Aberrant attentional modulation of the auditory steady state response (ASSR) is related to auditory hallucination severity in the first-episode schizophrenia-spectrum

Abstract

The 40-Hz auditory steady state response (ASSR) is reduced early in schizophrenia, with differences evident even at the first episode of schizophrenia-spectrum psychosis (FESz). Although robust, there is high variability in effect size across studies, possibly due to differences in experimental control of attention and heterogeneity of symptom profiles across studies, both of which may affect the ASSR. We investigated the relationships among ASSR deficits, attention-mediated sensory gain, and auditory hallucinations in 25 FESz (15 male; 23.3 ± 4.5 years) and 32 matched healthy comparison subjects (HC, 22 male; 24.7 ± 5.8 years). ASSR was measured to 40-Hz click trains at three intensities (75, 80, and 85 dB) while participants attended or ignored stimuli. ASSR evoked power and inter-trial phase coherence (ITPC) were measured using the Morlet wavelet transform. FESz did not show overall ASSR power reduction (p > 0.1), but power was significantly increased with attention in HC (p < 0.01), but not in FESz (p > 0.1). Likewise, FESz did not evince overall ASSR ITPC reduction (p > 0.1), and ITPC was significantly increased with attention in HC (p < 0.01), but not in FESz (p > 0.09). Attention-related change in ASSR correlated with auditory hallucination severity for power (r = −0.49, p < 0.05) and ITPC (r = −0.58, p < 0.01). FESz with auditory hallucinations may have pathologically increased basal excitability of auditory cortex and consequent reduced ability to further increase auditory cortex sensory gain with focused attention. These findings indicate hallucination-related pathophysiology early in schizophrenia and may guide novel intervention strategies aimed to modulate basal activity levels.

1. Introduction

Schizophrenia is characterized by perceptual abnormalities and severe cognitive decline, often leading to lifetime disability (Cloutier et al., 2016). Auditory hallucinations (AH; the perception of sounds or voices that do not exist in the physical environment) are a hallmark of schizophrenia. AH often prompt first clinical contact and are one of the most common symptoms reported as a priority for treatment, alongside the inability to concentrate and avoid distraction (Meddings and Perkins, 2002). Unfortunately for those who suffer from the disorder, AH and attentional control deficits have a synergistic relationship. Patient distress from AH is more strongly linked to cognitive factors, like the ability to suppress or ignore perceptual aberrations, than to physical characteristics (e.g., perceived loudness) of AH (Birchwood and Chadwick, 1997), and behavioral assays of auditory executive attentional control are inversely related to auditory hallucination severity (Hugdahl, 2009). At the systems-level, it has been hypothesized that AH are associated with both hyperactivity of auditory/verbal perceptual systems and hypoactivity of frontal attention/behavioral control systems that traditionally inhibit and reattribute perceptual misrepresentations (Hugdahl, 2009). This hypothesis aligns well with findings in neurological patients with prefrontal cortex damage who show enhancement of primary auditory and somatosensory responses to unattended stimuli, presumably due to reduced tonic inhibition from the damaged frontal regions (Knight et al., 1999). At the circuit level, abnormalities in parvalbumin(pv)-positive γ-aminobutyric acid (GABA)-ergic interneurons (Curley and Lewis, 2012; Enwright et al., 2016; Lewis et al., 2012) and their synaptic interactions with pyramidal neurons (Rotaru et al., 2012) are consistently observed in both temporal auditory perceptual and frontal attentional control systems in schizophrenia post-mortem studies. These cellular abnormalities further lead to disruption of gamma-band (30–100 Hz) cortical oscillations (Gonzalez-Burgos and Lewis, 2008), which reflect the local coordination of pyramidal cells and pv-positive GABAergic interneurons that plays an integral role in information processing in the brain (Varela et al., 2001).

