Bimodal distribution of tone-matching deficits indicates discrete pathophysiological entities within the syndrome of schizophrenia

Clément Dondé,Joshua T Kantrowitz,Daniel C Javitt,Juan Sanchez-Peña,Cheryl M Corcoran,Alice Saperstein,Blair Vail,Alice Medalia,Gaurav H Patel,Elisa C Dias,Antigona Martínez,Gail Silipo

doi:10.1038/s41398-019-0557-8

Abstract

To date, no measures are available that permit differentiation of discrete, clinically distinct subtypes of schizophrenia (SZ) with potential differential underlying pathophysiologies. Over recent years, there has been increasing recognition that SZ is heterogeneously associated with deficits in early auditory processing (EAP), as demonstrated using clinically applicable tasks such as tone-matching task (TMT). Here, we pooled TMT performances across 310 SZ individuals and 219 healthy controls (HC), along with clinical, cognitive, and resting-state functional-connectivity MRI (rsFC-MRI) measures. In addition, TMT was measured in a group of 24 patients at symptomatic clinical high risk (CHR) for SZ and 24 age-matched HC (age range 7–27 years). We provide the first demonstration that the EAP deficits are bimodally distributed across SZ subjects (P < 0.0001 vs. unimodal distribution), with one group showing entirely unimpaired TMT performance (SZ-EAP+), and a second showing an extremely large TMT impairment (SZ-EAP−), relative to both controls (d = 2.1) and SZ-EAP+ patients (d = 3.4). The SZ-EAP− group predominated among samples drawn from inpatient sites, showed higher levels of cognitive symptoms (PANSS), worse social cognition and a differential deficit in neurocognition (MATRICS battery), and reduced functional capacity. rsFC-MRI analyses showed significant reduction in SZ-EAP− relative to controls between subcortical and cortical auditory regions. As opposed to SZ, CHR patients showed intact EAP function. In HC age-matched to CHR, EAP ability was shown to increase across the age range of vulnerability preceding SZ onset. These results indicate that EAP measure segregates between discrete SZ subgroups. As TMT can be readily implemented within routine clinical settings, its use may be critical to account for the heterogeneity of clinical outcomes currently observed across SZ patients, as well as for pre-clinical detection and efficacious treatment selection.

Highlights

In 1911, Bleuler famously described the syndrome of dementia pracecox as including a “group of schizophrenias” (SZ), reflecting the strong heterogeneity of presentation across individuals[1]
Scores within the SZ-Early auditory processing (EAP)− group were significantly reduced from both controls (z = −14.5, P < 0.0001) and SZ-EAP + (z = −15.1, P < 0.0001)
The threshold between clusters was 77.7% correct tonematching responses. When this cut-off was applied across groups, 166 of 310 (53.5%) of SZ patients scored below this cut-off vs. only 46 of 219 (21.7%) of controls (LR: χ2 = 59.0, P < 0.00001) (Fig. 1c)

Summary

Introduction

In 1911, Bleuler famously described the syndrome of dementia pracecox as including a “group of schizophrenias” (SZ), reflecting the strong heterogeneity of presentation across individuals[1]. To date attempts to identify variables that divide individuals with. SZ into discrete, dichotomously distributed subtypes based upon symptoms have largely failed. Individuals with SZ show consistent deficits in neurocognitive functioning, such deficits are unimodally distributed across large populations, and so do not yield dichotomous subtypes[2]. Symptoms of SZ are both unimodally distributed and unstable over time, leading to recent abandonment of clinical subtyping in DSM-53. Auditory processing (EAP) deficits in SZ were first demonstrated in 19734 but were not studied systematically until ~20 years ago.

Results

Discussion

Conclusion