Abnormalities in functional limbic–anterior cingulate–prefrontal circuits associated with emotional reactivity, evaluation and regulation have been implicated in the pathophysiology of major depressive disorder (MDD). However, existing knowledge about structural alterations in depression is equivocal and based on cohorts of limited sample size. This study used voxel-based morphometry (VBM) and surface-based cortical thickness to investigate the structure of these circuits in a large and well-characterized patient cohort with MDD.
Non-geriatric MDD outpatients (n = 102) and age- and gender-matched healthy control participants (n = 34) provided T1-weighted magnetic resonance imaging data during their baseline visit as part of the International Study to Predict Optimized Treatment for Depression. Whole-brain VBM volumetric and surface-based cortical thickness assessments were performed voxel-wise and compared (at p < 0.05 corrected for multiple comparisons) between the MDD and control groups.
MDD participants had reduced gray matter volume in the anterior cingulate cortex, regions of the prefrontal circuits, including dorsolateral and dorsomedial prefrontal cortices, and lateral and medial orbitofrontal cortices, but not in limbic regions. Additional reductions were observed cortically in the posterior temporal and parieto-occipital cortices and, subcortically in the basal ganglia and cerebellum. Focal cortical thinning in the medial orbitofrontal cortex was also observed for the MDD group. These alterations in volume and cortical thickness were not associated with severity of depressive symptoms.
The findings demonstrate that widespread gray matter structural abnormalities are present in a well-powered study of patients with depression. The patterns of gray matter loss correspond to the same brain functional network regions that were previously established to be abnormal in MDD, which may support an underlying structural abnormality for these circuits.
•Focal gray matter volume decrease in depression exceeded loss via aging 11–50 years.•Gray matter differences were found in regions with established roles in depression.•Structural change findings support the idea of depression as a network abnormality.•Hippocampal gray matter volume loss likely has no role in non-geriatric depression.•Amygdala gray matter volume loss likely plays no role in depression pathophysiology.
AAL, Automated Anatomical Labeling; ACC, Anterior Cingulate Cortex; BAs, Brodmann Areas; CVNA, Change in Volume expected in that region through Normal Aging; DLPFC, Dorsolateral Prefrontal Cortex; DTI, Diffusion Tensor Imaging; FDR, False Discovery Rate; fMRI, functional Magnetic Resonance Imaging; GM, Gray Matter; HRSD17, 17-Item Hamilton Rating Scale for Depression; iSPOT-D, International Study to Predict Optimized Treatment in Depression; MDD, Major Depressive Disorder; MPFC, Medial Prefrontal Cortex; MRI, Magnetic Resonance Imaging; OFC, Orbitofrontal Cortex; PFC, Prefrontal Cortex; VBM, Voxel-Based Morphometry; Gray matter; Major depressive disorder; VBM; Volume; Cortical thickness; iSPOT-D
The microtubule-associated protein tau gene (MAPT) codes for a protein that plays an integral role in stabilisation of microtubules and axonal transport in neurons. As well as its role in susceptibility to neurodegeneration, previous studies have found an association between the MAPT haplotype and intracranial volume and regional grey matter volumes in healthy adults. The glycogen synthase kinase-3β gene (GSK3B) codes for a serine/threonine kinase that phosphorylates various proteins, including tau, and has also been associated with risk for neurodegenerative disorders and schizophrenia. We examined the effects of MAPT and two functional promoter polymorphisms in GSK3B (rs3755557 and rs334558) on total grey matter and intracranial volume in three independent cohorts totaling 776 neurologically healthy individuals. In vitro analyses revealed a significant effect of rs3755557 on gene expression, and altered binding of at least two transcription factors, Octamer transcription factor 1 (Oct-1) and Pre-B-cell leukemia transcription factor 1 (Pbx-1), to the GSK3B promoter. Meta-analysis across the three cohorts revealed a significant effect of rs3755557 on total grey matter volume (summary B = 0.082, 95% confidence interval = 0.037–0.128) and intracranial volume (summary B = 0.113, 95% confidence interval = 0.082–0.144). No significant effect was observed for MAPT H1/H2 diplotype or GSK3B rs334558 on total grey matter or intracranial volume. Our genetic and biochemical analyses have identified a role for GSK3B in brain development, which could have important aetiological implications for neurodegenerative and neurodevelopmental disorders.
