Reliability of dynamic causal modelling of resting-state magnetoencephalography.

This study assesses the reliability of resting-state dynamic causal modelling (DCM) of magnetoencephalography (MEG) under conductance-based canonical microcircuit models, in terms of both posterior parameter estimates and model evidence. We use resting-state MEG data from two sessions, acquired 2 weeks apart, from a cohort with high between-subject variance arising from Alzheimer's disease. Our focus is not on the effect of disease, but on the reliability of the methods (as within-subject between-session agreement), which is crucial for future studies of disease progression and drug intervention. To assess the reliability of first-level DCMs, we compare model evidence associated with the covariance among subject-specific free energies (i.e., the 'quality' of the models) with versus without interclass correlations. We then used parametric empirical Bayes (PEB) to investigate the differences between the inferred DCM parameter probability distributions at the between subject level. Specifically, we examined the evidence for or against parameter differences (i) within-subject, within-session, and between-epochs; (ii) within-subject between-session; and (iii) within-site between-subjects, accommodating the conditional dependency among parameter estimates. We show that for data acquired close in time, and under similar circumstances, more than 95% of inferred DCM parameters are unlikely to differ, speaking to mutual predictability over sessions. Using PEB, we show a reciprocal relationship between a conventional definition of 'reliability' and the conditional dependency among inferred model parameters. Our analyses confirm the reliability and reproducibility of the conductance-based DCMs for resting-state neurophysiological data. In this respect, the implicit generative modelling is suitable for interventional and longitudinal studies of neurological and psychiatric disorders.

Sports-related concussion not associated with long-term cognitive or behavioural deficits: the PROTECT-TBI study.

BACKGROUND: The cognitive effects of sports-related concussion (SRC) have been the subject of vigorous debate but there has been little research into long-term outcomes in non-athlete populations. METHODS: This cohort study of UK community-dwelling adults (aged 50-90 years) was conducted between November 2015 and November 2020, with up to 4 years annual follow-up (n=15 214). Lifetime history of concussions was collected at baseline using the Brain Injury Screening Questionnaire. The first analysis grouped participants by type of concussion (no concussion, only SRC, only non-SRC (nSRC), mixed concussions (both SRC and nSRC)) and the second grouped the participants by number (0, 1, 2 or 3+ SRC or nSRC). Mixed models were used to assess the effect of concussion on outcomes including four cognitive domains and one behavioural measure (Mild Behavioural Impairment-C). RESULTS: Analysis of the included participants (24% male, mean age=64) at baseline found that the SRC group had significantly better working memory (B=0.113, 95% CI 0.038, 0.188) and verbal reasoning (B=0.199, 95% CI 0.092, 0.306) compared with those without concussion. Those who had suffered one SRC had significantly better verbal reasoning (B=0.111, 95% CI 0.031, 0.19) and attention (B=0.115, 95% CI 0.028, 0.203) compared with those with no SRC at baseline. Those with 3+ nSRCs had significantly worse processing speed (B=-0.082, 95% CI -0.144 to -0.019) and attention (B=-0.156, 95% CI -0.248 to -0.063). Those with 3+ nSRCs had a significantly worse trajectory of verbal reasoning with increasing age (B=-0.088, 95% CI -0.149 to -0.026). CONCLUSIONS: Compared with those reporting no previous concussions, those with SRC had no cognitive or behavioural deficits and seemed to perform better in some tasks. As indicated by previous studies, sports participation may confer long-term cognitive benefits.

Artificial intelligence for dementia prevention.

INTRODUCTION: A wide range of modifiable risk factors for dementia have been identified. Considerable debate remains about these risk factors, possible interactions between them or with genetic risk, and causality, and how they can help in clinical trial recruitment and drug development. Artificial intelligence (AI) and machine learning (ML) may refine understanding. METHODS: ML approaches are being developed in dementia prevention. We discuss exemplar uses and evaluate the current applications and limitations in the dementia prevention field. RESULTS: Risk-profiling tools may help identify high-risk populations for clinical trials; however, their performance needs improvement. New risk-profiling and trial-recruitment tools underpinned by ML models may be effective in reducing costs and improving future trials. ML can inform drug-repurposing efforts and prioritization of disease-modifying therapeutics. DISCUSSION: ML is not yet widely used but has considerable potential to enhance precision in dementia prevention. HIGHLIGHTS: Artificial intelligence (AI) is not widely used in the dementia prevention field. Risk-profiling tools are not used in clinical practice. Causal insights are needed to understand risk factors over the lifespan. AI will help personalize risk-management tools for dementia prevention. AI could target specific patient groups that will benefit most for clinical trials.

