Auditory Steady-state Response Power Research Articles

40-Hz auditory steady-state response deficits are correlated with the severity of persistent auditory verbal hallucination in patients with schizophrenia

BackgroundAbnormal 40 Hz auditory steady-state response (ASSR) has been observed in some psychiatric disorders. Nevertheless, the role of 40 Hz ASSR in persistent auditory verbal hallucinations (pAVHs) schizophrenia (SCZ) is still unknown. This study aims to investigate whether the 40 Hz ASSR impairment is related to pAVHs and can detect pAVHs severity. MethodsWe analyzed high-density electroencephalography data that from 43 pAVHs patients (pAVH group), 20 moderate auditory verbal hallucinations patients (mid-AVH group), and 24 without auditory verbal hallucinations patients (non-AVH group). Event-related spectral perturbation and inter-trial phase coherence (ITPC) were calculated to quantify dynamic changes of the 40 Hz ASSR power and ITPC, respectively. ResultsFrontal-central, the 40 Hz ASSR power, and ITPC were significantly lower in the pAVH group than in the non-AVH group; There was no significant difference between the pAVH and mid-AVH group. The 40 Hz ASSR was significantly negatively correlated with the severity of pAVHs. The 40 Hz ASSR power, and ITPC could be used as a combinational marker to detect SCZ patients with and without pAVHs. ConclusionOur findings have shed light on the pathological mechanism of pAVHs in SCZ patients. These results can provide potential avenues for therapeutic intervention of pAVHs.

Alterations of auditory-evoked gamma oscillations are more pronounced than alterations of spontaneous power of gamma oscillation in early stages of schizophrenia

Several animal models of schizophrenia and patients with chronic schizophrenia have shown increased spontaneous power of gamma oscillations. However, the most robust alterations of gamma oscillations in patients with schizophrenia are reduced auditory–oscillatory responses. We hypothesized that patients with early-stage schizophrenia would have increased spontaneous power of gamma oscillations and reduced auditory–oscillatory responses. This study included 77 participants, including 27 ultra-high-risk (UHR) individuals, 19 patients with recent-onset schizophrenia (ROS), and 31 healthy controls (HCs). The auditory steady-state response (ASSR) and spontaneous power of gamma oscillations measured as induced power during the ASSR period were calculated using electroencephalography during 40-Hz auditory click-trains. The ASSRs were lower in the UHR and ROS groups than in the HC group, whereas the spontaneous power of gamma oscillations in the UHR and ROS groups did not significantly differ from power in the HC group. Both early-latency (0–100 ms) and late-latency (300–400 ms) ASSRs were significantly reduced and negatively correlated with the spontaneous power of gamma oscillations in the ROS group. In contrast, UHR individuals exhibited reduced late-latency ASSR and a correlation between the unchanged early-latency ASSR and the spontaneous power of gamma oscillations. ASSR was positively correlated with the hallucinatory behavior score in the ROS group. Correlation patterns between the ASSR and spontaneous power of gamma oscillations differed between the UHR and ROS groups, suggesting that the neural dynamics involved in non-stimulus-locked/task modulation change with disease progression and may be disrupted after psychosis onset.

Sub-anesthetic doses of ketamine increase single cell entrainment in the rat auditory cortex during auditory steady-state response.

Understanding the effects of the N-methyl-D-aspartate receptor (NMDA-R) antagonist ketamine on brain function is of considerable interest due to the discovery of its fast-acting antidepressant properties. It is well known that gamma oscillations are increased when ketamine is administered to rodents and humans, and increases in the auditory steady-state response (ASSR) have also been observed. To elucidate the cellular substrate of the increase in network activity and synchrony observed by sub-anesthetic doses of ketamine, the aim was to investigate spike timing and regularity and determine how this is affected by the animal's motor state. Single unit activity and local field potentials from the auditory cortex of awake, freely moving rats were recorded with microelectrode arrays during an ASSR paradigm. Ketamine administration yielded a significant increase in ASSR power and phase locking, both significantly modulated by motor activity. Before drug administration, putative fast-spiking interneurons (FSIs) were significantly more entrained to the stimulus than putative pyramidal neurons (PYRs). The degree of entrainment significantly increased at lower doses of ketamine (3 and 10 mg/kg for FSIs, 10 mg/kg for PYRs). At the highest dose (30 mg/kg), a strong increase in tonic firing of PYRs was observed. These findings suggest an involvement of FSIs in the increased network synchrony and provide a possible cellular explanation for the well-documented effects of ketamine-induced increase in power and synchronicity during ASSR. The results support the importance to evaluate different motor states separately for more translational preclinical research.

