Neuroimaging studies have shown that the average brain in patients with schizophrenia is functionally and structurally different from that of healthy controls (Wright 2000, Crossley 2016). MRI-based studies have shown differences between the subgroup of patients who respond and those who do not respond to treatment (Sarpal 2016, Crossley 2017). Similarly, studies have shown differences in MRI in those high-risk patients who develop schizophrenia from those who do not (Pantelis 2003, Cannon 2015). However, it has been difficult to move from group results to biomarkers from individual subjects that could provide useful clinical data to contribute to a precision medicine agenda. Imaging biomarkers are very necessary in this area.
Most imaging studies in schizophrenia and other mental health problems have focused on the cerebral cortex, leaving an important brain area little studied, namely the brain stem. The brain stem is the location of several small nuclei of neurons of great importance to the functioning of the brain, such as substantia nigra, locus ceruleus, and raphe nuclei, which provide neuromodulatory tone to the brain (Lee 2012). The substantia nigra is the neural source of dopaminergic tone in the brain, and there is widespread agreement that this system is central to the pathophysiology of schizophrenia and other psychoses (McCutcheon 2019). A similar situation occurs with the locus ceruleus (adrenaline, important for disorders such as attention deficit hyperactivity disorder) and the raphe nuclei (serotonin, important for depressive and anxiety disorders). The role of presymptomatic damage to these and other brain stem nuclei has been identified as markers of prodromal / presymptomatic phases of individuals at high risk of developing Parkinson’s or other neurodegenerative disorders, and the hope is that this prodromal phase may be an opportunity. for neuroprotection (Postuma 2016). An MRI-based approach that could examine these small and neurochemically diverse nuclei could solve most of these problems and possibly offer new biomarkers for serious mental health problems. Two specific MRI techniques (susceptibility and diffusion) could adequately characterize these nuclei and provide promising biomarkers for treatment response and prognosis.
We propose a collaborative approach to develop new biomarkers based on images of the human brain stem that could contribute to primary and secondary prevention in schizophrenia.
The scientific questions that guide our collaboration are the following:
- Can MRI-based susceptibility and diffusion characterize the human brain stem nuclei structurally and neurochemically as the substantia nigra?
- Could directionality information added to susceptibility images (ie, susceptibility tensor images) provide a better image of the brainstem nuclei?
- Are there structural and neurochemical changes in the substantia nigra in schizophrenia that predate the disorder and mark a poor response to treatment?