Alwyn Lishman's contribution to the neuropsychiatry of head injury (traumatic brain injury); two key papers.

INTRODUCTION: Alwyn Lishman appreciated that if we are to understand the psychological consequences of cerebral disorder we must study the interaction between organic disease and psychological processes. METHODS: We have reviewed Lishman's two major publications on the neuropsychiatry of head injury, published in 1968 and 1988, and considered their conclusions in the light of current knowledge. RESULTS: In his 1968 paper on the psychiatric sequelae of open head injuries sustained in World War II Lishman demonstrated associations between the type of psychiatric sequelae and the location of the injury. He also found that those with "somatic complaints", such as fatigue or sensitivity to light, showed less evidence of organic injury. In his 1988 paper, he attempted to explain why a mild head injury may be followed by long-lasting symptoms. He suggested that in the absence of complications early, organic, symptoms (physiogenesis) should recover quickly. However, this healthy recovery could be jeopardised by psychological factors (psychogenesis), resulting in long-lasting symptoms. This model of physiogenesis and psychogenesis remains relevant today. CONCLUSIONS: The ideas Lishman developed in these two papers were the basis for his huge contribution to the field of neuropsychiatry, and remain relevant today.

The impact of social isolation due to the COVID-19 pandemic on patients with dementia and caregivers.

OBJECTIVE: Social distancing to limit COVID-19 transmission has led to extensive lifestyle changes, including for people with dementia (PWD). The aim of this study, therefore, was to assess the impact of lockdown on the mental health of PWD and their carers. METHODS: Forty-five carers of PWD completed a telephone interview during the baseline assessment of the SOLITUDE study to gather information on life conditions and changes in symptoms of PWD during lockdown. Associations between changes in symptoms of PWD and carers' concerns and mental health were investigated. RESULTS: About 44% of carers experienced anxiety and irritability and reported changes in behavioural and cognitive symptoms in PWD. These changes were associated with worse carers' mental health and concerns about faster disease progression (χ2 = 13.542, p < 0.001). CONCLUSION: COVID-19-related social isolation has had a negative impact on patients' and carers' mental health. Potential long-term neurocognitive consequences require further investigation.

History for some or lesson for all? A systematic review and meta-analysis on the immediate and long-term mental health impact of the 2002-2003 Severe Acute Respiratory Syndrome (SARS) outbreak.

BACKGROUND: The aims of this systematic review and meta-analysis are to examine the prevalence of adverse mental health outcomes, both short-term and long-term, among SARS patients, healthcare workers and the general public of SARS-affected regions, and to examine the protective and risk factors associated with these mental health outcomes. METHODS: We conducted a systematic search of the literature using databases such as Medline, Pubmed, Embase, PsycInfo, Web of Science Core Collection, CNKI, the National Central Library Online Catalog and dissertation databases to identify studies in the English or Chinese language published between January 2003 to May 2020 which reported psychological distress and mental health morbidities among SARS patients, healthcare workers, and the general public in regions with major SARS outbreaks. RESULTS: The literature search yielded 6984 titles. Screening resulted in 80 papers for the review, 35 of which were included in the meta-analysis. The prevalence of post-recovery probable or clinician-diagnosed anxiety disorder, depressive disorder, and post-traumatic stress disorder (PTSD) among SARS survivors were 19, 20 and 28%, respectively. The prevalence of these outcomes among studies conducted within and beyond 6 months post-discharge was not significantly different. Certain aspects of mental health-related quality of life measures among SARS survivors remained impaired beyond 6 months post-discharge. The prevalence of probable depressive disorder and PTSD among healthcare workers post-SARS were 12 and 11%, respectively. The general public had increased anxiety levels during SARS, but whether there was a clinically significant population-wide mental health impact remained inconclusive. Narrative synthesis revealed occupational exposure to SARS patients and perceived stigmatisation to be risk factors for adverse mental health outcomes among healthcare workers, although causality could not be determined due to the limitations of the studies. CONCLUSIONS: The chronicity of psychiatric morbidities among SARS survivors should alert us to the potential long-term mental health complications of covid-19 patients. Healthcare workers working in high-risk venues should be given adequate mental health support. Stigmatisation against patients and healthcare workers should be explored and addressed. The significant risk of bias and high degree of heterogeneity among included studies limited the certainty of the body of evidence of the review.

