Evaluating global brain connectivity as an imaging marker for depression: influence of preprocessing strategies and placebo-controlled ketamine treatment.
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ABSTRACT:
SUBMITTER: Kraus C
PROVIDER: S-EPMC7162890 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Capitalizing on recent advances in resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) and the distinctive paradigm of rapid mood normalization following ketamine treatment, the current study investigated intrinsic brain networks in major depressive disorder (MDD) during a depressive episode and following treatment with ketamine. Medication-free patients with MDD and healthy control subjects (HC) completed baseline rs-fcMRI. MDD patients received a single infusion of ketamine and underwent repeated rs-fcMRI at 24?h posttreatment. Global brain connectivity with global signal regression (GBCr) values were computed as the average of correlations of each voxel with all other gray matter voxels in the brain. MDD group showed reduced GBCr in the prefrontal cortex (PFC) but increased GBCr in the posterior cingulate, precuneus, lingual gyrus, and cerebellum. Ketamine significantly increased GBCr in the PFC and reduced GBCr in the cerebellum. At baseline, 2174 voxels of altered GBCr were identified, but only 310 voxels significantly differed relative to controls following treatment (corrected ?<0.05). Responders to ketamine showed increased GBCr in the lateral PFC, caudate, and insula. Follow-up seed-based analyses illustrated a pattern of dysconnectivity between the PFC/subcortex and the rest of the brain in MDD, which appeared to normalize postketamine. The extent of the functional dysconnectivity identified in MDD and the swift and robust normalization following treatment suggest that GBCr may serve as a treatment response biomarker for the development of rapid acting antidepressants. The data also identified unique prefrontal and striatal circuitry as a putative marker of successful treatment and a target for antidepressants' development.
| S-EPMC5437875 | biostudies-other
Project description:BackgroundKetamine's potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor-dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states.MethodsResting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined.ResultsA reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P < .0001, FDR-corrected), right temporal pole (t = 4.97, P < .0001, FDR-corrected), right parahippocampal gyrus (t = 5.80, P = .001, FDR-corrected), and left lateral occipital cortex (t = 4.73, P = .03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results.ConclusionsThese preliminary results suggest that the Hb might be involved in ketamine's antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.
| S-EPMC8130203 | biostudies-literature
Project description:A potential venue to improve healthcare efficiency is to effectively tailor individualized treatment strategies by incorporating patient level predictor information such as environmental exposure, biological, and genetic marker measurements. Many useful statistical methods for deriving individualized treatment rules (ITR) have become available in recent years. Prior to adopting any ITR in clinical practice, it is crucial to evaluate its value in improving patient outcomes. Existing methods for quantifying such values mainly consider either a single marker or semi-parametric methods that are subject to bias under model misspecification. In this article, we consider a general setting with multiple markers and propose a two-step robust method to derive ITRs and evaluate their values. We also propose procedures for comparing different ITRs, which can be used to quantify the incremental value of new markers in improving treatment selection. While working models are used in step I to approximate optimal ITRs, we add a layer of calibration to guard against model misspecification and further assess the value of the ITR non-parametrically, which ensures the validity of the inference. To account for the sampling variability of the estimated rules and their corresponding values, we propose a resampling procedure to provide valid confidence intervals for the value functions as well as for the incremental value of new markers for treatment selection. Our proposals are examined through extensive simulation studies and illustrated with the data from a clinical trial that studies the effects of two drug combinations on HIV-1 infected patients.
| S-EPMC4213325 | biostudies-literature
Project description:Preprocessing choices present a particular challenge for researchers working with functional magnetic resonance imaging (fMRI) data from young children. Steps which have been shown to be important for mitigating head motion, such as censoring and global signal regression (GSR), remain controversial, and benchmarking studies comparing preprocessing pipelines have been conducted using resting data from older participants who tend to move less than young children. Here, we conducted benchmarking of fMRI preprocessing steps in a population with high head-motion, children aged 4-8 years, leveraging a unique longitudinal, passive viewing fMRI dataset. We systematically investigated combinations of global signal regression (GSR), volume censoring, and ICA-AROMA. Pipelines were compared using previously established metrics of noise removal as well as metrics sensitive to recovery of individual differences (i.e., connectome fingerprinting), and stimulus-evoked responses (i.e., intersubject correlations; ISC). We found that: 1) the most efficacious pipeline for both noise removal and information recovery included censoring, GSR, bandpass filtering, and head motion parameter (HMP) regression, 2) ICA-AROMA performed similarly to HMP regression and did not obviate the need for censoring, 3) GSR had a minimal impact on connectome fingerprinting but improved ISC, and 4) the strictest censoring approaches reduced motion correlated edges but negatively impacted identifiability.
