Relationship between N100 amplitude and T1w/T2w-ratio in the auditory cortex in schizophrenia spectrum disorders

doi:10.21203/rs.3.rs-3906183/v1

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Relationship between N100 amplitude and T1w/T2w-ratio in the auditory cortex in schizophrenia spectrum disorders

https://doi.org/10.21203/rs.3.rs-3906183/v1

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Schizophrenia spectrum disorders (SCZ_spect) are associated with altered function in the auditory cortex (AC), indicated by reduced N100 amplitude of the auditory evoked potential (AEP). While the neural substrate behind reduced N100 amplitude remains elusive, myelination in the AC may play a role. We compared N100 amplitude and magnetic resonance imaging (MRI) T1 weighted and T2 weighted ratio (T1w/T2w-ratio) as a proxy of myelination, in the primary AC (AC1) and secondary AC (AC2) between SCZ_spect (n = 33, 48% women) and healthy controls (HC, n = 144, 49% women). Further, we examined associations between N100 amplitude and T1w/T2w-ratios in SCZ_spect and HC. We finally explored N100 amplitude and T1w/T2w-ratios in the AC1/AC2 and association between N100 amplitude and T1w/T2w-ratios between male and female SCZ_spect and HC. N100 amplitude did not differ between SCZ_spect and HC or between female SCZ_spect and female HC, but was significantly reduced in male SCZ_spect compared to male HC (est = 4.3, se = 1.63, t = 2.63, p = 0.010). Further, T1w/T2w ratios in the AC1/AC2 did not differ between any groups. Finally, N100 amplitude was not associated with T1/T2-ratios in the AC1/AC2 in any groups. Reduced N100 amplitude in male SCZ_spect compared to male HC, suggest that sex-specific effects should be considered in research on SCZ_spect neurophysiology. Our findings did not support the hypothesis that reduced myelination in the AC1/AC2, as indexed by T1w/T2w-ratio, underlies N100 abnormalities in SCZ_spect. However, more precise estimates of intracortical myelin are needed to confirm this.

Biological sciences/Neuroscience

Health sciences/Diseases/Psychiatric disorders/Schizophrenia

Schizophrenia spectrum disorders (SCZ_spect) are severe mental disorders affecting approximately 1.0% of the general population ¹. Although the precise neural substrates of SCZ_spect remain elusive, structural magnetic resonance imaging (MRI) studies suggest the involvement of the auditory cortex (AC) ^2,3. At the functional level, electroencephalography (EEG) studies have consistently demonstrated reduced amplitude ^4–7 and delayed latency ⁸ of the N100 component of the auditory evoked potential (AEP) in SCZ_spect. The N100 amplitude is believed to reflect how pyramidal cells in the AC respond to auditory stimuli ^9,10. While the structural and biological correlates for N100 amplitude reductions in SCZ_spect remain unclear, altered myelination in the AC may play a role given that myelin is essential for fast and synchronized communication between neurons ¹¹. Thus, altered myelination in the AC in SCZ_spect ^12,13 may also partly explain the high prevalence of auditory hallucinations in these disorder ^12,14–16. Further, myelination directly impacts on key features of brain dynamics in the millisecond range as measured by EEG ^17–19 and previous studies have shown associations between myelin indices and evoked response potentials (ERPs) ^20,21 in healthy individuals. Further, individuals with multiple sclerosis (MS), a demyelination brain disorder, have reduced amplitude and delayed latency of the P100 component of the visual evoked potential ^22,23. While the relationship between the amplitude of the N100 component of the AEP and myelination in the AC in healthy individual remains elusive, here we examined the hypothesis that altered myelination in AC may be correlated with reduced N100 amplitude in SCZ_spect.

Altered cortical myelination is associated with a vulnerability towards SCZ_spect ^24–28. MRI studies using gray matter/white matter contrast (GWC) or diffusion tensor imaging (DTI), suggest altered myelination in auditory regions in SCZ_spect ^28,29. Further, connectivity in auditory fiber bundles is connected to auditory hallucinations in SCZ_spect ^30–33. The ratio between T1- (T1w) and T2- (T2w) weighted MRI (i.e., the T1w/T2w-ratio) has been used as a proxy for cortical myelin microstructure ^34–36 and has a close spatial correlation with myelin-based histology ^37–39. Further, patients with MS have reduced T1w/T2w-ratio ^40,41 that is associated with tissue damage ^42,43. Together, these studies support the use of T1w/T2w-ratio as a proxy for myelin. While one study found globally reduced T1w/T2w-ratio in SCZ_spect ⁴⁴, another study demonstrated reduced T1w/T2w-ratio in specific brain areas only ⁴⁵. However, none of these studies included intensity normalization, which has been shown to improve test-retest reliability of the T1w/T2w-ratio ³⁴. While several lines of evidence suggest altered myelination in the pathogenesis of SCZ_spect ^30,46, whether there is a direct link between myelination and function in the AC in SCZ_spect, remains unknown. To the best of our knowledge, no T1w/T2w-ratio abnormalities in the AC has been reported in SCZ_spect.

Understanding the influence of biological sex on AC function and structure in SCZ_spect may provide insight into the neural substrate behind the well-established sex differences in the pathophysiology and treatment response in SCZ_spect ^47,48. While previous studies report sex differences in the ERP- P300 component ⁴⁹ and in the mismatch negativity ⁵⁰ in SCZ_spect, studies investigating sex difference in the N100 amplitude are sparse ^51–53. While previous studies have reported sex difference in brain structure in SCZ_spect ⁴⁸ to our knowledge, no study has investigated sex difference in T1w/T2w-ratio in the AC in SCZ_spect.

