Aberrant associations between neuronal resting-state fluctuations and working memory-induced activity in major depressive disorder.

Previous investigations have revealed performance deficits and altered neural processes during working-memory (WM) tasks in major depressive disorder (MDD). While most of these studies used task-based functional magnetic resonance imaging (fMRI), there is an increasing interest in resting-state fMRI to characterize aberrant network dynamics involved in this and other MDD-associated symptoms. It has been proposed that activity during the resting-state represents characteristics of brain-wide functional organization, which could be highly relevant for the efficient execution of cognitive tasks. However, the dynamics linking resting-state properties and task-evoked activity remain poorly understood. Therefore, the present study investigated the association between spontaneous activity as indicated by the amplitude of low frequency fluctuations (ALFF) at rest and activity during an emotional n-back task. 60 patients diagnosed with an acute MDD episode, and 52 healthy controls underwent the fMRI scanning procedure. Within both groups, positive correlations between spontaneous activity at rest and task-activation were found in core regions of the central-executive network (CEN), whereas spontaneous activity correlated negatively with task-deactivation in regions of the default mode network (DMN). Compared to healthy controls, patients showed a decreased rest-task correlation in the left prefrontal cortex (CEN) and an increased negative correlation in the precuneus/posterior cingulate cortex (DMN). Interestingly, no significant group-differences within those regions were found solely at rest or during the task. The results underpin the potential value and importance of resting-state markers for the understanding of dysfunctional network dynamics and neural substrates of cognitive processing.

Negative emotionality shapes the modulatory effects of ketamine and lamotrigine in subregions of the anterior cingulate cortex.

Neuroimaging studies have identified the anterior cingulate cortex (ACC) as one of the major targets of ketamine in the human brain, which may be related to ketamine's antidepressant (AD) mechanisms of action. However, due to different methodological approaches, different investigated populations, and varying measurement timepoints, results are not consistent, and the functional significance of the observed brain changes remains a matter of open debate. Inhibition of glutamate release during acute ketamine administration by lamotrigine provides the opportunity to gain additional insight into the functional significance of ketamine-induced brain changes. Furthermore, the assessment of trait negative emotionality holds promise to link findings in healthy participants to potential AD mechanisms of ketamine. In this double-blind, placebo-controlled, randomized, single dose, parallel-group study, we collected resting-state fMRI data before, during, and 24 h after ketamine administration in a sample of 75 healthy male and female participants who were randomly allocated to one of three treatment conditions (ketamine, ketamine with lamotrigine pre- treatment, placebo). Spontaneous brain activity was extracted from two ventral and one dorsal subregions of the ACC. Our results showed activity decreases during the administration of ketamine in all three ACC subregions. However, only in the ventral subregions of the ACC this effect was attenuated by lamotrigine. 24 h after administration, ACC activity returned to baseline levels, but group differences were observed between the lamotrigine and the ketamine group. Trait negative emotionality was closely linked to activity changes in the subgenual ACC after ketamine administration. These results contribute to an understanding of the functional significance of ketamine effects in different subregions of the ACC by combining an approach to modulate glutamate release with the assessment of multiple timepoints and associations with trait negative emotionality in healthy participants.

Neural signatures of shared subjective affective engagement and disengagement during movie viewing.

When watching a negative emotional movie, we differ from person to person in the ease with which we engage and the difficulty with which we disengage throughout a temporally evolving narrative. We investigated neural responses of emotional processing, by considering inter-individual synchronization in subjective emotional engagement and disengagement. The neural underpinnings of these shared responses are ideally studied in naturalistic scenarios like movie viewing, wherein individuals emotionally engage and disengage at their own time and pace throughout the course of a narrative. Despite the rich data that naturalistic designs can bring to the study, there is a challenge in determining time-resolved behavioral markers of subjective engagement and disengagement and their underlying neural responses. We used a within-subject cross-over design instructing 22 subjects to watch clips of either neutral or sad content while undergoing functional magnetic resonance imaging (fMRI). Participants watched the same movies a second time while continuously annotating the perceived emotional intensity, thus enabling the mapping of brain activity and emotional experience. Our analyses revealed that between-participant similarity in waxing (engagement) and waning (disengagement) of emotional intensity was directly related to the between-participant similarity in spatiotemporal patterns of brain activation during the movie(s). Similar patterns of engagement reflected common activation in the bilateral ventromedial prefrontal cortex, regions often involved in self-referenced evaluation and generation of negative emotions. Similar patterns of disengagement reflected common activation in central executive and default mode network regions often involved in top-down emotion regulation. Together this work helps to better understand cognitive and neural mechanisms underpinning engagement and disengagement from emotionally evocative narratives.

