Discussion
TRD, anhedonia, lower anhedonia, TEPS-anticipatory, MDD, depression
BLIND, CORTEX, REGRESSIONS
Here we show that subregions of the ACC undergo differential modulation by intravenous ketamine, compared to placebo, in patients with TRD Post-hoc examination of rsFC changes within each ACC subregion separately highlighted that rsFC of ventral ACC divisions (pgACC and sgACC) to affective and DMN regions (posterior cingulate cortex and anterior vmPFC/hippocampus respectively) was modulated. By contrast, ketamine modulated connectivity of dACC to the supramarginal gyrus, which constitutes part of the somatosensory association cortex. These differential effects are consistent with known connectivity of the ACC: ventral regions contribute to affective networks and the DMN, whereas dorsal regions contribute to frontoparietal somatosensory and attention networks [In TRD patients, sgACC underwent the most substantial rsFC changes of ACC subregions in response to ketamine compared to placebo. Whilst post-hoc comparisons identified that ketamine significantly altered sgACC rsFC to pgACC, hippocampus/parahippocampal gyrus, ventral striatum, and anterior vmPFC, no significant changes were found for pgACC or dACC. We previously hypothesized that ketamine may change sgACC connectivity to nodes of the DMN [Connectivity changes between pgACC and sgACC have previously been implicated in MDD. Anatomically, these regions are densely interconnected, with pgACC/32 making excitatory contacts on sgACC/25 pyramidal cells as well as inhibitory interneurons [Connectivity between the ACC and the hippocampus has also been consistently implicated in depression, as these regions are particularly sensitive to the effects of chronic stress [Notably, sgACC-ventral striatal connectivity was significantly altered by ketamine. sgACC-ventral striatal rsFC changes correlated with improvements in TEPS-anticipatory scores but not TEPS-consummatory scores, suggesting differential involvement of these prefrontal-striatal circuits in temporally distinct aspects of anhedonia. This finding back-translates to preclinical primate work: connectivity between sgACC and ventral regions of the striatum has been causally implicated in ketamine’s ability to ameliorate anticipatory (but not consummatory) reward processing deficits in marmoset models [When we carried out whole-brain regressions exploring sgACC rsFC changes associated with ketamine’s anti-anhedonic effects, we identified a cluster in the dACC where connectivity was positively associated with lower anhedonia as measured by SHAPS scores. The dACC is known to be interconnected with sgACC [Limitations of this study include, firstly, the small sample size (particularly when exploring correlations between changes in rsFC and anhedonia scores) which may limit the power to detect changes in ACC rsFC and associations with improvements in symptoms. The within-subject crossover design mitigates this issue to a degree, but replication of these findings in trials with larger sample sizes is critical. Second, the sample size was too small to perform cross-validation using a leave-one-out framework, which would otherwise handle potential bias from the inferential tests being performed on clusters taken from the analysis. Third, the fixed time point analyzed in this study (two days), means we could not ascertain how changes in rsFC develop over the duration of ketamine’s antidepressant effects. Finally, whilst the integrity of the blind for score raters was assessed as reported in a prior manuscript [