Association of Lower Rostral Anterior Cingulate GABA+ and Dysregulated Cortisol Stress Response With Altered Functional Connectivity in Young Adults With Lifetime Depression: A Multimodal Imaging Investigation of Trait and State Effects.

OBJECTIVE: Preclinical work suggests that excess glucocorticoids and reduced cortical γ-aminobutyric acid (GABA) may affect sex-dependent differences in brain regions implicated in stress regulation and depressive phenotypes. The authors sought to address a critical gap in knowledge, namely, how stress circuitry is functionally affected by glucocorticoids and GABA in current or remitted major depressive disorder (MDD). METHODS: Multimodal imaging data were collected from 130 young adults (ages 18-25), of whom 44 had current MDD, 42 had remitted MDD, and 44 were healthy comparison subjects. GABA+ (γ-aminobutyric acid and macromolecules) was assessed using magnetic resonance spectroscopy, and task-related functional MRI data were collected under acute stress and analyzed using data-driven network modeling. RESULTS: Across modalities, trait-related abnormalities emerged. Relative to healthy comparison subjects, both clinical groups were characterized by lower rostral anterior cingulate cortex (rACC) GABA+ and frontoparietal network amplitude but higher amplitude in salience and stress-related networks. For the remitted MDD group, differences from the healthy comparison group emerged in the context of elevated cortisol levels, whereas the MDD group had lower cortisol levels than the healthy comparison group. In the comparison group, frontoparietal and stress-related network connectivity was positively associated with cortisol level (highlighting putative top-down regulation of stress), but the opposite relationship emerged in the MDD and remitted MDD groups. Finally, rACC GABA+ was associated with stress-induced changes in connectivity between overlapping default mode and salience networks. CONCLUSIONS: Lifetime MDD was characterized by reduced rACC GABA+ as well as dysregulated cortisol-related interactions between top-down control (frontoparietal) and threat (task-related) networks. These findings warrant further investigation of the role of GABA in the vulnerability to and treatment of MDD.

Effects of GABA, Sex, and Stress on Reward Learning in Current and Remitted Major Depression.

BACKGROUND: Neurocognitive factors including aberrant reward learning, blunted GABA (gamma-aminobutyric acid), and potentiated stress sensitivity have been linked to anhedonia, a hallmark depressive symptom, possibly in a sex-dependent manner. However, previous research has not investigated the putative associations among these factors or the extent to which they represent trait- or state-based vulnerabilities for depression. METHODS: Young adults with current major depressive disorder (MDD) (n = 44), remitted MDD (n = 42), and healthy control participants (HCs) (n = 44), stratified by sex assigned at birth, underwent magnetic resonance spectroscopy to assess macromolecular contaminated GABA (GABA+) and then a reward learning task before and after acute stress. We assessed changes in reward learning after stress and associations with GABA+. RESULTS: Results revealed blunted baseline reward learning in participants with remitted MDD versus participants with current MDD and HCs but, surprisingly, no differences between participants with current MDD and HCs. Reward learning was reduced following acute stress regardless of depressive history. GABA+ in the rostral anterior cingulate cortex, but not the dorsolateral prefrontal cortex, was associated with reduced baseline reward learning only in female participants. GABA+ did not predict stress-related changes in reward learning. CONCLUSIONS: To our knowledge, this is the first study to investigate associations among GABA, reward learning, and stress reactivity in current versus past depression. Hypothesized depression-related differences in reward learning did not emerge, precluding claims about state versus trait vulnerabilities. However, our finding that blunted GABA was associated with greater reward learning in female participants provides novel insights into sex-selective associations between the frontal GABAergic inhibitory system and reward processing.

Neural response to stress differs by sex in young adulthood.

Increase in stress-related disorders in women begins post-puberty and persists throughout the lifespan. To characterize sex differences in stress response in early adulthood, we used functional magnetic resonance imaging while participants underwent a stress task in conjunction with serum cortisol levels and questionnaires assessing anxiety and mood. Forty-two healthy subjects aged 18-25 years participated (21M, 21F). Interaction of stress and sex in brain activation and connectivity were examined. Results demonstrated significant sex differences in brain activity with women exhibiting increased activation in regions that inhibit arousal compared to men during the stress paradigm. Women had increased connectivity among stress circuitry regions and default mode network, whereas men had increased connectivity between stress and cognitive control regions. In a subset of subjects (13F, 17M), we obtained gamma-aminobutyric acid (GABA) magnetic resonance spectroscopy in rostral anterior cingulate cortex (rostral ACC) and dorsolateral prefrotal cortex (dlPFC) and conducted exploratory analyses to relate GABA measurements with sex differences in brain activation and connectivity. Prefrontal GABA levels were negatively associated with inferior temporal gyrus activation in men and women and with ventromedial prefrontal cortex activation in men. Despite sex differences in neural response, we found similar subjective ratings of anxiety and mood, cortisol levels, and GABA levels between sexes, suggesting sex differences in brain activity result in similar behavioral responses among the sexes. These results help establish sex differences in healthy brain activity from which we can better understand sex differences underlying stress-associated illnesses.

Reductions in rostral anterior cingulate GABA are associated with stress circuitry in females with major depression: a multimodal imaging investigation.

