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Hierarchical perceptual-inference models of psychosis may provide a holistic framework for understanding the psychotic syndrome of schizophrenia, including heterogeneity in its clinical presentations. Particularly, these models may explain why positive symptoms such as hallucinations and delusions tend to cluster together yet sometimes manifest in isolation: alterations at distinct levels of the perceptual-inference hierarchy (low vs. high) may cause individual symptoms (hallucinations vs. delusions), which in turn may tend to co-occur given interdependence across hierarchical levels. Here, using a recently developed resting-state fMRI measure of intrinsic neural timescale (INT)—reflecting the time window of neural integration in a brain region and capturing hierarchical brain gradients—we aimed to test whether hallucinations and delusions are associated with distinct hierarchical alterations. First, we examined the robustness of INT and its relationship to a structural measure of neural hierarchies in 100 healthy subjects. Next, we investigated differences in INT between 127 patients with schizophrenia and 152 age- and gender-matched controls, finding that patients exhibited a widespread INT reduction. Finally, by examining INT gradients within anatomically defined hierarchies of the visual and auditory systems, we found distinct hierarchical INT alterations that scaled respectively with hallucination and delusion severity in the auditory system. Altogether and supported by simulations from a large-scale biophysical model, our results suggest (1) a global reduction of INT in schizophrenia consistent with a global reduction in excitation-inhibition ratio, and (2) distinct hierarchical alterations associated with hallucinations and delusions that are consistent with focal increases in excitation-inhibition ratio at specific hierarchical levels.

Background p53 is a tumor suppressor and key regulator of glycolysis in cancer cells, however highly mutated in tumors. In ovarian cancer, studies concerning p53 mutations focus on the DNA binding domain since the majority of hotspot mutations affects this region. Yet, mutations in other regions such as the proline rich domain may also affect the protein’s expression and activity. The aim of this study is to investigate the effect of various positions of mutations in TP53 gene on glycolysis, apoptosis and transcription of p53 target genes. Methods Mutations frequency and their effect on p53 expression were assessed by PCR-SSCP, sequencing and immunohistochemistry on 30 ovarian cancer biopsies. Six tumors were cultured, as well as SK-OV-3, OVCAR-3 and Igrov-1. SK-OV-3 cells were transfected with 2 TP53 mutants. p53 transcriptional activity was assayed by qPCR, apoptosis by flow cytometry and glycolysis by glucose and lactate measurements, with quantification of glycolytic enzymes expression. Results Our results showed a high frequency of the P72R mutant, associated with p53 overexpression in the ovarian biopsies. However, P72R mutant cells showed similar apoptosis and glycolysis as WT cells. DNA binding domain mutations decreased the transcriptional activity of the protein and increased glucose consumption and lactate production. Conclusion Despite the overexpression of the P72R mutated protein in the biopsies, it showed a similar apoptotic activity and glucose regulation ability as WT p53. Knowing that p53 expression status is used for chemotherapeutic approaches and prognosis in ovarian cancer, the results obtained highlight the importance of locating TP53 mutations. Electronic supplementary material The online version of this article (10.1186/s12935-018-0514-2) contains supplementary material, which is available to authorized users.

Advances in functional brain imaging have improved the search for potential endophenotypic markers in schizophrenia. Here, we employed independent component analysis (ICA) and dynamic causal modeling (DCM) in resting state fMRI on a sample of 35 schizophrenia patients, 20 first-degree relatives and 35 control subjects. Analysis on ICA-derived networks revealed increased functional connectivity between the left frontoparietal network (FPN) and left temporal and parietal regions in schizophrenia patients (P

The most anterior portion of prefrontal cortex (aPFC), more specifically Brodman Area 10 (BA10), has been implicated in 'branching operations', or the ability to perform tasks related to one goal, while keeping in working memory information related to a secondary goal. Such findings have been based on fMRI recordings under complex behavioral paradigms that compare 'branching' tasks with tasks where one goal is pursued at a time, but are limited by their complete reliance on verbal working memory and by small sample sizes. Here, we test the specificity of BA 10 to branching in similar behavioral paradigms but with a larger sample and in two different conditions involving verbal and visual working memory respectively. We find that BA 10 and other frontal and parietal brain areas are activated in all tasks, with an extent and level of significance increasing with the complexity of the task. We conclude that the activation of BA 10 is not specific to branching as previously hypothesized, but is related to the level of complexity of working memory performance. For further insight into the specific role of anterior portions of the frontal cortex we highlight the importance of simple control tasks with gradual and incremental increase in complexity.

Introduction Use of electroconvulsive therapy (ECT) is limited by cognitive disturbance. Focal electrically-administered seizure therapy (FEAST) is designed to initiate focal seizures in the prefrontal cortex. To date, no studies have documented the effects of FEAST on regional cerebral blood flow (rCBF). Methods A 72 year old depressed man underwent three single photon emission computed tomography (SPECT) scans to capture the onset and resolution of seizures triggered with right unilateral FEAST. We used Bioimage Suite for within-subject statistical analyses of perfusion differences ictally and post-ictally compared with the baseline scan. Results Early ictal increases in regional cerebral blood flow (rCBF) were limited to the right prefrontal cortex. Post-ictally, perfusion was reduced in bilateral frontal and occipital cortices and increased in left motor and precuneus cortex. Conclusion FEAST appears to triggers focal onsets of seizure activity in the right prefrontal cortex with subsequent generalization. Future studies are needed on a larger sample.

