The neural substrates of neurological soft signs in schizophrenia: a systematic review

Neurological soft signs (NSS) are common in patients with schizophrenia. However, the neural substrates of NSS remain poorly understood. Using legacy PubMed, we performed a systematic review and included studies that assessed NSS and obtained neuroimaging data in patients with a schizophrenia spectrum disorder published up to June 2020. We systematically reviewed 35 relevant articles. Studies consistently implicate the basal ganglia and cerebellum as structural substrates of NSS and suggest that somatomotor and somatosensory regions as well as areas involved in visual processing and spatial orientation may underlie NSS in psychosis spectrum disorders. Additionally, dysfunction of frontoparietal and cerebellar networks has been implicated in the pathophysiology of NSS. The current literature outlines several structural and functional brain signatures that are relevant for NSS in schizophrenia spectrum disorder. The majority of studies assessed gray matter structure, but only a few studies leveraged other imaging methods such as diffusion weighted imaging, or molecular imaging. Due to this, it remains unclear if white matter integrity deficits or neurometabolic alterations contribute to NSS in the illness. While a substantial portion of the literature has been conducted in patients in the early illness stages, mitigating confounds of illness chronicity, few studies have been conducted in antipsychotic medication-naïve patients, which is a clear limitation. Furthermore, only little is known about the temporal evolution of NSS and associated brain signatures. Future studies addressing these pivotal gaps in our mechanistic understanding of NSS will be important.