Summary: Reduced activation of gamma waves in the brain was associated with the emergence of psychosis symptoms prior to the full-blown disorder appearing.
Communication between brain areas is crucial for the brain to correctly process sensory signals and adopt an appropriate behavioural response. Yet, dysfunctions in these communication pathways could be strongly correlated with the onset of schizophrenia.
For the first time, a team from the University of Geneva (UNIGE), Switzerland, within the framework of the Synapsy National Centre of Competence in Research, has succeeded in demonstrating this phenomenon in human beings.
By carrying out analyses of the brain activity of children, adolescents and young adults with a genetic risk of the disease, the research team has demonstrated that a reduction in the activation of gamma waves, that are known for their role in the proper transmission of information in the brain, was correlated with the emergence of psychotic symptoms even before full-blown disorders appear.
This work, published in the American Journal of Psychiatry, makes it possible to envisage a very early diagnosis.
In the mammalian brain, the electrical activity of neurons responds to oscillatory rhythms that can be detected by electroencephalography. The coordinated activation of these different waves, which governs, for example, the processing of sensory inputs or the consolidation of memories, enables the brain to function correctly.
“We suspected that gamma waves, the highest frequency of the brain rhythms, play a decisive role in the development of schizophrenia symptoms”, say Stephan Eliez, professor in the Department of Psychiatry, and Christoph Michel, professor in the Department of Basic Neuroscience, who co-directed the research.
“However, we still had to confirm that this impaired synchronisation of neural communication pathways observed in mice does indeed exist in humans.”
People with a chromosomal microdeletion 22q11 have a 25 to 30% risk of developing schizophrenia in adulthood. “They are therefore a particularly relevant at-risk population for studying the cerebral development of this disease,” says Valentina Mancini, a doctoral student in Stephan Eliez’s laboratory and the first author of this study.
People with schizophrenia often suffer from reduced capacity to process auditory information; in order to detect any disturbance in brain communication, the scientists therefore measured gamma wave activation following an auditory stimulus in 22q11 patients of all ages, compared with people without this microdeletion.
“Children and adolescents at genetic risk of schizophrenic disorders but without visible symptoms showed the same patterns of gamma wave disruption as patients actually suffering from the disease,” explains Vincent Rochas, a scientific collaborator in Christoph Michel’s laboratory.
In addition, a linear growth of the gamma-band oscillations was observed in people with no genetic predisposition to schizophrenia, showing a progressive maturation of communication between the cerebral areas during development.
“However, this maturation is absent in 22q11 patients, whatever their age, suggesting an abnormal development of circuits underlying neural oscillations in adolescence,” stresses Valentina Mancini.
Intervening as early as possible
The research team also identified a strong correlation between the gamma-band activation deficit and the severity of psychotic symptoms, such as auditory hallucinations, thus confirming the existence of a neurobiological progression of the disease.
“Our results confirm that this dysfunction appears very early”, the authors emphasise. “We now want to identify the best time during the child’s development to intervene in relation to this pathological shift.”
Moreover, studies on mice show that targeted neuroleptic treatments succeed in correcting neural dysfunctions; in addition, the gamma-band impairments identified here could be restored using techniques of non-invasive neurostimulation targeting the affected brain regions, thus opening the way to completely new therapeutic perspectives for treating an often devastating disease.
Aberrant Developmental Patterns of Gamma-Band Response and Long-Range Communication Disruption in Youths With 22q11.2 Deletion Syndrome
Brain oscillations play a pivotal role in synchronizing responses of local and global ensembles of neurons. Patients with schizophrenia exhibit impairments in oscillatory response, which are thought to stem from abnormal maturation during critical developmental stages. Studying individuals at genetic risk for psychosis, such as 22q11.2 deletion carriers, from childhood to adulthood may provide insights into developmental abnormalities.
The authors acquired 106 consecutive T1-weighted MR images and 40-Hz auditory steady-state responses (ASSRs) with high-density (256 channel) EEG in a group of 58 22q11.2 deletion carriers and 48 healthy control subjects. ASSRs were analyzed with 1) time-frequency analysis using Morlet wavelet decomposition, 2) intertrial phase coherence (ITPC), and 3) theta-gamma phase-amplitude coupling estimated in the source space between brain regions activated by the ASSRs. Additionally, volumetric analyses were performed with FreeSurfer. Subanalyses were conducted in deletion carriers who endorsed psychotic symptoms and in subgroups with different age bins.
Deletion carriers had decreased theta and late-latency 40-Hz ASSRs and phase synchronization compared with control subjects. Deletion carriers with psychotic symptoms displayed a further reduction of gamma-band response, decreased ITPC, and decreased top-down modulation of gamma-band response in the auditory cortex. Reduced gamma-band response was correlated with the atrophy of auditory cortex in individuals with psychotic symptoms. In addition, a linear increase of theta and gamma power from childhood to adulthood was found in control subjects but not in deletion carriers.
The results suggest that while all deletion carriers exhibit decreased gamma-band response, more severe local and long-range communication abnormalities are associated with the emergence of psychotic symptoms and gray matter loss. Additionally, the lack of age-related changes in deletion carriers indexes a potential developmental impairment in circuits underlying the maturation of neural oscillations during adolescence. The progressive disruption of gamma-band response in 22q11.2 deletion syndrome supports a developmental perspective toward understanding and treating psychotic disorders.