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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.

Background Ketamine provides rapid antidepressant response in those struggling with major depressive disorder (MDD). This study measured acute changes in brain activity over 24 h after a single infusion of ketamine using arterial spin labeled (ASL) functional magnetic resonance imaging (fMRI) in patients with MDD. ASL is a novel technique that provides quantitative values to measure cerebral blood flow (CBF). Methods A single sub-anesthetic dose (0.5 mg/kg) of ketamine was delivered intravenously. Treatment-refractory patients (n = 11) were assessed at: Baseline (pre-infusion), and approximately 1 h, 6 h, and 24 h post-infusion. Linear mixed-effects models detected changes in CBF with respect to treatment outcome, and results were corrected for false discovery rate (FDR). Results After ketamine infusion, increased CBF was observed in the thalamus, while decreased CBF was observed in lateral occipital cortex in all patients. Time-by-response interactions were noted in ventral basal ganglia and medial prefrontal cortex, where CBF change differed according to antidepressant response. Limitations Modest sample size is a limitation of this pilot study; strict statistical correction and visualization of single-subject data attempted to ameliorate this issue. Conclusion In this pilot study, a sub-anesthetic dose of ketamine was associated with acute neurofunctional changes that may be consistent with altered attention, specifically increased thalamus activity coupled with decreased cortical activity. By contrast, antidepressant response to ketamine was associated with changes in reward-system regions, specifically ventral basal ganglia and medial prefrontal cortex. Further work is needed to determine whether these results generalize to larger samples and/or serial ketamine infusions associated with longer-lasting clinical effects.

Highlights • Ketamine modulates cerebellar connectivity during response inhibition in depression. • Cerebellar–frontoparietal/sensory connectivity decreases in ketamine remitters. • Cerebellar-frontoparietal/salience connectivity predicts treatment outcome. • Cerebro-cerebellar loops serve as treatment biomarkers 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

Background Converging evidence suggests that electroconvulsive therapy (ECT) induces neuroplasticity in patients with severe depression, though how this relates to antidepressant response is less clear. Arterial spin-labeled functional magnetic resonance imaging tracks absolute changes in cerebral blood flow (CBF) linked with brain function and offers a potentially powerful tool when observing neurofunctional plasticity with functional magnetic resonance imaging. Methods Using arterial spin-labeled functional magnetic resonance imaging, we measured global and regional CBF associated with clinically prescribed ECT and therapeutic response in patients (n = 57, 30 female) before ECT, after two treatments, after completing an ECT treatment “index” (∼4 weeks), and after long-term follow-up (6 months). Age- and sex-matched control subjects were also scanned twice (n = 36, 19 female), ∼4 weeks apart. Results Patients with lower baseline global CBF were more likely to respond to ECT. Regional CBF increased in the right anterior hippocampus in all patients irrespective of clinical outcome, both after 2 treatments and after ECT index. However, hippocampal CBF increases postindex were more pronounced in nonresponders. ECT responders exhibited CBF increases in the dorsomedial thalamus and motor cortex near the vertex ECT electrode, as well as decreased CBF within lateral frontoparietal regions. Conclusions ECT induces functional neuroplasticity in the hippocampus, which could represent functional precursors of ECT-induced increases in hippocampal volume reported previously. However, excessive functional neuroplasticity within the hippocampus may not be conducive to positive clinical outcome. Instead, our results suggest that although hippocampal plasticity may contribute to antidepressant response in ECT, balanced plasticity in regions relevant to seizure physiology including thalamocortical networks may also play a critical role.

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.

BackgroundSubanesthetic ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depression. How single and repeated ketamine treatment modulates the whole-brain functional connectome to affect clinical outcomes remains uncharacterized.MethodsData-driven whole brain functional connectivity (FC) analysis was used to identify the functional connections modified by ketamine treatment in patients with major depressive disorder (MDD). MDD patients (N = 61, mean age = 38, 19 women) completed baseline resting-state (RS) functional magnetic resonance imaging and depression symptom scales. Of these patients, n = 48 and n = 51, completed the same assessments 24 h after receiving one and four 0.5 mg/kg intravenous ketamine infusions. Healthy controls (HC) (n = 40, 24 women) completed baseline assessments with no intervention. Analysis of RS FC addressed effects of diagnosis, time, and remitter status.ResultsSignificant differences (p < 0.05, corrected) in RS FC were observed between HC and MDD at baseline in the somatomotor network and between association and default mode networks. These disruptions in FC in MDD patients trended toward control patterns with ketamine treatment. Furthermore, following serial ketamine infusions, significant decreases in FC were observed between the cerebellum and salience network (SN) (p < 0.05, corrected). Patient remitters showed increased FC between the cerebellum and the striatum prior to treatment that decreased following treatment, whereas non-remitters showed the opposite pattern.ConclusionResults support that ketamine treatment leads to neurofunctional plasticity between distinct neural networks that are shown as disrupted in MDD patients. Cortico-striatal-cerebellar loops that encompass the SN could be a potential biomarker for ketamine 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