Approximately 50% of patients with major depressive disorder (MDD) do not respond optimally to antidepressant treatments. Given this is a large proportion of the patient population, pretreatment tests that predict which patients will respond to which types of treatment could save time, money and patient burden. Brain imaging offers a means to identify treatment predictors that are grounded in the neurobiology of the treatment and the pathophysiology of MDD.
The international Study to Predict Optimized Treatment in Depression is a multi-center, parallel model, randomized clinical trial with an embedded imaging sub-study to identify such predictors. We focus on brain circuits implicated in major depressive disorder and its treatment. In the full trial, depressed participants are randomized to receive escitalopram, sertraline or venlafaxine-XR (open-label). They are assessed using standardized multiple clinical, cognitive-emotional behavioral, electroencephalographic and genetic measures at baseline and at eight weeks post-treatment. Overall, 2,016 depressed participants (18 to 65 years old) will enter the study, of whom a target of 10% will be recruited into the brain imaging sub-study (approximately 67 participants in each treatment arm) and 67 controls. The imaging sub-study is conducted at the University of Sydney and at Stanford University. Structural studies include high-resolution three-dimensional T1-weighted, diffusion tensor and T2/Proton Density scans. Functional studies include standardized functional magnetic resonance imaging (MRI) with three cognitive tasks (auditory oddball, a continuous performance task, and Go-NoGo) and two emotion tasks (unmasked conscious and masked non-conscious emotion processing tasks). After eight weeks of treatment, the functional MRI is repeated with the above tasks. We will establish the methods in the first 30 patients. Then we will identify predictors in the first half (n = 102), test the findings in the second half, and then extend the analyses to the total sample.
International Study to Predict Optimized Treatment - in Depression (iSPOT-D). ClinicalTrials.gov, NCT00693849.
Major depressive disorder; Antidepressant treatments; Imaging; Biomarker; iSPOT-D
Few standardized tools are available for time-efficient screening of emotional health status across diagnostic categories, especially in primary care. We evaluated the 45-question Brief Risk-resilience Index for SCreening (BRISC) and the 15-question mini-BRISC in identifying poor emotional health and coping capacity across a range of diagnostic groups – compared with a detailed clinical assessment – in a large sample of adult outpatients. Participants 18–60 years of age (n = 1079) recruited from 12 medical research and clinical sites completed the computerized assessments. Three index scores were derived from the full BRISC and the mini-BRISC: one for risk (negativity–positivity bias) and two for coping (resilience and social capacity). Summed answers were converted to standardized z-scores. BRISC scores were compared with detailed health assessment and diagnostic interview (for current psychiatric, psychological, and neurological conditions) by clinicians at each site according to diagnostic criteria. Clinicians were blinded to BRISC scores. Clinical assessment stratified participants as having “clinical” (n = 435) or “healthy” (n = 644) diagnostic status. Receiver operating characteristic analyses showed that a z-score threshold of −1.57 on the full BRISC index of emotional health provided an optimal classification of “clinical” versus “healthy” status (sensitivity: 81.2%, specificity: 92.7%, positive predictive power: 80.2%, and negative predictive power: 93.1%). Comparable findings were revealed for the mini-BRISC. Negativity–positivity bias index scores contributed the most to prediction. The negativity–positivity index of emotional health was most sensitive to classifying major depressive disorder (100%), posttraumatic stress disorder (95.8%), and panic disorder (88.7%). The BRISC and mini-BRISC both offer a brief, clinically useful screen to identify individuals at risk of disorders characterized by poor emotion regulation, from those with good emotional health and coping.
