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Differences between ketamine's short-term and long-term effects on brain circuitry in depression.

ABSTRACT: Ketamine acts as a rapid clinical antidepressant at 25?min after injection with effects sustained for 7 days. As dissociative effects emerging acutely after injection are not entirely discernible from therapeutic action, we aimed to dissect the differences between short-term and long-term response to ketamine to elucidate potential imaging biomarkers of ketamine's antidepressant effect. We used a genetical model of depression, in which we bred depressed negative cognitive state (NC) and non-depressed positive cognitive state (PC) rat strains. Four parallel rat groups underwent stress-escape testing and a week later received either S-ketamine (12 NC, 13 PC) or saline (12 NC, 12 PC). We acquired resting-state functional magnetic resonance imaging time series before injection and at 30?min and 48?h after injection. Graph analysis was used to calculate brain network properties. We identified ketamine's distinct action over time in a qualitative manner. The rapid response entailed robust and strain-independent topological modifications in cognitive, sensory, emotion, and reward-related circuitry, including regions that exhibited correlation of connectivity metrics with depressive behavior, and which could explain ketamine's dissociative and antidepressant properties. At 48?h ketamine had mainly strain-specific action normalizing habenula, midline thalamus, and hippocampal connectivity measures in depressed rats. As these nodes mediate cognitive flexibility impaired in depression, action within this circuitry presumably reflects ketamine's procognitive effects induced only in depressed patients. This finding is especially valid, as our model represents cognitive aspects of depression. These empirically defined circuits explain ketamine's distinct action over time and might serve as translational imaging correlates of antidepressant response in preclinical testing.

SUBMITTER: Gass N

PROVIDER: S-EPMC6599014 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Differences between ketamine's short-term and long-term effects on brain circuitry in depression.

Gass Natalia N Becker Robert R Reinwald Jonathan J Cosa-Linan Alejandro A Sack Markus M Weber-Fahr Wolfgang W Vollmayr Barbara B Sartorius Alexander A

Translational psychiatry 20190628 1

Ketamine acts as a rapid clinical antidepressant at 25 min after injection with effects sustained for 7 days. As dissociative effects emerging acutely after injection are not entirely discernible from therapeutic action, we aimed to dissect the differences between short-term and long-term response to ketamine to elucidate potential imaging biomarkers of ketamine's antidepressant effect. We used a genetical model of depression, in which we bred depressed negative cognitive state (NC) and non-depr ...[more]

PMID: 31253763

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Project description:Bipolar disorder (BD) is common and debilitating and confounding effects of depression history on neural activity in BD are unknown. We aimed to dissociate neural activity reflecting past depression-load vs. present symptom severity using the Course and Outcome of Bipolar Youth (COBY), a prospective longitudinal cohort study of pediatric-onset BD. In n = 54 COBY (18-32 years), we modeled depression scores over time (up to 17.5 years) using a standardized autoregressive moving average (ARMA) model, followed by k-means cluster analysis. N = 36 healthy participants (HC, 20-36 years) were included. Using two factorial analyses, we parsed the impact of ARMA-defined past depression-load on neural activity from the impact of current symptoms on neural activity (p < 0.001, k > 30) and examined relationships with past and present symptoms (ps FDR-corrected). ARMA identified three COBY groups based on past depression-load. ARMA-defined COBY participants with the greatest past depression-load vs. other groups showed greater activity in right temporoparietal junction, thalamus, insula, premotor cortex, left fusiform gyrus, bilateral precuneus and cerebellum. In contrast, BD-COBY participants vs. HC showed greater activity in left hippocampus, dorsolateral prefrontal cortex, and right somatosensory cortex, plus the above thalamus, premotor cortex and cerebellum; activity positively correlated with present symptom severity in most regions. Past depression-load was related to social cognition and salience perception network activity, potentially reflecting heightened attention to socially relevant distracters, while present symptoms were associated with emotion processing and reappraisal network activity, potentially reflecting abnormal emotional experience and regulation. Differentiating aberrant neural activity related to long-term depression vs. present affective symptoms can help target interventions to networks associated with pathophysiological processes, rather than long-term illness effects.

Project description:IntroductionProgression of amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) is a clinical event with highly variable progression rates varying from 10-15% up to 30-34%. Functional connectivity (FC), the temporal similarity between spatially remote neurophysiological events, has previously been reported to differ between aMCI patients who progress to AD (pMCI) and those who do not (i.e., remain stable; sMCI). However, these reports had a short-term follow-up and do not provide insight into long-term AD progression.MethodsSeventy-nine participants with a baseline and 78 with a 12-month, 51 with a 24-month, and 22 with a +48-month follow-up resting-state fMRI with aMCI diagnosis from the Alzheimer's Disease Neuroimaging Initiative database were included. FC was assessed using the CONN toolbox. Local correlation and group independent component analysis were utilized to compare regional functional coupling and between-network FC, respectively, between sMCI and pMCI groups. Two-sample t tests were used to test for statistically significant differences between groups, and paired t-tests were used to assess cognitive changes over time.ResultsAll participants (i.e., 66 sMCI and 19 pMCI) had a baseline and a year follow-up fMRI scan. Progression from aMCI to AD occurred in 19 patients (10 at 12 months, 5 at 24 months, and 4 at >48 months), while 73 MCI patients remained cognitively stable (sMCI). The pMCI and sMCI cognitive profiles were different. More between-network FC than regional functional coupling differences were present between sMCI and pMCI patients. Activation in the salience network (SN) and the default mode network (DMN) was consistently different between sMCI and pMCI patients across time.DiscussionsMCI and pMCI patients have different cognitive and FC profiles. Only pMCI patients showed cognitive differences across time. The DMN and SN showed local correlation and between-network FC differences between the sMCI and pMCI patient groups at multiple moments in time.

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Differences between ketamine's short-term and long-term effects on brain circuitry in depression.

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Differences between ketamine's short-term and long-term effects on brain circuitry in depression.

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