Vedashree Meher, M.Sc.

Schizophrenia is a psychiatric illness that affects how a person thinks, feels and behaves. Schizophrenia can present as positive symptoms or negative symptoms. Positive symptoms include delusions, hallucinations and disorganized speech whereas, negative symptoms include apathy, lack of motivation and anhedonia (lack of pleasure) (Patel et al., 2014). In order to be diagnosed with this disease, the symptoms must persist for six months. While there is no cure for schizophrenia, positive symptoms are still manageable with treatments. However, the treatment options for negative symptoms are limited even though they account for a large part when assessing long-term morbidity and poor functional outcomes in patients. It is important to understand several aspects of a disease including the neurobiology, pathophysiology and etiology prior to effectively treating or managing the disease. 

The typical age of onset for schizophrenia symptoms is early adulthood. Although, it can still start in mid-30’s (Patel et al., 2014). Psychiatrists look into various risk factors for understanding the etiology for schizophrenia including genetic factors, biological factors, environmental factors, social or personal stressors and substance use. Looking into the neurobiology, schizophrenia is argued to be a manifestation for an imbalance in the dopamine, serotonin, glutamate and GABA neurotransmitters (Patel et al., 2014). Genetic alterations to Dysbindin gene, neuregulin 1 gene, Catechol O-methyltransferase gene, Metabotropic glutamate receptor gene 3, proline dehydrogenase gene and D-amino acid oxidase activator gene, to name a few, are known to play a role in the genesis of schizophrenia as these genes are involved in the release of some neurotransmitters and in neurodevelopment (Kirov et al., 2005). Multiple psychiatric illnesses including schizophrenia syndrome, bipolar disorder and amyotrophic lateral sclerosis show a repeat expansion mutation in C9ORF72 gene (Burhan et al., 2021). Such changes at a genetic or cellular level dictate anatomical and physiological changes. To study the structural abnormalities, post-mortem studies were conducted which showed abnormalities in the amygdala-hippocampal complex and parahippocampal gyrus, an increase in the temporal horns of the lateral ventricles which contain cerebrospinal fluid (Ledoux et al., 2014; Shenton et al., 2001) . Other studies found abnormalities in the cingulate gyrus and basal ganglia (Perez-Costas et al., 2010).

PET studies have provided evidence of dysregulation in the dopamine system in patients with schizophrenia whereby, there was difference in the dopamine levels observed in the prefrontal cortex, anterior cingulate gyrus and hippocampus. Furthermore, PET showed higher density of D2 receptors in the striatum (Patel et al., 2010). PET studies have also shown patients with schizophrenia to have lose synaptic connections. A study by Seethalakshmi et al. reported an increase in glucose metabolism in positive symptoms compared to negative symptoms. There was increased glucose metabolism in the medial temporal regions, basal ganglia and left thalamic regions whereas the cerebellum showed hypometabolism (Seethalakshmi et al., 2006). A study by Burhan et al, utilized FDG-PET to reveal hypometabolism in the medial superior frontal, insula, inferior temporal, thalamus and anterior cingulate gyrus (Burhan et al., 2021). With the applications of MRI, specific brain regions affected by this disorder were evaluated in depth. MRI findings have shown convergence with the post-mortem findings (Shenton et al., 2001). MRI gives an excellent soft-tissue contrast compared to other imaging modalities.

The benefits of PET/MR imaging of the brain in schizophrenia include the following:

1. From a technical standpoint, PET/MR allows for multi-parametric analysis of complex functions in neural networks (Burhan et al., 2015). Thus, this hybrid imaging modality has the potential to combine neurotransmitter release with simultaneous functional measures obtained by fMRI.
2. PET/MRI synergistic imaging has been applied to understand specific receptors targets. PET/MRI studies done in schizophrenia patients, showed that the dopamine response was blunted and showed a significant association to working-memory BOLD activation in the prefrontal cortex. Furthermore, it has shown an increased connectivity between striatal and extrastriatal D2 receptor availability with a high-affinity radiotracer in schizophrenia patients. Using an antagonist radiotracer [¹¹C]raclopride, simultaneous PET fMRI acquisition has shown neurovascular coupling (transient neural activity linked with cerebral blood flow – focal autoregulation) to D2/D3 dopamine receptor occupancy. This is a PET fMRI application for pharmacological studies (Sander et al., 2020).
3. MR-based motion correction may allow for faster scan time (Miller-Thomas & Benzinger, 2017)
4. One time sedation is required instead of sedation across two imaging sessions, which is a potential benefit for younger children or those feeling anxious or claustrophobic. For younger patients, another advantage includes the potential of maintaining a low dose of radiation while still achieving good imaging results (Jadvar & Colletti, 2014).
5. Hybrid PET/MR may be more tolerable for older patients who have difficulty management longer, or multiple, scanning sessions.
6. In psychiatric illnesses including schizophrenia, observable changes may occur between scanning sessions, an issue that may be mitigated by dual-modality imaging, as only session would be required.  (Miller-Thomas & Benzinger, 2017) (Catana et al., 2012).

