A combination of genetic and environmental factors, have been identified as the underlying mechanism in the development of schizophrenia.
Genetic association studies found several risk genes for schizophrenia. Environmental factors such as obstetric complications with hypoxia, the season of birth, prenatal infection, drug abuse, and migration may interact with genetic factors, influencing the onset and progression of the disease.
This gene-environmental interaction may comprise epigenetic alterations like DNA methylation and histone acetylation1.
Positive and negative symptoms are medical terms for two groups of symptoms in schizophrenia. Symptoms in schizophrenia are divided into three groups:
Transcranial magnetic stimulation (TMS) has been used for treatment of schizophrenia. A version of TMS called deep TMS or dTMS has shown significant improvements in negative symptoms when administered to the dorsolateral prefrontal cortex (DLPFC) in schizophrenia2.
In these studies, patients were treated using high-frequency (18 Hz) bilateral stimulation applied over the DLPFC, bilaterally, with deep TMS coils. Objective measures of improvement such as the Scale for the Assessment of Negative Symptoms and the Positive and Negative Syndrome Scales have been used to ensure the reliability of results.
Standard TMS has proven effective for positive symptoms in schizophrenia too. A review of clinical trials from the last 20 years on the effect of TMS for positive symptoms has found that TMS is effective3,4.
Resting-state functional connectivity MRI or rsFC MRI is an advanced imaging technique that provides functional connectivity (FC) of the brain which has proven to be a powerful measure of abnormalities of brain networks in schizophrenia5.
In one study5, comparing schizophrenia patients with healthy controls, individuals with a clinical high risk for psychosis (CHR) and schizophrenia patients showed hypo-connectivity between posterior insula (PI) and somatosensory areas, and between dorsal anterior insula (dAI) and putamen.
Furthermore, schizophrenia patients showed dAI and ventral anterior insula(vAI) hyper-connectivity with visual areas relative to controls and CHR individuals. In another study6, FC has offered evidence for the dysconnectivity hypothesis of schizophrenia.
As resting-state fMRI (rsfMRI) can map functional brain networks, such as the default mode network (DMN), it makes the study of the systems-level pathology of schizophrenia possible. From a wide range of studies, we know that connectivity of the DMN is altered in patients with schizophrenia7. Specifically, features discovered by rsfMRI are as follows:
We will use rsFC MRI and correlation analysis to identify targets for TMS treatment of schizophrenia. This is a powerful approach since studies have revealed that dAI functional connectivity with superior temporal gyrus does positively correlate with positive symptoms of CHR. Furthermore, vAI connectivity with dorsolateral prefrontal cortex (DLPFC) negatively correlates with the severity of the symptoms of first-episode schizophrenia5.
We also have the capability of using rsFC MRI to map the whole-brain network topology and to use graph theory. In the past, it has been shown that functional brain networks in schizophrenia are characterized by reduced small-worldness, lower degree connectivity of brain hubs, and decreased modularity.
The sensitivity of functional connectivity is so high that it can detect differences in unaffected relatives, suggesting that functional dysconnectivity is an endophenotype related to genetic risk for schizophrenia. As we have broad support for dysconnectivity theories of schizophrenia, we use this feature of rsFC MRI to identify our targets for TMS treatment.
1. Schmitt A, Hasan A, Gruber O, Falkai P. Schizophrenia as a disorder of disconnectivity. Eur Arch Psychiatry Clin Neurosci. 2011;261 Suppl 2(Suppl 2).S150–S154.
2. Linsambarth S, Jeria A, Avirame K, Todder D, Riquelme R, Stehberg J. Deep. Transcranial Magnetic Stimulation for the Treatment of Negative Symptoms in Schizophrenia: Beyond an Antidepressant Effect. J ECT. 2019 Dec;35(4):e46-e54.
3. Marzouk T, Winkelbeiner S, Azizi H, Malhotra AK, Homan P. Transcranial Magnetic Stimulation for Positive Symptoms in Schizophrenia: A Systematic Review. Neuropsychobiology. 2019 Sep 10:1-13.
4. Dougall N, Maayan N, Soares-Weiser K, McDermott LM, McIntosh A. Transcranial magnetic stimulation (TMS) for schizophrenia. Cochrane Database Syst Rev. 2015 Aug 20;(8):CD006081.
5. Li XB, Wang LB, Xiong YB, Bo QJ, He F, Li F, Hou WP, Wen YJ, Wang XQ, Yang NB, Mao Z, Dong QH, Zhang FF, Yang R, Wang D, Xiang YT, Zhu YY, Tang YL, Yang Z, Wang CY. Altered resting-state functional connectivity of the insula in individuals with clinical high-risk and patients with first-episode schizophrenia. Psychiatry Res. 2019 Dec;282:112608.
6. Zhou Y, Fan L, Qiu C, Jiang T. Prefrontal cortex and the dysconnectivity hypothesis of schizophrenia. Neurosci Bull. 2015 Apr;31(2):207-19.
7. Karbasforoushan H, Woodward ND. Resting-state networks in schizophrenia. Curr Top Med Chem. 2012;12(21):2404-14.