Patient attitudes towards remote memory clinic assessment.

BACKGROUND: Due to demand on UK memory clinic services, most patients have limited consultant interaction before diagnosis/discharge. Technology offers an opportunity for remote assessment, from telephone/video-based consultations to fully digitised cognitive assessments with potential to track disease progression. Whilst many acute services utilise remote assessment, there are perceived barriers in memory clinic populations. However, COVID-19 and related national restrictions may have altered patients' attitudes towards and experience with remote assessment tools. We aimed to investigate attitudes including confidence and perceived challenges towards remote assessment as well as access and experience with technology amongst Oxfordshire memory clinic patients. METHOD: Between June and September 2020, all patients awaiting initial memory clinic assessment were asked to participate in a standardised semi-quantitative survey as part of an Oxford Health NHS Foundation Trust service evaluation. Designed with service-user input, questions aimed to capture availability, experience and confidence using technology and patients' comfort with assessment, diagnosis and future care discussions being conducted remotely, as well as any concerns or comments. RESULT: Amongst 73 respondents (average age=79.1 years), access to technology was high; 82% reported telephone access and 58% to a laptop, tablet, smartphone or combination of the three. 17% reported previous use of web-based video conferencing tools, and although confidence using these tools was 7%, this increased with written instruction or relative assistance. Similarly, whilst under half of the respondents felt comfortable with assessments, diagnosis or future care discussions occurring remotely, this increased to approximately two thirds with relative presence (67%, 69% and 66%, respectively). Qualitative analysis of patient's comments regarding remote assessment also revealed concerns over wait times/urgent need for assessment. However, 62% preferred to wait for an in-person visit, rather than an immediate remote appointment. CONCLUSION: This survey demonstrates availability of technology in this population but a disparity in willingness to engage in remote assessment. Consequently, there is a need to diverge from one-size-fits-all models to a tiered approach that helps facilitate individual choice based on the availability/confidence with technology and level of relative support. The Oxford Brain Health Centre, an integrated clinical-research service, provides an opportunity to research this tiered approach in clinical practice.

Left rostrolateral prefrontal cortex lesions reduce suicidal ideation in penetrating traumatic brain injury.

OBJECTIVES: The objective of this study is to evaluate the relationship between suicidal ideation (SI), structural brain damage, and cognitive deficits in patients with penetrating traumatic brain injury (pTBI). METHODS: Vietnam War veterans (n = 142) with pTBI to the prefrontal cortex (PFC) underwent combination of neuropsychological and psychiatric examinations and non-contrast CT brain scan. Patients were divided into SI positive (SI+) and SI negative (SI-) groups according to the SI item of the Beck Depression Inventory. RESULTS: Lesions to the left rostrolateral PFC (rlPFC) were associated with a lower risk of SI independent of depression and global functioning. Left rlPFC lesion also reduced abstract reasoning skills, which mediated the lesion effects on suicide ideation. CONCLUSIONS: The left rlPFC plays a crucial role in SI independently of depression and global functioning.

Patients with Lesions to Left Prefrontal Cortex (BA 9 and BA 10) Have Less Entrenched Beliefs and Are More Skeptical Reasoners.

The effect of prior beliefs on reasoning and decision-making is a robust, poorly understood phenomenon, exhibiting considerable individual variation. Neuroimaging studies widely show the involvement of the left pFC in reasoning involving beliefs. However, little patient data exist to speak to the necessity and role of the left pFC in belief-based inference. To address this shortcoming, we tested 102 patients with unilateral focal penetrating traumatic brain injuries and 49 matched controls. Participants provided plausibility ratings (plausible/implausible) to simple inductive arguments and (separately) strength of believability ratings of the conclusion to those same arguments. A voxel-based lesion symptom mapping analysis identified 10 patients, all with lesions to the left pFC (BA 9 and BA 10) as rating significantly fewer arguments with highly believable conclusions as "plausible," compared with all other patients. Subsequent analyses, incorporating the right hemisphere homologue of these patients (n = 12) and normal controls (n = 24), revealed patients with lesions to left pFC found fewer arguments plausible in the high believable than either of these groups, and there was no difference in the behavioral scores of the right pFC patients and normal controls. Further analysis, utilizing the belief ratings as the dependent measure, revealed a Group × Belief Rating interaction, with left pFC patients having less intense beliefs about the conclusions of moderately believable and highly believable arguments. We interpreted these results to indicate that lesions to left pFC (BA 9, BA 10) increase incredulity and make these patients more skeptical reasoners. The former can partially, but not fully, explain the latter. The other relevant factor may be that unilateral left pFC lesions disrupt hemispheric equilibrium and allow for an increased inhibitory role of the right pFC. We speculate that individual differences in belief bias in reasoning in the normal population may be a function of individual differences in the left and right pFC interactional dynamics.