Phase Delay of the 40 Hz Auditory Steady-State Response Localizes to Left Auditory Cortex in Schizophrenia.

Background. The auditory steady state response (ASSR) is generated in bilateral auditory cortex and is the most used electroencephalographic (EEG) or magnetoencephalographic measure of gamma band abnormalities in schizophrenia. While the finding of reduced 40-Hz ASSR power and phase consistency in schizophrenia have been replicated many times, the 40-Hz ASSR phase locking angle (PLA), which assesses oscillation latency or phase delay, has rarely been examined. Furthermore, whether 40-Hz ASSR phase delay in schizophrenia is lateralized or common to left and right auditory cortical generators is unknown. Methods. Previously analyzed EEG data recorded from 24 schizophrenia patients and 24 healthy controls presented with 20-, 30-, and 40-Hz click trains to elicit ASSRs were re-analyzed to assess PLA in source space. Dipole moments in the right and left hemisphere were used to assess both frequency and hemisphere specificity of ASSR phase delay in schizophrenia. Results. Schizophrenia patients exhibited significantly reduced (ie, phase delayed) 40-Hz PLA in the left, but not the right, hemisphere, but their 20- and 30-Hz PLA values were normal. This left-lateralized 40-Hz phase delay was unrelated to symptoms or to previously reported left-lateralized PLF reductions in the schizophrenia patients. Conclusions. Consistent with sensor-based studies, the 40-Hz ASSR source-localized to left, but not right, auditory cortex was phase delayed in schizophrenia. Consistent with prior studies showing left temporal lobe volume deficits in schizophrenia, our findings suggest sluggish entrainment to 40-Hz auditory stimulation specific to left auditory cortex that are distinct from well-established deficits in gamma ASSR power and phase synchrony.

Effects of the Glycine Transporter-1 Inhibitor Iclepertin (BI 425809) on Sensory Processing, Neural Network Function, and Cognition in Animal Models Related to Schizophrenia.

N-methyl-D-aspartate (NMDA) receptor hypofunction leading to neural network dysfunction is thought to play an important role in the pathophysiology of cognitive impairment associated with schizophrenia (CIAS). Increasing extracellular concentrations of the NMDA receptor co-agonist glycine through inhibition of glycine transporter-1 (GlyT1) has the potential to treat CIAS by improving cortical network function through enhanced glutamatergic signaling. Indeed, the novel GlyT1 inhibitor iclepertin (BI 425809) improved cognition in a recent clinical study in patients with schizophrenia. The present study tested the ability of iclepertin to reverse deficits in auditory sensory processing and cortical network function induced by the uncompetetive NMDA receptor antagonist, MK-801, using electroencephalography (EEG) to measure auditory event-related potentials (AERPs) and 40 Hz auditory steady-state response (ASSR). In addition, improvements in memory performance with iclepertin were evaluated using the T-maze spontaneous alternation test in MK-801-treated mice and the social recognition test in naïve rats. Iclepertin reversed MK-801-induced deficits in the AERP readouts N1 amplitude and N1 gating, as well as reversing deficits in 40 Hz ASSR power and intertrial coherence. Additionally, iclepertin significantly attenuated an MK-801-induced increase in basal gamma power. Furthermore, iclepertin reversed MK-801-induced working memory deficits in mice and improved social recognition memory performance in rats. Overall, this study demonstrates that inhibition of GlyT1 is sufficient to attenuate MK-801-induced deficits in translatable EEG parameters relevant to schizophrenia. Moreover, iclepertin showed memory-enhancing effects in rodent cognition tasks, further demonstrating the potential for GlyT1 inhibition to treat CIAS. SIGNIFICANCE STATEMENT: Despite the significant patient burden caused by cognitive impairment associated with schizophrenia, there are currently no approved pharmacotherapies. In this preclinical study, the novel glycine transporter inhibitor iclepertin (BI 425809) reversed sensory processing deficits and neural network dysfunction evoked by inhibition of N-methyl-D-aspartate receptors and enhanced working memory performance and social recognition in rodents. These findings support previous clinical evidence for the procognitive effects of iclepertin.