Investigating the impact of rumination and adverse childhood experiences on resting-state neural activity and connectivity in depression.

BACKGROUND: Both ruminative thought processes and adverse childhood experiences (ACEs) are well-established risk factors for the emergence and maintenance of depression. However, the neurobiological mechanisms underlying these associations remain poorly understood. METHODS: We examined resting-state functional magnetic resonance imaging data (3 T Tim Trio MR scanner; Siemens, Erlangen) of 44 individuals diagnosed with an acute depressive episode. Specifically, we focused on investigating functional brain activity and connectivity within and between three large-scale neural networks associated with processes affected in depression: the default mode network (DMN), the salience network (SN), and the central executive network (CEN). Correlational and regression-based analyses were performed. RESULTS: Our regions of interest analyses revealed that region-specific spontaneous neural activity in the anterior DMN was associated with self-reported trait rumination, specifically, the pregenual anterior cingulate cortex (pgACC). Furthermore, using a liberal statistical threshold, we found that spontaneous neural activity of the ventromedial prefrontal cortex and the pgACC were associated with depression symptom severity. Neither spontaneous neural activity in the SN and CEN nor functional connectivity within and across the investigated networks was associated with depression severity or rumination. Furthermore, there was no association between ACEs and brain activity and connectivity. LIMITATIONS: Lack of a formal control group or low-risk group for comparison. CONCLUSIONS: Overall, our results indicate network-specific changes in spontaneous brain activity, that are linked to both depression severity and rumination. Findings underscore the crucial role of the pgACC in depression and contribute to a dimensional and symptom-based understanding of depression-related network imbalances.

The influence of electroconvulsive therapy on reconsolidation of autobiographical memories: A retrospective quasi-experimental study in patients with depression

Background/Objective: Electroconvulsive therapy (ECT) is effective for treatment-resistant and psychotic depression. One previously reported side effect of ECT is the disruption of memory reconsolidation. This study examines whether this disruption induced by ECT can be detected in routine neuropsychological assessments. Methods: In this retrospective study, the Autobiographical Memory Interview (AMI) was applied before and after ECT. Memories of the same events and facts were tested pre and post ECT treatments. 38 patients, receiving ECT for the treatment of unipolar or bipolar depression, were matched for age, sex, and stimulus intensity and divided into two groups: Group A was tested on the day before the first ECT treatment, whereas group B two or more days before. Results: Patients who were tested by AMI on the day before ECT and thus reactivated memorie shortly before the first ECT treatment deteriorated in AMI score. Patients who had at least two days between memory activation and treatment improved regarding the number of recalled memories. Memory impairment was not associated with depression severity. Conclusion: This finding suggests that ECT might be capable of impairing reconsolidation. The study demonstrates that memories of personal events can potentially be affected by ECT within a time interval of 24 h of memory vulnerability after reactivation. Implications for practice and future research are discussed. (AU)

Effects of a single dose of amisulpride on functional brain changes during reward- and motivation-related processing using task-based fMRI in healthy subjects and patients with major depressive disorder - study protocol for a randomized clinical trial.

