Ketamine is a rapidly-acting antidepressant treatment with robust response rates. Previous studies have reported that serial ketamine therapy modulates resting state functional connectivity in several large-scale networks, though it remains unknown whether variations in brain structure, function, and connectivity impact subsequent treatment success. We used a data-driven approach to determine whether pretreatment multimodal neuroimaging measures predict changes along symptom dimensions of depression following serial ketamine infusion.

Patients with depression (n = 60) received structural, resting state functional, and diffusion MRI scans before treatment. Depressive symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17), the Inventory of Depressive Symptomatology (IDS-C), and the Rumination Response Scale (RRS) before and 24 h after patients received four (0.5 mg/kg) infusions of racemic ketamine over 2 weeks. Nineteen unaffected controls were assessed at similar timepoints. Random forest regression models predicted symptom changes using pretreatment multimodal neuroimaging and demographic measures.

Two HDRS-17 subscales, the HDRS-6 and core mood and anhedonia (CMA) symptoms, and the RRS: reflection (RRSR) scale were predicted significantly with 19, 27, and 1% variance explained, respectively. Increased right medial prefrontal cortex/anterior cingulate and posterior insula (PoI) and lower kurtosis of the superior longitudinal fasciculus predicted reduced HDRS-6 and CMA symptoms following treatment. RRSR change was predicted by global connectivity of the left posterior cingulate, left insula, and right superior parietal lobule.

Our findings support that connectivity of the anterior default mode network and PoI may serve as potential biomarkers of antidepressant outcomes for core depressive symptoms.

The present study examined the differential effect of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on neuropsychological functioning in children with traumatic brain injury (TBI) relative to orthopedic injury (OI).

Participants were drawn from a prospective, longitudinal study of children who sustained a TBI (n = 69) or OI (n = 72) between 3 and 7 years of age. Children completed a battery of neuropsychological measures targeting attention, memory, and executive functions at four timepoints spanning the immediate post-acute period to 18 months post-injury. Children also completed a comparable age-appropriate battery of measures approximately 7 years post-injury. Parents rated children’s dysexecutive behaviors at all timepoints.

Longitudinal mixed models revealed a significant allele status × injury group interaction with a medium effect size for verbal fluency. Cross-sectional models at 7 years post-injury revealed non-significant but medium effect sizes for the allele status x injury group interaction for fluid reasoning and immediate and delayed verbal memory. Post hoc stratified analyses revealed a consistent pattern of poorer neuropsychological functioning in Met carriers relative to Val/Val homozygotes in the TBI group, with small effect sizes; the opposite trend or no appreciable effect was observed in the OI group.

The results suggest a differential effect of the BDNF Val66Met polymorphism on verbal fluency, and possibly fluid reasoning and immediate and delayed verbal memory, in children with early TBI relative to OI. The Met allele—associated with reduced activity-dependent secretion of BDNF—may confer risk for poorer neuropsychological functioning in children with TBI.

Sudden onset severe headache is usually caused by a primary headache disorder but may be secondary to a more serious problem, such as subarachnoid hemorrhage (SAH). Very few patients who present to hospital with headache have suffered a SAH, but early identification is important to improve patient outcomes. A systematic review was undertaken to assess the clinical effectiveness of different care pathways for the management of headache, suspicious for SAH, in the Emergency Department. Capturing the perspective of patients was an important part of the research.

The project team included a patient collaborator with experience of presenting to the Emergency Department with sudden onset severe headache. Three additional patients were recruited to our advisory group. The patient's perspective was collected at various points through the project including at team meetings, during protocol development and when interpreting the results of the systematic review and drawing conclusions.

Patients were reassured by the very high diagnostic accuracy of computed tomography (CT) for detecting SAH. Patients and clinicians emphasized the importance of shared decision making about whether to undergo additional tests to rule out SAH, after a negative CT result. When lumbar puncture was necessary, patients expressed a preference to have it on an ambulatory basis; further research on the safety and acceptability of ambulatory lumbar puncture was recommended.

