James H. Cole

Hippocampal atrophy in first episode depression: a meta-analysis of magnetic resonance imaging studies.

BACKGROUND Reduced hippocampal volume has been consistently observed in major depressive disorder. Hippocampal volume loss is particularly evident in patients with recurrent and chronic depression. However, the reports in first episode depression have been mixed. METHODS We performed a random effects meta-analysis to establish whether hippocampal atrophy exists from disease onset. We included magnetic resonance imaging studies of hippocampal volume in patients with first episode major depressive disorder and matched healthy controls. RESULTS A total of 7 studies met our inclusion and exclusion criteria, representing independent observations in a total sample of 191 patients and 282 healthy controls. The cumulative analysis revealed hippocampal volume loss in patients with first episode depression relative to controls in both the left (standardised mean difference, SMD = -0.41, 95% Confidence Interval: [-0.78;-0.03], z = -2.14, p = 0.0321) and right (SMD = -0.53[-0.98;-0.09], z = -2.38, p = 0.0173) hippocampi. The average volume reduction was -4.0% in the left and -4.5% in the right hippocampus. CONCLUSIONS Hippocampal volume loss in first episode depression is consistent with a neurodevelopmental model of depression, advocating hippocampal structure as a potential diagnostic neurobiomarker for depression.

Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.

White matter abnormalities and illness severity in major depressive disorder

BACKGROUND White matter abnormalities have been implicated in the aetiology of major depressive disorder; however, the relationship between the severity of symptoms and white matter integrity is currently unclear. AIMS To investigate white matter integrity in people with major depression and healthy controls, and to assess its relationship with depressive symptom severity. METHOD Diffusion tensor imaging data were acquired from 66 patients with recurrent major depression and a control group of 66 healthy individuals matched for age, gender and IQ score, and analysed with tract-based spatial statistics. The relationship between white matter integrity and severity of depression as measured by the Beck Depression Inventory was examined. RESULTS Depressive illness was associated with widespread regions of decreased white matter integrity, including regions in the corpus callosum, superior longitudinal fasciculus and anterior corona radiata, compared with the control group. Increasing symptom severity was negatively correlated with white matter integrity, predominantly in the corpus callosum. CONCLUSIONS Widespread alterations in white matter integrity are evident in major depressive disorder. These abnormalities are heightened with increasing severity of depressive symptoms.

Subregional hippocampal deformations in major depressive disorder

BACKGROUND Hippocampal atrophy is a well reported feature of major depressive disorder, although the evidence has been mixed. The present study sought to examine hippocampal volume and subregional morphology in patients with major depressive disorder, who were all medication-free and in an acute depressive episode of moderate severity. METHODS Structural magnetic resonance imaging scans were acquired in 37 patients (mean age 42 years) and 37 age, gender and IQ-matched healthy individuals. Hippocampal volume and subregional structural differences were measured by manual tracings and identification of homologous surface points to the central core of each hippocampus. RESULTS Both right (P=0.001) and left (P=0.005) hippocampal volumes were reduced in patients relative to healthy controls (n=37 patients and n=37 controls), while only the right hippocampus (P=0.016) showed a reduced volume in a subgroup of first-episode depression patients (n=13) relative to healthy controls. Shape analysis localised the subregional deformations to the subiculum and CA1 subfield extending into the CA2-3 subfields predominantly in the tail regions in the right (P=0.017) and left (P=0.011) hippocampi. LIMITATIONS As all patients were in an acute depressive episode, effects associated with depressive state cannot be distinguished from trait effects. CONCLUSIONS Subregional hippocampal deficits are present early in the course of major depression. The deformations may reflect structural correlates underlying functional memory impairments and distinguish depression from other psychiatric disorders.

