Methylphenidate modulates activity within cognitive neural networks of patients with post-stroke major depression: A placebo-controlled fMRI study

Rajamannar Ramasubbu1, Bradley G Goodyear21Departments of Psychiatry and Clinical Neurosciences; 2Department of Radiology and Clinical Neurosciences, University of Calgary, Hotchkiss Brain Institute, Calgary, AB, CanadaBackground: Methylphenidate (MP) is a dopamine- and noradrenaline-enhancing agent beneficial for post-stroke depression (PSD) and stroke recovery due to its therapeutic effects on cognition, motivation, and mood; however, the neural mechanisms underlying its clinical effects remain unknown. This study used functional magnetic resonance imaging (fMRI) to investigate the effect of MP on brain activity in response to cognitive tasks in patients with PSD.Methods: Nine stroke outpatients with DSM IV defined major depression underwent fMRI during two cognitive tasks (2-back and serial subtraction) on four occasions, on the first and third day of a three-day treatment of MP and placebo. Nine healthy control (HC) subjects matched for age and sex scanned during a single session served as normative data for comparison. The main outcome measure was cognitive task-dependent brain activity.Results: For the 2-back task, left prefrontal, right parietal, posterior cingulate, and temporal and bilateral cerebellar regions exhibited significantly greater activity during the MP condition relative to placebo. Less activity was detected in rostral prefrontal and left parietal regions. For serial subtraction, greater activity was detected in medial prefrontal, biparietal, bitemporal, posterior cingulate, and bilateral cerebellar regions, as well as thalamus, putamen, and insula. Further, underactivation observed during the placebo condition relative to HC improved or reversed during MP treatment. No significant differences in behavioral measures were found between MP and placebo conditions or between patients and HC.Conclusions: Short-term MP treatment may improve and normalize activity in cognitive neuronal networks in patients with PSD.Keywords: methylphenidate, post-stroke depression, functional MRI, cognitio

Thalamocortical connectivity in major depressive disorder

Background: Major Depressive Disorder (MDD) is highly prevalent and potentially devastating, with widespread aberrations in brain activity. Thalamocortical networks are a potential candidate marker for psychopathology in MDD, but have not yet been thoroughly investigated. Here we examined functional connectivity between major cortical areas and thalamus. Method: Resting-state fMRI from 54 MDD patients and 40 healthy controls were collected. The cortex was segmented into six regions of interest (ROIs) consisting of frontal, temporal, parietal, and occipital lobes and pre-central and post-central gyri. BOLD signal time courses were extracted from each ROI and correlated with voxels in thalamus, while removing signals from every other ROI. Results: Our main findings showed that MDD patients had predominantly increased connectivity between medial thalamus and temporal areas, and between medial thalamus and somatosensory areas. Furthermore, a positive correlation was found between thalamo-temporal connectivity and severity of symptoms. Limitations: Most of the patients in this study were not medication naïve and therefore we cannot rule out possible long-term effects of antidepressant use on the findings. Conclusion: The abnormal connectivity between thalamus and temporal, and thalamus and somatosensory regions may represent impaired cortico-thalamo-cortical modulation underlying emotional, and sensory disturbances in MDD. In the context of similar abnormalities in thalamocortical systems across major psychiatric disorders, thalamocortical dysconnectivity could be a reliable transdiagnostic marker

Treatment-resistant major depressive disorder: Canadian expert consensus on definition and assessment

Background: Treatment-resistant depression (TRD) is a debilitating chronic mental illness that confers increased morbidity and mortality, decreases the quality of life, impairs occupational, social, and offspring development, and translates into increased costs on the healthcare system. The goal of this study is to reach an agreement on the concept, definition, staging model, and assessment of TRD. Methods: This study involved a review of the literature and a modified Delphi process for consensus agreement. The Appraisal of Guidelines for Research & Evaluation II guidelines were followed for the literature appraisal. Literature was assessed for quality and strength of evidence using the grading, assessment, development, and evaluations system. Canadian national experts in depression were invited for the modified Delphi process based on their prior clinical and research expertize. Survey items were considered to have reached a consensus if 80% or more of the experts supported the statement. Results: Fourteen Canadian experts were recruited for three rounds of surveys to reach a consensus on a total of 27 items. Experts agreed that a dimensional definition for treatment resistance was a useful concept to describe the heterogeneity of this illness. The use of staging models and clinical scales was recommended in evaluating depression. Risk factors and comorbidities were identified as potential predictors for treatment resistance. Conclusions: TRD is a meaningful concept both for clinical practice and research. An operational definition for TRD will allow for opportunities to improve the validity of predictors and therapeutic options for these patients

A Blue Spectral Shift of the Hemoglobin Soret Band Correlates with the Age (Time Since Deposition) of Dried Bloodstains

The ability to determine the time since deposition of a bloodstain found at a crime scene could prove invaluable to law enforcement investigators, defining the time frame in which the individual depositing the evidence was present. Although various methods of accomplishing this have been proposed, none has gained widespread use due to poor time resolution and weak age correlation. We have developed a method for the estimation of the time since deposition (TSD) of dried bloodstains using UV-VIS spectrophotometric analysis of hemoglobin (Hb) that is based upon its characteristic oxidation chemistry. A detailed study of the Hb Soret band (λmax = 412 nm) in aged bloodstains revealed a blue shift (shift to shorter wavelength) as the age of the stain increases. The extent of this shift permits, for the first time, a distinction to be made between bloodstains that were deposited minutes, hours, days and weeks prior to recovery and analysis. The extent of the blue shift was found to be a function of ambient relative humidity and temperature. The method is extremely sensitive, requiring as little as a 1 µl dried bloodstain for analysis. We demonstrate that it might be possible to perform TSD measurements at the crime scene using a portable low-sample-volume spectrophotometer

Serotonergic fuctioning in depressed stroke, nondepressed stroke, and in healthy elderly

grantor: University of TorontoBackground. Considering age-related decline in 5HT function, we examined the effect of aging, gender, and a fixed dose of 30mg of oral d-fenfluramine (d-FEN) on prolactin (PRL) and cortisol (CORT) responses in healthy elderly subjects. Method. Twenty-three healthy male and female volunteers aged 60-86 years participated in a single-blind, placebo-controlled, fixed-order, crossover-design challenge test. Baseline PRL and CORT values and the responses of these hormones to 30mg of oral d-FEN and placebo over a 4 hour period were measured on two separate sessions. Results. Compared with placebo, the net changes in PRL and CORT responses (change scores from baseline) were significantly greater following d-FEN, (drug by time, F = 18.60, df = 3.66, p = 0.001; F = 4.13, df = 3.66, p = 0.01). Peak PRL responses (maximum change from baseline following d-FEN) were relatively robust compared to CORT responses. Women had greater peak PRL concentration than men (p = 0.014). Peak PRL concentration was positively correlated with plasma nor-d-FEN concentration (p = 0.039) and negatively correlated with body weight (p = 0.037). Although the weight adjusted dose used in this study (0.44mg/Kg) was higher than the recommended therapeutic dose of d-FEN (0.2-0.3mg/Kg), the peak PRL responses were modest and only two participants experienced side effects. Within this group of elderly subjects, age had no effect on d-FEN induced PRL and CORT responses. Conclusions. d-FEN can be employed as a safe serotonergic probe in the elderly and PRL responsivity to d-FEN is a reliable index of central 5HT function in this age group. Given the modest prolactin responses, it might be desirable to employ a dose in the upper therapeutic range (45-60mg) to maximise hormonal responses to d-FEN challenge tests in the elderly.M.Sc