Geoffrey B. Hall

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen’s d=−0.14, % difference=−1.24). This effect was driven by patients with recurrent MDD (Cohen’s d=−0.17, % difference=−1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen’s d=−0.20, % difference=−1.85) and a trend toward smaller amygdala (Cohen’s d=−0.11, % difference=−1.23) and larger lateral ventricles (Cohen’s d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Biomarkers in bipolar disorder: A positional paper from the International Society for Bipolar Disorders Biomarkers Task Force

Although the etiology of bipolar disorder remains uncertain, multiple studies examining neuroimaging, peripheral markers and genetics have provided important insights into the pathophysiologic processes underlying bipolar disorder. Neuroimaging studies have consistently demonstrated loss of gray matter, as well as altered activation of subcortical, anterior temporal and ventral prefrontal regions in response to emotional stimuli in bipolar disorder. Genetics studies have identified several potential candidate genes associated with increased risk for developing bipolar disorder that involve circadian rhythm, neuronal development and calcium metabolism. Notably, several groups have found decreased levels of neurotrophic factors and increased pro-inflammatory cytokines and oxidative stress markers. Together these findings provide the background for the identification of potential biomarkers for vulnerability, disease expression and to help understand the course of illness and treatment response. In other areas of medicine, validated biomarkers now inform clinical decision-making. Although the findings reviewed herein hold promise, further research involving large collaborative studies is needed to validate these potential biomarkers prior to employing them for clinical purposes. Therefore, in this positional paper from the ISBD-BIONET (biomarkers network from the International Society for Bipolar Disorders), we will discuss our view of biomarkers for these three areas: neuroimaging, peripheral measurements and genetics; and conclude the paper with our position for the next steps in the search for biomarkers for bipolar disorder.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen’s d effect sizes: −0.10 to −0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: −0.26 to −0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Maternal affect and quality of parenting experiences are related to amygdala response to infant faces

We examined how individual differences in mood and anxiety in the early postpartum period are related to brain response to infant stimuli during fMRI, with particular focus on regions implicated in both maternal behavior and mood/anxiety, that is, the subgenual anterior cingulate cortex (sgACC) and the amygdala. At approximately 3 months postpartum, 22 mothers completed an affect-rating task (ART) during fMRI, where their affective response to infant stimuli was explicitly probed. Mothers viewed/rated four infant face conditions: own positive (OP), own negative (ON), unfamiliar positive (UP), and unfamiliar negative (UN). Mood and anxiety were measured by the Edinburgh Postnatal Depression Scale (EDPS) and the State-Trait Anxiety Inventory-Trait Version (STAI-T); maternal factors related to parental stress and attachment were also assessed. Brain-imaging data underwent a random-effects analysis, and cluster-based statistical thresholding was applied to the following contrasts: OP–UP, ON–UN, OP–ON, and UP–UN. Our main finding was that poorer quality of maternal experience was significantly related to reduced amygdala response to OP compared to UP infant faces. Our results suggest that, in human mothers, infant-related amygdala function may be an important factor in maternal anxiety/mood, in quality of mothering, and in individual differences in the motivation to mother. We are very grateful to the staff at the Imaging Research Center of the Brain-Body Institute for their contributions to this project. This work was supported by an Ontario Mental Health Foundation operating grant awarded to Alison Fleming and a postdoctoral fellowship awarded to Jennifer Barrett.

Hippocampal metabolic abnormalities at first onset and with recurrent episodes of a major depressive disorder: A proton magnetic resonance spectroscopy study☆

The neural underpinnings of major depressive disorder (MDD) are unknown but there is evidence for structural alteration in the hippocampus that may become more pronounced over the course of illness. The aim of the present study was to examine metabolite levels of N-acetyl-aspartate (NAA), Myo-inositol (MI), Glutamate-glutamine (Glx) and choline-containing compounds (GPC and GPC+PCh) in patients presenting for first treatment of a depressive episode compared to those with multiple past episodes and age and sex matched controls. We used single voxel proton magnetic resonance spectroscopy ((1)H-MRS) centered on the hippocampus. Choline-containing compounds were significantly increased in patients with a high past illness burden relative to controls after controlling for hippocampal volume. The group presenting for first treatment had only increases in MI levels compared with matched controls. These results suggest that abnormal membrane turnover in the hippocampus is greater in patients with highly recurrent illness, and provide support for the hypothesis that there are neuronal changes in this region over the course of illness.

Sex differences in functional activation patterns revealed by increased emotion processing demands.

Two [O15] PET studies assessed sex differences regional brain activation in the recognition of emotional stimuli. Study I revealed that the recognition of emotion in visual faces resulted in bilateral frontal activation in women, and unilateral right-sided activation in men. In study II, the complexity of the emotional face task was increased through tje addition of associated auditory emotional stimuli. Men again showed unilateral frontal activation, in this case to the left; whereas women did not show bilateral frontal activation, but showed greater limbic activity. These results suggest that when processing broader cross-modal emotional stimuli, men engage more in associative cofnitive strategies while women draw more on primary emotional references.

