Genetic influences on externalizing psychopathology overlap with cognitive functioning and show developmental variation

BackgroundQuestions remain regarding whether genetic influences on early life psychopathology overlap with cognition and show developmental variation.MethodsUsing data from 9,421 individuals aged 8–21 from the Philadelphia Neurodevelopmental Cohort, factors of psychopathology were generated using a bifactor model of item-level data from a psychiatric interview. Five orthogonal factors were generated: anxious-misery (mood and anxiety), externalizing (attention deficit hyperactivity and conduct disorder), fear (phobias), psychosis-spectrum, and a general factor. Genetic analyses were conducted on a subsample of 4,662 individuals of European American ancestry. A genetic relatedness matrix was used to estimate heritability of these factors, and genetic correlations with executive function, episodic memory, complex reasoning, social cognition, motor speed, and general cognitive ability. Gene × Age analyses determined whether genetic influences on these factors show developmental variation.ResultsExternalizing was heritable (h² = 0.46, p = 1 × 10⁻⁶), but not anxious-misery (h² = 0.09, p = 0.183), fear (h² = 0.04, p = 0.337), psychosis-spectrum (h² = 0.00, p = 0.494), or general psychopathology (h² = 0.21, p = 0.040). Externalizing showed genetic overlap with face memory (ρ_g = −0.412, p = 0.004), verbal reasoning (ρ_g = −0.485, p = 0.001), spatial reasoning (ρ_g = −0.426, p = 0.010), motor speed (ρ_g = 0.659, p = 1x10⁻⁴), verbal knowledge (ρ_g = −0.314, p = 0.002), and general cognitive ability (g)(ρ_g = −0.394, p = 0.002). Gene × Age analyses revealed decreasing genetic variance (γ_g = −0.146, p = 0.004) and increasing environmental variance (γ_e = 0.059, p = 0.009) on externalizing.ConclusionsCognitive impairment may be a useful endophenotype of externalizing psychopathology and, therefore, help elucidate its pathophysiological underpinnings. Decreasing genetic variance suggests that gene discovery efforts may be more fruitful in children than adolescents or young adults.     

Intelligence,educational attainment,and brain structure in those at familial high‐risk for schizophrenia or bipolar disorder

First‐degree relatives of patients diagnosed with schizophrenia (SZ‐FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First‐degree relatives of patients diagnosed with bipolar disorder (BD‐FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD‐FDRs are inconsistent. Here, we performed a meta‐analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ‐FDRs, 867 BD‐FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ‐FDRs showed a pattern of widespread thinner cortex, while BD‐FDRs had widespread larger cortical surface area. IQ was lower in SZ‐FDRs (d = −0.42, p = 3 × 10⁻⁵), with weak evidence of IQ reductions among BD‐FDRs (d = −0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group‐effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ‐FDRs and more pronounced effects in BD‐FDRs. To conclude, SZ‐FDRs and BD‐FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ‐FDRs and BD‐FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.     

Genome-wide association studies in non-anxiety individuals identified novel risk loci for depression

BackgroundDepression is a debilitating mental disorder that often coexists with anxiety. The genetic mechanisms of depression and anxiety have considerable overlap, and studying depression in non-anxiety samples could help to discover novel gene. We assess the genetic variation of depression in non-anxiety samples, using genome-wide association studies (GWAS) and linkage disequilibrium score regression (LDSC).MethodsThe GWAS of depression score and self-reported depression were conducted using the UK Biobank samples, comprising 99,178 non-anxiety participants with anxiety score <5 and 86,503 non-anxiety participants without self-reported anxiety, respectively. Replication analysis was then performed using two large-scale GWAS summary data of depression from Psychiatric Genomics Consortium (PGC). LDSC was finally used to evaluate genetic correlations with 855 health-related traits based on the primary GWAS.ResultsTwo genome-wide significant loci for non-anxiety depression were identified: rs139702470 (p = 1.54 × 10⁻⁸, OR = 0.29) locate in PIEZO2, and rs6046722 (p = 2.52 × 10⁻⁸, OR = 1.09) locate in CFAP61. These associated genes were replicated in two GWAS of depression from PGC, such as rs1040582 (p_{replication GWAS1} = 0.02, p_{replication GWAS2} = 2.71 × 10⁻³) in CFAP61, and rs11661122 (p_{replication GWAS1} = 8.16 × 10⁻³, p_{replication GWAS2} = 8.08 × 10⁻³) in PIEZO2. LDSC identified 19 traits genetically associated with non-anxiety depression (p < 0.001), such as marital separation/divorce (rg = 0.45, SE = 0.15).ConclusionsOur findings provide novel clues for understanding of the complex genetic architecture of depression.     