| S-EPMC8866685 | biostudies-literature
Project description:BackgroundKetamine 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.MethodsPatients 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.ResultsKetamine 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).ConclusionsKetamine 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.
| S-EPMC8629108 | biostudies-literature
Project description:BackgroundPrefrontal global brain connectivity with global signal regression (GBCr) was proposed as a robust biomarker of depression, and was associated with ketamine's mechanism of action. Here, we investigated prefrontal GBCr in treatment-resistant depression (TRD) at baseline and following treatment. Then, we conducted a set of pharmacological challenges in healthy subjects to investigate the glutamate neurotransmission correlates of GBCr.MethodsIn study A, we used functional magnetic resonance imaging (fMRI) to compare GBCr between 22 TRD and 29 healthy control. Then, we examined the effects of ketamine and midazolam on GBCr in TRD patients 24h post-treatment. In study B, we acquired repeated fMRI in 18 healthy subjects to determine the effects of lamotrigine (a glutamate release inhibitor), ketamine, and lamotrigine-by-ketamine interaction.ResultsIn study A, TRD patients showed significant reduction in dorsomedial and dorsolateral prefrontal GBCr compared to healthy control. In TRD patients, GBCr in the altered clusters significantly increased 24h following ketamine (effect size = 1.0 [0.3 1.8]), but not midazolam (effect size = 0.5 [-0.6 1.3]). In study B, oral lamotrigine reduced GBCr 2h post-administration, while ketamine increased medial prefrontal GBCr during infusion. Lamotrigine significantly reduced the ketamine-induced GBCr surge. Exploratory analyses showed elevated ventral prefrontal GBCr in TRD and significant reduction of ventral prefrontal GBCr during ketamine infusion in healthy subjects.ConclusionsThis study provides first replication of the ability of ketamine to normalize depression-related prefrontal dysconnectivity. It also provides indirect evidence that these effects may be triggered by the capacity of ketamine to enhance glutamate neurotransmission.
| S-EPMC5635826 | biostudies-literature
Project description:BackgroundRecent neuroimaging studies have demonstrated resting-state functional connectivity (rsFC) abnormalities among intrinsic brain networks in Major Depressive Disorder (MDD); however, their role as predictors of treatment response has not yet been explored. Here, we investigate whether network-based rsFC predicts antidepressant and placebo effects in MDD.MethodsWe performed a randomized controlled trial of two weeklong, identical placebos (described as having either "active" fast-acting, antidepressant effects or as "inactive") followed by a ten-week open-label antidepressant medication treatment. Twenty-nine participants underwent a rsFC fMRI scan at the completion of each placebo condition. Networks were isolated from resting-state blood-oxygen-level-dependent signal fluctuations using independent component analysis. Baseline and placebo-induced changes in rsFC within the default-mode, salience, and executive networks were examined for associations with placebo and antidepressant treatment response.ResultsIncreased baseline rsFC in the rostral anterior cingulate (rACC) within the salience network, a region classically implicated in the formation of placebo analgesia and the prediction of treatment response in MDD, was associated with greater response to one week of active placebo and ten weeks of antidepressant treatment. Machine learning further demonstrated that increased salience network rsFC, mainly within the rACC, significantly predicts individual responses to placebo administration.ConclusionsThese data demonstrate that baseline rsFC within the salience network is linked to clinical placebo responses. This information could be employed to identify patients who would benefit from lower doses of antidepressant medication or non-pharmacological approaches, or to develop biomarkers of placebo effects in clinical trials.
| S-EPMC4689203 | biostudies-literature
Project description:Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov : Treatment Resistant Depression (Pilot), NCT01179009.