Electroencephalography (EEG) studies have identified widespread deficits in gamma-band oscillatory activity in schizophrenia. Gamma abnormalities are observed during cognitive tasks (Basar-Eroglu et al., 2007; Coffman et al., 2020), visual perceptual tasks (Uhlhaas et al., 2006; Uhlhaas and Singer, 2010), and in response to basic sensory stimuli (Grützner et al., 2013; Leicht et al., 2015; O’Donnell et al., 2013). In the auditory system, tone stimuli presented with amplitude modulation at a fundamental frequency between 1 and 200 Hz or clicks presented at these frequencies will generate an evoked potential that phase-locks to the fundamental frequency (Picton et al., 2003). This auditory steady state response (ASSR) reflects the “resonant” local circuit dynamics of auditory cortex. ASSR phase-locks most strongly to acoustic stimuli at 40 Hz, which evoke gamma-band neural oscillations (Brenner et al., 2009). The ASSR is commonly measured by evoked power – the amplitude of the average ASSR signal across trials – and inter-trial phase coherence (ITPC) – the degree to which the phase of the ASSR signal is consistent from trial-to-trial (Cohen, 2014). Reduced ASSR power and ITPC are considered a stable index of auditory circuit dysfunction associated with schizophrenia and other related psychiatric disorders (Roach et al., 2019; Tada et al., 2019; Tan et al., 2015). However, effect sizes (Hedge’s G) for studies included in a recent meta-analysis of ASSR deficits in schizophrenia were highly variable, with a composite effect size of 0.46 (Thuné et al., 2016). More recently, ASSR studies have focused on individuals at first episode of psychosis (Koshiyama et al., 2018; Wang et al., 2018) and those at risk of later developing of a psychotic disorder (Ahmed et al., 2020; Tada et al., 2016a) to investigate the possible utility of ASSR for diagnosis or for tracking outcomes of early intervention. Review of the six published studies of ASSR in FESz indicated reduced ITPC but not power in one study (Spencer et al., 2008b), while the 5 remaining reports showed both reduced power and reduced ITPC (Alegre et al., 2017; Koshiyama et al., 2018; Spencer et al., 2008c; Tada et al., 2016a; Wang et al., 2018). However, as indicated in Table 1, effect sizes vary substantially and only one study experimentally controlled attention. Further, one study of the early evoked auditory gamma-band response found that deficits in the ability to generate gamma power while attending to stimuli may be progressive, with deficits observed at follow-up, but not baseline EEG assessment (Oribe et al., 2019). Understanding the conditions which maximize group differences in ASSR would facilitate its utility in diagnosis and early outcome tracking.

Table 1. Attentional Control, Symptoms, and Effect Size in Prior ASSR research.

All click-train ASSR studies in FESz and selected studies in long-term schizophrenia (Sz) are shown, sorted by effect size Effect sizes vary in a complex manner which may be related to attentional control and/or positive symptoms. All click-train ASSR studies in FESz and selected studies in long-term Sz are shown, sorted by effect size. Effect sizes vary in a complex manner which may be related to attentional control and/or positive symptoms. NC = Not Controlled.

Source, Year	Sample	Attention	PANSS Negative	PANSS Positive	Hedges g ( Thuné et al., 2016)
Long-Term/Chronic
Rass et al. (2012)	Sz	Attend	15.4	14.7	0.35
Edgar et al. (2014)	Sz	NC	17.8	15.8	0.64
Sun et al. (2018)	Sz	NC	23.9	20.6	0.65
Krishnan et al. (2009)	Sz	Ignore	–	–	0.66
Roach et al. (2013)	Sz	NC	14.3	15.4	0.71
Kwon et al. (1999)	Sz	NC	18.1	17.4	0.81
Hamm et al. (2015)	Sz	NC	14.8	13.7	0.89
Wilson et al. (2008)	Sz	NC	–	–	1.23
First-Episode/Early Course
Spencer et al. (2008a)	FESz	NC	17.9	20.9	0.55
Tada et al. (2016a)	FESz	NC	17.9	14.1	0.90
Spencer et al. (2009)	FESz	NC	–	–	0.92
Wang et al. (2018)	FESz	Attend	15.9	20.7	0.98
Alegre et al. (2017)	FESz	NC	–	–	1.09
Koshiyama et al. (2018)	FESz	NC	18.8	15.2	1.27

Much like other cortical auditory evoked potentials (Bidet-Caulet et al., 2007; Hansen et al., 1983; Woldorff et al., 1993), the ASSR is sensitive to stimulus parameters and attention effects. For example, louder stimuli evoke greater ASSR (Grasel et al., 2015), as do stimuli of shorter duration (Hamm et al., 2015). Intensity-dependence of other auditory evoked responses is impaired in schizophrenia (Gudlowski et al., 2009; Juckel et al., 2003; Park et al., 2010), and the effect of stimulus duration on ASSR is completely absent in these individuals (Hamm et al., 2015). For this reason, intensity and duration of stimuli used in ASSR studies is carefully controlled to avoid confounds in study design. However, another important potential confound exists that is seldom considered in the design of studies investigating ASSR deficits in schizophrenia. Although initial reports suggested that ASSR could not be modulated endogenously (Linden et al., 1987), increasing evidence suggests that the ASSR can be affected by shifts of attention between the auditory and visual sensory modalities (Gander et al., 2010; Griskova et al., 2007; Saupe et al., 2009). Compared to passive conditions, directing attention away from the auditory modality (e.g., by reading a book, watching a silent movie, or performing a visual task) reduces the ASSR (Griskova et al., 2007; Roth et al., 2013). Similarly, ASSR is enhanced by attention directed towards auditory stimuli (e.g., active listening without directing attention to another sense) (Gander et al., 2010; Saupe et al., 2009). Further, sizable correlations between ASSR power and cognitive/attentional functioning have been detected early in the disorder (Tada et al., 2016b), and a brief qualitative review of 11 studies indicates that attention is seldom controlled toward or away from the stimulus (Table 1).