Comparing personalized brain-based and genetic risk scores for major depressive disorder in large population samples of adults and adolescents

BackgroundMajor depressive disorder (MDD) is a polygenic disorder associated with brain alterations but until recently, there have been no brain-based metrics to quantify individual-level variation in brain morphology. Here, we evaluated and compared the performance of a new brain-based ‘Regional Vulnerability Index’ (RVI) with polygenic risk scores (PRS), in the context of MDD. We assessed associations with syndromal MDD in an adult sample (N = 702, age = 59 ± 10) and with subclinical depressive symptoms in a longitudinal adolescent sample (baseline N = 3,825, age = 10 ± 1; 2-year follow-up N = 2,081, age = 12 ± 1).MethodsMDD-RVIs quantify the correlation of the individual’s corresponding brain metric with the expected pattern for MDD derived in an independent sample. Using the same methodology across samples, subject-specific MDD-PRS and six MDD-RVIs based on different brain modalities (subcortical volume, cortical thickness, cortical surface area, mean diffusivity, fractional anisotropy, and multimodal) were computed.ResultsIn adults, MDD-RVIs (based on white matter and multimodal measures) were more strongly associated with MDD (β = 0.099–0.281, P_FDR = 0.001–0.043) than MDD-PRS (β = 0.056–0.152, P_FDR = 0.140–0.140). In adolescents, depressive symptoms were associated with MDD-PRS at baseline and follow-up (β = 0.084–0.086, p = 1.38 × 10⁻⁴−4.77 × 10⁻⁴) but not with any MDD-RVIs (β < 0.05, p > 0.05).ConclusionsOur results potentially indicate the ability of brain-based risk scores to capture a broader range of risk exposures than genetic risk scores in adults and are also useful in helping us to understand the temporal origins of depression-related brain features. Longitudinal data, specific to the developmental period and on white matter measures, will be useful in informing risk for subsequent psychiatric illness.     

Changes in striatal dopamine transporters in bipolar disorder and valproate treatment

BackgroundPrevious studies suggested that a disturbance of the dopamine system underlies the pathophysiology of bipolar disorder (BD). In addition, the therapeutic action of medications for treating BD, such as valproate (VPA), might modulate dopamine system activity, but it remains unclear. Here, we aimed to investigate the role of the striatal dopamine transporter (DAT) in BD patients and in social defeat (SD) mice treated with VPA.MethodsWe enrolled community-dwelling controls (N = 18) and BD patients (N = 23) who were treated with VPA in a euthymic stage. The striatal DAT availabilities were approached by TRODAT-1 single photon emission computed tomography. We also established a chronic SD mouse model and treated mice with 350 mg/kg VPA for 3 weeks. Behavioral tests were administered, and striatal DAT expression levels were determined.ResultsIn humans, the level of striatal DAT availability was significantly higher in euthymic BD patients (1.52 ± 0.17 and 1.37 ± 0.23, p = 0.015). Moreover, the level of striatal DAT availability was also negatively correlated with the VPA concentration in BD patients (r = −0.653, p = 0.003). In SD mice, the expression of striatal DAT significantly increased (p < 0.001), and the SD effect on DAT expression was rescued by VPA treatment.ConclusionsThe striatal DAT might play a role in the pathophysiology of BD and in the therapeutic mechanism of VPA. The homeostasis of DAT might represent a new therapeutic strategy for BD patients.     

