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INTRODUCTION: Cellular prion protein (PrPC) was implicated in amyloid beta (Aβ)‐induced toxicity in Alzheimer's disease (AD), but the precise molecular mechanisms involved in this process are unclear. METHODS: Double transgenic mice were generated by crossing Prnp knockout (KO) with 5xFAD mice, and light‐sheet microscopy was used for whole brain tissue analyses. PrPC‐overexpressing cells were developed for in vitro studies, and microscopy was used to assess co‐localization of proteins of interest. Surface‐plasmon resonance (SPR) was used to investigate protein‐binding characteristics. RESULTS: In vivo, PrPC levels correlated with reduced lifespan and cognitive and motor function, and its ablation disconnected behavior deficits from Aβ levels. Light‐sheet microscopy showed that PrPC influenced Aβ‐plaque burden but not the distribution of those plaques. Interestingly, caveolin‐1 (Cav‐1) KO neurons significantly reduced intracellular Aβ‐oligomer (Aβo) uptake when compared to wild‐type neurons. DISCUSSION: The findings shed new light on the relevance of intracellular Aβo, suggesting that PrPC and Cav‐1 modulate intracellular Aβ levels and the Aβ‐plaque load. Highlights: PrPC expression adversely affects lifespan and behavior in 5xFAD mice.PrPC increases Aβ1‐40 and Aβ1‐42 levels and Aβ‐plaque load in 5xFAD mice.Cav‐1 interacts with both PrPC and Aβ peptides.Knocking out Cav‐1 leads to a significant reduction in intracellular Aβ levels. [ABSTRACT FROM AUTHOR]

Quantifying pathology‐related patterns in patient data with pattern expression score (PES) is a standard approach in medical image analysis. In order to estimate the PES error, we here propose to express the uncertainty contained in read‐out patterns in terms of the expected squared Euclidean distance between the read‐out pattern and the unknown "true" pattern (squared standard error of the read‐out pattern, SE2). Using SE2, we predicted and optimized the net benefit (NBe) of the recently suggested method controls‐based denoising (CODE) by weighting patterns of nonpathological variance (NPV). Multi‐center MRI (1192 patients with various neurodegenerative and neuropsychiatric diseases, 1832 healthy controls) were analysed with voxel‐based morphometry. For each pathology, accounting for SE2, NBe correctly predicted classification improvement and allowed to optimize NPV pattern weights. Using these weights, CODE improved classification performances in all but one analyses, for example, for prediction of conversion to Alzheimer's disease (AUC 0.81 vs. 0.75, p =.01), diagnosis of autism (AUC 0.66 vs. 0.60, p <.001), and of major depressive disorder (AUC 0.62 vs. 0.50, p =.03). We conclude that the degree of uncertainty in a read‐out pattern should generally be reported in PES‐based analyses and suggest using weighted CODE as a complement to PES‐based analyses. [ABSTRACT FROM AUTHOR]

Objectives: Suicidality is a serious public health problem and is closely associated with the severity of depression. In this work, we examined the effects of accelerated intermittent theta burst stimulation (iTBS) on suicidal status, risk factors for suicide, and severity of depressive symptoms in subjects with major depressive disorder (MDD). Methods: We present data from a quadruple‐blind (patient, care provider, investigator, rater) sham‐controlled crossover randomized clinical trial. During a 6‐week observation period, each participant underwent 2 weeks of stimulation ‐ each week with 20 sessions of active or sham iTBS. A suicide score was created using a composite of individual items from Montgomery–Åsberg Depression Scale (MADRS), Hamilton Depression Scale, and Beck Depression Inventory. The severity of depression was determined by MADRS total scores. In addition, we used demographic and Columbia Suicidality Rating Scale information to assess suicide risk. Results: Among 81 participants, we observed a significant reduction in suicidality and this change was positively correlated with a change in depressive symptoms. A significant difference between active and sham iTBS provided evidence for antidepressant effects. Higher changes in levels of anxiety and impulsiviness also correlated with larger changes in suicidality. Conclusions: As neither suicide nor other serious adverse events were evidenced, this intervention was a safe and viable procedure to reduce suicidality and severity of depressive symptoms. Moreover, we identified more pronounced anti‐suicidal effects in those with higher risk profiles. Unlike MADRS, composite suicidal scores did not provide evidence of an effect between stimulation conditions in this crossover design study. Even so, based on our promising results, parallel and larger studies could contribute to a better characterization of the anti‐suicidal placebo effect and the benefit of using iTBS against suicidal symptoms. [ABSTRACT FROM AUTHOR]

The exploration of the spatial relationship between gene expression profiles and task‐evoked response patterns known to be altered in neuropsychiatric disorders, for example depression, can guide the development of more targeted therapies. Here, we estimated the correlation between human transcriptome data and two different brain activation maps measured with functional magnetic resonance imaging (fMRI) in healthy subjects. Whole‐brain activation patterns evoked during an emotional face recognition task were associated with topological mRNA expression of genes involved in cellular transport. In contrast, fMRI activation patterns related to the acceptance of monetary rewards were associated with genes implicated in cellular localization processes, metabolism, translation, and synapse regulation. An overlap of these genes with risk genes from major depressive disorder genome‐wide association studies revealed the involvement of the master regulators TCF4 and PAX6 in emotion and reward processing. Overall, the identification of stable relationships between spatial gene expression profiles and fMRI data may reshape the prospects for imaging transcriptomics studies. [ABSTRACT FROM AUTHOR]

