Dictionary Learning and Sparse Coding-based Denoising for High-Resolution Task Functional Connectivity MRI Analysis

We propose a novel denoising framework for task functional Magnetic Resonance Imaging (tfMRI) data to delineate the high-resolution spatial pattern of the brain functional connectivity via dictionary learning and sparse coding (DLSC). In order to address the limitations of the unsupervised DLSC-based fMRI studies, we utilize the prior knowledge of task paradigm in the learning step to train a data-driven dictionary and to model the sparse representation. We apply the proposed DLSC-based method to Human Connectome Project (HCP) motor tfMRI dataset. Studies on the functional connectivity of cerebrocerebellar circuits in somatomotor networks show that the DLSC-based denoising framework can significantly improve the prominent connectivity patterns, in comparison to the temporal non-local means (tNLM)-based denoising method as well as the case without denoising, which is consistent and neuroscientifically meaningful within motor area. The promising results show that the proposed method can provide an important foundation for the high-resolution functional connectivity analysis, and provide a better approach for fMRI preprocessing.Comment: 8 pages, 3 figures, MLMI201

Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg) in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS−), in a T- or Y-maze configuration. This was followed by three conditions; (1) Full reversal, where contingencies reversed; (2) Perseverance, where the previous CS+ became CS− and the previous CS− was replaced by a novel CS+; (3) Learned non-reward, where the previous CS− became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss on the development and maintenance of cognitive function

Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine–glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine–glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine–glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine–glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine–glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine–glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP

From Computation to Clinic

Theory-driven and data-driven computational approaches to psychiatry have enormous potential for elucidating mechanism of disease and providing translational linkages between basic science findings and the clinic. These approaches have already demonstrated utility in providing clinically relevant understanding, primarily via back translation from clinic to computation, revealing how specific disorders or symptoms map onto specific computational processes. Nonetheless, forward translation, from computation to clinic, remains rare. In addition, consensus regarding specific barriers to forward translation—and on the best strategies to overcome these barriers—is limited. This perspective review brings together expert basic and computationally trained researchers and clinicians to 1) identify challenges specific to preclinical model systems and clinical translation of computational models of cognition and affect, and 2) discuss practical approaches to overcoming these challenges. In doing so, we highlight recent evidence for the ability of computational approaches to predict treatment responses in psychiatric disorders and discuss considerations for maximizing the clinical relevance of such models (e.g., via longitudinal testing) and the likelihood of stakeholder adoption (e.g., via cost-effectiveness analyses)

The NEWMEDS rodent touchscreen test battery for cognition relevant to schizophrenia.

RATIONALE: The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia, http://www.newmeds-europe.com ) is a large industrial-academic collaborative project aimed at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia. OBJECTIVES: This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere. METHODS: The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory. RESULTS: The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks. CONCLUSION: This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.This work was supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). The authors thank Charlotte Oomen for valuable comments on the manuscript.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00213-015-4007-

Confidence and psychosis: a neuro-computational account of contingency learning disruption by NMDA blockade.

A state of pathological uncertainty about environmental regularities might represent a key step in the pathway to psychotic illness. Early psychosis can be investigated in healthy volunteers under ketamine, an NMDA receptor antagonist. Here, we explored the effects of ketamine on contingency learning using a placebo-controlled, double-blind, crossover design. During functional magnetic resonance imaging, participants performed an instrumental learning task, in which cue-outcome contingencies were probabilistic and reversed between blocks. Bayesian model comparison indicated that in such an unstable environment, reinforcement learning parameters are downregulated depending on confidence level, an adaptive mechanism that was specifically disrupted by ketamine administration. Drug effects were underpinned by altered neural activity in a fronto-parietal network, which reflected the confidence-based shift to exploitation of learned contingencies. Our findings suggest that an early characteristic of psychosis lies in a persistent doubt that undermines the stabilization of behavioral policy resulting in a failure to exploit regularities in the environment.FV was supported by the Groupe Pasteur Mutualité. RG was supported by the Fondation pour la Recherche Médicale and the Fondation Bettencourt Schueller. SP is supported by a Marie Curie Intra-European fellowship (FP7-PEOPLE-2012-IEF). AF was supported by National Health and Medical Research Council grants (IDs : 1050504 and 1066779) and an Australian Research Council Future Fellowship (ID: FT130100589). This work was supported by the Wellcome Trust and the Bernard Wolfe Health Neuroscience Fund.This is the final version of the article. It first appeared from the Nature Publishing Group via http://dx.doi.org/10.1038/mp.2015.7

Abnormal Frontostriatal Activity During Unexpected Reward Receipt in Depression and Schizophrenia: Relationship to Anhedonia.

