Faculty Bibliography

Depression is a common and debilitating disorder affecting millions. First-line treatments fail to achieve remission in about one-third of patients, highlighting a critical treatment need. Transcranial direct current stimulation (tDCS) has emerged as a novel treatment for depression. Therefore, the aim of this review was to provide a comprehensive overview of the last decade of tDCS trials for depression and propose future research directions. To compile studies of the past decade, we conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) of tDCS for depression. A total of 21 RCTs were included, presenting a moderate effect for active tDCS compared to placebo. We also provided a description of study designs, stimulation parameters, and patients' characteristics. Following, we proposed possible strategies to enhance clinical effectiveness and reduce variability in results, including 1) optimization/personalization of tDCS via spatial and temporal target localization; 2) optimized methodological strategies, including home-based, accelerated tDCS protocols and novel trial designs; and 3) investigate patient profile to identify features that can predict treatment response. In conclusion, tDCS holds promise as a treatment for depression, but variability in trial parameters and outcomes underscores the need for its further optimization. Refining and standardizing protocols may enhance its effectiveness.

Repetitive head impacts are common in contact and collision sports and are linked to structural brain changes and an elevated risk of neurodegenerative diseases such as Chronic Traumatic Encephalopathy. Identifying early in vivo structural markers remains challenging. Although diagnosis currently requires post-mortem confirmation, clinical symptoms, including cognitive impairment and behavioural changes, are reflected in the diagnosis of Traumatic Encephalopathy Syndrome. These symptoms align with dysfunction in key brain regions-amygdala, hippocampus and thalamus-which support memory, emotion and behaviour and commonly show tau pathology in Chronic Traumatic Encephalopathy. This study uses shape analysis to examine structural differences in these regions between former American football players and unexposed asymptomatic controls and evaluates the influence of age, head impact exposure and clinical diagnosis on brain structure. We analyzed brain morphology in former American football players (n = 163) and unexposed, asymptomatic controls (n = 53). Structural segmentation was performed with FreeSurfer 7.1, and the shape analysis pipeline was used to generate subregional reconstructions. Vertex-level morphometry, based on the logarithm of the Jacobian determinant and radial distance, quantified local surface area dilation and thickness. Group differences were examined with covariate-adjusted linear regression models contrasting football players and controls, as well as participants with and without a Traumatic Encephalopathy Syndrome diagnosis. Partial correlations examined the influence of age, age of first football exposure and cumulative head impact index metrics, including frequency, linear acceleration and rotational force. Models were adjusted accordingly for age, body mass index, education, race, imaging site, apolipoprotein

We present real-world data on patients switching from anti-CD20s to fumarates for various motivations in this retrospective observational study of 43 patients from three multiple sclerosis centers. Recurrent infections on anti-CD20s were the most common reason for switching to fumarates. Patients experienced limited disease activity on fumarates (83.7% were free from relapse and new MRI lesions), suggesting effectiveness was maintained. Of the 16.3% with disease activity on fumarates, 57.1% also had disease activity on anti-CD20s. Tolerability was the main reason for discontinuing fumarates. Future studies will provide additional insight into how to effectively and safely transition from anti-CD20s to fumarates.

