Abstract Electroconvulsive therapy (ECT) and ketamine treatment both induce rapidly acting antidepressant effects in patients with major depressive disorder unresponsive to standard treatments, yet their specific impact on emotion processing is unknown. Here, we examined the neural underpinnings of emotion processing within and across patients ( N = 44) receiving either ECT ( N = 17, mean age: 36.8, 11.0 SD ) or repeated subanesthetic (0.5 mg/kg) intravenous ketamine therapy ( N = 27, mean age: 37.3, 10.8 SD ) using a naturalistic study design. MRI and clinical data were collected before (TP1) and after treatment (TP2); healthy controls ( N = 31, mean age: 34.5, 13.5 SD ) completed one MRI session (TP1). An fMRI face‐matching task probed negative‐ and positive‐valence systems. Whole‐brain analysis, comparing neurofunctional changes within and across treatment groups, targeted brain regions involved in emotional facial processing, and included regions‐of‐interest analysis of amygdala responsivity. Main findings revealed a decrease in amygdalar reactivity after both ECT and ketamine for positive and negative emotional face processing ( p < .05 family wise‐error (FWE) corrected). Subthreshold changes were observed between treatments within the dorsolateral prefrontal cortex and insula ( p < .005, uncorrected). BOLD change for positive faces in the inferior parietal cortex significantly correlated with overall symptom improvement, and BOLD change in frontal regions correlated with anxiety for negative faces, and anhedonia for positive faces ( p < .05 FWE corrected). Both serial ketamine and ECT treatment modulate amygdala response, while more subtle treatment‐specific changes occur in the larger functional network. Findings point to both common and differential mechanistic upstream systems‐level effects relating to fast‐acting antidepressant response, and symptoms of anxiety and anhedonia, for the processing of emotionally valenced stimuli.
Patients with major depressive disorder (MDD) exhibit impaired control of cognitive and emotional systems, including deficient response selection and inhibition. Though these deficits are typically attributed to abnormal communication between macro-scale cortical networks, altered communication with the cerebellum also plays an important role. Yet, how the circuitry between the cerebellum and large-scale functional networks impact treatment outcome in MDD is not understood. We thus examined how ketamine, which elicits rapid therapeutic effects in MDD, modulates cerebro-cerebellar circuitry during response-inhibition using a functional imaging NoGo/Go task in MDD patients (N = 46, mean age: 39.2, 38.1% female) receiving four ketamine infusions, and healthy controls (N = 32, mean age:35.2, 71.4% female). We fitted psychophysiological-interaction (PPI) models for a functionally-derived cerebellar-seed and extracted average PPI in three target functional networks, frontoparietal (FPN), sensory-motor (SMN) and salience (SN) networks. Time and remission status were then evaluated for each of the networks and their network-nodes. Follow-up tests examined whether PPI-connectivity differed between patient remitter/non-remitters and controls. Results showed significant decreases in PPI-connectivity after ketamine between the cerebellum and FPN (p < 0.001) and SMN networks (p = 0.008) in remitters only (N = 20). However, ketamine-related changes in PPI-connectivity between the cerebellum and the SN (p = 0.003) did not vary with remitter status. Cerebellar-FPN, -SN PPI values at baseline were also associated with treatment outcome. Using novel methodology to quantify the functional coupling of cerebro-cerebellar circuitry during response-inhibition, our findings highlight that these loops play distinct roles in treatment response and could potentially serve as novel biomarkers for fast-acting antidepressant therapies in MDD.
Background Total sleep deprivation (TSD) transiently reverses depressive symptoms in a majority of patients with depression. How TSD modulates diffusion tensor imaging (DTI) measures of white matter (WM) microstructure, which may be linked with TSD’s rapid antidepressant effects, remains uncharacterized. Methods Patients with depression ( N = 48, mean age = 33, 26 women) completed diffusion-weighted imaging and Hamilton Depression Rating (HDRS) and rumination scales before and after >24 h of TSD. Healthy controls (HC) ( N = 53, 23 women) completed the same assessments at baseline, and after receiving TSD in a subset of HCs ( N = 15). Tract based spatial statistics (TBSS) investigated voxelwise changes in fractional anisotropy (FA) across major WM pathways pre-to-post TSD in patients and HCs and between patients and HCs at baseline. Post hoc analyses tested for TSD effects for other diffusion metrics, and the relationships between change in diffusion measures with change in mood and rumination symptoms. Results Significant improvements in mood and rumination occurred in patients with depression (both p < 0.001), but not in HCs following TSD. Patients showed significant ( p < 0.05, corrected) decreases in FA values in multiple WM tracts, including the body of the corpus callosum and anterior corona radiata post-TSD. Significant voxel-level changes in FA were not observed in HCs who received TSD ( p > 0.05). However, differential effects of TSD between HCs and patients were found in the superior corona radiata, frontal WM and the posterior thalamic radiation ( p < 0.05, corrected). A significant ( p < 0.05) association between change in FA and axial diffusivity within the right superior corona radiata and improvement in rumination was found post-TSD in patients. Conclusion Total sleep deprivation leads to rapid microstructural changes in WM pathways in patients with depression that are distinct from WM changes associated with TSD observed in HCs. WM tracts including the superior corona radiata and posterior thalamic radiation could be potential biomarkers of the rapid therapeutic effects of TSD. Changes in superior corona radiata FA, in particular, may relate to improvements in maladaptive rumination.
Abstract The extent of white matter (WM) and Grey matter (GM) structural neuroplasticity following cognitive behavioral therapy for chronic pain management remains undetermined. In the current study, we investigated structural alterations in GM morphometry, as well as WM complexity and connectivity, before and after an 11-week group CBT for the treatment of chronic musculoskeletal pain. We hypothesized that effective pain management would influence WM structural metrics indicative of brain plasticity, particularly within cognitive and limbic circuitry as well as GM volume within pain matrix structures. To determine this, patients were randomized into two groups: 1) CBT group that received CBT once-weekly for 11-weeks, or 2) EDU group consisting of an active patient control group that received educational materials by mail. All subjects completed behavioral assessments and underwent neuroimaging at: baseline prior to any intervention (TP1), 11-weeks following either CBT or EDU (TP2), and four months following completion of the intervention (TP3). CBT resulted in significant clinical improvements, assessed via behavioral self-reports, compared to EDU. Compared to EDU, region of interest WM analysis revealed several fiber tracts that had significantly increased WM complexity following CBT intervention, including the bilateral posterior internal capsule and the left cingulum within the temporal lobe. Conversely, several tracts exhibited a decrease in WM complexity including the right external capsule, the left posterior internal capsule, and the right cingulum within the temporal lobe. Changes in clinical outcomes were predictive of alterations in WM complexity metrics immediately following intervention and at long-term follow-up. No between-group differences were observed in either WM connectivity or GM volume. In conclusion, psychotherapeutic interventions such as group CBT influence coping strategies for effective pain relief that influence WM microstructure, however, the mechanisms of these changes remain undetermined. Future studies will be required to uncover the biological underpinnings of these alterations in pain populations. Clinicaltrialsgov Can Therapy Alter CNS Processing of Chronic Pain: A Longitudinal Study ( https://clinicaltrials.gov/ct2/show/NCT01794988?term=naylor&cntry=US&state=US%3AVT&draw=2&rank=1;NCT01794988 ). The study protocol was registered in the Clinical Trials Database.