Genetic Overlap Between Measures of Hyperactivity/Inattention and Mood in Children and Adolescents

OBJECTIVE Evidence suggests that there is substantial comorbidity between attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder in childhood and adolescence. This study aims to investigate the degree to which etiological factors are shared between the symptoms of these significantly heritable disorders. METHOD A twin study design was used to determine to what extent the covariation between the traits of ADHD and depression is genetically or environmentally mediated, based on parental reports. A general community sample of 645 twin pairs aged 5 to 17 years from the Cardiff Study of All Wales and North England Twins project took part in the study. Parent-rated measures of hyperactivity/inattention (Abbreviated Conners Hyperactivity subscale) and depression (Short Mood and Feelings Questionnaire). RESULTS Phenotypes derived from the scales were significantly correlated in both boys and girls. Bivariate structural equation modeling revealed a large overlap in underlying genetic factors (boys, rA = 0.77; girls, rA = 0.67) along with a smaller influence of nonshared environment. CONCLUSIONS These findings suggest that there are common genes conferring liability to both hyperactive/inattentive and depressive traits in children and adolescents. This has implications for future molecular genetic research into ADHD and major depressive disorder. Additionally, it indicates that the comorbid clinical presentation of these disorders may reflect a common genetic pathway.

Amyloid pathology and axonal injury after brain trauma

Objective: To image β-amyloid (Aβ) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aβ are correlated, and compare the spatial distribution of Aβ to Alzheimer disease (AD). Methods: Patients 11 months to 17 years after moderate–severe TBI underwent 11C-Pittsburgh compound B (11C-PiB)-PET, structural and diffusion MRI, and neuropsychological examination. Healthy aged controls and patients with AD underwent PET and structural MRI. Binding potential (BPND) images of 11C-PiB, which index Aβ plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BPND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy, was estimated and correlated with 11C-PiB BPND. Results: Twenty-eight participants (9 with TBI, 9 controls, 10 with AD) were assessed. Increased 11C-PiB BPND was found in TBI vs controls in the posterior cingulate cortex and cerebellum. Binding in the posterior cingulate cortex increased with decreasing fractional anisotropy of associated white matter tracts and increased with time since injury. Compared to AD, binding after TBI was lower in neocortical regions but increased in the cerebellum. Conclusions: Increased Aβ burden was observed in TBI. The distribution overlaps with, but is distinct from, that of AD. This suggests a mechanistic link between TBI and the development of neuropathologic features of dementia, which may relate to axonal damage produced by the injury.

Increased brain-predicted aging in treated HIV disease

Objective: To establish whether HIV disease is associated with abnormal levels of age-related brain atrophy, by estimating apparent brain age using neuroimaging and exploring whether these estimates related to HIV status, age, cognitive performance, and HIV-related clinical parameters. Methods: A large sample of virologically suppressed HIV-positive adults (n = 162, age 45–82 years) and highly comparable HIV-negative controls (n = 105) were recruited as part of the Comorbidity in Relation to AIDS (COBRA) collaboration. Using T1-weighted MRI scans, a machine-learning model of healthy brain aging was defined in an independent cohort (n = 2,001, aged 18–90 years). Neuroimaging data from HIV-positive and HIV-negative individuals were then used to estimate brain-predicted age; then brain-predicted age difference (brain-PAD = brain-predicted brain age − chronological age) scores were calculated. Neuropsychological and clinical assessments were also carried out. Results: HIV-positive individuals had greater brain-PAD score (mean ± SD 2.15 ± 7.79 years) compared to HIV-negative individuals (−0.87 ± 8.40 years; b = 3.48, p < 0.01). Increased brain-PAD score was associated with decreased performance in multiple cognitive domains (information processing speed, executive function, memory) and general cognitive performance across all participants. Brain-PAD score was not associated with age, duration of HIV infection, or other HIV-related measures. Conclusion: Increased apparent brain aging, predicted using neuroimaging, was observed in HIV-positive adults, despite effective viral suppression. Furthermore, the magnitude of increased apparent brain aging related to cognitive deficits. However, predicted brain age difference did not correlate with chronological age or duration of HIV infection, suggesting that HIV disease may accentuate rather than accelerate brain aging.