Here we aimed to provide new insight into the biological and structural correlates of N100 amplitude in SCZ_spect and healthy controls (HC) by combining EEG and MRI, two non-invasive neuroimaging methods to study brain function and structure, respectively. To accomplish this, we examined the relationship between the N100 amplitude and the T1w/T2w-ratio in the primary auditory cortex (AC1) and in the secondary auditory cortex (AC2). These relationships are especially intriguing since reduced N100 amplitude is among one of the most consistently observed EEG changes in SCZ_spect ^{4–7,10,54–56}. Given reports of important sex-differences in SCZ_spect pathophysiology ^48,57–60, we also aimed to assess whether sex has an impact on these relationships.

Participants

Participants with a DSM-IV diagnosis within the SCZ_spect and HC were included from the ongoing Thematically Organized Psychosis (TOP) research study and partly overlap with the participants included in our previous study ⁶¹. HC were randomly drawn from the national population register within the same catchment area and asked to participate in the study. The study was approved by the Regional Committees for Medical and Health Research Ethics of South-Eastern Norway and conducted in accordance with the Helsinki declaration. Participants provided written informed consent. Participants with a history of head trauma resulting in loss of consciousness, an IQ < 70, or somatic or neurological disorders believed to influence brain function, were excluded from the study. In addition, HC with a history of mental disorders and/or severe mental disorders in first degree relatives or a history of alcohol- and substance abuse or dependence were excluded. In total, MRI and EEG data was available for 442 participants (50 SCZ_spect and 392 HC). We excluded participants (7 SCZ_spect and 20 HC) with clinically relevant incidental findings on their MRI scan (cysts > 1x1cm, empty sella turcica, greater pituitary gland abnormalities, arterial-venous malformations, multiple sclerosis changes, tumors or infarctions), with poor AEP on visual inspection (10 SCZ_spect and 61 HC) and with a time interval between MRI scanning and EEG recording of more than 12 months (1 HC). Since our healthy controls were significantly older than patients with SCZ_spect, we selected controls that were similar in age with patients and excluded all participants that were older than 54 years. This resulted in the exclusion of 133 HC. The final sample consisted of 177 participants, including 33 individuals with SCZ_spect (schizophrenia [n = 21], schizophreniform [n = 1] and psychosis not otherwise specified [n = 11]) and 144 HC. In this sample, MRI, EEG and clinical investigations were performed between 2015 and 2019 with a median time interval between MRI and EEG examinations of 12 days (0-337 days; interquartile range = 32 days).

Clinical assessment

Diagnosis, age of onset, duration of illness (DOI), psychosocial functioning, current symptoms and the use of antipsychotic medication(s) was assessed as described previously ⁶¹. Trained clinical psychologists or physicians diagnosed the patients according to DSM-IV criteria using the Structural clinical interview for DSM-IV (SCID-I) ⁶². We defined age of onset as age at first positive psychotic symptoms (verified by SCID-I) and the duration of illness (DOI) as years from age of onset to age at MRI. To assess psychosocial functioning we used the split version of the Global assessment of function (GAF-S and GAF-F) scale ⁶³. Current symptoms were evaluated using the Positive and negative syndrome scale (PANSS) interview ⁶⁴. For each patient, the current dosage of antipsychotic medication(s) was converted into Defined Daily Dose (DDD), where 1 DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults (www.whocc.no/atc_ddd_index/). In total, 21 patients were using antipsychotic medication, 7 patients were not using antipsychotic medication. Information about medication use was missing for 5 patients.

MRI processing

MRI were processed in the recon-all stream of FreeSurfer version 6.0.0 (https://surfer.nmr.mgh.harvard.edu) ⁶⁵. Briefly, this processing stream include removal of non-brain tissue, Talairach transformation, and intensity non-uniformity correction. Intensity information was used to reconstruct the inner (i.e., the gray/white matter boundary) and outer (i.e., the gray matter/cerebrospinal fluid boundary) surfaces of the cerebral cortex. Quality control and editing was conducted by trained research assistants following standard FreeSurfer procedures. At this stage, no participants were excluded. The T1w/T2w-ratio was computed using an approach previously found to have high test-retest reliability ³⁴. Briefly, this approach performs post hoc corrections for field inhomogeneities, partial voluming, and the presence of surface outliers, and intensity normalization using WhiteStripe ⁶⁶, which uses intensity values in normal-appearing white matter to harmonize T1w/T2w-ratio values. The mean T1w/T2w-ratios were extracted in three bilateral regions of interest in the Destrieux atlas ⁶⁷: The anterior transverse temporal gyrus of Heschl (HG), the transverse temporal sulcus (HS) and the temporal plane of the superior temporal gyrus (PT). Cortical labels were visually inspected to ensure correct placement. No subjects were excluded due to poor cortical labelling. For the main analyses, we defined two main regions of interest; the HG, referred to as the AC1 in the manuscript, and the combined HS and PT, referred to as AC2 in the manuscript. The T1w/T2w-ratio was calculated as an area-weighted mean across hemispheres and sub-regions. See Supplementary Note 1 for a discussion around parcellation of the AC and Supplementary Note 2 for details on how T1w/T2w-ratio was calculated. Supplementary Figs. 1 and 2 show the AC1 (HG) and AC2

(HS-PT) regions of interest. Figure 1 shows example T1- and T2-weighted volumes and the T1w/T2w-ratio volumes.

