Dinesh Sangroula, M.D., Muhammad Ovais, M.D., Bivek Wagle, B.S.

Abstract
Background: Schizophrenia is a chronic debilitating mental disorder, whose early diagnosis is crucial for patients’ better outcome. Since neuro-imaging techniques are rarely used for the management of schizophrenia in the clinical settings, the aim of this article is to provide a deeper insight about the importance of using the rapidly developing imaging modalities.
Method: Using the search terms like “neuroimaging”, “radioimaging”, “schizophrenia”, “MRI”, “CT scan”, “PET scan”, “fMRI”, and “SPECT”, journal articles were searched from various databases like Pubmed, Embase and other medical journals and reviewed.
Results: Subtle variations are evident before the manifestation of the illness in the brain of schizophrenic patients from the structural imaging techniques, like Computed Tomography (CT) scan and Magnetic Resonance Imaging (MRI). Similarly, during the onset of schizophrenia, dysfunction in specific neural networks is reported by functional imaging methods, like functional-MRI (fMRI), Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT).
Conclusion: Structural neuroimaging techniques like CT scan and MRI are definitely helpful to rule out the organic origin of psychotic symptoms in schizophrenic patients. Moreover, there are additional benefits of the functional imaging techniques in the early diagnosis and treatment, but the benefits should be weighed with the cost and feasibility for implementing their routine use in the clinical setting.

KEY WORDS: Computed Tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), functional MRI (fMRI), Neuro-imaging, Schizophrenia.

INTRODUCTION
Schizophrenia is a disabling clinical syndrome characterized by positive, negative, and cognitive symptoms. It significantly contributes to the global burden of diseases [1]. In the United States, the incidence is 15.2 per 100,000 populations per year, and the prevalence is about 1.1 % among the adult population [2], with the rate being higher among immigrants than Native Americans [3]. However, it has a low prevalence in developing countries, with no major differences between the sexes [3].

Positive symptoms of schizophrenia are hallucinations (auditory and/or visual), delusions, and disorganized behavior and communication. Likewise, avolition, apathy, anhedonia, and social withdrawal constitute the negative symptoms, and cognitive symptoms include impairment in executive functioning, trouble in concentrating, and problem with working memory. While CT scan and MRI are widely used to rule out the organic cause of the positive symptoms, modern techniques like PET and fMRI have contributed to detect functional abnormalities; this promising development has resulted in an increased number of research studies on the negative symptoms [4-5].

METHOD
The search terms used were “neuroimaging”, “radioimaging”, “schizophrenia”, “MRI”, “CT scan”, “PET scan”, “fMRI”, and “SPECT”. Databases like Pubmed, Embase were used to search relevant articles published in various journals. The relevant articles were reviewed to find the answer to our question “what is the role of neuroimaging in schizophrenia?”

RESULTS
In order to exclude organic causes of the psychotic symptoms, radio-imaging techniques have been used in clinical settings, but they have not been routinely done. Common modalities used in clinical and research studies are CT, MRI, fMRI, PET, and SPECT scan.

CT Scan:
CT scans of the schizophrenics’ reported dilation of sulcul markings on cortical surface and enlarged lateral and third ventricles [6-8]. Six out of seven twin studies demonstrated larger ventricles in schizophrenic identical twins than in healthy identical twins [9]. Moreover, schizophrenics appeared to show ventriculo-megaly at the onset of illness without any marked progression over time [10-12]. These observations suggest that the ventricular pathology begins before the onset of clinical symptoms and remains static in terms of progression. The non-specific lateral ventricular enlargement has been associated with increased negative symptoms and poor premorbid adjustment, cognitive adjustment, and response to neuroleptics outcomes, all of which suggest a poor prognosis [8]. CT scan is cheap, easily available, non-invasive and quick technique. However, it exposes patients to harmful radiation, and its poor technical resolution poses hurdle for investigators from finding affected areas of brain [13] (Table1).

MRI:
MRI replicates the findings of CT scan, but with a higher resolution [14]. It can be used to study, both, acute and chronic schizophrenia [15]. Some studies suggested a subtle decrease in size and grey mater in the temporal lobe [16-17] while others demonstrated reduction in size of the lateral and mesial structures in temporal lobe [18-20]. However, no changes were noted on the size of the mesial temporal lobe with the progression of disease, which suggests a possibly static neuro-pathological condition [21]. The changes in size of the temporal lobe on MRI have been found to be associated with an increase in auditory hallucinations [22], thought disorder [20], and negative symptoms [23]. Furthermore, the presence of morphological and cyto-architectural changes in the regions of temporal lobe and cortex without gliosis, suggest that these changes occurred during the neuro-developmental period in utero rather than during or after the birth [22, 24-26]. MRI has better resolution than CT scan, enabling visualization of structures in more details; however, it exposes the patient to the magnetic waves limiting its use in-patients with metal implants, like pacemakers (Table 1).

