Alterations in interhemispheric gamma-band connectivity are related to the emergence of auditory verbal hallucinations in healthy subjects during NMDA-receptor blockade

Abstract

Auditory verbal hallucinations (AVH) are a common positive symptom of schizophrenia. Excitatory-to-inhibitory (E/I) imbalance related to disturbed N-methyl-D-aspartate receptor (NMDAR) functioning has been suggested as a possible mechanism underlying altered connectivity and AVH in schizophrenia. The current study examined the effects of ketamine, a NMDAR antagonist, on glutamate-related mechanisms underlying interhemispheric gamma-band connectivity, conscious auditory perception during dichotic listening (DL), and the emergence of auditory verbal distortions and hallucinations (AVD/AVH) in healthy volunteers. In a single-blind, pseudo-randomized, placebo-controlled crossover design, nineteen male, right-handed volunteers were measured using 64 channel electroencephalography (EEG). Psychopathology was assessed with the PANSS interview and the 5D-ASC questionnaire, including a subscale to detect auditory alterations with regard to AVD/AVH (AUA-AVD/AVH). Interhemispheric connectivity analysis was performed using eLORETA source estimation and lagged phase synchronization (LPS) in the gamma-band range (30-100 Hz). Ketamine induced positive symptoms such as hallucinations in a subgroup of healthy subjects. In addition, interhemispheric gamma-band connectivity was found to be altered under ketamine compared to placebo, and subjects with AUA-AVD/AVH under ketamine showed significantly higher interhemispheric gamma-band connectivity than subjects without AUA-AVD/AVH. These findings demonstrate a relationship between NMDAR functioning, interhemispheric connectivity in the gamma-band frequency range between bilateral auditory cortices and the emergence of AVD/AVH in healthy subjects. The result is in accordance with the interhemispheric miscommunication hypothesis of AVH and argues for a possible role of glutamate in AVH in schizophrenia.

Fig. 1

a Schematic illustration of the dichotic listening (DL) procedure, demonstrating the requirement of interhemispheric transfer when participants consciously perceive the auditory stimulus presented to the left ear (LE). Two different syllables are presented simultaneously: one to the right ear (GA) and one to the left ear (DA). Although both ears are connected anatomically via ipsilateral and contralateral pathways with the auditory cortices, ipsilateral pathways are suggested to be blocked during dichotic listening. The blue line indicates the contralateral pathway connecting the stimulus presented to the right ear (RE) directly with the speech-dominant left hemisphere. In contrast, the syllable arriving from the LE to the right hemisphere requires interhemispheric transfer via the corpus callosum (CC) to be efficiently processed (red line). Yellow: right and left auditory cortices, LH: left hemisphere, RH: right hemisphere. b Regions-of-interests (ROIs) within the left and right primary auditory cortices (PACs, BA41, red) and the left and right secondary auditory cortices (SACs, BA42, green). BA41-ROI covered a region extended from x: 35 to 55 and −35 to −55, y: −15 to −40, z: 5 to 15 and included all voxels of BA41. BA42-ROI covered a region extended from x: 55 to 70 and −55 to −65, y: −10 to −35, z: 5 to 20 and included all voxels of BA42

Fig. 2

Bar charts of mean values of the five PANSS subscores (a) and the positive items (b) of the PANSS with error bars representing ±1 standard error. Bar charts of the subscore auditory alterations in the form of auditory verbal distortions and hallucinations (AUA-AVD/AVH) of the 5D-ASC (in %) (c) for each subject in descending order under ketamine administration compared to placebo administration. The black, horizontal line indicates where the median split was conducted. P1 = delusion; P2 = conceptual disorganization; P3 = hallucinations; P4 = excitement; P5 = grandiosity; P6 = suspiciousness/persecution; P7 = hostility. *p < 0.05; **p < 0.01; ***p < 0.001; n = 19

Fig. 3

Time course of interhemispheric auditory connectivity in the gamma-band (30–100 Hz) between bilateral auditory cortices (BA41 and BA42) during left ear (LE) reports for ketamine (red line) and placebo (blue line) (n = 19). Syllable presentation starts at 0 ms and ends around 500 ms. The quality of gamma-band connectivity was found to be significantly altered under ketamine administration in contrast to placebo. Shaded error bars: ±1 standard error

Fig. 4

Time course of interhemispheric auditory connectivity in the gamma-band (30–100 Hz) between bilateral auditory cortices (BA41 and BA42) during left ear (LE) reports for AVD/AVH (n = 9; red line) and non-AVD/AVH (n = 10; cyan line) subjects under ketamine (a) and under placebo (b) administration. Syllable presentation starts at 0 ms and ends around 500 ms. Shaded error bars: ±1 standard error. Gamma-band connectivity was significantly increased in the AVD/AVH group compared to the non-AVD/AVH group over time under ketamine administration: bar charts of mean lagged phase synchronization (LPS) during LE reports under ketamine (c) and under placebo (d) administration for AVD/AVH (n = 9) and non-AVD/AVH (n = 10; with error bars representing ±1 standard error). **p < 0.01; n.s. = not significant