In vivo hippocampal subfield volumes in bipolar disorder—A mega‐analysis from The Enhancing Neuro Imaging Genetics through Meta‐Analysis Bipolar Disorder Working Group

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta‐Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1‐weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed‐effects models and mega‐analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen''s d = −0.20), cornu ammonis (CA)1 (d = −0.18), CA2/3 (d = −0.11), CA4 (d = −0.19), molecular layer (d = −0.21), granule cell layer of dentate gyrus (d = −0.21), hippocampal tail (d = −0.10), subiculum (d = −0.15), presubiculum (d = −0.18), and hippocampal amygdala transition area (d = −0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non‐users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.     

Examining the association between exposome score for schizophrenia and functioning in schizophrenia,siblings, and healthy controls: Results from the EUGEI study

BackgroundA cumulative environmental exposure score for schizophrenia (exposome score for schizophrenia [ES-SCZ]) may provide potential utility for risk stratification and outcome prediction. Here, we investigated whether ES-SCZ was associated with functioning in patients with schizophrenia spectrum disorder, unaffected siblings, and healthy controls.MethodsThis cross-sectional sample consisted of 1,261 patients, 1,282 unaffected siblings, and 1,525 healthy controls. The Global Assessment of Functioning (GAF) scale was used to assess functioning. ES-SCZ was calculated based on our previously validated method. The association between ES-SCZ and the GAF dimensions (symptom and disability) was analyzed by applying regression models in each group (patients, siblings, and controls). Additional models included polygenic risk score for schizophrenia (PRS-SCZ) as a covariate.ResultsES-SCZ was associated with the GAF dimensions in patients (symptom: B = −1.53, p-value = 0.001; disability: B = −1.44, p-value = 0.001), siblings (symptom: B = −3.07, p-value < 0.001; disability: B = −2.52, p-value < 0.001), and healthy controls (symptom: B = −1.50, p-value < 0.001; disability: B = −1.31, p-value < 0.001). The results remained the same after adjusting for PRS-SCZ. The degree of associations of ES-SCZ with both symptom and disability dimensions were higher in unaffected siblings than in patients and controls. By analyzing an independent dataset (the Genetic Risk and Outcome of Psychosis study), we replicated the results observed in the patient group.ConclusionsOur findings suggest that ES-SCZ shows promise for enhancing risk prediction and stratification in research practice. From a clinical perspective, ES-SCZ may aid in efforts of clinical characterization, operationalizing transdiagnostic clinical staging models, and personalizing clinical management.     

The additive impact of cardio‐metabolic disorders and psychiatric illnesses on accelerated brain aging

Severe mental illnesses (SMI) including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorder (SSD) elevate accelerated brain aging risks. Cardio‐metabolic disorders (CMD) are common comorbidities in SMI and negatively impact brain health. We validated a linear quantile regression index (QRI) approach against the machine learning “BrainAge” index in an independent SSD cohort (N = 206). We tested the direct and additive effects of SMI and CMD effects on accelerated brain aging in the N = 1,618 (604 M/1,014 F, average age = 63.53 ± 7.38) subjects with SMI and N = 11,849 (5,719 M/6,130 F; 64.42 ± 7.38) controls from the UK Biobank. Subjects were subdivided based on diagnostic status: SMI+/CMD+ (N = 665), SMI+/CMD− (N = 964), SMI−/CMD+ (N = 3,765), SMI−/CMD− (N = 8,083). SMI (F = 40.47, p = 2.06 × 10⁻¹⁰) and CMD (F = 24.69, p = 6.82 × 10⁻⁷) significantly, independently impacted whole‐brain QRI in SMI+. SSD had the largest effect (Cohen’s d = 1.42) then BD (d = 0.55), and MDD (d = 0.15). Hypertension had a significant effect on SMI+ (d = 0.19) and SMI− (d = 0.14). SMI effects were direct, independent of MD, and remained significant after correcting for effects of antipsychotic medications. Whole‐brain QRI was significantly (p < 10⁻¹⁶) associated with the volume of white matter hyperintensities (WMH). However, WMH did not show significant association with SMI and was driven by CMD, chiefly hypertension (p < 10⁻¹⁶). We used a simple and robust index, QRI, the demonstrate additive effect of SMI and CMD on accelerated brain aging. We showed a greater effect of psychiatric illnesses on QRI compared to cardio‐metabolic illness. Our findings suggest that subjects with SMI should be among the targets for interventions to protect against age‐related cognitive decline.     

