Reduced mu opioid receptor availability in schizophrenia revealed with [11C]-carfentanil positron emission tomographic Imaging.

Negative symptoms, such as amotivation and anhedonia, are a major cause of functional impairment in schizophrenia. There are currently no licensed treatments for negative symptoms, highlighting the need to understand the molecular mechanisms underlying them. Mu-opioid receptors (MOR) in the striatum play a key role in hedonic processing and reward function and are reduced post-mortem in schizophrenia. However, it is unknown if mu-opioid receptor availability is altered in-vivo or related to negative symptoms in schizophrenia. Using [11 C]-carfentanil positron emission tomography (PET) scans in 19 schizophrenia patients and 20 age-matched healthy controls, here we show a significantly lower MOR availability in patients with schizophrenia in the striatum (Cohen's d = 0.7), and the hedonic network. In addition, we report a marked global increase in inter-regional covariance of MOR availability in schizophrenia, largely due to increased cortical-subcortical covariance

Cognitive correlates of abnormal myelination in psychosis

Psychotic illness has consistently been associated with deficits in cognitive function and reduced white matter integrity in the brain. However, the link between white matter disruptions and deficits in cognitive domains remains poorly understood. We assessed cognitive performance and white matter myelin water fraction (MWF) using multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) in recent-onset psychosis patients and age-matched healthy controls (HC). Psychosis patients showed deficits in working memory, phonological and semantic fluency, general intelligence quotient and reduced MWF in the left temporal white matter compared to HC. MWF in the left inferior fronto-occipital fasciculus and inferior longitudinal fasciculus was positively associated with intelligence quotient and verbal fluency in patients, and fully mediated group differences in performance in both phonological and semantic verbal fluency. There was no association between working memory and MWF in the left temporal white matter. Negative symptoms demonstrated a negative association with MWF within the left inferior and superior longitudinal fasciculi. These findings indicate that psychosis-related deficits in distinct cognitive domains, such as verbal fluency and working memory, are not underpinned by a single common dysfunction in white matter connectivity

A review of the models of schizophrenia: and a putative novel, more unified model

Schizophrenia is a debilitating disease state which causes immense pain to sufferers and to their families. Although some proximate causes of symptoms of the disease have been identified, no ultimate cause has been uncovered which can explain all of the symptoms. This paper presents a novel theory of the ultimate cause of some forms of chronic schizophrenia with the potential to explain many (if not all) symptomologies associated with the disease. In addition to its explanatory power, this putative model may also give rise to new early diagnostic tools and treatments for schizophrenia. After the model is fully explained, suggestions for further research to confirm this model\u27s validity are put forth

Abnormal Structural Connectivity Patterns in Large-Scale Brain Networks in Schizophrenia

Background: While cognitive impairment is a core feature of schizophrenia, a minority of patients demonstrate average to superior ability on many standard cognitive measures with no attenuation of the psychotic disease process (Heinrichs et al. 2008; Muharib et al., 2014). The data imply a dissociation of cognitive and psychosis-generating neural mechanisms whereby patients share a disease process that leads to psychosis but vary in terms of the pathophysiology that causes cognitive impairment. Furthermore, current views hold that schizophrenia involves abnormalities in the connectivity of large-scale brain networks [default mode (DMN), salience (SN), central executive (CEN), and social brain (SBN)]. However, these findings may reflect pathophysiology related to both the cognitive and psychotic features of schizophrenia. Therefore, we asked: Are aberrations in cortical thickness and/or structural connectivity within and between networks associated with cognitive impairment and/or the severity of psychotic psychopathology? Method: Structural magnetic resonance (MRI) and diffusion tensor imaging (DTI), cognitive, and clinical data were collected from 121 participants, which include 16 cognitively-intact and 48 cognitively-impaired schizophrenia patients as well as 36 cognitively normal and 21 below-normal controls. Between-group comparisons and region-of-interest analyses of cortical thickness and structural integrity in the DMN, SN, CEN, and SBN were performed on MRI and DTI data. Results: Cognitively normal controls had greater DMN and SN cortical thickness than both cognitively normal and below-normal patients. Structural integrity of the genu of the corpus callosum was significantly different between cognitively normal controls and both patient groups. Superior longitudinal fasciculus connectivity patterns differed between cognitively normal controls and below-normal patients. Lastly, the inferior longitudinal and inferior fronto-occipital fasciculi combined were significantly different between cognitively normal controls and patients. Conclusions: The results suggest that cortical thinning may represent the presence of psychotic psychopathology independent of cognitive impairment. However, tract integrity may index cognitive status, the psychotic disease process, or both. The similarities in white matter integrity associations with cognition among cognitively normal patients and controls suggest shared neurocognitive processes, and the dissimilarities may point to cortical structure aberrations that give rise to psychotic psychopathology. Taken together, this study contributes to the advancement of the literature by providing evidence for dissociable or partially dissociable disease processes in psychotic illness