Auditory evoked potentials obtained from the PPI paradigm

AEPs were elicited during a prepulse-inhibition (PPI) task and EEG data was acquired and processed as described previously ⁶¹. Supplementary Fig. 3 shows the timeline of the entire EEG session, where the PPI-paradigm was presented together with other tasks. During the PPI paradigm, the participants focused on a red dot in the middle of a computer-screen while exposed to a constant background noise at 70 dB for 3-minutes (to allow for habituation) followed by the main PPI experiment. This consisted of five main conditions, with 12 presentations each: 1) Startle-stimuli presented alone (40 ms white noise with near instantaneous rise/fall times presented at 115 dB); 2; startle stimuli preceded 30 ms earlier by weaker prepulse stimuli (20 ms white noise with near instantaneous rise/fall times presented at 85 dB); 3; startle stimuli preceded 60 ms earlier by the weaker prepulse stimuli; Startle stimuli preceded 120 ms earlier by the weaker prepulse; and 5) the weaker prepulse stimuli presented alone. The current paper focuses on AEPs elicited by the prepulse stimulus alone (presented at 85 dB), since this typically does not elicit a muscular startle response. While we thus compute ERPs from relatively few trials, the long average interstimulus interval (ISI: approximately 9 seconds), in combination with the relatively strong stimulus intensity (85 dB), nonetheless elicited robust AEPs ⁶⁸. Prior to the EEG examination, hearing was assessed at 20 dB and 40 dB. All participants that were included in the current study were able to hear the auditory stimuli at < 40 dB. Figure 2 illustrates individual AEP from 12 randomly selected individuals with SCZ_spect. Figure 3 illustrates individual AEP from 24 randomly selected HC. Supplementary Fig. 4A-B illustrate mean AEPs from all SCZ_spect and HC.

EEG acquisition and processing

We recorded EEG data at 2048 Hz from 64 Ag-AgCl scalp electrodes arranged according to the international 10–5 system using a BioSemi ActiveTwo amplifier. In addition, four external electrodes recorded lateral and vertical eye movements and two recorded the heart rhythm (electrocardiography). The Biosemi system uses a common mode sense with a driven right leg electrode in order to minimize common mode voltages. All offline EEG processing was conducted using the MATLAB-based EEGLAB toolbox ⁶⁹. After down-sampling to 512 Hz, we removed noisy channels using the PREP Pipeline algorithms with default setting ⁷⁰. We referenced remaining channels to the average of all good channels before we interpolated removed channels from surrounding channel potentials. Next, we re-referenced all channels to the new common average obtained after interpolation of bad channels. After average referencing, we removed the mean offset from all channels and applied a high pass filter of 1 Hz. The Trimoutlier eeglab plugin (https://sccn.ucsd.edu/wiki/TrimOutlier) identifies and remove sections of bad data (defined as +/- 500 ms around any datapoint exceeding 500 µV across the 64 scalp channels) in the continuous EEG files. Next, independent component analysis (ICA) and automated detection of eye-blink artifacts (ICLABEL) ⁷¹ were used to automatically identify EEG artifacts such as eye blinks, line noise, muscle movements, heart noise, and channel noise. All independent components were also visually inspected, before rejection of components with < 50% chance of originating from brain activity (assigned by ICLabel). Cleaned EEG data was next low pass filtered to 40 Hz and separate epochs were extracted for each stimulus event with the time window of -200 ms to 700 ms. Finally, epoched data was baseline-corrected from − 100-0 ms. Prior to extraction of ERP voltages, the ERPs were re-referenced to linked mastoids to capture both the negative (on centro-frontal electrodes) and positive (on inferior temporal and posterior electrodes) polarity of the auditory ERP (which inverts over the Sylvian fissure). Trials containing amplitudes exceeding +/- 100 µV were excluded prior to averaging. All 12 prepulse alone trials were included. Peak latency and amplitude for the N100 component was defined as the minimal amplitude within a time window from 50–200 ms after stimulus onset and extracted from channel Cz. In our main analyses we focused on the N100 amplitude from the Cz electrode. However, we also examined N100 latency (Supplementary analysis 2). AEPs of individual participants were visually inspected in EEGLAB to ensure that the time windows used in the scripts were correct and that they accurately identified peaks and latencies (between 50–200 ms). After visual inspection of individual AEPs, we concluded that for the majority of subjects 12 prepulse alone trials were indeed sufficient for eliciting robust AEPs. Further, after visual inspection of individual AEPs, we excluded 74 participants where the peak N100 amplitude (the most negative peak) was outside of the latency range of 50-200ms. N100 amplitude that is generated at 85 db and a longer ISI will elicit a higher amplitude than N100 generated at lower db and shorter ISI ⁷². Visual inspection revealed that N100 amplitudes were negative for all participants (from: -3.18µV to − 43.62µV). To ease interpretation on the direction of correlation, we multiplied all negative values with − 1, giving N100 amplitudes of 3.18µV − 43.62µV, so that a higher number reflects a more prominent N100.

Statistical analyses

Statistical analyses were conducted using R version 3.6 (https://www.r-project.org; R Core Team, 2014). Group differences in demographics and clinical variables, as provided in Table 1, were calculated using the t-test for continuous variables and the chi-squared test for categorical variables.

