The priming effect of repetitive transcranial magnetic stimulation on clinical response to electroconvulsive therapy in treatment-resistant depression: a randomized, double-blind, sham-controlled study.

BACKGROUND: Electroconvulsive therapy (ECT) is one of the most effective treatments for treatment-resistant depression (TRD). However, due to response delay and cognitive impairment, ECT remains an imperfect treatment. Compared to ECT, repetitive transcranial magnetic stimulation (rTMS) is less effective at treating severe depression, but has the advantage of being quick, easy to use, and producing almost no side effects. In this study, our objective was to assess the priming effect of rTMS sessions before ECT on clinical response in patients with TRD. METHODS: In this multicenter, randomized, double-blind, sham-controlled trial, 56 patients with TRD were assigned to active or sham rTMS before ECT treatment. Five sessions of active/sham neuronavigated rTMS were administered over the left dorsolateral prefrontal cortex (20 Hz, 90% resting motor threshold, 20 2 s trains with 60-s intervals, 800 pulses/session) before ECT (which was active for all patients) started. Any relative improvements were then compared between both groups after five ECT sessions, in order to assess the early response to treatment. RESULTS: After ECT, the active rTMS group exhibited a significantly greater relative improvement than the sham group [43.4% (28.6%) v. 25.4% (17.2%)]. The responder rate in the active group was at least three times higher. Cognitive complaints, which were assessed using the Cognitive Failures Questionnaire, were higher in the sham rTMS group compared to the active rTMS group, but this difference was not corroborated by cognitive tests. CONCLUSIONS: rTMS could be used to enhance the efficacy of ECT in patients with TRD. ClinicalTrials.gov: NCT02830399.

A Prospective Open-Label Pilot Study of Transcranial Direct Current Stimulation in High-Functioning Autistic Patients with a Dysexecutive Syndrome.

BACKGROUND: Executive functions (EF) are often impaired in autism spectrum disorder (ASD). Such dysfunctions are associated with anxiety, depression, and a lack of autonomy. Transcranial direct current stimulation (tDCS) has been shown to enhance EF in healthy adults and clinical populations and to improve working memory - a component of the EF - in adults with high-functioning ASD (HF-ASD). We hypothesized that tDCS could improve the EF of HF-ASD patients. Such enhancement could improve their adaptive behaviors. METHOD: Eight patients with HF-ASD received 10 consecutive cathodal tDCS sessions (2 mA) over the left dorsolateral prefrontal cortex (F3) for 15 min each in an open trial. EF (with the Stroop test, Trail Making Test [TMT] A and B, Modified Wisconsin Card Sorting Test [mWCST], and Verbal Fluency Test) and behavioral dysexecutive syndrome (with the Behavioral Dysexecutive Syndrome Inventory and the Repetitive and Restricted Behaviour scale) were assessed before and 10 days after treatment. RESULTS: This study showed significant improvement in initiation (TMT-A time: p = 0.018) and cognitive flexibility (TMT-B time: p = 0.009; letter Verbal Fluency Test: p = 0.017; mWCST total errors: p = 0.028) after tDCS. Regarding behavior, the hypoactivity of the patients improved, as well as their repetitive and restrictive behaviors. In addition, this noninvasive neurostimulation technique was well tolerated. CONCLUSIONS: Flexibility and initiation are the most impaired EF in autism. These are promising results which justify a randomized and placebo-controlled study in a wider population. If these results were confirmed by a randomized controlled trial, tDCS could be an easy and well-tolerated adjunctive treatment aiming to improve the quality of life and the autonomy of ASD patients.

Dissociation between Private and Social Counterfactual Value Signals Following Ventromedial Prefrontal Cortex Damage.

Individuals learn by comparing the outcome of chosen and unchosen actions. A negative counterfactual value signal is generated when this comparison is unfavorable. This can happen in private as well as in social settings-where the foregone outcome results from the choice of another person. We hypothesized that, despite sharing similar features such as supporting learning, these two counterfactual signals might implicate distinct brain networks. We conducted a neuropsychological study on the role of private and social counterfactual value signals in risky decision-making. Patients with lesions in the ventromedial prefrontal cortex (vmPFC), lesion controls, and healthy controls repeatedly chose between lotteries. In private trials, participants could observe the outcomes of their choices and the outcomes of the unselected lotteries. In social trials, participants could also see the other player's choices and outcome. At the time of outcome, vmPFC patients were insensitive to private counterfactual value signals, whereas their responses to social comparison were similar to those of control participants. At the time of choice, intact vmPFC was necessary to integrate counterfactual signals in decisions, although amelioration was observed during the course of the task, possibly driven by social trials. We conclude that if the vmPFC is critical in processing private counterfactual signals and in integrating those signals in decision-making, then distinct brain areas might support the processing of social counterfactual signals.

Dementia in middle-aged patients with schizophrenia.

BACKGROUND: Although numerous studies have assessed cognitive dysfunction in patients with schizophrenia, very few have focused on the diagnosis of dementia. OBJECTIVE: Our objectives were to accurately diagnose dementia in a cohort of middle-aged patients with schizophrenia and to assess the type of dementia. METHODS: 96 patients with schizophrenia (46 inpatients and 50 outpatients), aged 50 to 70 years, underwent a psychiatric, neurological, and neuropsychological evaluation at baseline and after a 20-month follow-up. We established a 3-step procedure: 1) diagnose dementia according to the DSM-IV criteria, using the Mattis Dementia Rating and Activities of Daily Living scales; 2) characterize dementia using brain imaging, perfusion by 99mTc-ECD-SPECT and laboratory tests including Alzheimer's disease cerebrospinal fluid biomarkers; and 3) search for genetic determinants. RESULTS: Fourteen patients fulfilled the diagnostic criteria of dementia. Four were diagnosed with possible or probable behavioral-variant frontotemporal dementia (bvFTD), two with probable Alzheimer's disease, two with probable vascular dementia (including one due to CADASIL), one with CNS inflammatory disease, and six could not be fully characterized. CONCLUSIONS: The diagnosis of dementia in middle-aged patients with schizophrenia is challenging but possible, using a multistep procedure. The most frequent condition, bvFTD, could reflect the presence of an evolutive neurodegenerative process in some patients.

