Effect of Intermittent Theta Burst Stimulation on the Neural Processing of Emotional Stimuli in Healthy Volunteers.

BACKGROUND: Intermittent theta burst stimulation (iTBS) is a form of repetitive transcranial magnetic stimulation that has shown to be effective in treatment-resistant depression. Through studying the effect of iTBS on healthy subjects, we wished to attain a greater understanding of its impact on the brain. Our objective was to assess whether 10 iTBS sessions altered the neural processing of emotional stimuli, mood and brain anatomy in healthy subjects. METHODS: In this double-blind randomized sham-controlled study, 30 subjects received either active iTBS treatment (10 sessions, two sessions a day) or sham treatment over the left dorsolateral prefrontal cortex. Assessments of mood, structural magnetic resonance imaging (MRI) and functional MRI (fMRI) were performed before and after iTBS sessions. During the fMRI, three different categories of stimuli were presented: positive, negative and neutral photographs. RESULTS: This study showed that, during the presentation of negative stimuli (compared with neutral stimuli), 10 sessions of iTBS increased activity in the left anterior insula. However, iTBS did not induce any change in mood, regional gray matter volume or cortical thickness. CONCLUSIONS: iTBS modifies healthy subjects' brain activity in a key region that processes emotional stimuli. (AFSSAPS: ID-RCB 2010A01032-37).

Cognitive Impact of Cerebellar Non-invasive Stimulation in a Patient With Schizophrenia.

Cerebellum plays a role in the regulation of cognitive processes. Cerebellar alterations could explain cognitive impairments in schizophrenia. We describe the case of a 50 years old patient with schizophrenia whom underwent cerebellar transcranial direct current stimulation (tDCS). In order to study the effect of cerebellar stimulation on cognitive functions, the patient underwent a neuropsychological assessment and an eyeblink conditioning (EBC) protocol. Although the effect of brain stimulation cannot be only assessed in a single-case study, our results suggest that cerebellar stimulation may have an effect on a broad range of cognitive functions typically impaired in patients with schizophrenia, including verbal episodic, short term, and working memory. In addition to neuropsychological tests, we evaluated the cerebellar function by performing EBC before and after tDCS. Our data suggest that tDCS can improve EBC. Further clinical trials are required for better understanding of how cerebellar stimulation can modulate cognitive processes in patients with schizophrenia and healthy controls.

Structural and functional brain biomarkers of clinical response to rTMS of medication-resistant auditory hallucinations in schizophrenia patients: study protocol for a randomized sham-controlled double-blind clinical trial.

BACKGROUND: The potential of non-invasive repetitive transcranial magnetic stimulation (rTMS) to improve auditory verbal hallucinations (AVH) in schizophrenia patients has been increasingly explored over the past decade. Despite highly promising results, high inter-individual variability of clinical response and ineffective outcomes in a significant number of patients underscored the need to identify factors associated with the clinical response to rTMS. It should help improve the efficacy of rTMS in patients with medication-resistant AVH, and allow a better understanding of its neural impact. Here, we describe an exploratory study protocol which aims to identify structural and functional brain biomarkers associated with clinical response after an rTMS treatment for medication-resistant AVH in schizophrenia. METHODS: Forty-five schizophrenia patients with medication-resistant AVH will be enrolled in a double-blind randomized sham-controlled monocentric clinical trial. Patients will be assigned to a regime of 20 sessions of active or sham 1 Hz rTMS delivered twice a day, 5 days a week for 2 weeks over the left temporo-parietal junction. Response will be assessed after rTMS and patients will be classified in responders or non-responders to treatment. Magnetic resonance imaging (MRI) sessions including diffusion weighted imaging and resting-state functional MRI sequences will be recorded before the onset of the rTMS treatment and 3 days following its discontinuation. The primary outcome measure is difference in fractional anisotropy between responder and non-responder patients at baseline. Differences in resting-state functional MRI data at baseline will be also investigated between responder and non-responder groups. Clinical, neuropsychological, neurophysiological, and blood serum BDNF assessments will be performed at baseline, 3 days, 1 month, and 3 months following rTMS. DISCUSSION: The aim of this research project is to identify and assess the biomarker value of MRI-based structural and functional biomarkers predicting clinical response to rTMS for AVH in schizophrenia patients. The outcome of the trial should improve patient care by offering them a novel suitable therapy and deepen our understanding on how rTMS may impact AVH and develop more effective therapies adapted to individual patient needs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02755623 . Registered on 22 April 2016.

Emotional Memory in Post-traumatic Stress Disorder: A Systematic PRISMA Review of Controlled Studies.

Background: Emotional memory is an adaptive process that improves the memorization of emotional events or stimuli. In Post-Traumatic Stress Disorder (PTSD), emotional memory may be altered, which in turn may affect symptoms. Having a clearer view of the processes of interaction between memory and emotional stimuli in PTSD may improve our knowledge of this disorder, and could create new therapeutic management tools. Thus, we performed a systematic review of the evidence of specific emotional memory in PTSD patients. Method: Following PRISMA guidelines, a systematic review of MEDLINE, PsycInfo, and ScienceDirect was undertaken to identify controlled studies on emotional memory that used cognitive tasks on PTSD patients. The initial research was conducted from June 2017 to July 2017, and search terms included: Post-Traumatic Stress Disorder; PTSD; emotional memory; emotion; emotional; memory; and episodic memory. Results: Eighteen studies reporting on 387 PTSD patients met the eligibility criteria. Among the studies selected, 11 observed specific memory processing in PTSD patients, such as a greater memorization of negative information, or a trend to false recognition of negative information. In addition, attentional and inhibition processing seem to play an important role in emotional memory in PTSD sufferers. Furthermore, other studies that did not find behavioral differences between PTSD and control groups nevertheless showed differences in both specific cerebral activities and neurohormone levels during emotional memory tasks. Conclusion: This review has several limitations, including a limited number of controlled studies, small sample sizes, different tasks and methods. Nevertheless, the results of this systematic review provide interesting information on emotional memory for clinicians and researchers, as they seem to highlight facilitated memory processing for negative information in PTSD patients. This topic needs further controlled studies with sensitive behavioral tasks. Also, future studies may evaluate emotional memory after symptom amelioration.

Discovery of (2S)-8-[(3R)-3-methylmorpholin-4-yl]-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido[1,2-a]pyrimidin-6-one: a novel potent and selective inhibitor of Vps34 for the treatment of solid tumors.

Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.