Depression and anxiety; emotional well-being; Internet; mental health screen; risk and resilience; sensitivity and specificity
Chronic pain has been associated with impaired cognitive function. We examined cognitive performance in patients with severe chronic pancreatitis pain. We explored the following factors for their contribution to observed cognitive deficits: pain duration, comorbidity (depression, sleep disturbance), use of opioids, and premorbid alcohol abuse. The cognitive profiles of 16 patients with severe pain due to chronic pancreatitis were determined using an extensive neuropsychological test battery. Data from three cognitive domains (psychomotor performance, memory, executive functions) were compared to data from healthy controls matched for age, gender and education. Multivariate multilevel analysis of the data showed decreased test scores in patients with chronic pancreatitis pain in different cognitive domains. Psychomotor performance and executive functions showed the most prominent decline. Interestingly, pain duration appeared to be the strongest predictor for observed cognitive decline. Depressive symptoms, sleep disturbance, opioid use and history of alcohol abuse provided additional explanations for the observed cognitive decline in some of the tests, but to a lesser extent than pain duration. The negative effect of pain duration on cognitive performance is compatible with the theory of neurodegenerative properties of chronic pain. Therefore, early and effective therapeutic interventions might reduce or prevent decline in cognitive performance, thereby improving outcomes and quality of life in these patients.
Clinically useful treatment moderators of Major Depressive Disorder (MDD) have not yet been identified, though some baseline predictors of treatment outcome have been proposed. The aim of iSPOT-D is to identify pretreatment measures that predict or moderate MDD treatment response or remission to escitalopram, sertraline or venlafaxine; and develop a model that incorporates multiple predictors and moderators.
The International Study to Predict Optimized Treatment - in Depression (iSPOT-D) is a multi-centre, international, randomized, prospective, open-label trial. It is enrolling 2016 MDD outpatients (ages 18-65) from primary or specialty care practices (672 per treatment arm; 672 age-, sex- and education-matched healthy controls). Study-eligible patients are antidepressant medication (ADM) naïve or willing to undergo a one-week wash-out of any non-protocol ADM, and cannot have had an inadequate response to protocol ADM. Baseline assessments include symptoms; distress; daily function; cognitive performance; electroencephalogram and event-related potentials; heart rate and genetic measures. A subset of these baseline assessments are repeated after eight weeks of treatment. Outcomes include the 17-item Hamilton Rating Scale for Depression (primary) and self-reported depressive symptoms, social functioning, quality of life, emotional regulation, and side-effect burden (secondary). Participants may then enter a naturalistic telephone follow-up at weeks 12, 16, 24 and 52. The first half of the sample will be used to identify potential predictors and moderators, and the second half to replicate and confirm.
First enrolment was in December 2008, and is ongoing. iSPOT-D evaluates clinical and biological predictors of treatment response in the largest known sample of MDD collected worldwide.
International Study to Predict Optimised Treatment - in Depression (iSPOT-D) ClinicalTrials.gov Identifier: NCT00693849
Identification of the biological markers of anorexia nervosa (AN) is crucial for the development of new treatments. We aimed to determine whether AN is associated with disturbances in the nonconscious neural processing of innate signals of emotion and whether these disturbances persist after weight gain.
In a retest design, 28 adolescent females with AN were tested at first admission to hospital and again after they had gained weight. Matched healthy control participants were tested at the same times. We assessed emotion-elicited event-related potentials (ERPs) during overt and covert presentation of emotion expressions, scores on an emotion-identification behavioural task, and symptom measures. We performed between and within group analyses.
Individuals with AN had a marked alteration in ERPs relative to healthy controls. Irrespective of the form of stimulus, early and late ERP components were significantly reduced in AN patients at baseline (when underweight) and on retest (after weight gain), especially in the temporo-occipital regions, suggesting a persistent disruption of the early automatic appraisal of salient emotional signals.
This study could have been improved with a longer standardized retest interval.