There also exist effects of positive symptoms on cognitive function. The presence of AH (one of the most common symptoms of schizophrenia) has been linked to reduced cognitive function in people with schizophrenia (Anthony, 2004; Waters et al., 2003) and in non-clinical populations (Daalman et al., 2011). However, this has not been well considered in ASSR study design. The first study examining ASSR and AH in schizophrenia reported that increased left hemisphere ASSR was related to greater AH severity (Spencer et al., 2009). A subsequent study showed that interhemispheric synchrony of the ASSR was also related to more severe AH (Mulert et al., 2011). In the research studies reviewed in Table 1, a clear relationship can be identified between reported effect size and positive symptoms identified with the Positive and Negative Syndrome Scale (PANSS) with greater effect sizes in studies with lower mean positive symptom scores. Further, a recent experiment using transcranial alternating current stimulation (tACS) demonstrated that enhancing the ASSR with 10-Hz frontotemporal tACS in people with schizophrenia resulted in a concomitant reduction of AH symptoms, not an aggravation as would be predicted by positive correlations observed previously (Ahn et al., 2019). In each of these studies, subjects were asked to attend to stimuli while focusing their gaze upon a visual fixation cross. Each of them used similar stimuli and methods in general. We posit that enhanced alpha-band functional connectivity between frontal and temporoparietal brain regions with 10-Hz tACS intervention served to increase top-down attentional control, leading to a reduction in AH. This hypothesis is in-line with results from Salisbury et al. (2020), who reported reduced auditory N100 amplitude in FESz with AH compared to those without AH, indicating functional deficits in inhibitory interneuron and pyramidal cell circuits. There have also been reports of no relationship between AH and ASSR power or ITPC when participants were instructed to sit with eyes closed and pay no attention to the stimuli (Griskova-Bulanova et al., 2016). Thus, it is possible that the relationship between AH and ASSR is linked to control of attention (either endogenously or exogenously) toward the stimulus. By comparing ASSR with attention directed toward the stimuli to ASSR when attention is directed away, the interaction between attentional control and schizophrenia on ASSR can be directly investigated.

Here, we tested whether first-episode schizophrenia affected ASSR response to click trains of varying intensity and with attention devoted either toward or away from the auditory stimulus (and a competing visual stimulus) in a fully crossed design. Thus, we include within-subjects manipulation of exogenous (intensity) and endogenous (attention) control of evoked gamma oscillations in auditory cortex, as measured by ASSR. We hypothesized that FESz would show reduced attention modulation of ASSR and that the degree to which attention modulation was reduced would correlate with AH severity. We further predicted that ASSR would not be affected by stimulus intensity manipulation in FESz, while the healthy comparison group would demonstrate larger ASSR with increased auditory intensity. Lastly, we predicted that overall ASSR power would be greater with increased severity of auditory hallucinations, reflecting hyperactivity of auditory sensory circuit functioning due to reduced frontal inhibition.

2. Methods

2.1. Participants

Twenty-five FESz and 32 healthy comparison (HC) individuals participated. HC were recruited to approximately match FESz group mean age, sex, parental socioeconomic status (pSES) assessed by the Hollingshead Index (Hollingshead, 1975), and IQ assessed by the Wechsler Abbreviated Scale of Intelligence (WASI-I) (Axelrod, 2002) (see Table 2 for demographics). Participants were excluded for a) history of concussion or head injury with sequelae, b) history of alcohol or drug addiction or detox in the last five years, c) presence of neurological disease or disorder, d) < 9 years education, or e) IQ < 75. All subjects had normal hearing assessed by audiometry (within 30 dB nHL and <15 dB difference between ears from 500 to 4000 Hz). All participants completed the MATRICS Cognitive Consensus Battery. Participants provided voluntary informed consent and were compensated for participation. Procedures were approved by the University of Pittsburgh IRB.

Table 2. Participant Information.

Descriptive and inferential statistics are reported for first-episode schizophrenia subjects (FESz) and healthy controls (HC). Significant p-values are bolded. M = male; F = female; W = white; B = Black or African American; A = Asian; N = American Indian or Alaska Native; M = Multiracial.

	Mean ± SD		t/χ 2	p-value
	FESz	HC
Sociodemographic data
Age (years)	24.0 ± 4.0	24.0 ± 5.5	0.1	0.991
Sex (M/F)	21/4	21/11	2.4	0.118
Race (W/B/A/N/M)	10/12/2/0/0	18/3/7/2/2	14.8	0.011
Participant	31.1 ± 13.1	38.0 ± 14.4	1.8	0.076
Parental	43.1 ± 13.8	47.6 ± 12.5	1.2	0.232
Education (years)	13.0 ± 1.2	15.1 ± 2.8	3.3	0.003
Neuropsychological Tests
WASI – IQ	100.0 ± 12.1	109.8 ± 8.9	3.3	0.002
WASI – Verbal	49.0 ± 9.7	52.5 ± 6.3	1.6	0.126
WASI – Performance	50.6 ± 6.8	58.8 ± 6.5	4.5	<0.001
MCCB – Processing speed	33.8 ± 10.0	51.1 ± 8.3	6.8	<0.001
MCCB – Attention	34.2 ± 10.9	50.0 ± 9.8	5.6	<0.001
MCCB – Working memory	37.4 ± 11.6	48.4 ± 8.6	3.9	<0.001
MCCB – Verbal learning	41.8 ± 10.6	52.6 ± 8.1	4.1	<0.001
MCCB – Visual learning	37.4 ± 12.3	45.9 ± 7.3	3.1	0.002
MCCB – Reasoning	40.6 ± 11.9	50.9 ± 8.1	3.7	<0.001
MCCB – Social cognition	41.3 ± 12.2	53.4 ± 8.6	4.1	<0.001
MCCB – Total	30.4 ± 13.4	50.3 ± 7.1	6.1	<0.001
Task Behavior
1/Button-Press Rate	7.9 ± 1.0	9.0 ± 4.8	1.1	0.273
Symptoms
PANSS – General	40.4 ± 7.6
PANSS – Negative	18.7 ± 5.9
PANSS – Positive	20.1 ± 5.0
PANSS – Total	79.9 ± 14.1
PSYRATS Hallucinations – Physical	1.5 ± 1.5
PSYRATS Hallucinations – Emotional	1.3 ± 1.5
PSYRATS Hallucinations – Cognitive	1.4 ± 1.4
PSYRATS Hallucinations – Total	15.3 ± 15.7
PSYRATS Delusions	12.4 ± 7.4
Medication data
Cpz. equivalent dose (mg)*	199.2 ± 154.9
Medicated**/unmedicated	16/9