Behavioral and neural correlates of chronic blast-related mild traumatic brain injury

Blast-related mild traumatic brain injury (mTBI) is a common injury among Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans due to the frequent use of improvised explosive devices (IEDs). A significant minority of veterans with blast-related mTBI complain of postconcussion symptoms (PCS) and cognitive difficulties, even years after the injury. Studies have suggested that these behavioral sequelae are primarily linked to mental health disorders such as posttraumatic stress disorder (PTSD). However, mTBI is associated with neural changes and the impact of these changes on behavioral sequelae is unclear. As such, this dissertation had three goals. First, this dissertation assessed whether the severity of PCS in blast-exposed individuals is associated with the extent of mTBI-related neural injury. Results revealed that individuals with mTBI with loss of consciousness (LOC) had significantly more white matter abnormalities than no-TBI controls and that these white matter abnormalities were spatially variable across individuals. Importantly, the extent of white matter abnormality was associated with physical PCS severity and mediated the relationship between mTBI with LOC and physical PCS. Second, this dissertation examined whether these white matter abnormalities were also associated with overall cognitive impairment. In light of the observed variability in white matter injury, a measure of overall cognitive status that takes into account heterogeneity of cognitive impairment was used. Results showed that the extent of white matter abnormality was associated with cognitive status and mediated the relationship between mTBI with LOC and cognitive impairment. Third, this dissertation examined performance and brain function in the context of an experimental measure of cognitive control known to be sensitive to residual effects of mTBI. Results revealed that although behavioral performance was similar across groups, the mTBI group had enhanced functional connectivity between brain networks important for task performance, suggesting a potential compensatory mechanism in mTBI. Together, the findings of this dissertation suggest that mTBI is associated with structural and functional connectivity alterations years after the injury. Further, this dissertation suggests that whereas structural connectivity changes may have negative behavioral consequences, changes in functional connectivity may serve as a compensatory mechanism for successful performance

Social deficits in schizophrenia : pinpointing illness-and task-related factors linked to impairments