Functional MRI:
This is one of the most advanced innovations which studies the neural activity in the brain using the nonradioactive contrast agents like gadolinium or oxidized form of hemoglobin from patients or controls [27]. Although, this technique has been used on schizophrenic patients to perform preliminary studies, it is uncertain whether it will augment our understanding of schizophrenia. However, this technique helps to identify the dysfunctional neural network and to develop the best possible pharmacological or cognitive intervention for decreasing patients’ symptoms and increasing their functioning [28-29] (Table 1).

PET:
It is a functional neuro-imaging technique that uses specific tracers and neurotransmitters’ function to measures glucose metabolism and cerebral chemistry, like the distribution of neurotransmitters in brain. Compared to other functional imaging techniques, PET detects the tracer activity, both, quantitatively and qualitatively. A variety of PET tracers have been used to identify brain abnormalities, including 11C, 15O-water, 18F-fallypride, and L-3, 4-dihydroxy-6-18 , F-fluorophenylalanine (18F-FDOPA). These tracers produce positron that interacts with adjacent electrons-producing gamma photons, which are detected by scanners to create an image of tracer’s uptake [30]. PET imaging studies consistently showed a decreased function of the frontal lobe and increased metabolism in the basal ganglia associated with Neuroleptics treatment. However, because of its invasiveness, it has limited use and can’t be performed in very sick patients [31-35] (Table 1).

SPECT:
Similar to PET scan, SPECT scan is used to visualize cerebral blood flow. In schizophrenics, SPECT shows abnormalities in the functionally active neural network and perfusion anomalies in temporal and frontal lobes. Compared to PET, it is less sensitive, readily available, and cheaper and has low resolution [35-36] (Table1)

Table 1: Summary of the neuro-imaging techniques [30-36]

Neuro-imaging study	Type of Imaging	Findings	Advantage	Disadvantage
CT Scan	Structural Brain Imaging	Enlarged ventricles	Relatively cheaper, tolerable and painless	Exposure to ionizing radiation; Contrast-related allergic reaction; Nephro-toxicity
MRI	Structural Brain Imaging	Decreased size of grey mater and temporal lobe	Higher resolution; No radiological exposure	Expensive; unfeasible for patients with metal implants
fMRI	Functional Brain Imaging	Abnormal activity in motor task, working memory, attention span, word fluency, emotion processing, and decision making	No side effects caused by radio and magnetic waves; relatively in-expensive; good temporal and spatial resolution	Expensive
SPECT	Functional Brain Imaging	Perfusion anomaly in the temporal and frontal areas	Cheaper; No side effects caused by radio and magnetic waves	Unsuited for very sick patients; invasive; requires sedation
PET	Functional Brain Imaging	Hypo-functioning of frontal lobe; increased metabolism in the basal ganglia	Studies blood flow and metabolism of brain; helps in early detection of abnormalities	Expensive; poor spatial resolution; invasive; requires sedation

DISCUSSION: POTENTIAL CLINICAL IMPLICATION
In a number of previous imaging studies, the overall findings have been heterogeneous. Neuroimaging of brain may show large cavum septum palladium in schizophrenics, but this does not elucidate the cause of the disorder. This abnormality is found in 30 to 40 percent of the patients with schizophrenia, which apparently supports the neuro-developmental abnormality as a possible cause which includes ventriculomegaly and cortical atrophy [37]. It is always vital to weigh the cost of neuroimaging against the cost of delaying appropriate treatment or giving inappropriate treatment and increasing hospital stay. The potential use of neuro-imaging for schizophrenia may be as follows:
1. Rule out organic causes: It has been found that organic cause contributes to 5% of the psychosis. The clinical indications for CT/MRI in schizophrenia are first presentation of psychosis, late onset of symptoms and presence of any focal neurological deficits [38].
2. Predicting clinical outcome: Evidences supported that the volume of a brain during the initial and later stages of schizophrenia predicts the clinical outcome and severity. However, recent studies suggested that changes within the brain could be a better predictor of outcomes. Some studies suggested that the there is a strong association between the extent of grey mater loss and clinical presentation while other data reported lesser association between baseline abnormalities and the clinical outcome. [36].
3. Drug selection and dosing: The minimum dose required depends on the optimal dopamine receptor (D2) occupancy. Functional imaging like PET scan can be used to examine D2 receptor occupancy which helps to establish the minimum dose [38].
4. Predicting response to treatment: Neuro-imaging could be used in antipsychotics-treated schizophrenics to predict the likelihood of response to treatment, especially during the first episode of symptoms. Earlier studies suggested that the outcomes could be correlated to average cortical sulcal width in CT scan and relative increase in grey mater on MRI [39].