^*Chlorpromazine (Cpz) equivalent dose is calculated only for medicated participants.

^**Of the 16 medicated participants, 13 were prescribed risperidone, 5 were prescribed olanzapine, and 2 were prescribed aripiprazole (3 participants were prescribed two medications).

Diagnosis was based on the Structured Clinical Interview for DSM-IV-TR (SCID-IV) and consensus conference review, initially at protocol entrance and again 5–7 months after initial clinical assessment based on all available longitudinal data. Broad symptoms were rated using the Positive and Negative Symptom Scale (PANSS). Symptoms were also assessed with the AH scale of the PSYRATS, which provides scores for physical, emotional, and cognitive factors of AH using 11 Likert-scale (0–4) questions (Drake et al., 2007). The delusions scale of the PSYRATS was also administered. Participants were asked to rate their responses according to symptom severity over the prior 2-week period. All interviews and tests were conducted by an expert (Masters’- or PhD-level) clinical assessor. Of the 25 FESz participants, 19 received diagnoses of Schizophrenia (paranoid, n = 9; undifferentiated, n = 10), two of Schizoaffective Disorder (bipolar type, n = 1; depressive type, n = 1), one of Schizophreniform Disorder, and one of Psychotic Disorder NOS. Two FESz participants were lost to follow-up and therefore remain with the diagnosis of Schizophreniform Disorder (Provisional). All FESz participated within their first episode of psychosis and all but one had <3-months lifetime antipsychotic medication exposure. The individual with the schizophreniform diagnosis had <1-year total antipsychotic exposure. Analysis without this participant did not produce different results. See Table 2 for clinical characteristics.

2.2. Procedures

Participants listened to binaural auditory click stimuli generated with Audacity and presented using Presentation (Neurobehavioral Systems, Inc.) over Etymotic 3A insert earphones in two blocks (450 stimuli per block). Simultaneously, a silent nature video was presented. In one block, participants were instructed to attend and count the auditory stimuli (respond with a button press on every 7th stimulus) and ignore the video. In the other, they were asked to ignore the stimuli and watch the video. Block order was counterbalanced. Stimuli consisted of trains of 1 ms biphasic clicks presented at a stimulation rate of 40 Hz (500 ms duration, 750–1150 ms stimulus onset asynchrony). Click train stimuli were presented with one of three intensities (75 dB, 80 dB, or 85 dB), resulting in 150 trials per condition. Participants were monitored by video to ensure that they were awake with gaze directed toward the silent video throughout the task.

2.3. ASSR measurement

EEG data were obtained in conjunction with magnetoencephalography (MEG) in a magnetically shielded room (Imedco AG, Hägendorf, Switzerland) using a 63-channel EEG system (Elekta Neuromag) with a sampling rate of 3000 Hz (online half-power bandpass filter = 0.1–1000 Hz). MEG results will be reported in a subsequent manuscript. EEG channels included 61 scalp EEG channels arranged according to the 10-10 system, one lead below the left eye (VEOG), and one ECG lead below the left clavicle. All EEG channels were referenced to the left mastoid. Bipolar leads were placed lateral to the outer canthi of both eyes (HEOG). Using the MATLAB-based EEGLAB Toolbox (Delorme and Makeig, 2004), channels/segments with excessive noise were removed via visual inspection and a high-pass filter (0.5 Hz; 12 dB/oct) was applied. ICA was then performed to detect and remove eye-blink and ECG components. Using the Brainstorm toolbox, scalp EEG data were then re-referenced to the average of all channels (average reference) and a 60 Hz low-pass filter was applied. Trials were then segmented from 200 ms before to 700 ms after stimulus onset, average baseline voltage was subtracted, and trials were rejected when the voltage in any electrode exceeded 100 μV difference from baseline. For calculation of evoked power, Morlet wavelet deconvolution was applied to trial-averaged ERPs using 5 cycles at 1 Hz increments from 25 to 55 Hz. For calculation of ITPC, the wavelet transformation was applied separately to each trial using the same parameters. ITPC was calculated by dividing the complex output of the wavelet transform by its complex norm (absolute value), which was then averaged across trials (Cohen, 2014). ASSR evoked power and ITPC were measured as the average across 35–45 Hz, 100–500 ms post-stimulus, and over six frontocentral sites (F1/z/2 and FC1/z/2). Channels removed in EEGLAB were not included in the average (minimum number of sites = 4 of 6).

