Faculty Bibliography

In controlled and observational studies, outcome measures are often observed longitudinally. Such data are difficult to compare among units directly because there is no natural ordering of curves. This is relevant not only in clinical trials, where typically the goal is to evaluate the relative efficacy of treatments on average, but also in the growing and increasingly important area of personalized medicine, where treatment decisions are optimized with respect to a relevant patient outcome. In personalized medicine, there are no methods for optimizing treatment decision rules using longitudinal outcomes, e.g., symptom trajectories, because of the lack of a natural ordering of curves. A typical practice is to summarize the longitudinal response by a scalar outcome that can then be compared across patients, treatments, etc. We describe some of the summaries that are in common use, especially in clinical trials. We consider a general summary measure (weighted average tangent slope) with weights that can be chosen to optimize specific inference depending on the application. We illustrate the methodology on a study of depression treatment, in which it is difficult to separate placebo effects from the specific effects of the antidepressant. We argue that this approach provides a better summary for estimating the benefits of an active treatment than traditional non-weighted averages.

Background: Despite evidence-based national guidelines for ADHD in the United Kingdom (UK), ADHD is under-identified, under-diagnosed, and under-treated. Many seeking help for ADHD face prejudice, long waiting lists, and patchy or unavailable services, and are turning to service-user support groups and/or private healthcare for help. Methods: A group of UK experts representing clinical and healthcare providers from public and private healthcare, academia, ADHD patient groups, educational, and occupational specialists, met to discuss shortfalls in ADHD service provision in the UK. Discussions explored causes of under-diagnosis, examined biases operating across referral, diagnosis and treatment, together with recommendations for resolving these matters. Results: Cultural and structural barriers operate at all levels of the healthcare system, resulting in a de-prioritization of ADHD. Services for ADHD are insufficient in many regions, and problems with service provision have intensified as a result of the response to the COVID-19 pandemic. Research has established a range of adverse outcomes of untreated ADHD, and associated long-term personal, social, health and economic costs are high. The consensus group called for training of professionals who come into contact with people with ADHD, increased funding, commissioning and monitoring to improve service provision, and streamlined communication between health services to support better outcomes for people with ADHD. Conclusions: Evidence-based national clinical guidelines for ADHD are not being met. People with ADHD should have access to healthcare free from discrimination, and in line with their legal rights. UK Governments and clinical and regulatory bodies must act urgently on this important public health issue.

Cannabis (marijuana) has been known to humans for thousands of years but its neurophysiological effects were sparsely understood until recently. Preclinical and clinical studies in the past two decades have indisputably supported the clinical proposition that the endocannabinoid system plays an important role in the etiopathogeneses of many neuropsychiatric disorders, including mood and addictive disorders. In this review, we discuss the existing knowledge of exo- and endo-cannabinoids, and role of the endocannabinoid system in depressive and suicidal behavior. A dysfunction in this system, located in brain regions such as prefrontal cortex and limbic structures is implicated in mood regulation, impulsivity and decision-making, may increase the risk of negative mood and cognition as well as suicidality. The literature discussed here also suggests that the endocannabinoid system may be a viable target for treatments of these neuropsychiatric conditions.

Decades of research have informed our understanding of how stress impacts the brain to perturb behavior. However, stress during development has received specific attention as this occurs during a sensitive period for scaffolding lifelong socio-emotional behavior. In this review, we focus the developmental neurobiology of stress-related pathology during infancy and focus on one of the many important variables that can switch outcomes from adaptive to maladaptive outcome: caregiver presence during infants' exposure to chronic stress. While this review relies heavily on rodent neuroscience research, we frequently connect this work with the human behavioral and brain literature to facilitate translation. Bowlby's Attachment Theory is used as a guiding framework in order to understand how early care quality impacts caregiver regulation of the infant to produce lasting outcomes on mental health.

Atypical visual attention patterns have been observed among carriers of the fragile X mental retardation gene (FMR1) premutation (PM), with some similarities to visual attention patterns observed in autism spectrum disorder (ASD) and among clinically unaffected relatives of individuals with ASD. Patterns of visual attention could constitute biomarkers that can help to inform the neurocognitive profile of the PM, and that potentially span diagnostic boundaries. This study examined patterns of eye movement across an array of fixation measurements from three distinct eye-tracking tasks in order to investigate potentially overlapping profiles of visual attention among PM carriers, ASD parents, and parent controls. Logistic regression analyses were conducted to examine whether variables constituting a PM-specific looking profile were able to effectively predict group membership. Participants included 65PM female carriers, 188 ASD parents, and 84 parent controls. Analyses of fixations across the eye-tracking tasks, and their corresponding areas of interest, revealed a distinct visual attention pattern in carriers of the FMR1 PM, characterized by increased fixations on the mouth when viewing faces, more intense focus on bodies in socially complex scenes, and decreased fixations on salient characters and faces while narrating a wordless picture book. This set of variables was able to successfully differentiate individuals with the PM from controls (Sensitivity = 0.76, Specificity = 0.85, Accuracy = 0.77) as well as from ASD parents (Sensitivity = 0.70, Specificity = 0.80, Accuracy = 0.72), but did not show a strong distinction between ASD parents and controls (Accuracy = 0.62), indicating that this set of variables comprises a profile that is unique to PM carriers. Regarding predictive power, fixations toward the mouth when viewing faces was able to differentiate PM carriers from both ASD parents and controls, whereas fixations toward other social stimuli did not differentiate PM carriers from ASD parents, highlighting some overlap in visual attention patterns that could point toward shared neurobiological mechanisms. Results demonstrate a profile of visual attention that appears strongly associated with the FMR1 PM in women, and may constitute a meaningful biomarker.

Down syndrome (DS) is the primary genetic cause of intellectual disability (ID), which is due to the triplication of human chromosome 21 (HSA21). In addition to ID, HSA21 trisomy results in a number of neurological and physiological pathologies in individuals with DS, including progressive cognitive dysfunction and learning and memory deficits which worsen with age. Further exacerbating neurological dysfunction associated with DS is the concomitant basal forebrain cholinergic neuron (BFCN) degeneration and onset of Alzheimer's disease (AD) pathology in early mid-life. Recent single population RNA sequencing (RNA-seq) analysis in the Ts65Dn mouse model of DS, specifically the medial septal cholinergic neurons of the basal forebrain (BF), revealed the mitochondrial oxidative phosphorylation pathway was significantly impacted, with a large subset of genes within this pathway being downregulated. We further queried oxidative phosphorylation pathway dysregulation in Ts65Dn mice by examining genes and encoded proteins within brain regions comprising the basocortical system at the start of BFCN degeneration (6 months of age). In select Ts65Dn mice we demonstrate significant deficits in gene and/or encoded protein levels of Complex I-V of the mitochondrial oxidative phosphorylation pathway in the BF. In the frontal cortex (Fr Ctx) these complexes had concomitant alterations in select gene expression but not of the proteins queried from Complex I-V, suggesting that defects at this time point in the BF are more severe and occur prior to cortical dysfunction within the basocortical circuit. We propose dysregulation within mitochondrial oxidative phosphorylation complexes is an early marker of cognitive decline onset and specifically linked to BFCN degeneration that may propagate pathology throughout cortical memory and executive function circuits in DS and AD.