The association between C-reactive protein,mood disorder,and cognitive function in UK Biobank

BackgroundSystemic inflammation has been linked with mood disorder and cognitive impairment. The extent of this relationship remains uncertain, with the effects of serum inflammatory biomarkers compared to genetic predisposition toward inflammation yet to be clearly established.MethodsWe investigated the magnitude of associations between C-reactive protein (CRP) measures, lifetime history of bipolar disorder or major depression, and cognitive function (reaction time and visuospatial memory) in 84,268 UK Biobank participants. CRP was measured in serum and a polygenic risk score for CRP was calculated, based on a published genome-wide association study. Multiple regression models adjusted for sociodemographic and clinical confounders.ResultsIncreased serum CRP was significantly associated with mood disorder history (Kruskal–Wallis H = 196.06, p < 0.001, η² = 0.002) but increased polygenic risk for CRP was not (F = 0.668, p = 0.648, η² < 0.001). Compared to the lowest quintile, the highest serum CRP quintile was significantly associated with both negative and positive differences in cognitive performance (fully adjusted models: reaction time B = −0.030, 95% CI = −0.052, −0.008; visuospatial memory B = 0.066, 95% CI = 0.042, 0.089). More severe mood disorder categories were significantly associated with worse cognitive performance and this was not moderated by serum or genetic CRP level.ConclusionsIn this large cohort study, we found that measured inflammation was associated with mood disorder history, but genetic predisposition to inflammation was not. The association between mood disorder and worse cognitive performance was very small and did not vary by CRP level. The inconsistent relationship between CRP measures and cognitive performance warrants further study.     

Effects of media stories featuring coping with suicidal crises on psychiatric patients: Randomized controlled trial

BackgroundAccumulating evidence suggests beneficial effects of media stories featuring individuals mastering their suicidal crises, but effects have not been assessed for psychiatric patients.MethodsWe randomized n = 172 adult psychiatric patients (n = 172, 97.1% inpatients) to read an educative article featuring a person mastering a suicidal crisis (n = 92) or an unrelated article (n = 80) in a single-blind randomized controlled trial. Questionnaire data were collected before (T ₁) and after exposure (T ₂) as well as 1 week later (study end-point, T ₃). The primary outcome was suicidal ideation as assessed with the Reasons for Living Inventory; secondary outcomes were help-seeking intentions, mood, hopelessness, and stigmatization. Differences between patients with affective versus other diagnoses were explored based on interaction tests.ResultsWe found that patients with affective disorders (n = 99) experienced a small-sized reduction of suicidal ideation at 1-week follow up (mean difference to control group [MD] at T ₃ = −0.17 [95% CI −0.33, −0.03], d = −0.15), whereas patients with nonaffective diagnoses (n = 73) experienced a small-sized increase (T ₂: MD = 0.24 [95% CI 0.06, 0.42], d = 0.19). Intervention group participants further experienced a nonsustained increase of help-seeking intentions (T ₂: MD = 0.53 [95% CI 0.11, 0.95], d = 0.19) and a nonsustained deterioration of mood (T ₂: MD = −0.14 [95% CI −0.27, −0.02], d = −0.17).ConclusionsThis study suggests that patients with affective disorders appear to benefit from media materials featuring mastery of suicidal crises. More research is needed to better understand which patient groups are at possible risk of unintended effects.     

