Iveta Fajnerová

Bridging disparate symptoms of schizophrenia: a triple network dysfunction theory.

Schizophrenia is a complex neuropsychiatric disorder with variable symptomatology, traditionally divided into positive and negative symptoms, and cognitive deficits. However, the etiology of this disorder has yet to be fully understood. Recent findings suggest that alteration of the basic sense of self-awareness may be an essential distortion of schizophrenia spectrum disorders. In addition, extensive research of social and mentalizing abilities has stressed the role of distortion of social skills in schizophrenia.This article aims to propose and support a concept of a triple brain network model of the dysfunctional switching between default mode and central executive network (CEN) related to the aberrant activity of the salience network. This model could represent a unitary mechanism of a wide array of symptom domains present in schizophrenia including the deficit of self (self-awareness and self-representation) and theory of mind (ToM) dysfunctions along with the traditional positive, negative and cognitive domains. We review previous studies which document the dysfunctions of self and ToM in schizophrenia together with neuroimaging data that support the triple brain network model as a common neuronal substrate of this dysfunction.

Two learning tasks provide evidence for disrupted behavioural flexibility in an animal model of schizophrenia-like behaviour induced by acute MK-801: a dose-response study.

Schizophrenia is a chronic and devastating illness. Exact causes of the disease remain elusive; however, neurodevelopmental changes in the brain glutamate system are recognized to play an important role. Several animal models of the disease are induced by a systemic blockade of N-methyl-d-aspartate (NMDA) receptors. This study examined the animal model of schizophrenia-like behaviours induced by acute treatment with MK-801, a non-competitive NMDA-receptor antagonist. Behavioural flexibility is an ability to adapt to the changes in environment, and schizophrenia is often accompanied by its decrease. The study tested the effect of MK-801 on behavioural flexibility in an active place avoidance task and the Morris water maze (MWM). Flexibility was tested under reversal conditions, i.e., after changing the location of the target. Each spatial task addressed different functions; continuous coordinate-frame segregation was present in the active place avoidance and precise place representation in the MWM. Results showed that reversal was altered in both tasks by MK-801 at doses of 0.10-0.15 mgkg(-1). Some impairment was observed in the active place avoidance task at 0.08 mgkg(-1). Swimming towards a visible platform was impaired only by the highest dose (0.15 mgkg(-1)). The results demonstrate that a significant impairment of behavioural flexibility accompanies this acute animal model of schizophrenia-like behaviours, and that active place avoidance had higher sensitivity for such deficits than the MWM. This suggests the usefulness of the reversal paradigm in both tasks for examining novel drugs with antipsychotic and procognitive actions.

A virtual reality task based on animal research – spatial learning and memory in patients after the first episode of schizophrenia

Objectives: Cognitive deficit is considered to be a characteristic feature of schizophrenia disorder. A similar cognitive dysfunction was demonstrated in animal models of schizophrenia. However, the poor comparability of methods used to assess cognition in animals and humans could be responsible for low predictive validity of current animal models. In order to assess spatial abilities in schizophrenia and compare our results with the data obtained in animal models, we designed a virtual analog of the Morris water maze (MWM), the virtual Four Goals Navigation (vFGN) task. Methods: Twenty-nine patients after the first psychotic episode with schizophrenia symptoms and a matched group of healthy volunteers performed the vFGN task. They were required to find and remember four hidden goal positions in an enclosed virtual arena. The task consisted of two parts. The Reference memory (RM) session with a stable goal position was designed to test spatial learning. The Delayed-matching-to-place (DMP) session presented a modified working memory protocol designed to test the ability to remember a sequence of three hidden goal positions. Results: Data obtained in the RM session show impaired spatial learning in schizophrenia patients compared to the healthy controls in pointing and navigation accuracy. The DMP session showed impaired spatial memory in schizophrenia during the recall of spatial sequence and a similar deficit in spatial bias in the probe trials. The pointing accuracy and the quadrant preference showed higher sensitivity toward the cognitive deficit than the navigation accuracy. Direct navigation to the goal was affected by sex and age of the tested subjects. The age affected spatial performance only in healthy controls. Conclusions: Despite some limitations of the study, our results correspond well with the previous studies in animal models of schizophrenia and support the decline of spatial cognition in schizophrenia, indicating the usefulness of the vFGN task in comparative research.

Visuospatial working memory is impaired in an animal model of schizophrenia induced by acute MK-801: An effect of pretraining

Deficient working memory was proposed as an endophenotype of schizophrenia. Such deficits are also commonly found in animal models of schizophrenia-like behavior of various origins. An allothetic place avoidance alternation task was proposed as a behavioral test of visuospatial working memory. This study tested the hypothesis that working memory in this test would be impaired by acute pre-test treatment with MK-801 (dizocilpine) in an animal model possessing high phenomenological and predictive validity. Furthermore, the study sought to determine the effect of pretraining to the task prior to treatment on the subsequent learning in the animal model. The results show that both doses of MK-801 (0.12 mg/kg and 0.15 mg/kg) significantly impaired working memory in the alternation paradigm, and both doses also increased locomotor activity. Notably, in previously pretrained animals, the significant effect of MK-801 on working memory was absent, despite persistent hyperlocomotion. These results showed that a deficit in working memory was detectable in this animal model of schizophrenia-like behavior, but its occurrence depended on the previous experience of animals with familiarization in the task.