'Attending to the wound and the person' - patients' experiences and expectations of a newly established traumatic brain injury clinic.

PRIMARY OBJECTIVE: This qualitative study aimed to gain a better understanding of how medical and social services in the UK currently support patients with Traumatic Brain Injury (TBI) in the community. Furthermore, we explored patients' wishes and expectations of a newly established TBI clinic. METHODS AND PROCEDURES: We conducted semi-structured interviews with 10 patients with mild-to-severe TBI. The interview schedule was designed to cover contacts with health services, information provided, post-discharge support, current social circumstances, expectations from the newly established brain injury service and participants' desires for any new service. Transcripts were analysed using a thematic analysis. MAIN RESULTS: Participants highlighted the importance of the human component of their care and of fostering trusting relationships. This validates patients' experience and helps them to regain confidence. Follow-up and education are important for patients and relatives through all stages of care, regardless of the severity of the injury. Patients strive for meaningful lives and need to be supported to engage in activities. They need hands-on support, particularly with the UK's bureaucratic welfare system. CONCLUSIONS: There is much room for improvement in the TBI community care in the UK. Our findings support the development of a holistic service that can address the multifactorial problems which the patients with TBI and their families face.

Brain Regions Associated With Internalizing and Externalizing Psychiatric Symptoms in Patients With Penetrating Traumatic Brain Injury.

A factor structure underlying DSM-IV diagnoses has been previously reported in neurologically intact patients. The authors determined the brain regions associated with factors underlying DSM-IV diagnoses and compared the ability of DSM-IV diagnoses, factor scores, and self-report measures to account for the neuroanatomical findings in patients with penetrating brain injuries. This prospective cohort study included 254 Vietnam War veterans: 199 with penetrating brain injuries and 55 matched control participants. Measures include DSM-IV diagnoses (from a Structured Clinical Interview for DSM), self-report measures of depression and anxiety, and CT scans. Factors underlying DSM-IV diagnoses were determined using an exploratory factor analysis and correlated with percent of brain regions affected. The ability of the factor scores, DSM-IV diagnoses, and the self-report psychiatric measures to account for the anatomical variance was compared with multiple regressions. Internalizing and externalizing factors were identified in these brain-injured patients. Damage to the left amygdala and bilateral basal ganglia was associated with lower internalizing factor scores, and damage to the left medial orbitofrontal cortex (OFC) with higher, and bilateral hippocampi with lower, externalizing factor scores. Factor scores best predicted left amygdala and bilateral hippocampal involvement, whereas DSM-IV diagnoses best predicted bilateral basal ganglia and left OFC involvement. Damage to the limbic areas involved in the processing of emotional and reward information, including structures involved in the National Institute of Mental Health's Research Domain Criteria Negative Valence Domain, influences the development of internalizing and externalizing psychiatric symptoms. Self-report measures underperformed DSM-IV and factor scores in predicting neuroanatomical findings.

Areas of Brain Damage Underlying Increased Reports of Behavioral Disinhibition.

Disinhibition, the inability to inhibit inappropriate behavior, is seen in frontal-temporal degeneration, Alzheimer's disease, and stroke. Behavioral disinhibition leads to social and emotional impairments, including impulsive behavior and disregard for social conventions. The authors investigated the effects of lesions on behavioral disinhibition measured by the Neuropsychiatric Inventory in 177 veterans with traumatic brain injuries. The authors performed voxel-based lesion-symptom mapping using MEDx. Damage in the frontal and temporal lobes, gyrus rectus, and insula was associated with greater behavioral disinhibition, providing further evidence of the frontal lobe's involvement in behavioral inhibition and suggesting that these regions are necessary to inhibit improper behavior.

