Klaus P. Ebmeier

A meta-analysis of depression severity and cognitive function

BACKGROUND Studies examining the way in which cognitive impairment is associated with depression have produced inconsistent findings. Different severity of depressed mood across studies may account for such conflicting reports. However, inconsistent results have also been reported in relation to the specific association of depression severity with cognitive performance. METHODS A meta-analysis was conducted to examine the relationship between severity of depression and cognitive function, using the correlation (Pearsons r) between depression severity scores and neuropsychological test performance. Individual meta-analyses were conducted for composite measures of cognitive functional domains (episodic memory, executive function, processing speed, semantic memory, and visuo-spatial memory). Analyses were also done across functional domains for timed and un-timed tests. RESULTS Significant correlations between depression severity and cognitive performance were found in the domains of episodic memory, executive function, and processing speed, but not for semantic memory or visuo-spatial memory. For both timed and un-timed cognitive measures there were equally significant correlations with depression severity. LIMITATIONS There were few studies meeting inclusion criteria in some cognitive domains, papers had to be excluded due to insufficient data reporting, and there are limitations associated with the cross-sectional design. CONCLUSIONS The results suggest that previous inconsistent findings of the relationship between the severity of depression and cognitive function may be attributed to random variations and lack of power within studies.

Timing of onset of cognitive decline: results from Whitehall II prospective cohort study.

Objectives To estimate 10 year decline in cognitive function from longitudinal data in a middle aged cohort and to examine whether age cohorts can be compared with cross sectional data to infer the effect of age on cognitive decline. Design Prospective cohort study. At study inception in 1985-8, there were 10 308 participants, representing a recruitment rate of 73%. Setting Civil service departments in London, United Kingdom. Participants 5198 men and 2192 women, aged 45-70 at the beginning of cognitive testing in 1997-9. Main outcome measure Tests of memory, reasoning, vocabulary, and phonemic and semantic fluency, assessed three times over 10 years. Results All cognitive scores, except vocabulary, declined in all five age categories (age 45-49, 50-54, 55-59, 60-64, and 65-70 at baseline), with evidence of faster decline in older people. In men, the 10 year decline, shown as change/range of test×100, in reasoning was −3.6% (95% confidence interval −4.1% to −3.0%) in those aged 45-49 at baseline and −9.6% (−10.6% to −8.6%) in those aged 65-70. In women, the corresponding decline was −3.6% (−4.6% to −2.7%) and −7.4% (−9.1% to −5.7%). Comparisons of longitudinal and cross sectional effects of age suggest that the latter overestimate decline in women because of cohort differences in education. For example, in women aged 45-49 the longitudinal analysis showed reasoning to have declined by −3.6% (−4.5% to −2.8%) but the cross sectional effects suggested a decline of −11.4% (−14.0% to −8.9%). Conclusions Cognitive decline is already evident in middle age (age 45-49).

Magnetic resonance imaging studies in bipolar disorder and schizophrenia: meta-analysis.

BACKGROUND Several magnetic resonance imaging (MRI) studies have identified structural abnormalities in association with bipolar disorder. The literature is, however, heterogeneous and there is remaining uncertainty about which brain areas are pivotal to the pathogenesis of the condition. AIMS To identify, appraise and summarise volumetric MRI studies of brain regions comparing bipolar disorder with an unrelated control group and individuals with schizophrenia. METHOD A systematic review and random-effects meta-analysis was carried out to identify key areas of structural abnormality in bipolar disorder and whether the pattern of affected areas separated bipolar disorder from schizophrenia. Significant heterogeneity was explored using meta-regression. RESULTS Participants with bipolar disorder are characterised by whole brain and prefrontal lobe volume reductions, and also by increases in the volume of the globus pallidus and lateral ventricles. In comparison with schizophrenia, bipolar disorder is associated with smaller lateral ventricular volume and enlarged amygdala volume. Heterogeneity was widespread and could be partly explained by clinical variables and year of publication, but generally not by differences in image acquisition. CONCLUSIONS There appear to be robust changes in brain volume in bipolar disorder compared with healthy volunteers, although most changes do not seem to be diagnostically specific. Age and duration of illness appear to be key issues in determining the magnitude of observed effect sizes.