Subcallosal cingulate (SCC) activity is associated with treatment response in major depressive disorder (MDD). Using electroconvulsive therapy (ECT) as a treatment model in this exploratory study, we addressed whether pretreatment SCC structural connectivity with corticolimbic-striatal circuitry relates to therapeutic outcome and whether these connectivity patterns change with treatment.Diffusion magnetic resonance imaging scans were acquired in 43 patients with MDD (mean [SD] age = 41 [13] years; men/women: 18/25) before and within 1 week of completing an ECT index series and in 31 healthy control subjects scanned twice (mean [SD] age = 38 [11] years; men/women: 17/18). Probabilistic tractography from subject-specific anatomically defined SCC seed regions to the ventral striatum (VS), anterior cingulate cortex (ACC), and bilateral medial prefrontal cortex (mPFC) was used to estimate structural connectivity in the target network.SCC-mPFC connectivity was lower in responders (50% symptom improvement) than nonresponders both before (p.014) (difference 37%-96% left and right hemispheres) and after (p = .023) (difference 100% right hemisphere) treatment. SCC-mPFC connectivity in responders was also decreased compared with control subjects both at baseline (p = .012) and after ECT (p = .006), whereas nonresponders had SCC-right mPFC connectivity similar to that of control subjects. Subjects with MDD also showed decreased SCC-ACC connectivity compared with control subjects (baseline: p.003, after ECT: p = .001), although SCC-ACC connectivity did not distinguish responders from nonresponders. Bilateral SCC-VS connectivity decreased (11%) with ECT (p = .021) regardless of treatment response.While SCC-ACC connectivity may be a hallmark of MDD compared with control subjects, lower pretreatment SCC-mPFC connectivity in ECT responders (compared with nonresponders and control subjects) suggests that connectivity in this pathway may serve as a potential biomarker of therapeutic outcome and be relevant for treatment selection.

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

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: β=-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 (β=-0.458, p=0.03), but not in males (β=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.

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.

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 24h after receiving single, and four subanesthetic (0.5mg/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.

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

Though electroconvulsive therapy (ECT) is an established treatment for severe depression, the neurobiological factors accounting for the clinical effects of ECT are largely unknown. Myo-inositol, a neurometabolite linked with glial activity, is reported as reduced in fronto-limbic regions in patients with depression. Whether changes in myo-inositol relate to the antidepressant effects of ECT is unknown. Using magnetic resonance spectroscopy ((1)H-MRS), we measured dorsomedial anterior cingulate cortex (dmACC) and left and right hippocampal myo-inositol in 50 ECT patients (mean age: 43.78, 14 SD) and 33 controls (mean age: 39.33, 12 SD) to determine cross sectional effects of diagnosis and longitudinal effects of ECT. Patients were scanned prior to treatment, after the second ECT and at completion of the ECT index series. Controls were scanned twice at intervals corresponding to patients' baseline and end of treatment scans. Myo-inositol increased over the course of ECT in the dmACC (p=0.042). A significant hemisphere by clinical response effect was observed for the hippocampus (p=0.003) where decreased myo-inositol related to symptom improvement in the left hippocampus. Cross-sectional differences between patients and controls at baseline were not detected. Changes in myo-inositol observed in the dmACC in association with ECT and in the hippocampus in association with ECT-related clinical response suggest the mechanisms of ECT could include gliogenesis or a reversal of gliosis that differentially affect dorsal and ventral limbic regions. Change in dmACC myo-inositol diverged from control values with ECT suggesting compensation, while hippocampal change suggested normalization.