Neural correlates of apathy revealed by lesion mapping in participants with traumatic brain injuries.

Apathy, common in neurological disorders, is defined as disinterest and loss of motivation, with a reduction in self-initiated activity. Research in diseased populations has shown that apathy is associated with variations in the volume of brain regions such as the anterior cingulate and the frontal lobes. The goal of this study was to determine the neural signatures of apathy in people with penetrating traumatic brain injuries (pTBIs), as to our knowledge, these have not been studied in this sample. We studied 176 male Vietnam War veterans with pTBIs using voxel-based lesion-symptom mapping (VLSM) and apathy scores from the UCLA Neuropsychiatric Inventory (NPI), a structured inventory of symptoms completed by a caregiver. Our results revealed that increased apathy symptoms were associated with brain damage in limbic and cortical areas of the left hemisphere including the anterior cingulate, inferior, middle, and superior frontal regions, insula, and supplementary motor area. Our results are consistent with the literature, and extend them to people with focal pTBI. Apathy is a significant symptom since it can reduce participation of the patient in family and other social interactions, and diminish affective decision-making.

Aggression, DRD1 polymorphism, and lesion location in penetrating traumatic brain injury.

OBJECTIVE: This study evaluated whether structural brain lesions modulate the relationship between pathological aggression and the dopaminergic system in traumatic brain injury (TBI). While converging evidence suggests that different areas of the prefrontal cortex modulate dopaminergic activity, to date no evidence exists of a modulation of endogenous dopaminergic tone by lesion localization in penetrating TBI (pTBI). METHODS: This study included 141 male Caucasian veterans who suffered penetrating pTBI during their service in Vietnam and 29 healthy male Caucasian Vietnam veterans. Participants were genotyped for 3 functional single nucleotide polymorphisms (SNPs): dopamine receptor D1 (DRD1) rs686, dopamine receptor D2 (DRD2) rs4648317, and catechol-O-methyltransferase (COMT) Val158Met. Patients underwent brain CT scans and were divided into medial prefrontal cortex, lateral prefrontal cortex, and posterior cortex lesion groups. Long-term aggression levels were evaluated with the agitation/aggression subscale of the Neuropsychiatric Inventory. RESULTS: Our data showed that carriers of more transcriptionally active DRD1 alleles compared to noncarriers demonstrated greater aggression levels due to medial prefrontal cortex lesions but reduced aggression levels due to lateral prefrontal cortex lesions independently of DRD2 rs4648317 or COMT Val158Met genotypes. CONCLUSIONS: Our results suggest that the relationship between pTBI-related aggression and the dopaminergic system is modulated by lesion location. Potentially lesion location could represent an easy-to-use, widely available, para-clinical marker to help in the development of an individualized therapeutic approach to pTBI-related pathological aggression.

Mental paper folding performance following penetrating traumatic brain injury in combat veterans: a lesion mapping study.

Mental paper folding is a complex measure of visuospatial ability involving a coordinated sequence of mental transformations and is often considered a measure of mental ability. The literature is inconclusive regarding the precise neural architecture that underlies performance. We combined the administration of the Armed Forces Qualification Test boxes subtest measuring mental paper folding ability, with a voxel-based lesion symptom mapping approach to identify brain regions associated with impaired mental paper folding ability. Using a large sample of subjects with penetrating traumatic brain injury and defined lesions studied over 2 time points, roughly 15 and 35 years post-injury, enabled us to answer the causal questions regarding mental paper folding impairment. Our results revealed that brain injury significantly exacerbates the decline of performance on mental paper folding tasks over time. Our study adds novel neuropsychological and neuroimaging support for parietal lobe involvement; specifically the right inferior parietal lobule (Broadmann's Area [BA] 40) and the left parahippocampal region (BAs 19, 36). Both areas were consistently associated with mental paper folding performance and demonstrate that the right parietal lobe and the left parahippocampal gyrus play an integral role in mental paper folding tasks.

Digitally augmented, parent-led CBT versus treatment as usual for child anxiety problems in child mental health services in England and Northern Ireland: a pragmatic, non-inferiority, clinical effectiveness and cost-effectiveness randomised controlled trial.

