Long-latency auditory evoked response amplitudes at first episode of psychosis predict six-month recovery in positive symptom severity.

Predicting treatment response would facilitate individualized medical treatment in first-episode psychosis (FEP). We examined relationships between auditory-evoked M100 and longitudinal change in positive symptoms in FEP. M100 was measured from source-resolved magnetoencephalography and symptoms were assessed at initial contact and six months later. M100 at baseline significantly predicted symptom change. Larger M100 at baseline predicted symptom improvement, as did shorter untreated psychosis. Shorter untreated psychosis also correlated with larger M100, and M100 mediated the effect of untreated psychosis on treatment response. Thus, M100 may provide a proximal and objective index of untreated psychosis and a viable route to individualized medicine.

Development of Biomarkers Potentially Sensitive to Early Psychosis Using Mismatch Negativity (MMN) to Complex Pattern Deviations.

Infrequent stimulus deviations from repetitive sequences elicit mismatch negativity (MMN) even passively, making MMN practical for clinical applications. Auditory MMN is typically elicited by a change in one (or more) physical stimulus parameters (eg, pitch, duration). This lower-order simple MMN (sMMN) is impaired in long-term schizophrenia. However, sMMN contains activity from release from stimulus adaptation, clouding its face validity as purely deviance-related. More importantly, it is unreliably reduced in samples of first-episode psychosis, limiting its utility as a biomarker. Complex pattern-deviant MMN (cMMN) tasks, which elicit early and late responses, are based on higher-order abstractions and better isolate deviance detection. Their abstract nature may increase the sensitivity to processing deficits in early psychosis. However, both the early and late cMMNs are small, limiting separation between healthy and psychotic samples. In 29 healthy individuals, we tested a new dual-rule cMMN paradigm to assess additivity of deviance. Sounds alternated lateralization between left and right, and low and high pitches, creating a left-low, right-high alternating pattern. Deviants were a repeated left-low, violating lateralization and pitch patterns. Early and late cMMNs on the dual-rule task were significantly larger than those on the one-rule extra tone cMMN task (P < .05). Further, the dual-rule early cMMN was not significantly smaller than pitch or duration sMMNs (P > .48, .28, respectively). These results demonstrate additivity for cMMN pattern-violating rules. This increase in cMMN amplitude should increase group difference effect size, making it a prime candidate for a biomarker of disease presence at first psychotic episode, and perhaps even prior to the emergence of psychosis.

Intensity-dependent modulation of the early auditory gamma-band response in first-episode schizophrenia and its association with disease symptoms.

BACKGROUND: Gamma-band activity has been the focus of considerable research in schizophrenia. Discrepancies exist regarding the integrity of the early auditory gamma-band response (EAGBR), a stimulus-evoked oscillation, and its relationship to symptoms in early disease. Variability in task design may play a role. This study examined sensitivity of the EAGBR to stimulus intensity and its relation to symptoms and functional impairments in the first-episode schizophrenia spectrum (FESz). METHOD: Magnetoencephalography was recorded from 35 FESz and 40 matched healthy controls (HC) during presentation of 3 tone intensities (75 dB, 80 dB, 85 dB). MRIs were collected to localize auditory cortex activity. Wavelet-transformed single trial epochs and trial averages were used to assess EAGBR intertrial phase coherence (ITPC) and evoked power, respectively. Symptoms were assessed using the Positive and Negative Syndrome Scale. RESULTS: Groups did not differ in overall EAGBR power or ITPC. While HC exhibited EAGBR enhancement to increasing intensity, FESz exhibited reduced power to the 80 dB tone and, relative to HC, increased power to the 75 dB tone. Larger power and ITPC were correlated with more severe negative, thought disorganization, and resistance symptoms. Stronger ITPC was associated with impaired social functioning. DISCUSSION: EAGBR showed no overall deficit at disease onset. Rather, FESz exhibited a differential response across tone intensity relative to HC, emphasizing the importance of stimulus characteristics in EAGBR studies. Associations between larger EAGBR and more severe symptoms suggest aberrant synchronization driving overinclusive perceptual binding that may relate to deficits in executive inhibition of initial sensory activity.

Is source-resolved magnetoencephalographic mismatch negativity a viable biomarker for early psychosis?

