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OBJECTIVE - In schizophrenia, the anterior hippocampus is hyperactive and shows reduced task-related recruitment, but the relationship between these two findings is unclear. The authors tested the hypothesis that hyperactivity impairs recruitment of the anterior hippocampus during scene processing.
METHODS - Functional MRI data from 45 early-psychosis patients and 35 demographically matched healthy control subjects were analyzed using a block-design 1-back scene-processing task. Hippocampal activation in response to scenes and faces compared with scrambled images was measured. In a subset of 20 early-psychosis patients and 31 healthy control subjects, baseline hippocampal activity using cerebral blood volume (CBV) mapping was measured. Correlation analyses were used to examine the association between baseline hippocampal activity and task-related hippocampal activation.
RESULTS - Activation of the anterior hippocampus was significantly reduced and CBV in the anterior hippocampus was significantly increased in the early stages of psychosis. Increased CBV in early-psychosis patients was inversely correlated with task-related activation during scene processing in the anterior hippocampus.
CONCLUSIONS - Anterior hippocampal hyperactivity in early-psychosis patients appears to limit effective recruitment of this region during task performance. These findings provide novel support for the anterior hippocampus as a therapeutic target in the treatment of cognitive deficits in psychosis.

During our everyday lives, we are confronted with a vast amount of information from several sensory modalities. This multisensory information needs to be appropriately integrated for us to effectively engage with and learn from our world. Research carried out over the last half century has provided new insights into the way such multisensory processing improves human performance and perception; the neurophysiological foundations of multisensory function; the time course for its development; how multisensory abilities differ in clinical populations; and, most recently, the links between multisensory processing and cognitive abilities. This review summarizes the extant literature on multisensory function in typical and atypical circumstances, discusses the implications of the work carried out to date for theory and research, and points toward next steps for advancing the field.

BACKGROUND - Learning and memory are impaired in schizophrenia. Some theories have proposed that one form of memory, habituation, is particularly impaired. Preliminary evidence suggests that memory impairment is associated with failed hippocampal habituation in patients with chronic schizophrenia. We studied how abnormal habituation of the hippocampus is related to relational memory deficits in the early stage of psychosis.
METHODS - We measured hippocampal activity in 62 patients with early psychosis and 70 healthy individuals using functional magnetic resonance imaging. Habituation was defined as the slope of functional magnetic resonance imaging signal change to repeated presentations of faces and objects. Relational memory ability was measured as the slope of preferential viewing during a face-scene pair eye movement task outside the scanner.
RESULTS - Patients with early psychosis showed impaired relational memory (p < .001) and less hippocampal habituation to objects (p = .01) than healthy control subjects. In the healthy control group, better relational memory was associated with faster anterior hippocampal habituation (faces, r = -.28, p = .03). In contrast, patients with early psychosis showed no brain-behavior relationship (r = .12, p = .40).
CONCLUSIONS - We found evidence for disrupted hippocampal habituation in the early stage of psychosis along with an altered association between hippocampal habituation and relational memory ability. These results suggest that neural habituation may provide a novel target for early cognitive interventions in psychosis.
Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

BACKGROUND - Humans constantly take in vast amounts of information, which must be filtered, flexibly manipulated, and integrated into cohesive relational memories in order to choose relevant behaviors. Relational memory is impaired in chronic schizophrenia, which has been linked to hippocampal dysfunction. It is unclear whether relational memory is impaired in the early stage of psychosis.
METHODS - We studied eye movements during a face-scene pairs task as an indirect measure of relational memory in 89 patients in the early stage of psychosis and 84 healthy control participants. During testing, scenes were overlaid with three equally-familiar faces and participants were asked to recall the matching (i.e. previously-paired) face. During Match trials, one face had been previously paired with the scene. During Non-Match trials, no faces matched the scene. Forced-choice explicit recognition was recorded as a direct measure of relational memory.
RESULTS - Healthy control subjects rapidly (within 250-500 ms) showed preferential viewing of the matching face during Match trials. In contrast, preferential viewing was delayed in patients in the early stage of psychosis. Explicit recognition of the matching face was also impaired in the patient group.
CONCLUSIONS - This study provides novel evidence for a relational memory deficit in the early stage of psychosis. Patients showed deficits in both explicit recognition as well as abnormal eye-movement patterns during memory recall. Eye movements provide a promising avenue for the study of relational memory in psychosis, as they allow for the assessment of rapid, nonverbal memory processes.
Copyright © 2019 Elsevier B.V. All rights reserved.

