Multimodal imaging reveals a complex pattern of dysfunction in corticolimbic pathways in major depressive disorder.

Major depressive disorder (MDD) is highly prevalent and associated with considerable morbidity, yet its pathophysiology remains only partially understood. While numerous studies have investigated the neurobiological correlates of MDD, most have used only a single neuroimaging modality. In particular, diffusion tensor imaging (DTI) studies have failed to yield uniform results. In this context, examining key tracts and using information from multiple neuroimaging modalities may better characterize potential abnormalities in the MDD brain. This study analyzed data from 30 participants with MDD and 26 healthy participants who underwent DTI, magnetic resonance spectroscopy (MRS), resting-state functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Tracts connecting the subgenual anterior cingulate cortex (sgACC) and the left and right amygdala, as well as connections to the left and right hippocampus and thalamus, were examined as target areas. Reduced fractional anisotropy (FA) was observed in the studied tracts. Significant differences in the correlation between medial prefrontal glutamate concentrations and FA were also observed between MDD and healthy participants along tracts connecting the sgACC and right amygdala; healthy participants exhibited a strong correlation but MDD participants showed no such relationship. In the same tract, a correlation was observed between FA and subsequent antidepressant response to ketamine infusion in MDD participants. Exploratory models also suggested group differences in the relationship between DTI, fMRI, and MEG measures. This study is the first to combine MRS, DTI, fMRI, and MEG data to obtain multimodal indices of MDD and antidepressant response and may lay the foundation for similar future analyses.

The Atypical MAP Kinase SWIP-13/ERK8 Regulates Dopamine Transporters through a Rho-Dependent Mechanism.

The neurotransmitter dopamine (DA) regulates multiple behaviors across phylogeny, with disrupted DA signaling in humans associated with addiction, attention-deficit/ hyperactivity disorder, schizophrenia, and Parkinson's disease. The DA transporter (DAT) imposes spatial and temporal limits on DA action, and provides for presynaptic DA recycling to replenish neurotransmitter pools. Molecular mechanisms that regulate DAT expression, trafficking, and function, particularly in vivo, remain poorly understood, though recent studies have implicated rho-linked pathways in psychostimulant action. To identify genes that dictate the ability of DAT to sustain normal levels of DA clearance, we pursued a forward genetic screen in Caenorhabditis elegans based on the phenotype swimming-induced paralysis (Swip), a paralytic behavior observed in hermaphrodite worms with loss-of-function dat-1 mutations. Here, we report the identity of swip-13, which encodes a highly conserved ortholog of the human atypical MAP kinase ERK8. We present evidence that SWIP-13 acts presynaptically to insure adequate levels of surface DAT expression and DA clearance. Moreover, we provide in vitro and in vivo evidence supporting a conserved pathway involving SWIP-13/ERK8 activation of Rho GTPases that dictates DAT surface expression and function.SIGNIFICANCE STATEMENT Signaling by the neurotransmitter dopamine (DA) is tightly regulated by the DA transporter (DAT), insuring efficient DA clearance after release. Molecular networks that regulate DAT are poorly understood, particularly in vivo Using a forward genetic screen in the nematode Caenorhabditis elegans, we implicate the atypical mitogen activated protein kinase, SWIP-13, in DAT regulation. Moreover, we provide in vitro and in vivo evidence that SWIP-13, as well as its human counterpart ERK8, regulate DAT surface availability via the activation of Rho proteins. Our findings implicate a novel pathway that regulates DA synaptic availability and that may contribute to risk for disorders linked to perturbed DA signaling. Targeting this pathway may be of value in the development of therapeutics in such disorders.

Timing of perioperative transversus abdominis plane block at the time of radical cystectomy does not affect perioperative outcomes.