Mismatch negativity (MMN) is an auditory event-related response reflecting the pre-attentive detection of novel stimuli and is a biomarker of cortical dysfunction in schizophrenia (SZ). MMN to pitch (pMMN) and to duration (dMMN) deviant stimuli are impaired in chronic SZ, but it is less clear if MMN is reduced in first-episode SZ, with inconsistent findings in scalp-level EEG studies. Here, we investigated the neural generators of pMMN and dMMN with MEG recordings in 26 first-episode schizophrenia spectrum (FEsz) and 26 matched healthy controls (C). We projected MEG inverse solutions into precise functionally meaningful auditory cortex areas. MEG-derived MMN sources were in bilateral primary auditory cortex (A1) and belt areas. In A1, pMMN FEsz reduction showed a trend towards statistical significance (F(1,50) = 3.31; p = .07), and dMMN was reduced in FEsz (F(1,50) = 4.11; p = .04). Hypothesis-driven comparisons at each hemisphere revealed dMMN reduction in FEsz occurred in the left (t(56) = 2.23; p = .03; d = .61) but not right (t(56) = 1.02; p = .31; d = .28) hemisphere, with a moderate effect size. The added precision of MEG source solution with high-resolution MRI and parcellation of A1 may be requisite to detect the emerging pathophysiology and indicates a critical role for left hemisphere pathology at psychosis onset. However, the moderate effect size in left A1, albeit larger than reported in scalp MMN meta-analyses, casts doubt on the clinical utility of MMN for differential diagnosis, as a majority of patients will overlap with the healthy individual's distribution.

Intensity and inter-stimulus-interval effects on human middle- and long-latency auditory evoked potentials in an unpredictable auditory context.

It is not known how Auditory-Evoked Responses (AERs) comprising Middle Latency Responses (MLRs) and Long Latency Responses (LLRs) are modulated by stimulus intensity and inter-stimulus interval (ISI) in an unpredictable auditory context. Further, intensity and ISI effects on MLR and LLR have never been assessed simultaneously in the same humans. To address this important question, thirty participants passively listened to a random sequence of auditory clicks of three possible intensities (65, 75, and 85 dB) at five possible ISI ranges (0.25 to 0.5 s, 0.5 to 1 s, 1 to 2 s, 2 to 4 s, 4 to 8 s) over four to seven one-hour sessions while EEG was recorded. P0, Na, Pa, Nb, and Pb MLR peaks and N1 and P2 LLR peaks were measured. MLRs P0 (p = .005), Pa (p = .021), and Pb (p = <.001) were modulated by intensity, while only MLR Pb (p = <.001) was modulated by ISI. LLR N1 and P2 were modulated by both intensity and ISI (all p values < .001). Intensity and ISI interacted at Pb, N1, and P2 (all p values < .001), with greater intensity effects at longer ISIs and greater ISI effects at louder intensities. Together, these results provide a comprehensive picture of intensity and ISI effects on AER across the entire thalamocortical auditory pathway, while controlling for stimulus predictability. Moreover, they highlight P0 as the earliest MLR response sensitive to stimulus intensity and Pb (~50 ms) as the earliest cortical response coding for ISIs above 250 ms and showing an interdependence between intensity and ISI effects.

Effects of cTBS on the Frequency-Following Response and Other Auditory Evoked Potentials.

The frequency-following response (FFR) is an auditory evoked potential (AEP) that follows the periodic characteristics of a sound. Despite being a widely studied biosignal in auditory neuroscience, the neural underpinnings of the FFR are still unclear. Traditionally, FFR was associated with subcortical activity, but recent evidence suggested cortical contributions which may be dependent on the stimulus frequency. We combined electroencephalography (EEG) with an inhibitory transcranial magnetic stimulation protocol, the continuous theta burst stimulation (cTBS), to disentangle the cortical contribution to the FFR elicited to stimuli of high and low frequency. We recorded FFR to the syllable /ba/ at two fundamental frequencies (Low: 113 Hz; High: 317 Hz) in healthy participants. FFR, cortical potentials, and auditory brainstem response (ABR) were recorded before and after real and sham cTBS in the right primary auditory cortex. Results showed that cTBS did not produce a significant change in the FFR recorded, in any of the frequencies. No effect was observed in the ABR and cortical potentials, despite the latter known contributions from the auditory cortex. Possible reasons behind the negative results include compensatory mechanisms from the non-targeted areas, intraindividual variability of the cTBS effectiveness, and the particular location of our target area, the primary auditory cortex.

The Potential Effect of Forbrain as an Altered Auditory Feedback Device.