Pre‐ and post‐conditioning with poly I:C exerts neuroprotective effect against cerebral ischemia injury in animal models: A systematic review and meta‐analysis

BackgroundToll‐like receptor (TLR) agonist polyinosinic–polycytidylic acid (poly I:C) exerts neuroprotective effects against cerebral ischemia (CI), but concrete evidence supporting its exact mechanism of action is unclear.MethodsWe evaluated the neuroprotective role of poly I:C by assessing CI indicators such as brain infarct volume (BIV), neurological deficit score (N.S.), and signaling pathway proteins. Moreover, we performed a narrative review to illustrate the mechanism of action of TLRs and their role in CI. Our search identified 164 articles and 10 met the inclusion criterion.ResultsPoly I:C reduces BIV and N.S. (p = 0.00 and p = 0.03). Interestingly, both pre‐ and post‐conditioning decrease BIV (preC p = 0.04 and postC p = 0.00) and N.S. (preC p = 0.03 and postC p = 0.00). Furthermore, poly I:C upregulates TLR3 [SMD = 0.64; CIs (0.56, 0.72); p = 0.00], downregulates nuclear factor‐κB (NF‐κB) [SMD = −1.78; CIs (−2.67, −0.88); p = 0.0)], and tumor necrosis factor alpha (TNF‐α) [SMD = −16.83; CIs (−22.63, −11.02); p = 0.00].ConclusionWe showed that poly I:C is neuroprotective and acts via the TLR3/NF‐κB/TNF‐α pathway. Our review indicated that suppressing TLR 2/4 may illicit neuroprotection against CI. Further research on simultaneous activation of TLR3 with poly I:C and suppression of TLR 2/4 might open new vistas for the development of therapeutics against CI.     

Reading skills deficits in people with mental illness: A systematic review and meta-analysis

BackgroundGood reading skills are important for appropriate functioning in everyday life, scholastic performance, and acquiring a higher socioeconomic status. We conducted the first systematic review and meta-analysis to quantify possible deficits in specific reading skills in people with a variety of mental illnesses, including personality disorders (PDs).MethodsWe performed a systematic search of multiple databases from inception until February 2020 and conducted random-effects meta-analyses.ResultsThe search yielded 34 studies with standardized assessments of reading skills in people with one or more mental illnesses. Of these, 19 studies provided data for the meta-analysis. Most studies (k = 27; meta-analysis, k = 17) were in people with schizophrenia and revealed large deficits in phonological processing (Hedge’s g = −0.88, p < 0.00001), comprehension (Hedge’s g = −0.96, p < 0.00001) and reading rate (Hedge’s g = −1.22, p = 0.002), relative to healthy controls; the single-word reading was less affected (Hedge’s g = −0.70, p < 0.00001). A few studies in affective disorders and nonforensic PDs suggested weaker deficits (for all, Hedge’s g < −0.60). In forensic populations with PDs, there was evidence of marked phonological processing (Hedge’s g = −0.85, p < 0.0001) and comprehension deficits (Hedge’s g = −0.95, p = 0.0003).ConclusionsPeople with schizophrenia, and possibly forensic PD populations, demonstrate a range of reading skills deficits. Future studies are needed to establish how these deficits directly compare to those seen in developmental or acquired dyslexia and to explore the potential of dyslexia interventions to improve reading skills in these populations.     

Did we learn something positive out of the COVID-19 pandemic? Post-traumatic growth and mental health in the general population

BackgroundWhen facing a traumatic event, some people may experience positive changes, defined as posttraumatic growth (PTG).MethodsUnderstanding the possible positive consequences of the pandemic on the individual level is crucial for the development of supportive psychosocial interventions. The present paper aims to: 1) evaluate the levels of PTG in the general population; 2) to identify predictors of each dimension of post-traumatic growth.ResultsThe majority of the sample (67%, N = 13,889) did not report any significant improvement in any domain of PTG. Participants reported the highest levels of growth in the dimension of “appreciation of life” (2.3 ± 1.4), while the lowest level was found in the “spiritual change” (1.2 ± 1.2). Female participants reported a slightly higher level of PTG in areas of personal strength (p < .002) and appreciation for life (p < .007) compared to male participants, while no significant association was found with age. At the multivariate regression models, weighted for the propensity score, only the initial week of lockdown (between 9-15 April) had a negative impact on the dimension of “relating to others” (B = −.107, 95% CI = −.181 to −.032, p < .005), while over time no other effects were found. The duration of exposure to lockdown measures did not influence the other dimensions of PTG.ConclusionsThe assessment of the levels of PTG is of great importance for the development of ad hoc supportive psychosocial interventions. From a public health perspective, the identification of protective factors is crucial for developing ad-hoc tailored interventions and for preventing the development of full-blown mental disorders in large scale.     

