Modulation of amygdala reactivity following rapidly acting interventions for major depression.

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.

Ketamine's modulation of cerebro-cerebellar circuitry during response inhibition in major depression.

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.

Ultra-High Field MRI in Alzheimer's Disease: Effective Transverse Relaxation Rate and Quantitative Susceptibility Mapping of Human Brain In Vivo and Ex Vivo compared to Histology.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. So far, diagnosis of AD is only unequivocally defined through postmortem histology. Amyloid plaques are a classical hallmark of AD and amyloid load is currently quantified by Positron Emission tomography (PET) in vivo. Ultra-high field magnetic resonance imaging (UHF-MRI) can potentially provide a non-invasive biomarker for AD by allowing imaging of pathological processes at a very-high spatial resolution. The first aim of this work was to reproduce the characteristic cortical pattern previously observed in vivo in AD patients using weighted-imaging at 7T. We extended these findings using quantitative susceptibility mapping (QSM) and quantification of the effective transverse relaxation rate (R2*) at 9.4T. The second aim was to investigate the origin of the contrast patterns observed in vivo in the cortex of AD patients at 9.4T by comparing quantitative UHF-MRI (9.4T and 14.1T) of postmortem samples with histology. We observed a distinctive cortical pattern in vivo in patients compared to healthy controls (HC), and these findings were confirmed ex vivo. Specifically, we found a close link between the signal changes detected by QSM in the AD sample at 14.1T and the distribution pattern of amyloid plaques in the histological sections of the same specimen. Our findings showed that QSM and R2* maps can distinguish AD from HC at UHF by detecting cortical alterations directly related to amyloid plaques in AD patients. Furthermore, we provided a method to quantify amyloid plaque load in AD patients at UHF non-invasively.

Single and repeated ketamine treatment induces perfusion changes in sensory and limbic networks in major depressive disorder.

Ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depressive disorder (MDD). Yet, how single and repeated ketamine treatment induces brain systems-level neuroplasticity underlying symptom improvement is unknown. Advanced multiband imaging (MB) pseudo-continuous arterial spin labeling (pCASL) perfusion MRI data was acquired from patients with treatment resistant depression (TRD) (N = 22, mean age=35.2 ± 9.95 SD, 27% female) at baseline, and 24 h after receiving single, and four subanesthetic (0.5 mg/kg) intravenous ketamine infusions. Changes in global and regional CBF were compared across time points, and relationships with overall mood, anhedonia and apathy were examined. Comparisons between patients at baseline and controls (N = 18, mean age=36.11 ± 14.5 SD, 57% female) established normalization of treatment effects. Results showed increased regional CBF in the cingulate and primary and higher-order visual association regions after first ketamine treatment. Baseline CBF in the fusiform, and acute changes in CBF in visual areas were related to symptom improvement after single and repeated ketamine treatment, respectively. In contrast, after serial infusion therapy, decreases in regional CBF were observed in the bilateral hippocampus and right insula with ketamine treatment. Findings demonstrate that neurophysiological changes occurring with single and repeated ketamine treatment follow both a regional and temporal pattern including sensory and limbic regions. Initial changes are observed in the posterior cingulate and precuneus and primary and higher-order visual areas, which relate to clinical responses. However, repeated exposure to ketamine, though not relating to clinical outcome, appears to engage deeper limbic structures and insula. ClinicalTrials.gov: Biomarkers of Fast Acting Therapies in Major Depression, https://clinicaltrials.gov/ct2/show/NCT02165449, NCT02165449.