Inflammation and depression treatment response to electroconvulsive therapy: Sex-specific role of interleukin-8.

Females suffer from depression at twice the rate of males and have differential neural and emotional responses to inflammation. However, sex-specific evaluation of relationships between inflammation and response to depression treatments are lacking. Some data suggest that interleukin(IL)-8 predicts treatment response to antidepressants and has a relationship with depressive symptom severity. This study examines whether IL-8 predicts treatment response to electroconvulsive therapy (ECT), and whether there are sex specific effects. In 40 depressed patients (22 female), plasma levels of IL-8, as well as other markers of inflammation including IL-6, IL-10, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) were obtained prior to administration of ECT and after completion of the index treatment series. Depression treatment response was defined as ≥ 50% reduction in Hamilton Depression Rating Scale (HAM-D) Score. Baseline levels of IL-8 differed by responder status, depending on sex (group × sex interaction: ß = -0.571, p = 0.04), with female responders having lower levels of IL-8 at baseline as compared to female non-responders [t(20) = 2.37, p = 0.03]. Further, IL-8 levels from baseline to end of treatment differed by responder status, depending on sex (group × sex × time interaction: [F(1,36) = 9.48, p = 0.004]), and change in IL-8 from baseline to end of treatment was negatively correlated with percentage change in HAM-D score in females (ß = -0.458, p = 0.03), but not in males (ß = 0.315, p = 0.20). Other inflammatory markers did not differ in relation to responder status and sex. Further evaluation of sex differences in the relationship between IL-8, depression, and treatment response, across disparate treatment modalities, may inform mechanisms of response and aid in development of personalized medicine strategies.

Short- and Long-term Cognitive Outcomes in Patients With Major Depression Treated With Electroconvulsive Therapy.

OBJECTIVES: The risk of cognitive impairment is a concern for patients with major depressive disorder receiving electroconvulsive therapy (ECT). Here, we evaluate the acute, short-term and long-term effects of ECT on tests of processing speed, executive function, memory, and attention. METHODS: Forty-four patients with major depressive disorder receiving ECT (61% right unilateral, 39% mixed right unilateral-bitemporal, left unilateral, and/or bitemporal lead placement) underwent a cognitive battery prior to ECT (T1), after 2 sessions (T2), and at the end of the index (T3). Thirty-two patients returned for a 6-month follow-up (T4). Thirty-three control subjects were assessed at 2 times approximately 4 weeks apart (C1 and C2). RESULTS: At baseline, patients showed deficits in processing speed, executive function, and memory compared with control subjects. Including depression severity and lead placement covariates, linear mixed-model analysis showed significant improvement in only processing speed between T1 and T3 and between T1 and T4 in patients. An acute decline in attention and verbal memory was observed at T2, but performance returned to baseline levels at T3. Longitudinal cognitive outcomes did not differ in patients defined as ECT responders/nonresponders. LIMITATIONS: Episodic memory was not measured, and medications were not controlled between T3 and T4. Control subjects also showed improvements in processing speed, suggesting practice effects for some measures. CONCLUSIONS: In this naturalistic ECT treatment study, results show that the initiation of ECT may transiently affect memory and executive function, but cognition is largely unaffected during and after ECT. Whereas some functions might improve, others will at least remain stable up to 6 months following the ECT index.

Effects of Serial Ketamine Infusions on Corticolimbic Functional Connectivity in Major Depression.

BACKGROUND: Ketamine is a highly effective antidepressant for patients with treatment-resistant major depressive disorder (MDD). Resting-state functional magnetic resonance imaging studies show disruptions of functional connectivity (FC) between limbic regions and resting-state networks (RSNs) in MDD, including the default mode network, central executive network (CEN), and salience network (SN). Here, we investigated whether serial ketamine treatments change FC between limbic structures and RSNs. METHODS: Patients with MDD (n = 44) were scanned at baseline (time 1 [T1]) and 24 hours after the first (T2) and fourth (T3) infusions of ketamine. Healthy control subjects (n = 50) were scanned at baseline, with a subgroup (n = 17) being rescanned at 2 weeks. Limbic regions included the amygdala and hippocampus, and RSNs included the default mode network, CEN, and SN. RESULTS: Ketamine increased right amygdala FC to the right CEN (p = .05), decreased amygdala FC to the left CEN (p = .005) at T2 versus T1 (p = .015), which then increased at T3 versus T2 (p = .002), and decreased left amygdala FC to the SN (p = .016). Decreased left amygdala to SN FC at T2 predicted improvements in anxiety at T3 (p = .006). Ketamine increased right hippocampus FC to the left CEN (p = .001), and this change at T2 predicted decreased anhedonia at T3 (p = .005). CONCLUSIONS: Ketamine modulates FC between limbic regions and RSNs implicated in MDD. Increases in FC between limbic regions and the CEN suggest that ketamine may be involved in restoring top-down control of emotion processing. FC decreases between the left amygdala and SN suggest that ketamine may ameliorate MDD-related dysconnectivity in these circuits. Early FC changes between limbic regions and RSNs may be predictive of clinical improvements.