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

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.

Auditory steady-state responses during and after a stimulus: Cortical sources, and the influence of attention and musicality

The auditory steady-state response (ASSR) is an oscillatory brain response generated by periodic auditory stimuli and originates mainly from the temporal auditory cortices. Recent data show that while the auditory cortices are indeed strongly activated by the stimulus when it is present (ON ASSR), the anatomical distribution of ASSR sources involves also parietal and frontal cortices, indicating that the ASSR is a more complex phenomenon than previously believed. Furthermore, while the ASSR typically continues to oscillate even after the stimulus has stopped (OFF ASSR), very little is known about the characteristics of the OFF ASSR and how it compares to the ON ASSR. Here, we assessed whether the OFF and ON ASSR powers are modulated by the stimulus properties (i.e. volume and pitch), selective attention, as well as individual musical sophistication. We also investigated the cortical source distribution of the OFF ASSR using a melody tracking task, in which attention was directed between uniquely amplitude-modulated melody streams that differed in pitch. The ON and OFF ASSRs were recorded with magnetoencephalography (MEG) on a group of participants varying from low to high degree of musical sophistication. Our results show that the OFF ASSR is different from the ON ASSR in nearly every aspect. While the ON ASSR was modulated by the stimulus properties and selective attention, the OFF ASSR was not influenced by any of these factors. Furthermore, while the ON ASSR was generated primarily from temporal sources, the OFF ASSR originated mainly from the frontal cortex. These findings challenge the notion that the OFF ASSR is merely a continuation of the ON ASSR. Rather, they suggest that the OFF ASSR is an internally-driven signal that develops from an initial sensory processing state (ON ASSR), with both types of ASSRs clearly differing in cortical representation and character. Furthermore, our results show that the ON ASSR power was enhanced by selective attention at cortical sources within each of the bilateral frontal, temporal, parietal and insular lobes. Finally, the ON ASSR proved sensitive to musicality, demonstrating positive correlations between musical sophistication and ASSR power, as well as with the degree of attentional ASSR modulation at the left and right parietal cortices. Taken together, these results show new aspects of the ASSR response, and demonstrate its usefulness as an effective tool for analysing how selective attention interacts with individual abilities in music perception.

Attentional modulation of the auditory steady-state response across the cortex

Selective auditory attention allows us to focus on relevant sounds within noisy or complex auditory environments, and is essential for the processing of speech and music. The auditory steady-state response (ASSR) has been proposed as a neural measure for tracking selective auditory attention, even within continuous and complex soundscapes. However, the current literature is inconsistent on how the ASSR is influenced by selective attention, with findings based primarily on attention being directed to either ear rather than to sound content. In this experiment, a mixture of melody streams was presented to both ears identically (diotically) as we examined if selective auditory attention to sound content influences the ASSR. Using magnetoencephalography (MEG), we assessed the stream-specific ASSRs from three frequency-tagged melody streams when attention was directed between each melody stream, based on their respective pitch and timing. Our main results showed that selective attention enhances the ASSR power of an attended melody stream by 14% at a general sensor level. This ability to readily capture attentional changes in a stimuli-precise manner makes the ASSR a useful tool for studying selective auditory attention, especially in complex auditory environments. As a secondary aim, we explored the distribution of cortical ASSR sources and their respective attentional modulation using a distributed source model of the ASSR activity. Notably, we uncovered the existence of ASSR attentional modulation outside the temporal cortices. Across-subject averages of the attentional enhancement over the cortical surface suggest that frontal regions show up to ~80% enhancement, while temporal and parietal cortices were enhanced by 20–25%. Importantly, this work advocates a novel ‘beyond the temporal cortex’ perspective on ASSR modulation and also serves as a template for future studies to precisely pin-point which cortical sites are more susceptible to ASSR attentional modulation.

