4. Current Studies of Schizophrenia

Current Studies of Schizophrenia
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Figure 1. An example of white matter fiber bundles mapped using diffusion tractography.
Each different color represents a separate fiber bundle

The nature of schizophrenia as a disorder is still not well understood today and remains controversial within the field of neuroscience and psychology. Without fully understanding the nature of schizophrenia, a proper, effective treatment is unfeasible. For that reason, research in schizophrenia has branched out into a multitude of directions in recent years with the assistance of technological and technical advancements. Advancement in technology such as neuroimaging and analysis techniques in genomics, etc. has provided us with much greater insight into schizophrenia than previously possible. A great example of technological advancement include diffusion tractography, which incorporates modern techniques of 3D modelling, diffusion MRI and image analysis to produce a 3D model of white-matter fiber bundles in the brain, allowing us to easily recognize structural deficits quickly[1]. Emerging analytical techniques such as Genome-Wide Association Studies (GWAS) allow for identification and association of symptoms and genes. With the emergence of these advancements, previous studies were strengthened or refuted based on new evidence, such as the neurochemistry and neurodevelopmental basis for schizophrenia, and current studies have branched out into completely new directions that were previously largely unexplored, such as neuroimmunology of schizophrenia[2], and new trends are still constantly emerging today.

1. Emerging Technology and Techniques

1.1 Neuroimaging

Medical imaging stands in the forefront of medical technological advancement. Prior to the 2000s, neuroimaging have mostly been experimental and most techniques remained theoretical until the 1980s. It was not until the last decade that neuroimaging became widely accessible to medical facilities and researchers. With the advancement of both digital technology and engineering, innovation in neuroimaging grew rapidly, resulting in many new neuroimaging techniques that allow us to observe the brain in previously impossible ways.
The accessibility of new neuroimaging techniques gave rise to research that schizophrenia is a disorder of abnormal connectomics and brain connectivity[3]. There are a few particular types of neuroimaging that are of interest to schizophrenia research:

1.1.1 Magnetic Resonance Imaging

Magnetic Resonance Imaging (MRI) is an imaging technique that utilizes a magnetic field to align the magnetic moments of hydrogen atoms in water. By capturing the radio frequency released by excited hydrogen atoms, we can create an image of of the tissue containing these atoms. When used on the human body, particularly the brain, it can reveal different structures of the body non-invasively. While MRI isn't new technology in the 21st century, the widespread growth in accessibility made it an invaluable tool in the research of the neurosctructural aspect of schizophrenia. Recent studies using MRI have found that schizophrenic patients often have reduced cerebral asymmetry compared to healthy individuals[4]. Many studies involving anatomical studies reduced white matter volume in various areas, often in the frontal lobes, amygdala, hippocampus, superior temporal gyrus, corpus callosum and the cerebellum, are associated with increased schizophrenic symptoms such as hallucinations and delusions[5].

1.1.2 Diffusion Tensor Imaging

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Figure 2. Comparison of fractional anistropy values with
control group reveals structural changes.
The red area represents an area observing a change.

Diffusion Tensor Imaging (DTI) is an application of Magnetic Resonance Imaging (MRI) that measures the diffusion of water molecules within tissue. In areas, particularly the brain, water does not diffuse freely and the pattern of it's diffusion can reveal the structural details of the brain, as well as the diffusion of particles in the brain. In the brain, it can be used to identify individual white matter fiber bundles, allowing us to observe the connectome of the brain. Using this data, it is possible to reconstruct a detailed 3D model of the white matter fiber bundles in the brain, such as in figure 1 above. Currently, DTI is the only method to observe white matter tract integrity in vivo. Recent studies have utilized this advantage in order to observe white matter abnormalities in schizophrenia patients. Schizophrenic patients are often observed to have a reduced fractional anisotropy in white matter, indicating a structural change compared to a control group. These changes are most often observed in the prefrontal cortex, corpus callousm and arcuate fasciculus[6]. Virtually all areas of the brain have been observed to have structural changes in schizophrenic patients from various studies. The wide range of neurosubstrates involved indicate that schizophrenia is a highly complicated disorder.

1.2 Genomic Analysis Techniques

New techniques to analyze the correlation between geneotypes and phenotypes allow us to accurately identify the particular genes that are associated with schizophrenic symptoms. While genome sequencing was possible in the early 2000s, it was prohibitively expensive for most researchers (see: Human Genome Project). The advancement of bioinformatics and genome sequencing technology significantly lowered the cost of sequencing, allowing researchers to analyze significantly more genetic samples using the same budget.

