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

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

Dosing of Electrical Parameters in Deep Brain Stimulation (DBS) for Intractable Depression: A Review of Clinical Studies

Background: The electrical parameters used for deep brain stimulation (DBS) in movement disorders have been relatively well studied, however for the newer indications of DBS for psychiatric indications these are less clear. Based on the movement disorder literature, use of the correct stimulation parameters should be crucial for clinical outcomes. This review examines the stimulation parameters used in DBS studies for treatment resistant depression (TRD) and their relevance to clinical outcome and brain targets.Methods: We examined the published studies on DBS for TRD archived in major databases. Data on stimulus parameters (frequency, pulse width, amplitude), stimulation mode, brain target, efficacy, safety, and duration of follow up were extracted from 29 observational studies including case reports of patients with treatment resistant unipolar, bipolar, and co-morbid depression.Results: The algorithms commonly used to optimize efficacy were increasing amplitude followed by changing the electric contacts or increasing pulse width. High frequency stimulation (>100 Hz) was applied in most cases across brain targets. Keeping the high frequency stimulation constant, three different combinations of parameters were mainly used: (i) short pulse width (60–90 us) and low amplitude (0–4 V), (ii) short pulse width and high amplitude (5–10 V), (iii) long pulse width (120–450 us) and low amplitude. There were individual variations in clinical response to electrical dosing and also in the time of clinical recovery. There was no significant difference in mean stimulation parameters between responders and non-responders suggesting a role for stimulation unrelated factors in response.Conclusions: Although limited by open trials and small sample size, three optimal stimulation parameter combinations emerged from this review. Studies are needed to assess the comparative efficacy and safety of these combinations, such as a registry of data from patients undergoing DBS for TRD with individual data on stimulation parameters

Dosing of Electrical Parameters in Deep Brain Stimulation (DBS) for Intractable Depression: A Review of Clinical Studies

Background: The electrical parameters used for deep brain stimulation (DBS) in movement disorders have been relatively well studied, however for the newer indications of DBS for psychiatric indications these are less clear. Based on the movement disorder literature, use of the correct stimulation parameters should be crucial for clinical outcomes. This review examines the stimulation parameters used in DBS studies for treatment resistant depression (TRD) and their relevance to clinical outcome and brain targets. Methods: We examined the published studies on DBS for TRD archived in major databases. Data on stimulus parameters (frequency, pulse width, amplitude), stimulation mode, brain target, efficacy, safety, and duration of follow up were extracted from 29 observational studies including case reports of patients with treatment resistant unipolar, bipolar, and co-morbid depression. Results: The algorithms commonly used to optimize efficacy were increasing amplitude followed by changing the electric contacts or increasing pulse width. High frequency stimulation (>100 Hz) was applied in most cases across brain targets. Keeping the high frequency stimulation constant, three different combinations of parameters were mainly used: (i) short pulse width (60-90 us) and low amplitude (0-4 V), (ii) short pulse width and high amplitude (5-10 V), (iii) long pulse width (120-450 us) and low amplitude. There were individual variations in clinical response to electrical dosing and also in the time of clinical recovery. There was no significant difference in mean stimulation parameters between responders and non-responders suggesting a role for stimulation unrelated factors in response. Conclusions: Although limited by open trials and small sample size, three optimal stimulation parameter combinations emerged from this review. Studies are needed to assess the comparative efficacy and safety of these combinations, such as a registry of data from patients undergoing DBS for TRD with individual data on stimulation parameters

A Preliminary Study of the Influence of Age of Onset and Childhood Trauma on Cortical Thickness in Major Depressive Disorder

Background. Major depressive disorder (MDD) neural underpinnings may differ based on onset age and childhood trauma. We assessed cortical thickness in patients who differed in age of MDD onset and examined trauma history influence. Methods. Adults with MDD (N=36) and controls (HC; N=18) underwent magnetic resonance imaging. Twenty patients had MDD onset <24 years of age (pediatric onset) and 16 had onset >25 years of age (adult onset). The MDD group was also subdivided into those with (N=12) and without (N=19) physical and/or sexual abuse as assessed by the Childhood Trauma Questionnaire (CTQ). Cortical thickness was analyzed with FreeSurfer software. Results. Thicker frontal pole and a tendency for thinner transverse temporal cortices existed in MDD. The former was driven by the pediatric onset group and abuse history (independently), particularly in the right frontal pole. Inverse correlations existed between CTQ scores and frontal pole cortex thickness. A similar inverse relation existed with left inferior and right superior parietal cortex thickness. The superior temporal cortex tended to be thinner in pediatric versus adult onset groups with childhood abuse. Conclusions. This preliminary work suggests neural differences between pediatric and adult MDD onset. Trauma history also contributes to cytoarchitectural modulation. Thickened frontal pole cortices as a compensatory mechanism in MDD warrant evaluation

A Preliminary Study of the Influence of Age of Onset and Childhood Trauma on Cortical Thickness in Major Depressive Disorder

Background. Major depressive disorder (MDD) neural underpinnings may differ based on onset age and childhood trauma. We assessed cortical thickness in patients who differed in age of MDD onset and examined trauma history influence. Methods. Adults with MDD () and controls (HC; ) underwent magnetic resonance imaging. Twenty patients had MDD onset 24 years of age (pediatric onset) and 16 had onset 25 years of age (adult onset). The MDD group was also subdivided into those with () and without () physical and/or sexual abuse as assessed by the Childhood Trauma Questionnaire (CTQ). Cortical thickness was analyzed with FreeSurfer software. Results. Thicker frontal pole and a tendency for thinner transverse temporal cortices existed in MDD. The former was driven by the pediatric onset group and abuse history (independently), particularly in the right frontal pole. Inverse correlations existed between CTQ scores and frontal pole cortex thickness. A similar inverse relation existed with left inferior and right superior parietal cortex thickness. The superior temporal cortex tended to be thinner in pediatric versus adult onset groups with childhood abuse. Conclusions. This preliminary work suggests neural differences between pediatric and adult MDD onset. Trauma history also contributes to cytoarchitectural modulation. Thickened frontal pole cortices as a compensatory mechanism in MDD warrant evaluation.Peer Reviewe