The interplay between cortical and limbic regions in stress circuitry calls for a neural systems approach to investigations of acute stress responses in major depressive disorder (MDD). Advances in multimodal imaging allow inferences between regional neurotransmitter function and activation in circuits linked to MDD, which could inform treatment development. The current study investigated the role of the inhibitory neurotransmitter GABA in stress circuitry in females with current and remitted MDD. Multimodal imaging data were analyzed from 49 young female adults across three groups (current MDD, remitted MDD (rMDD), and healthy controls). GABA was assessed at baseline using magnetic resonance spectroscopy, and functional MRI data were collected before, during, and after an acute stressor and analyzed using a network modeling approach. The MDD group showed an overall lower cortisol response than the rMDD group and lower rostral anterior cingulate cortex (ACC) GABA than healthy controls. Across groups, stress decreased activation in the frontoparietal network (FPN) but increased activation in the default mode network (DMN) and a network encompassing the ventromedial prefrontal cortex-striatum-anterior cingulate cortex (vmPFC-Str-ACC). Relative to controls, the MDD and rMDD groups were characterized by decreased FPN and salience network (SN) activation overall. Rostral ACC GABA was positively associated with connectivity between an overlapping limbic network (Temporal-Insula-Amygdala) and two other circuits (FPN and DMN). Collectively, these findings indicate that reduced GABA in females with MDD was associated with connectivity differences within and across key networks implicated in depression. GABAergic treatments for MDD might alleviate stress circuitry abnormalities in females.

Concordant neurophysiological signatures of cognitive control in humans and rats.

Progress towards understanding neural mechanisms in humans relevant to psychiatric conditions has been hindered by a lack of translationally-relevant cognitive tasks for laboratory animals. Accordingly, there is a critical need to develop parallel neurophysiological assessments of domains of cognition, such as cognitive control, in humans and laboratory animals. To address this, we developed a touchscreen-based cognitive (Eriksen Flanker) task in rats and used its key characteristics to construct a novel human version, with similar testing parameters and endpoints across species. We obtained continuous electroencephalogram (EEG) recordings, including local field potentials in rats, and compared electrophysiological signatures locked to stimulus onset and responses across species. We also assessed whether behavioral or physiological task effects were modulated by modafinil, which enhances aspects of cognitive function in humans. In both species, the task elicited expected flanker interference effects (reduced accuracy) during high-conflict trials. Across homologous neuroanatomical loci, stimulus-locked increases in theta power during high-conflict trials as well as error-related negative potentials were observed. These endpoints were not affected by modafinil in either species. Despite some species-specific patterns, our findings demonstrate the feasibility of a rat Flanker task as well as cross-species behavioral and neurophysiological similarities, which may enable novel insights into the neural correlates of healthy and aberrant behavior and provide mechanistic insights relevant to treatment.

Repeatability and reliability of GABA measurements with magnetic resonance spectroscopy in healthy young adults.

PURPOSE: Gamma-aminobutyric acid (GABA) abnormalities have been implicated in a range of neuropsychiatric disorders. Despite substantial interest in probing GABA in vivo, human imaging studies relying on magnetic resonance spectroscopy (MRS) have generally been hindered by technical challenges, including GABA's relatively low concentration and spectral overlap with other metabolites. Although past studies have shown moderate-to-strong test-retest repeatability and reliability of GABA within certain brain regions, many of these studies have been limited by small sample sizes. METHODS: GABA+ (macromolecular-contaminated) test-retest reliability and repeatability were assessed via a Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) MRS sequence in the rostral anterior cingulate cortex (rACC; n = 21) and dorsolateral prefrontal cortex (dlPFC; n = 20) in healthy young adults. Data were collected on a 3T scanner (Siemens Prisma, Siemens Healthcare, Erlangen, Germany) and GABA+ results were reported in reference to both total creatine (GABA+/tCr) and water (GABA+/water). RESULTS: Results showed strong test-retest repeatability (mean GABA+/tCr coefficient of variation [CV] = 4.6%; mean GABA+/water CV = 4.0%) and reliability (GABA+/tCr intraclass correlation coefficient [ICC] = 0.77; GABA+/water ICC = 0.87) in the dlPFC. The rACC showed acceptable (but comparatively lower) repeatability (mean GABA+/tCr CV = 8.0%; mean GABA+/water CV = 7.5%), yet low-moderate reliability (GABA+/tCr ICC = 0.40; GABA+/water ICC = 0.44). CONCLUSION: The present study found excellent GABA+ MRS repeatability and reliability in the dlPFC. The rACC showed inferior results, possibly because of a combination of shimming impedance and measurement error. These data suggest that MEGA-PRESS can be utilized to reliably distinguish participants based on dlPFC GABA+ levels, whereas the mixed results in the rACC merit further investigation.

Optimizing assessments of post-error slowing: A neurobehavioral investigation of a flanker task.

Appropriately adjusting to errors is essential for adaptive behavior. Post-error slowing (PES) refers to the increased reaction times on trials following incorrect relative to correct responses. PES has been used as a metric of cognitive control in basic cognitive neuroscience research as well as clinical contexts. However, calculation of PES varies widely among studies and has not yet been standardized, despite recent calls to optimize its measurement. Here, using behavioral and electrophysiological data from a modified flanker task, we considered different methods of calculating PES, assessed their internal consistency, examined their convergent correlations with behavioral performance and error-related event-related brain potentials (ERPs), and evaluated their sensitivity to task demands (e.g., presence of trial-to-trial feedback). Results indicated that the so-called robust measure of PES, calculated using only error-surrounding trials, provided an estimate of PES that was three times larger in magnitude than the traditional calculation. This robust PES correlated with the amplitude of the error positivity (Pe), an index of attention allocation to errors, just as well as the traditional method. However, all PES estimates had very weak internal consistency. Implications for measurement are discussed.