Prolonged impact of the COVID-19 pandemic on self-harm hospitalizations in France: A nationwide retrospective observational study

BackgroundThe first wave of the COVID-19 pandemic in France was associated with a reduced number of hospitalizations for self-harm, with the exception of older people. The on-going pandemic may have both sustained and delayed effects.MethodsData were extracted from the French national hospital database (PMSI), a nationwide exhaustive database. The number of self-harm hospitalizations (ICD-10 codes X60–84) between September 1, 2020 and August 31, 2021 (N = 85,679) was compared to 2019 (N = 88,782) using Poisson regression models.ResultsThere was a decrease in the total number of self-harm hospitalizations during the studied period versus 2019 (−3.5%; Relative Risk [RR] [95% Confidence Intervals] = 0.97 [0.96–0.97]; p < 0.0001). However, sex and age effects were identified. While adults aged 30–59-years-old showed a decrease (monthly decreases: −12.6 to −15.0%), we found an increase in adolescent girls (+27.7%, RR = 1.28 [1.25–1.31]; p < 0.0001), notably since January 2021. Moreover, the numbers were similar to 2019 in adolescent boys, in youths aged 20–29 years, and in people aged 70 and more. Hospitalizations in intensive care units decreased (−6.7%, RR = 0.93 [0.91–0.96]; p < 0.0001) and deaths at hospital following self-harm remained stable (+0.6%, Hazard Ratio = 0.99 [0.91–1.08], p = 0.79).ConclusionsDuring this second stage, the number of self-harm hospitalizations remained at a lower level than in the prepandemic period. However, significant variations over time, age, and sex were observed. Young people (notably adolescent girls) appear to have particularly suffered from the persistence of the pandemic, while older people did not show any decrease since the beginning. Vigilance and continuing prevention are warranted.     

Mixed‐effects multilevel analysis followed by canonical correlation analysis is an effective fMRI tool for the investigation of idiosyncrasies

We report that regions‐of‐interest (ROIs) associated with idiosyncratic individual behavior can be identified from functional magnetic resonance imaging (fMRI) data using statistical approaches that explicitly model individual variability in neuronal activations, such as mixed‐effects multilevel analysis (MEMA). We also show that the relationship between neuronal activation in fMRI and behavioral data can be modeled using canonical correlation analysis (CCA). A real‐world dataset for the neuronal response to nicotine use was acquired using a custom‐made MRI‐compatible apparatus for the smoking of electronic cigarettes (e‐cigarettes). Nineteen participants smoked e‐cigarettes in an MRI scanner using the apparatus with two experimental conditions: e‐cigarettes with nicotine (ECIG) and sham e‐cigarettes without nicotine (SCIG) and subjective ratings were collected. The right insula was identified in the ECIG condition from the χ ²‐test of the MEMA but not from the t‐test, and the corresponding activations were significantly associated with the similarity scores (r = −.52, p = .041, confidence interval [CI] = [−0.78, −0.17]) and the urge‐to‐smoke scores (r = .73, p <.001, CI = [0.52, 0.88]). From the contrast between the two conditions (i.e., ECIG > SCIG), the right orbitofrontal cortex was identified from the χ ²‐tests, and the corresponding neuronal activations showed a statistically meaningful association with similarity (r = −.58, p = .01, CI = [−0.84, −0.17]) and the urge to smoke (r = .34, p = .15, CI = [0.09, 0.56]). The validity of our analysis pipeline (i.e., MEMA followed by CCA) was further evaluated using the fMRI and behavioral data acquired from the working memory and gambling tasks available from the Human Connectome Project.     