Electroconvulsive therapy (ECT) is an effective treatment for severe depression and is shown to increase hippocampal volume and modulate hippocampal functional connectivity. Whether variations in hippocampal structural connectivity occur with ECT and relate to clinical response is unknown.Patients with major depression (n = 36, 20 women, age 41.49 ± 13.57 years) underwent diffusion magnetic resonance imaging at baseline and after ECT. Control subjects (n = 32, 17 women, age 39.34 ± 12.27 years) underwent scanning twice. Functionally defined seeds in the left and right anterior hippocampus and probabilistic tractography were used to extract tract volume and diffusion metrics (fractional anisotropy and axial, radial, and mean diffusivity). Statistical analyses determined effects of ECT and time-by-response group interactions (50% change in symptoms before and after ECT defined response). Differences between baseline measures across diagnostic groups and in association with treatment outcome were also examined.Significant effects of ECT (all p.01) and time-by-response group interactions (all p.04) were observed for axial, radial, and mean diffusivity for right, but not left, hippocampal pathways. Follow-up analyses showed that ECT-related changes occurred in responders only (all p.01) as well as in relation to change in mood examined continuously (all p.004). Baseline measures did not relate to symptom change or differ between patients and control subjects. All measures remained stable across time in control subjects. No significant effects were observed for fractional anisotropy and volume.Structural connectivity of hippocampal neural circuits changed with ECT and distinguished treatment responders. The findings suggested neurotrophic, glial, or inflammatory response mechanisms affecting axonal integrity.

BackgroundKetamine 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.MethodsFSL'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.ResultsWhole brain TBSS (p

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.

The study of human olfaction is a highly complex and valuable field with applications ranging from biomedical research to clinical evaluation. Currently, evaluation of the functions of the human central olfactory system with functional magnetic resonance imaging (fMRI) is still a challenge because of several technical difficulties. There are some significant variables to take into account when considering an effective method for mapping the function of the central olfactory system using fMRI, including proper odorant selection, the interaction between odor presentation and respiration, and potential anticipation of or habituation to odorants. An event-related, respiration-triggered olfactory fMRI technique can accurately administer odorants to stimulate the olfactory system while minimizing potential interference. It can effectively capture the precise onsets of fMRI signals in the primary olfactory cortex using our data post-processing method. The technique presented here provides an efficient and practical means for generating reliable olfactory fMRI results. Such a technique can ultimately be applied in the clinical realm as a diagnostic tool for diseases associated with olfactory degeneration, including Alzheimer's and Parkinson's disease, as we begin to further understand the complexities of the human olfactory system.

Background: 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. Methods: 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. Results: 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. Limitations: Attrition and clinical heterogeneity may have masked more subtle findings. Conclusion: 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.

Electroconvulsive therapy (ECT) is a highly effective and rapidly acting treatment for severe depression. To understand the biological bases of therapeutic response, we examined variations in cortical thickness from magnetic resonance imaging (MRI) data in 29 patients scanned at three time points during an ECT treatment index series and in 29 controls at two time points. Changes in thickness across time and with symptom improvement were evaluated at high spatial resolution across the cortex and within discrete cortical regions of interest. Patients showed increased thickness over the course of ECT in the bilateral anterior cingulate cortex (ACC), inferior and superior temporal, parahippocampal, entorhinal and fusiform cortex and in distributed prefrontal areas. No changes across time occurred in controls. In temporal and fusiform regions showing significant ECT effects, thickness differed between patients and controls at baseline and change in thickness related to therapeutic response in patients. In the ACC, these relationships occurred in treatment responders only, and thickness measured soon after treatment initiation predicted the overall ECT response. ECT leads to widespread neuroplasticity in neocortical, limbic and paralimbic regions and changes relate to the extent of antidepressant response. Variations in ACC thickness, which discriminate treatment responders and predict response early in the course of ECT, may represent a biomarker of overall clinical outcome. Because post-mortem studies show focal reductions in glial density and neuronal size in patients with severe depression, ECT-related increases in thickness may be attributable to neuroplastic processes affecting the size and/or density of neurons and glia and their connections.