White matter hyperintensities in late life depression: a systematic review

Background: White matter hyperintensities in MRI scans are age related but appear to be more prevalent in depressed patients. They may be more pronounced in late onset depression. This finding, if confirmed, would potentially illuminate the heterogeneity of depression in elderly subjects. Methods: We conducted a systematic literature search of studies investigating white matter changes in late life depression, identifying 98 studies. The 30 remaining eligible studies were scrutinised for the presence and severity measures of periventricular and deep white matter changes in late life, late onset and, if available, early onset depression as well as in controls. Comparisons between groups were entered into random effects meta-analyses using odds ratios and Cohen’s d, as appropriate. Correlations with potential confounders, such as age difference between groups, were explored. Results: Late life depression and, to a greater extent, late onset depression in late life were characterised by more frequent and intense white matter abnormalities. In particular, the odds of having white matter changes were over 4 for late compared with early onset depression. Similarly, on severity scales, late onset depression had scores of 0.7–0.8 standard deviations above early onset patients. Conclusions: Significant differences between early and late onset depression suggest different aetiological mechanisms, in accordance with a theory of “cerebrovascular” depression of late onset. Greater duration of depressive symptoms, signs and treatment does not appear to have a measurable impact on white matter signal in MRI scans.

ICA-based artefact removal and accelerated fMRI acquisition for improved resting state network imaging

The identification of resting state networks (RSNs) and the quantification of their functional connectivity in resting-state fMRI (rfMRI) are seriously hindered by the presence of artefacts, many of which overlap spatially or spectrally with RSNs. Moreover, recent developments in fMRI acquisition yield data with higher spatial and temporal resolutions, but may increase artefacts both spatially and/or temporally. Hence the correct identification and removal of non-neural fluctuations is crucial, especially in accelerated acquisitions. In this paper we investigate the effectiveness of three data-driven cleaning procedures, compare standard against higher (spatial and temporal) resolution accelerated fMRI acquisitions, and investigate the combined effect of different acquisitions and different cleanup approaches. We applied single-subject independent component analysis (ICA), followed by automatic component classification with FMRIBs ICA-based X-noiseifier (FIX) to identify artefactual components. We then compared two first-level (within-subject) cleaning approaches for removing those artefacts and motion-related fluctuations from the data. The effectiveness of the cleaning procedures was assessed using time series (amplitude and spectra), network matrix and spatial map analyses. For time series and network analyses we also tested the effect of a second-level cleaning (informed by group-level analysis). Comparing these approaches, the preferable balance between noise removal and signal loss was achieved by regressing out of the data the full space of motion-related fluctuations and only the unique variance of the artefactual ICA components. Using similar analyses, we also investigated the effects of different cleaning approaches on data from different acquisition sequences. With the optimal cleaning procedures, functional connectivity results from accelerated data were statistically comparable or significantly better than the standard (unaccelerated) acquisition, and, crucially, with higher spatial and temporal resolution. Moreover, we were able to perform higher dimensionality ICA decompositions with the accelerated data, which is very valuable for detailed network analyses.

Cognitive function in major depression.

Forty patients with a major depressive episode were divided into equal endogenous and neurotic sub-groups using the Newcastle scale. They were all rated on the 17-item Hamilton scale and with a variety of neuropsychological tests. They were compared with 20 age- and education-matched control subjects. Both endogenous and neurotic groups had impaired memory function on the auditory verbal learning test; recall and recognition were equally impaired suggesting that effort was not a major determinant of performance. The endogenous group was more impaired on digit symbol substitution and the Trail making test (A and B). Impairment was correlated with symptom scores on the Hamilton and Newcastle scales, even after allowing for the effect of age. It is concluded that the conventional distinction between organic and functional impairment breaks down in severe depressive illness. The implications of this for clinical neuropsychological testing and the anatomy of the brain dysfunction in depressive illness are discussed.