BACKGROUND:Despite fall-related injuries accounting for over two-thirds of older adult trauma injuries, fall-related injuries are more likely to be under-triaged. The Score for Trauma Triage in the Geriatric and Middle-Aged (STTGMA) is an injury risk-triage tool. This study aims to validate STTGMA's accuracy in predicting fall-related mortality among older adult trauma patients and compare its predictive accuracy with the Geriatric Trauma Outcome Score (GTOS) and the Revised Trauma Score (RTS). METHODS:Using a retrospective cohort design, we selected 6,458 older adult trauma patients (aged 65 years and older) from a single institutional trauma database (2017-2023). The primary outcome variable was in-hospital death, measured as a binary variable. The primary predictor variable was the STTGMA score, measured as a continuous variable and a four-level categorical variable. The secondary predictor variables were the GTOS and the RTS. We compared the predictive accuracy (95% confidence interval (CI)) of the STTGMA, GTOS, and RTS. We further assessed the relationships between the STTGMA risk categories and time-to-death and hospital length of stay using multivariable time-varying Cox proportional hazard analysis and multivariable quantile regression analysis, respectively. RESULTS:A total of 130 patients (2.0%) died during admission, and the median hospital length of stay was 2 days. STTGMA exhibited 84% (95% CI: 77.3-89.8) accuracy in predicting in-hospital fall-related mortality, while the GTOS and RTS both exhibited 71% diagnostic accuracies. Compared to the minimal risk category, older adult trauma patients classified as low, moderate, and high risks each had significantly longer hospital stays and adjusted mortality risks, in a dose-response pattern. CONCLUSION/CONCLUSIONS:STTGMA can accurately predict in-hospital mortality and risk-stratify the length of stay and the time to death among older adult trauma patients with fall-related injuries.

BACKGROUND/UNASSIGNED:There is a greater risk of complications from severe COVID-19 in immunocompromised patients with multiple sclerosis (pwMS) treated with certain disease-modifying therapies (DMTs), as well as a diminished vaccine response. METHODS/UNASSIGNED:In this exploratory, observational study, we recruited 28 patients with Relapsing Remitting MS (RRMS, n=24) or Secondary Progressive MS (SPMS, n=4), that were receiving treatment with either natalizumab or fumarates (diroximel or dimethyl) prior to baseline sample collection. Blood samples were collected before vaccination (baseline), between 4 weeks and 6 months post vaccination, and post booster administration. A multiplex bead immunoassay (MBI) was used to measure anti-Spike IgG, while IFNγ and IL-2 ELISpot assays were used to determine T cell activation. A 35-color spectral flow cytometry panel was used to phenotype bulk B and T cells and SARS-CoV-2-specific T cells, while dimensionality reduction was performed for further phenotypic analysis. RESULTS/UNASSIGNED:We observed a significantly increased absolute lymphocyte count (ALC) (p=0.0003) in natalizumab-treated pwMS when compared to fumarate-treated pwMS primarily due to increased circulating CD19+ B cells. Fumarate-treated pwMS exhibited a diminished Th1/Th2 ratio when compared to natalizumab-treated pwMS (p=0.0004) or healthy controls (p=0.0745), while natalizumab treatment marginally increased the Th1/Th2 ratio compared to healthy controls (p=0.1311). The observed increase in B cells in natalizumab-treated pwMS were predominantly memory B cells, and double negative (DN) B cells. However, no significant differences between the treatment groups were seen in terms of Spike IgG titers following the initial vaccination course or booster dose, nor in SARS-CoV-2-specific CD4+ responses, all of which remained robust for at least 6 months post-vaccination. The magnitude of humoral and cellular immune responses in both treatment groups were comparable to vaccinated healthy controls. Additionally, SARS-CoV-2 spike-specific CD4+ T cell phenotyping revealed a Th2 dominant response to booster dose in natalizumab-treated pwMS (p=0.0485) but not fumarate-treated pwMS. CONCLUSION/UNASSIGNED:pwMS treated with natalizumab or fumarates exhibit similarly robust and durable SARS-CoV-2 specific T cell and humoral responses following vaccination and booster dose. DMT-treated pwMS showing comparable responses to healthy individuals following initial vaccination supports the notion that treatment with these specific DMTs does not diminish strong, long-lasting immunity conferred by COVID-19 vaccination, despite the phenotypic differences modulated by each therapy.