2.4. Data analysis

Group demographics and button-press frequency were compared between groups using t-tests and chi-squared tests where appropriate. ASSR power and ITPC were compared using repeated measures ANOVA with one between-subjects factor (group: FESz or HC) and two within-subject factors (attention: attend or ignore, and intensity: 75 dB, 80 dB, or 85 dB). For intensity analyses, Huynh-Feldt epsilon was used to correct for possible violations of sphericity. Simple effects were examined using one-way, between-subjects ANOVA or repeated-measures ANOVA as appropriate. Given that the distribution of auditory hallucination severity was bimodal in our sample, with roughly half (N = 12) of FESz reporting no auditory hallucinations, we performed a categorical analysis of ASSR power and ITPC using repeated measures ANOVA comparing attention, stimulus intensity, and diagnosis/auditory hallucination group (control, FESz with AH [AH+], or FESz without AH [AH−]). All pairwise comparisons utilized Bonferroni-corrected alpha. Sequential multiple regression was used to test the hypothesis that AH severity will predict the modulation of ASSR by attention (ASSR change). Presence/absence of AH symptoms was first entered into the model as a dichotomous categorical variable to account for variance inhomogeneity (Robertson et al., 1994). Scores from each of the three PSYRATS subscales (continuous; physical, emotional, and cognitive factors of AH) were then entered into the regression model using a forward-regression approach with an entry criterion of p (F change) < 0.05. To further examine relationships identified between AH and attentional modulation of ASSR, we repeated this analysis twice using mean ASSR within either the attend or ignore conditions as dependent variables, rather than their difference. Finally, Spearman correlation analysis was performed to determine whether any relationships exist between neurocognitive variables assessed by the MATRICS and WASI and the primary dependent variables of the study. Due to the exploratory nature of these correlations, there was no correction of alpha for the number of comparisons made.

3. Results

FESz did not differ from HC in demographic composition (e.g., age, sex, parental SES), apart from having lower education level and slightly different distribution of race (Table 2). There were no significant differences in task performance during the attend condition (p’s > 0.1); HC pressed the button once for every 7.5 stimuli (0.2 SD) on average, while FESz pressed the button once for every 7.7 stimuli (0.2 SD). Within FESz, AH+ pressed the button every 7.5 stimuli (0.3 SD), while AH− responded to every 7.8 stimuli (0.2 SD).

Comparison of evoked power differences between groups indicated no differences between FESz and HC when averaged across all stimulus conditions (p > 0.1). A main effect of stimulus intensity was found (F_(2,110) = 20.52; p < 0.001), with greater power with increasing stimulus intensity; however, this effect was primarily driven by greater response in the loudest condition (p’s < 0.001), and difference in evoked power at 75 dB and 80 dB stimulus intensity was negligible. Stimulus intensity did not interact with any other variable (p’s > 0.1), nor between attend and ignore conditions across all participants (F_(1,110) = 2.69; p > 0.1). There was no significant effect of attention on ASSR power overall (p > 0.1). Of primary importance, however, the effect of attention on evoked power differed between FESz and HC (group × attention interaction (F_(1,110) = 4.57; p = 0.037). Evoked power increased with attention in HC (attend = 0.0015 ± 0.0012 μV², ignore = 0.0013 ± 0.0012 μV²; p < 0.01); but not in FESz (p > 0.1). Evoked power spectrograms are shown in Fig. 1.

Fig. 1.

Spectrograms of ASSR evoked power for healthy controls and FESz (with and without auditory hallucinations) in attend and ignore conditions. FESz = First Episode Schizophrenia. AH+ = individuals reporting auditory hallucinations on the PSYRATS. AH− = individuals not reporting auditory hallucinations.

Similar effects were observed for ITPC. There were no differences in ITPC between FESz and HC when averaged across all stimulus conditions (p > 0.1). ITPC differences were observed as a function of stimulus intensity (F_(2,110) = 31.35; p < 0.001), with greater ITPC with increasing intensity; however, this effect was primarily driven by greater ITPC in the loudest condition (p’s < 0.001), and difference in ITPC at 75 dB and 80 dB stimulus intensity was negligible. Stimulus intensity did not interact with any other variable (p’s > 0.1). ITPC was also increased with attention directed toward the stimulus (F_(1,110) = 5.84; p = 0.019). Attention effects were different between groups (F_(1,110) = 6.47; p = 0.014), where ITPC was increased with attention in HC (attend = 0.26 ± 0.11 [SD]), ignore = 0.23 ± 0.08 p < 0.01), but not FESz (attend = 0.21 ± 0.10 [SD]), ignore = 0.21 ± 0.10 p > 0.9). There was no significant group difference in ITPC within attend or ignore conditions (p > 0.1). ITPC topographies and spectrograms are shown in Fig. 2.