CONCLUSION
Clinical symptoms of schizophrenia are manifested late in the course of disease and the structural and functional changes in brain are not detected early because the neuroimaging techniques are not routinely done. In addition, social discrimination, stigma, and stereotyping prevent schizophrenic patients or their families from seeking help from psychiatrists and hence it’s already late to start treatment. Judicious use of neuroimaging modalities could make sigificant difference by visualizing small internal invisible changes in the brain. Moreover, neuroimaging combined with thoughtful clinical judgment, and neurological and genetic studies can provide us deeper insights about debilitating psychiatric illness. To summarize, a few areas where there is hope for research-imaging to become clinical imaging are baseline MRI at first presentation, exclusion of other disorders or organic causes, prediction of clinical outcome and most importantly the ability to scan individuals who are at risk before they present with full blown psychosis and a wise decision making in terms of whom to treat.

REFERENCES
1. Murray, C., & Lopez, A. (1996). The global burden of disease: A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020; summary. Cambridge, MA: Published by the Harvard School of Public Health on behalf of the World Health Organization and the World Bank;
2. McGrath J, Saha S, Welham J, El Saadi O, MacCauley C, et al (2004). A systematic review of the incidence of schizophrenia: The distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Med;
3. Saha, S., Chant, D., Welham, J., & Mcgrath, J. (2005). A Systematic Review of the Prevalence of Schizophrenia. Plos Med PLoS Medicine.
4. Gur, RE., Turetsky, BI., Bilker, WB., Gur, RC., (1999). Reduced gray matter volume in schizophrenia. Arch Gen Psychiatry 56:905–1110.1001.
5. Schröder, J., Buchsbaum, M., Siegel, B., Geider, F., & Niethammer, R. (1996). Structural and Functional Correlates of Subsyndromes in Chronic Schizophrenia. Psychopathology, 38-45.
6. Potkin, SG., Alva, G., Fleming, K., Anand, R., Keator, D., Carreon, D. (2002). A PET study of the pathophysiology of negative symptoms in schizophrenia. Am J Psychiatry 159:227–3710.1176.
7. Johnstone, EC., Crow, TJ., Frith, CD. (1976). Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Lancet 2:924–26.
8. Shelton, RC., Weinberger, DR., (1986). Computerized tomography in schizophrenia: a review and synthesis. In Handbook of Schizophrenia, Vol. 1: The Neurology of Schizophrenia, ed. HA Nasrallah, DR Weinberger, pp. 207–50. Amsterdam: Elsevier
9. Reveley, AM., Reveley, MA., Clifford, CA., Murray, RM. (1982). Cerebral ventricular size in twins discordant for schizophrenia. Lancet 1:540–41;
10. Weinberger, DR., DeLisi, LE., Perman, GP., (1982). Computed tomography in schizophreniform disorder and other acute psychiatric disorders. Arch. Gen. Psychiatry 39:778–83.
11. Andreasen, NC., Swayze, VW., Flaum, M., (1990). Ventricular enlargement in schizophrenia evaluated with computed tomographic scanning. Arch. Gen. Psychiatry 47:1008–15.
12. Illowsky, BP., Juliano, DM., Bigelow, LB., Weinberger, DR., (1988). Stability of CT scan findings in schizophrenia. Results of an 8 year follow-up study. Neurosurgical Psychiatry 51:209–13.
13. Andreasen, NC. (1988). Evaluation of brain imaging techniques in mental illness. Annu. Rev. Med. 39:335–45;
14. Kelsoe, Jr., Cadet, JL., Pickar, D., Weinberger, DR., (1988). Quantitative neuroanatomy in schizophrenia. A controlled magnetic resonance imaging study. Archives of General Psychiatry 45:533–41.
15. Mccarley, R., Wible, C., Frumin, M., Hirayasu, Y., Levitt, J., Fischer, I., & Shenton, M. (1999). MRI anatomy of schizophrenia. Biological Psychiatry, 1099-1119;
16. Dauphinais, ID., DeLisi, LE., Crow, TJ., (1990). Reduction in temporal lobe size in siblings with schizophrenia: a magnetic resonance imaging study. Psychiatry Research Neuroimaging 35:137–47;
17. Suddath. RL., Casanova, MF., Goldberg, TE., (1989). Temporal lobe pathology in schizophrenia: a quantitative magnetic resonance imaging study. American Journal of Psychiatry 146:464–72;
18. Shenton, ME., Kikinis, R., Jolesz, FA. (1992). Abnormalities of the left temporal lobe and thought disorder in schizophrenia. New England Journal of Medicine. 327:604–12;
