Maria Steffens

Genetics, Cognition, and Neurobiology of Schizotypal Personality: A Review of the Overlap with Schizophrenia

Schizotypy refers to a set of temporally stable traits that are observed in the general population and that resemble the signs and symptoms of schizophrenia. Here, we review evidence from studies on genetics, cognition, perception, motor and oculomotor control, brain structure, brain function, and psychopharmacology in schizotypy. We specifically focused on identifying areas of overlap between schizotypy and schizophrenia. Evidence was corroborated that significant overlap exists between the two, covering the behavioral brain structural and functional as well molecular levels. In particular, several studies showed that individuals with high levels of schizotypal traits exhibit alterations in neurocognitive task performance and underlying brain function similar to the deficits seen in patients with schizophrenia. Studies of brain structure have shown both volume reductions and increase in schizotypy, pointing to schizophrenia-like deficits as well as possible protective or compensatory mechanisms. Experimental pharmacological studies have shown that high levels of schizotypy are associated with (i) enhanced dopaminergic response in striatum following administration of amphetamine and (ii) improvement of cognitive performance following administration of antipsychotic compounds. Together, this body of work suggests that schizotypy shows overlap with schizophrenia across multiple behavioral and neurobiological domains, suggesting that the study of schizotypal traits may be useful in improving our understanding of the etiology of schizophrenia.

Functional magnetic resonance imaging of sensorimotor transformations in saccades and antisaccades

Saccades to peripheral targets require a direct visuomotor transformation. In contrast, antisaccades, saccades in opposite direction of a peripheral target, require more complex transformation processes due to the inversion of the spatial vector. Here, the differential neural mechanisms underlying sensorimotor control in saccades and antisaccades were investigated using functional magnetic resonance imaging (fMRI) at 3T field strength in 22 human volunteers. We combined a task factor (prosaccades: look towards target; antisaccades: look away from target) with a parametric factor of transformation demand (single vs. multiple peripheral targets) in a two-factorial block design. Behaviorally, a greater number of peripheral targets resulted in decreased spatial accuracy and increased reaction times in antisaccades. No effects were seen on the percentage of antisaccade direction errors or on any prosaccade measures. Neurally, a greater number of targets led to increased BOLD signal in the posterior parietal cortex (PPC) bilaterally. This effect was partially qualified by an interaction that extended into somatosensory cortex, indicating greater increases during antisaccades than prosaccades. The results implicate the PPC as a sensorimotor interface that is especially important in nonstandard mapping for antisaccades and point to a supportive role of somatosensory areas in antisaccade sensorimotor control, possibly by means of proprioceptive processes.

Neural mechanisms of smooth pursuit eye movements in schizotypy.

Patients with schizophrenia as well as individuals with high levels of schizotypy are known to have deficits in smooth pursuit eye movements (SPEM). Here, we investigated, for the first time, the neural mechanisms underlying SPEM performance in high schizotypy. Thirty‐one healthy participants [N = 19 low schizotypes, N = 12 high schizotypes (HS)] underwent functional magnetic resonance imaging at 3T with concurrent oculographic recording while performing a SPEM task with sinusoidal stimuli at two velocities (0.2 and 0.4 Hz). Behaviorally, a significant interaction between schizotypy group and velocity was found for frequency of saccades during SPEM, indicating impairments in HS in the slow but not the fast condition. On the neural level, HS demonstrated lower brain activation in different regions of the occipital lobe known to be associated with early sensory and attentional processing and motion perception (V3A, middle occipital gyrus, and fusiform gyrus). This group difference in neural activation was independent of target velocity. Together, these findings replicate the observation of altered pursuit performance in highly schizotypal individuals and, for the first time, identify brain activation patterns accompanying these performance changes. These posterior activation differences are compatible with evidence of motion processing deficits from the schizophrenia literature and, therefore, suggest overlap between schizotypy and schizophrenia both on cognitive‐perceptual and neurophysiological levels. However, deficits in frontal motor areas observed during pursuit in schizophrenia were not seen here, suggesting the operation of additional genetic and/or illness‐related influences in the clinical disorder. Hum Brain Mapp, 36:340–353, 2015.