BACKGROUND - The striatum is abnormal in schizophrenia and possibly represents a common neurobiological mechanism underlying psychotic disorders. Resting-state functional magnetic resonance imaging studies have not reached a consensus regarding striatal dysconnectivity in schizophrenia, although these studies generally find impaired frontoparietal and salience network connectivity. The goal of the current study was to clarify the pattern of corticostriatal connectivity, including whether corticostriatal dysconnectivity is transdiagnostic and extends into psychotic bipolar disorder.
METHODS - We examined corticostriatal functional connectivity in 60 healthy subjects and 117 individuals with psychosis, including 77 with a schizophrenia spectrum illness and 40 with psychotic bipolar disorder. We conducted a cortical seed-based region-of-interest analysis with follow-up voxelwise analysis for any significant results. Further, a striatum seed-based analysis was conducted to examine group differences in connectivity between the striatum and the whole cortex.
RESULTS - Cortical region-of-interest analysis indicated that overall connectivity of the salience network with the striatum was reduced in psychotic disorders, which follow-up voxelwise analysis localized to the left putamen. Striatum seed-based analyses showed reduced ventral rostral putamen connectivity with the salience network portion of the medial prefrontal cortex in both schizophrenia and psychotic bipolar disorder.
CONCLUSIONS - The current study found evidence of transdiagnostic corticostriatal dysconnectivity in both schizophrenia and psychotic bipolar disorder, including reduced salience network connectivity, as well as reduced connectivity between the putamen and the medial prefrontal cortex. Overall, the current study points to the relative importance of salience network hypoconnectivity in psychotic disorders.
Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Muscarinic acetylcholine receptor (mAChRs) subtypes represent exciting new targets for the treatment of schizophrenia and substance use disorder (SUD). Recent advances in the development of subtype-selective allosteric modulators have revealed promising effects in preclinical models targeting the different symptoms observed in schizophrenia and SUD. M PAMs display potential for addressing the negative and cognitive symptoms of schizophrenia, while M PAMs exhibit promise in treating preclinical models predictive of antipsychotic-like activity. In SUD, there is increasing support for modulation of mesocorticolimbic dopaminergic circuitry involved in SUD with selective M mAChR PAMs or M mAChR NAMs. Allosteric modulators of these mAChR subtypes have demonstrated efficacy in rodent models of cocaine and ethanol seeking, with indications that these ligand may also be useful for other substances of abuse, as well as in various stages in the cycle of addiction. Importantly, allosteric modulators of the different mAChR subtypes may provide viable treatment options, while conferring greater subtype specificity and corresponding enhanced therapeutic index than orthosteric muscarinic ligands and maintaining endogenous temporo-spatial ACh signaling. Overall, subtype specific mAChR allosteric modulators represent important novel therapeutic mechanisms for schizophrenia and SUD.
© 2019 Elsevier Inc. All rights reserved.