Gamma Oscillations and Excitation/Inhibition Imbalance: Parallel Effects of NMDA Receptor Antagonism and the Psychosis Risk Syndrome

NMDA receptor (NMDAR) hypofunction is a putative pathophysiological mechanism theorized to contribute to deficient stimulus-evoked gamma oscillations and excessive baseline gamma power (reflecting excitation/inhibition (E/I) imbalance) in schizophrenia. We examined the effect of the NMDAR antagonist, ketamine, on the 40Hz auditory steady state response (ASSR) and pre-stimulus baseline gamma power. Further, we examined 40Hz ASSR and baseline gamma power in psychosis risk syndrome (PRS) youth.

Relationship of Metacognition and Insight to Neural Synchronization and Cognitive Function in Early Phase Psychosis.

Metacognition is the process of thinking about one's own mental states. It involves a range of faculties that allow an individual to integrate information and form understanding of self and others, and use this understanding to respond to life challenges. Clinical insight is the awareness of one's mental illness, its consequences, and the need for treatment. Persons with psychotic disorders show impaired metacognition and insight, but the neurobiological bases for these impairments are not well characterized. We hypothesized that metacognition and insight may depend on capacity of neural circuits to synchronize at gamma frequencies, as well as the integrity of underlying cognitive processes. In order to test these hypotheses, 17 adults with early phase psychosis were evaluated. Metacognition was assessed with the Metacognition Assessment Scale-Abbreviated, and insight was assessed with the Scale of Unawareness of Illness-Abbreviated. The auditory steady state response (ASSR) to gamma range stimulation (40 Hz) was used as an index of neural synchronization. Cognitive function was assessed using the Brief Assessment of Cognition in Schizophrenia. Increases in ASSR power were associated with poorer metacognition and insight. Higher cognitive performance was associated with higher levels of metacognitive function and insight. These findings suggest that altered neural synchronization and constituent cognitive processes affect both metacognition and insight in early phase psychosis and may offer targets for both pharmacological and psychotherapeutic interventions.

Gamma Band Phase Delay in Schizophrenia

BackgroundIn 1999, Kwon et al. reported several electroencephalographic gamma band auditory steady-state response (ASSR) abnormalities in schizophrenia, spawning approximately 100 subsequent studies. While many studies replicated the finding of reduced 40-Hz ASSR power in schizophrenia and extended this by showing that 40-Hz phase synchrony (phase-locking factor [PLF]) was also reduced, none attempted to replicate the original phase delay finding of Kwon et al. Accordingly, we measured the 40-Hz ASSR phase-locking angle (PLA) to assess phase delay and examined its differential sensitivity to schizophrenia, relative to power and PLF measures. MethodsTo obtain ASSRs, electroencephalography data were recorded from 28 patients with schizophrenia and 25 healthy control subjects listening to repeated 40-Hz 500-ms click trains. Evoked power, total power, PLF, and PLA were calculated after Morlet wavelet time-frequency decomposition of single trial data from electrode Fz. ResultsIn patients with schizophrenia, 40-Hz PLA was significantly reduced (i.e., phase delayed) (p < .0001) and was unrelated to reductions in their 40-Hz power or PLF. PLA discriminated patients from healthy control subjects with 85% accuracy compared with 67% for power and 65% for PLF. ConclusionsConsistent with the original Kwon et al. study, 40-Hz click train–driven gamma oscillations were phase delayed in schizophrenia. Importantly, this phase delay abnormality was substantially larger than the gamma power and phase synchrony abnormalities that have been the focus of prior 40-Hz ASSR studies in schizophrenia. PLA provides a unique neurobiological measure of gamma band abnormalities in schizophrenia, likely reflecting a distinct pathophysiological mechanism from those underlying PLF and power abnormalities.

TACS-mediated modulation of the auditory steady-state response as seen with MEG

BackgroundPrevious studies have shown that transcranial electrical stimulation can be successfully applied during simultaneous MEG measurements. In particular, using beamforming they have established that changes of stimulus induced as well as evoked activity can be inspected during transcranial alternating current stimulation (tACS).Objective/Hypothesis: We studied tACS-mediated changes of the auditory steady-state response (ASSR), hypothesizing that—due to the putatively inhibitory role of alpha oscillations—these evoked responses would be diminished. MethodsWe compared ASSRs in conditions with and without 12-Hz and 6.5-Hz sinusoidal 1.5 mA tACS, applied bilaterally over temporal areas. Source-level activity was estimated using a linearly constrained minimum variance beamformer and compared across tACS conditions using paired t-tests following a condition-internal normalization procedure. ConclusionsBy separating the electrical and auditory stimulation to non-overlapping parts of the frequency spectrum, we were able to compare auditory-evoked steady-state activity across tACS conditions. We observed a significant decrease in normalized ASSR power in the 12-Hz tACS condition, illustrating that tACS could induce immediate changes in auditory evoked activity. This study sets a methodology to further interrogate the causal roles of oscillatory dynamics in auditory cortices, as well as suggests perspectives for employing tACS in clinical contexts.