Effects of ketamine on brain function during smooth pursuit eye movements

The uncompetitive NMDA receptor antagonist ketamine has been proposed to model symptoms of psychosis. Smooth pursuit eye movements (SPEM) are an established biomarker of schizophrenia. SPEM performance has been shown to be impaired in the schizophrenia spectrum and during ketamine administration in healthy volunteers. However, the neural mechanisms mediating SPEM impairments during ketamine administration are unknown. In a counter‐balanced, placebo‐controlled, double‐blind, within‐subjects design, 27 healthy participants received intravenous racemic ketamine (100 ng/mL target plasma concentration) on one of two assessment days and placebo (intravenous saline) on the other. Participants performed a block‐design SPEM task during functional magnetic resonance imaging (fMRI) at 3 Tesla field strength. Self‐ratings of psychosis‐like experiences were obtained using the Psychotomimetic States Inventory (PSI). Ketamine administration induced psychosis‐like symptoms, during ketamine infusion, participants showed increased ratings on the PSI dimensions cognitive disorganization, delusional thinking, perceptual distortion and mania. Ketamine led to robust deficits in SPEM performance, which were accompanied by reduced blood oxygen level dependent (BOLD) signal in the SPEM network including primary visual cortex, area V5 and the right frontal eye field (FEF), compared to placebo. A measure of connectivity with V5 and FEF as seed regions, however, was not significantly affected by ketamine. These results are similar to the deviations found in schizophrenia patients. Our findings support the role of glutamate dysfunction in impaired smooth pursuit performance and the use of ketamine as a pharmacological model of psychosis, especially when combined with oculomotor biomarkers. Hum Brain Mapp 37:4047–4060, 2016.

General and emotion-specific neural effects of ketamine during emotional memory formation

Abstract Animal studies suggest that N‐methyl‐D‐aspartate receptor (NMDAR) dependent signalling in limbic and prefrontal regions is critically involved in both cognitive and emotional functions. In humans, ketamine‐induced transient, and disorder associated chronic NMDAR hypofunction (i.e. in schizophrenia) has been associated with deficient performance in the domains of memory and higher‐order emotional functioning, as well as altered neural activity in the underlying limbic‐prefrontal circuits. To model the effects of NMDAR hypofunction on the integration of emotion and cognition the present pharmacological fMRI study applied the NMDAR antagonist ketamine (target plasma level=100 ng/ml) to 21 healthy volunteers in a within‐subject placebo‐controlled crossover design during encoding of neutral, positive and negative pictures. Our results show that irrespective of emotion, ketamine suppressed parahippocampal and medial prefrontal activity. In contrast, ketamine selectively increased amygdala and orbitofrontal activity during successful encoding of negative stimuli. On the network level ketamine generally increased medial prefrontal‐parahippocampal coupling while specifically decreasing amygdala‐orbitofrontal interplay during encoding of negative stimuli. On the behavioural level, ketamine produced generally decreased memory performance and abolished the emotional enhancement of memory after a wash‐out period of 5 days. The present findings suggest that ketamine produces general as well as valence‐specific effects during emotional memory formation. The pattern partly overlaps with alterations previously observed in patients with schizophrenia. HighlightsKetamine suppresses parahippocampal and prefrontal activity during encoding.Amygdala and orbitofrontal activity is increased for negative stimuli by ketamine.Ketamine generally increases medial prefrontal‐parahippocampal coupling.The general and emotion‐specific effects overlap with alterations in schizophrenia.