Depression treatment response to ketamine: sex-specific role of interleukin-8, but not other inflammatory markers.

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 (ß = -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.

Modulation of inhibitory control networks relate to clinical response following ketamine therapy in major depression.

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.

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.

Central Olfactory Dysfunction in Alzheimer's Disease and Mild Cognitive Impairment: A Functional MRI Study.

BACKGROUND: Olfactory deficits are present in early Alzheimer's disease (AD) and mild cognitively impaired (MCI) patients. However, whether these deficits are due to dysfunction of the central or peripheral olfactory nervous system remains uncertain. This question is fundamentally important for developing imaging biomarkers for AD using olfactory testing. OBJECTIVE: This study sought to use olfactory functional magnetic resonance imaging (fMRI) to further demonstrate the involvement of the central olfactory system in olfactory deficits in MCI and AD. METHODS: We investigated the central olfactory system in 27 cognitively normal controls (CN), 21 MCI, and 15 AD subjects using olfactory fMRI with an odor-visual association paradigm during which a visual cue was paired with lavender odorant (odor condition) or odorless air (no-odor condition). RESULTS: The CN subjects had significantly greater activated volume in the primary olfactory cortex during both the odor and no-odor conditions compared to either the MCI or AD groups (p < 0.05). No significant differences were observed between the odor and no-odor conditions within each group. No-odor condition activation in AD and MCI correlated with the cognitive and olfactory assessments. CONCLUSION: The no-odor condition, allowing investigation of activation patterns when the peripheral olfactory system was not directly involved, elicited the same functional response as the odor condition for each of the three groups. Thus, the olfactory activation deficits present in AD and MCI patients are most likely caused by degeneration of the central olfactory nervous system.

Structural connectivity and response to ketamine therapy in major depression: A preliminary study.

BACKGROUND: Ketamine elicits an acute antidepressant effect in patients with major depressive disorder (MDD). Here, we used diffusion imaging to explore whether regional differences in white matter microstructure prior to treatment may predict clinical response 24h following ketamine infusion in 10 MDD patients. METHODS: FSL's Tract-Based Spatial Statistics (TBSS) established voxel-level differences in fractional anisotropy (FA) between responders (patients showing >50% improvement in symptoms 24h post-infusion) and non-responders in major white matter pathways. Follow-up regions-of-interest (ROI) analyses examined differences in FA and radial (RD), axial (AD) and mean diffusivity (MD) between responders and non-responders and 15 age- and sex-matched controls, with groups compared pairwise. RESULTS: Whole brain TBSS (p<0.05, corrected) and confirmatory tract-based regions-of-interest analyses showed larger FA values in the cingulum and forceps minor in responders compared to non-responders; complementary decreases in RD occurred in the cingulum (p<0.05). Only non-responders differed from controls showing decreased FA in the forceps minor, increased RD in the cingulum and forceps minor, and increased MD in the forceps minor (p<0.05). LIMITATIONS: Non-responders showed an earlier age of onset and longer current depressive episode than responders. Though these factors did not interact with diffusion metrics, results may be impacted by the limited sample size. CONCLUSIONS: Though findings are considered preliminary, significant differences in FA, RD and MD shown in non-responders compared to responders and controls in fronto-limbic and ventral striatal pathways suggest that the structural architecture of specific functional networks mediating emotion may predict ketamine response in MDD.

Olfactory cortex degeneration in Alzheimer's disease and mild cognitive impairment.

BACKGROUND: Olfactory deficits are prevalent in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). These symptoms precede clinical onset of cognitive and memory deficits and coincide with AD pathology preferentially in the central olfactory structures, suggesting a potential biomarker for AD early detection and progression. OBJECTIVE: Therefore, we tested the hypothesis that structural degeneration of the primary olfactory cortex (POC) could be detected in AD as well as in MCI patients and would be correlated with olfactory functional magnetic resonance imaging (fMRI) alterations, reflecting loss of olfactory cortex activity. METHODS: Total structural volumes and fMRI activation volumes of the POC and hippocampus were measured along with olfactory and cognitive behavioral tests in 27 cognitively normal (CN), 21 MCI, and 15 AD subjects. RESULTS: Prominent atrophy in the POC and hippocampus was found in both AD and MCI subjects and correlated with behavioral measurements. While behavioral and volumetric measurements showed a gradual decline from CN to MCI to AD, olfactory activation volume in the POC and hippocampus showed a steeper decline in the MCI group compared to corresponding tissue volume, resembling the AD group. CONCLUSIONS: Decline in olfactory activity was correlated with the AD structural degeneration in the POC. A more prominent olfactory activity deficit than that of behavioral and tissue volume measurements was shown in the MCI stage. Olfactory fMRI may thus provide an earlier and more sensitive measure of functional neurodegeneration in AD and MCI patients.