Depression and executive functioning bidirectionally impair one another across 9 years: Evidence from within-person latent change and cross-lagged models

BackgroundScar and vulnerability models assert that increased psychopathology may predict subsequent executive functioning (EF) deficits (and vice versa) over protracted timescales, yet most prior work on this topic has been cross-sectional. Thus, we tested the within- and between-person relations between EF, depression, and anxiety.MethodsOlder adult participants (n = 856) were assessed across four waves, approximately 2 years apart. Performance-based EF and caregiver-rated symptom measures were administered. Bivariate latent change score and random-intercept cross-lagged panel models were conducted.ResultsWithin persons, random-intercept cross-lagged panel models revealed that prior greater depression forecasted lower subsequent EF, and vice versa (d = −0.292 vs. −0.292). Bivariate dual latent change score models showed that within-person rise in depression predicted EF decreases, and vice versa (d = −0.245 vs. −0.245). No within-person, cross-lagged, EF-anxiety relations emerged. Further, significant negative between-person EF-symptom relations were observed (d = −0.264 to −0.395).ConclusionProspective, within-person findings offer some evidence for developmental scar and vulnerability models.     

Effect of stress‐induced hyperglycemia after non‐traumatic non‐aneurysmal subarachnoid hemorrhage on clinical complications and functional outcomes

BackgroundDespite having an overall benign course, non‐traumatic non‐aneurysmal subarachnoid hemorrhage (naSAH) is still accompanied by a risk of clinical complications and poor outcomes. Risk factors and mechanisms of complications and poor outcomes after naSAH remain unknown. Our aim was to explore the effect of stress‐induced hyperglycemia (SIH) on complication rates and functional outcomes in naSAH patients.MethodsWe retrospectively reviewed patients with naSAH admitted to our institution between 2013 and 2018. SIH was identified according to previous criterion. Symptomatic vasospasm, delayed cerebral infarction, and hydrocephalus were identified as main complications. Outcomes were reviewed using a modified Rankin Scale (mRS) at discharge, 3 months, and 12 months. A statistical analysis was conducted to reveal the associations of SIH with complications and outcomes.ResultsA total of 244 naSAH patients were included in the cohort with 74 (30.3%) SIH. After adjusting for age, gender, hypertension, Hunt and Hess (HH) grade, modified Fisher Scale (mFS), intraventricular hemorrhage (IVH), and subarachnoid blood distribution, SIH was significantly associated with symptomatic vasospasm (p < 0.001, 12.176 [4.904–30.231]), delayed cerebral infarction (p < 0.001, 12.434 [3.850–40.161]), hydrocephalus (p = 0.008, 5.771 [1.570–21.222]), and poor outcome at 12 months (p = 0.006, 5.506 [1.632–18.581]), whereas the correlation between SIH and poor outcome at discharge (p = 0.064, 2.409 [0.951–6.100]) or 3 months (p = 0.110, 2.029 [0.852–4.833]) was not significant. Incorporation of SIH increased the area under curve (AUC) of ROC in the combined model for predicting symptomatic vasospasm (p = 0.002), delayed cerebral infarction (p = 0.024), hydrocephalus (p = 0.037), and 12‐month poor outcome (p = 0.087).ConclusionsSIH is a significant and independent risk factor for symptomatic vasospasm, delayed cerebral infarction, hydrocephalus, and long‐term poor outcome in naSAH patients. Identifying SIH early after naSAH is important for decision‐making and treatment planning.     

Different sensorimotor mechanism in fast and slow progression amyotrophic lateral sclerosis

The huge heterogeneity of the disease progression rate may cause inconsistent findings between local activity and functional connectivity of the primary sensorimotor area (PSMA) in amyotrophic lateral sclerosis (ALS). For illustration of this hypothesis, resting‐state fMRI (RS‐fMRI) data were collected and analyzed on 38 “definite” or “probable” ALS patients (19 fast and 19 slow, cut off median = 0.41) and 37 matched healthy controls. Amplitude of low frequency fluctuations (ALFFs) and functional connectivity strength (FCS) were analyzed within the PSMA. There was a decreased ALFF (p _FDR <.05) and FCS (p = .022) in all ALS patients. The two metrics shared about 50% of variance (R = .7) and both showed significant positive correlation with ALS Functional Rating Scale‐Revised (ALSFRS‐R) in the fast (p values <.034) but not in the slow progression groups. Interestingly, when regressing out the ALFF, the PSMA network FCS, especially the inter‐hemisphere FCS, showed negative correlation with the ALSFRS‐R score in the slow (R = −.54, p = .026) but not the fast progression group. In summary, the current results suggest that RS‐fMRI local activity and network functional connectivity accounts for the severity differently in the slow and fast progression ALS patients.     