Inter-rater and test–retest reliability of quality assessments by novice student raters using the Jadad and Newcastle–Ottawa Scales

Introduction Quality assessment of included studies is an important component of systematic reviews. Objective The authors investigated inter-rater and test–retest reliability for quality assessments conducted by inexperienced student raters. Design Student raters received a training session on quality assessment using the Jadad Scale for randomised controlled trials and the Newcastle–Ottawa Scale (NOS) for observational studies. Raters were randomly assigned into five pairs and they each independently rated the quality of 13–20 articles. These articles were drawn from a pool of 78 papers examining cognitive impairment following electroconvulsive therapy to treat major depressive disorder. The articles were randomly distributed to the raters. Two months later, each rater re-assessed the quality of half of their assigned articles. Setting McMaster Integrative Neuroscience Discovery and Study Program. Participants 10 students taking McMaster Integrative Neuroscience Discovery and Study Program courses. Main outcome measures The authors measured inter-rater reliability using κ and the intraclass correlation coefficient type 2,1 or ICC(2,1). The authors measured test–retest reliability using ICC(2,1). Results Inter-rater reliability varied by scale question. For the six-item Jadad Scale, question-specific κs ranged from 0.13 (95% CI −0.11 to 0.37) to 0.56 (95% CI 0.29 to 0.83). The ranges were −0.14 (95% CI −0.28 to 0.00) to 0.39 (95% CI −0.02 to 0.81) for the NOS cohort and −0.20 (95% CI −0.49 to 0.09) to 1.00 (95% CI 1.00 to 1.00) for the NOS case–control. For overall scores on the six-item Jadad Scale, ICC(2,1)s for inter-rater and test–retest reliability (accounting for systematic differences between raters) were 0.32 (95% CI 0.08 to 0.52) and 0.55 (95% CI 0.41 to 0.67), respectively. Corresponding ICC(2,1)s for the NOS cohort were −0.19 (95% CI −0.67 to 0.35) and 0.62 (95% CI 0.25 to 0.83), and for the NOS case–control, the ICC(2,1)s were 0.46 (95% CI −0.13 to 0.92) and 0.83 (95% CI 0.48 to 0.95). Conclusions Inter-rater reliability was generally poor to fair and test–retest reliability was fair to excellent. A pilot rating phase following rater training may be one way to improve agreement.

Abnormal hippocampal activation in patients with extensive history of major depression: an fMRI study

BACKGROUND Impairment of recollection memory is consistently reported in patients with major depressive disorder (MDD) and may reflect underlying functional hippocampal changes, particularly in those with extensive histories of illness. We hypothesized that relative to controls, patients with a protracted course of illness would show diminished hippocampal activation on functional magnetic resonance imaging (fMRI) during a recollection memory task. METHODS Patients who experienced 3 or more previously treated depressive episodes were compared with age- and sex-matched controls. We acquired fMRI data while participants performed a recollection memory process dissociation task. RESULTS Using bilateral regions of interest (ROIs) prescribed for the right and left hippocampal/parahippocampal complex, we observed increased activation of the right hippocampal and left parahippocampal gyrus in controls compared with patients with MDD during recollection memory trials. Within-group comparisons revealed heightened engagement of the hippocampal head (R/L) for controls during recollection trials, and greater activation of the hippocampal body/tail (R/L) during the learn-list encoding period in both the MDD and control groups. Recollection memory performance was significantly correlated with changes in blood oxygen level-dependent signal during recollection trials in the ROIs of the right hippocampus and right hippocampal head. LIMITATIONS This study was limited by the inclusion of patients taking antidepressant medication, raising the possibility that the reported findings were treatment effects. CONCLUSION The findings of decreased recruitment of the right hippocampal and left parahippocampalgyrus in patients with MDD suggest that these regions may be sensitive to the impact of disease burden and repeated episodes of MDD. This attenuated activation may represent stable changes in hippocampal function that occur over the course of illness in patients with MDD. The findings from within-group comparisons show that the group differences in the activation of the right hippocampal head were driven by greater engagement of this region among controls during recollection memory performance. These results also associate recollection performance impairments in patients with MDD with diminished hippocampal engagement.

Increased choline-containing compounds in the orbitofrontal cortex and hippocampus in euthymic patients with bipolar disorder: a proton magnetic resonance spectroscopy study.

The neuronal mechanisms underlying the pathophysiology of bipolar disorder (BD) have not been fully characterized. The aim of this study was to compare metabolite levels in the hippocampus and the orbitofrontal cortex in a homogenous population of 12 euthymic patients with well-established BD and 12 age- and sex-matched healthy comparison subjects. Using a GE Signa, 3-Tesla scanner, we performed proton magnetic resonance spectroscopy (H-MRS) to examine levels of N-acetyl aspartate, glutamate and choline-containing compounds. Choline-containing compounds were significantly increased in the hippocampus and the orbitofrontal cortex in BD patients relative to control subjects. Significant elevations of glycerophosphocholine+phosphocholine (GPC+PCh) were measured in the hippocampus and the orbitofrontal cortex of patients. As choline is a marker of membrane phospholipid metabolism, the elevated choline in patients may indicate increased membrane breakdown in the brain regions examined. Abnormal neuronal loss within the hippocampus and orbitofrontal cortex further supports previous work suggesting that these regions are involved in the pathophysiology of BD.

Autonomic predictors of Stroop performance in young and middle-aged adults.

Although changes in autonomic activity have been extensively examined as responses to cognitive challenges, relatively few studies have used individual differences in autonomic parameters to predict executive performance in healthy adults. Here we examined baseline and task-related changes in heart rate and heart rate variability (measured by respiratory sinus arrhythmia (RSA)) to predict performance of a pictorial Stroop task in a group of 81 healthy adults aged 17-55. Greater autonomic reactivity (increased heart rate and reduced RSA for task performance) was associated with faster colour naming of faces in the Stroop task. Dividing the group by median age revealed that middle-aged adults reduced RSA to a greater degree than their younger counterparts in the context of equivalent performance across groups. Findings suggest that performance of executive function tasks that evoke attentional control may depend in part on the responsiveness of autonomic control parameters via age-dependent mechanisms.