How Academic Health Systems Can Be Ready for the Next Pandemic.

The COVID-19 pandemic created significant challenges for academic health systems (AHSs) across their tripartite mission of providing clinical care, conducting research, and educating learners. Despite these challenges, AHSs played an invaluable role in responding to the pandemic. Clinicians worked tirelessly to care for patients, and institutions quickly reoriented their care delivery systems. Furthermore, AHSs played an important role in advancing science, launching studies and clinical trials to examine new vaccines and treatments for COVID-19. However, there is room for improvement; AHSs can use lessons learned from the COVID-19 pandemic to reshape their operations for the future. To prepare for the next pandemic, AHSs must modernize, adapt, and transform their clinical operations, research infrastructure, and educational programs to include public health and to build surveillance capacity for detecting, monitoring, and managing emerging outbreaks. In this Invited Commentary, the authors describe the opportunities AHSs have to build on their experiences during the COVID-19 pandemic and the ways they can take advantage of their unique strengths in each of their 3 mission areas. Within clinical care, AHSs can reach patients outside traditional clinical settings, build national and regional networks, advance data-driven insights, engage with the community, and support and protect the workforce. Within research, they can leverage data science and artificial intelligence, perform pandemic forecasting, leverage the social and behavioral sciences, conduct clinical trials, and build a research and development preparedness and operational plan. Within education, AHSs can promote remote learning, make interprofessional learning the norm, and build a system of continuing education.

Effectiveness of a Personalized Brain-Computer Interface System for Cognitive Training in Healthy Elderly: A Randomized Controlled Trial.

BACKGROUND: Cognitive training has been demonstrated to improve cognitive performance in older adults. To date, no study has explored personalized training that targets the brain activity of each individual. OBJECTIVE: This is the first large-scale trial that examines the usefulness of personalized neurofeedback cognitive training. METHODS: We conducted a randomized-controlled trial with participants who were 60-80 years old, with Clinical Dementia Rating (CDR) score of 0-0.5, Mini-Mental State Examination (MMSE) score of 24 and above, and with no neuropsychiatric diagnosis. Participants were randomly assigned to the Intervention or Waitlist-Control group. The training system, BRAINMEM, has attention, working memory, and delayed recall game components. The intervention schedule comprised 24 sessions over eight weeks and three monthly booster sessions. The primary outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score after the 24-session training. RESULTS: There were no significant between-subjects differences in overall cognitive performance post-intervention. However, a sex moderation effect (p = 0.014) was present. Men in the intervention group performed better than those in the waitlist group (mean difference, +4.03 (95% CI 0.1 to 8.0), p = 0.046. Among females, however, both waitlist-control and intervention participants improved from baseline, although the between-group difference in improvement did not reach significance. BRAINMEM also received positive appraisal and intervention adherence from the participants. CONCLUSION: A personalized neurofeedback intervention is potentially feasible for use in cognitive training for older males. The sex moderation effect warrants further investigation and highlights the importance of taking sex into account during cognitive training.

Adjunctive 5-Hydroxytryptophan Slow-Release for Treatment-Resistant Depression: Clinical and Preclinical Rationale.

Serotonin transporter (SERT) inhibitors treat depression by elevating brain extracellular 5-hydroxytryptamine (5-HTExt). However, only one-third of patients respond adequately. Treatment-resistant depression (TRD) is a major unmet need. Interestingly, elevating 5-HTExt beyond what is achieved by a SERT inhibitor appears to treat TRD. Adjunctive administration of 5-hydroxytryptophan (5-HTP) safely elevates 5-HTExt beyond the SERT inhibitor effect in humans; however, 5-HTP cannot be a clinically viable drug because of its poor pharmacokinetics. A slow-release (SR) delivery mode would be predicted to overcome the pharmacokinetic limitations of 5-HTP, substantially enhancing the pharmacological action and transforming 5-HTP into a clinically viable drug. Animal studies bear out this prediction. Thus, adjunct 5-HTP SR could be an important new treatment for TRD. Here, we review the clinical and preclinical evidence for this treatment.

Suicidal ideation and sex differences in relation to 18 major psychiatric disorders in college and university students: anonymous web-based assessment.

