Structural alterations of the pyramidal pathway in schizoid and schizotypal cluster A personality disorders

Highlights

• Brain structure was studied in subjects with schizoid/schizotypal personality disorders.

• Greater white matter volume was found in the corona radiata and pyramidal tract.

• Differences remained for each group alone compared with controls.

• O-LIFE cognitive disorganization scores were associated with white matter changes.

• Alterations in motor pathways might be a biomarker for negative-like symptoms.

Abstract

Aim

Schizoid (ScPD) and Schizotypal (SPD) personality disorders are rare and severe disorders. They are associated with high liability to schizophrenia and present an attenuated form of its negative symptoms, which are considered a putative endophenotype for schizophrenia. The trans-diagnostic study of negative symptoms in non-psychotic populations such as ScPD/SPD might provide useful markers of a negative-symptom domain; however, little is known about their neurobiological substrates. The aim of the study was to investigate differences in gray and white matter volumes in subjects with ScPD/SPD compared to a group of healthy controls.

Methods

Structural magnetic resonance images were obtained from 20 never-psychotic subjects with ScPD/SPD and 28 healthy controls. Resulting values from clusters of differences were correlated in patients with relevant clinical variables (O-LIFE scale).

Results

ScPD/SPD presented greater bilateral white matter volume compared to healthy controls in the superior part of the corona radiata, close to motor/premotor regions, which correlated with the O-LIFE subtest of cognitive disorganization. No differences were found in regional gray matter or global gray/white matter volumes.

Conclusion

Greater volumes in motor pathways might relate to cognitive symptoms and motor alterations commonly present in schizophrenia-related disorders. Given the established link between motor signs and psychosis, structural alterations in motor pathways are suggested as a putative biomarker of a negative-symptom domain in psychosis subject to further testing.

Introduction

Schizoid (ScPD) and schizotypal (SPD) personality disorders - together with paranoid personality disorder - are clustered within the group A of personality disorders, and are characterized by an eccentric and odd behavior - including suspiciousness and odd and paranoid ideas - as well as general deficits in interpersonal relationships, such as isolation and social anhedonia (American Psychiatric Association, 2013). They have low prevalence in the general population (ScPD: < 1%, SPD: 3–4%) (Grant et al., 2004, Johnson et al., 2000, Weissman, n.d), but are severe disorders (Esterberg et al., 2010), highly resistant to treatment (Thorne, 2001). In addition, they are considered closely related to schizophrenia because of the frequent presence of such personality traits prior to schizophrenia onset, the frequent comorbid association with schizophrenia, and the high transition rate to psychotic disorders (Bleuer, 1950, Bolinskey et al., 2015, Hoch, 1910, Nestadt et al., 1994, Niemi et al., 2005). For example, a study performed in a sample of patients with schizophrenia found that 85% of subjects showed premorbid personality disorders, including ScPD (27.5%) and SPD (12.5%) (Rodríguez Solano and González De Chávez, 2000). Other studies found either a 4.7- or a 3-fold increase of comorbid schizophrenia or a psychotic episode in SPD and ScPD, respectively, as well as a transition to psychosis between 25% to 48% in SPD or a higher presence of ScPD traits in at-high-risk schizophrenia converters (Odds Ratio = 1.69) (Asarnow, 2005, Esterberg et al., 2010, Nordentoft et al., 2006, Schultze-Lutter et al., 2012). Moreover, the common genetic influences and the familial relationship found between these disorders (American Psychiatric Association, 2013, Kendler and Baker, 2007, Kendler et al., 1993), as well as the phenomenological parallelism between cluster A personality clinical features and those observed in schizophrenia and its prodromal state (Esterberg et al., 2010, Kendler et al., 1993), give further support to the idea of shared genetic and environmental risk factors. To date, however, only SPD has been considered as part of the schizophrenia spectrum in DSM 5 (American Psychiatric Association, 2013).

