On the Relation of White Matter Brain

RESEARCH PAPER Acta Neurobiol Exp 2021, 81: 80–95 DOI: 10.21307/ane‑2021‑009 On the relation of white matter brain abnormalities and the asociality symptoms in schizophrenia outpatients – a DTI study Przemysław Adamczyk1*, Olga Płonka1, Dawid Kruk2,4, Martin Jáni1,3, Piotr Błądziński4, Aneta Kalisz4, Stynke Castelein5,6, Andrzej Cechnicki2,4 and Miroslaw Wyczesany1 1 Institute of Psychology, Jagiellonian University, Krakow, Poland, 2 Psychosis Research and Psychotherapy Unit, Association for the Development of Community Psychiatry and Care, Krakow, Poland, 3 Department of Psychiatry, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czech Republic, 4 Community Psychiatry and Psychosis Research Center, Chair of Psychiatry, Medical College, Jagiellonian University, Krakow, Poland, 5 Lentis Research, Lentis Psychiatric Institute, Groningen, The Netherlands, 6 Faculty of Behavioural and Social Sciences, University of Groningen, Groningen, The Netherlands, * Email: [email protected] The study was conducted by the Krakow Schizophrenia Research Group, Krakow, Poland Recent MRI studies have shown that abnormal functional connections in schizophrenia coexist with subtle changes in the structure of axons in the brain. However, there is a discrepancy in the literature concerning the relationship between white matter abnormalities and the occurrence of negative psychopathological symptoms. In the present study, we investigate the relationship between the altered white matter structure and specific psychopathology symptoms, i.e., subscales of Positive and Negative Syndrome Scale (PANSS) and Brief Negative Symptoms Scale (BNSS) in a sample of schizophrenia outpatients. For investigation on white matter abnormalities in schizophrenia, the diffusion tensor imaging analysis of between‑group differences in main diffusion parameters by tract‑based spatial statistics was conducted on schizophrenia outpatients and healthy controls. Hence, the correlation of PANSS and BNSS psychopathology subscales in the clinical group with fractional anisotropy was analyzed in the 17 selected cortical regions of interest. Presented between‑group results revealed widespread loss of white matter integrity located across the brain in schizophrenia outpatients. Results on the white matter relationship with psychopathology revealed the negative correlation between fractional anisotropy in the left orbital prefrontal cortex, right Heschl’s gyrus, bilateral precuneus and posterior cingulate cortex and the severity of asociality, as assessed with the BNSS. In conclusion, the presented study confirms the previous evidence on the widespread white matter abnormalities in schizophrenia outpatients and indicates the existence of the subtle but specific association between fractional anisotropy in the fronto‑temporo‑parietal regions with the asociality. Key words: schizophrenia, diffusion tensor imaging, white matter, negative symptoms, psychopathology INTRODUCTION Friston et al., 2016), where neuropathology of schizo‑ phrenia points at abnormal functional connections as‑ The brain origins of psychotic symptoms, known as sociated with subtle changes in the structure of axons Kraepelin’s ‘dementia praecox’, were further indicated located across the brain. by Bleuer as an essential disintegration of mental pro‑ Recent evidence implicates that altered white mat‑ cesses in schizophrenia (Jablensky, 2010). Nowadays, it ter (WM) structure in schizophrenia can be regarded © 2021 by Acta Neurobiologiae Experimentalis © 2021 by Acta Neurobiologiae resonates with the disconnection theory (Friston, 2002; as a long‑term effect of disturbed myelinogenesis, e.g. Received 11 September 2020, accepted 29 January 2021 Acta Neurobiol Exp 2021, 8181: 80–95 White matter abnormalities in schizophrenia 81 lower levels of oligodendrocyte‑ and myelin‑related (AD), regarded as the index of axonal damage; radial proteins (Cassoli et al., 2015; Schoonover et al., 2019), diffusivity (RD), a measure of the level of myeliniza‑ but also as a consequence of excitotoxicity, cytoskele‑ tion (Karlsgodt, 2016); mean diffusivity (MD), consid‑ tal abnormalities (Uranova et al., 2004) or disturbanc‑ ered a complex measure of the surrounding cytoarchi‑ es in neurogenesis, e.g. weakened synaptic pruning tecture (Emsell et al., 2016). (Alba‑Ferrara and de Erausquin, 2013; Klauser et al., Recent data undoubtedly indicate the existence of 2016). Finally, the abnormal structural connectivity abnormal WM structure in schizophrenia (Kelly et al., and microstructural changes on synapses lead to the 2018; Koshiyama et al., 2020). In particular, a recent functional disturbances and manifestation of psycho‑ meta‑analysis of 29 DTI studies in schizophrenia, in‑ pathological symptoms related to schizophrenia (Fris‑ cluding 1963 patients, showed differences in the diffu‑ ton 2002; Friston et al., 2016). sion parameters between clinical and healthy subjects Apart from positive symptoms (e.g. hallucinations, in 20 tracts in total, indicating the WM alterations in delusions, paranoid thoughts) and various socio‑cog‑ schizophrenia are widespread and affecting the ma‑ nitive deficiencies, negative symptoms (i.e., alogia, jority of fiber bundles in the brain, with the greatest apathy, avolition, anhedonia, asociality, blunted af‑ effect size in the corpus callosum and the anterior co‑ fect, and poverty of speech) remain as an extremely rona radiate (Kelly et al., 2018). Other research consis‑ important hallmark of the diagnosis and considered tently revealed that WM abnormalities were detected a core feature of schizophrenia. Indeed, negative in different structures, in various groups of patients symptoms are believed to be the most stable char‑ (e.g. medication naïve, after the first episode, chron‑ acteristics for schizophrenia psychopathology (An‑ ic) and WM alteration has a potential to be a biomark‑ dreasen, 1982; Harrow and Jobe, 2018), and social an‑ er used as a diagnostic criterion, even in a prodromal hedonia is recognized as a predictor of later schizo‑ stage of the illness (Pettersson‑Yeo et al., 2011; Al‑ phrenia spectrum disorder development in young ba‑Ferrara and de Erausquin, 2013). adults (Kwapil, 1998). Yet, regarding the existing DTI studies on the However, despite long and extensive clinical re‑ structural biomarkers of the negative symptoms in search on negative symptoms, the effectiveness of its schizophrenia, the observed inconsistency of the re‑ treatment remains at the pretty unsatisfactory level sults could be due to the high heterogeneity of clin‑ of low to moderate, while its neural basis remains ical images between schizophrenic individuals. The largely unknown (Kaiser et al., 2011; Asami et al., 2014; lack of application of detailed clinical assessment of Bijanki et al., 2015; Garcia‑Portilla et al., 2015; Shaffer specific negative symptoms is also one of the most et al., 2015; İnce and Üçok 2018; Strauss et al., 2018; important issues. Kochunov et al., 2019). First of all, two clinical tools were commonly Hence, the investigation on biomarkers of this phe‑ used in a majority of DTI research in schizophrenia nomenon, including structural changes in brain con‑ the Scale for the Assessment of Negative Symptoms nectivity, that affect various aspects of brain function‑ (SANS, Andreasen 1982) or the negative subscale of ing is of great importance, as the occurrence of nega‑ the Positive and Negative Symptoms Scale (PANSS, tive symptoms has a destructive impact on individual Kay et al., 1987; van der Gaag et al., 2006; Liemburg functioning in schizophrenia (e.g. occupational impair‑ et al., 2013; Stiekema et al., 2016). In brief, most of ment, financial dependence, poor social relationships the studies involving these scales find no association and worse quality of life) and remains one of the most between their scores and reduced WM integrity, i.e., important scientific and societal problems related to lower FA values (Fujiwara et al., 2007; Skelly et al., schizophrenic psychosis remediation (Kaiser et al., 2008; Abdul‑Rahman et al., 2011; Choi et al., 2011; Yan 2011; Bijanki et al., 2015; Dollfus and Lyne 2017; Correll et al., 2012; Kelly et al., 2018), whereas some find neg‑ and Schooler, 2020). ative (Whitford et al., 2014; Balevich et al., 2015; Ochi Recently, analyses of WM alterations in the schizo‑ et al., 2020) or positive associations (Camchong et al., phrenic brain are performed using diffusion tensor 2011; Bijanki et al., 2015). imaging (DTI). DTI is based on the estimation of the Furthermore, in some studies (Balevich et al., 2015; diffusion of water molecules in tissues as this allows Sun et al., 2015) clinical assessment did not seem to be a reconstruction of images of brain fibers’ cytoarchi‑ prioritized, as the calculated associations were provided tecture (Emsell et al., 2016). One of the most widely only between a total score of each scale, instead of cor‑ used DTI measurements is fractional anisotropy (FA), relations between particular subscales. The specific which is generally interpreted as a biomarker of the investigations on the relationships between diffusion integrity of WM bundles (Assaf and Pasternak, 2008). parameters and clinical subscales or even single items Other commonly used parameters are axial diffusivity concerning negative symptoms are still scarce. 82 Adamczyk et al. Acta Neurobiol Exp 2021, 81: 80–95 Pieces of evidence indicate that lower FA in the left authors emphasize that the use of specialized scales frontal lobe were related

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