Ilvana Dzafic

Theory of mind and the social brain: implications for understanding the genetic basis of schizophrenia

Genome‐wide association studies in schizophrenia have recently made significant progress in our understanding of the complex genetic architecture of this disorder. Many genetic loci have been identified and now require functional investigation. One approach involves studying their correlation with neuroimaging and neurocognitive endophenotypes. Theory of Mind (ToM) deficits are well established in schizophrenia and they appear to fulfill criteria for being considered an endophenotype. We aim to review the behavioral and neuroimaging‐based studies of ToM in schizophrenia, assess its suitability as an endophenotype, discuss current findings, and propose future research directions. Suitable research articles were sourced from a comprehensive literature search and from references identified through other studies. ToM deficits are repeatable, stable, and heritable: First‐episode patients, those in remission and unaffected relatives all show deficits. Activation and structural differences in brain regions believed important for ToM are also consistently reported in schizophrenia patients at all stages of illness, although no research to date has examined unaffected relatives. Studies using ToM as an endophenotype are providing interesting genetic associations with both single nucleotide polymorphisms (SNPs) and specific copy number variations (CNVs) such as the 22q11.2 deletion syndrome. We conclude that ToM is an important cognitive endophenotype for consideration in future studies addressing the complex genetic architecture of schizophrenia, and may help identify more homogeneous clinical sub‐types for further study

NESSTI: Norms for Environmental Sound Stimuli

In this paper we provide normative data along multiple cognitive and affective variable dimensions for a set of 110 sounds, including living and manmade stimuli. Environmental sounds are being increasingly utilized as stimuli in the cognitive, neuropsychological and neuroimaging fields, yet there is no comprehensive set of normative information for these type of stimuli available for use across these experimental domains. Experiment 1 collected data from 162 participants in an on-line questionnaire, which included measures of identification and categorization as well as cognitive and affective variables. A subsequent experiment collected response times to these sounds. Sounds were normalized to the same length (1 second) in order to maximize usage across multiple paradigms and experimental fields. These sounds can be freely downloaded for use, and all response data have also been made available in order that researchers can choose one or many of the cognitive and affective dimensions along which they would like to control their stimuli. Our hope is that the availability of such information will assist researchers in the fields of cognitive and clinical psychology and the neuroimaging community in choosing well-controlled environmental sound stimuli, and allow comparison across multiple studies.

Causal evidence for task-specific involvement of the dorsomedial prefrontal cortex in human social cognition

Abstract The dorsomedial prefrontal cortex (dmPFC) is a key hub of the ‘social brain’, but little is known about specific processes supported by this region. Using focal high-definition transcranial direct current stimulation (HD-tDCS) and a social cognitive battery with differing demands on self-other processing, we demonstrate specific involvement of the dmPFC in tasks placing high demands on self-other processing. Specifically, excitatory (anodal) HD-tDCS enhanced the integration of external information into the self for explicit higher-order socio-cognitive tasks across cognitive domains; i.e. visual perspective taking (VPT) and episodic memory. These effects were task specific, as no stimulation effects were found for attributing mental states from the eyes or implicit VPT. Inhibitory (cathodal) HD-tDCS had weaker effects in the opposite direction towards reduced integration of external information into the self. We thus demonstrate for the first time a specific and causal role of the dmPFC in integrating higher-order information from others/external source into that of the self across cognitive domains.

Mentalizing in schizophrenia: A multivariate functional MRI study

Schizophrenia is associated with mentalizing deficits that impact on social functioning and quality of life. Recently, schizophrenia has been conceptualized as a disorder of neural dysconnectivity and network level analyses offers a means of understanding the underlying deficits leading to mentalizing difficulty. Using an established mentalizing task (The Triangles Task), functional magnetic resonance images (fMRI) were acquired from 19 patients with schizophrenia and 17 age- and sex-matched healthy controls (HCs). Participants were required to watch short animations of two triangles interacting with each other with the interactions either random (no interaction), physical (patterned movement), or mental (intentional movement). Task-based Partial Least Squares (PLS) was used to analyze activation differences and commonalities between the three conditions and the two groups. Seed-based PLS was used to assess functional connectivity with peaks identified in the task-based PLS. Behavioural PLS was then performed using the accuracy from the mental conditions. Patients with schizophrenia performed worse on the mentalizing condition compared to HCs. Task-based PLS revealed one significant latent variable (LV) that explained 42.9% of the variance in the task, with theLV separating the mental condition from the physical and random conditions in patients with schizophrenia, but only the mental from physical in healthy controls. The mental animations were associated with increased modulation of the inferior frontal gyri bilaterally, left superior temporal gyrus, right postcentral gyrus, and left caudate nucleus. The physical/random animations were associated with increased modulation of the right medial frontal gyrus and left superior frontal gyrus. Seed-based PLS identified increased functional connectivity with the left inferior frontal gyrus (liFG) and caudate nucleus in patients with schizophrenia, during the mental and physical interactions, with functional connectivity with the liFG associated with increased performance on the mental animations. The results suggest that mentalizing deficits in schizophrenia may arise due to inefficient social brain networks.