BACKGROUND: Anxiety problems are common in children, yet few affected children access evidence-based treatment. Digitally augmented psychological therapies bring potential to increase availability of effective help for children with mental health problems. This study aimed to establish whether therapist-supported, digitally augmented, parent-led cognitive behavioural therapy (CBT) could increase the efficiency of treatment without compromising clinical effectiveness and acceptability. METHODS: We conducted a pragmatic, unblinded, two-arm, multisite, randomised controlled non-inferiority trial to evaluate the clinical effectiveness and cost-effectiveness of therapist-supported, parent-led CBT using the Online Support and Intervention (OSI) for child anxiety platform compared with treatment as usual for child (aged 5-12 years) anxiety problems in 34 Child and Adolescent Mental Health Services in England and Northern Ireland. We examined acceptability of OSI plus therapist support via qualitative interviews. Participants were randomly assigned (1:1) to OSI plus therapist support or treatment as usual, minimised by child age, gender, service type, and baseline child anxiety interference. Outcomes were assessed at week 14 and week 26 after randomisation. The primary clinical outcome was parent-reported interference caused by child anxiety at week 26 assessment, using the Child Anxiety Impact Scale-parent report (CAIS-P). The primary measure of health economic effect was quality-adjusted life-years (QALYs). Outcome analyses were conducted blind in the intention-to-treat (ITT) population with a standardised non-inferiority margin of 0·33 for clinical analyses. The trial was registered with ISRCTN, 12890382. FINDINGS: Between Dec 5, 2020, and Aug 3, 2022, 706 families (706 children and their parents or carers) were referred to the study information. 444 families were enrolled. Parents reported 255 (58%) child participants' gender to be female, 184 (41%) male, three (<1%) other, and one (<1%) preferred not to report their child's gender. 400 (90%) children were White and the mean age was 9·20 years (SD 1·79). 85% of families for whom clinicians provided information in the treatment as usual group received CBT. OSI plus therapist support was non-inferior for parent-reported anxiety interference on the CAIS-P (SMD 0·01, 95% CI -0·15 to 0·17; p<0·0001) and all secondary outcomes. The mean difference in QALYs across trial arms approximated to zero, and OSI plus therapist support was associated with lower costs than treatment as usual. OSI plus therapist support was likely to be cost effective under certain scenarios, but uncertainty was high. OSI plus therapist support acceptability was good. No serious adverse events were reported. INTERPRETATION: Digitally augmented intervention brought promising savings without compromising outcomes and as such presents a valuable tool for increasing access to psychological therapies and meeting the demand for treatment of child anxiety problems. FUNDING: Department for Health and Social Care and United Kingdom Research and Innovation Research Grant, National Institute for Health and Care (NIHR) Research Policy Research Programme, Oxford and Thames Valley NIHR Applied Research Collaboration, Oxford Health NIHR Biomedical Research Centre.

Neuroimaging and Clinical Findings in Healthy Middle-Aged Adults With Mild Traumatic Brain Injury in the PREVENT Dementia Study.

Importance: Traumatic brain injuries (TBI) represent an important, potentially modifiable risk factor for dementia. Despite frequently observed vascular imaging changes in individuals with TBI, the relationships between TBI-associated changes in brain imaging and clinical outcomes have largely been overlooked in community cases of TBI. Objective: To assess whether TBI are associated with and interact with midlife changes in neuroimaging and clinical features in otherwise healthy individuals. Design, Setting, and Participants: This cross-sectional analysis used baseline data from the PREVENT Dementia program collected across 5 sites in the UK and Ireland between 2014 and 2020. Eligible participants were cognitively healthy midlife adults aged between 40 and 59 years. Data were analyzed between January 2023 and April 2024. Exposure: Lifetime TBI history was assessed using the Brain Injury Screening Questionnaire. Main Outcomes and Measures: Cerebral microbleeds and other markers of cerebral small vessel disease (white matter hyperintensities [WMH], lacunes, perivascular spaces) were assessed on 3T magnetic resonance imaging. Clinical measures were cognition, sleep, depression, gait, and cardiovascular disease (CVD) risk, assessed using Computerized Assessment of Information Processing (COGNITO), Pittsburgh Sleep Quality Index, Center for Epidemiologic Studies Depression Scale, clinical interviews, and the Framingham Risk Score, respectively. Results: Of 617 participants (median [IQR] age, 52 [47-56] years; 380 female [61.6%]), 223 (36.1%) had a history of TBI. TBI was associated with higher microbleed count (ß = 0.10; 95% CI, 0.01-0.18; P = .03), with a dose-response association observed with increasing number of TBI events (ß = 0.05; 95% CI, 0.01-0.09; P = .03). Conversely, TBI was not associated with other measures of small vessel disease, including WMH. Furthermore, TBI moderated microbleed associations with vascular risk factors and clinical outcomes, such that associations were present only in the absence of TBI. Importantly, observations held when analyses were restricted to individuals reporting only mild TBI. Conclusions and Relevance: In this cross-sectional study of healthy middle-aged adults, detectable changes in brain imaging and clinical features were associated with remote, even mild, TBI in the general population. The potential contribution of vascular injury to TBI-related neurodegeneration presents promising avenues to identify potential targets, with findings highlighting the need to reduce TBI through early intervention and prevention in both clinical care and policymaking.

