, double-blind, counterbalanced randomized, within-subject crossover design. We show that stimulation vs. sham significantly increased slow-wave density and the temporal coupling of fast spindles and slow-waves. While retention of episodic memories across sleep was not affected across the entire sample of participants, it was impaired in participants with below-average pre-sleep memory performance. Hence, bi-temporal anodal direct current stimulation applied during sleep enhanced sleep parameters that are typically involved in memory consolidation, but it failed to improve memory consolidation and even tended to impair consolidation in poor learners. These findings suggest that artificially enhancing memory-related sleep parameters to improve memory consolidation can actually backfire in those participants who are in most need of memory improvement.

Functional connectivity and upper limb function in patients after pediatric arterial ischemic stroke with contralateral corticospinal tract wiring.

To develop individualized motor rehabilitation, knowledge of the relationship between neuroplastic reorganization and motor recovery after pediatric arterial ischemic stroke (AIS) is crucial. Thus, we investigated functional connectivity in patients after AIS with good motor outcome and in patients with hemiparesis compared with typically developing peers. We included 18 patients (n = 9 with hemiparesis, n = 9 with good motor outcome) with pediatric AIS in the chronic phase (≥ 2 years after diagnosis, diagnosed > 16 years) and 18 peers matched by age and gender. Participants underwent a standardized motor assessment, single-pulse transcranial magnetic stimulation to determine the type of corticospinal tract wiring, and resting-state functional magnetic resonance imaging to examine motor network connectivity. Corticospinal tract wiring was contralateral in all participants. Patients with hemiparesis had lower interhemispheric connectivity strength compared with patients with good clinical outcome and peers. Patients with good clinical outcome had higher intrahemispheric connectivity strength compared with peers. Further, higher intrahemispheric connectivity was related to better motor outcome in patients. Our findings suggest that better motor outcome after pediatric AIS is related to higher motor network connectivity strength. Thus, resting-state functional connectivity might be predictive for motor recovery after pediatric AIS.

Treatment effect variability in brain stimulation across psychiatric disorders: A meta-analysis of variance.

Noninvasive brain stimulation methods such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are promising add-on treatments for a number of psychiatric conditions. Yet, some of the initial excitement is wearing off. Randomized controlled trials (RCT) have found inconsistent results. This inconsistency is suspected to be the consequence of variation in treatment effects and solvable by identifying responders in RCTs and individualizing treatment. However, is there enough evidence from RCTs that patients respond differently to treatment? This question can be addressed by comparing the variability in the active stimulation group with the variability in the sham group. We searched MEDLINE/PubMed and included all double-blinded, sham-controlled RCTs and crossover trials that used TMS or tDCS in adults with a unipolar or bipolar depression, bipolar disorder, schizophrenia spectrum disorder, or obsessive compulsive disorder. In accordance with the PRISMA guidelines to ensure data quality and validity, we extracted a measure of variability of the primary outcome. A total of 130 studies with 5748 patients were considered in the analysis. We calculated variance-weighted variability ratios for each comparison of active stimulation vs sham and entered them into a random-effects model. We hypothesized that treatment effect variability in TMS or tDCS would be reflected by increased variability after active compared with sham stimulation, or in other words, a variability ratio greater than one. Across diagnoses, we found only a minimal increase in variability after active stimulation compared with sham that did not reach statistical significance (variability ratio = 1.03; 95% CI, 0.97, 1.08, P = 0.358). In conclusion, this study found little evidence for treatment effect variability in brain stimulation, suggesting that the need for personalized or stratified medicine is still an open question.

Ultrafast Exciton Dissociation and Long-Lived Charge Separation in a Photovoltaic Pentacene-MoS2 van der Waals Heterojunction.

van der Waals heterojunctions between two-dimensional (2D) layered materials and nanomaterials of different dimensions present unique opportunities for gate-tunable optoelectronic devices. Mixed-dimensional p-n heterojunction diodes, such as p-type pentacene (0D) and n-type monolayer MoS2 (2D), are especially interesting for photovoltaic applications where the absorption cross-section and charge transfer processes can be tailored by rational selection from the vast library of organic molecules and 2D materials. Here, we study the kinetics of excited carriers in pentacene-MoS2 p-n type-II heterojunctions by transient absorption spectroscopy. These measurements show that the dissociation of MoS2 excitons occurs by hole transfer to pentacene on the time scale of 6.7 ps. In addition, the charge-separated state lives for 5.1 ns, up to an order of magnitude longer than the recombination lifetimes from previously reported 2D material heterojunctions. By studying the fractional amplitudes of the MoS2 decay processes, the hole transfer yield from MoS2 to pentacene is found to be ∼50%, with the remaining holes undergoing trapping due to surface defects. Overall, the ultrafast charge transfer and long-lived charge-separated state in pentacene-MoS2 p-n heterojunctions suggest significant promise for mixed-dimensional van der Waals heterostructures in photovoltaics, photodetectors, and related optoelectronic technologies.

Electronic Processes within Quantum Dot-Molecule Complexes.

The subject of this review is the colloidal quantum dot (QD) and specifically the interaction of the QD with proximate molecules. It covers various functions of these molecules, including (i) ligands for the QDs, coupled electronically or vibrationally to localized surface states or to the delocalized states of the QD core, (ii) energy or electron donors or acceptors for the QDs, and (iii) structural components of QD assemblies that dictate QD-QD or QD-molecule interactions. Research on interactions of ligands with colloidal QDs has revealed that ligands determine not only the excited state dynamics of the QD but also, in some cases, its ground state electronic structure. Specifically, the article discusses (i) measurement of the electronic structure of colloidal QDs and the influence of their surface chemistry, in particular, dipolar ligands and exciton-delocalizing ligands, on their electronic energies; (ii) the role of molecules in interfacial electron and energy transfer processes involving QDs, including electron-to-vibrational energy transfer and the use of the ligand shell of a QD as a semipermeable membrane that gates its redox activity; and (iii) a particular application of colloidal QDs, photoredox catalysis, which exploits the combination of the electronic structure of the QD core and the chemistry at its surface to use the energy of the QD excited state to drive chemical reactions.

Photocatalytic Conversion of Nitrobenzene to Aniline through Sequential Proton-Coupled One-Electron Transfers from a Cadmium Sulfide Quantum Dot.

This paper describes the use of cadmium sulfide quantum dots (CdS QDs) as visible-light photocatalysts for the reduction of nitrobenzene to aniline through six sequential photoinduced, proton-coupled electron transfers. At pH 3.6-4.3, the internal quantum yield of photons-to-reducing electrons is 37.1% over 54 h of illumination, with no apparent decrease in catalyst activity. Monitoring of the QD exciton by transient absorption reveals that, for each step in the catalytic cycle, the sacrificial reductant, 3-mercaptopropionic acid, scavenges the excitonic hole in ∼5 ps to form QD(•-); electron transfer to nitrobenzene or the intermediates nitrosobenzene and phenylhydroxylamine then occurs on the nanosecond time scale. The rate constants for the single-electron transfer reactions are correlated with the driving forces for the corresponding proton-coupled electron transfers. This result suggests, but does not prove, that electron transfer, not proton transfer, is rate-limiting for these reactions. Nuclear magnetic resonance analysis of the QD-molecule systems shows that the photoproduct aniline, left unprotonated, serves as a poison for the QD catalyst by adsorbing to its surface. Performing the reaction at an acidic pH not only encourages aniline to desorb but also increases the probability of protonated intermediates; the latter effect probably ensures that recruitment of protons is not rate-limiting.