College/university students are at high risk for psychiatric disorder and suicide secondary to age, campus stressors, and social pressures. We therefore report frequencies of 18 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision disorders and suicidal ideation (SI) acquired anonymously from a Web site receiving 113,181 visits from more than 1,500 predominantly US colleges/universities. Depression was foremost, followed by social phobia and eating disorders. Substance-related disorders were less frequent than expected. SI occurred in 47.1% of students, with women evidencing somewhat stronger findings than men. SI was more associated with substance, bipolar, and panic disorders than depression. Self-reported emotional volatility exceeded thoughts of self-harm for all disorders. The results support two subtypes of suicide risk: dysphoric premeditators and those primarily angry and/or impulsive. Clinicians and researchers should therefore consider suicide as an independent psychopathological phenomenon that includes emotional volatility as a risk factor and thoroughly evaluate psychiatric disorders potentially conferring greater suicidal propensity than depression.

A pilot randomized controlled trial using EEG-based brain-computer interface training for a Chinese-speaking group of healthy elderly.

BACKGROUND: There is growing evidence that cognitive training (CT) can improve the cognitive functioning of the elderly. CT may be influenced by cultural and linguistic factors, but research examining CT programs has mostly been conducted on Western populations. We have developed an innovative electroencephalography (EEG)-based brain-computer interface (BCI) CT program that has shown preliminary efficacy in improving cognition in 32 healthy English-speaking elderly adults in Singapore. In this second pilot trial, we examine the acceptability, safety, and preliminary efficacy of our BCI CT program in healthy Chinese-speaking Singaporean elderly. METHODS: Thirty-nine elderly participants were randomized into intervention (n=21) and wait-list control (n=18) arms. Intervention consisted of 24 half-hour sessions with our BCI-based CT training system to be completed in 8 weeks; the control arm received the same intervention after an initial 8-week waiting period. At the end of the training, a usability and acceptability questionnaire was administered. Efficacy was measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which was translated and culturally adapted for the Chinese-speaking local population. Users were asked about any adverse events experienced after each session as a safety measure. RESULTS: The training was deemed easily usable and acceptable by senior users. The median difference in the change scores pre- and post-training of the modified RBANS total score was 8.0 (95% confidence interval [CI]: 0.0-16.0, P=0.042) higher in the intervention arm than waitlist control, while the mean difference was 9.0 (95% CI: 1.7-16.2, P=0.017). Ten (30.3%) participants reported a total of 16 adverse events - all of which were graded "mild" except for one graded "moderate". CONCLUSION: Our BCI training system shows potential in improving cognition in both English- and Chinese-speaking elderly, and deserves further evaluation in a Phase III trial. Overall, participants responded positively on the usability and acceptability questionnaire.

Proceedings of the 2013 CINP summit: innovative partnerships to accelerate CNS drug discovery for improved patient care.

Central nervous system (CNS) diseases and, in particular, mental health disorders, are becoming recognized as the health challenge of the 21(st) century. Currently, at least 10% of the global population is affected by a mental health disorder, a figure that is set to increase year on year. Meanwhile, the rate of development of new CNS drugs has not increased for many years, despite unprecedented levels of investment. In response to this state of affairs, the Collegium Internationale Neuro-Psychopharmacologicum (CINP) convened a summit to discuss ways to reverse this disturbing trend through new partnerships to accelerate CNS drug discovery. The objectives of the Summit were to explore the issues affecting the value chain (i.e. the chain of activities or stakeholders that a company engages in/with to deliver a product to market) in brain research, thereby gaining insights from key stakeholders and developing actions to address unmet needs; to identify achievable objectives to address the issues; to develop action plans to bring about measurable improvements across the value chain and accelerate CNS drug discovery; and finally, to communicate recommendations to governments, the research and development community, and other relevant stakeholders. Summit outputs include the following action plans, aligned to the pressure points within the brain research-drug development value chain: Code of conduct dealing with conflict of interest issues, Prevention, early diagnosis, and treatment, Linking science and regulation, Patient involvement in trial design, definition of endpoints, etc., Novel trial design, Reproduction and confirmation of data, Update of intellectual property (IP) laws to facilitate repurposing and combination therapy (low priority), Large-scale, global patient registries, Editorials on nomenclature, biomarkers, and diagnostic tools, and Public awareness, with brain disease advocates to attend G8 meetings and World Economic Forum (WEF) Annual meetings in Davos, Switzerland. In this context Professor Barbara Sahakian recently made a formal presentation at the World Economic Forum (see Barbara Sahakian Blog from April 11, 2014, at https://forumblog.org/people/barbara-sahakian/) Full details of the discussions that formed the bases for these actions are presented in the main body of this document.