Purpose: The purpose of this study was to run a proof of concept on a new commercially available device, Forbrain® (Sound For Life Ltd/Soundev, Luxemburg, model UN38.3), to test whether it can modulate the speech of its users. Method: Participants were instructed to read aloud a text of their choice during 3 experimental phases: baseline, test, and posttest, while wearing a Forbrain® headset. Critically, for half of the participants (Forbrain group), the device was turned on during the test phase, whereas for the other half (control group), the device was kept off. Voice recordings were analyzed to derive 6 quantitative measures of voice quality over each of the phases of the experiment. Results: A significant Group × Phase interaction was obtained for the smoothed cepstral peak prominence, a measure of voice harmony, and for the trendline of the long-term average spectrum, a measure of voice robustness, this latter surviving Bonferroni correction for multiple comparisons. Conclusions: The results of this study indicate the effectiveness of Forbrain® in modifying the speech of its users. It is suggested that Forbrain® works as an altered auditory feedback device. It may hence be used as a clinical device in speech therapy clinics, yet further studies are warranted to test its usefulness in clinical groups.

Binaural Beat: A Failure to Enhance EEG Power and Emotional Arousal.

When two pure tones of slightly different frequencies are delivered simultaneously to the two ears, is generated a beat whose frequency corresponds to the frequency difference between them. That beat is known as acoustic beat. If these two tones are presented one to each ear, they still produce the sensation of the same beat, although no physical combination of the tones occurs outside the auditory system. This phenomenon is called binaural beat. In the present study, we explored the potential contribution of binaural beats to the enhancement of specific electroencephalographic (EEG) bands, as previous studies suggest the potential usefulness of binaural beats as a brainwave entrainment tool. Additionally, we analyzed the effects of binaural-beat stimulation on two psychophysiological measures related to emotional arousal: heart rate and skin conductance. Beats of five different frequencies (4.53 Hz -theta-, 8.97 Hz -alpha-, 17.93 Hz -beta-, 34.49 Hz -gamma- or 57.3 Hz -upper-gamma) were presented binaurally and acoustically for epochs of 3 min (Beat epochs), preceded and followed by pink noise epochs of 90 s (Baseline and Post epochs, respectively). In each of these epochs, we analyzed the EEG spectral power, as well as calculated the heart rate and skin conductance response (SCR). For all the beat frequencies used for stimulation, no significant changes between Baseline and Beat epochs were observed within the corresponding EEG bands, neither with binaural or with acoustic beats. Additional analysis of spectral EEG topographies yielded negative results for the effect of binaural beats in the scalp distribution of EEG spectral power. In the psychophysiological measures, no changes in heart rate and skin conductance were observed for any of the beat frequencies presented. Our results do not support binaural-beat stimulation as a potential tool for the enhancement of EEG oscillatory activity, nor to induce changes in emotional arousal.

Differential deviant probability effects on two hierarchical levels of the auditory novelty system.

Deviance detection is a key functional property of the auditory system that allows pre-attentive discrimination of incoming stimuli not conforming to a rule extracted from the ongoing constant stimulation, thereby proving that regularities in the auditory scene have been encoded in the auditory system. Using simple-feature stimulus deviations, regularity encoding and deviance detection have been reported in brain responses at multiple latencies of the human Auditory Evoked Potential (AEP), such as the Mismatch Negativity (MMN; peaking at 100-250ms from stimulus onset) and Middle-Latency Responses (MLR; peaking at 12-50ms). More complex levels of regularity violations, however, are only indexed by AEPs generated at higher stages of the auditory system, suggesting a hierarchical organization in the encoding of auditory regularities. The aim of the current study is to further characterize the auditory hierarchy of novelty responses, by assessing the sensitivity of MLR components to deviant probability manipulations. MMNs and MLRs were recorded in 24 healthy participants, using an oddball location paradigm with three different deviant probabilities (5%, 10% and 20%), and a reversed-standard (91.5%). We analyzed differences in the MLRs elicited to each of the deviant stimuli and the reversed-standard, as well as within deviant stimuli. Our results confirmed deviance detection at the level of both MLRs and MMN, but significant differences for deviant probabilities were found only for the MMN. These results suggest a functional dissociation between regularity encoding, already present at early stages of auditory processing, and the encoding of the probability with which this regularity is disrupted, which is only processed at higher stages of the auditory hierarchy.