First, to calculate mean N100 amplitude, T1w/T2w-ratio in AC1 and in AC2 in SCZ_spect (n = 33) and HC (n = 144), we performed separate analysis of covariance (ANCOVA), where N100 amplitude, T1w/T2w-ratio in AC1 or in AC2 was set as outcome variable, diagnostic group (SCZ_spect or HC) and sex (female or male) as factors, and age as a covariate. To compare the N100 amplitude and the T1w/T2w-ratio in AC1 and AC2 between patients and controls, we used linear models where N100 amplitude or the T1w/T2w-ratio in AC1 or in AC2 were dependent variables and diagnostic group was the independent variable of interest. The models were adjusted for age and sex. Cohen’s d and Hedge´s g for group comparisons were calculated from differences in predicted means ⁷³. For the linear regression analyses a p-value < 0.017 was considered significant (Bonferroni correction for three comparisons, i.e., differences in N100 amplitude, in T1w/T2w in AC1 and in T1w/T2w in AC2).

To test for associations between N100 amplitude and T1w/T2w-ratio in AC1 and in AC2, we ran separate linear models in SCZ_spect and HC, where the N100 amplitude was the dependent variable and T1w/T2w-ratio in AC1 or in AC2 as well as age and sex were independent variables. Thereafter, to examine whether the associations between N100 and T1w/T2w-ratio in AC1 and in AC2 differed between diagnostic groups (SCZ_spect and HC), we ran linear models in the combined sample (n = 177) of SCZ_spect and HC with N100 amplitude as dependent variable and diagnosis, T1w/T2w-ratio in AC1 or in AC2 and the interaction term (diagnosis* T1w/T2w-ratio) as independent variables. For these analyses a p-value < 0.025 was considered significant (Bonferroni correction for two comparisons, i.e., associations between N100 amplitude and T1w/T2w-ratio in AC1/AC2).

We performed sex stratified ANCOVA, where N100 amplitude, T1w/T2w-ratio in AC1 or in AC2 were set as outcome variables, diagnostic group as factor and age as a covariate. We ran this analysis in female and males separately. To compare the N100 amplitude and the T1w/T2w-ratio in AC1 and AC2 between female SCZ_spect and female HC and between male SCZ_spect and male HC, we used linear models where N100 amplitude, the T1w/T2w-ratio in AC1 or in AC2 were dependent variables and diagnostic group (SCZ_spect or HC) was the independent variable of interest. The models were adjusted for age. We ran this model in females (n = 76) and males (n = 91) separately. Cohen’s d and Hedge´s g for group comparisons were calculated from differences in predicted means ⁷³. For the linear regression analyses a p-value < 0.017 was considered significant.

To test for associations between N100 amplitude and T1w/T2-ratio in AC1 or in AC2 in female and male SCZ_spect and HC, we ran models in the female SCZ_spect, female HC, male SCZ_spect and male HC samples separately. In these models, the N100 amplitude was the dependent variable and T1w/T2w-ratio in AC1 or in AC2, as well as age were independent variables. Thereafter, to examine whether the associations between N100 amplitude and T1w/T2w-ratio in AC1 and in AC2 differed between sex, we ran linear models with N100 amplitude as the dependent variable and sex, T1w/T2w-ratio in AC1/AC2 and the interaction term (sex*T1w/T2w-ratio in AC1/AC2) as well as age and diagnosis (SCZ_spect or HC), as independent variables. We fitted this model in the combined sample (n = 177) of female and male patients and controls. For these analyses a p-value < 0.025 was considered significant.

In addition to our main analyses, we ran supplementary analyses assessing T1w/T2w-ratio in AC1 and in AC2 in each hemisphere and its association with N100 amplitude in SCZ_spect and HC. In addition, we examined N100 latency and its association with T1w/T2w-ratio in AC1 and in AC2 in SCZ_spect and HC. Further, we examined how much of the variance in N100 amplitude was explained by age and sex and assessed differences in demographics and in our EEG and MRI data between female and male patients and controls. We also examined differences in N100 amplitude and T1w/T2w-ratios in AC1/AC2 in female SCZ_spect compared to male SCZ_spect, in female HC compared to male HC and between the combined sample of male SCZ_spect and male HC and the combined sample of female SCZ_spect and female HC. Further, we examined N100 amplitude and T1wT2w ratio in the AC1 and AC2 and the association between N100 amplitude and T1wT2w ratios in patients with auditory hallucinations (AH+) and without auditory hallucinations (AH-). As two sensitivity analyses, we also examined N100 amplitude and T1wT2w ratio in the AC1 and AC2 and the N100-T1w/T2w associations in a sample prior to excluding older controls and in a sample where we performed strict age matching between patients and controls. Lastly, we examined the effect of use of antipsychotics and PANSS scores on our EEG and MRI data.

Demographics and clinical data

There were no significant differences in age or sex distribution between SCZ_spect and HC (Table 1).

Table 1. Participant characteristics

	SCZ_spect [n=33]	HC [n=144]	SCZ_spect vs. HC
			p-value
Women, n (%)	16 (48)	70 (49)	0.99
Age, Mean (range, sd)	29.96 (18.46-54.06, 9.03)	32.94 (18.50-45.58, 7.42)	0.09
Time between EEG and MRI, Median (range, IQR)	6 (0-337, 37)	13 (0-278, 31)	0.51
Age of Onset, Mean (range, sd)	24.50 (17-37, 5.18)	/	/
DOI, Mean (range, sd)	4.13 (0-20.47, 5.35)	/	/
GAF-S, Mean (range, sd)	54.48 (38-85, 11.54)	/	/
GAF-F, Mean (range, sd)	55.18 (35-85, 14.11)	/	/
PANSS total, Mean (range, sd)	56.12 (33-91, 14.41)	/	/
PANSS G, Mean (range, sd)	29.79 (18-47, 7.24)	/	/
PANSS P, Mean (range, sd)	12.97 (7-24, 3.84)	/	/
PANSS N, Mean (range, sd)	13.36 (7-25, 5.23)	/	/
Antipsychotic drug use, DDD, Mean (range, sd)	1.01 (0.19-2.25, 0.58)	/	/