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 < 0.001). First-degree relatives shared this hyperconnectivity, in particular in the supramarginal gyrus (SMG; P = 0.008). DCM analysis was employed to further explore underlying effective connectivity. Results showed increased inhibitory connections to the left angular gyrus (AG) in schizophrenia patients from all other nodes of the left FPN ( P < 0.001), and in particular from the left SMG ( P = 0.001). Relatives also showed a pattern of increased inhibitory connections to the left AG ( P = 0.008). Furthermore, the patient group showed increased excitatory connectivity between the left fusiform gyrus and the left SMG ( P = 0.002). This connection was negatively correlated to inhibitory afferents to the left AG ( P = 0.005) and to the negative symptom score on the PANSS scale ( P = 0.001, r = −0.51). Left frontoparietotemporal dysfunction in schizophrenia has been previously associated with a range of abnormalities, including formal thought disorder, working memory dysfunction and sensory hallucinations. Our analysis uncovered new potential endophenotypic markers of schizophrenia and shed light on the organization of the left FPN in patients and their first-degree relatives. Hum Brain Mapp 38:1741-1750, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) involves impairment in cognitive and interpersonal functioning. The right temporoparietal junction (RTPJ) is a key brain region subserving cognitive-attentional and social processes. Yet, findings on the involvement of the RTPJ in the pathophysiology of MDD have so far been controversial. Recent connectivity-based parcellation data revealed a topofunctional dualism within the RTPJ, linking its anterior and posterior part (aRTPJ/pRTPJ) to antagonistic brain networks for attentional and social processing, respectively. Comparing functional resting-state connectivity of the aRTPJ and pRTPJ in 72 MDD patients and 76 well-matched healthy controls, we found a seed (aRTPJ/pRTPJ) × diagnosis (MDD/controls) interaction in functional connectivity for eight regions. Employing meta-data from a large-scale neuroimaging database, functional characterization of these regions exhibiting differentially altered connectivity with the aRTPJ/pRTPJ revealed associations with cognitive (dorsolateral prefrontal cortex, parahippocampus) and behavioral (posterior medial frontal cortex) control, visuospatial processing (dorsal visual cortex), reward (subgenual anterior cingulate cortex, medial orbitofrontal cortex, posterior cingulate cortex), as well as memory retrieval and social cognition (precuneus). These findings suggest that an imbalance in connectivity of subregions, rather than disturbed connectivity of the RTPJ as a whole, characterizes the connectional disruption of the RTPJ in MDD. This imbalance may account for key symptoms of MDD in cognitive, emotional, and social domains. Hum Brain Mapp 37:2931-2942, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Misdiagnosing bipolar depression can lead to very deleterious consequences of mistreatment. Although depressive symptoms may be similarly expressed in unipolar and bipolar disorder, changes in specific brain networks could be very distinct, being therefore informative markers for the differential diagnosis. We aimed to characterize specific alterations in candidate large-scale networks (frontoparietal, cingulo-opercular, and default mode) in symptomatic unipolar and bipolar patients using resting state fMRI, a cognitively low demanding paradigm ideal to investigate patients. Methods Networks were selected after independent component analysis, compared across 40 patients acutely depressed (20 unipolar, 20 bipolar), and 20 controls well-matched for age, gender, and education levels, and alterations were correlated to clinical parameters. Results Despite comparable symptoms, patient groups were robustly differentiated by large-scale network alterations. Differences were driven in bipolar patients by increased functional connectivity in the frontoparietal network, a central executive and externally-oriented network. Conversely, unipolar patients presented increased functional connectivity in the default mode network, an introspective and self-referential network, as much as reduced connectivity of the cingulo-opercular network to default mode regions, a network involved in detecting the need to switch between internally and externally oriented demands. These findings were mostly unaffected by current medication, comorbidity, and structural changes. Moreover, network alterations in unipolar patients were significantly correlated to the number of depressive episodes. Conclusion: Unipolar and bipolar groups displaying similar symptomatology could be clearly distinguished by characteristic changes in large-scale networks, encouraging further investigation of network fingerprints for clinical use. Hum Brain Mapp 37:808-818, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In a temporal difference learning approach of classical conditioning, a theoretical error signal shifts from outcome deliverance to the onset of the conditioned stimulus. Omission of an expected outcome results in a negative prediction error signal, which is the initial step towards successful extinction and may therefore be relevant for fear extinction recall. As studies in rodents have observed a bidirectional relationship between fear extinction and rapid eye movement (REM) sleep, we aimed to test the hypothesis that REM sleep deprivation impairs recall of fear extinction through prediction error signaling in humans. In a three-day design with polysomnographically controlled REM sleep deprivation, 18 young, healthy subjects performed a fear conditioning, extinction and recall of extinction task with visual stimuli, and mild electrical shocks during combined functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) measurements. Compared to the control group, the REM sleep deprivation group had increased SCR scores to a previously extinguished stimulus at early recall of extinction trials, which was associated with an altered fMRI time-course in the left middle temporal gyrus. Post-hoc contrasts corrected for measures of NREM sleep variability also revealed between-group differences primarily in the temporal lobe. Our results demonstrate altered prediction error signaling during recall of fear extinction after REM sleep deprivation, which may further our understanding of anxiety disorders in which disturbed sleep and impaired fear extinction learning coincide. Moreover, our findings are indicative of REM sleep related plasticity in regions that also show an increase in activity during REM sleep. Hum Brain Mapp 33:2362-2376, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]