Fig. 2.

Spectrograms and scalp topographies of ASSR ITPC for healthy controls and FESz (with and without auditory hallucinations) in attend and ignore conditions. FESz = First Episode Schizophrenia. AH+ = individuals reporting auditory hallucinations on the PSYRATS. AH− = individuals not reporting auditory hallucinations.

In HC, attentional modulation of ASSR power/ITPC showed the expected positive relationship with overall power/ITPC in both the attend (power: r = 0.69, p < 0.001; ITPC: r = 0.72, p < 0.001) and ignore conditions (power: r = 0.47, p < 0.01; ITPC: r = 0.45, p < 0.01), where greater overall amplitudes were related to greater attentional modulation (Fig. 3A). In FESz, the correlation between ASSR power change and attend ASSR power was not significant (power: r = −0.37, p = 0.08; ITPC: r = 0.16 p > 0.1). More importantly, there was a strong negative correlation between ASSR change and ignore ASSR (power: r = −0.63; p < 0.001; ITPC: r = —0.47, p < 0.01), indicating that as amplitude of the ASSR in the ignore condition increased in FESz, the modulation of the ASSR with attention decreased (Fig. 3B). Neither power nor ITPC were correlated with chlorpromazine-equivalent dosages of antipsychotic medications (p’s > 0.1).

Fig. 3.

Scatterplots showing the relationships between A) power of the ASSR during the attend condition and the difference between power of the ASSR in the attend and ignore conditions (ASSR change), B) power of the ASSR during the ignore condition and ASSR change C) PSYRATS cognitive scale and ASSR Change, and D) PSYRATS physical scale and power of the ASSR during the ignore condition.

Within the FESz group, AH+ and AH− individuals were next compared. As in our main analysis, ASSR response increased with stimulus intensity (power: F_(2,46) = 8.32; p = 0.003; ITPC: F_(2,46) = 13.0; p < 0.001) and did not interact with other variables. Differences in ASSR between FESz with (AH+) and those without AH (AH−) were dependent on the allocation of attention (group × attention interaction; power: F_(2,46) = 4.34; p = 0.049; ITPC: F_(2,46) = 5.14; p = 0.033). AH− had reduced ASSR compared to AH+ when ignoring auditory stimuli (power: F_(1,23) = 4.39; p = 0.047; ITPC: F_(1,23) = 4.37; p = 0.048), but not when devoting attention toward auditory stimuli (p > 0.1; see Table 3 for descriptive statistics). Simple attention effects were only significant for ITPC, and only within AH− (F_(1,22) = 5.53; p = 0.039). No additional main effects or interactions were significant.

Table 3. Descriptive statistics for ASSR evoked power and ITPC.

Descriptive statistics (mean ± SEM) are reported for first-episode schizophrenia subjects (FESz) and healthy controls (HC) for each stimulus condition.

Evoked Power (μV2 x 10−3)					ITPC
	HC (N = 32)	FESz (N = 25)	AH− (N = 12)	AH+ (N = 13)	HC (N = 32)	FESz (N = 25)	AH− (N = 12)	AH+ (N = 13)
Attend
75 dB	1.4 ± 1.2	1.0 ± 1.0	0.7 ± 0.5	1.4 ± 1.3	.25 ± .02	.20 ± .02	.18 ± .02	.22 ± .03
80 dB	1.4 ± 1.5	1.1 ± 1.1	0.7 ± 0.7	1.4 ± 1.3	.25 ± .02	.21 ± .02	.17 ± .02	.23 ± .03
85 dB	1.7 ± 1.6	1.4 ± 1.4	1.0 ± 1.1	1.8 ± 1.6	.27 ± .02	.23 ± .02	.20 ± .02	.25 ± .03
Ignore
75 dB	1.2 ± 1.1	1.1 ± 1.3	0.6 ± 0.5	1.6 ± 1.7	.23 ± .02	.21 ± .02	.17 ± .02	.23 ± .03
80 dB	1.2 ± 1.0	1.2 ± 1.3	0.6 ± 0.5	1.7 ± 1.7	.22 ± .02	.21 ± .02	.17 ± .02	.24 ± .03
85 dB	1.5 ± 1.5	1.4 ± 1.5	0.7 ± 0.6	1.9 ± 1.9	.25 ± .02	.22 ± .02	.18 ± .02	.26 ± .03