Facing competition: Neural mechanisms underlying parallel programming of antisaccades and prosaccades

The antisaccade task is a prominent tool to investigate the response inhibition component of cognitive control. Recent theoretical accounts explain performance in terms of parallel programming of exogenous and endogenous saccades, linked to the horse race metaphor. Previous studies have tested the hypothesis of competing saccade signals at the behavioral level by selectively slowing the programming of endogenous or exogenous processes e.g. by manipulating the probability of antisaccades in an experimental block. To gain a better understanding of inhibitory control processes in parallel saccade programming, we analyzed task-related eye movements and blood oxygenation level dependent (BOLD) responses obtained using functional magnetic resonance imaging (fMRI) at 3T from 16 healthy participants in a mixed antisaccade and prosaccade task. The frequency of antisaccade trials was manipulated across blocks of high (75%) and low (25%) antisaccade frequency. In blocks with high antisaccade frequency, antisaccade latencies were shorter and error rates lower whilst prosaccade latencies were longer and error rates were higher. At the level of BOLD, activations in the task-related saccade network (left inferior parietal lobe, right inferior parietal sulcus, left precentral gyrus reaching into left middle frontal gyrus and inferior frontal junction) and deactivations in components of the default mode network (bilateral temporal cortex, ventromedial prefrontal cortex) compensated increased cognitive control demands. These findings illustrate context dependent mechanisms underlying the coordination of competing decision signals in volitional gaze control.

Combining two model systems of psychosis: The effects of schizotypy and sleep deprivation on oculomotor control and psychotomimetic states

Model systems of psychosis, such as schizotypy or sleep deprivation, are valuable in informing our understanding of the etiology of the disorder and aiding the development of new treatments. Schizophrenia patients, high schizotypes, and sleep-deprived subjects are known to share deficits in oculomotor biomarkers. Here, we aimed to further validate the schizotypy and sleep deprivation models and investigated, for the first time, their interactive effects on smooth pursuit eye movements (SPEM), prosaccades, antisaccades, predictive saccades, and measures of psychotomimetic states, anxiety, depression, and stress. To do so, n = 19 controls and n = 17 high positive schizotypes were examined after both a normal sleep night and 24 h of sleep deprivation. Schizotypes displayed higher SPEM global position error, catch-up saccade amplitude, and increased psychotomimetic states. Sleep deprivation impaired SPEM, prosaccade, antisaccade, and predictive saccade performance and increased levels of psychotomimetic experiences. Additionally, sleep deprivation reduced SPEM gain in schizotypes but not controls. We conclude that oculomotor impairments are observed in relation to schizotypy and following sleep deprivation, supporting their utility as biomarkers in model systems of psychosis. The combination of these models with oculomotor biomarkers may be particularly fruitful in assisting the development of new antipsychotic or pro-cognitive drugs.

Association of Schizotypy With Dimensions of Cognitive Control: A Meta-Analysis

Schizotypy is defined as a time-stable multidimensional personality trait consisting of positive, negative, and disorganized facets. Schizotypy is considered as a model system of psychosis, as there is considerable overlap between the 2 constructs. High schizotypy is associated with subtle but fairly widespread cognitive alterations, which include poorer performance in tasks measuring cognitive control. Similar but more pronounced impairments in cognitive control have been described extensively in psychosis. We here sought to provide a quantitative estimation of the effect size of impairments in schizotypy in the updating, shifting, and inhibition dimensions of cognitive control. We included studies of healthy adults from both general population and college samples, which used either categorical or correlative designs. Negative schizotypy was associated with significantly poorer performance on shifting (g = 0.32) and updating (g = 0.11). Positive schizotypy was associated with significantly poorer performance on shifting (g = 0.18). There were no significant associations between schizotypy and inhibition. The divergence in results for positive, negative, and disorganized schizotypy emphasizes the importance of examining relationships between cognition and the facets of schizotypy rather than using the overall score. Our findings also underline the importance of more detailed research to further understand and define this complex personality construct, which will also be of importance when applying schizotypy as a model system for psychosis.