BACKGROUND: Anhedonia and other deficits in reward- and motivation-related processing in psychiatric patients, including patients with major depressive disorder (MDD), represent a high unmet medical need. Neurobiologically, these deficits in MDD patients are mainly associated with low dopamine function in a frontostriatal network. In this study, alterations in brain activation changes during reward processing and at rest in MDD patients compared with healthy subjects are explored and the effects of a single low dose of the dopamine D2 receptor antagonist amisulpride are investigated. METHODS: This is a randomized, controlled, double-blind, single-dose, single-center parallel-group clinical trial to assess the effects of a single dose of amisulpride (100 mg) on blood-oxygenation-level-dependent (BOLD) responses during reward- and motivation-related processing in healthy subjects (n = 60) and MDD patients (n = 60). Using functional magnetic resonance imaging (fMRI), BOLD responses are assessed during the monetary incentive delay (MID) task (primary outcome). Exploratory outcomes include BOLD responses and behavioral measures during the MID task, instrumental learning task, effort-based decision-making task, social incentive delay task, and probabilistic reward task as well as changes in resting state functional connectivity and cerebral blood flow. DISCUSSION: This study broadly covers all aspects of reward- and motivation-related processing as categorized by the National Institute of Mental Health Research Domain Criteria and is thereby an important step towards precision psychiatry. Results regarding the immediate effects of a dopaminergic drug on deficits in reward- and motivation-related processing not only have the potential to significantly broaden our understanding of underlying neurobiological processes but might eventually also pave the way for new treatment options. TRIAL REGISTRATION: ClinicalTrials.gov NCT05347199. April 12, 2022.

The influence of electroconvulsive therapy on reconsolidation of autobiographical memories: A retrospective quasi-experimental study in patients with depression.

Background/Objective: Electroconvulsive therapy (ECT) is effective for treatment-resistant and psychotic depression. One previously reported side effect of ECT is the disruption of memory reconsolidation. This study examines whether this disruption induced by ECT can be detected in routine neuropsychological assessments. Methods: In this retrospective study, the Autobiographical Memory Interview (AMI) was applied before and after ECT. Memories of the same events and facts were tested pre and post ECT treatments. 38 patients, receiving ECT for the treatment of unipolar or bipolar depression, were matched for age, sex, and stimulus intensity and divided into two groups: Group A was tested on the day before the first ECT treatment, whereas group B two or more days before. Results: Patients who were tested by AMI on the day before ECT and thus reactivated memorie shortly before the first ECT treatment deteriorated in AMI score. Patients who had at least two days between memory activation and treatment improved regarding the number of recalled memories. Memory impairment was not associated with depression severity. Conclusion: This finding suggests that ECT might be capable of impairing reconsolidation. The study demonstrates that memories of personal events can potentially be affected by ECT within a time interval of 24 h of memory vulnerability after reactivation. Implications for practice and future research are discussed.

Transdiagnostic phenomena of psychopathology in the context of the RDoC: protocol of a multimodal cross-sectional study.

In the past, affective and cognitive processes related to psychopathology have been examined within the boundaries of phenotype-based diagnostic labels, which has led to inconsistent findings regarding their underlying operating principles. Investigating these processes dimensionally in healthy individuals and by means of multiple modalities may provide additional insights into the psychological and neuronal mechanisms at their core. The transdiagnostic phenomena Neuroticism and Rumination are known to be closely linked. However, the exact nature of their relationship remains to be elucidated. The same applies to the associations between Hedonic Capacity, Negativity Bias and different Emotion Regulation strategies.This multimodal cross-sectional study examines the relationship of the transdiagnostic phenomena Neuroticism and Rumination as well as Hedonic Capacity, the Negativity Bias and Emotion Regulation from a RDoC (Research Domain Criteria) perspective. A total of 120 currently healthy subjects (past 12 months) will complete several questionnaires regarding personality, emotion regulation, hedonic capacity, and psychopathologies as well as functional magnetic resonance imaging (fMRI) during cognitive and emotional processing, to obtain data on the circuit, behavioral and self-report level.This study aims to contribute to the understanding of the relationship between cognitive and affective processes associated with psychopathologies as well as their neuronal correlates. Ultimately, a grounded understanding of these processes could guide improvement of diagnostic labels and treatments. Limitations include the cross-sectional design and the limited variability in psychopathology scores due to the restriction of the sample to currently healthy subjects.

Effects of Psychotherapy on Glutamatergic Neurotransmission.