Note: Table 1 shows the demographics of the final study sample. SCZ_spect, patients with schizophrenia spectrum disorders and in HC, healthy controls; n, number; %, percentage; range (min-max); sd, standard deviation; EEG, electroencephalography; MRI, magnetic resonance imaging; IQR, interquartile range; Age of onset, age of onset of first positive psychotic symptom in years; DOI, duration of illness in years; GAF, Global assessment of function; GAF-S, GAF-symptoms, GAF-F, GAF- functioning; PANSS, positive and negative syndrome scale; G, general; P, positive; N, negative; DDD, defined daily dose of antipsychotics; 9 SCZ_spect had missing information about age of onset and DOI. 5 had missing information about DDD.

Mean N100 amplitude, T1w/T2w-ratio in AC1 and T1w/T2w-ratio in AC2 in SCZ_spect and HC

Estimated marginal means and differences in means between SCZ_spect and HC are provided in Table 2.

Table 2 Mean N100 amplitude, T1w/T2w-ratio in AC1 and AC2 in SCZ_spect and HC

	N100 amplitude (microvolts) Mean (SE) [95% CI]	AC1 T1w/T2w-ratio Mean (SE) [95% CI]	AC2 T1w/T2w-ratio Mean (SE) [95% CI]
SCZ_spect [n=33]	12.19 (1.29) [9.65-14.74]	0.89 (0.002) [0.88-0.89]	0.88 (0.002) [0.87-0.88]
HC [n=144]	15.30 (0.61) [14.09-16.51]	0.89 (0.001) [0.89-0.89]	0.88 (0.001) [0.88-0.88]
SCZ_spect vs. HC	est=-3.11 se=1.43 p=0.03 Cohen’s d=0.42 Hedges´g=0.42	est=-1.87e-04 se=2.32e-03 p=0.94 Cohen’s d=0.02 Hedges´g=0.02	est=7.20e-04 se=2.34e-03 p=0.76 Cohen’s d=0.06 Hedges´g=0.06

Note: Table 2 shows mean N100 amplitude, T1w/T2w-ratio in AC1, primary auditory cortex and in AC2, secondary auditory cortex in SCZ_spect, patients with schizophrenia spectrum disorder, in HC, healthy controls. Estimated marginal means were calculated using ANCOVA, where N100 amplitude, T1w/T2w-ratio in AC1 or T1w/T2w-ratio in AC2 were set as dependent variables with age, sex and diagnosis as independent variables. Estimated marginal means are provided with SE (standard error of the mean) and 95% CI, confidence interval. In addition, Table 2 shows differences in means between SCZ_spect and HC. Est, estimate; p, p-value; *, significant p-value (p<0.017). N100 amplitude nominally smaller in SCZ_spect compared to HC.

Association between N100 amplitude and T1w/T2w-ratio in AC1/AC2 in SCZ_spect and HC

We found no significant association between N100 amplitude and T1w/T2w-ratio in AC1/AC2 in SCZ_spect or in HC (Figure 4). Results from the regression models with interaction terms (diagnosis×T1w/T2w-ratio) indicate that the associations between N100 amplitude and T1w/T2w-ratio in AC1/AC2 did not differ between SCZ_spect and HC (AC1: estimate (est)=132.26, standard error (se)=139.63, p-value (p)=0.34; AC2: est=144.76, se=124.74, p=0.25).

Mean N100 amplitude, T1w/T2w-ratio in AC1 and T1w/T2w-ratio in AC2 in female/male SCZ_spect and HC

Estimated marginal means and differences in means between female SCZ_spect and female HC and between male SCZ_spect and male HC are provided in Table 3. Of interest, N100 amplitude was significantly smaller in male SCZ_spect compared to male HC (est=4.30, se=1.63, p=0.01).

Table 3 Mean N100 amplitude, T1w/T2w-ratio in AC1 and AC2 in female/male SCZ_spect and HC

	N100 amplitude (microvolts) Mean (SE) [95% CI]	AC1 T1w/T2w-ratio Mean (SE) [95% CI]	AC2 T1w/T2w-ratio Mean (SE) [95% CI]
SCZ_spect F [n=16]	15.40 (2.11) [11.21-19.60]	0.89 (0.003) [0.88-0.89]	0.87 (0.003) [0.87-0.88]
HC F [n=70]	16.53 (1.01) [14.53-18.54]	0.89 (0.001) [0.89-0.89]	0.88 (0.001) [0.88-0.88]
SCZ_spect M [n=17]	9.62 (1.46) [6.72-12.53]	0.89 (0.003) [0.88-0.90]	0.88 (0.003) [0.88-0.89]
HC M [n=74]	13.92 (0.67) [12.56-15.29]	0.89 (0.001) [0.88-0.89]	0.88 (0.001) [0.87-0.88]
SCZ_spect F vs. HC F	est=-1.13 se=2.34 p=0.63 Cohen’s d=0.13 Hedges´g=0.13	est=-0.01 se=0.003 p=0.10 Cohen’s d=0.47 Hedges´g=0.47	est=-5.31e-03 se=3.22e-03 p=0.10 Cohen’s d=0.47 Hedges´g=0.46
SCZ_spect M vs. HC M	est=-4.30 se=1.63 p=0.010* Cohen’s d=0.72 Hedges´g=0.73	est=0.004 se=0.003 p=0.21 Cohen’s d=0.65 Hedges´g=0.66	est=0.01 se=0.003 p=0.09 Cohen’s d=0.47 Hedges´g=0.48

