Auditory processing in schizophrenia during the middle latency period (10-50 ms): high-density electrical mapping and source analysis reveal subcortical antecedents to early cortical deficits

Abstract

Introduction: Auditory sensory processing dysfunction is a core component of schizophrenia, with deficits occurring at 50 ms post-stimulus firmly established in the literature. Given that the initial afference of primary auditory cortex occurs at least 35 ms earlier, however, an essential question remains: how early in sensory processing do such deficits arise, and do they occur during initial cortical afference or earlier, which would implicate subcortical auditory dysfunction.

Objective: To establish the onset of the earliest deficits in auditory processing, we examined the time window demarcating the transition from subcortical to cortical processing: 10 ms to 50 ms during the so-called middle latency responses (MLRs). These remain to be adequately characterized in patients with schizophrenia.

Methods: We recorded auditory evoked potentials (AEPs) to simple tone-pips from 15 control subjects and 21 medicated patients with longer-term schizophrenia or schizoaffective disorder (illness duration 16 yr, standard deviation [SD] 9.4 yr), using high-density electrical scalp recordings. Between-group analyses assessed the integrity of the MLRs across groups. In addition, 2 source-localization models were conducted to address whether a distinction between subcortical and cortical generators of the MLRs can be made and whether evidence for differential dorsal and ventral pathway contributions to auditory processing deficits can be established.

Results: Robust auditory processing deficits were found for patients as early as 15 ms. Evidence for subcortical generators of the earliest MLR component (P20) was provided by source analysis. Topographical mapping and source localization also pointed to greater decrements in processing in the dorsal auditory pathway of patients, providing support for a theory of pervasive deficits that are organized along the lines of a dorsal-ventral distinction.

Conclusions: Auditory sensory dysfunction in schizophrenia begins extremely early in processing, is evident during initial cortical afference and is also seen at earlier subcortical processing stages in the thalamus. The implication is that well-established sensory processing deficits in schizophrenia may be secondary to earlier subcortical dysfunction. Our findings do not preclude the possibility of even earlier deficits in auditory sensory processing during the auditory brainstem responses.

Keywords: auditory-evoked potentials; electroencephalography; event-related potentials.

Fig. 1: Selected scalp areas used to analyze each component of interest. Maximum amplitude for each component was found in the outlined regions.

Fig. 2: Early components of the auditory evoked potential in a group of healthy control subjects (n = 15). Waveforms are derived from group averages taken from a representative anterior site (grey waveform) and a posterior electrode (black waveform). Components are labelled on the basis of the latency of the peak amplitude, polarity and sequential position of the major deflections. Most of the early AEPs are clearly identified in the waveform from the anterior site. The P₂₀ is best viewed in the posterior waveform. A magnified view of the period 0–200 ms is included above the entire epoch view.

Fig. 3: Auditory evoked potentials in control subjects (n = 15) are blue and in patients (n = 21) are red (interstimulus interval = 500 ms). Data from 10 electrodes spanning anterior to posterior scalp sites are presented.

Fig. 4: Voltage scalp topographies from the control and patient group-averaged waveforms, for the P_o, P₂₀, P_a, and P1, and the corresponding difference between the control subject and the patient.

Fig. 5: The N_p65: A pronounced negative-going deflection over the posterior scalp, peaking at 65 ms. This is shown for patients (red) and control subjects (blue), from right and left occipital sites where the response was maximal.

Fig. 6: Statistical cluster plot of the results of the point-wise running t tests comparing the amplitudes of the patient and control subject auditory evoked potentials. Time, with respect to stimulus onset, is presented on the x axis and topographic regions of 168 electrode positions on the y axis. Colour corresponds to significance level. Note that there is overlap between the P₂₀ and P_a.

Fig. 7: Dipole source analysis I. Panel A: source analysis of the P₀ in control subjects and patients reliably models the generators bilaterally in the thalamus; this 2-dipole model explains 95.8% of the variance for control subjects and 87.6% for patients during a 12–18 ms time window. Panel B: overlay of the fit of dipoles 1 (red) and 2 (blue) in patients and control subjects.

Fig. 8: Source analysis II. Panel A: source analysis of the P1 for both patients and control subjects reveals remarkably similar localizations of the generators for both groups. Panel B: the green and purple dipoles demarcate the modelled source of the P1 in control subjects. The red and blue dipoles, which show the modelled difference (control subjects minus patients) for the P_a, are both posterior and superior to the first pair.