INTRODUCTION: Psychodynamic psychotherapy is an effective and widely used treatment for major depressive disorder (MDD); however, little is known about neurobiological changes associated with induced symptom improvement. METHODS: Proton magnetic resonance spectroscopy with a two-dimensional J-resolved sequence served to test the relationship between glutamate (Glu) and glutamine (Gln) levels, measured separately in pregenual anterior cingulate cortex (pgACC) and the anterior midcingulate cortex (aMCC) as a control region, with change in depression symptoms after 6 months of weekly psychodynamic psychotherapy sessions in MDD patients. Depressed (N = 45) and healthy (N = 30) subjects participated in a baseline proton magnetic resonance spectroscopy measurement and a subgroup of MDD subjects (N = 21) then received once-a-week psychodynamic psychotherapy and participated in a second proton magnetic resonance spectroscopy measurement after 6 months. Change in depression symptoms was assessed using the Hamilton Depression Rating Scale (HAMD). RESULTS: Higher pretreatment pgACC Gln concentrations in MDD patients compared to healthy controls were associated with symptom severity. Patients and controls did not differ regarding Gln levels in aMCC nor regarding Glu levels in both regions. The association of pgACC Gln concentration and severity of depressive symptoms was reversed after 6 months of psychotherapy in MDD subjects. Regarding Gln in aMCC as well as Glu in both regions, there were no significant associations with improvement of depressive symptoms in the course of psychotherapy. DISCUSSION: Findings indicate specific regional effects of psychodynamic psychotherapy on glutamatergic neurotransmission and thereby highlight the key role of the pgACC in both depression pathophysiology and recovery.

The influence of childhood emotional maltreatment on cognitive symptoms, rumination, and hopelessness in adulthood depression.

Childhood emotional maltreatment (CEM) is a risk factor for the pathogenesis of depressive disorders. However, it is not clear whether CEM is more strongly related to specific symptoms of depression and whether specific traits or cognitive states may mediate the association between CEM and depressive symptoms. In our cross-sectional study, including 72 patients with a current depressive episode, we investigated if CEM is specifically related to cognitive symptoms of depression. In addition, we evaluated whether CEM also influences the extent of rumination and hopelessness in adult depression. Using multiple regression analyses, we tested if CEM and rumination could predict cognitive symptoms and hopelessness. A structural equation model (SEM) was used to examine if rumination mediates the relationship between CEM and cognitive symptoms. Correlational analyses revealed that CEM was related to cognitive symptoms, rumination, and hopelessness. The regression analyses showed that only rumination was a significant predictor for cognitive symptoms and hopelessness, whereas CEM could not significantly predict the two constructs. SEM revealed that the association between CEM and cognitive symptoms in adult depression was mediated by rumination. Our results thereby suggest that CEM is a risk factor particularly for the development of cognitive symptoms as well as rumination and hopelessness in adult depression. However, the influence on cognitive symptomatology seems to be indirectly regulated by rumination. These findings may contribute to a better understanding of processes that promote depression, as well as provide guidance for more targeted treatment options.

Region- and time- specific effects of ketamine on cerebral blood flow: a randomized controlled trial.

There is intriguing evidence suggesting that ketamine might have distinct acute and delayed neurofunctional effects, as its acute administration transiently induces schizophrenia-like symptoms, while antidepressant effects slowly emerge and are most pronounced 24 h after administration. Studies attempting to characterize ketamine's mechanism of action by using blood oxygen level dependent (BOLD) imaging have yielded inconsistent results regarding implicated brain regions and direction of effects. This may be due to intrinsic properties of the BOLD contrast, while cerebral blood flow (CBF), as measured with arterial spin labeling, is a single physiological marker more directly related to neural activity. As effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release, a combination of these approaches should be particularly suited to offer novel insights. In total, 75 healthy participants were investigated in a double blind, placebo-controlled, randomized, parallel-group study and underwent two scanning sessions (acute/post 24 h.). Acute ketamine administration was associated with higher perfusion in interior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC), but no other investigated brain region. Inhibition of glutamate release by pretreatment with lamotrigine abolished ketamine's effect on perfusion. At the delayed time point, pretreatment with lamotrigine was associated with lower perfusion in IFG. These findings underscore the idea that regionally selective patterns of CBF changes reflect proximate effects of modulated glutamate release on neuronal activity. Furthermore, region- specific sustained effects indicate both a swift restoration of disturbed homeostasis in DLPFC as well changes occurring beyond the immediate effects on glutamate signaling in IFG.

Modulatory Effects of Ketamine and Lamotrigine on Cognition: Emotion Interaction in the Brain.

