Assessing remission in major depressive disorder using a functional-structural data fusion pipeline: A CAN-BIND-1 study.

Neural network-level changes underlying symptom remission in major depressive disorder (MDD) are often studied from a single perspective. Multimodal approaches to assess neuropsychiatric disorders are evolving, as they offer richer information about brain networks. A FATCAT-awFC pipeline was developed to integrate a computationally intense data fusion method with a toolbox, to produce a faster and more intuitive pipeline for combining functional connectivity with structural connectivity (denoted as anatomically weighted functional connectivity (awFC)). Ninety-three participants from the Canadian Biomarker Integration Network for Depression study (CAN-BIND-1) were included. Patients with MDD were treated with 8 weeks of escitalopram and adjunctive aripiprazole for another 8 weeks. Between-group connectivity (SC, FC, awFC) comparisons contrasted remitters (REM) with non-remitters (NREM) at baseline and 8 weeks. Additionally, a longitudinal study analysis was performed to compare connectivity changes across time for REM, from baseline to week-8. Association between cognitive variables and connectivity were also assessed. REM were distinguished from NREM by lower awFC within the default mode, frontoparietal, and ventral attention networks. Compared to REM at baseline, REM at week-8 revealed increased awFC within the dorsal attention network and decreased awFC within the frontoparietal network. A medium effect size was observed for most results. AwFC in the frontoparietal network was associated with neurocognitive index and cognitive flexibility for the NREM group at week-8. In conclusion, the FATCAT-awFC pipeline has the benefit of providing insight on the 'full picture' of connectivity changes for REMs and NREMs while making for an easy intuitive approach.

Exploring brain connectivity changes in major depressive disorder using functional-structural data fusion: A CAN-BIND-1 study.

There is a growing interest in examining the wealth of data generated by fusing functional and structural imaging information sources. These approaches may have clinical utility in identifying disruptions in the brain networks that underlie major depressive disorder (MDD). We combined an existing software toolbox with a mathematically dense statistical method to produce a novel processing pipeline for the fast and easy implementation of data fusion analysis (FATCAT-awFC). The novel FATCAT-awFC pipeline was then utilized to identify connectivity (conventional functional, conventional structural and anatomically weighted functional connectivy) changes in MDD patients compared to healthy comparison participants (HC). Data were acquired from the Canadian Biomarker Integration Network for Depression (CAN-BIND-1) study. Large-scale resting-state networks were assessed. We found statistically significant anatomically-weighted functional connectivity (awFC) group differences in the default mode network and the ventral attention network, with a modest effect size (d < 0.4). Functional and structural connectivity seemed to overlap in significance between one region-pair within the default mode network. By combining structural and functional data, awFC served to heighten or reduce the magnitude of connectivity differences in various regions distinguishing MDD from HC. This method can help us more fully understand the interconnected nature of structural and functional connectivity as it relates to depression.

An investigation of cortical thickness and antidepressant response in major depressive disorder: A CAN-BIND study report.

Major depressive disorder (MDD) is considered a highly heterogeneous clinical and neurobiological mental disorder. We employed a novel layered treatment design to investigate whether cortical thickness features at baseline differentiated treatment responders from non-responders after 8 and 16 weeks of a standardized sequential antidepressant treatment. Secondary analyses examined baseline differences between MDD and controls as a replication analysis and longitudinal changes in thickness after 8 weeks of escitalopram treatment. 181 MDD and 95 healthy comparison (HC) participants were studied. After 8 weeks of escitalopram treatment (10-20 mg/d, flexible dosage), responders (>50% decrease in Montgomery-Åsberg Depression Scale score) were continued on escitalopram; non-responders received adjunctive aripiprazole (2-10 mg/d, flexible dosage). MDD participants were classified into subgroups according to their response profiles at weeks 8 and 16. Baseline group differences in cortical thickness were analyzed with FreeSurfer between HC and MDD groups as well as between response groups. Two-stage longitudinal processing was used to investigate 8-week escitalopram treatment-related changes in cortical thickness. Compared to HC, the MDD group exhibited thinner cortex in the left rostral middle frontal cortex [MNI(X,Y,Z=-29,9,54.5,-7.7); CWP=0.0002]. No baseline differences in cortical thickness were observed between responders and non-responders based on week-8 or week-16 response profile. No changes in cortical thickness was observed after 8 weeks of escitalopram monotherapy. In a two-step 16-week sequential clinical trial we found that baseline cortical thickness does not appear to be associated to clinical response to pharmacotherapy at 8 or 16 weeks.

Escitalopram ameliorates differences in neural activity between healthy comparison and major depressive disorder groups on an fMRI Emotional conflict task: A CAN-BIND-1 study.

