Rostral Anterior Cingulate Cortex Oscillatory Power Indexes Treatment-Resistance to Multiple Therapies in Major Depressive Disorder.

INTRODUCTION: High rostral anterior cingulate cortex (rACC) activity is proposed as a nonspecific prognostic marker for treatment response in major depressive disorder, independent of treatment modality. However, other studies report a negative association between baseline high rACC activation and treatment response. Interestingly, these contradictory findings were also found when focusing on oscillatory markers, specifically rACC-theta power. An explanation could be that rACC-theta activity dynamically changes according to number of previous treatment attempts and thus is mediated by level of treatment-resistance. METHODS: Primarily, we analyzed differences in rACC- and frontal-theta activity in large national cross-sectional samples representing various levels of treatment-resistance and resistance to multimodal treatments in depressed patients (psychotherapy [n = 175], antidepressant medication [AD; n = 106], repetitive transcranial magnetic stimulation [rTMS; n = 196], and electroconvulsive therapy [ECT; n = 41]), and the respective difference between remitters and non-remitters. For exploratory purposes, we also investigated other frequency bands (delta, alpha, beta, gamma). RESULTS: rACC-theta activity was higher (p < 0.001) in the more resistant rTMS and ECT patients relative to the less resistant psychotherapy and AD patients (psychotherapy-rTMS: d = 0.315; AD-rTMS: d = 0.320; psychotherapy-ECT: d = 1.031; AD-ECT: d = 1.034), with no difference between psychotherapy and AD patients. This association was even more pronounced after controlling for frontal-theta. Post hoc analyses also yielded effects for delta, beta, and gamma bands. CONCLUSION: Our findings suggest that by factoring in degree of treatment-resistance during interpretation of the rACC-theta biomarker, its usefulness in treatment selection and prognosis could potentially be improved substantially in future real-world practice. Future research should however also investigate specificity of the theta band.

Abnormal habenula functional connectivity characterizes treatment-resistant depression.

BACKGROUND: A significant proportion of patients with major depressive disorder are resistant to antidepressant medication and psychological treatments. A core symptom of treatment-resistant depression (TRD) is anhedonia, or the inability to feel pleasure, which has been attributed to disrupted habenula function - a component of the reward network. This study aimed to map detailed neural circuitry architecture related to the habenula to identify neural mechanisms of TRD. METHODS: 35 TRD patients, 35 patients with treatment-sensitive depression (TSD), and 38 healthy controls (HC) underwent resting-state functional magnetic resonance imaging. Functional connectivity analyses were performed using the left and right habenula as seed regions of interest, and the three groups were compared using whole-brain voxel-wise comparisons. RESULTS: The TRD group demonstrated hyperconnectivity of the left habenula to the left precuneus cortex and the right precentral gyrus, compared to the TSD group, and to the right precuneus cortex, compared to the TSD and HC groups. In contrast, TSD demonstrated hypoconnectivity than HC for both connectivity measures. These connectivity values were significantly higher in patients with a history of suicidal ideation. CONCLUSIONS: This study provides evidence that, unlike TSD, TRD is characterized by hyperconnectivity of the left habenula particularly with regions of the default mode network. An increased interplay between reward and default mode networks is linked to suicidality and could be a possible mechanism for anhedonia in hard to treat depression.

Meta-analysis of randomised controlled trials with N-acetylcysteine in the treatment of schizophrenia.

OBJECTIVE: There is accumulating evidence that adjunctive treatment with N-acetylcysteine may be effective for schizophrenia. This study aimed to conduct a comprehensive meta-analysis examining the efficacy of randomised control trials investigating N-acetylcysteine as an adjunct treatment for schizophrenia and the first to investigate cognition as an outcome. METHODS: We systematically reviewed Medline, EmCare, PsycINFO, Embase, CINAHL Complete, China Knowledge Resource Integrated Database and the Cochrane Clinical Trials online registry for randomised control trials of N-acetylcysteine for schizophrenia. We undertook pairwise meta-analyses of N-acetylcysteine vs placebo for psychosis symptoms and cognition. RESULTS: Seven studies, including n = 220 receiving N-acetylcysteine and n = 220 receiving placebo, met inclusion criteria for the pairwise meta-analyses. Positive and Negative Syndrome Scale negative and total scores were significantly improved in the N-acetylcysteine group after 24 weeks of treatment. The cognitive domain of working memory improved with N-acetylcysteine supplementation. CONCLUSION: Evidence supports the notion that N-acetylcysteine may be a useful adjunct to standard treatment for the improvement of schizophrenia symptoms, as well as the cognitive domain of working memory. Treatment effects were observed at the later time point (⩾24 weeks), suggesting that longer interventions are required for the success of N-acetylcysteine treatment.

Amygdala Modulation During Emotion Regulation Training With fMRI-Based Neurofeedback.

Available evidence suggests that individuals can enhance their ability to modulate brain activity in target regions, within the Emotion Regulation network, using fMRI-based neurofeedback. However, there is no systematic review that investigates the effectiveness of this method on amygdala modulation, a core region within this network. The major goal of this study was to systematically review and analyze the effects of real-time fMRI-Neurofeedback concerning the neuromodulation of the amygdala during Emotion Regulation training. A search was performed in PubMed, Science Direct, and Web of Science with the following key terms: ≪("neurofeedback" or "neuro feedback" or "neuro-feedback") and ("emotion regulation") and (fMRI OR "functional magnetic resonance"),≫ and afterwards two additional searches were performed, replacing the term "emotion regulation" for "amygdala" and "neurofeedback" for "feedback." Of the 531 identified articles, only 19 articles reported results of amygdala modulation during Emotional Regulation training through rtfMRI-NF, using healthy participants or patients, in original research articles. The results, systematically reviewed here, provide evidence for amygdala's modulation during rtfMRI-NF training, although studies' heterogeneity precluded a quantitative meta-analysis-the included studies relied on different outcome measures to infer the success of neurofeedback intervention. Thus, a qualitative analysis was done instead. We identified critical features influencing inference on the quality of the intervention as: the inclusion of a Practice Run, a Transfer Run and a Control Group in the protocol, and to choose adequate Emotion Regulation strategies-in particular, the effective recall of autobiographic memories. Surprisingly, the Regulated vs. Control Condition was lacking in most of the studies, precluding valid inference of amygdala neuromodulation within Session. The best controlled studies nevertheless showed positive effects. The type of stimulus/interface did not seem critical for amygdala modulation. We also identified potential effects of lateralization of amygdala responses following Up- or Down-Regulation, and the impact of fMRI parameters for data acquisition and analysis. Despite qualitative evidence for amygdala modulation during rtfMRI-NF, there are still important limitations in the design of a clear conceptual framework of NF-training research. Future studies should focus on more homogeneous guidelines concerning design, protocol structure and, particularly, harmonized outcome measures to provide quantitative estimates of neuromodulatory effects in the amygdala.