INTRODUCTION: Cognition and emotion are fundamentally integrated in the brain and mutually contribute to behavior. The relation between working memory (WM) and emotion is particularly suited to investigate cognition-emotion interaction since WM is an essential component of many higher cognitive functions. Ketamine affects not only WM but also has a profound impact on emotional processing. Effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release. Accordingly, a combination of these approaches should be particularly suited to investigate cognition-emotion interaction. METHODS: Seventy five healthy subjects were investigated in a double-blind, placebo-controlled, randomized, single-dose, parallel-group study with three treatment conditions. All subjects underwent two scanning sessions (acute/post 24 h). RESULTS: Compared to placebo, acute ketamine administration induced significant dissociative, psychotomimetic, and cognitive effects, as well as an increase in neural activity during WM for positive stimuli. Inhibition of glutamate release by pretreatment with lamotrigine did not influence ketamine's subjective effects, but significantly attenuated its impact on emotional WM and associated neural activity. There was no effect on these measures 24 h after ketamine administration. CONCLUSION: Our results demonstrate differential acute effects of modulated glutamate release and a swift restoration of disturbed neurobehavioral homeostasis in healthy subjects.

Functional connectivity signatures of major depressive disorder: machine learning analysis of two multicenter neuroimaging studies.

The promise of machine learning has fueled the hope for developing diagnostic tools for psychiatry. Initial studies showed high accuracy for the identification of major depressive disorder (MDD) with resting-state connectivity, but progress has been hampered by the absence of large datasets. Here we used regular machine learning and advanced deep learning algorithms to differentiate patients with MDD from healthy controls and identify neurophysiological signatures of depression in two of the largest resting-state datasets for MDD. We obtained resting-state functional magnetic resonance imaging data from the REST-meta-MDD (N = 2338) and PsyMRI (N = 1039) consortia. Classification of functional connectivity matrices was done using support vector machines (SVM) and graph convolutional neural networks (GCN), and performance was evaluated using 5-fold cross-validation. Features were visualized using GCN-Explainer, an ablation study and univariate t-testing. The results showed a mean classification accuracy of 61% for MDD versus controls. Mean accuracy for classifying (non-)medicated subgroups was 62%. Sex classification accuracy was substantially better across datasets (73-81%). Visualization of the results showed that classifications were driven by stronger thalamic connections in both datasets, while nearly all other connections were weaker with small univariate effect sizes. These results suggest that whole brain resting-state connectivity is a reliable though poor biomarker for MDD, presumably due to disease heterogeneity as further supported by the higher accuracy for sex classification using the same methods. Deep learning revealed thalamic hyperconnectivity as a prominent neurophysiological signature of depression in both multicenter studies, which may guide the development of biomarkers in future studies.

Functional connectivity changes between amygdala and prefrontal cortex after ECT are associated with improvement in distinct depressive symptoms.

Electroconvulsive therapy (ECT) is one of the most effective treatments for treatment-resistant depression. However, the underlying mechanisms of action are not yet fully understood. The investigation of depression-specific networks using resting-state fMRI and the relation to differential symptom improvement might be an innovative approach providing new insights into the underlying processes. In this naturalistic study, we investigated the relationship between changes in resting-state functional connectivity (rsFC) and symptom improvement after ECT in 21 patients with treatment-resistant depression. We investigated rsFC before and after ECT and focused our analyses on FC changes directly related to symptom reduction and on FC at baseline to identify neural targets that might predict individual clinical responses to ECT. Additional analyses were performed to identify the direct relationship between rsFC change and symptom dimensions such as sadness, negative thoughts, detachment, and neurovegetative symptoms. An increase in rsFC between the left amygdala and left dorsolateral prefrontal cortex (DLPFC) after ECT was related to overall symptom reduction (Bonferroni-corrected p = 0.033) as well as to a reduction in specific symptoms such as sadness (r = 0.524, uncorrected p = 0.014), negative thoughts (r = 0.700, Bonferroni-corrected p = 0.002) and detachment (r = 0.663, p = 0.004), but not in neurovegetative symptoms. Furthermore, high baseline rsFC between the left amygdala and the right frontal pole (FP) predicted treatment outcome (uncorrected p = 0.039). We conclude that changes in FC in regions of the limbic-prefrontal network are associated with symptom improvement, particularly in affective and cognitive dimensions. Frontal-limbic connectivity has the potential to predict symptom improvement after ECT. Further research combining functional imaging biomarkers and a symptom-based approach might be promising.