Differential modulation of the auditory steady state response and inhibitory gating by chloral hydrate anesthesia

Auditory steady state response (ASSR) and inhibitory gating (IG) are electrophysiological examinations commonly used to evaluate the sensory and cognitive functions of the brain. In some clinic examinations and animal experiments, general anesthesia is necessary to conduct electrophysiological recordings. However, the effects of anesthesia on ASSR and IG remain unclear. For this reason, we recorded local field potentials though electrodes implanted in different brain areas of rats: the auditory cortex (AC), hippocampus (HC), amygdala (AMY), and prefrontal cortex (PFC), and compared the characteristics of ASSR and IG under anesthetized and conscious conditions. We found that ASSR signals were the strongest in the AC, and decreased sequentially in the HP, AMY, and PFC. Chloral hydrate anesthesia significantly reduced the power and phase-locking of ASSR in the AC, HP, and AMY. In contrast, the extent of IG in the AC was weakest and it increased sequentially in the HP, AMY, and PFC. Anesthesia had less effect on the extent of IG. Our results suggest that ASSR and IG may originate from different neural circuits and that IG is more resistant to general anesthesia and therefore better suited to examining the functioning of non-auditory brain regions.

Did You Listen to the Beat? Auditory Steady-State Responses in the Human Electroencephalogram at 4 and 7Hz Modulation Rates Reflect Selective Attention.

The acoustic envelope of human speech correlates with the syllabic rate (4-8Hz) and carries important information for intelligibility, which is typically compromised in multi-talker, noisy environments. In order to better understand the dynamics of selective auditory attention to low frequency modulated sound sources, we conducted a two-stream auditory steady-state response (ASSR) selective attention electroencephalogram (EEG) study. The two streams consisted of 4 and 7Hz amplitude and frequency modulated sounds presented from the left and right side. One of two streams had to be attended while the other had to be ignored. The attended stream always contained a target, allowing for the behavioral confirmation of the attention manipulation. EEG ASSR power analysis revealed a significant increase in 7Hz power for the attend compared to the ignore conditions. There was no significant difference in 4Hz power when the 4Hz stream had to be attended compared to when it had to be ignored. This lack of 4Hz attention modulation could be explained by a distracting effect of a third frequency at 3Hz (beat frequency) perceivable when the 4 and 7Hz streams are presented simultaneously. Taken together our results show that low frequency modulations at syllabic rate are modulated by selective spatial attention. Whether attention effects act as enhancement of the attended stream or suppression of to be ignored stream may depend on how well auditory streams can be segregated.

Deficits in the 30-Hz auditory steady-state response in patients with major depressive disorder.

The auditory steady-state response (ASSR) is an auditory evoked potential that occurs in response to periodically presented auditory stimuli. The ASSR has drawn attention as a biomarker of psychiatric disorders owing to its connection with neural oscillations as well as its easy and noninvasive recording. Abnormalities in the γ band ASSR have been found consistently in patients with schizophrenia and bipolar disorder. However, although major depressive disorder (MDD) is also part of the common psychiatric diseases, the relationship between the ASSR and MDD has not been characterized sufficiently. Thus, the aim of the present study was to examine the ASSRs from patients with MDD and compare them with those from healthy control (HC) participants. The experiment was designed to obtain the ASSRs elicited by 20-, 30-, and 40-Hz click trains. Patients and HCs were evaluated separately. The response power and phase synchronization were measured at each stimulation frequency. Patients with MDD showed significantly reduced ASSR power for 30-Hz stimuli compared with HC participants, whereas no significant differences in the power were observed at 20 and 40 Hz for patients with MDD. In addition, no significant difference in the phase synchronization was observed for 20-, 30-, and 40-Hz stimuli. Conclusively, patients with MDD were characterized by deficits in 30-Hz ASSR power, which may be associated with spontaneous γ activity dysfunction. The present findings suggest that ASSR could potentially be used as a biomarker for MDD.

