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Inflammation plays a role in depression pathophysiology and treatment response, with effects varying by sex and therapeutic modality. Lower levels of interleukin(IL)-8 predict depression response to antidepressant medication and to electroconvulsive therapy (ECT), although ECT effects are specific to females. Whether IL-8 predicts depression response to ketamine and in a sex-specific manner is not known. Here, depressed patients (n = 46; female, n = 17) received open label infusion of ketamine (0.5 mg/kg over 40 min; NCT02165449). Plasma levels of IL-8 were evaluated at baseline and post-treatment. Baseline levels of IL-8 had a trending association with response to ketamine, depending upon sex (responder status × sex interaction: p = 0.096), in which lower baseline levels of IL-8 in females (p = 0.095) but not males (p = 0.96) trended with treatment response. Change in levels of IL-8 from baseline to post-treatment differed significantly by responder status (defined as ≥50% reduction in Hamilton Depression Rating Scale [HAM-D] Score), depending upon sex (responder status × sex × time interaction: F(1,42)=6.68, p = 0.01). In addition, change in IL-8 interacted with sex to predict change in HAM-D score (β = -0.63, p = 0.003); increasing IL-8 was associated with decreasing HAM-D score in females (p = 0.08) whereas the inverse was found in males (p = 0.02). Other inflammatory markers (IL-6, IL-10, tumor necrosis factor-α, C-reactive protein) were explored with no significant relationships identified. Given these preliminary findings, further evaluation of sex differences in the relationship between IL-8 and treatment response is warranted to elucidate mechanisms of response and aid in the development of personalized approaches to depression treatment.

Subanesthetic ketamine is found to induce fast-acting and pronounced antidepressant effects, even in treatment resistant depression (TRD). However, it remains unclear how ketamine modulates neural function at the brain systems-level to regulate emotion and behavior. Here, we examined treatment-related changes in the inhibitory control network after single and repeated ketamine therapy in TRD. Forty-seven TRD patients (mean age = 38, 19 women) and 32 healthy controls (mean age = 35, 18 women) performed a functional magnetic resonance imaging (fMRI) response inhibition task at baseline, and 37 patients completed the fMRI task and symptom scales again 24 h after receiving both one and four 0.5 mg/kg intravenous ketamine infusions. Analyses of fMRI data addressed effects of diagnosis, time, and differences between treatment remitters and non-remitters. Significant decreases in brain activation were observed in the inhibitory control network, including in prefrontal and parietal regions, and visual cortex following serial ketamine treatment, p  < 0.05 corrected. Remitters were distinguished from non-remitters by having lower functional activation in the supplementary motor area (SMA) prior to treatment, which normalized towards controls following serial ketamine treatment. Results suggest that ketamine treatment leads to neurofunctional plasticity in executive control networks including the SMA during a response-inhibitory task. SMA changes relate to reductions in depressive symptoms, suggesting modulation of this network play an important role in therapeutic response. In addition, early changes in the SMA network during response inhibition appear predictive of overall treatment outcome, and may serve as a biomarker of treatment response.

Transcranial direct current stimulation (tDCS) can influence performance on behavioral tasks and improve symptoms of brain conditions. Yet, it remains unclear precisely how tDCS affects brain function and connectivity. Here, we measured changes in functional connectivity (FC) metrics in blood-oxygenation-level-dependent (BOLD) fMRI data acquired during MR-compatible tDCS in a whole-brain analysis with corrections for false discovery rate. Volunteers (n = 64) received active tDCS, sham tDCS, and rest (no stimulation), using one of three previously established electrode tDCS montages targeting left dorsolateral prefrontal cortex (DLPFC, n = 37), lateral temporoparietal area (LTA, n = 16), or superior temporal cortex (STC, n = 11). In brain networks where simulated E field was highest in each montage, connectivity with remote nodes decreased during active tDCS. During active DLPFC-tDCS, connectivity decreased between a fronto-parietal network and subgenual ACC, while during LTA-tDCS connectivity decreased between an auditory-somatomotor network and frontal operculum. Active DLPFC-tDCS was also associated with increased connectivity within an orbitofrontal network overlapping subgenual ACC. Irrespective of montage, FC metrics increased in sensorimotor and attention regions during both active and sham tDCS, which may reflect the cognitive-perceptual demands of tDCS. Taken together, these results indicate that tDCS may have both intended and unintended effects on ongoing brain activity, stressing the importance of including sham, stimulation-absent, and active comparators in basic science and clinical trials of tDCS.

Electroconvulsive therapy (ECT) has been repeatedly linked to hippocampal plasticity. However, it remains unclear what role hippocampal plasticity plays in the antidepressant response to ECT. This magnetic resonance imaging (MRI) study tracks changes in separate hippocampal subregions and hippocampal networks in patients with depression (n = 44, 23 female) to determine their relationship, if any, with improvement after ECT. Voxelwise analyses were restricted to the hippocampus, amygdala, and parahippocampal cortex, and applied separately for responders and nonresponders to ECT. In analyses of arterial spin-labeled (ASL) MRI, nonresponders exhibited increased cerebral blood flow (CBF) in bilateral anterior hippocampus, while responders showed CBF increases in right middle and left posterior hippocampus. In analyses of gray matter volume (GMV) using T1-weighted MRI, GMV increased throughout bilateral hippocampus and surrounding tissue in nonresponders, while responders showed increased GMV in right anterior hippocampus only. Using CBF loci as seed regions, BOLD-fMRI data from healthy controls (n = 36, 19 female) identified spatially separable neurofunctional networks comprised of different brain regions. In graph theory analyses of these networks, functional connectivity within a hippocampus-thalamus-striatum network decreased only in responders after two treatments and after index. In sum, our results suggest that the location of ECT-related plasticity within the hippocampus may differ according to antidepressant outcome, and that larger amounts of hippocampal plasticity may not be conducive to positive antidepressant response. More focused targeting of hippocampal subregions and/or circuits may be a way to improve ECT outcome.

