The translocator protein 18kDa ligand etifoxine in the treatment of depressive disorders-a double-blind, randomized, placebo-controlled proof-of-concept study.

BACKGROUND: Recent developments suggest that neurosteroids may achieve rapid antidepressant effects. As such, neurosteroidogenesis mediated by the translocator protein 18 kDa (TSPO) might constitute a promising option for the treatment of depression. Therefore, the current clinical trial aims to get the first evidence of whether TPSO ligands promote rapid antidepressant effects. Furthermore, we study which mechanisms of action, e.g., modulation of distinct neuronal networks, neurosteroidogenesis, endocrinological mechanisms, TSPO expression or microbiome composition, contribute to their putative antidepressant effects. METHODS: This is a randomized, placebo-controlled, double-blind single-center trial of 2-week treatment with the TSPO ligand etifoxine versus placebo in depressive patients. Main eligibility criteria: male or female individuals aged 18 to 65 years with unipolar/bipolar depressive disorder with no other psychiatric main diagnosis or acute neurological/somatic disorder or drug/alcohol dependence during their lifetime. The primary endpoint is the time point at which 50% of the maximal effect has occurred (ET50) estimated by the scores of the Hamilton Depression Scale (HAMD-21). A total of 20 patients per group are needed to detect changes of therapeutic efficacy about 5% and changes of ET50 about 10% with a power of 70%. Assuming a drop-out rate of 10-20%, 50 patients will be randomized in total. The study will be conducted at the Department of Psychiatry and Psychotherapy of the University of Regensburg. DISCUSSION: This study will provide a first proof-of-concept on the potential of the TSPO ligand etifoxine in the treatment of depressive disorders. TRIAL REGISTRATION: Clinical Trials Register (EudraCT number: 2021-006773-38 , registration date: 14 September 2022) and German Register of Clinical Studies (DRKS number: DRKS00031099 , registration date: 23 January 2023).

Inhalation-modulated detection of olfactory BOLD responses in the human brain.

Introduction: In contrast to other sensory domains, detection of primary olfactory processes using functional magnetic resonance imaging has proven to be notably challenging with conventional block designs. This difficulty arises from significant habituation and hemodynamic responses in olfactory areas that do not appear to align with extended boxcar functions convolved with a generic hemodynamic response model. Consequently, some researchers have advocated for a transition to event-related designs, despite their known lower detection power compared to block designs. Methods: Here, we conducted a block design experiment with 16s of continuous odorant stimulation alternating with 16s of continuous odorless air stimulation in 33 healthy participants. We compared four statistical analyses that relied either on standard block designs (SBD1-2) or on block designs that were modulated by the participants' individual breathing patterns (MBD1-2). Results: We found that such modulated block designs were comparatively more powerful than standard block designs, despite having a substantially lower design efficiency. Using whole-brain effect size maps, we observed that the right insular and medial aspects of the left piriform cortex exhibited a preference for a breathing-modulated analysis approach. Discussion: Research in olfaction that necessitates designs with longer-lasting blocks, such as those employed in the investigation of state-dependent processing, will benefit from the breathing-modulated analyses outlined in this study.

Investigation of an efficient multi-modal convolutional neural network for multiple sclerosis lesion detection.

In this study, an automated 2D machine learning approach for fast and precise segmentation of MS lesions from multi-modal magnetic resonance images (mmMRI) is presented. The method is based on an U-Net like convolutional neural network (CNN) for automated 2D slice-based-segmentation of brain MRI volumes. The individual modalities are encoded in separate downsampling branches without weight sharing, to leverage the specific features. Skip connections input feature maps to multi-scale feature fusion (MSFF) blocks at every decoder stage of the network. Those are followed by multi-scale feature upsampling (MSFU) blocks which use the information about lesion shape and location. The CNN is evaluated on two publicly available datasets: The ISBI 2015 longitudinal MS lesion segmentation challenge dataset containing 19 subjects and the MICCAI 2016 MSSEG challenge dataset containing 15 subjects from various scanners. The proposed multi-input 2D architecture is among the top performing approaches in the ISBI challenge, to which open-access papers are available, is able to outperform state-of-the-art 3D approaches without additional post-processing, can be adapted to other scanners quickly, is robust against scanner variability and can be deployed for inference even on a standard laptop without a dedicated GPU.

Lack of orientation specific adaptation to vertically oriented Glass patterns in human visual cortex: an fMRI adaptation investigation.