Development of a virtual reality assessment of everyday living skills.

Cognitive impairments affect the majority of patients with schizophrenia and these impairments predict poor long term psychosocial outcomes.  Treatment studies aimed at cognitive impairment in patients with schizophrenia not only require demonstration of improvements on cognitive tests, but also evidence that any cognitive changes lead to clinically meaningful improvements.  Measures of "functional capacity" index the extent to which individuals have the potential to perform skills required for real world functioning.  Current data do not support the recommendation of any single instrument for measurement of functional capacity.  The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is a novel, interactive gaming based measure of functional capacity that uses a realistic simulated environment to recreate routine activities of daily living. Studies are currently underway to evaluate and establish the VRFCAT's sensitivity, reliability, validity, and practicality. This new measure of functional capacity is practical, relevant, easy to use, and has several features that improve validity and sensitivity of measurement of function in clinical trials of patients with CNS disorders.

A brain-computer interface based cognitive training system for healthy elderly: a randomized control pilot study for usability and preliminary efficacy.

UNLABELLED: Cognitive decline in aging is a pressing issue associated with significant healthcare costs and deterioration in quality of life. Previously, we reported the successful use of a novel brain-computer interface (BCI) training system in improving symptoms of attention deficit hyperactivity disorder. Here, we examine the feasibility of the BCI system with a new game that incorporates memory training in improving memory and attention in a pilot sample of healthy elderly. This study investigates the safety, usability and acceptability of our BCI system to elderly, and obtains an efficacy estimate to warrant a phase III trial. Thirty-one healthy elderly were randomized into intervention (n = 15) and waitlist control arms (n = 16). Intervention consisted of an 8-week training comprising 24 half-hour sessions. A usability and acceptability questionnaire was administered at the end of training. Safety was investigated by querying users about adverse events after every session. Efficacy of the system was measured by the change of total score from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) before and after training. Feedback on the usability and acceptability questionnaire was positive. No adverse events were reported for all participants across all sessions. Though the median difference in the RBANS change scores between arms was not statistically significant, an effect size of 0.6SD was obtained, which reflects potential clinical utility according to Simon's randomized phase II trial design. Pooled data from both arms also showed that the median change in total scores pre and post-training was statistically significant (Mdn = 4.0; p<0.001). Specifically, there were significant improvements in immediate memory (p = 0.038), visuospatial/constructional (p = 0.014), attention (p = 0.039), and delayed memory (p<0.001) scores. Our BCI-based system shows promise in improving memory and attention in healthy elderly, and appears to be safe, user-friendly and acceptable to senior users. Given the efficacy signal, a phase III trial is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01661894.

Associations between elevated homocysteine, cognitive impairment, and reduced white matter volume in healthy old adults.

OBJECTIVES: Elevated homocysteine has emerged as a risk factor for cognitive impairment even in healthy elderly persons. Reduced brain volume and white matter hyperintensities also occur in healthy elderly as well, but the interrelationships between these have not been well studied. We report these interrelationships in non demented, relatively healthy, community-dwelling older adults from a single East Asian population. METHODS: Two hundred twenty-eight right-handed participants age 55 years and above were evaluated. Persons with medical conditions or neurological diseases other than well-controlled diabetes mellitus and hypertension were excluded. Participants underwent quantitative magnetic resonance imaging of the brain using a standardized protocol and neuropsychological evaluation. Plasma homocysteine, folate, vitamin B(12), and markers for cardiovascular risk: blood pressure, body mass index, fasting blood glucose, and lipid profile were measured. RESULTS: Elevated homocysteine was associated with reduced global cerebral volume, larger ventricles, reduced cerebral white matter volume, and lower cognitive performance in several domains. Elevated homocysteine was associated with reduced white matter volume (ß = -20.80, t = -2.9, df = 223, p = 0.004) and lower speed of processing (ß = -0.38, t = -2.1, df = 223, p = 0.03), even after controlling for age, gender, and education. However, the association between homocysteine and lower speed of processing disappeared after controlling for white matter volume. Elevated homocysteine was not associated with white matter hyperintensity volume or with hippocampal volume. Although homocysteine and folate levels were correlated, their effects on white matter volume were dissociated. CONCLUSION: In non demented, relatively healthy adults, elevated homocysteine is associated with lower cognitive scores and reduced cerebral white matter volume. These effects can be dissociated from those related to white matter hyperintensities or reduced folate level.