19. Suddath, RL., Christison, GW., Torrey, EF., (1990). Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. New England Journal of Medicine . 322:789– 94;
20. Bogerts, B., Ashtari, M, Degreef, G. (1990). Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia. Psychiatry Research Neuroimaging 35:1–13.;
21. Marsh, L., Suddath, RL., Higgins, N., Weinberger, DR. (1994). Medial temporal lobe structures in schizophrenia: relationship of size to duration of illness. Schizophrenia Research 11: 225–38;
22. Barta, PE., Pearlson, GD., Powers, RE., (1990). Auditory hallucinations and smaller superior temporal gyral volume in schizophrenia. American Journal of Psychiatry 147:1457–62;
23. Degreef, G., Ashtari, M., Bogerts, B., (1992). Volumes of ventricular system subdivisions measured from magnetic resonance images in first-episode schizophrenic patients. Arch Gen Psychiatry Archives of General Psychiatry 49: 531–37 11.
24. Schlaepfer, TE., Harris, GJ., Tien, AY., (1994). Decreased regional cortical gray matter volume in schizophrenia. American Journal of Psychiatry 151:842–48;
25. Benes, FM., McSparren, J., Bird, ED., (1991). Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Archives of General Psychiatry 48:996–1001;
26. Akbarian, S., Bunney, WE., Potkin, SG., (1993). Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development. Archives of General Psychiatry 50: 169–77;
27. Belliveau, JW., Kennedy, DN., McKinstry, RC., (1991). Functional mapping of the human visual cortex by magnetic resonance imaging. Biological Psychiatric 254:716–19;
28. Kwong, KK., Belliveau, JW., Chesler, DA. (1992). Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation. Proceedings of the National Academy of Sciences 89:5675–79;
29. Duyn, J., Mattay, V., Sexton, R., Sobering, G., Barrios, F., Liu, G., Moonen, C. (1994). 3-dimensional functional imaging of human brain using echo-shifted FLASH MRI. Magnetic Resonance in Medicine 150-155;
30. Gullickson, T. (1995). Positron-Emission Tomography in Schizophrenia Research. PsycCRITIQUES. 511-520; doi:10.2967/jnumade.1009066076
31. Delisi, L., Holcomb, H., Cohen, R., Pickar, D., Carpenter, W., Morihisa, J., . . . Buchsbaum, M. (1996). Positron Emission Tomography in Schizophrenic Patients With and Without Neuroleptic Medication. Journal of Cerebral Blood Flow & Metabolism, 201-206;
32. Bartlett, E.J, Wolkin, A., Brodie, J.D., (1991). Importance of pharmacologic control in PET studies: effects of thiothixene and haloperidol on cerebral glucose utilization in chronic schizophrenia. Psychiatry Research of Neuroimaging 40:115–24;
33. Cohen, R.M., Semple, W.E., Gross, M., Nordahl, T.E. (1988). From syndrome to illness: delineating the pathophysiology of schizophrenia with PET. Schizophrenia Bulletin. 14:169– 76;
34. Weinberger, D.R., Berman, K.F., (1988). Speculation on the meaning of cerebral metabolic hypofrontality in schizophrenia. Schizophreni Bulletin. 14:157–68;
35. Malhotra, S., Gupta, N., Bhattacharya, A., & Kapoor, M. (2006). Study of childhood onset schizophrenia (COS) using SPECT and neuropsychological assessment. Indian Journal of Psychiatry, 48(4), 215–222. doi:10.4103/0019-5545.31552
36. Kotrla, K.J., & Weinberger, D.R., (1995). Brain imaging in schizophrenia 1. Annual Review of Medicine, 46(1), 113–122.
37. National Institute of Mental Health. Schizophrenia Retrieved from http://www.nimh.nih.gov/health/statistics/prevalence/schizophrenia.shtml on July 24, 2015.
38. Kapur, S., Zipursky, R., Jones, C., Remington, G., Houle, S. (2000). Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET
study of first-episode schizophrenia. Am J Psychiatry. 157(4):514-20. PubMed PMID: 10739409.
39. Woolley, J. (2005). Neuroimaging in schizophrenia: What does it tell the clinician? Advances in Psychiatric Treatment, 195-202; doi:10.1192/1pt.11.3.195

Affiliations:
Dinesh Sangroula, M.D.: North Shore LIJ, The Zucker Hillside Hospital, NY, USA
Muhammad Ovais, M.D.: St Louis University, St Louis, MO, USA
Bivek Wagle, B.S.: California State University – East Bay, CA, USA

Correspondence:
Dinesh Sangroula, M.D.,North Shore LIJ, The Zucker Hillside Hospital, 75-59 263rd Street, Glen Oaks, NY 11004, USA.