Cholinergic modulation of auditory steady-state response in the auditory cortex of the freely moving rat

As disturbance in auditory steady-state response (ASSR) has been consistently found in many neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, there is considerable interest in the development of translational rat models to elucidate the underlying neural and neurochemical mechanisms involved in ASSR. This is the first study to investigate the effects of the non-selective muscarinic antagonist scopolamine and the cholinesterase inhibitor donepezil (also in combination with scopolamine) on ASSR. We recorded the local field potentials through the chronic microelectrodes implanted in the auditory cortex of freely moving rat. ASSRs were recorded in response to auditory stimuli delivered over a range of frequencies (10–80Hz) and averaged over 60 trials. We found that a single dose of scopolamine produced a temporal attenuation in response to auditory stimuli; the most attenuation occurred at 40Hz. Time–frequency analysis revealed deficits in both power and phase-locking to 40Hz. Donepezil augmented 40-Hz steady-state power and phase-locking. Scopolamine combined with donepezil had an enhanced effect on the phase-locking, but not power of ASSR. These changes induced by cholinergic drugs suggest an involvement of muscarinic neurotransmission in auditory processing and provide a rodent model investigating the neurochemical mechanism of neurophysiological deficits seen in patients.

Differentiation between major depressive disorder and bipolar disorder by auditory steady-state responses

BackgroundThe auditory steady-state response (ASSR) elicited by gamma band neural oscillations has received considerable interest as a biomarker of psychiatric disorders. Although recent ASSR studies have reported that patients with bipolar disorder (BD) show altered ASSRs, little is known about ASSRs in patients with major depressive disorder (MDD). The aim of this study was to evaluate whether ASSRs in MDD subjects differed from those in BD subjects or normal controls (NC). MethodWe analyzed ASSRs in 14 MDD patients, 19 BD patients, and 29 normal control subjects. We used whole-head 306-channel magnetoencephalography to evaluate ASSR power and phase-locking factors (PLF) elicited by 20-, 30-, 40-, and 80-Hz click trains. We determined optimal sensitivity and specificity of ASSR power and PLF for the diagnosis of MDD or BD via receiver operating characteristic (ROC) curve analysis using a nonparametric approach. ResultsMDD patients exhibited no significant differences in ASSR power or PLF compared with NC subjects, while BD patients showed deficits on the ASSR measures. MDD patients showed significantly larger ASSR power and PLF for 30-, 40-, and 80-Hz stimuli compared with BD patients. The area under the curve (AUC) for the ROC analysis (MDD vs. BD) was 0.81 [95% CI=0.66–0.96, p=0.003] concerning 40-Hz ASSR power. LimitationsWe could not exclude the effect of medication and the sample size of the current study is relatively small. ConclusionsWe could differentiate between MDD and BD subjects in terms of gamma band ASSR. Our data suggest that the 40-Hz ASSR may be a potential biomarker for differentiation between MDD and BD patients.

Phencyclidine Disrupts the Auditory Steady State Response in Rats.

The Auditory Steady-State Response (ASSR) in the electroencephalogram (EEG) is usually reduced in schizophrenia (SZ), particularly to 40 Hz stimulation. The gamma frequency ASSR deficit has been attributed to N-methyl-D-aspartate receptor (NMDAR) hypofunction. We tested whether the NMDAR antagonist, phencyclidine (PCP), produced similar ASSR deficits in rats. EEG was recorded from awake rats via intracranial electrodes overlaying the auditory cortex and at the vertex of the skull. ASSRs to click trains were recorded at 10, 20, 30, 40, 50, and 55 Hz and measured by ASSR Mean Power (MP) and Phase Locking Factor (PLF). In Experiment 1, the effect of different subcutaneous doses of PCP (1.0, 2.5 and 4.0 mg/kg) on the ASSR in 12 rats was assessed. In Experiment 2, ASSRs were compared in PCP treated rats and control rats at baseline, after acute injection (5 mg/kg), following two weeks of subchronic, continuous administration (5 mg/kg/day), and one week after drug cessation. Acute administration of PCP increased PLF and MP at frequencies of stimulation below 50 Hz, and decreased responses at higher frequencies at the auditory cortex site. Acute administration had a less pronounced effect at the vertex site, with a reduction of either PLF or MP observed at frequencies above 20 Hz. Acute effects increased in magnitude with higher doses of PCP. Consistent effects were not observed after subchronic PCP administration. These data indicate that acute administration of PCP, a NMDAR antagonist, produces an increase in ASSR synchrony and power at low frequencies of stimulation and a reduction of high frequency (> 40 Hz) ASSR activity in rats. Subchronic, continuous administration of PCP, on the other hand, has little impact on ASSRs. Thus, while ASSRs are highly sensitive to NMDAR antagonists, their translational utility as a cross-species biomarker for NMDAR hypofunction in SZ and other disorders may be dependent on dose and schedule.