There is likely a core, generic disturbance in AN in the early “automatic” neural processing of emotion irrespective of weight or nutritional status. New innovative emotion-based psychologic or pharmacologic treatments targeting these nonconscious processes may prove beneficial.
The purpose of this study was to examine the impact of age, sex, and education on category and letter verbal fluency task performance. A secondary goal was to examine whether resting EEG theta power in bilateral frontal and temporal lobes impacts age-associated decline in verbal fluency task performance. A large sample (N=471) of healthy, normal participants, age 21–82, was assessed for letter fluency (i.e., FAS), and for category fluency (i.e., Animal Naming), and with a 32-channel EEG system for ‘eyes-open’ resting theta power. The effects of age, sex, and education were examined using analyses of variance. Correlation analyses were used to test the impact of theta power on age and fluency performance by controlling for the effects of theta when examining the relationship between the other two variables. The results indicated that performance on both fluency tests declined linearly with age, but that the rate of decline was greater for category fluency. These age changes were not associated with education level, and there were no sex differences. While theta power was negatively associated with age and positively associated with Animal Naming performance, it did not moderate the relationship between the two. The differential age-associated decline between category and letter fluency suggests separate neurobiological substrates underlying the two domains of performance, which is not related to theta activity.
Normal aging; Category fluency; Letter fluency; EEG; Theta
Previous studies have examined the impact of subcortical hyperintensities (SH), a proxy measure of cerebrovascular disease, on the cognitive abilities of otherwise healthy older adults. However, there remains a limited understanding as to what extent this MRI marker of pathological processes explains the decline in specific cognitive functions that occur nearly ubiquitously with advanced age, especially in relation to other age-related imaging markers. In the present study we compared cognitive abilities between a sample of 53 older healthy adults (age range = 50–79) and a sample of 53 younger adults (age range = 21–40). As expected, the older group performed significantly worse on most cognitive measures compared to the younger group. Frontal volume and total grey matter volume were also significantly reduced among the older individuals compared to the younger individuals. SH volume was consistently associated with cognitive function in older adults, though, this relationship was evident only for a relatively small subset of older individuals with the most severe SH. These data suggest that the relationship between SH and cognition in the elderly is driven by a subset of individuals who may be in the earliest stages of vascular cognitive impairment. Further, the findings suggest that cognitive aging is largely determined by factors other than SH for most older adults.
Subcortical hyperintensities; Cognition; Elderly; MRI
Schizophrenia may be understood as a disorder of neural synchrony. There is also increasing evidence that emotional and social cognitive impairments are central to this disorder. In patients with first-episode schizophrenia, we examined whether emotion perception is associated with disruptions to high-frequency (40 Hz) gamma synchrony and whether these disruptions predict self-regulatory adaptive compensations reflected in social cognitive behaviours.
We obtained electroencephalography recordings from 28 patients with first-episode schizophrenia and matched healthy controls during perception of facial emotion under both conscious and nonconscious conditions. We extracted gamma-band synchrony from the electroencephalogram. We also used behavioural measures of emotion identification, emotional intelligence, negativity bias and social function, along with ratings of first-episode schizophrenia symptoms. We analyzed group differences and predicted social cognition to assess the potential contribution of medication.
Within 200 ms poststimulus, patients with first-episode schizophrenia showed alterations in gamma synchrony during both conscious and nonconscious emotion perception. Stimulus-locked synchrony was reduced in patients, particularly over the temporal cortex, whereas complementary enhancements in absolute gamma synchrony (independent of stimuli) were more distributed over temporal and left parieto-occipital regions. This pattern of altered synchrony predicted poor performance on each measure of social cognition among these patients. Medication dosage did not correlate significantly with either gamma synchrony or behavioural measures in this group.
Limitations to our study include the lack of comparison between medicated and unmedicated patients or between types of medication.
These findings suggest that disruptions in integrative processing of motivationally important stimuli show promise as a potential biological marker of social cognitive impairments, present from the first episode of schizophrenia, and their outcomes.