Nevertheless, subjects with ScPD or SPD are considered a diluted form – subclinical symptom expression – of the schizophrenia phenotype (Lenzenweger, 2013) and typically present some traits which are similar to some of the negative symptoms of schizophrenia (i.e., affective flattering, diminished emotional expression, avolition, social cognitive deficits), although SPD also present cognitive-perceptual experiences characteristic of the positive ones (American Psychiatric Association, 2013, Esterberg et al., 2010). Negative-like symptoms have been scarcely studied in ScPD/SPD, but widely evaluated in schizophrenic patients, showing a tendency to persist longer than positive symptoms, and being not only resistant to treatment (Alphs, 2006) but also predictors of worse prognosis (Breier et al., 1991) and poor global functioning (Breier et al., 1991, Milev et al., 2005). Interestingly, negative symptoms such as depression, motor signs and difficulties in social relationships seem to be present prior to the first psychotic episode, and possibly associated with prior personality traits (Donnoli et al., 1995, Esterberg et al., 2010, Häfner et al., 1999). Moreover, they are also present in healthy at-high risk populations and are considered a putative endophenotype - a marker of disease liability - of schizophrenia (Gottesman and Gould, 2003, Lenzenweger, 2013, Mackowick et al., 2014). Thus, the study of SPD and ScPD offer the opportunity of studying trans-diagnostic negative symptoms and their biological substrate.

However, neurobiological bases of SPD and ScPD have been insufficiently studied, and most studies have focused on SPD samples, reporting both increases and decreases in regional gray and white matter volumes. Gray matter decreases have been observed in regions of the inferior, middle and superior temporal cortex - BA20, BA21 and BA22 (Hazlett et al., 2008) - , the parahippocampus - (Dickey et al., 2007, Mitropoulou et al., 2005, Siever and Davis, 2004, Voglmaier et al., 1997), and, less consistently, in areas of the frontal lobe (premotor cortex and left inferior and right superior prefrontal areas) (Kawasaki et al., 2004, Koo et al., 2006) and the cingulate gyrus (Siever and Davis, 2004). Similar results have been observed in healthy subjects with high versus low schizotypy scores at the level of frontal and temporal regions (DeRosse et al., 2015). Remarkably, some of these alterations have been also reported in schizophrenia (Suzuki et al., 2005), and have been associated with negative symptoms in both conditions (Hazlett et al., 2008), suggesting the existence of a continuum of structural alterations linking SPD with schizophrenia (Hazlett et al., 2008). Conversely, gray matter increases have been found in other prefrontal regions (frontopolar cortex - BA10 - and middle frontal gyrus (Hazlett et al., 2008, Suzuki et al., 2005)) in SPD patients in comparison to healthy controls and schizophrenic patients, which have been suggested to be a resilience marker, protecting SPD patients from the development of psychotic symptoms and schizophrenia (Hazlett et al., 2012). Lastly, although white matter alterations have been less studied, the few existing diffusion tensor imaging studies suggested similar results, with alterations in prefrontal, temporal and cingulate cortices, a pattern of alteration similar, albeit less marked, to that found in schizophrenia (DeRosse et al., 2015, Hazlett et al., 2012).

Therefore, the study of structural alterations in ScPD/SPD might provide information relevant to understanding negative-like symptoms in the schizophrenia spectrum and related disorders, as well as putative neurobiological markers. However, structural studies in SPD and ScPD have been scarce, probably due to their low prevalence and the low disease insight of affected subjects (Thorne, 2001). The objective of this study was to investigate differences in regional gray and white matter volumes in a group of subjects with SPD and ScPD compared to healthy controls. Subjects with paranoid personality - included in the Cluster A of personality disorders but more associated with the presence of positive-like symptoms - were excluded in order to obtain a more homogeneous sample from a phenomenological point of view. In view of previous studies, we hypothesized gray/white matter volume increases in prefrontal regions and/or volume decreases in temporal/cingulate areas. In addition, we also aimed at exploring the association between putative volume alterations and a measure of dysfunctional personality traits.