T18. MULTIVARIATE BRAIN ANATOMICAL DIFFERENCES IN POSITIVE AND NEGATIVE SCHIZOTYPY: PRELIMINARY RESULTS FROM THE TYPIA STUDY

Abstract Background In schizotypy, a factor structure similar to the one observed in schizophrenia has been unraveled, being the positive and negative the most consistently replicated dimensions. Despite this fact, most of the studies on brain volume patterns in schizotypy consider it as an unitary rather than a multidimensional construct. Hence, based on previous results showing that schizophrenia and schizotypal personality traits share common neurodevelopmental patterns, it is hypothesized that brain volumetric patterns in individuals with high positive schizotypy are intrinsically different to those observed in persons reporting high negative schizotypy and to individuals with overall low schizotypal traits. The present study aims to evaluate this hypothesis using novel machine learning techniques to address the multivariate nature of psychotic diseases and the brain itself. Methods Data from the TYPIA Study, an ongoing project conducted at the Ludwig-Maximilian University of Munich and the University of Bonn in Germany, was used to investigate whether brain volumetric patterns are distinct in healthy individuals with high positive (HPS) and high negative schizotypy (HNS) when compared to one another (HPS vs HNS) and to individuals with self-reported low schizotypy (LS vs HNS and LS vs HPS). A preliminary analysis on grey matter volumetric patterns from 29 LS (19 f., mean age: 24.6 y.), 28 HNS (20 f., mean age: 26.8 y.) and 23 HPS (17 f., mean age: 26.4 years) individuals from the general population without any current psychiatric diagnosis was performed. Group divisions were based on the introvertive anhedonia and unusual experiences subscales from the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE). Structural images were preprocessed with a standard voxel based morphometry pipeline using the SPM-based CAT12 toolbox in Matlab. After age, sex and grey matter intracranial volume and center corrections, a linear support vector classification (SVC) algorithm was used to assess separability between the groups. Results Our preliminary cross-validated results showed that LS and HNS can be separated with 56.0 % balanced accuracy (BAC), whereas LS vs HPS and HNS vs HPS allowed for only 42.87% and 48.8% BAC respectively. Interestingly, a post-hoc analysis comparing LS vs both high schizotypy groups merged together showed the highest BAC (59.2%). As expected, the brain differences between groups are rather small, since the sample consists fully of healthy controls. However, these results indicate that personality traits related to HNS are linked to more pronounced changes in the brain as compared to HPS. Nevertheless, schizotypy as a combination of the positive and negative dimensions allowed for a higher classification accuracy when compared to LS, supporting the notion of schizotypy as a unitary construct as observed from the post-hoc analysis. Furthermore, HNS and HPS were not separable by the algorithm, most likely due to the intrinsic heterogeneity of the construct. Discussion Our results align with previous studies claiming that negative symptoms are associated with structural changes in the CNS whereas positive symptoms relate to changes in functioning and activation of the brain. A larger sample as well as using other data modalities will confirm the stability of our findings. Research on volumetric patterns of the brain areas related to negative symptoms in non-clinical samples might lead to a better understanding of the underlying causes of schizophrenia. Above all, our results show that investigating non-clinical expression of psychosis-like symptoms is a promising strategy to understand the prodromal stadium of schizophrenia.

Combining trait and state model systems of psychosis: The effect of sleep deprivation on cognitive functions in schizotypal individuals

Model systems of psychosis play an important role in pathophysiology and drug development research. Schizotypal individuals display similar cognitive impairments as schizophrenia patients in several domains. Therefore, schizotypy may be interpreted as a trait model system of psychosis. In addition, experimentally controlled sleep deprivation is a putative state psychosis model that evokes subclinical psychosis-like states. We aimed to further validate these model systems by examining them in relation to central cognitive biomarkers of schizophrenia. Most of all, we were interested in investigating, for the first time, effects of their combination on cognitive function. Healthy subjects with high (N = 17) or low (N = 19) levels of schizotypy performed a cognitive task battery after one night of normal sleep and after 24 h of sleep deprivation. Sleep deprivation impaired performance in the go/nogo and n-back tasks relative to the normal sleep control condition. No differences between groups or interactions of group with sleep condition were found. The role of sleep deprivation as a model of psychosis is thus supported to some extent by impairments in inhibitory control. However, classical measures of cognition may be less able to detect deficits in schizotypy, in line with evidence of more basic information processing dysfunctions in schizotypy.