Investigation of Neurofunctional Changes Over the Course of Electroconvulsive Therapy.

BACKGROUND: Electroconvulsive therapy (ECT) is an effective treatment for patients suffering from depression. Yet the exact neurobiological mechanisms underlying the efficacy of ECT and indicators of who might respond best to it remain to be elucidated. Identifying neural markers that can inform about an individual's response to ECT would enable more optimal treatment strategies and increase clinical efficacy. METHODS: Twenty-one acutely depressed inpatients completed an emotional working memory task during functional magnetic resonance imaging before and after receiving treatment with ECT. Neural activity was assessed in 5 key regions associated with the pathophysiology of depression: bilateral dorsolateral prefrontal cortex and pregenual, subgenual, and dorsal anterior cingulate cortex. Associations between brain activation and clinical improvement, as reflected by Montgomery-Åsberg Depression Rating Scale scores, were computed using linear regression models, t tests, and Pearson correlational analyses. RESULTS: Significant neurobiological prognostic markers or changes in neural activity from pre- to post ECT did not emerge. CONCLUSIONS: We could not confirm normalization effects and did not find significant neural markers related to treatment response. These results demonstrate that the search for reliable and clinically useful biomarkers for ECT treatment remains in its initial stages and still faces challenges.

The effects of transient receptor potential cation channel inhibition by BI 1358894 on cortico-limbic brain reactivity to negative emotional stimuli in major depressive disorder.

Abnormal emotional processing in major depressive disorder (MDD) has been associated with increased activation to negative stimuli in cortico-limbic brain regions. The authors investigated whether treatment with BI 1358894, a small-molecule inhibitor of the transient receptor potential cation channel subfamily C leads to attenuated activity in these areas in MDD patients. 73 MDD patients were randomized to receive a single oral dose of BI 1358894 (100 mg), citalopram (20 mg), or matching placebo. Brain responses to emotional faces and scenes were investigated using functional magnetic resonance imaging. Primary endpoints were BOLD signal changes in response to negative faces in cortico-limbic brain regions, i.e. bilateral amygdala (AMY), dorsolateral prefrontal cortex, anterior insula (AI), and anterior cingulate cortex. Secondary endpoints were BOLD signal changes in response to negative scenes. For each region, separate ANOVA models were computed for the comparison of treatments (BI 1358894 or citalopram) vs. placebo. The adjusted treatment differences in the % BOLD signal changes in the faces task showed that BI 1358894 induced signal reduction in bilateral AMY and left AI. In the scenes task, BI 1358894 demonstrated significant signal reduction in bilateral AMY, AI, anterior cingulate cortex and left dorsolateral prefrontal cortex. Citalopram failed to induce any significant reductions in BOLD signal in both tasks. BI 1358894-mediated inhibition of the transient receptor potential cation channel subfamily resulted in strong signal reduction in cortico-limbic brain regions, thereby supporting development of this mechanism of action for MDD patients.

Does route of administration affect antidepressant efficacy of ketamine? A meta-analysis of double-blind randomized controlled trials comparing intravenous and intranasal administration.

Intranasal (IN) and intravenous (IV) applications of ketamine have been proven effective for the treatment of depression, but direct comparative trials or meta-analyses on whether both differ in their antidepressant efficacy are lacking. We aimed to meta-analytically compare the short-term efficacy of a single dose of IV and IN ketamine in adult patients with major depressive disorder (MDD) and included double-blind, randomized controlled trials published until February 2022 in our analyses. The main outcome was a response 24 h after the administration of a single dose of ketamine. A random-effects model was used to calculate odds ratios and confidence intervals. Differences in efficacy between intranasal and intravenous application were statistically assessed by calculating a z-test. A total of eleven studies, comprising 1340 patients, were included. Results showed, that while both IN and IV ketamine were associated with increased response rates, efficacy did not differ significantly between these routes. Heterogeneity and funnel plot asymmetry was found in the intranasal sample only. The results of the present meta-analysis corroborate the efficacy of both IN and IV application of ketamine for the treatment of MDD but suggest no difference between both routes of administration. Accordingly, future large-scale trials as well as direct comparative trials are needed to further investigate this question.