Although schizophrenia has been characterized by disruptions to neural synchrony, it remains unknown whether these disturbances are related to symptoms and loss of grey matter. We examined relations between 40 Hz Gamma band synchrony and grey matter in patients with schizophrenia at first episode and after 2.5 years.
From an initial recruitment of 35 medicated patients with a first episode of schizophrenia, 25 patients completed clinical and oddball task-elicited Gamma synchrony within 3 months of health service contact and again after 2.5 years, 23 completed magnetic resonance imaging (MRI) at these time points, and 13 completed all sessions. We compared patients with 35 matched healthy controls. We identified early (0–150 ms) and late (250–500 ms) peaks in Gamma synchrony locked to oddball targets, and we analyzed MRI data using voxel-based morphometry. We evaluated group and test–retest differences using repeated-measures analyses of variance.
Compared with controls, at first contact, patients with a first episode of schizophrenia showed a disruption to the laterality of early Gamma synchrony and global reduction in late Gamma synchrony, with a corresponding loss of fronto–temporal–parietal grey matter. Gamma synchrony was increased at follow-up among patients with a first episode of schizophrenia. It related negatively to further loss of grey matter, but positively to improvement in reality distortion symptoms. These relations could not be explained by medication dose.
Our study did not include unmedicated patients or normative follow-up testing.
Gamma synchrony may track the progression of schizophrenia from first episode. An increase in Gamma synchrony over time might reflect an attempt to adapt to a progressive loss of cortical grey matter and associated changes in cognitive and emotional function.
Posttraumatic stress disorder (PTSD) involves deficits in information processing that may reflect hypervigilence and deficient inhibitory control. To date, however, no PTSD neuroimaging study has directly examined PTSD-related changes in executive inhibition. Our objective was to investigate the hypothesis that executive inhibitory control networks are compromised in PTSD.
Functional magnetic resonance imaging (fMRI) was used during a Go/No-Go inhibition task completed by a sample of patients with PTSD (n = 23), a matched sample of healthy (i.e. without trauma exposure) control participants (n = 23) and a sample of control participants with trauma exposure who did not meet criteria for PTSD (n = 17).
Participants with PTSD showed more inhibition-related errors than did individuals without trauma exposure. During inhibition, control participants activated a right-lateralized cortical inhibitory network, whereas patients with PTSD activated only the left lateral frontal cortex. PTSD was associated with a reduction in right cortical activation and increased activation of striatal and somatosensory regions.
The increased inhibitory error and reduced right frontal cortical activation are consistent with compromised inhibitory control in PTSD, while the increased activation of brain regions associated with sensory processing and a greater demand on inhibitory control may reflect enhanced stimulus processing in PTSD, which may undermine cortical control mechanisms.
inhibition; stress disorders, posttraumatic; motor activity; neurophysiology
Previous studies have examined the impact of early life stress (ELS) on the gross morphometry of brain regions, including the corpus callosum. However, studies have not examined the relationship between ELS and the microstructural integrity of the brain.
In the present study we evaluated this relationship in healthy non-clinical participants using diffusion tensor imaging (DTI) and self-reported history of ELS.
Regression analyses revealed significant reductions in fractional anisotropy (FA) within the genu of the corpus callosum among those exposed to the greatest number of early life stressors, suggesting reduced microstructural integrity associated with increased ELS. These effects were most pronounced in the genu of the corpus callosum compared to the body and splenium, and were evident for females rather than males despite no differences in total ELS exposure between the sexes. In addition, a further comparison of those participants who were exposed to no ELS vs. three or more ELS events revealed lower FA in the genu of the corpus callosum among the ELS-exposed group, with trends of FA reduction in the body and the whole corpus callosum. By contrast, there were no relationships between ELS and volumetric analysis of the CC regions. The two group did not differ significantly on measures of current depression, stress or anxiety.