The treatment of advanced renal cell carcinoma (RCC) has advanced significantly over the last two decades. This multicenter study was designed with the primary objective to evaluate the efficacy and safety of sorafenib as first-line treatment in patients with advanced or metastatic RCC in the Middle East, who were considered to be ineligible for other approved first-line therapies. A total of 75 eligible patients from 8 centers in the Middle East were included in this study. The patients comprised 48 men and 27 women, with a median age of 52 years (range, 19–78 years). A total of 50 patients had clear cell carcinoma, 17 had papillary carcinoma and 8 had other pathological subtypes. At enrollment, 55 of the 75 patients had undergone previous nephrectomy. A total of 67 patients presented with metastatic disease, while 8 patients had regional residual lesions or local recurrence. The patients were treated with 400 mg oral sorafenib twice daily on a continuous basis as a single agent. Treatment was discontinued upon disease progression, prohibitive toxicity, surgical complications, loss to follow-up, or refusal to continue therapy. The median treatment duration was 21 weeks (range, 1–137 weeks). Sorafenib was tolerated by the majority of the patients. Grade 3/4 hand-foot syndrome occurred in 17 patients; diarrhea, elevated liver enzymes and fatigue were observed in 3 patients each; and grade 3/4 vomiting, hypertension and anemia, in 1 patient each. Of the 75 patients included in this study, 60 were evaluable for response. One patient achieved a complete response for 91 weeks and 6 patients exhibited a partial response (median duration of 23 weeks) with an overall response rate of 11.7%. Disease stabilization occurred in 37 patients (61.7%). Thus, disease control was achieved in 44 of the 60 patientrs (73%). At a median follow-up period of 53.5 weeks (range, 8.5–192 weeks), an intention-to-treat analysis demonstrated a median time-to-disease progression of 25.7 weeks, with a median overall survival of 54.8 weeks. In conclusion, sorafenib was found to be tolerable and effective as first-line therapy in patients with advanced RCC.

Background: Major depressive disorder has been associated with abnormal resting-state functional connectivity (FC), especially in cognitive processing and emotional regulation networks. Although studies have found abnormal FC in regions of the default mode network (DMN), no study has investigated the FC of specific regions within the anterior DMN based on cytoarchitectonic subdivisions of the antero-medial pre-frontal cortex (PFC). Studies from different areas in the field have shown regions within the anterior DMN to be involved in emotional intelligence. Although abnormalities in this region have been observed in depression, the relationship between the ventromedial PFC (vmPFC) function and emotional intelligence has yet to be investigated in depressed individuals. Methods: Twenty-one medication-free, non–treatment resistant, depressed patients and 21 healthy controls underwent a resting state functional magnetic resonance imaging session. The participants also completed an ability-based measure of emotional intelligence: the Mayer-Salovey-Caruso Emotional Intelligence Test. FC maps of Brodmann areas (BA) 25, 10m, 10r, and 10p were created and compared between the two groups. Results: Mixed-effects analyses showed that the more anterior seeds encompassed larger areas of the DMN. Compared to healthy controls, depressed patients had significantly lower connectivity between BA10p and the right insula and between BA25 and the perigenual anterior cingulate cortex. Exploratory analyses showed an association between vmPFC connectivity and emotional intelligence. Conclusions: These results suggest that individuals with depression have reduced FC between antero-medial PFC regions and regions involved in emotional regulation compared to control subjects. Moreover, vmPFC functional connectivity appears linked to emotional intelligence.

The stability of visual perception is partly maintained by saccadic suppression: the selective reduction of visual sensitivity that accompanies rapid eye movements. The neural mechanisms responsible for this reduced perisaccadic visibility remain unknown, but the Lateral Geniculate Nucleus (LGN) has been proposed as a likely site. Our data show, however, that the saccadic suppression of a target flashed in the right visual hemifield increased with an increase in background luminance in the left visual hemifield. Because each LGN only receives retinal input from a single hemifield, this hemifield interaction cannot be explained solely on the basis of neural mechanisms operating in the LGN. Instead, this suggests that saccadic suppression must involve processing in higher level cortical areas that have access to a considerable part of the ipsilateral hemifield.

Advances in functional brain imaging have improved the search for potential endophenotypic markers in schizophrenia. Here, we employed independent component analysis (ICA) and dynamic causal modeling (DCM) in resting state fMRI on a sample of 35 schizophrenia patients, 20 first‐degree relatives and 35 control subjects. Analysis on ICA‐derived networks revealed increased functional connectivity between the left frontoparietal network (FPN) and left temporal and parietal regions in schizophrenia patients (P