Morphometric analysis of vascular pathology in the orbitofrontal cortex of older subjects with major depression.

OBJECTIVE: Late-life depression has been associated with risk for cerebrovascular pathology, as demonstrated in neuroimaging studies of older depressed patients, as well as mood disorder following cerebrovascular accidents. However, more research is needed on neuroanatomical changes in late-life depression, where there has been no clearly documented link to brain injury. Such studies should examine morphological changes in medium and small sized vessels that supply the cortical gray and white matter. METHODS: The present study used a non-specific histological Nissl staining and a more vessel-specific immunolabeling with endothelial marker von Willebrand Factor (vWF) to estimate density and size of blood vessel segments in the orbitofrontal cortex of 16 older subjects with major depressive disorder (MDD) and 9 non-psychiatric comparison subjects. RESULTS: The density of Nissl-stained vessel segments and of segments with perivascular spaces was higher in subjects with MDD than in comparison subjects in gray (GM) and white matter (WM). In GM, the density of vWF-immunoreactive segments with cross-sectional areas greater than 800 µm2 was higher in MDD. In WM, only the density of vWF-immunoreactive segments with patent perivascular spaces and diameters larger than 60 µm was higher in subjects with MDD. Also in the WM, only subjects with late-onset MDD presented a significantly higher density of vWF-positive segments than comparison subjects. CONCLUSIONS: In older subjects with MDD, there appear to be morphological changes that increase visibility of medium-sized vessel segments with some labeling techniques, and this increased visibility may be related to increased patency of perivascular spaces around arterioles.

A brain-computer interface based attention training program for treating attention deficit hyperactivity disorder.

UNLABELLED: Attention deficit hyperactivity disorder (ADHD) symptoms can be difficult to treat. We previously reported that a 20-session brain-computer interface (BCI) attention training programme improved ADHD symptoms. Here, we investigated a new more intensive BCI-based attention training game system on 20 unmedicated ADHD children (16 males, 4 females) with significant inattentive symptoms (combined and inattentive ADHD subtypes). This new system monitored attention through a head band with dry EEG sensors, which was used to drive a feed forward game. The system was calibrated for each user by measuring the EEG parameters during a Stroop task. Treatment consisted of an 8-week training comprising 24 sessions followed by 3 once-monthly booster training sessions. Following intervention, both parent-rated inattentive and hyperactive-impulsive symptoms on the ADHD Rating Scale showed significant improvement. At week 8, the mean improvement was -4.6 (5.9) and -4.7 (5.6) respectively for inattentive symptoms and hyperactive-impulsive symptoms (both p<0.01). Cohen's d effect size for inattentive symptoms was large at 0.78 at week 8 and 0.84 at week 24 (post-boosters). Further analysis showed that the change in the EEG based BCI ADHD severity measure correlated with the change ADHD Rating Scale scores. The BCI-based attention training game system is a potential new treatment for ADHD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01344044.

Downregulation of TOMM40 expression in the blood of Alzheimer disease subjects compared with matched controls.

Translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene has been reported in several GWAS to be associated with Alzheimer disease (AD). Gene expression studies thus far only showed TOMM40 differential expression in one study on brain cortex and not in peripheral blood. We studied the gene expression profiles of AD blood versus controls in an Asian population in Singapore. In this first analysis we focused on genes that have been previously reported on GWAS. We found TOMM40 to be significantly down-regulated in blood samples of AD in one discovery and two validation sets, totalling 45 subjects (mean age 76.90, SD 6.46) and 45 controls (mean age 76.23, SD 5.09), matched for ethnicity and gender. The function of TOMM40 is not yet fully characterized but is believed to be involved in import and trafficking of protein into mitochondria. Therefore TOMM40 downregulation, found in the brain in severe AD and in our blood profile, may be a potential marker for AD, disease severity or progression and merit further investigation.

The effectiveness of antidepressant monotherapy in a naturalistic outpatient setting.

OBJECTIVE: To assess a representative sample of clinically depressed outpatients during acute treatment with antidepressant medication monotherapy to determine clinical outcomes and evaluate relationships between outcomes and selected baseline/treatment features. METHOD: This naturalistic study examined data on outpatients at the Department of Psychiatry, Duke University Medical Center, Durham, North Carolina, from January 2000 through December 2010. Eligible patients (N = 1,722) had a diagnosis of clinical depression (major depressive disorder, dysthymic disorder, or depressive disorder not otherwise specified as defined in DSM-IV-TR). Sociodemographic/clinical data were gathered at study entry (date of first treatment). The Clinical Global Impressions-improvement (CGI-I) and -severity of illness (CGI-S) scales were administered at entry and at study exit (end of follow-up) after 1 to 9 weeks of treatment. Analysis of variance, F tests, and t tests determined relationships between outcomes and treatment duration, baseline severity, and sociodemographic/clinical features. RESULTS: Thirty-nine percent of participants reported substantial improvement (CGI-I score = 1 or 2) from entry to exit, 33% reported minimal improvement (CGI-I score = 3), 22% reported no change, and approximately 7% reported worsened illness. Greater improvement (CGI-I score) and greater reduction in depressive severity (CGI-S score) were associated with greater baseline depressive severity and longer treatment duration (all P < .001). Participants with greater baseline depressive severity experienced larger reductions in depressive severity but reported worse CGI-I scores at exit. Less improvement in CGI-I scores was seen in women compared to men (P = .018). Less improvement in CGI-I scores and less reduction in CGI-S scores were seen in participants ≤ 60 years of age (P = .040 and P = .025, respectively) and those with comorbid substance abuse (P < .001 and P = .010, respectively) or anxiety (P = .018 and P < .001, respectively) disorders. CONCLUSIONS: Most depressive symptom improvement occurred within the first 4 to 6 weeks of antidepressant monotherapy. Greater baseline severity, comorbid substance abuse, and comorbid anxiety disorders are associated with worse outcomes.

Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: two randomized, placebo- and active-controlled clinical trials.

GSK372475 is a triple reuptake inhibitor with approximately equipotent inhibition of serotonin, norepinephrine, and dopamine transporters. Two randomized, placebo- and active-controlled, double-blind studies examined the efficacy and safety of GSK372475 in outpatients (aged 18-64 years) with a diagnosis of major depressive episode associated with major depressive disorder (MDD). Patients were randomized 1:1:1 to placebo, GSK372475 (1-2 mg/d), or active control (Study 1: venlafaxine XR 150-225 mg/d; Study 2: paroxetine 20-30 mg/d). GSK372475 did not significantly differ from placebo on any of the key efficacy endpoints (six-item Bech scale, IDS-Clinician Rated, MADRS) in either study. Both active controls demonstrated significant antidepressant activity compared with placebo on both primary and secondary endpoints. The most common adverse effects (AEs) with GSK372475 were dry mouth, headache, insomnia, and nausea. AEs were more frequent for GSK372475 versus placebo for sleep, anxiety-related, gastrointestinal, and tachycardia events. Increases in mean change from baseline in heart rate and sitting blood pressure were greater for GSK372475 than observed for either placebo or active control groups. Completion rates were lower for GSK372475 (49%, 58%) compared with placebo (67%, 74%), venlafaxine XR (63%), or paroxetine (77%). GSK372475 was neither efficacious nor well tolerated in patients with MDD in two 10-week studies.

Results from 2 randomized, double-blind, placebo-controlled studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder.