Our results reveal that greater exposure to ELS is associated with microstructural alterations in the white matter in the absence of significant volumetric changes. Importantly, our results indicate that exposure to ELS is associated with abnormalities on DTI despite the absence of clinically significant psychiatric symptoms. Future studies are needed to determine whether specific types of ELS are more likely to impact brain structure and function.
Results from recent studies suggest that chronic cigarette smoking is associated with increased white matter volume in the brain as determined by in vivo neuroimaging. We used diffusion tensor imaging to examine the microstructural integrity of the white matter in 10 chronic smokers and 10 nonsmokers. All individuals were healthy, without histories of medical or psychiatric illness. Fractional anisotropy (FA) and trace were measured in the genu, body, and splenium of the corpus callosum. FA provides a measure of directional versus nondirectional water diffusion, whereas trace provides a measure of nondirectional water diffusion. Lower FA and higher trace values are considered to reflect less brain integrity. Voxel-based morphometry was used to define volumes in each of these regions of the corpus callosum. Chronic smokers exhibited significantly higher FA in the body and whole corpus callosum and a strong trend for higher FA in the splenium compared with nonsmokers. FA did not differ between groups in the genu, and neither trace nor white matter volumes differed between groups in any of the regions of interest. When subdivided by Fagerström score (low vs. high), the low Fagerström group exhibited significantly higher FA in the body of the corpus callosum compared with the high Fagerström group and the nonsmokers. These results suggest that, among healthy adults, lower exposure to cigarette smoking is associated with increased microstructural integrity of the white matter compared with either no exposure or higher exposure. Additional studies are needed to further explore differences in white matter integrity between smokers and nonsmokers.
Efforts to identify genetic factors that confer an increased risk for the expression of psychiatric symptoms have focused on polymorphisms in variety of candidate genes, including the catechol-O-methyltransferase (COMT) gene. Results from previous studies that have examined associations between the functional COMT polymorphism (Val158Met) and mental health have been mixed. In the present study, we examined the relationships between COMT, early life stress, and personality in a healthy adult sample. Consistent with previous studies, we hypothesized that individuals with the low-activity genotype would have higher neuroticism and lower extraversion and that this effect would be more pronounced in females. In addition, we extended the previous literature by investigating the potential influence of early life stress. A total of 486 healthy adults underwent genetic testing and personality assessment. Results revealed that individuals homozygous for the COMT low enzyme activity allele had lower extraversion on the NEO-FFI and demonstrated a trend toward greater neuroticism. These relationships were not influenced by sex or the presence of reported early life stress. The finding that COMT genotype was associated with extraversion, and more weakly with neuroticism, is consistent with previous studies. Future research to clarify the influence of sex and gene–environmental interactions is warranted.
anxiety; depression; gene-environment interaction; early life stress
Symptoms of borderline personality disorder (BPD) may reflect distinct breakdowns in the integration of posterior and frontal brain networks. We used a high temporal resolution measure (40-Hz gamma phase synchrony) of brain activity to examine the connectivity of brain function in BPD.
Unmedicated patients with BPD (n = 15) and age-and sex-matched healthy control subjects (n = 15) undertook a task requiring discrimination of salient from background tones. In response to salient stimuli, the magnitude and latency of peak gamma phase synchrony for early (0–150 ms post stimulus) and late (250–500 ms post stimulus) phases were calculated for frontal and posterior regions and for left and right hemispheres. We recorded skin conductance responses (SCRs) and reaction time (RT) simultaneously to examine the contribution of arousal and performance.
Compared with controls, patients with BPD had a significant delay in early posterior gamma synchrony and a reduction in right hemisphere late gamma synchrony in response to salient stimuli. Both SCR onset and RT were also delayed in BPD, but independently from differences in synchrony. The delay in posterior synchrony was associated with cognitive symptoms, and reduced right hemisphere synchrony was associated with impulsivity.
These findings suggest that distinct impairments in the functional connectivity of neural systems for orienting to salient input underlie core dimensions of cognitive disturbance and poor impulse control in BPD.
brain; borderline personality disorder; cognition; electroencephalography; gamma synchrony