References

Burhan, A. M., Anazodo, U. C., Marlatt, N. M., Palaniyappan, L., Blair, M., & Finger, E. (2021). Schizophrenia syndrome due to C9ORF72 mutation case report: a cautionary tale and role of hybrid brain imaging! BMC Psychiatry, 21(1). https://doi.org/10.1186/s12888-021-03341-9

Burhan, A. M., Marlatt, N. M., Palaniyappan, L., Anazodo, U. C., & Prato, F. S. (2015). Role of Hybrid Brain Imaging in Neuropsychiatric Disorders. Diagnostics (Basel), 5(4), 577-614. https://doi.org/10.3390/diagnostics5040577

Catana, C., Drzezga, A., Heiss, W.-D., & Rosen, B. R. (2012). PET/MRI for Neurologic Applications. Journal of Nuclear Medicine, 53(12), 1916-1925. https://doi.org/10.2967/jnumed.112.105346

Jadvar, H., & Colletti, P. M. (2014). Competitive advantage of PET/MRI. European Journal of Radiology, 83(1), 84-94. https://doi.org/10.1016/j.ejrad.2013.05.028

Kirov, G., O’Donovan, M. C., & Owen, M. J. (2005). Finding schizophrenia genes. J Clin Invest, 115(6), 1440-1448. https://doi.org/10.1172/jci24759

Ledoux, A. A., Boyer, P., Phillips, J. L., Labelle, A., Smith, A., & Bohbot, V. D. (2014). Structural hippocampal anomalies in a schizophrenia population correlate with navigation performance on a wayfinding task. Front Behav Neurosci, 8, 88. https://doi.org/10.3389/fnbeh.2014.00088

Miller-Thomas, M. M., & Benzinger, T. L. S. (2017). Neurologic Applications of PET/MR Imaging. Magnetic Resonance Imaging Clinics of North America, 25(2), 297-313. https://doi.org/10.1016/j.mric.2016.12.003

Patel, K. R., Cherian, J., Gohil, K., & Atkinson, D. (2014). Schizophrenia: overview and treatment options. P t, 39(9), 638-645.

Patel, N. H., Vyas, N. S., Puri, B. K., Nijran, K. S., & Al-Nahhas, A. (2010). Positron Emission Tomography in Schizophrenia: A New Perspective. Journal of Nuclear Medicine, 51(4), 511-520. https://doi.org/10.2967/jnumed.109.066076

Perez-Costas, E., Melendez-Ferro, M., & Roberts, R. C. (2010). Basal ganglia pathology in schizophrenia: dopamine connections and anomalies. J Neurochem, 113(2), 287-302. https://doi.org/10.1111/j.1471-4159.2010.06604.x

Sander, C. Y., Hansen, H. D., & Wey, H.-Y. (2020). Advances in simultaneous PET/MR for imaging neuroreceptor function. Journal of Cerebral Blood Flow & Metabolism, 40(6), 1148-1166. https://doi.org/10.1177/0271678×20910038

Seethalakshmi, R., Parkar, S. R., Nair, N., Adarkar, S. A., Pandit, A. G., Batra, S. A., Baghel, N. S., & Moghe, S. H. (2006). Regional brain metabolism in schizophrenia: An FDG-PET study. Indian J Psychiatry, 48(3), 149-153. https://doi.org/10.4103/0019-5545.31577

Shenton, M. E., Dickey, C. C., Frumin, M., & McCarley, R. W. (2001). A review of MRI findings in schizophrenia. Schizophr Res, 49(1-2), 1-52. https://doi.org/10.1016/s0920-9964(01)00163-3

Prepared by: Vedashree Meher, M.Sc.