Clinical study results for neurokinin (NK) receptor antagonists in the treatment of depression have been mixed, with Phase III studies failing to fulfill the early promise demonstrated in Phase II studies. Casopitant, a selective NK1 antagonist that achieves nearly complete receptor occupancy was studied in 2 randomized, placebo-controlled, double-blind, Phase II trials in depressed outpatients to test the hypothesis that nearly complete NK1 receptor occupancy is required to achieve antidepressant efficacy. Study 092 used an interactive voice response system to recruit depressed patients with baseline Hamilton Depression (17-item, HAMD17) total scores higher than 24 who were randomized to fixed-dose casopitant 30 mg/d, 80 mg/d, or placebo for 8 weeks (n = 356). Study 096 required Carroll Depression Scale-Revised self-assessment scores of higher than 24 for randomization to casopitant 120 mg/d, paroxetine 30 mg/d (both reached via forced titration), or placebo for 8 weeks (n = 362). In study 092, casopitant 80 mg but not 30 mg achieved statistically significant improvement versus placebo on the primary outcome measure, week 8 last observation carried forward change from baseline HAMD17 (difference = -2.7; 95% confidence interval, -5.1 to -0.4, P = 0.023). In study 096, neither casopitant nor paroxetine achieved statistical separation from placebo at end point on HAMD17 (casopitant difference = -1.7; 95% CI, -3.8 to 0.4, P = 0.282). Casopitant and paroxetine were generally well tolerated in most patients. These studies suggest that NK1 antagonists that have nearly complete receptor occupancy may be effective in the treatment of depression.

Reduction of dorsolateral prefrontal cortex gray matter in late-life depression.

Postmortem studies have documented abnormalities in the dorsolateral prefrontal cortex (dlPFC) in depressed subjects. In this study we used magnetic resonance imaging to test for dlPFC volume differences between older depressed and non-depressed individuals. Eighty-eight subjects meeting DSM IV criteria for major depressive disorder and thirty-five control subjects completed clinical evaluations and cranial 3T magnetic resonance imaging. After tissue types were identified using an automated segmentation process, the dlPFC was measured in both hemispheres using manual delineation based on anatomical landmarks. Depressed subjects had significantly lower gray matter in the left and right dorsolateral prefrontal cortex (standardized to cerebral parenchyma) after controlling for age and sex. Our study confirmed the reduction of dorsolateral prefrontal cortex in elderly depressed subjects, especially in the gray matter. These regional abnormalities may be associated with psychopathological changes in late-life depression.

Variability in frontotemporal brain structure: the importance of recruitment of African Americans in neuroscience research.

BACKGROUND: Variation in brain structure is both genetically and environmentally influenced. The question about potential differences in brain anatomy across populations of differing race and ethnicity remains a controversial issue. There are few studies specifically examining racial or ethnic differences and also few studies that test for race-related differences in context of other neuropsychiatric research, possibly due to the underrepresentation of ethnic minorities in clinical research. It is within this context that we conducted a secondary data analysis examining volumetric MRI data from healthy participants and compared the volumes of the amygdala, hippocampus, lateral ventricles, caudate nucleus, orbitofrontal cortex (OFC) and total cerebral volume between Caucasian and African-American participants. We discuss the importance of this finding in context of neuroimaging methodology, but also the need for improved recruitment of African Americans in clinical research and its broader implications for a better understanding of the neural basis of neuropsychiatric disorders. METHODOLOGY/PRINCIPAL FINDINGS: This was a case control study in the setting of an academic medical center outpatient service. Participants consisted of 44 Caucasians and 33 ethnic minorities. The following volumetric data were obtained: amygdala, hippocampus, lateral ventricles, caudate nucleus, orbitofrontal cortex (OFC) and total cerebrum. Each participant completed a 1.5 T magnetic resonance imaging (MRI). Our primary finding in analyses of brain subregions was that when compared to Caucasians, African Americans exhibited larger left OFC volumes (F (1,68) = 7.50, p = 0.008). CONCLUSIONS: The biological implications of our findings are unclear as we do not know what factors may be contributing to these observed differences. However, this study raises several questions that have important implications for the future of neuropsychiatric research.