Mutations within the HFE protein gene sequence have been associated with increased risk of developing a number of neurodegenerative disorders. To this effect, an animal model has been created which incorporates the mouse homologue to the human H63D-HFE mutation: the H67D-HFE knock-in mouse. These mice exhibit alterations in iron management proteins, have increased neuronal oxidative stress, and a disruption in cholesterol regulation. However, it remains undetermined how these differences translate to human H63D carriers in regards to white matter (WM) integrity. To this endeavor, MRI transverse relaxation rate (R2) parametrics were employed to test the hypothesis that WM alterations are present in H63D human carriers and are recapitulated in the H67D mice. H63D carriers exhibit widespread reductions in brain R2 compared to non-carriers within white matter association fibers in the brain. Similar R2 decreases within white matter tracts were observed in the H67D mouse brain. Additionally, an exacerbation of age-related R2 decrease is found in the H67D animal model in white matter regions of interest. The decrease in R2 within white matter tracts of both species is speculated to be multifaceted. The R2 changes are hypothesized to be due to alterations in axonal biochemical tissue composition. The R2 changes observed in both the human-H63D and mouse-H67D data suggest that modified white matter myelination is occurring in subjects with HFE mutations, potentially increasing vulnerability to neurodegenerative disorders.

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

Background The formation of an odor percept in humans is strongly associated with visual information. However, much less is known about the roles of learning and memory in shaping the multisensory nature of odor representations in the brain. Method The dynamics of odor and visual association in olfaction was investigated using three functional magnetic resonance imaging (fMRI) paradigms. In two paradigms, a visual cue was paired with an odor. In the third, the same visual cue was never paired with an odor. In this experimental design, if the visual cue was not influenced by odor–visual pairing, then the blood‐oxygen‐level‐dependent (BOLD) signal elicited by subsequent visual cues should be similar across all three paradigms. Additionally, intensity, a major dimension of odor perception, was used as a modulator of associative learning which was characterized in terms of the spatiotemporal behavior of the BOLD signal in olfactory structures. Results A single odor–visual pairing cue could subsequently induce primary olfactory cortex activity when only the visual cue was presented. This activity was intensity dependent and was also detected in secondary olfactory structures and hippocampus. Conclusion This study provides evidence for a rapid learning response in the olfactory system by a visual cue following odor and visual cue pairing. The novel data and paradigms suggest new avenues to explore the dynamics of odor learning and multisensory representations that contribute to the construction of a unified odor percept in the human brain.

Major depressive disorder (MDD) is associated with dysfunctional corticolimbic networks, making functional connectivity studies integral for understanding the mechanisms underlying MDD pathophysiology and treatment. Resting-state functional connectivity (RSFC) studies analyze patterns of temporally coherent intrinsic brain activity in "resting-state networks" (RSNs). The default-mode network (DMN) has been of particular interest to depression research; however, a single RSN is unlikely to capture MDD pathophysiology in its entirety, and the DMN itself can be characterized by multiple RSNs. This, coupled with conflicting previous results, underscores the need for further research. Here, we measured RSFC in MDD by targeting RSNs overlapping with corticolimbic regions and further determined whether altered patterns of RSFC were restored with electroconvulsive therapy (ECT). MDD patients exhibited hyperconnectivity between ventral striatum (VS) and the ventral default-mode network (vDMN), while simultaneously demonstrating hypoconnectivity with the anterior DMN (aDMN). ECT influenced this pattern: VS-vDMN hyperconnectivity was significantly reduced while VS-aDMN hypoconnectivity only modestly improved. RSFC between the salience RSN and dorsomedial prefrontal cortex was also reduced in MDD, but was not affected by ECT. Taken together, our results support a model of ventral/dorsal imbalance in MDD and further suggest that the VS is a key structure contributing to this desynchronization.

Introduction: The motor symptoms and signs of early-onset idiopathic Parkinson's disease (PD) in Hoehn and Yahr (H&Y) stage-1 are generally unilateral. We hypothesized that there would be detectable differences in the quantitative MRI parameters in these PD patients between the hemispheres contralateral to the clinically symptomatic and non-symptomatic body side. Methods: We tested this hypothesis by comparing transverse relaxation rates and diffusion tensor imaging (DTI) parameters in the substantia nigra and putamen between the two hemispheres contralateral to the symptomatic and non-symptomatic side in H&Y stage-1 PD patients who had onset of symptoms between ages of 40e59 years. Results: There were quantifiable hemispheric asymmetries in transverse relaxation rates in the substantia nigra, as well as fractional anisotropy and mean diffusivity in the putamen in early PD, which correlated with the unilaterality of motor symptoms as evaluated using the motor portion of the Unified Parkinson's Disease Rating Scale. Conclusion: Transverse relaxation mapping and DTI demonstrated significant differences between the symptomatic and non-symptomatic hemispheres at the early stage of early-onset PD. These findings support the hypothesis of asymmetric neurodegeneration in the bilateral nigrostriatal pathways in the early stage of the disease.