Auditory Steady-State Responses Probe GABA-Related Oscillatory Cortical Circuits and Their Relation to Neurodevelopmental Mental Disorders

Most mental disorders are rooted in abnormal neurodevelopment. Aberrant neurodevelopmental trajectories impair the maturation of the central nervous system, causing brain network dysfunction and ultimately affecting mental health. There is mounting evidence that in individuals affected by schizophrenia, abnormal developmental trajectories are expressed before the clinical symptoms start (1). The neurodevelopmental dimension of mental disorders motivates neuroimaging research into brain function and structure during the presymptomatic phase preceding clinical manifestation. Most brain mapping studies have been carried out in patients already expressing symptoms that show them to be either at clinically high risk of developing schizophrenia or already clinically affected by schizophrenia. However, cross-sectional studies in clinically high-risk populations or drug-naive patients with first-episode psychosis are not able to disentangle changes in brain structure and function that reflect abnormal neurodevelopmental trajectories from brain alterations related to the presence of clinical symptoms.

This limitation can be overcome by studying individuals before the emergence of clinical symptoms. Direct insights into the neurodevelopmental dimension of mental disorders can be obtained by studying individuals who have no symptoms but bear a higher risk for the disorder than the general population. 22q11.2 deletion syndrome (22q11DS) is one of the most common copy number variants, and it is associated with a high penetrance of a range of psychiatric disorders, including schizophrenia (2). Given the high risk of psychosis in 22q11DS carriers, this condition is an obvious genetic model to study the developmental factors that precede the possible emergence of psychosis. Neuroimaging studies of 22q11DS have to date been limited by relatively small sample sizes, mainly because recruitment of individuals with this syndrome is logistically demanding given the relatively small prevalence of approximately 1:4,000 (3, 4).

In this issue of the Journal, Mancini et al. (5) use 22q11DS as a genetic model for schizophrenia and investigate developmental patterns of gamma band oscillations. They report findings from 40-Hz auditory steady-state responses (ASSRs). ASSRs can be evoked by brief tones or clicks and provide a noninvasive means of the ability to generate neural synchrony in the gamma range in the auditory system. The oscillatory activity evoked by these 40-Hz responses relies on the fast-spiking parvalbumin positive GABAergic interneurons by exerting a finely tuned inhibition onto the pyramidal cells as well as other inhibitory interneurons. These oscillations are therefore considered to be an electrophysiological reflection of the excitation-inhibition balance, providing an insight into the underlying circuit dysfunction and thereby pathophysiology of schizophrenia (6).

Mancini et al. report a reduction in power and an attenuation in phase coherence of 40-Hz ASSR in 22q11DS carriers, which replicates a previous study in young nonpsychotic 22q11DS carriers (7). This is an important replication which indicates that reduced 40-Hz ASSR is a robust finding in 22q11DS and thereby mirrors findings in chronic schizophrenia. Extending those previous findings, Mancini et al. report that individuals with 22q11DS experiencing psychotic symptoms had a more pronounced reduction in the gamma band response than did those without psychotic symptoms. In line with this they further found a reduction of gamma power with increased hallucinatory symptoms, suggesting that the severity of gamma impairment is tied to the strength of the symptoms. When interpreting these findings, one should be aware of the large age range of the individuals included in the study, ranging from 7 to 30 years. This implies that more psychotic symptoms are present in the older participants, and thus the link between the gamma read-out and symptom severity may be confounded by age.

Mancini et al. also performed structural MRI of the brain. In agreement with previous work (8), they found that cortical volume of the auditory cortex was reduced in those individuals with 22q11DS experiencing psychotic symptoms relative to asymptomatic 22q11DS individuals. The study does not report if the volume is reduced overall in the 22q11DS group relative to healthy controls or if this reduction in cortical volume only was present in individuals experiencing psychosis. Therefore, it remains unclear whether a regional loss in cortical volume in the auditory cortex is already present in the preclinical stage.

The multimodal nature of the study enabled Mancini et al. to test for a relationship between alterations at the functional (ASSR) and structural (cortical volume) level. Critically, the alterations in gamma-band activity expressed during the ASSR scaled with the volume change in auditory cortex in the psychotic deletion carriers. The stronger the reduction in gamma band responses, the smaller was the gray matter of the auditory cortex. The auditory cortex is a key structure regarding the generation of 40-Hz ASSR. Accordingly, source localization revealed that ASSR reduction in the individuals with 22q11DS was expressed in the auditory cortex. Together, the results provide a convincing link between aberrant structural brain architecture and brain function in 22q11DS. While this is an important new contribution, it also raises new questions for investigation. Is it a causal relationship, with the structural changes leading to functional deficits? Or is it the functional alterations that cause the changes of the structure? Or could it simply be that both structure and function are affected by the disorder but are independent of each other? A way to tackle these questions is to look at the developmental changes in both structure and function.

This paper by Mancini et al. makes a highly needed contribution to the field by trying to fill in a gap in the current literature, namely whether reduction in 40-Hz ASSR is a stable trait marker or if this reduction is associated with aberrant development. While a linear increase in gamma power with age was found in controls, mirroring current literature in healthy individuals, this increase was not observed in the 22q11DS carriers. One confounding factor is psychotic symptoms that emerge from adolescence to adulthood; however, excluding individuals experiencing psychosis did not change the results. Results therefore point toward a lack of maturation in 22q11DS. Unfortunately, the study does not report how the gray matter volume of the auditory cortex changes with age. Given the link between the structure function relationship in 22q11DS found in this paper, the changes in cortical volume with age would have been an important contribution. In addition, the cross-sectional nature of the study implies that developmental trajectories are explored using age bins. This limits conclusions about the developmental aspect of ASSR given the lack of individual trajectories. Therefore, the main question of whether the reduced 40-Hz ASSR is a stable trait or a consequence of aberrant development remains unanswered, although results are suggestive.

Another important aspect that can be addressed utilizing a longitudinal design is resilience. Why is it that some individuals with 22q11DS go on to develop a psychiatric disorder while others do not? Given that 40-Hz ASSR has previously been used to predict psychosis development (9), part of the answer to this question of resilience might be found in the underlying mechanism of 40-Hz ASSR. While the neuroimaging field has been very much focused on predictors of psychosis, the factors related to resilience will further increase our understanding of the disorder (10). Being able to delineate these factors related to resilience may guide the development of targeted preventive interventions. To move this field forward, a crucial step is to push for longitudinal designs to be able to address the neurodevelopmental hypothesis as well as to tap into resilience factors.

In summary, Mancini et al. show that individuals with 22q11DS who experience psychotic symptoms have more pronounced 40-Hz ASSR impairment and that 40-Hz ASSR reduction in 22q11DS individuals is positively related with the degree of regional volume loss in the auditory cortex. The results motivate future longitudinal studies that focus on individual developmental trajectories as well as resilience factors.