Note: Table 3 shows mean N100 amplitude, mean T1w/T2w-ratio in AC1, primary auditory cortex and in AC2, secondary auditory cortex in SCZ_spect F, female patients with schizophrenia spectrum disorder, in F HC, female healthy controls, in SCZ_spect M, male SCZ_spect and in M HC, male HC. Estimated marginal means were calculated using ANCOVA, where N100 amplitude, T1w/T2w-ratio in AC1 or T1w/T2w-ratio in AC2 were set as dependent variables with age and diagnosis as independent variables. Estimated marginal means are provided with SE (standard error of the mean) and 95% CI, confidence interval. In addition, Table 3 shows differences in means between female SCZ_spect and female HC and between male SCZ_spect and male HC. Est, estimate; p, p-value; *, significant p-value (p<0.017). N100 amplitude was significantly smaller in male SCZ_spect compared to male HC.

Association between N100 amplitude and T1w/T2w-ratio in AC1/AC2 in female/male SCZ_spect and HC

We found no significant association between N100 amplitude and T1w/T2w-ratio in AC1 or in AC2 in female or male SCZ_spect (Figure 5.1.) or in female or male HC (Figure 5.2.) The associations between N100 amplitude and T1w/T2w-ratio in AC1/AC2 did not differ between sex (AC1: est=91.98, se=96.04, p=0.34; AC2: est=-59.05, se=95.87, p=0.92).

In addition to our main results, of interest, we found no difference in T1w/T2w-ratios in the left or right AC1 or AC2 between SCZ_spect and HC (Supplementary analyses 1). N100 amplitude was not associated with T1w/Tw2-ratios in the left or right AC1/AC2 in any groups (Supplementary analyses 2). Further, N100 latency did not differ between SCZ_spect and HC and was not associated with T1w/T2w-ratio in AC1/AC2 in any groups (Supplementary analyses 3). In the combined sample of SCZ_spectand HC, sex explained 4.5%, while age explained 2.7% of variance in N100 amplitude. In SCZ_spectonly, sex explained 13.67%, while age explained 9.91% of the variance in N100 amplitude. In HC only, sex explained 3.17 % and age explained 1.62% of variance in N100 amplitude (Supplementary analyses 4). Further, N100 amplitude was nominally reduced in male SCZ_spect compared to female SCZ_spect (p=0.03), in male HC compared to female HC (p=0.03) and significantly reduced in the combined sample of males (patients and controls) compared to females (patients and controls) (p=0.004) (Supplementary analyses 6). We found reduced T1w/T2w-ratio in the AC2 in female SCZ_spectcompared to male SCZ_spect (p=0.01) and reduced N100 amplitude in the combined sample of male SCZ_spect and HC compared to the combined sample of female SCZ_spect and HC (p=0.004) (Supplementary analyses 6). We did not find any significant difference in N100 amplitude and T1w/T2w-ratio in AC1 or AC2 between AH+ or AH, and the associations did not differ between AH+ and AH- (Supplementary analyses 7). Further, when comparing means between SCZ_spect and HC prior to excluding older HC from the sample, SCZ_spect had significantly smaller N100 amplitude compared to HC (p=0.017) (Supplementary analyses 8.1.). When comparing means between SCZ_spect and HC after stricter age-matching than in our main analysis, we found no significant difference in N100 amplitude or in T1w/T2w-ratio in AC1/AC2 between SCZ_spect and HC (Supplementary analyses 8.2.). Further, antipsychotic use explained 2.25% of variance in N100 amplitude, 6.60% of variance in T1w/T2w-ratio in AC1 and 4.58% of variance in T1w/T2w-ratio in AC2 (Supplementary analyses 9.2.). Total PANSS score explained 2.7% of variance in N100 amplitude, 10.12% of variance in T1w/T2w-ratio in AC1 and 10.54% of variance in T1w/T2w-ratio in AC2 (Supplementary analyses 10.).

The current study yielded three main findings. First, N100 amplitude was significantly reduced in male SCZ_spect compared to male HC and nominally reduced in the combined sample of SCZ_spect compared to the combined sample of HC. Second, T1w/T2w-ratio in AC1/AC2 did not differ between any groups. Finally, we did not find any significant association between N100 amplitude and T1w/T2w-ratio in the AC1 or in AC2.

To our knowledge, this is the first published report showing reduced N100 amplitude in male SCZ_spect compared to male HC ⁵³. While we at this point can only speculate why N100 amplitude was reduced in males with SCZ_spect, but not in females with SCZ_spect, the neuroprotective abilities of estrogen may play a role ⁷⁴.