Selective vulnerability of Rich Club brain regions is an organizational principle of structural connectivity loss in Huntington's disease

Diffuse structural connectivity loss occurs early in Huntington’s disease. However, the organizational principles underlying these changes are unclear. Using whole brain diffusion tractography and graph theoretical analysis, McColgan, Seunarine et al. identify a specific role for highly connected rich club regions as a substrate for structural connectivity loss in Huntington’s disease.

Modulation of amygdala response and connectivity in depression by serotonin transporter polymorphism and diagnosis

BACKGROUND Polymorphisms in the serotonin transporter gene (5-HTTLPR) modulate amygdala activity in healthy individuals. Increased responses to negative stimuli in carriers of low transcription alleles have been proposed to contribute to the pathogenesis of depression. We sought to investigate the effects of genotype as well as diagnosis in patients with depression. METHODS Subjects with recurrent depression (n=67) and matched healthy controls (n=49) participated in a fMRI task of implicit processing of sad facial stimuli. Effects of biallelic (short (S) and long (L) alleles) and triallelic (including rs25531 A/G single nucleotide variation) models of 5-HTTLPR polymorphisms on amygdala activity and connectivity were investigated. RESULTS Significant effects were observed of both genotype and diagnosis on amygdala activity. Increased amygdala activity was associated with 5-HTTLPR genotype in low transcription allele carriers as well as with a diagnosis of depression. The connectivity analysis revealed a main effect of genotype with reduced connectivity to the subgenual region of the anterior cingulate in carriers of the low transcription alleles. There was also a main effect of diagnosis with reduced connectivity to the dorsal region of the anterior cingulate and to the dorsolateral prefrontal cortex in depression. There were no interaction effects between genotype and diagnosis in amygdala activity or connectivity. CONCLUSIONS Significant independent effects of genotype and diagnosis on amygdala responsivity were revealed. The effects of genotype and diagnosis on amygdala connectivity showed a regional segregation, suggesting that 5-HTTLPR polymorphisms bias frontal-limbic connectivity while the development of depression involves more extensive neural disturbances. These findings point to the potential of connectivity maps as a diagnostic biomarker for depression.

Neuroinflammation in treated HIV-positive individuals A TSPO PET study

Objective: To explore the effects of microglial activation on brain function and structure, and its relationship with peripheral inflammatory markers, in treated, HIV-positive individuals, using in vivo [11C]PBR28 PET (to measure the 18 kDa translocator protein [TSPO]). Methods: Cognitively healthy HIV-positive individuals on suppressive antiretroviral therapy and HIV-negative individuals (controls) underwent brain [11C]PBR28 PET and MRI. HIV-positive patients completed neuropsychological testing and CSF testing for chemokines. The concentration of bacterial ribosomal 16sDNA in plasma was measured as a marker of microbial translocation. Results: HIV-positive individuals showed global increases in TSPO expression compared to controls (corrected p < 0.01), with significant regional increases in the parietal (p = 0.001) and occipital (p = 0.046) lobes and in the globus pallidus (p = 0.035). TSPO binding in the hippocampus, amygdala, and thalamus were associated with poorer global cognitive performance in tasks assessing verbal and visual memory (p < 0.05). Increased TSPO binding was associated with increased brain white matter diffusion MRI mean diffusivity in HIV-positive individuals, a lower CD4/CD8 ratio, and both high pretreatment HIV RNA and plasma concentration ribosomal 16s DNA (p < 0.05). Conclusions: Cognitively healthy HIV-positive individuals show evidence for a chronically activated brain innate immune response and elevated blood markers of microbial translocation despite effective control of plasma viremia. Increased brain inflammation is associated with poorer cognitive performance and white matter microstructural pathology, suggesting a possible role in cognitive impairments found in some HIV-positive patients despite effective treatment.