Patients with major depression show reductions in striatal and paleostriatal volumes. The functional integrity and connectivity of these regions are also shown to change with antidepressant response. Electroconvulsive therapy (ECT) is a robust and rapidly acting treatment for severe depression. However, whether morphological changes in the dorsal and ventral striatum/pallidum relate to or predict therapeutic response to ECT is unknown. Using structural MRI, we assessed cross-sectional effects of diagnosis and longitudinal effects of ECT for volume and surface-based shape metrics of the caudate, putamen, pallidum, and nucleus accumbens in 53 depressed patients (mean age: 44.1 years, 13.8 SD; 52% female) and 33 healthy controls (mean age: 39.3 years, 12.4 SD; 57% female). Patients were assessed before ECT, after their second ECT, and after completing an ECT treatment index. Controls were evaluated at two time points. Support vector machines determined whether morphometric measures at baseline predicted ECT-related clinical response. Patients showed smaller baseline accumbens and pallidal volumes than controls (P<0.05). Increases in left putamen volume (P<0.03) occurred with ECT. Global increases in accumbens volume and local changes in pallidum and caudate volume occurred in patients defined as treatment responders. Morphometric changes were absent across time in controls. Baseline volume and shape metrics predicted overall response to ECT with up to 89% accuracy. Results support that ECT elicits structural plasticity in the dorsal and ventral striatum/pallidum. The morphometry of these structures, forming key components of limbic-cortical-striatal-pallidal-thalamic circuitry involved in mood and emotional regulation, may determine patients likely to benefit from treatment.

Electroconvulsive therapy (ECT) is a highly effective brain stimulation treatment for severe depression. Identifying neurochemical changes linked with ECT may point to biomarkers and predictors of successful treatment response. We used proton magnetic resonance spectroscopy (1H-MRS) to measure longitudinal changes in glutamate/glutamine (Glx), creatine (Cre), choline (Cho) and N-acetylaspartate (NAA) in the dorsal (dACC) and subgenual anterior cingulate cortex (sgACC) and bilateral hippocampus in patients receiving ECT scanned at baseline, after the second ECT session and after the ECT treatment series. Patients were compared with demographically similar controls at baseline. Controls were assessed twice to establish normative values and variance. We included 50 patients (mean age 43.78 ± 14 yr) and 33 controls (mean age 39.33 ± 12 yr) in our study. Patients underwent a mean of 9 ± 4.1 sessions of ECT. At baseline, patients showed reduced Glx in the sgACC, reduced NAA in the left hippocampus and increased Glx in the left hippocampus relative to controls. ECT was associated with significant increases in Cre in the dACC and sgACC and decreases in NAA in the dACC and right hippocampus. Lower NAA levels in the dACC at baseline predicted reductions in depressive symptoms. Both ECT and symptom improvement were associated with decreased Glx in the left hippocampus and increased Glx in the sgACC. Attrition and clinical heterogeneity may have masked more subtle findings. ECT elicits robust effects on brain chemistry, impacting Cre, NAA and Glx, which suggests restorative and neurotrophic processes. Differential effects of Glx in the sgACC and hippocampus, which approach control values with treatment, may reflect previously implicated underactive cortical and overactive subcortical limbic circuitry in patients with major depression. NAA levels at baseline are predictive of therapeutic outcome and could inform future treatment strategies.

Purpose. To compare the outcomes of trabeculectomy using two different routes of bevacizumab administration as an adjunct in patients with primary open angle glaucoma. Methods. Prospective, randomized, masked trial that included 180 eyes of 180 patients of documented primary open angle glaucoma were eligible for surgery. Patients were randomized to receive either a single intraoperative dose of subconjunctival bevacizumab (1.25 mg, Group I) or topical bevacizumab (5 mg/ml) for 30 days (Group II). One eye was randomly selected, if both were eligible for surgery. All patients underwent a complete ocular and systemic examination. Bleb morphology was examined and scored as per Moorfields system (MBGS) at 1, 3, 6, 12, 18, and 24 months postoperatively. Visual field, fundus photography, and disc analysis were performed. Outcome measures (at one year) included (1) comparison of bleb morphology in both groups, (2) proportion of patients achieving surgical success, and (3) side effects of treatment. Results. The groups did not differ with respect to age, sex, and crystalline lens status. Group II patients had significantly lower vascularity scores for central (P=0.042) and peripheral bleb areas (P=0.023) and peripheral nonbleb area (P=0.03). A significantly larger proportion of Group II (n = 88) patients achieved average vascular scores of less than 2.5 (P=0.0056, Fisher’s test) than Group I (n = 85). The groups did not differ in terms of surgical success (96% vs. 94%; P=0.54). No major complications were noted in either group. Conclusion. Topical bevacizumab gives a better vascularity profile at one year, but the studied routes appear equally safe and do not seem to affect the outcome in any other way.