Patient input at the protocol development stage helped researchers understand the patient experience and highlighted important outcomes for assessment. Patient involvement added context to the review findings and highlighted the preferences of patients regarding the management of headache.

Sudden onset severe headache is usually caused by a primary headache disorder but occasionally is secondary to a more serious problem, such as subarachnoid hemorrhage (SAH). Guidelines recommend non-contrast brain computed tomography (CT) followed by lumbar puncture (LP) to exclude SAH. However, guidelines pre-date the introduction of more sensitive modern CT scanners. A systematic review was undertaken to assess the clinical effectiveness of different care pathways for the management of headache in the Emergency Department.

Eighteen databases (including MEDLINE and Embase) were searched to February 2020. Studies were quality assessed using criteria relevant to the study design; most studies were assessed using the QUADAS-2 tool for diagnostic accuracy studies. Where sufficient information was reported, diagnostic accuracy data were extracted into 2 × 2 tables to calculate sensitivity, specificity, false-positive and false-negative rates. Where possible, hierarchical bivariate meta-analysis was used to synthesize results, otherwise studies were synthesized narratively.

Fifty-one studies were included in the review. Eight studies assessing the accuracy of the Ottawa SAH clinical decision rule were pooled; sensitivity was 99.5 percent, specificity was 23.7 percent. The high false positive rate suggests that 76.3 percent SAH-negative patients would undergo further investigation unnecessarily. Four studies assessing the accuracy of CT within six hours of headache onset were pooled; sensitivity was 98.7 percent, specificity was 100 percent. CT sensitivity beyond six hours was considerably lower (≤90%; 2 studies). Three studies assessing LP following negative CT were pooled; sensitivity was 100 percent, specificity was 95.2 percent. LP-related adverse events were reported in 5.3–9.5 percent of patients.

The evidence suggests that the Ottawa SAH Rule is not sufficiently accurate for ruling out SAH and does little to aid clinical decision making. Modern CT within six hours of headache onset (with images assessed by a neuroradiologist) is highly accurate, but sensitivity reduces considerably over time. The CT-LP pathway is highly sensitive for detecting SAH, although LP resulted in some false-positives and adverse events.

Meta-analyses show an association between perfectionism and depression and anxiety (negative affect), and that therapy for perfectionism impacts positively on negative affect. No systematic reviews have focused on qualitative studies of perfectionism.

Our aim was to perform a systematic, meta-synthesis of qualitative literature to (i) help inform our understanding of how perfectionism is associated with negative affect, so that we can (ii) inform future development of treatment for perfectionism in young people and to make it more effective.

Included in the meta-synthesis were 37 qualitative studies.

Six themes related to perfectionism were found: (1) the association with negative affect, (2) self-worth dependent on achievement, (3) cognitive and behavioural maintaining factors, (4) the expectations of others, (5) effective elements of interventions, and (6) barriers to treatment.

The qualitative literature supports the notion of perfectionism as an important construct to consider in reducing negative affect. While cognitive behavioural therapy for perfectionism holds promise as a treatment to target negative affect, there was a paucity of qualitative research, particularly related to young people. A greater understanding of the views of young people are required to help tailor more effective interventions for perfectionism that can impact negative affect in this group.

Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.

To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.

Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.

Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.

AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

Studies examining the impact of adolescent and young adult cannabis use on structural outcomes have been heterogeneous. One already-identified moderator is sex, while a novel potential moderator is extent of aerobic fitness. Here, we sought to investigate the associations of cannabis use, sex, and aerobic fitness levels on brain volume. Second, we explored brain–behavior relationships to interpret these findings.

Seventy-four adolescents and young adults (36 cannabis users and 38 controls) underwent 3 weeks of monitored cannabis abstinence, aerobic fitness testing, structural neuroimaging, and neuropsychological testing. Linear regressions examined cannabis use and its interaction with sex and aerobic fitness on whole-brain cortical volume and subcortical regions of interests.