Of interest, our supplementary analyses revealed reduced N100 amplitude in the combined sample of male patients and controls compared to the combined sample of female patients and controls (Supplementary Table 6). These findings are in accordance with previous reports of sex differences in auditory functioning in healthy individuals. Females have larger auditory brainstem response ^75–77 and larger P300 amplitude, indicating enhanced auditory function, compared to males ⁴⁹. Further, females are more sensitive to high frequency sounds ⁷⁸ while males have a superior spatial auditory perception ^79–81. In females the AC1 is more sensitive to noise compared to males ⁸². Together, these findings indicate sex differences in auditory function and estrogen may play a role. Estrogen is believed to protect the auditory system from noise and age-related damage and to optimize auditory processing ⁸³. Sex differences in auditory function are already present in infants ^84,85, indicating that exposure to sex steroids’ metabolites during prenatal development may lead to fundamental sex differences in auditory function ⁸⁶. Further, auditory function changes during the menstrual cycle ^87–89 and during pregnancy, a period when estrogen (and progesterone) levels rise continuously until giving birth ^90,91. Peri- and postmenopausal women have diminished auditory function ⁹² and hormone-replacement therapy may reverse this decline ^93,94. Further females with Turner´s syndrome, a disorder characterized by estrogen deficiency, have increased rate of hearing decline ⁸³ and auditory pathology ⁹⁵. Together, these findings indicate that estrogen has a neuroprotective role in auditory function ⁹⁶. The neuroprotective effect of estrogen is believed to be partly mediated through its interaction with brain-derived neurotrophic factor (BDNF), gamma-aminobutyric acid (GABA), norepinephrine ^83,97 and through enhancing myelination ^46,98,99. Women with MS have fewer MS relapses during pregnancy, suggesting a neuroprotective effect of estrogen through promoting myelination ¹⁰⁰. More research is needed to fully understand the effect of sex steroids and myelination on auditory function in humans ⁸³. In addition, the relationship between sex steroids and N100 amplitude remains elusive.

The effect of sex steroids on auditory function in SCZ_spect remain unknown. However, animal models of SCZ_spect show that estrogen plays a neuroprotective role in auditory function when interacting with BDNF, ¹⁰¹. Further, sex differences in dopamine ¹⁰² and GABA ¹⁰³, neurotransmitters believed to have implications for generating post-synaptic potentials ^104–106 which are important for auditory function, are reported in SCZ_spect.. Thus, sex differences in these neurotransmitters may also be involved in the current findings of reduced N100 amplitude in males with SCZ_spect. Understanding the relationship between sex steroids and N100 amplitude in SCZ_spect may provide insight into new treatment targets. Animal models of SCZ_spect show evidence suggesting that estrogen may be protective of the disorder through its interaction with BDNF and thus that estrogen–BDNF interactions may be new treatment targets ¹⁰¹.

The N100 amplitude may help us understand basic elemental mechanisms of brain function in SCZ_spect. In a previous study, we found positive associations between AC thickness and N100 amplitude in SCZ_spect, suggesting that a common neural substrate may underlie AC thickness and N100 amplitude alterations ⁶¹. Based on these previous findings, as well as on a growing literature indicating myelination abnormalities in SCZ_spect ^107–114, we here aimed to examine whether myelination in AC may play a role in this association. Myelination plays an important role in spike synchrony ¹¹⁵. Thus, impaired myelination of pyramidal neurons in the AC could lead to abnormal neural synchrony and altered auditory processing, reflected by reduced N100 amplitude in SCZ_spect ^16,116. Based on the assumption of altered myelination and altered synchronization of auditory pyramidal neurons in SCZ_spect, we expected to find reduced N100 amplitude and decreased T1w/T2w-ratio in AC in SCZ_spect and an association between reduced N100 amplitude and decreased T1w/T2w-ratio. However, in the current study N100 amplitude and T1w/T2w-ratio did not differ significantly between patients and controls and N100 amplitude was not associated with T1w/T2w-ratio in any groups. Thus, our findings did not support the hypothesis that altered myelination in the AC1/AC2, indexed by T1w/T2w-ratio, underlies N100 abnormalities in SCZ_spect. However, it has been questioned to what degree T1w/T2w-ratio measures myelin. In one combined MRI and post-mortem study of patients with MS, the T1w/T2w-ratio correlated with dendritic density rather than myelin density ⁴². Furthermore, while a high spatial correlation with cortical myelination was demonstrated by Glasser et al. (2014) ¹¹⁷, recent studies have reported lower correlations with indices of myelin in white matter ^118,119, which shows that the T1w/T2w-ratio is a complex signal and not a quantitative marker of myelin content only. While the current findings point towards a lack of association between N100 amplitude and T1w/T2w-ratio in SCZ_spect, we cannot exclude altered myelination in the AC as a neural substrate for N100 amplitude reduction as previously reported in these disorders. To fully understand how myelination in the AC may relate to N100 amplitude in SCZ_spect, we need more precise measures of intracortical myelin. In theory, although speculative, another way to investigate the relationship between N100 amplitude and myelination in the AC may be combining intracortical EEG examinations with postmortem examination of myelin content in the AC. However, this method is hampered by ethical and technical challenges. Therefore, a combination of EEG and MRI measures acquired in vivo is more feasible.

Other factors than altered myelination, indexed by T1w/T2w-ratio, may explain reduced N100 amplitude in SCZ_spect. At this point we can only speculate what neural substrate may underly reduced N100 amplitude and thus altered function of AC pyramidal cells in SCZ_spect. Altered synaptic pruning ^120,121 resulting in reduced dendritic spine density on cortical pyramidal neurons ^122,123, is part of the pathogenesis of SCZ_spect. Reduced dendritic spine density on AC pyramidal cells (and interneurons) may result in desynchronized firing, a decreased summation of postsynaptic potentials and thus in reduced N100 amplitude in SCZ_spect ^116,124. Further, excessive synaptic pruning in the AC in SCZ_spect may lead to impaired neural communication in cortical areas involved in auditory processing and may result in auditory hallucinations ^125–127. Of note, these two alternative potential mechanisms are consistent with our previous finding of an association between AC cortical thickness and N100 amplitude in SCZ_spect ⁶¹. While the current study focused on cortical structures, deeper subcortical white matter may be associated with N100 amplitude.

