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

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.

Deficits in Auditory and Visual Sensory Discrimination Reflect a Genetic Liability for Psychosis and Predict Disruptions in Global Cognitive Functioning

“…Consistent with previous work ( 36 ), individuals with psychosis and their biological realtives who had worse auditory discrimination thresholds had worse global cognition, indicating that auditory processing deficits are related to downstream disruptions in various aspects of cognition, including memory, attention, processing speed, and problem solving. These findings were found to be significant even when controlling for psychiatric symptoms, and is consistent with recent findings demonstrating that deficits in early auditory processing in schizophrenia reflect cognitive impairments, but may not be related to positive or negative symptoms ( 46 ). Together, these findings suggest that early sensory processing disruptions may be more reflective of cognitive disruptions than psychotic symptomatology.…”

Pitch and Duration Mismatch Negativity are Associated With Distinct Auditory Cortex and Inferior Frontal Cortex Volumes in the First-Episode Schizophrenia Spectrum

“…Right A5 may be important for tone-matching performance in schizophrenia, as schizophrenia patients with tone-matching deficits have decreased connectivity between the medial geniculate nucleus and A5. 57 In the inferior frontal cortex, area 47L is functionally connected to several cortical regions, including dorsolateral frontal, medial frontal, premotor, parietal, and temporal cortex. In the left hemisphere, commonly referred to as part of Broca’s area, it is important for language production and semantic processing.…”

Neural and functional correlates of impaired reading ability in schizophrenia

“…2C), but not SLOF scores within patients, and with multiple neurocognitive domains of the MCCB (Processing Speed: r = 0.50, p = 0.005; Attention/Vigilance: r = 0.39, p = 0.03; Working memory: r = 0.54, p = 0.002; Verbal Learning: r = 0.59, p = 0.001; Total: r = 0.59, p = 0.001).

Figure 2Relationships (Pearson’s r ) between reading, tone-matching and functioning measures in the SZ group. SZ-EAP- and SZ-EAP + refers to subtypes of patients that are significantly different according to tone-matching performance, with SZ-EAP- defined as below a threshold of 77.7% correct responses 12 .

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“…Relationships (Pearson’s r ) between reading, tone-matching and functioning measures in the SZ group. SZ-EAP- and SZ-EAP + refers to subtypes of patients that are significantly different according to tone-matching performance, with SZ-EAP- defined as below a threshold of 77.7% correct responses 12 .…”

“…EAP deficits were assessed using a previously described delayed tone-matching paradigm 2 . In our prior study involving over 500 subjects, we observed that EAP deficits were bimodally distributed in SZ, with one group of patients – termed SZ-EAP + – showing preserved abilities (mean 87.8 ± 6.8%) that overlapped those of HC (mean 84.9 ± 9.6%)) and a second group of patients –termed SZ-EAP- — showing marked impairments (mean 64.1 ± 8.4%) relative to controls 12 . The critical threshold separating the EAP + and EAP- groups was 77.7% correct performance, which was therefore implemented here to define the groups.…”