Disentangling the cognitive components supporting Austin Maze performance in left versus right temporal lobe epilepsy.

Neuropsychological tests requiring patients to find a path through a maze can be used to assess visuospatial memory performance in temporal lobe pathology, particularly in the hippocampus. Alternatively, they have been used as a task sensitive to executive function in patients with frontal lobe damage. We measured performance on the Austin Maze in patients with unilateral left and right temporal lobe epilepsy (TLE), with and without hippocampal sclerosis, compared to healthy controls. Performance was correlated with a number of other neuropsychological tests to identify the cognitive components that may be associated with poor Austin Maze performance. Patients with right TLE were significantly impaired on the Austin Maze task relative to patients with left TLE and controls, and error scores correlated with their performance on the Block Design task. The performance of patients with left TLE was also impaired relative to controls; however, errors correlated with performance on tests of executive function and delayed recall. The presence of hippocampal sclerosis did not have an impact on maze performance. A discriminant function analysis indicated that the Austin Maze alone correctly classified 73.5% of patients as having right TLE. In summary, impaired performance on the Austin Maze task is more suggestive of right than left TLE; however, impaired performance on this visuospatial task does not necessarily involve the hippocampus. The relationship of the Austin Maze task with other neuropsychological tests suggests that differential cognitive components may underlie performance decrements in right versus left TLE.

Association between schizophrenia polygenic risk and neural correlates of emotion perception

The neural correlates of emotion perception have been shown to be significantly altered in schizophrenia (SCZ) patients as well as their healthy relatives, possibly reflecting genetic susceptibility to the disease. The aim of the study was to investigate the association between SCZ polygenic risk and brain activity whilst testing perception of multisensory, dynamic emotional stimuli. We created SCZ polygenic risk scores (PRS) for a sample of twenty-eight healthy individuals. The PRS was based on data from the Psychiatric Genomics Consortium and was used as a regressor score in the neuroimaging analysis. The results of a multivariate brain-behaviour analysis show that higher SCZ PRS are related to increased activity in brain regions critical for emotion during the perception of threatening (angry) emotions. These results suggest that individuals with higher SCZ PRS over-activate the neural correlates underlying emotion during perception of threat, perhaps due to an increased experience of fear or neural inefficiency in emotion-regulation areas. Moreover, over-recruitment of emotion regulation regions might function as a compensation to maintain normal emotion regulation during threat perception. If replicated in larger studies, these findings may have important implications for understanding the neurophysiological biomarkers relevant in SCZ.

Predicting Individual Psychotic Experiences on a Continuum Using Machine Learning

Previous studies of psychosis using machine learning methods have primarily been concerned with binary classification of patients and healthy controls. The aim of this study was to use electroencephalographic (EEG) data and pattern recognition to predict individual psychotic experiences on a continuum between these two extremes in otherwise healthy people. From responses evoked by an auditory oddball paradigm, behavioural measures, neural activity, and effective connectivity were extracted as potential contributing features. Optimal performance was achieved using spatiotemporal maps of neural activity in response to frequent sounds, with late-P50 and early-N100 time windows contributing most to higher schizotypy scores. Effective connectivity estimates, in particular top-down frontotemporal connections, were also predictive of psychotic symptoms. As a proof-of-concept, these findings demonstrate that individual psychotic experiences in healthy people can be predicted from EEG data alone, whilst also supporting the idea of altered sensory responses and the dysconnection hypothesis in schizophrenia, as well as the notion that psychosis may exist on a continuum.