Few studies have investigated the effect of APs on N100 amplitude and findings are inconclusive ^128–130. APs commonly used to treat SCZ_spect have high affinity to the dopamine D2 receptor and to the 5-hydroxytryptamine 2 A receptor ¹³¹. Thus, APs may influence N100 amplitude either directly by having effect on neural generators of the N100 or indirectly by decreasing symptoms in SCZ_spect ^128,132. Studies investigating correlations between the dose of APs and N100 amplitude are inconclusive ^133,134. Further, one study has shown no effect of APs on the gray/white-matter contrast along the cortical surface ¹³⁵. To conclude, longitudinal studies investigating N100 amplitude and myelination in individuals with SCZ_spect before and after starting on APs are needed to untangle the exact effect of APs on N100 amplitude and myelination.

Some limitations should be considered when interpreting the current findings. As mentioned above, while the T1w/T2w-ratio is spatially correlated with myelination of the cortex, it is not a direct measure of myelin content. Second, the small sample of SCZ_spect is an issue, although the study was hypothesis-driven and focusing on specific regions of interest, limiting the number of tests. Further, the way that we generated AEPs, using a small number of trials instead of what is typically recommended for AEPs is unusual. However, after visual inspection of AEPs, we found that the relatively strong stimulus intensity and the long ISI did elicit robust and large-amplitude AEPs as described by others ⁶⁸. Strengths of this study include the use of multimodal imaging (EEG and MRI), a sample of clinically well characterized participants, rigorous quality control and assessment of sex differences.

In conclusion, our results are consistent with previous findings of reduced N100 amplitude in SCZ_spect although the finding was restricted to males only. We did not find altered T1w-T2w-ratio within AC in SCZ_spect compared to HC and found no associations between the N100 amplitude and T1w-T2w-ratio. More precise estimates of intracortical myelin in the AC and larger patient samples are needed to disentangle whether altered myelination explains N100 amplitude reduction in SCZ_spect.

Acknowledgments

This work was supported by the Research Council of Norway (223273, 274359, 249795, 248238), the South – Eastern Norway Regional Health Authority (2014097, 2015044, 2015073, 2017097, 2018037, 2018076, 2019104), the Norwegian Extra Foundation for Health and Rehabilitation (2015/FO5146), the European Research Council under the European Union's Horizon 2020 research and Innovation program (ERC StG 802998), the Ebbe Frøland foundation, and a research grant from Mrs. Throne-Holst.

Conflict of interest

T.E. is a consultant to BrainWaveBank and Sunovion and received speaker’s honoraria from Lundbeck and Janssen Cilag. O.A.A. is a consultant to cortechs.ai and received speaker’s honoraria from Lundbeck, Janssen, Sunovion. I.A. has received speaker’s honoraria from Lundbeck. The other authors report no conflict of interest.

Data and Code Availability Statement

MRI and EEG data used in the following study was collected at our research center, NORMENT, Oslo, Norway, as part of the TOP study. The data was collected between 2015 and 2019. The MRI and EEG data is currently not openly available due to ethical and privacy issues of clinical data. The study was approved by the Regional Committees for Medical and Health Research Ethics of South – Eastern Norway, and all participants provided written informed consent.

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You are reading this latest preprint version

Relationship between N100 amplitude and T1w/T2w-ratio in the auditory cortex in schizophrenia spectrum disorders

Status:

Version 1

Abstract

Figures

Introduction

Methods

Participants

Clinical assessment

MRI processing

Auditory evoked potentials obtained from the PPI paradigm

EEG acquisition and processing

Statistical analyses

Results

Demographics and clinical data

Mean N100 amplitude, T1w/T2w-ratio in AC1 and T1w/T2w-ratio in AC2 in SCZ_spect and HC

Association between N100 amplitude and T1w/T2w-ratio in AC1/AC2 in SCZ_spect and HC

Mean N100 amplitude, T1w/T2w-ratio in AC1 and T1w/T2w-ratio in AC2 in female/male SCZ_spect and HC

Association between N100 amplitude and T1w/T2w-ratio in AC1/AC2 in female/male SCZ_spect and HC

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1

Relationship between N100 amplitude and T1w/T2w-ratio in the auditory cortex in schizophrenia spectrum disorders

Status:

Version 1

Abstract

Figures

Introduction

Methods

Participants

Clinical assessment

MRI processing

Auditory evoked potentials obtained from the PPI paradigm

EEG acquisition and processing

Statistical analyses

Results

Demographics and clinical data

Mean N100 amplitude, T1w/T2w-ratio in AC1 and T1w/T2w-ratio in AC2 in SCZspect and HC

Association between N100 amplitude and T1w/T2w-ratio in AC1/AC2 in SCZspect and HC

Mean N100 amplitude, T1w/T2w-ratio in AC1 and T1w/T2w-ratio in AC2 in female/male SCZspect and HC

Association between N100 amplitude and T1w/T2w-ratio in AC1/AC2 in female/male SCZspect and HC

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1

Mean N100 amplitude, T1w/T2w-ratio in AC1 and T1w/T2w-ratio in AC2 in SCZ_spect and HC

Association between N100 amplitude and T1w/T2w-ratio in AC1/AC2 in SCZ_spect and HC

Mean N100 amplitude, T1w/T2w-ratio in AC1 and T1w/T2w-ratio in AC2 in female/male SCZ_spect and HC

Association between N100 amplitude and T1w/T2w-ratio in AC1/AC2 in female/male SCZ_spect and HC