No main-effect differences between cannabis users and nonusers were observed; however, cannabis-by-sex interactions identified differences in frontal, temporal, and paracentral volumes. Female cannabis users generally exhibited greater volume while male users exhibited less volume compared to same-sex controls. Positive associations between aerobic fitness and frontal, parietal, cerebellum, and caudate volumes were observed. Cannabis-by-fitness interaction was linked with left superior temporal volume. Preliminary brain–behavior correlations revealed that abnormal volumes were not advantageous in either male or female cannabis users.

Aerobic fitness was linked with greater brain volume and sex moderated the effect of cannabis use on volume; preliminary brain–behavior correlations revealed that differences in cannabis users were not linked with advantageous cognitive performance. Implications of sex-specific subtleties and mechanisms of aerobic fitness require large-scale investigation. Furthermore, present findings and prior literature on aerobic exercise warrant examinations of aerobic fitness interventions that aimed at improving neurocognitive health in substance-using youth.

Verbal memory deficits are linked to cannabis use. However, self-reported episodic use does not allow for assessment of variance from other factors (e.g., cannabis potency, route of consumption) that are important for assessing brain-behavior relationships. Further, co-occurring nicotine use may moderate the influence of cannabis on cognition. Here we utilized objective urinary measurements to assess the relationship between metabolites of cannabis, 11-nor-9-carboxy-∆9-tetrahydrocannabinol (THCCOOH), and nicotine (cotinine) on verbal memory in young adults.

Adolescents and young adults (n = 103) aged 16–22 completed urinary drug testing and verbal memory assessment (RAVLT). Linear regressions examined the influence of THCCOOH and cotinine quantitative concentrations, and their interaction, on RAVLT scores, controlling for demographics and alcohol. Cannabis intake frequency was also investigated. Secondary analyses examined whether past month or recency of use related to performance, while controlling for THCCOOH and cotinine concentrations.

THCCOOH concentration related to both poorer total learning and long delay recall. Cotinine concentration related to poorer short delay recall. Higher frequency cannabis use status was associated with poorer initial learning and poorer short delay. When comparing to self-report, THCCOOH and cotinine concentrations were negatively related to learning and memory performance, while self-report was not.

Results confirm the negative relationship between verbal memory and cannabis use, extending findings with objective urinary THCCOOH, and cotinine concentration measurements. No moderating relationship with nicotine was found, though cotinine concentration independently associated with negative short delay performance. Findings support the use of both urinary and self-report metrics as complementary methods in substance use research.

We examined parent- and adolescent-reported executive functioning (EF) behaviors following pediatric traumatic brain injury (TBI) in the context of Online Family Problem-Solving Therapy (OFPST) and moderators of change in EF behaviors.

In total, 274 families were randomized to OFPST or an internet resource comparison group. Parents and adolescents completed the Behavior Rating Inventory of Executive Function at four time points. Mixed models were used to examine EF behaviors, assessing the effects of visit, treatment group, rater, TBI severity, age, socioeconomic status, and family functioning.

Parents rated their adolescents’ EF as poorer (F(3,1156) = 220.15, p < .001; M = 58.11, SE = 0.73) than adolescents rated themselves (M = 51.81, SE = 0.73). Across raters, EF behaviors were poorer for adolescents whose parents had less education (F(3,1156) = 8.60, p = .003; M = 56.76, SE = 0.98) than for those with more education (M = 53.16, SE = 0.88). Age at baseline interacted with visit (F(3,1156) = 5.05, p = .002), such that families of older adolescents reported improvement in EF behaviors over time. Family functioning also interacted with visit (F(3, 1156) = 2.61, p = .049), indicating more improvement in EF behaviors over time in higher functioning families. There were no effects of treatment or TBI severity.

We identified a discrepancy between parent- and adolescent-reported EF, suggesting reduced awareness of deficits in adolescents with TBI. We also found that poorer family functioning and younger age were associated with poorer recovery after TBI, whereas adolescents of parents with less education were reported as having greater EF deficits across time points.