Comparison of Visuospatial and Verbal Abilities in First Psychotic Episode of Schizophrenia Spectrum Disorder: Impact on Global Functioning and Quality of Life

Objectives: Deficit in visuospatial functions can influence both simple and complex daily life activities. Despite the fact that visuospatial deficit was reported in schizophrenia, research on visuospatial functions as an independent entity is limited. Our study aims to elucidate the impact of visuospatial deficit in comparison with verbal deficit on global functioning and quality of life in the first psychotic episode of schizophrenia spectrum disorder (FES). The significance of clinical symptoms and antipsychotic medication was also studied. Methods: Thirty-six FES patients and a matched group of healthy controls (HC group) were assessed with a neuropsychological battery focused on visuospatial (VIS) and verbal (VERB) functions. Using multiple regression analysis, we evaluated the cumulative effect of VERB and VIS functions, psychiatric symptoms (PANSS) and antipsychotic medication on global functioning (GAF) and quality of life (WHOQOL-BREF) in the FES group. Results: The FES group demonstrated significant impairment both in VIS and VERB cognitive abilities compared to the HC group. Antipsychotic medication did not significantly affect either VIS or VERB functioning. PANSS was not related to cognitive functioning, apart from the Trail Making Test B. In the FES group, the GAF score was significantly affected by the severity of positive symptoms and VERB functioning, explaining together 60% of GAF variability. The severity of negative and positive symptoms affected only the Physical health domain of WHOQOL-BREF. The degree of VERB deficit was associated with both Physical and Psychological health. Although we did not find any relation between VIS functioning, GAF, and WHOQOL-BREF, a paradoxical finding emerged in the Environment quality domain, where a worse quality of the environment was associated with better VIS functioning. Conclusions: Our results suggest that the deficit in VIS functions is an integral part of cognitive deficit in schizophrenia spectrum disorders, rather than a side effect of symptomatology or antipsychotic medication. Moreover, VERB functioning was a better predictor of GAF and WHOQOL-BREF than VIS functioning. Given the findings of negative or missing effect of VIS deficit on WHOQOL-BREF and GAF, the accuracy of these measures in evaluating the impact of global cognitive deficit on everyday life in schizophrenia could be questioned.

Can rats solve the active place avoidance task without the room-bound cues?

The active place avoidance task is used in the research of spatial cognition. Rats are trained on a rotating arena to avoid an aversive stimulus delivered in a part of the room while being transported toward it by the arena rotation. The task tests the ability of rats to navigate with respect to distal cues in the room and to ignore confusing cues on the arena. The demand for cue segregation makes the task suitable for studying neural mechanisms responsible for cognitive coordination. An incidental observation made in our laboratory implied that overtrained rats may be able to solve the task without the room-bound cues. The aim of this study was to test this observation. The room-bound cues were hidden by switching off the lights. Rats trained only in darkness did not learn the task at all. Rats that were initially pre-trained in light performed considerably better. In a few exceptional dark sessions they even reached the level of performance observed in light. The rats needed the aversive stimuli to keep off the to-be-avoided sector. Without them, they continued their behavior, but with no spatial relationship to the to-be-avoided sector. We conclude that rats are able to solve the place avoidance task without the room-bound cues, but not as efficiently as in their presence.

Acute systemic MK-801 induced functional uncoupling between hippocampal areas CA3 and CA1 with distant effect in the retrosplenial cortex

The hippocampus and retrosplenial cortex are integrated within a higher‐order cognitive circuit supporting relational (spatial, contextual, episodic) forms of learning and memory. Hippocampal place cells can coordinate multiple parallel representations in the same physical environment. Novel environment exploration triggers expression of immediate‐early genes (IEGs) Arc and Homer1a in spatial context‐specific ensembles of CA1 and CA3 neurons. Less is know about ensemble coding in the retrosplenial cortex (RSC), a region directly connected and functionally coupled to CA1. Hippocampal and retrosplenial damage is found in patients with schizophrenia alongside cognitive deficits affecting relational memory. Systemic administration of non‐competitive NMDAR antagonists such as MK‐801 is used to model psychosis in animals and humans. Acute systemic MK‐801 (0.15 mg/kg) impaired cognitive control in rats and ensemble code for spatial context in CA1. Here, we use expression of immediate‐early genes Arc and Homer 1a to examine ensemble coding in rat CA3 and RSC to test if the effect of MK‐801 extends upstream and downstream of CA1, respectively. Different rats explored the same context twice (A/A), explored two distinct contexts (A/B) or remained in their home cage (CC). In contrast to CA1, MK‐801 did not affect ensemble coding in CA3. Unlike CA3 and CA1, similarity of RSC ensembles active during exploration did not reflect change in spatial context, but MK‐801 (0.15 mg/kg) increased similarity in RSC ensembles active during spontaneous behavior in the home cage. The data provide support for MK‐801‐induced functional uncoupling between CA3 and CA1 and suggest that ensemble coding deficit may extend downstream of CA1. This deficit may reflect hyperassociative state in the cognitive circuit underlying cognitive disorganization in psychosis.