La schizophrénie est une maladie invalidante caractérisée par d’importants déficits sociaux qui affecte la capacité de comprendre et d’interagir avec autrui. Plus précisément, des déficits de théorie de l’esprit, c’est-à-dire la capacité de déduire les états mentaux d’autres personnes, sont un facteur prédictif important du niveau de fonctionnement au sein de la communauté en schizophrénie. La délimitation des facteurs sous-jacents aux déficits sociaux dans la schizophrénie est donc cruciale pour améliorer les interventions. L’hétérogénéité de la présentation clinique de la schizophrénie peut influencer les habiletés sociales. Par exemple, plusieurs patients démontrent de l’anxiété sociale, et la présence de cette comorbidité peut influencer davantage leur intégration sociale. De plus, l’hétérogénéité des types de tâches utilisées pour mesurer les déficits sociaux, et notamment le degré de dépendance de ces tâches au contexte, peut affecter les déficits observés dans la schizophrénie. La présente thèse décrit trois études visant à cerner si ces composantes reliées à la pathologie et aux tâches jouent un rôle dans les déficits sociaux en schizophrénie. Cette souligne particulièrement le rôle de la théorie de l’esprit (l’habilité à inférer l’état mental d’autrui), puisque cette habilité a un lien important avec le fonctionnement en schizophrénie. Cette thèse démontre que le trouble d’anxiété social est une comorbidité prévalente dans la schizophrénie, liée à la fois à la représentation clinique de la schizophrénie et au rang social (i.e. comment ils se comparent aux autres vis-à-vis leurs attributs personnels (chapitre 1). Globalement chez les patients atteints de schizophrénie, il est démontré que le traitement du contexte est une composante importante reliée aux déficits de théorie de l’esprit (chapitre 2). De plus, des résultats d’analyse IRMf démontrent que les patients atteints de schizophrénie présentent des activations altérées dans des régions du cerveau, telles que la jonction temporopariétale droite et le cortex cingulaire postérieur, lors du traitement du contexte dans des scénarios sociaux et non sociaux (chapitre 2, chapitre 3). Plus précisément, le chapitre 4 souligne que les patients ont une capacité réduite à moduler les réseaux cérébraux à grande échelle en réponse à des types de contexte différents. Le traitement du contexte peut représenter un déficit fondamental en schizophrénie qui pourrait être une cible lors d’interventions futures visant à améliorer les capacités sociales. Globalement, cette thèse souligne l’importance de prendre en compte l’hétérogénéité à la fois dans la schizophrénie et dans les tâches de la théorie de l’esprit dans de futures recherches sur le traitement social de la schizophrénie, en soulignant spécifiquement le rôle important du trouble de l’anxiété sociale et du traitement du contexte.Schizophrenia is a highly disabling disorder characterized by significant social deficits that impair one’s ability to interact with and understand others. Specifically, impairments in Theory of Mind, i.e. the ability to infer the mental states of others, are an important predictor of community functioning in schizophrenia. Delineating the factors underlying social deficits in schizophrenia is thus crucial to developing improved treatment targets for functioning. Heterogeneity in the clinical presentation of schizophrenia may influence one’s socia l abilities. For instance, many patients also present with social anxiety, and this comorbid presentation may further affect their abilities to integrate in the social world. Additionally, heterogeneity in the types of tasks used to measure social deficits, and notably, the degree to which these tasks rely on context, may affect deficits observed in schizophrenia. The present thesis describes three studies that aim to pinpoint whether these illness- and task-related components play a role in social deficits in schizophrenia, with a particular focus on Theory of Mind abilities. This thesis demonstrates that social anxiety disorder is a prevalent comorbidity in schizophrenia related to both the clinical presentation of schizophrenia and to social rank (i.e. how they rank themselves compared to others on personal attributes; Chapter 1). In patients with schizophrenia overall, results also highlight that context processing is an important component related to deficits on Theory of Mind tasks (Chapter 2). Additionally, fMRI results demonstrate that patients with schizophrenia display altered activation in brain regions (e.g. right temporo-parietal junction, posterior cingulate cortex) during processing context in social and non-social scenarios (Chapter 2, Chapter 3). Specifically, Chapter 3 highlights that patients have a reduced ability to modulate large-scale brain networks in response to different types of context. Context processing may represent a core deficit in schizophrenia that could be a target in future interventions to improve social abilities. Overall, this thesis underlines the importance of considering heterogeneity in both schizophrenia and in Theory of Mind tasks in future research of social processing in schizophrenia, specifically highlighting the important role of social anxiety disorder and context processing

Left auditory cortex gamma synchronization and auditory hallucination symptoms in schizophrenia

<p>Abstract</p> <p>Background</p> <p>Oscillatory electroencephalogram (EEG) abnormalities may reflect neural circuit dysfunction in neuropsychiatric disorders. Previously we have found positive correlations between the phase synchronization of beta and gamma oscillations and hallucination symptoms in schizophrenia patients. These findings suggest that the propensity for hallucinations is associated with an increased tendency for neural circuits in sensory cortex to enter states of oscillatory synchrony. Here we tested this hypothesis by examining whether the 40 Hz auditory steady-state response (ASSR) generated in the left primary auditory cortex is positively correlated with auditory hallucination symptoms in schizophrenia. We also examined whether the 40 Hz ASSR deficit in schizophrenia was associated with cross-frequency interactions.</p> <p>Sixteen healthy control subjects (HC) and 18 chronic schizophrenia patients (SZ) listened to 40 Hz binaural click trains. The EEG was recorded from 60 electrodes and average-referenced offline. A 5-dipole model was fit from the HC grand average ASSR, with 2 pairs of superior temporal dipoles and a deep midline dipole. Time-frequency decomposition was performed on the scalp EEG and source data.</p> <p>Results</p> <p>Phase locking factor (PLF) and evoked power were reduced in SZ at fronto-central electrodes, replicating prior findings. PLF was reduced in SZ for non-homologous right and left hemisphere sources. Left hemisphere source PLF in SZ was positively correlated with auditory hallucination symptoms, and was modulated by delta phase. Furthermore, the correlations between source evoked power and PLF found in HC was reduced in SZ for the LH sources.</p> <p>Conclusion</p> <p>These findings suggest that differential neural circuit abnormalities may be present in the left and right auditory cortices in schizophrenia. In addition, they provide further support for the hypothesis that hallucinations are related to cortical hyperexcitability, which is manifested by an increased propensity for high-frequency synchronization in modality-specific cortical areas.</p