The perception of coherent form configurations in natural scenes relies on the activity of early visual areas that respond to local orientation cues. Subsequently, high-level visual areas pool these local signals to construct a global representation of the initial visual input. However, it is still debated whether neurons in the early visual cortex respond also to global form features. Glass patterns (GPs) are visual stimuli employed to investigate local and global form processing and consist of randomly distributed dots pairs called dipoles arranged to form specific global configurations. In the current study, we used GPs and functional magnetic resonance imaging (fMRI) adaptation to reveal the visual areas that subserve the processing of oriented GPs. Specifically, we adapted participants to vertically oriented GP, then we presented test GPs having either the same or different orientations with respect to the adapting GP. We hypothesized that if local form features are processed exclusively by early visual areas and global form by higher-order visual areas, then the effect of visual adaptation should be more pronounced in higher tier visual areas as it requires global processing of the pattern. Contrary to this expectation, our results revealed that adaptation to GPs is robust in early visual areas (V1, V2, and V3), but not in higher tier visual areas (V3AB and V4v), suggesting that form cues in oriented GPs are primarily derived from local-processing mechanisms that originate in V1. Finally, adaptation to vertically oriented GPs causes a modification in the BOLD response within early visual areas, regardless of the relative orientations of the adapting and test stimuli, indicating a lack of orientation selectivity.

Use of Medical Cannabis by Patients With Cancer: Attitudes, Knowledge, and Practice.

CONTEXT: Demand for medical cannabis (MC) is growing among Israeli patients with cancer. OBJECTIVES: The study sought to assess factors contributing to the demand for MC among patients with cancer. METHODS: Patients applying for a permit to receive MC at a pain and palliative clinic of a university-affiliated cancer center in Israel in 2020-2021 were asked to complete self-report questionnaires assessing attitudes, knowledge, and expectations regarding MC use. Findings were compared between first-time and repeat applicants. Repeat applicants were asked to report their indications for requesting MC, patterns of use, and treatment effect. RESULTS: The cohort included 146 patients: 63 first-time applicants and 83 repeat applicants. First-time applicants were more likely to consult sources other than their oncologist for MC-related information (P < 0.01) and expressed more concern about addiction (P < 0.001) and side effects (P < 0.05). They often erroneously assumed the treatment was subsidized (P < 0.001). Repeat applicants were younger (P < 0.05) and included more smokers (P < 0.05) and recreational cannabis users (P < 0.05); 56.6% were cancer survivors and 78% used high-potency MC. Most patients believed to some degree that MC is more effective than conventional medications for symptom control, and over half thought that MC helps to cure cancer. CONCLUSION: Misconceptions regarding the effectiveness of MC for symptom management and treatment may explain the motivation of patients with cancer to apply for a permit. There seems to be an association of young age, cigarette smoking, and recreational cannabis use with ongoing use of MC among cancer survivors.

Neurosteroids and translocator protein 18 kDa (TSPO) in depression: implications for synaptic plasticity, cognition, and treatment options.

There is need for novel fast acting treatment options in affective disorders. 3α-reduced neurosteroids such as allopregnanolone are powerful positive allosteric modulators of GABAA receptors and target also extrasynaptic receptors. Their synthesis is mediated by the translocator protein 18 kDa (TSPO). TSPO ligands not only promote endogenous neurosteroidogenesis, but also exert a broad spectrum of functions involving modulation of mitochondrial activity and acting as anti-inflammatory and neuroregenerative agents. Besides affective symptoms, in depression cognitive impairment can be frequently observed, which may be ameliorated through targeting of extrasynaptic GABAA receptors either via TSPO ligands or exogenously administered 3α-reduced neurosteroids. Interestingly, recent findings indicate an enhanced activation of the complement system, e.g., enhanced expression of C1q, both in depression and dementia. It is of note that benzodiazepines have been shown to reduce long-term potentiation and to cause cognitive decline. Intriguingly, TSPO may be crucial in mediating the effects of benzodiazepines on synaptic pruning. Here, we discuss how benzodiazepines and TSPO may interfere with synaptic pruning. Moreover, we highlight recent developments of TSPO ligands and 3α-reduced neurosteroids as therapeutic agents. Etifoxine is the only clinically available TSPO ligand so far and has been studied in anxiety disorders. Regarding 3α-reduced neurosteroids, brexanolone, an intravenous formulation of allopregnanolone, has been approved for the treatment of postpartum depression and zuranolone, an orally available 3α-reduced neurosteroid, is currently being studied in major depressive disorder and postpartum depression. As such, 3α-reduced neurosteroids and TSPO ligands may constitute promising treatment approaches for affective disorders.