Table 4 displays the correlations among variables and Tables 5 and 6 display the unstandardized regression coefficients (B), standardized regression coefficients (β), and partial correlations for sequential regression models achieving statistical significance. The regression model predicting attention-related change in ASSR evoked power was statistically significant (R² = 0.33, F(2,22) = 5.73, p = 0.013) and PSYRATS cognitive factor score accounted for a significant proportion of the variance over and above presence/absence of AH in predicting attention-related change in ASSR evoked power (ΔR² = 0.17, F(1,22) = 5.55, p = 0.028). For every 1-point increase in PSYRATS cognitive score (greater severity), difference in ASSR power between attend and ignore conditions decreased by 0.0033 ± 0.0014 μV² (t(23) = −2.36, p = 0.028; Fig 3C). The regression models predicting ASSR evoked power and ITPC during the attend condition did not achieve statistical significance (p’s > 0.1); however, statistical significance was achieved for regression models predicting evoked power while participants ignored ASSR stimuli (R² = 0.32, F(1,22) = 5.19, p = 0.014), where this time PSYRATS physical factor score accounted for a significant proportion of the variance in ASSR evoked power over and above presence/absence of AH (ΔR² = 0.16, F(1,22) = 5.19, p = 0.014). For every 1-point increase in PSYRATS physical factor score, ASSR power during the ignore condition increased by 0.013 ± 0.0055 μV² (t(23) = 2.28, p = 0.033), indicating greater auditory cortex response to 40 Hz stimulation with greater hallucinations, despite reduced ability to modulate this response with attention (Fig 3D). Regression models predicting ITPC (ignore, attend, and attention-related change) did not achieve statistical significance (p’s > 0.1).

Table 4.

Pearson Correlation Statistics are presented for relationships among ITPC and evoked power in attend and ignore conditions, ITPC and evoked power difference between conditions, and PSYRATS measures of auditory hallucination severity. Significant correlation statistics are bolded, using Bonferroni-adjusted alpha as described in the methods section. N = 25 for all comparisons.

	PSYRATS Auditory Hallucinations Score
	Total	Physical Scale	Emotional Scale	Cognitive Scale
ITPC
Attend	0.32	0.38	0.25	0.31
Ignore	0.48	0.52	0.41	0.47
Attend - Ignore	−0.58	−0.42	−0.57	−0.60
Power
Attend	0.39	0.44	0.34	0.31
Ignore	0.48	0.51	0.44	0.42
Attend - Ignore	−0.49	−0.46	−0.48	−0.51

Table 5.

Sequential Regression of Auditory Hallucination Presence/Absence (AH±) and Auditory Hallucination Severity on Attention-Related Change in ASSR Evoked Power. Asterisks represent statistical significance (p < 0.05). Asterisks are not shown for beta statistics, as p-values for these statistics are identical to partial correlation statistics.

	B	SE B	β	rpartial	R2	ΔR2
Step 1: AH±	−0.34	0.16	−0.40	−0.40*	0.16*
Step 2: AH±	0.49	0.39	0.57	0.26	0.33*	0.17*
PSYRATS (Cognitive)	−0.33	0.14	−1.05	−0.45*

Table 6.

Sequential Regression of Auditory Hallucination Presence/Absence (AH±) and Auditory Hallucination Severity on Evoked Power while Ignoring ASSR Stimuli. Asterisks represent statistical significance (p < 0.05). Asterisks are not shown for beta statistics, as p-values for these statistics are identical to partial correlation statistics.

	B	SE B	β	rpartial	R2	ΔR2
Step 1: AH±	1.11	0.53	0.40	0.40*	0.16*
Step 2: AH±	−2.42	1.67	−0.88	−0.30	0.32*	0.16*
PSYRATS (Physical)	1.26	0.55	1.34	0.44*

Exploratory nonparametric correlations among ASSR/AH and MATRICS/WASI neurocognitive scores achieved significance for the relationship between attention-related difference in ASSR evoked power and MATRICS Attention/Vigilance score (ρ = 0.58; p < 0.05), and the relationship between attention-related difference in ASSR evoked power and WASI IQ (ρ = 0.63; p < 0.05). Both relationships indicate that greater difference in ASSR between attend and ignore conditions is related to greater neurocognitive performance. Further, although they did not achieve significance, the relationships between PSYRATS total AH score and WASI IQ (ρ = −0.39) and MATRICS Attention/Vigilance scores (ρ = −0.26) trended in the hypothesized direction, as did the relationships between ASSR during ignore condition and WASI IQ (ρ = −0.27) and MATRICS Attention/Vigilance scores (ρ = −0.43).

4. Discussion

People with schizophrenia have problems executing goal-directed behavior (Barch, 2005; Cohen et al., 1999), devoting attention toward or away from sensory (particularly auditory) stimuli (Bellgrove et al., 2003; Carter et al., 1997), and focusing on items held in short-term memory (Bachman et al., 2009; Lee and Park, 2005). We now add an important steppingstone in understanding the relationship between auditory attention and AH in schizophrenia. In this study, people within the first episode of schizophrenia-spectrum psychosis were less able to use attentional control to modulate auditory sensory responses to simple stimuli. There was a relationship between AH and the ability to modulate ASSR with attention, where those with greater attentional modulation had less severe auditory hallucinations. However, while ASSR ITPC was successfully modulated by attention in AH− FESz, evoked power was not significantly increased, indicating only partial ability to use attention to affect sensory processing. Further, cognitive factors of AH severity, which include disrupted daily functioning, controllability, and insight into hallucinations, showed the strongest relationship with ASSR power modulation by auditory attention.