Alterations in reward processes may underlie motivational and anhedonic symptoms in depression and schizophrenia. However it remains unclear whether these alterations are disorder-specific or shared, and whether they clearly relate to symptom generation or not. We studied brain responses to unexpected rewards during a simulated slot-machine game in 24 patients with depression, 21 patients with schizophrenia, and 21 healthy controls using functional magnetic resonance imaging. We investigated relationships between brain activation, task-related motivation, and questionnaire rated anhedonia. There was reduced activation in the orbitofrontal cortex, ventral striatum, inferior temporal gyrus, and occipital cortex in both depression and schizophrenia in comparison with healthy participants during receipt of unexpected reward. In the medial prefrontal cortex both patient groups showed reduced activation, with activation significantly more abnormal in schizophrenia than depression. Anterior cingulate and medial frontal cortical activation predicted task-related motivation, which in turn predicted anhedonia severity in schizophrenia. Our findings provide evidence for overlapping hypofunction in ventral striatal and orbitofrontal regions in depression and schizophrenia during unexpected reward receipt, and for a relationship between unexpected reward processing in the medial prefrontal cortex and the generation of motivational states.Supported by a MRC Clinician Scientist award (G0701911), a Brain and Behaviour Research Foundation Young Investigator, and an Isaac Newton Trust award to Dr Murray; an award to Dr Segarra from the Secretary for Universities and Research of the Ministry of Economy and Knowledge of the Government of Catalonia and the European Union; by the University of Cambridge Behavioural and Clinical Neuroscience Institute, funded by a joint award from the Medical Research Council and Wellcome Trust (G1000183 and 093875/Z/10Z respectively); by awards from the Wellcome Trust (095692) and the Bernard Wolfe Health Neuroscience Fund to Professor Fletcher, and by awards from the Wellcome Trust Institutional Strategic Support Fund (097814/Z/11) and Cambridge NIHR Biomedical Research Centre. The authors are grateful for the help of clinical staff in CAMEO, in the Cambridge Rehabilitation and Recovery service and Pathways, and in the Cambridge IAPT service, for help with participant recruitment.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/npp.2015.37

The Lifespan Human Connectome Project in Development: A large-scale study of brain connectivity development in 5-21 year olds

Recent technological and analytical progress in brain imaging has enabled the examination of brain organization and connectivity at unprecedented levels of detail. The Human Connectome Project in Development (HCP-D) is exploiting these tools to chart developmental changes in brain connectivity. When complete, the HCP-D will comprise approximately ∼1750 open access datasets from 1300 + healthy human participants, ages 5–21 years, acquired at four sites across the USA. The participants are from diverse geographical, ethnic, and socioeconomic backgrounds. While most participants are tested once, others take part in a three-wave longitudinal component focused on the pubertal period (ages 9–17 years). Brain imaging sessions are acquired on a 3 T Siemens Prisma platform and include structural, functional (resting state and task-based), diffusion, and perfusion imaging, physiological monitoring, and a battery of cognitive tasks and self-reports. For minors, parents additionally complete a battery of instruments to characterize cognitive and emotional development, and environmental variables relevant to development. Participants provide biological samples of blood, saliva, and hair, enabling assays of pubertal hormones, health markers, and banked DNA samples. This paper outlines the overarching aims of the project, the approach taken to acquire maximally informative data while minimizing participant burden, preliminary analyses, and discussion of the intended uses and limitations of the dataset

Pavlovian Reward Prediction and Receipt in Schizophrenia: Relationship to Anhedonia

Reward processing abnormalities have been implicated in the pathophysiology of negative symptoms such as anhedonia and avolition in schizophrenia. However, studies examining neural responses to reward anticipation and receipt have largely relied on instrumental tasks, which may confound reward processing abnormalities with deficits in response selection and execution. 25 chronic, medicated outpatients with schizophrenia and 20 healthy controls underwent functional magnetic resonance imaging using a Pavlovian reward prediction paradigm with no response requirements. Subjects passively viewed cues that predicted subsequent receipt of monetary reward or non-reward, and blood-oxygen-level-dependent signal was measured at the time of cue presentation and receipt. At the group level, neural responses to both reward anticipation and receipt were largely similar between groups. At the time of cue presentation, striatal anticipatory responses did not differ between patients and controls. Right anterior insula demonstrated greater activation for nonreward than reward cues in controls, and for reward than nonreward cues in patients. At the time of receipt, robust responses to receipt of reward vs. nonreward were seen in striatum, midbrain, and frontal cortex in both groups. Furthermore, both groups demonstrated responses to unexpected versus expected outcomes in cortical areas including bilateral dorsolateral prefrontal cortex. Individual difference analyses in patients revealed an association between physical anhedonia and activity in ventral striatum and ventromedial prefrontal cortex during anticipation of reward, in which greater anhedonia severity was associated with reduced activation to money versus no-money cues. In ventromedial prefrontal cortex, this relationship held among both controls and patients, suggesting a relationship between anticipatory activity and anhedonia irrespective of diagnosis. These findings suggest that in the absence of response requirements, brain responses to reward receipt are largely intact in medicated individuals with chronic schizophrenia, while reward anticipation responses in left ventral striatum are reduced in those patients with greater anhedonia severity