Asymmetric distribution of enlarged perivascular spaces in centrum semiovale may be associated with epilepsy after acute ischemic stroke

ObjectiveTo investigate the factors influencing enlarged perivascular space (EPVS) characteristics at the onset of acute ischemic stroke (AIS), and whether the PVS characteristics can predict later post‐stroke epilepsy (PSE).MethodsA total of 312 patients with AIS were identified, of whom 58/312 (18.6%) developed PSE. Twenty healthy participants were included as the control group. The number of PVS in the basal ganglia (BG), centrum semiovale (CS), and midbrain (MB) was manually calculated on T₂‐weighted MRI. The scores and asymmetry index (AI) of EPVS in each region were compared among the enrolled participants. Other potential risk factors for PSE were also analyzed, including NIHSS at admission and stroke etiologies.ResultsThe EPVS scores were significantly higher in the bilateral BG and CS of AIS patients compared to those of the control group (both p < 0.01). No statistical differences in EPVS scores in BG, CS, and MB were obtained between the PSE group and the nonepilepsy AIS group (all p > 0.01). However, markedly different AI scores in CS were found between the PSE group and the nonepilepsy AIS group (p = 0.004). Multivariable analysis showed that high asymmetry index of EPVS (AI≥0.2) in CS was an independent predictor for PSE (OR = 3.7, 95% confidence interval 1.5–9.1, p = 0.004).ConclusionsAsymmetric distribution of EPVS in CS may be an independent risk factor and a novel imaging biomarker for the development of PSE. Further studies to understand the mechanisms of this association and confirmation with larger patient populations are warranted.     

Neuroanatomical correlates of reality monitoring in patients with schizophrenia and auditory hallucinations

BackgroundReality-monitoring process enables to discriminate memories of internally generated information from memories of externally derived information. Studies have reported impaired reality-monitoring abilities in schizophrenia patients with auditory hallucinations (AHs), specifically with an exacerbated externalization bias, as well as alterations in neural activity within frontotemporoparietal areas. In healthy subjects, impaired reality-monitoring abilities have been associated with reduction of the paracingulate sulcus (PCS). The current study aimed to identify neuroanatomical correlates of reality monitoring in patients with schizophrenia.MethodsThirty-five patients with schizophrenia and AHs underwent a reality-monitoring task and a 3D anatomical MRI scan at 1.5 T. PCS lengths were measured separately for each hemisphere, and whole-brain voxel-based morphometry analyses were performed using the Computational Anatomy Toolbox (version 12.6) to evaluate the gray-matter volume (GMV). Partial correlation analyses were used to investigate the relationship between reality-monitoring and neuroanatomical outcomes (PCS length and GMV), with age and intracranial volume as covariates.ResultsThe right PCS length was positively correlated with reality-monitoring accuracy (Spearman’s ρ = 0.431, p = 0.012) and negatively with the externalization bias (Spearman’s ρ = −0.379, p = 0.029). Reality-monitoring accuracy was positively correlated with GMV in the right angular gyrus, whereas externalization bias was negatively correlated with GMV in the left supramarginal gyrus/superior temporal gyrus, in the right lingual gyrus and in the bilateral inferior temporal/fusiform gyri (voxel-level p < 0.001 and cluster-level p < 0.05, FDR-corrected).ConclusionsReduced reality-monitoring abilities were significantly associated with shorter right PCS and reduced GMV in temporal and parietal regions of the reality-monitoring network in schizophrenia patients with AHs.