BACKGROUND: Identifying objective biomarkers can assist in predicting remission/non-remission to treatment, improving remission rates, and reducing illness burden in major depressive disorder (MDD). METHODS: Sixteen MDD 8-week remitters (MDD-8), twelve 16-week remitters (MDD-16), 14 non-remitters (MDD-NR) and 30 healthy comparison participants (HC) completed a functional magnetic resonance imaging emotional conflict task at baseline, prior to treatment with escitalopram, and 8 weeks after treatment initiation. Patients were followed 16 weeks to assess remitter status. RESULTS: All groups demonstrated emotional Stroop in reaction time (RT) at baseline and Week 8. There were no baseline differences between HC and MDD-8, MDD-16, or MDD-NR in RT or accuracy. By Week 8, MDD-8 demonstrated poorer accuracy compared to HC. Compared to HC, the baseline blood-oxygen level dependent (BOLD) signal was decreased in MDD-8 in brain-stem and thalamus; in MDD-16 in lateral occipital cortex, middle temporal gyrus, and cuneal cortex; in MDD-NR in lingual and occipital fusiform gyri, thalamus, putamen, caudate, cingulate gyrus, insula, cuneal cortex, and middle temporal gyrus. By Week 8, there were no BOLD activity differences between MDD groups and HC. LIMITATIONS: The Emotional Conflict Task lacks a neutral (non-emotional) condition, restricting interpretation of how mood may influence perception of non-emotionally valenced stimuli. CONCLUSIONS: The Emotional Conflict Task is not an objective biomarker for remission trajectory in patients with MDD receiving escitalopram treatment. Escitalopram may have influenced emotion recognition in MDD groups in terms of augmented accuracy and BOLD signal in response to an Emotional Conflict Task, following 8 weeks of escitalopram treatment.

Reliability of a functional magnetic resonance imaging task of emotional conflict in healthy participants.

Task-based functional neuroimaging methods are increasingly being used to identify biomarkers of treatment response in psychiatric disorders. To facilitate meaningful interpretation of neural correlates of tasks and their potential changes with treatment over time, understanding the reliability of the blood-oxygen-level dependent (BOLD) signal of such tasks is essential. We assessed test-retest reliability of an emotional conflict task in healthy participants collected as part of the Canadian Biomarker Integration Network in Depression. Data for 36 participants, scanned at three time points (weeks 0, 2, and 8) were analyzed, and intra-class correlation coefficients (ICC) were used to quantify reliability. We observed moderate reliability (median ICC values between 0.5 and 0.6), within occipital, parietal, and temporal regions, specifically for conditions of lower cognitive complexity, that is, face, congruent or incongruent trials. For these conditions, activation was also observed within frontal and sub-cortical regions, however, their reliability was poor (median ICC < 0.2). Clinically relevant prognostic markers based on task-based fMRI require high predictive accuracy at an individual level. For this to be achieved, reliability of BOLD responses needs to be high. We have shown that reliability of the BOLD response to an emotional conflict task in healthy individuals is moderate. Implications of these findings to further inform studies of treatment effects and biomarker discovery are discussed.

Reduced accuracy accompanied by reduced neural activity during the performance of an emotional conflict task by unmedicated patients with major depression: A CAN-BIND fMRI study.

METHODS: We studied 48 MDD and 30 HC who performed an emotional conflict task in a functional magnetic resonance imaging (fMRI) scanner. RESULTS: On the emotional conflict task, MDD and HC demonstrated a robust emotional Stroop effect in reaction time and accuracy. Overall, accuracy was lower in MDD compared to HC with no significant reaction time differences. The fMRI data indicated lower BOLD activation in MDD compared to HC on comparisons of all trials, congruent, incongruent, and incongruent > congruent trials in regions including right inferior temporal gyrus, lateral occipital cortex, and occipital fusiform gyrus. Behavioural and neuroimaging data indicated no group differences in fearful versus happy face processing. LIMITATIONS: Inclusion of a neutral condition may have provided a valuable contrast to how MDD and HC process stimuli without emotional valence compared to stimuli with a strong emotional valence. CONCLUSIONS: MDD and HC demonstrated a robust emotional Stroop effect. Compared to HC, MDD demonstrated an overall reduced accuracy on the emotional conflict task and reduced BOLD activity in regions important for face perception and emotion information processing, with no differences in responding to fearful versus happy faces. These findings provide support for the theory of emotion context insensitivity in individuals with depression.

Altered hippocampal function with preserved cognitive performance in treatment-naive major depressive disorder.