Predicting Antidepressant Effects of Ketamine: the Role of the Pregenual Anterior Cingulate Cortex as a Multimodal Neuroimaging Biomarker.

BACKGROUND: Growing evidence underscores the utility of ketamine as an effective and rapid-acting treatment option for major depressive disorder (MDD). However, clinical outcomes vary between patients. Predicting successful response may enable personalized treatment decisions and increase clinical efficacy. METHODS: We here explored the potential of pregenual anterior cingulate cortex (pgACC) activity to predict antidepressant effects of ketamine in relation to ketamine-induced changes in glutamatergic metabolism. Prior to a single i.v. infusion of ketamine, 24 patients with MDD underwent functional magnetic resonance imaging during an emotional picture-viewing task and magnetic resonance spectroscopy. Changes in depressive symptoms were evaluated using the Beck Depression Inventory measured 24 hours pre- and post-intervention. A subsample of 17 patients underwent a follow-up magnetic resonance spectroscopy scan. RESULTS: Antidepressant efficacy of ketamine was predicted by pgACC activity during emotional stimulation. In addition, pgACC activity was associated with glutamate increase 24 hours after the ketamine infusion, which was in turn related to better clinical outcome. CONCLUSIONS: Our results add to the growing literature implicating a key role of the pgACC in mediating antidepressant effects and highlighting its potential as a multimodal neuroimaging biomarker of early treatment response to ketamine.

Acute effects of ketamine on the pregenual anterior cingulate: linking spontaneous activation, functional connectivity, and glutamate metabolism.

Ketamine exerts its rapid antidepressant effects via modulation of the glutamatergic system. While numerous imaging studies have investigated the effects of ketamine on a functional macroscopic brain level, it remains unclear how altered glutamate metabolism and changes in brain function are linked. To shed light on this topic we here conducted a multimodal imaging study in healthy volunteers (N = 23) using resting state fMRI and proton (1H) magnetic resonance spectroscopy (MRS) to investigate linkage between metabolic and functional brain changes induced by ketamine. Subjects were investigated before and during an intravenous ketamine infusion. The MRS voxel was placed in the pregenual anterior cingulate cortex (pgACC), as this region has been repeatedly shown to be involved in ketamine's effects. Our results showed functional connectivity changes from the pgACC to the right frontal pole and anterior mid cingulate cortex (aMCC). Absolute glutamate and glutamine concentrations in the pgACC did not differ significantly from baseline. However, we found that stronger pgACC activation during ketamine was linked to lower glutamine concentration in this region. Furthermore, reduced functional connectivity between pgACC and aMCC was related to increased pgACC activation and reduced glutamine. Our results thereby demonstrate how multimodal investigations in a single brain region could help to advance our understanding of the association between metabolic and functional changes.

Increase in thalamic cerebral blood flow is associated with antidepressant effects of ketamine in major depressive disorder.

Ketamine is a promising treatment option for patients with Major Depressive Disorder (MDD) and has become an important research tool to investigate antidepressant mechanisms of action. However, imaging studies attempting to characterise ketamine's mechanism of action using blood oxygen level-dependent signal (BOLD) imaging have yielded inconsistent results- at least partly due to intrinsic properties of the BOLD contrast, which measures a complex signal related to neural activity. To circumvent the limitations associated with the BOLD signal, we used arterial spin labelling (ASL) as an unambiguous marker of neuronal activity-related changes in cerebral blood flow (CBF). We measured CBF in 21 MDD patients at baseline and 24 h after receiving a single intravenous infusion of subanesthetic ketamine and examined relationships with clinical outcomes. Our findings demonstrate that increase in thalamus perfusion 24 h after ketamine administration is associated with greater improvement of depressive symptoms. Furthermore, lower thalamus perfusion at baseline is associated both with larger increases in perfusion 24 h after ketamine administration and with stronger reduction of depressive symptoms. These findings indicate that ASL is not only a useful tool to broaden our understanding of ketamine's mechanism of action but might also have the potential to inform treatment decisions based on CBF-defined regional disruptions.