The benefit of directly comparing autism and schizophrenia for revealing mechanisms of social cognitive impairment

Autism and schizophrenia share a history of diagnostic conflation that was not definitively resolved until the publication of the DSM-III in 1980. Though now recognized as heterogeneous disorders with distinct developmental trajectories and dissociative features, much of the early nosological confusion stemmed from apparent overlap in certain areas of social dysfunction. In more recent years, separate but substantial literatures have accumulated for autism and schizophrenia demonstrating that abnormalities in social cognition directly contribute to the characteristic social deficits of both disorders. The current paper argues that direct comparison of social cognitive impairment can highlight shared and divergent mechanisms underlying pathways to social dysfunction, a process that can provide significant clinical benefit by informing the development of tailored treatment efforts. Thus, while the history of diagnostic conflation between autism and schizophrenia may have originated in similarities in social dysfunction, the goal of direct comparisons is not to conflate them once again but rather to reveal distinctions that illuminate disorder-specific mechanisms and pathways that contribute to social cognitive impairment

The contribution of executive dysfunction to memory impairment and confabulation in schizophrenia

Study 1. Using a cognitive-process approach, 25 schizophrenic patients were matched with 25 healthy volunteers and compared on tests of memory and executive function. The schizophrenia group was found to have a significant impairment in immediate memory with relatively spared long-delay and recognition memory. Memory deficits were irrespective of the encoding strategies used and were unrelated to chronicity. In addition, the schizophrenic patients performed worse than controls on tests of executive function which was supported by some significant correlations between aspects of memory and executive function. The pattern of performance resembled that found in patients with subcortical or frontal lesions. Study 2. To examine further executive aspects of memory, an attempt to demonstrate confabulation in schizophrenia was made. Twelve schizophrenic patients were matched with 12 volunteers, 8 of whom were normal healthy subjects, with the remained being depressed patients. The subjects were asked to recall a set of experimental narratives, with confabulation being defined as the recall of ideas not present in the narrative. Subjects were also examined on a number of neuropsychological tests and the patients were assessed on the Krawiecka scale. Variable amounts of confabulation were observed in all the schizophrenic patients while only one control subject confabulated. The form of confabulation differed from those observed in other patients in that the original ideas were spontaneously rearranged to produce new ones. Confabulation was found to be related to difficulties in suppressing inappropriate responses and formal thought disorder. Study 3. Three schizophrenic patients previously identified as confabulators, were intensively studied to establish the mechanisms of narrative confabulation in schizophrenia. Patients were administered experimental tasks as well as standard neuropsychological tests of memory and executive function. Assessment of current symptoms was made using the SANS and SAPS scales. The severity of cognitive impairment was found to reflect the severity of confabulation, but memory impairment was neither nor sufficient to account for confabulation. Within the spectrum of executive deficits, impairments in response suppression and response monitoring, but not planning or generation were consistently associated with confabulation. The findings from the experimental tasks suggest that faults occur at both input and output. At the input stage, narrative material is encoded in a disorganised manner while at the output stage, this disorganisation is compounded by faulty editing processes. Study 4. Four schizophrenic patients who were known confabulators with narrative material, were subjected to an experimental autobiographical questionnaire designed to establish whether schizophrenic patients confabulate in response to questions calling on the recollection of personal facts and events. In addition, a number of neuropsychological tests were administered and current symptoms was assessed with the SANS and SAPS scales. All patients were observed to confabulate to varying degrees, particularly in response to questions relating to personal episodes rather than facts. For two patients, personal delusional systems were found to play a role in confabulation by providing a framework on which to base certain confabulatory recollections. Memory impairment was not found to be a necessary component to autobiographical confabulation but deficits in response suppression and response monitoring were observed to be related to the verification process performed during this task. Study 5. In an attempt to establish which anatomical regions may be at fault in schizophrenia when patients are engaged in response suppression tasks, six normal subjects were studied using positron emission tomography (PET) to identify anatomical regions involved when performing the Hayling Test. Subjects were also required to perform a control condition in which they had to read out the last word of given sentences. Compared to the control task, response initiation was associated with left sided activation of the frontal operculum, inferior frontal gyrus, middle temporal gyrus and right anterior cingulate gyrus, whereas response suppression was associated with left frontal operculum, inferior frontal gyrus and right anterior cingulate gyrus activation only. The difference between the two parts of the Hayling Test was in the increased activation of the left middle temporal gyrus and the left inferior frontal region (Brodmann's area 44/6) during response initiation