Spatial knowledge impairment after GPS guided navigation: Eye-tracking study in a virtual town

Abstract There is a vibrant debate about consequences of mobile devices on our cognitive capabilities. Use of technology guided navigation has been linked with poor spatial knowledge and wayfinding in both virtual and real world experiments. Our goal was to investigate how the attention people pay to the GPS aid influences their navigation performance. We developed navigation tasks in a virtual city environment and during the experiment, we measured participants’ eye movements. We also tested their cognitive traits and interviewed them about their navigation confidence and experience. Our results show that the more time participants spend with the GPS-like map, the less accurate spatial knowledge they manifest and the longer paths they travel without GPS guidance. This poor performance cannot be explained by individual differences in cognitive skills. We also show that the amount of time spent with the GPS is related to participant’s subjective evaluation of their own navigation skills, with less confident navigators using GPS more intensively. We therefore suggest that despite an extensive use of navigation aids may have a detrimental effect on person’s spatial learning, its general use is modulated by a perception of one’s own navigation abilities.

Do Personality Features Influence Our Intuitions of the Mind-Body Problem? A Pilot Study

The elusive relationship between the mental domain and the physical brain, known as the mind-body problem, is still a hot topic of discussion among philosophers and neuroscientists. Rather than solving this problem, our pilot study addresses the question as to whether personality features could influence intuitions of the mind-body problem, or more precisely, whether it is possible to identify a person’s intuitive inclinations toward dualism or materialism and their inclinations toward reduction of the mind to the brain. For the purposes of this pilot study, we developed a questionnaire, which employed several theories of analytic philosophy of the mind, in order to determine which category the participants would belong to. These main categories were dualism, non-reductive materialism and reductive materialism. To test whether personality features affect preferences for these categories, the participants were investigated by Cloninger’s Temperament and Character Inventory (TCI). We found significant differences in the self-transcendence dimension of the TCI between participants who were evaluated as dualists and those who were assessed as reductive materialists. Our data show that the personality dimension of self-transcendence correlates with intuitive inclination toward reductive materialism or dualism. In addition, our results suggest that ideas, theories, and hypothetical solutions of the mind-body problem and possibly even conclusions, acceptance, and disputations of thought experiments of philosophy of the mind can be biased by personality traits. This fact should be taken into account in future discussions of the philosophy of the mind and may also be important for empirical research and an empirical understanding of the mind.

Theoretical modelling of cognitive dysfunction in schizophrenia by means of errors and corresponding brain networks

The current evidence of cognitive disturbances and brain alterations in schizophrenia does not provide the plausible explanation of the underlying mechanisms. Neuropsychological studies outlined the cognitive profile of patients with schizophrenia, that embodied the substantial disturbances in perceptual and motor processes, spatial functions, verbal and non-verbal memory, processing speed and executive functioning. Standardized scoring in the majority of the neurocognitive tests renders the index scores or the achievement indicating the severity of the cognitive impairment rather than the actual performance by means of errors. At the same time, the quantitative evaluation may lead to the situation when two patients with the same index score of the particular cognitive test, demonstrate qualitatively different performances. This may support the view why test paradigms that habitually incorporate different cognitive variables associate weakly, reflecting an ambiguity in the interpretation of noted cognitive constructs. With minor exceptions, cognitive functions are not attributed to the localized activity but eventuate from the coordinated activity in the generally dispersed brain networks. Functional neuroimaging has progressively explored the connectivity in the brain networks in the absence of the specific task and during the task processing. The spatio-temporal fluctuations of the activity of the brain areas detected in the resting state and being highly reproducible in numerous studies, resemble the activation and communication patterns during the task performance. Relatedly, the activation in the specific brain regions oftentimes is attributed to a number of cognitive processes. Given the complex organization of the cognitive functions, it becomes crucial to designate the roles of the brain networks in relation to the specific cognitive functions. One possible approach is to identify the commonalities of the deficits across the number of cognitive tests or, common errors in the various tests and identify their common “denominators” in the brain networks. The qualitative characterization of cognitive performance might be beneficial in addressing diffuse cognitive alterations presumably caused by the dysconnectivity of the distributed brain networks. Therefore, in the review, we use this approach in the description of standardized tests in the scope of potential errors in patients with schizophrenia with a subsequent reference to the brain networks.