| S-EPMC7969576 | biostudies-literature
Project description:Identifying the neural correlates of ketamine treatment may facilitate and expedite the development of novel, robust, and safe rapid-acting antidepressants. Prefrontal cortex (PFC) global brain connectivity with global signal regression (GBCr) was recently identified as a putative biomarker of major depressive disorder (MDD). Accumulating evidence have repeatedly shown reduced PFC GBCr in MDD, an abnormality which appears to normalize following ketamine treatment. Fifty-six unmedicated participants with MDD were randomized to intravenous placebo (normal saline; n = 18), ketamine (0.5mg/kg; n = 19) or lanicemine (100mg; n = 19). PFC GBCr was computed using time series from functional magnetic resonance imaging (fMRI) scans that were completed at baseline, during infusion, and 24h post-treatment. Compared to placebo, ketamine significantly increased average PFC GBCr during infusion (p = 0.01) and 24h post-treatment (p = 0.02). Lanicemine had no significant effects on GBCr during infusion (p = 0.45) and 24h post-treatment (p = 0.23), compared to placebo. Average delta PFC GBCr (during minus baseline) showed a pattern of positively predicting depression improvement in participants receiving ketamine (r = 0.44; p = 0.06; d = 1.0) or lanicemine (r = 0.55; p = 0.01; d = 1.3), but not those receiving placebo (r = -0.1; p = 0.69; d = 0.02). Follow-up vertex-wise analyses showed ketamine-induced GBCr increases in the dorsolateral, dorsomedial, and frontomedial PFC during infusion, and in the dorsolateral and dorsomedial PFC 24h post-treatment (corrected p < 0.05). Exploratory vertex-wise analyses examining the relationship with depression improvement showed positive correlation with GBCr in the dorsal PFC during infusion and 24h post-treatment, but negative correlation with GBCr in the ventral PFC during infusion (uncorrected p < 0.01). In a randomized placebo-controlled approach, the results provide the first evidence in MDD of ketamine-induced increases in PFC GBCr during infusion, and suggests that ketamine's rapid-acting antidepressant properties are related to its acute effects on prefrontal connectivity. Overall, the study findings underscore the similarity and differences between ketamine and another N-methyl-D-aspartate receptor (NMDAR) antagonist, while proposing a pharmacoimaging paradigm for optimization of novel rapid-acting antidepressants prior to testing in costly clinical trials.
| S-EPMC6154502 | biostudies-literature
Project description:Dysfunctional reward processing in major depressive disorder (MDD) involves functional circuitry of the habenula (Hb) and nucleus accumbens (NAc). Ketamine elicits rapid antidepressant and alleviates anhedonia in MDD. To clarify how ketamine perturbs reward circuitry in MDD, we examined how serial ketamine infusions (SKI) modulate static and dynamic functional connectivity (FC) in Hb and NAc networks. MDD participants (n=58, mean age=40.7 years, female=28) received four ketamine infusions (0.5mg/kg) 2-3 times weekly. Resting-state fMRI scans and clinical assessments were collected at baseline and 24 hours post-SKI completion. Static FC (sFC) and dynamic FC variability (dFCv) were calculated from left and right Hb and NAc seeds to all other brain regions. Paired t-tests examined changes in FC pre-to-post SKI, and correlations were used to determine relationships between FC changes with mood and anhedonia. Following SKI, significant increases in left Hb-bilateral visual cortex FC, decreases in left Hb-left inferior parietal cortex FC, and decreases in left NAc-right cerebellum FC occurred. Decreased dFCv between left Hb and right precuneus and visual cortex, and decreased dFCv between right NAc and right visual cortex both significantly correlated with improvements in Hamilton Depression Rating Scale. Decreased FC between left Hb and bilateral visual/parietal cortices as well as increased FC between left NAc and right visual/parietal cortices both significantly correlated with improvements in anhedonia. Subanesthetic ketamine modulates functional pathways linking the Hb and NAc with visual, parietal, and cerebellar regions. Overlapping effects between Hb and NAc functional systems were associated with ketamine's therapeutic response.
| S-EPMC10723506 | biostudies-literature