Morbid risk for schizophrenia in first-degree relatives of people with frontotemporal dementia.

BACKGROUND: Familial co-occurrence of frontotemporal dementia and schizophrenia has never been investigated. AIMS: To test the hypothesis that frontotemporal dementia and schizophrenia might have a common aetiology in some families in which both syndromes coexist (mixed families). METHOD: The morbid risk for schizophrenia, calculated in first-degree relatives of 100 frontotemporal dementia probands, was compared with that calculated in first-degree relatives of 100 Alzheimer's disease probands. In mixed families, sequencing analysis of known frontotemporal dementia genes and detailed phenotype characterisation of individuals with frontotemporal dementia and schizophrenia were performed. RESULTS: The morbid risk for schizophrenia was significantly higher in relatives of frontotemporal dementia probands (1.35, s.e. = 0.45) than in relatives of Alzheimer's disease probands (0.32, s.e. = 0.22). Ten mixed families were characterised. In three of them a frontotemporal dementia causal mutation was identified that was present in individuals with schizophrenia. Several specific clinical features were noted in people with schizophrenia and frontotemporal dementia in mixed families. CONCLUSIONS: Co-occurrence of schizophrenia and frontotemporal dementia could indicate, in some families, a common aetiology for both conditions.

Impaired decision making in schizophrenia and orbitofrontal cortex lesion patients.

BACKGROUND: The aim of this study was to examine impaired decision making in patients with schizophrenia and in patients with orbitofrontal cortex lesions. METHODS: Schizophrenia patients (N=21), healthy controls (N=20) and an independent group of orbitofrontal patients (N=10) underwent a computerized version of the "Regret Gambling Task". Participants chose between two gambles, each having different probabilities and different expected monetary outcomes, and rated their emotional states after seeing the obtained outcome. Regret was induced by providing information about the outcome of the unchosen gamble. RESULTS: Healthy controls reported emotional responses consistent with counterfactual reasoning between obtained and unobtained outcomes; they chose minimizing future regret and were able to learn from their emotional experience. In contrast, orbitofrontal patients and schizophrenia patients with prominent positive symptoms did not report any regret and did not anticipate any negative consequences of their choices. Our results demonstrate first the presence of very different behavioural deficits within the spectrum of schizophrenia patients which may have contributed to the discrepancies observed in previous studies. Second, the results suggest that a subgroup of schizophrenia patients might have an orbitofrontal dysfunction, in fact, schizophrenia patients with positive symptoms have a behavioural dysfunction analogous to that of the orbitofrontal patients. CONCLUSION: Schizophrenia patients with prominent positive symptoms were unable to integrate cognitive and emotional components of decision making which may contribute to their inability to generate adaptive behaviours in social and individual environments.

Relevant category-specific effect on naming in Alzheimer's disease.

AIM: To determine category effect on naming in Alzheimer's disease (AD) and its relation with severity of the disease or naming deficit. METHODS: A group of 50 patients suffering from probable AD was tested in a naming task involving 99 pictures of items belonging to living and non-living categories. Parameters relating to pictures (percentage of majority responses, familiarity, visual complexity and image agreement) were determined using a control group and parameters relating to words (frequency, age of acquisition, number of letters and syllables) were controlled. RESULTS: A category-specific effect was demonstrated and individual stepwise logistic regression demonstrated a significant category effect in 9 cases (living items more failed than non-living). CONCLUSION: Our results suggest a categorical effect on naming in favor of the non-living items, especially for mild AD with predominant naming deficit.

Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome.

Microdeletions of the 22q11 region, responsible for the velo-cardio-facial syndrome (VCFS), are associated with an increased risk for psychosis and mental retardation. Recently, it has been shown in a hyperprolinemic mouse model that an interaction between two genes localized in the hemideleted region, proline dehydrogenase (PRODH) and catechol-o-methyl-transferase (COMT), could be involved in this phenotype. Here, we further characterize in eight children the molecular basis of type I hyperprolinemia (HPI), a recessive disorder resulting from reduced activity of proline dehydrogenase (POX). We show that these patients present with mental retardation, epilepsy and, in some cases, psychiatric features. We next report that, among 92 adult or adolescent VCFS subjects, a subset of patients with severe hyperprolinemia has a phenotype distinguishable from that of other VCFS patients and reminiscent of HPI. Forward stepwise multiple regression analysis selected hyperprolinemia, psychosis and COMT genotype as independent variables influencing IQ in the whole VCFS sample. An inverse correlation between plasma proline level and IQ was found. In addition, as predicted from the mouse model, hyperprolinemic VCFS subjects bearing the Met-COMT low activity allele are at risk for psychosis (OR = 2.8, 95% CI = 1.04-7.4). Finally, from the extensive analysis of the PRODH gene coding sequence variations, it is predicted that POX residual activity in the 0-30% range results into HPI, whereas residual activity in the 30-50% range is associated either with normal plasma proline levels or with mild-to-moderate hyperprolinemia.