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.

The role of functional and structural interhemispheric auditory connectivity for language lateralization - A combined EEG and DTI study

“…This is of special interest, because even though the majority (80–85%) of right-handed humans exhibit a clear REA 76 , some do not, and in particular those who suffer from AVH in schizophrenia 77–79 . Further, emerging evidence emphasized that abnormal gamma rhythm in AVH patients are due to an E/I imbalance related to glutamate NMDA receptor hypofunction 80,81 . In support, initial 1 H MR spectroscopy studies reported glutamate over-activation in cortical prefrontal and auditory brain areas 82,83 , which in turn goes along with the typical observed neural hyperexcitation of auditory cortices during AVH 84–86 .…”

“…Moreover, a multitude of different measures to quantify functional connectivity are currently available that differ concerning the weighting of phase and amplitude or regarding the removal of zero-phase lag components. We used lagged phase synchronization as this metric removes confounding zero-phase lag contributions, is especially well-established in the auditory domain using dichotic listening tasks 1,15,81 , and commonly used in the clinical field 32,89–91 . However, there might be alternative methods to examine the structure-function relationship, although no metric has emerged as being superior 92 .…”

Glutamatergic Deficits in Schizophrenia – Biomarkers and Pharmacological Interventions within the Ketamine Model

“…The attenuated task-evoked gamma-band response has been demonstrated across all stages of schizophrenia [ 63 - 66 ] and is suggested to constitute a pathomechanism of cognitive dysfunction in schizophrenia [ 67 , 68 ]. Notably, a recent study demonstrated a relationship between increased interhemispheric gamma-band connectivity and the emergence of auditory verbal distortions and hallucinations under ketamine [ 69 ]. Using a visuomotor paradigm in a single-blind, placebo-controlled MEG study, Shaw et al [ 70 ] revealed increased amplitudes of movement-related gamma synchrony and ipsilateral movement-related beta desynchrony elicited by ketamine within the motor cortex.…”

Exploring concomitant neuroimaging and genetic alterations in patients with and patients without auditory verbal hallucinations: A pilot study and mini review

“…The development of qualitative diagnostic and therapeutic efficacy prediction models in patients with AVHs who have various diagnoses may improve the accuracy and repeatability of prediction models, and may, ultimately, facilitate the delivery of early, potentially curative treatments. 7 , 52 – 60 …”

“…The development of qualitative diagnostic and therapeutic efficacy prediction models in patients with AVHs who have various diagnoses may improve the accuracy and repeatability of prediction models, and may, ultimately, facilitate the delivery of early, potentially curative treatments. 7,[52][53][54][55][56][57][58][59][60] Data related to genomic characteristics, brain characterizations (endophenotypes), clinical manifestations, and prognostic characteristics (phenotypes) may be submitted to machine learning algorithms to establish disease optimization classifiers that reveal characteristics that are specific to particular diagnoses or common across neurological conditions accompanied by AVHs. This approach may provide a basis for early AVH diagnosis and treatment models in different diagnostic contexts based on imaging and genetic features.…”