BACKGROUND/UNASSIGNED:Pyridostigmine bromide is a short-acting carbamate acetylcholinesterase inhibitor that has been shown to acutely augment parasympathetic signaling in cardiovascular disease populations. OBJECTIVE/UNASSIGNED:This study was undertaken to characterize pharmacodynamics, safety, and tolerability of pyridostigmine during repeated dosing in patients with heart failure. METHODS/UNASSIGNED:A prospective ascending-dose, forced titration, double-blind Phase II randomized clinical trial was conducted to compare the effects of pyridostigmine bromide (15, 30, and 60 mg TID over 8 weeks) versus matching placebo on red blood cell (RBC) acetylcholinesterase activity, cholinergic side effects, and physiologic measures of parasympathetic heart rate modulation and sympathovagal balance in ambulatory patients with chronic systolic heart failure. RESULTS/UNASSIGNED:< 0.001 vs placebo). Physiologic measures of parasympathetic heart rate modulation and sympathovagal balance did not differ between treatment groups. In the pyridostigmine bromide group, RBC acetylcholinesterase activity was not significantly associated with postexercise parasympathetic heart modulation. CONCLUSIONS/UNASSIGNED:Pyridostigmine bromide administered over 8 weeks was associated with a significant reduction of RBC acetylcholinesterase activity and relatively mild symptoms of cholinergic excess, but changes in parasympathetic signaling in the sinoatrial node previously reported after acute administration were not observed. Further investigations are needed to delineate pharmacodynamic and pathobiological factors contributing to these findings. ClinicalTrials.gov identifier: NCT01415921.

BACKGROUND/OBJECTIVES/UNASSIGNED:Primary progressive aphasia (PPA) is managed with speech-language therapy (SLT) to slow language decline. Pairing transcranial direct current stimulation (tDCS) with SLT can enhance its effects. However, further research is needed to confirm these findings and guide its clinical use. We evaluated the feasibility of providing an intervention combining tDCS with SLT as a home-based and remotely supervised intervention. METHODS/UNASSIGNED:Participants with confirmed PPA who had word-finding difficulties were recruited for an open-label observational study. The intervention consisted of 20 daily sessions over 1 month, each with 45-min of personalized word retrieval training. During the first 30-min, participants received tDCS over the left inferior frontal gyrus (anode F7, cathode O1) at 2.0 mA. Language measures were remotely administered at baseline and intervention end. RESULTS/UNASSIGNED:= 0.016) from baseline to intervention end. CONCLUSIONS/UNASSIGNED:Our case series demonstrates that home-based tDCS added to SLT is feasible for patients with PPA. However, larger controlled studies are required to confirm its effectiveness in slowing language decline and to fully determine the benefits of this approach. This approach not only facilitates broader access to participation but also enables the extended treatment necessary to evaluate its clinical benefits, moving this treatment closer to clinical availability as a telehealth treatment.

Flickering light is a new promising, fully non-invasive brain stimulation technique that utilizes intermittent sensory stimulation to induce brainwave synchronization (entrainment). While the effects of 40 Hz externally induced neural entrainment have been extensively described, little is known about 60 Hz entrainment in humans. This study presents preliminary observations on the neural and somatic response to flickering 60 Hz light in healthy volunteers over a 3-week period. Fourteen volunteers were randomized to receive either 60 Hz flickering white light or constant light as sham (30-min sessions, 3 weeks, 5 days/week on weekdays). Neural entrainment was assessed with EEG on days 1, 5 and 19. Salivary cortisol and C-reactive protein (CRP) levels, measured with ELISA, assessed the somatic response to stimulation. Side effects and well-being were monitored via questionnaires. EEG recordings showed neural entrainment and synchrony in response to 60 Hz flickering light across multiple cortical regions, including occipital, central, temporal, and frontal areas. The entrainment power and synchronization between different cortical regions declined significantly by day 19 compared to day 1, indicating possible neural habituation. Cortisol and CRP salivary levels were unchanged, and minor side effects were reported with equal frequency in the active and sham groups. Our findings show that 60 Hz flickering light can induce significant neural entrainment and synchrony in healthy adults and is well tolerated. The decline in entrainment strength and neural synchrony observed with repeated 60 Hz stimulations suggests plastic changes in the cortex. To the best of our knowledge, this is the first study to characterize neural and somatic responses to repeated 60 Hz flickering visual stimuli. Given the well-known connection between 60 Hz brain oscillations and cognition, neuroplasticity, and their role in neuropsychiatric disorders, additional research in both preclinical and clinical settings is warranted.