Working memory (WM) is impaired in psychotic disorders and linked to functional outcome. Most neurobiological models emphasize prefrontal cortex (PFC) dysfunction in the etiology of WM impairment. However, WM is composed of multiple processes, including encoding and maintenance, and the delineation of the neurobiology of these sub-processes has not been well characterized in schizophrenia and psychotic bipolar disorder. Functional MRI was obtained during an event-related spatial delayed match-to-sample task from 58 healthy individuals, 72 individuals with schizophrenia and 41 people with bipolar I disorder with psychotic features in order to: 1) characterize neural responses during encoding, maintenance and retrieval stages of WM using complementary region-of-interest and whole brain approaches; 2) determine whether schizophrenia and psychotic bipolar disorder exhibit similar abnormalities in WM-related brain function; and 3) elucidate the associations between WM-related brain function, task performance, and neuropsychological functioning. Both schizophrenia and psychotic bipolar disorder groups showed encoding- and maintenance-related impairments in the posterior parietal cortex (PPC) and frontal eye fields (FEF). BOLD response in the PPC and FEF, during encoding and maintenance respectively, was associated with task performance independent of group. Additionally, encoding-related activation in the PPC correlated with general neuropsychological functioning independent of group. Only encoding-related activation in the right ventral striatum differed between schizophrenia and psychotic bipolar disorder; individuals with schizophrenia showed significantly lower activation than both psychotic bipolar disorder and healthy groups. Our results are consistent with emerging evidence implicating PPC dysfunction in WM impairment and suggest interventions targeting neural activation in PPC may improve WM and neuropsychological functioning across psychotic disorders.

BACKGROUND - Neuropsychological impairment is common in schizophrenia and psychotic bipolar disorder. It has been hypothesized that the pathways leading to impairment differ between disorders. Cognitive impairment in schizophrenia is believed to result largely from atypical neurodevelopment, whereas bipolar disorder is increasingly conceptualized as a neuroprogressive disorder. The current investigation tested several key predictions of this hypothesis.
METHODS - Current neuropsychological functioning and estimated premorbid intellectual ability were assessed in healthy individuals (n = 260) and a large, cross-sectional sample of individuals in the early and chronic stages of psychosis (n = 410). We tested the following hypotheses: 1) cognitive impairment is more severe in schizophrenia in the early stage of psychosis; and 2) cognitive decline between early and chronic stages is relatively greater in psychotic bipolar disorder. Additionally, individuals with psychosis were classified as neuropsychologically normal, deteriorated, and compromised (i.e. below average intellectual functioning) to determine if the frequencies of neuropsychologically compromised and deteriorated patients were higher in schizophrenia and psychotic bipolar disorder, respectively.
RESULTS - Neuropsychological impairment in the early stage of psychosis was more severe in schizophrenia. Psychotic bipolar disorder was not associated with relatively greater cognitive decline between illness stages. The frequency of neuropsychologically compromised patients was higher in schizophrenia; however, substantial portions of both schizophrenia and psychotic bipolar disorder patients were classified as neuropsychologically compromised and deteriorated.
CONCLUSIONS - While schizophrenia is associated with relatively greater neurodevelopmental involvement, psychotic bipolar disorder and schizophrenia cannot be strictly dichotomized into purely neuroprogressive and neurodevelopmental illness trajectories; there is evidence of both processes in each disorder.
Copyright © 2018 Elsevier B.V. All rights reserved.

Schizophrenia is conceptualized as a neurodevelopmental disorder and pre-morbid differences in social function and cognition have been well-established. Less is known about pre-morbid temperament and personality. Inhibited temperament-the predisposition to respond to novelty with wariness, fear, or caution-is a premorbid risk factor for anxiety, depression, and substance use but is understudied in schizophrenia. Participants were patients with schizophrenia spectrum disorders (n = 166) and healthy controls (n = 180). Patients completed measures of childhood inhibited temperament, clinical symptoms (anxiety, depression, PANSS factors), and quality of life. Patients had significantly higher levels of inhibited temperament relative to healthy controls. In patients with schizophrenia, higher inhibited temperament was significantly associated with co-morbid anxiety disorders, greater anxiety and depression symptoms, higher PANSS Distress scores, lower PANSS Excitement scores, and lower quality of life. The current findings replicate and extend previous research with a larger sample and are consistent with vulnerability in an affective path to psychosis. In schizophrenia, higher inhibited temperament was associated with a cluster of mood and anxiety symptoms. Inhibited temperament was not associated with psychosis symptoms. Patients with high inhibited temperament may especially benefit from treatments that specifically target anxiety and depression.
Copyright © 2019. Published by Elsevier B.V.