Magnetic resonance imaging studies in unipolar depression: Systematic review and meta-regression analyses

Previous meta-analyses of structural MRI studies have shown diffuse cortical and sub-cortical abnormalities in unipolar depression. However, the presence of duplicate publications, recruitment of particular age groups and the selection of specific regions of interest means that there is uncertainty about the balance of current research. Moreover, the lack of systematic exploration of highly significant heterogeneity has prevented the generalisability of finding. A systematic review and random-effects meta-analysis was carried out to estimate effect sizes. Possible publication bias, and the impact of various study design characteristics on the magnitude of the observed effect size were systematically explored. The aim of this study was 1) to include structural MRI studies systematically comparing unipolar depression with bipolar disorder and healthy volunteers; 2) to consider all available structures of interest without specific age limits, avoiding data duplication, and 3) to explore the influence of factors contributing to the measured effect sizes systematically with meta-regression analyses. Unipolar depression was characterised by reduced brain volume in areas involved in emotional processing, including the frontal cortex, orbitofrontal cortex, cingulate cortex, hippocampus and striatum. There was also evidence of pituitary enlargement and an excess of white matter hyperintensity volume in unipolar depression. Factors which influenced the magnitude of the observed effect sizes were differences in methods, clinical variables, pharmacological interventions and sample age.

A Systematic Review of Diffusion Tensor Imaging Studies in Affective Disorders

White matter abnormalities constitute one element of the network dysfunction that underlies affective disorders: differences between the white matter of subjects with affective disorders and control subjects have been identified using a range of neuroimaging and histological techniques. Diffusion tensor imaging (DTI) can uniquely study the orientation and integrity of white matter tracts and is thus an ideal tool to shed light on white matter abnormalities in subjects with affective disorders. Here, we systematically review DTI studies of affective disorders. We identified DTI studies of affective disorders from EMBASE and MEDLINE and searched the reference lists of relevant papers. Twenty-seven articles comparing subjects with affective disorders with control subjects were included in the review, with eight studies included in a meta-analysis of superior frontal regions. Twenty-one of 27 studies found significantly lower anisotropy in subjects with affective disorders compared with control subjects, more specifically within the frontal and temporal lobes or tracts. A large effect size was detected within the superior frontal gyrus, although heterogeneity and one index of publication bias were significant. Although there is significant heterogeneity of acquisition and analysis methods and subject properties, DTI studies of affective disorders consistently identify reduced anisotropy in the frontal and temporal lobes and tracts of subjects with affective disorders relative to control subjects.

Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder

Highlights • This meta-analysis confirms a robust link between IL-6, CRP and major depression.• The role of TNF-α and IL-1β in major depression remains uncertain.• Further mechanistic and immunotherapeutic studies on IL-6 and CRP are needed.

Single photon emission tomography with 99mTc-exametazime in major depression and the pattern of brain activity underlying the psychotic/neurotic continuum.

Forty patients with a major depressive episode were investigated at rest using Single Photon Emission Tomography (SPET or SPECT) with 99mTc-exametazime, an intravenous ligand taken into brain in proportion to regional cerebral blood flow, thereby providing an estimate of regional metabolism. All patients were unipolar and were rated on the Newcastle scale and with the 17-item Hamilton scale. They also completed a range of neuropsychological tests. They were compared with 20 control subjects matched for age, gender, premorbid intelligence and education. The uptake of 99mTc-exametazime was expressed for a range of anatomically defined regions of interest relative to calcarine/occipital cortex. The depressed group showed reduced uptake in the majority of cortical and sub-cortical regions examined, most significantly in temporal, inferior frontal and parietal areas. Unexpectedly, there was a strong positive association between uptake and scores on the Newcastle scale, especially in cingulate areas and frontal cortex. After removing the variance attributable to the Newcastle ratings, however, there emerged the expected negative association between Hamilton scores and anterior tracer uptake. The associations between neuropsychological impairment and regional brain uptake of tracer in part reflected the pattern seen with the Newcastle scale: for example, impairment of memory function correlated with higher uptake into posterior cingulate areas. We propose that depressive illness may be characterised by two processes. One leads to an overall reduction in anterior neocortical function, perhaps related to symptom severity. The other mechanism is manifest as relatively increased function, most notably within cingulate and frontal areas of the cerebral cortex in association with psychotic symptoms. The findings offer new understanding of the brain states underlying depressive illness and a potential focus to subsequent neuropharmacological analysis.