Characterization of [11C]RO5013853, a novel PET tracer for the glycine transporter type 1 (GlyT1) in humans.

We characterize a novel radioligand for the glycine transporter type 1 (GlyT1), [(11)C]RO5013853, in humans. Ten healthy male volunteers, 23-60 years of age, were enrolled in this PET study; seven subjects participated in the evaluation of test-retest reliability and three subjects in whole body dosimetry. Subjects were administered intravenous bolus injections of approximately 1100 MBq (30 mCi) [(11)C]RO5013853 with a high specific activity of about 481 GBq (13 Ci)/µmol. Standard compartmental model analysis with arterial plasma input function, and an alternative noninvasive analysis method which was evaluated and validated by occupancy studies in both baboons and humans, were performed. Mean parameter estimates of the volumes of distribution (VT) obtained by a 2-tissue 5-parameter model were higher in the cerebellum, pons, and thalamus (1.99 to 2.59 mL/mL), and lower in the putamen, caudate, and cortical areas (0.86 to 1.13 mL/mL), with estimates showing less than 10% difference between test and retest scans. Tracer retention was effectively blocked by the specific glycine reuptake inhibitor (GRI), bitopertin (RG1678). [(11)C]RO5013853 was safe and well tolerated. Human dosimetry studies showed that the effective dose was approximately 0.0033 mSv/MBq, with the liver receiving the highest absorbed dose. In conclusion, quantitative dynamic PET of the human brain after intravenous injection of [(11)C]RO5013853 attains reliable measurements of GlyT1 binding in accordance with the expected transporter distribution in the human brain. [(11)C]RO5013853 is a radioligand suitable for further clinical PET studies. Full characterization of a novel radiotracer for GlyT1 in humans is provided. The tracer has subsequently been used to assess receptor occupancy in healthy volunteers and to estimate occupancy at doses associated with best efficacy in a clinical trial with schizophrenic patients with predominantly negative symptoms.

Decision-making capacity for treatment in psychiatric and medical in-patients: cross-sectional, comparative study.

BACKGROUND: Is the nature of decision-making capacity (DMC) for treatment significantly different in medical and psychiatric patients? AIMS: To compare the abilities relevant to DMC for treatment in medical and psychiatric patients who are able to communicate a treatment choice. METHOD: A secondary analysis of two cross-sectional studies of consecutive admissions: 125 to a psychiatric hospital and 164 to a medical hospital. The MacArthur Competence Assessment Tool - Treatment and a clinical interview were used to assess decision-making abilities (understanding, appreciating and reasoning) and judgements of DMC. We limited analysis to patients able to express a choice about treatment and stratified the analysis by low and high understanding ability. RESULTS: Most people scoring low on understanding were judged to lack DMC and there was no difference by hospital (P = 0.14). In both hospitals there were patients who were able to understand yet lacked DMC (39% psychiatric v. 13% medical in-patients, P<0.001). Appreciation was a better 'test' of DMC in the psychiatric hospital (where psychotic and severe affective disorders predominated) (P<0.001), whereas reasoning was a better test of DMC in the medical hospital (where cognitive impairment was common) (P = 0.02). CONCLUSIONS: Among those with good understanding, the appreciation ability had more salience to DMC for treatment in a psychiatric setting and the reasoning ability had more salience in a medical setting.

Understanding and managing the long-term cognitive consequences of traumatic brain injuries.

This editorial critically evaluates the current data on traumatic brain injuries and their effects on cognitive function. It discusses management strategies and clinical considerations to improve patient outcomes in light of these findings.