EEG Biomarkers of reduced inhibition in human cortical microcircuits in depression

Major depressive disorder (depression) is a complex condition that involves multiple physiological mechanisms, spanning a range of spatial scales. Altered cortical inhibition is associated with treatment-resistant depression, and reduced dendritic inhibition by somatostatin-expressing (SST) interneurons has been strongly implicated in this aspect of the pathology. However, whether the effects of reduced SST inhibition on microcircuit activity have signatures detectible in electroencephalography (EEG) signals remains unknown. We used detailed models of human cortical layer 2/3 microcircuits with normal or reduced SST inhibition to simulate resting-state activity together with EEG signals in health and depression. We first show that the healthy microcircuit models exhibit emergent key features of resting-state EEG. We then simulated EEG from depression microcircuits and found a significant power increase in theta, alpha and low beta frequencies (4 - 15 Hz). Following spectral decomposition, we show that the power increase involved a combination of aperiodic broadband component, and a periodic theta and low beta components. Neuronal spiking showed a spike preference for the phase preceding the EEG trough, which did not differ between conditions. Our study thus used detailed computational models to identify EEG biomarkers of reduced SST inhibition in human cortical microcircuits in depression, which may serve to improve the diagnosis and stratification of depression subtypes, and in monitoring the effects of pharmacological modulation of inhibition for treating depression.

Differential Alterations in Resting State Functional Connectivity Associated with Depressive Symptoms and Early Life Adversity

Depression and early life adversity (ELA) are associated with aberrant resting state functional connectivity (FC) of the default mode (DMN), salience (SN), and central executive networks (CEN). However, the specific and differential associations of depression and ELA with FC of these networks remain unclear. Applying a dimensional approach, here we analyzed associations of FC between major nodes of the DMN, SN, and CEN with severity of depressive symptoms and ELA defined as childhood abuse and neglect in a sample of 83 healthy and depressed subjects. Depressive symptoms were linked to increased FC within the SN and decreased FC of the SN with the DMN and CEN. Childhood abuse was associated with increased FC within the SN, whereas childhood neglect was associated with decreased FC within the SN and increased FC between the SN and the DMN. Our study thus provides evidence for differential associations of depressive symptoms and ELA with resting state FC and contributes to a clarification of previously contradictory findings. Specific FC abnormalities may underlie specific cognitive and emotional impairments. Future research should link specific clinical symptoms resulting from ELA to FC patterns thereby characterizing depression subtypes with specific neurobiological signatures.

Structural brain changes and neuroticism in late-life depression: a neural basis for depression subtypes

ABSTRACT The neurobiological basis of neuroticism in late-life depression (LLD) is understudied. We hypothesized that older depressed subjects scoring high in measures of neuroticism would have smaller hippocampal and prefrontal volumes compared with non-neurotic older depressed subjects and with nondepressed comparison subjects based on previous research. Non-demented subjects were recruited and were either depressed with high neuroticism (n = 65), depressed with low neuroticism (n = 36), or never depressed (n = 27). For imaging outcomes focused on volumetric analyses, we found no significant between-group differences in hippocampal volume. However, we found several frontal lobe regions for which depressed subjects with high neuroticism scores had smaller volumes compared with non-neurotic older depressed subjects and with nondepressed comparison subjects, controlling for age and gender. These regions included the frontal pole, medial orbitofrontal cortex, and left pars orbitalis. In addition, we found that non-neurotic depressed subjects had a higher volume of non-white matter hypointensities on T1-weighted images (possibly related to cerebrovascular disease) than did neurotic depressed subjects. Our finding that depressed subjects low in neuroticism had higher volumes of non-white matter hypointensities is consistent with prior literature on “vascular depression.” In contrast, the finding that those high in neuroticism had smaller frontal volume than depressed subjects low in neuroticism and never-depressed subjects highlight the importance of frontal circuitry in the subgroup of older depressed individuals with comorbid neuroticism. Together, these results implicate different neural mechanisms in older neurotic and non-neurotic depressed groups and suggest that multiple biological pathologies may lead to different clinical expressions of LLD.

Dietary Patterns Are Differentially Associated with Atypical and Melancholic Subtypes of Depression

Diet has been associated with the risk of depression, whereas different subtypes of depression have been linked with different cardiovascular risk factors (CVRFs). In this study, our aims were to (1) identify dietary patterns with exploratory factor analysis, (2) assess cross-sectional associations between dietary patterns and depression subtypes, and (3) examine the potentially mediating effect of dietary patterns in the associations between CVRFs and depression subtypes. In the first follow-up of the population-based CoLaus|PsyCoLaus study (2009–2013, 3554 participants, 45.6% men, mean age 57.5 years), a food frequency questionnaire assessed dietary intake and a semi-structured interview allowed to characterize major depressive disorder into current or remitted atypical, melancholic, and unspecified subtypes. Three dietary patterns were identified: Western, Mediterranean, and Sweet-Dairy. Western diet was positively associated with current atypical depression, but negatively associated with current and remitted melancholic depression. Sweet-Dairy was positively associated with current melancholic depression. However, these dietary patterns did not mediate the associations between CVRFs and depression subtypes. Hence, although we could show that people with different subtypes of depression make different choices regarding their diet, it is unlikely that these differential dietary choices account for the well-established associations between depression subtypes and CVRFs.

Default mode network activity in depression subtypes

Depression continues to carry a major disease burden worldwide, with limitations on the success of traditional pharmacological or psychological treatments. Recent approaches have therefore focused upon the neurobiological underpinnings of depression, and on the “individualization” of depression symptom profiles. One such model of depression has divided the standard diagnostic criteria into four “depression subtypes”, with neurological and behavioral pathways. At the same time, attention has been focused upon the region of the brain known as the “default mode network” (DMN) and its role in attention and problem-solving. However, to date, no review has been published of the links between the DMN and the four subtypes of depression. By searching the literature studies from the last 20 years, 62 relevant papers were identified, and their findings are described for the association they demonstrate between aspects of the DMN and the four depression subtypes. It is apparent from this review that there are potential positive clinical and therapeutic outcomes from focusing upon DMN activation and connectivity, via psychological therapies, transcranial magnetic stimulation, and some emerging pharmacological models.