Neurological soft signs predict abnormal cerebellar-thalamic tract development and negative symptoms in adolescents at high risk for psychosis: a longitudinal perspective

Abstract

Introduction: There is an emerging consensus that neurological soft signs (NSS) may not be "soft" at all but rather may reflect neuropathy, particularly in the cerebellum and thalamus. However, our understanding of connective tract abnormalities is limited, and to date, there have been no investigations examining NSS and longitudinal white matter development during the prodrome. Mapping the correlates of NSS in ultrahigh-risk (UHR) youth offers potential for highlighting a viable biomarker as well as for advancing understanding of pathogenic processes during the adolescent risk period.

Methods: A total of 68 (33 UHR and 35 healthy control) adolescents were assessed with an NSS inventory, structured interviews, and diffusion tensor imaging. Fractional anisotropy (FA) of theoretically relevant cerebellar-thalamic tracts was calculated (left/right superior cerebellar peduncles [SCPs]). Twelve months later, a subset of 30 (15 UHR and 15 control) participants returned for follow-up diffusion tension imaging/clinical assessments.

Results: UHR youth exhibited elevated NSS across domains. While there were no group differences in the integrity of the SCPs at baseline, controls showed a normative increase while the UHR group showed a decrease in FA over 12 months. NSS predicted a longitudinal decrease in cerebellar-thalamic FA and elevations in negative but not positive symptoms 12 months later.

Discussion: Findings of abnormal white matter development provide direct empirical evidence to support prominent neurodevelopmental theories. The predictive relationships between NSS and longitudinal cerebellar-thalamic tract integrity and negative symptom course provide insight into the role of cognitive dysmetria in the high-risk period and inform on a unique biomarker tied to core features underlying psychosis.

Keywords: DTI; UHR; cognitive dysmetria; neurological soft signs; prodrome; psychosis; superior cerebellar peduncle.

Fig. 1.

Superior cerebellar peduncle (SCP). Note: target regions of interest include the left and right SCPs (shown in red). The SCPs represent the primary efferent neural fibers through which the cerebellum communicates with the thalamus and cerebral cortex.

Fig. 2.

Neurological soft signs in ultrahigh-risk and healthy control participants. Note: *P ≤ .05, **P ≤ .01. Neurological soft sign scores for each composite and total summary (assessed at baseline) are from the Neurological Evaluation Scale (NES). The error bars represent mean standard error.

Fig. 3.

Superior cerebellar peduncle development over 1 y in ultrahigh-risk and healthy control youth. Note: results represent fractional anisotropy values for those participants with scans at 2 time points (n = 30; 15 in each group). Error bars represent the mean standard error.