Reduced top-down connectivity as an underlying mechanism for psychotic experiences in healthy people

Perception results from our brain’s ability to make predictive models of sensory information. Recently, it has been proposed that psychotic traits may be linked to impaired predictive processes. Here, we examine the brain dynamics underlying prediction formation in a population of healthy individuals with a range of psychotic experiences. We designed a novel paradigm, which incorporated both stable and volatile sound sequences by manipulating their probability. We measured prediction error with electroencephalography and gauged prediction formation explicitly by behaviourally recording sensory ‘regularity’ learning errors. Critically, we show that top-down frontotemporal connectivity may be a neural mechanism by which impaired regularity learning influences psychotic experiences. These findings further our understanding of the neurobiological underpinnings of prediction formation and provide evidence for a continuum of psychosis in the healthy, non-clinical population. One Sentence Summary Healthy individuals with psychotic experiences have impaired sensory learning, mediated by reduced top-down frontotemporal connectivity.Our perceptions result from the brains ability to make inferences, or predictive models, of sensory information. Recently, it has been proposed that psychotic traits may be linked to impaired predictive processes. Here, we examine the brain dynamics underlying sensory learning and inference in stable and volatile environments, in a population of healthy individuals (N=75) with a range of psychotic-like experiences. We measured prediction error responses to sound sequences with electroencephalography, gauged sensory inference explicitly by behaviourally recording sensory regularity learning errors, and used dynamic causal modelling to tap into the underlying neural circuitry. We discuss the findings that were robust to replication across the two experiments (N=31 and N=44 for the discovery and the validation datasets, respectively). First, we found that during stable conditions, participants demonstrated a stronger predictive model, reflected in a larger prediction error response to unexpected sounds, and decreased regularity learning errors. Moreover, individuals with attenuated prediction errors in stable conditions were found to make greater incorrect predictions about sensory information. Critically, we show that greater errors in sensory learning and inference are related to increased psychotic-like experiences. These findings link neurophysiology to behaviour during sensory learning and prediction formation, as well as providing further evidence for the idea of a continuum of psychosis in the healthy, non-clinical population.

Neural correlates of dynamic emotion perception in schizophrenia and the influence of prior expectations

Impaired emotion perception is a well-established and stable deficit in schizophrenia; however, there is limited knowledge about the underlying aberrant cognitive and brain processes that result in emotion perception deficits. Recent influential work has shown that perceptual deficits in schizophrenia may result from aberrant precision in prior expectations, associated with disrupted activity in frontal regions. In the present study, we investigated the perception of dynamic, multisensory emotion, the influence of prior expectations and the underlying aberrant brain processes in schizophrenia. During a functional Magnetic Resonance Imaging scan, participants completed the Dynamic Emotion Perception task, which induces prior expectations with emotion instruction cues. We delineated neural responses and functional connectivity in whole-brain large-scale networks underlying emotion perception. Compared to healthy individuals, schizophrenia patients had lower accuracy specifically for emotions that were congruent with prior expectations. At the neural level, schizophrenia patients had less engagement of right inferior frontal and parietal regions, as well as right amygdala dysconnectivity during discrimination of emotions congruent with prior expectations. The results indicate that individuals with schizophrenia may have aberrant prior expectations about emotional expressions, associated with under-activity in inferior frontoparietal regions and right amygdala dysconnectivity, which results in impaired perception of emotion.

Alteration of functional brain architecture in 22q11.2 deletion syndrome – Insights into susceptibility for psychosis

The 22q11.2 deletion is one of the most common copy number variants in humans. Carriers of the deletion have a markedly increased risk for neurodevelopmental brain disorders, including schizophrenia, autism spectrum disorders, and attention deficit hyperactivity disorder. The high risk of psychiatric disorders associated with 22q11.2 deletion syndrome offers a unique possibility to identify the functional abnormalities that precede the emergence of psychosis. Carriers of a 22q11.2 deletion show a broad range of sensory processing and cognitive abnormalities similar as in schizophrenia, such as auditory and visual sensory processing, response inhibition, working memory, social cognition, reward processing and arithmetic processing. All these processes have a significant negative impact on daily life if impaired and have been studied extensively in schizophrenia using task-based functional neuroimaging. Here, we review task-related functional brain mapping studies that have used electroencephalography or functional magnetic resonance imaging to identify functional alterations in carriers with 22q11.2 deletion syndrome within the above mentioned cognitive and sensory domains. We discuss how the identification of functional changes at the brain system level can advance the general understanding of which neurobiological alterations set the frame for the emergence of neurodevelopmental disorders in the human brain. The task-based functional neuroimaging literature shows conflicting results in many domains. Nevertheless, consistent similarities between 22q11.2 deletion syndrome and schizophrenia have been found for sensory processing, social cognition and working memory. We discuss these functional brain alterations in terms of potential biomarkers of increased risk for psychosis in the general population.