Measuring auditory selective attention using frequency tagging

Frequency tagging of sensory inputs (presenting stimuli that fluctuate periodically at rates to which the cortex can phase lock) has been used to study attentional modulation of neural responses to inputs in different sensory modalities. For visual inputs, the visual steady-state response (VSSR) at the frequency modulating an attended object is enhanced, while the VSSR to a distracting object is suppressed. In contrast, the effect of attention on the auditory steady-state response (ASSR) is inconsistent across studies. However, most auditory studies analyzed results at the sensor level or used only a small number of equivalent current dipoles to fit cortical responses. In addition, most studies of auditory spatial attention used dichotic stimuli (independent signals at the ears) rather than more natural, binaural stimuli. Here, we asked whether these methodological choices help explain discrepant results. Listeners attended to one of two competing speech streams, one simulated from the left and one from the right, that were modulated at different frequencies. Using distributed source modeling of magnetoencephalography results, we estimate how spatially directed attention modulates the ASSR in neural regions across the whole brain. Attention enhances the ASSR power at the frequency of the attended stream in contralateral auditory cortex. The attended-stream modulation frequency also drives phase-locked responses in the left (but not right) precentral sulcus (lPCS), a region implicated in control of eye gaze and visual spatial attention. Importantly, this region shows no phase locking to the distracting stream. Results suggest that the lPCS in engaged in an attention-specific manner. Modeling results that take account of the geometry and phases of the cortical sources phase locked to the two streams (including hemispheric asymmetry of lPCS activity) help to explain why past ASSR studies of auditory spatial attention yield seemingly contradictory results.

Dexamphetamine selectively increases 40 Hz auditory steady state response power to target and nontarget stimuli in healthy humans

An emerging endophenotype of schizophrenia is the reduction of both power and phase locking of the 40 Hz auditory steady state response (ASSR), and there have been a number of reports linking increased γ activity with positive psychotic symptoms. Schizophrenia and, more specifically, positive psychotic symptoms have been closely linked to increased dopamine (DA) neurophysiology. Therefore, we gave dexamphetamine to healthy participants to determine the effect that increased DA transmission would have on the ASSR. We administered 0.45 mg/kg of dexamphetamine orally in a double-blind placebo-controlled crossover study. Stimuli were 20 Hz and 40 Hz click trains presented in an auditory oddball-type stimulus format (probability of stimulus presentation: 0.2 for targets, 0.8 for nontargets). We included 44 healthy volunteers (18 women) in the study. Dexamphetamine significantly increased the 40 Hz power for both target and nontarget ASSR stimuli. Dexamphetamine did not significantly affect the 40 Hz phase-locking factor (PLF) or the 20 Hz power and PLF. Whereas there were significant effects of selective attention on power and PLF for 20 and 40 Hz ASSR, there were no significant interactions between dexamphetamine and selective attention. Dexamphetamine releases both noradrenaline and DA with equal potency. Further research with selective dopaminergic and noradrenergic agents will better characterize the effects of monoamines on γ activity. The results demonstrate a frequency-specific effect of dexamphetamine on the ASSR. This finding is consistent with previous research that has found an association between increased γ and positive symptoms of psychosis. However, this result also raises the possibility that previous 40 Hz ASSR findings in people with schizophrenia may be confounded by effects of antipsychotic medication. Possible neural mechanisms by which dexamphetamine specifically increases 40 Hz power are also discussed. AUSTRALIAN AND NEW ZEALAND CLINICAL TRIALS REGISTRY NUMBER: ACTRN12608000610336.