The inability to modulate ASSR with attention in FESz may be relevant to a broad array of cognitive disabilities observed in schizophrenia, including deficits in working memory, sustained attention, selective attention, and verbal learning. Further, problems with social cognition in FESz may be directly related to reduced auditory attentional control. Social interactions rely heavily on the ability to selectively attend to auditory stimuli. Auditory attention is also critical when listening to speech in noise (Anderson et al., 2013) or to non-native-accented speech (Van Engen and Peelle, 2014). Selective attention has long been understood as a fundamental cognitive deficit in psychosis (Bleuler, 1911). Our findings of reduced ability to modulate ASSR with attention confirms that this is the case, even at the level of basic auditory neurophysiology.

As anticipated, ASSR amplitudes increased with increasing intensity of the stimuli. Stimulus intensity was not, however, related to group differences in ASSR, nor was it related to the effect of attention on ASSR amplitude. Stimulus intensity can drive attention toward stimuli exogenously in some instances, particularly with large disparities between stimulus intensity of different stimuli, or when the frequency of presentation differs between loud and quiet stimuli, inducing an “alerting” effect. We did not find that to be the case with the ASSR responses measured here, although our stimuli were equiprobable and spanned only a 10-dB range of stimulus intensity. It is possible that different results would be found with a wider range or with altered stimulus presentation probabilities, as in an “oddball” paradigm.

Another somewhat surprising outcome of this study was the inverse correlation strengths identified in the relationship of AH and differential ASSR (attend minus ignore) compared to its relationship with the attend ASSR and ignore ASSR amplitudes themselves. With greater auditory hallucination severity, people with FESz showed larger ASSR, but reduced ability to modulate that response. In other words, hallucination severity was related to an oversensitivity of the auditory sensory response, and reduced ability to modify that response with attention. This is further supported by the strong negative relationship between ignore ASSR and differential ASSR identified in our post-hoc analysis within FESz participants, a relationship that is as strongly negative in FESz as the same correlation is positive in HC. This ASSR “ceiling effect” in AH+ FESz suggests that the auditory system has become hyperexcited, with reduced capacity for modulation. Conversely, FESz who do not experience AH show reduced ASSR consistent with prior reports in first-episode and long-term/chronic schizophrenia (Spencer et al., 2004; 2008a; 2008b), which has been linked to gray matter loss in auditory cortex (Hirano et al., 2020; Tada et al., 2019). Our future work will further examine ASSR deficits, gray matter, and AH severity in FESz to further determine the underling pathophysiology relating these functional structural, and symptom measures.

These findings, along with our previous findings of impaired N100 in individuals with AH (Salisbury et al., 2020), directly inform the neurophysiological circuit model of ASSR deficits in FESz. Differences observed between FESz with and without AH suggest two separate pathways of impairment: one resulting in hypersensitivity of auditory cortex and inability to modulate the response with attention, and one resulting in reduced ASSR power and ITPC with preserved ability to use attention to modulate the ASSR. While the results in the latter group align well with our prior investigations of auditory N100 to suggest a deficit in local inhibitory interneuron function, the hypersensitivity of ASSR and reduced attentional modulation observed in those experiencing AH may indicate dysfunction in inhibitory control of auditory areas by frontal cortex. This relationship between AH severity and cortical hyperexcitability is also in-line with previous reports in the context of auditory mismatch negativity (Fisher et al., 2012). Our results are particularly relevant to treatment efforts in the disorder, which have recently begun to focus on the non-invasive modulation of local cortical activity via electromagnetic field stimulation. Increased cognitive control through direct transcranial stimulation and behavioral training of frontal cortex function may not only result in normalization of the ASSR, but also may reduce auditory hallucination severity. Future work will examine the lateralization of this response using MEG to determine whether any lateralization of deficit exists in this sample to guide treatment studies using transcranial stimulation.

These results provide compelling evidence that auditory hallucinations, particularly cognitive factors associated with these hallucinations, are related to deficits in cognitive control of auditory neurophysiology in first-episode schizophrenia. This finding has implications for the etiology of the symptoms of schizophrenia as well as providing potential avenues for therapeutic intervention early in the disorder. Problems with auditory attention may also impact multiple aspects of schizophrenia, such as verbal learning and the guidance of attention during social interaction. Perhaps by improving cognitive control of auditory attention via cognitive/behavioral training, pharmacological intervention, or noninvasive brain stimulation, positive symptoms such as AH can be reduced, and functional outcomes can be improved.

Abbreviations:

AH

Auditory Hallucinations

ASSR

Auditory Steady State Response

EEG

Electroencephalography

FESz

First Episode Schizophrenia

ITPC

Inter-trial Phase Coherence

HC

Healthy Control

PANSS

Positive and Negative Syndrome Scale

pSES

Parental Socioeconomic Status

PSYRATS

Psychosis Symptom Rating Scale

WASI

Weschler Abbreviated Scale of Inteligence

tACS

Transcranial Alternating Current Stimulation