The hippocampus is implicated in the pathophysiology of major depressive disorder (MDD), with evidence that morphological changes occur with disease progression. It was hypothesized that treatment-naive patients with depression would show performance deficits in hippocampus-dependent memory trials, with concurrent hippocampal activation deficits on functional magnetic resonance imaging, compared with control participants. Thirteen treatment-naive patients with MDD and 13 control participants completed a hippocampus-dependent memory functional magnetic resonance imaging process-dissociation task. On behavioural measures of habit memory and guessing, there were no significant differences between groups. Functional magnetic resonance imaging analysis indicated that compared with the control group, the MDD group showed increased activation in the parahippocampal gyrus and hippocampus on habit memory and nonitem trials. These alterations in hippocampal functioning with preserved cognitive performance on a test of hippocampus-dependent memory in MDD may be indicative of a compensatory mechanism.

Volumetric MRI Analysis of a Case of Severe Ventriculomegaly.

We present a case of a 60-year-old male referred to a tertiary psychiatric facility for diagnostic assessment due to low mood and behavioral changes. Neurological examination of the patient was unremarkable. Magnetic resonance imaging (MRI) indicated overt ventriculomegaly with gross dilatation of lateral and third ventricles. Manual segmentation of gray matter, white matter and cerebrospinal fluid demonstrated that the patient had a ventricular volume almost 46 times greater than that of healthy volunteers in the same age range. Despite his striking degree of ventriculomegaly and cortical thinning, he presented primarily with psychiatric and cognitive complaints. These represented a major neurocognitive disorder. His behavior improved with a structured environment and routine instituted by the treating team. This is a dramatic example of the brain's response to extreme structural remodeling. Elements of pluripotentiality may counteract degeneracy to preserve functions in cases of serious structural stress in the brain. Changes in the neural circuitry of emotional processing, and/or disruption in signaling pathways important for synaptogenesis may influence depression pathophysiology. How this circuitry is modified in cases of extreme structural stress such as long-standing overt ventriculomegaly, is unclear. This case demonstrates the ability of the brain to generate a normal phenotype despite structural changes that seem incompatible with advanced cognitive function, illustrating the substantial potential for adaptability and plasticity in the brain.

Do fearful eyes activate empathy-related brain regions in individuals with callous traits?

Psychopathy, a developmental disorder characterized by profound social disturbance, is associated with impaired recognition of distress cues. Since distress processing and moral socialization are closely linked, uncovering techniques to improve distress recognition could have positive treatment implications for developmental disorders that feature empathy impairments. Previous studies demonstrate that fear-recognition deficits can be remedied by redirecting attention to critical cues (the eyes for fearful faces). However, it remains unclear whether this manipulation increases activity in empathy-related brain regions, or has an alternate compensatory effect that may not promote prosocial behaviours. In this fMRI study, a community sample of individuals with high vs low callous traits completed an emotion recognition task that varied whether the most or least socially meaningful facial features were visible (the eyes were isolated or occluded). For fearful faces, individuals with high callous traits showed significantly less amygdala and medial prefrontal cortex activity than those with low callous traits when the eyes were occluded, but not when they were isolated. Consistent with recent models of the amygdala that emphasize orientation to disambiguate stimuli rather than represent distress, individuals with low trait empathy showed greater amygdala activity to the least vs most socially meaningful features of fearful faces.

Echogenicity of the substantia nigra in relatives of patients with sporadic Parkinson's disease.

Increased echogenicity of the substantia nigra (SN) on ultrasound is a typical sonographic finding in Parkinson's disease (PD). Sonographic signal intensity of the SN is related to tissue iron content with higher iron level being associated with increased echogenicity. Recent findings indicate that hyperechogenicity of the SN represents an important susceptibility factor for nigrostriatal degeneration. In this study we determined the prevalence of a characteristic ultrasound sign of Parkinson's disease in first-degree relatives of PD patients. Fourteen patients with sporadic PD and 58 of their relatives underwent neurological, neuropsychological, and ultrasound examination. In addition, four pairs of relatives (one member of each pair exhibiting increased echogenicity of the SN and the other with regular SN echogenicity) underwent (18)F-Dopa PET examination. On transcranial sonography, 26 of the 58 relatives exhibited SN hyperechogenicity. Twenty-four relatives showed minor signs of motor slowing. Relatives with SN hyperechogenicity more often showed signs of hypokinesia (16 v 8 relatives; U test, P = 0.01) and impaired executive functions (Tower of London task, problems solved with the minimum number of moves; U test, P = 0.012) than relatives without this echo pattern. In addition, (18)F-Dopa uptake (influx constants) at the putamen was reduced in subjects with SN hyperechogenicity compared to their relatives without this ultrasound sign (Wilcoxon, P = 0.03). In conclusion, approximately 45% of relatives of PD patients exhibited an increased echogenicity of the SN. This sign is associated with clinical findings and objective measurements, indicating some degree of impaired nigrostriatal function.