PURPOSE: The transversus abdominis plane (TAP) block has been effective in providing adequate pain control, limiting opioid use, and improving perioperative outcomes in patients undergoing major abdominal surgeries. Little is known regarding the efficacy of preoperative (pre-incisional) versus postoperative TAP block in patients who undergo cystectomy. METHODS: This is a retrospective study that reviewed all patients who underwent cystectomy between January 2011 and January 2020 at a single institution. Patients were stratified into three cohorts: preoperative TAP block, postoperative TAP block, no TAP block. A multivariable linear regression model was constructed that assessed factors associated with total morphine milligram equivalents (MME) per hospital stay. RESULTS: In 463 patients, baseline characteristics were similar. There were 66(14.3%) patients who received a perioperative TAP block, 16 (24.2%) of whom received a preoperative TAP block. There were no significant differences in baseline factors. A TAP block was associated with lower MME used per day (41.8 mg vs 53.1 mg, p = 0.009) and per hospital stay (232 mg vs 320.5 mg, p = 0.001). The median MME per hospital stay and per day was lowest in the preoperative TAP cohort (194.0 mg, p = 0.011 and 38.0 mg, p = 0.042, respectively). On multivariable analysis of a subset of patients who received a TAP block, there was no significant difference in MME use in patients who received a preoperative vs postoperative TAP block (- 84.8, p = 0.339). CONCLUSION: The use of TAP blocks was associated with lower MME use in the entire population; however, there was no difference in MME use when comparing preoperative and postoperative TAP blocks.

7T 1H-MRS in major depressive disorder: a Ketamine Treatment Study.

The glutamatergic modulator ketamine has striking and rapid antidepressant effects in major depressive disorder (MDD), but its mechanism of action remains unknown. Proton magnetic resonance spectroscopy (1H-MRS) is the only non-invasive method able to directly measure glutamate levels in vivo; in particular, glutamate and glutamine metabolite concentrations are separable by 1H-MRS at 7T. This double-blind, placebo-controlled, crossover study that included 1H-MRS scans at baseline and at 24 h post ketamine and post-placebo infusions sought to determine glutamate levels in the pregenual anterior cingulate (pgACC) of 20 medication-free MDD subjects and 17 healthy volunteers (HVs) 24 h post ketamine administration, and to evaluate any other measured metabolite changes, correlates, or predictors of antidepressant response. Metabolite levels were compared at three scan times (baseline, post-ketamine, and post-placebo) in HVs and MDD subjects at 7T using a 1H-MRS sequence specifically optimized for glutamate. No significant between-group differences in 1H-MRS-measured metabolites were observed at baseline. Antidepressant response was not predicted by baseline glutamate levels. Our results suggest that any infusion-induced increases in glutamate at the 24-h post ketamine time point were below the sensitivity of the current technique; that these increases may occur in different brain regions than the pgACC; or that subgroups of MDD subjects may exist that have a differential glutamate response to ketamine.

Active suicidal ideation during clinical antidepressant trials.

Suicidal patients are often excluded from clinical trials of psychiatric medications and from investigations using neurobiological techniques. To evaluate the presence, impact, and stability of active suicidal ideation (SI) across a range of antidepressant trials, we reviewed 14 clinical trials conducted in patients with either major depressive disorder (MDD) or bipolar disorder (BD) (N = 269). Active SI at any time point in the clinical trial was identified and linked to participation in other research procedures. Stability of active SI across subsequent days was evaluated using intraclass correlation coefficients (ICCs) and compared to other depressive symptoms. Across 14 clinical trials, 63 participants (23%) reported active SI at some point during study participation. Of these participants, 33 completed a neuroimaging procedure and 16 completed polysomnography within a week of active SI. When active SI was subsequently assessed, only 39% of patients continued to report active SI after three days of assessment, despite receiving no additional treatment. ICCs were not significant for either SI or pessimism; other depressive symptoms showed stability over time. The results suggest that research can be conducted in depressed patients with active SI if such research coincides with careful observation. Active SI and pessimism may be particularly vulnerable to fluctuation.