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Abstract:
Introduction: The therapeutic potential of a single subanesthetic dose of ketamine in various mental illnesses, particularly treatment-resistant depression (TRD), has gained significant attention in the past decade (Kryst et al 2020). Beyond the rapid onset of therapeutic efficacy, ketamine administration can induce altered states of consciousness, which is known as dissociative states, encompassing disorientation, confusion, sensory perception changes (such as visual or auditory hallucinations), and feelings of detachment. The vital role of the thalamus in the ketamine-induced loss and return of consciousness, as well as altered states of consciousness, has been broadly reported (Krystal et al. 1994). Although the regional effect of ketamine on thalamic nuclei has been reported (Ferrer et al 1973; Rogers et al 2004), to date, it remains unclear how changes in the thalamo-cortical interactions lead to ketamine-induced dissociative states on the level of thalamus functional anatomy. This study aimed to investigate resting-state functional connectivity changes within the thalamus functional anatomy (Kumar et al., 2017) and their relation to ketamine-induced dissociative states. Methods: In a randomized, double-blind, placebo-controlled, crossover study, thirty-five healthy males (mean age ± standard deviation (SD) = 25.08 ± 4.18 years) underwent 7T high-field functional MRI scans before and one day after ketamine or placebo infusions. fMRI data was acquired using echo-planar imaging (EPI) sequence with the following parameters: TE = 25 ms, TR = 1500 ms, flip angle = 70 °, FoV = 212 mm, 60 slices, isotropic voxel size = 2 mm3, multi-band acceleration factor = 3, grappa acceleration factor PE = 2. The data underwent preprocessing using fMRIPrep, and rsFC was calculated using parcels from the functional anatomy atlas of the human thalamus (Kumar et al., 2017). To examine ketamine's effect on seed-based rsFC in the different parcels of the thalamus functional anatomy, a within-subject flexible factorial ANOVA was performed for each functional parcel separately in SPM, assessing the main effects of session (baseline vs. infusion), treatment (placebo vs. ketamine), and their interaction. Additionally, rsFC values from significant clusters were correlated with subjective consciousness levels measured by the score of Oceanic Boundlessness score (OB) from the five-dimensional altered states of consciousness. Results: Within-subject flexible factorial ANOVA revealed a significant treatment * session interaction (clusterwise FWE-corrected at p < 0.05) in the FC of four thalamic parcel (bilateral 08, left 02, and 15) to the medial/inferior frontal gyrus (Figure 01; pFWE-cluster corrected, initial height threshold p< 0.001). The FC of left 15 and right 08 to the right-medial frontal gyrus during infusion showed significant negative correlations [left 15 (r = -38, p= 0.27), and right 08 (r= -42, p= 0.013)] with subjective consciousness measured by the OB score (Figure 02).