1.2.1 Genome-Wide Association Study

Genome-Wide Association Study (GWAS) is a new analysis technique that involves scanning through full genetic sequences of a large sample size, identifying any recurring genotypes in the samples to find if any particular gene is associated with a particular phenotype. In schizophrenia research, it can be used to identify the genes that results in schizophrenic symptoms. Several genes have been repeatedly found to be positively tied to schizophrenia. These genes include NRXN1, 1q21.1, 15q13.3, 16p11.2, and 22q11.2[7]. Mutations in these areas often result in schizophrenia-like symptoms. While GWAS is a reliable and powerful technique in identifying associations between genotypes and phenotypes, it relies on having a well-controlled sample group of substantial size, or it may result in unreliable information such as false positives and statistically insignificant results. Schizophrenia research using this technique is still developing and currently suffers from this problem, as there are very few sufficiently large sample groups that are adequately phenotyped, due to the fact that schizophrenia symptoms vary significantly from patient to patient.[8]

2. Emerging Insights

2.1 Neuroimmunology

Neuroimmunology is an emerging field of research that focuses on the immunology of the nervous system. While previous studies have mainly focused on genetic and environmental factors, there is growing interest in the immunological system as explanation for the cause of schizophrenia. Although there is currently insufficient evidence to claim schizophrenia as an immunological disorder, recent finding are pointing towards more and more evidence. A recent study has suggested that aberrant immunological responses in the central nervous system are observed before and after the onset of schizophrenic symptoms [9]. Meta-analysis of previous studies show that mutations in inflammatory cytokines are positively tied to the the occurrence of schizophrenic symptoms. The genetic nature of immune disorders are in line with the fact that schizophrenia is known to be highly heritable as well. In another recent study, the addition of asprin, estrogens and NAC,three anti-inflammatory drugs, in antipsychotic treatment resulted in an increase in treatment effectiveness.[10]

2.2 Neuroanatomy

Schizophrenia is strongly associated with aberrant neuroanatomy, either from lesions or abnormal neurodevelopment. Thus, the structure of the brain is frequently observed to vary in schizophrenic patients to healthy individuals. A recent study, using a technique referred as dissimilarity-based detection, which involves neuroimaging using MRI and statistically comparing several regions known to be related to schizophrenia to a control base group, were able to achieve accuracies as high as 86.8% in diagnosing a patient, a large improvement compared to standard practices at 68% accuracy. The regions involved include the hippocampus, amygdala, entorhinal cortex, dorsolateral prefrontal cortex, thalamus, superior temporal gyrus and Heschl's gyrus[11].

2.3 Neurochemistry

The Glutamate Hypothesis of Schizophrenia
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Figure 3. The Glutamate Hypothesis of Schizophrenia.
The top figure shows a healthy neuron receiving excitation from NMDAR by GABA.
The bottom figure shots a dysfunctional neuron with either a mutated NMDAR or insufficient GABA.

The Dopamine Hypothesis of schizophrenia is one of the longest-standing theories in schizophrenia research. It suggested that schizophrenia is the result of disruptions in signal transduction caused by abnormal levels of dopamine. More recently, however, the focus of research has shifted to glutamate imbalance at the NMDA receptors[12] as another neurochemical mechanism of schizophrenia.

1. Shenton, M. E., Whitford, T. J., Kubicki, M. (2010). Structural neuroimaging in schizophrenia from methods to insights to treatments. Dialogues in Clinical Neuroscience, 12(3): 317–332.
2. Müller, N. (2014). Immunology of Schizophrenia. Neuroimmunomodulation.21:109-116.
3. Fornito, A., Zalesky, A., Pantelis, C., & Bullmore, E. T. (2012). Schizophrenia, neuroimaging and connectomics. NeuroImage,62(4), 2296-2314. doi:http://dx.doi.org/10.1016/j.neuroimage.2011.12.090
4. Oertel-Knöchel, V., & Linden, D. (2011). Cerebral asymmetry in schizophrenia. The Neuroscientist, 17(5), 456-467. doi:10.1177/1073858410386493
5. Makris, N., Seidman, L. J., Ahern, T., Kennedy, D. N., Caviness, V. S., Tsuang, M. T., & Goldstein, J. M. (2010). White matter volume abnormalities and associations with symptomatology in schizophrenia. Psychiatry Research: Neuroimaging, 183(1), 21-29.
6. Kyriakopoulos, M., Bargiotas, T., Barker, G. J., & Frangou, S. (2008). Diffusion tensor imaging in schizophrenia. European Psychiatry, 23(4), 255-273. doi:10.1016/j.eurpsy.2007.12.004
7. Doherty, J., O’Donovan, M., & Owen, M. (2012). Recent genomic advances in schizophrenia. Clinical Genetics, 81(2), 103-109. doi:10.1111/j.1399-0004.2011.01773.x
8. Levinson, D. F., Shi, J., Wang, K., Oh, S., Riley, B., Pulver, A. E., … Holmans, P. A. (2012). Genome-wide association study of multiplex schizophrenia pedigrees. The American Journal of Psychiatry, 169(9), 963-73.
9. Annya M. Smyth and Stephen M. Lawrie. (2013). The Neuroimmunology of Schizophrenia. Clin Psychopharmacol Neurosci. Dec 2013; 11(3): 107–117.
10. Sommer IE, van Westrhenen R, Begemann MJ, de Witte LD, Leucht S, Kahn RS. (2013) Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2014 Jan;40(1):181-91.
11. Ulaş, A., Duin, R. P. W., Castellani, U., Loog, M., Mirtuono, P., Bicego, M., … Brambilla, P. (2011). Dissimilarity‐based detection of schizophrenia. International Journal of Imaging Systems and Technology, 21(2), 179-192. doi:10.1002/ima.20279
12. Morrison, P. D., & Pilowsky, L. S. (2007). Schizophrenia: More evidence for less glutamate. Expert Review of Neurotherapeutics, 7(1), 29-31. doi:http://dx.doi.org/10.1586/14737175.7.1.29

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