Close-up with Dr. Albert Wong – Why Should We Care About Neuroscience?

Close-up with Dr. Albert Wong – Why Should We Care About Neuroscience?

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By Jill Cates

Dr. Albert Wong is not your traditional white-coat psychiatrist. Long flowing hair, black t-shirt and jeans, Wong has the look of a rock star. In fact, he is the lead singer and guitarist of an electronic psychedelic band that performs at local concerts in Toronto. But during the day, Wong works as a full-time psychiatrist at the Center for Addiction and Mental Health (CAMH) and as an associate professor at the Institute of Medical Science (IMS) and the Departments of Psychiatry and Pharmacology at the University of Toronto (U of T). As both a clinician and neuroscientist, Wong splits his time between treating patients with schizophrenia and researching the underlying mechanisms of their illness in the lab.

In his recent talk, entitled “Why should we care about neuroscience?” at the TEDMED IMS Day, Wong presented the rationale for why neuroscience should represent the basis of psychiatry. He simply explains, “Neuroscience can help us understand the emotions and behaviors in our patients. While we do not know the neurobiology of schizophrenia, we do know a lot about the neurobiology of anger, love, and fear.” These concepts of neuroscience are further examined in the weeklong neuroscience lecture series that Wong runs for second-year psychiatry residents at U of T. With wide-ranging topics such as partner preferences in mates, violence and aggression, cross-species comparisons, and receptor biology, the lectures are meant to expose interesting, quirky, and controversial elements of human behavior that have a neurobiological explanation. The lectures showcase breakthroughs and discoveries in neuroscience to reveal the potential impact that neuroscience research may have on the future of psychiatry. The overarching goal of the lecture series is to provide residents with a greater appreciation and understanding for the role that neuroscience plays in psychiatry.

Wong, though, still has difficulties convincing others that neuroscience is important to psychiatry. “There is a lack of interest in neuroscience among psychiatry residents because—just like any other resident—they want to learn practical things that will help them directly treat their patients,” says Wong. These residents raise a good point: our current knowledge of neuroscience has not yet led to breakthrough new treatments for psychiatric illnesses, nor has understanding more about the etiology of these disorders greatly improved clinical practice. In fact, most drug treatments in psychiatry have been developed from trial and error without an a priori understanding of the brain mechanisms involved. Even at the individual patient level, the “trial and error” method is used to determine the most effective dosage or cocktail of drugs for the patient, as well-exemplified by treatment practices of patients with depression.[1]

This slow progress in understanding psychiatric illnesses can be attributed to the complexity of the brain, the most enigmatic organ in the human body. In contrast to cancer, which in some cases can now be diagnosed and treated at the genomic level, psychiatric disorders lack a clear pathological signature, thus leading to difficulties in characterization.[2]

Studies have identified some subtle structural abnormalities in the brains of individuals with psychiatric illnesses. For example, brain volumes and the architecture of the cortex is abnormal in schizophrenia.[3] However, such abnormalities are too subtle, variable, or non-specific to the disease to be used to distinctly identify a diseased brain. “At present, no animal model can capture the complexity of human psychiatric disease,” explains Wong, “but some models can highlight certain parts of disease that allow us to indirectly test treatments.” The complexity of the brain has resulted in slower advances in the field of psychiatry than other disciplines. Wong explains, “In psychiatry, we are at the same stage that people were at treating other symptoms 50 years ago.” Despite current limitations, the future of neuroscience is promising. The recent development of cutting-edge tools has opened new opportunities for neuroscientists to study the pathways involved in psychiatric illness. Understanding these pathways may lead to novel hypothesis-driven treatments that effectively target the root cause of illness, and change the way psychiatrists diagnose their patients.

At CAMH, Wong’s research group is investigating the mechanisms underlying schizophrenia at the genetic, cellular, developmental, and clinical level. His lab takes both a basic science and clinical science approach to the study of schizophrenia. Wong’s wet bench research uses mouse models to investigate gene-environment interactions, epigenetics, gene transcription, and neurodevelopment. More specifically, his research team studies the disrupted in schizophrenia 1 (Disc1) gene in mutant mouse models to characterize genetic and environmental effects on neuron migration during cortical development. A former graduate student, Frankie Lee, showed that Disc1 mutants have abnormal cortex lamination, reflecting irregularities in neuron migration.[4] In terms of clinical applications, Wong hopes that these mouse models can be used as “a platform to test novel drugs that directly target the biology of illness rather than only counteracting symptoms of the illness.”[5]

In a recent research endeavour at the clinical level, Wong and his IMS graduate student, John Zawadzki, investigated spatial navigation in patients with schizophrenia using a virtual reality (VR) environment. An early example of using VR technology in psychiatry comes from Emory University, where Dr. Kerry Ressler’s group treated patients with post-traumatic stress disorder (PTSD) and anxiety by using a virtual environment for exposure therapy.6 For example, war veterans with PTSD view VR environments that resemble war zones in order to help desensitize them to the anxiety responses those stimuli provoke.[7] Others have used virtual environments to understand how humans navigate through space,[8,9] and Wong aims to expand the use of VR technology to study the mechanisms underlying schizophrenia through spatial navigation simulations.

“There are many brain areas that have to work together to complete any complicated task,” Wong explains, “and there are some that are more critical than others.” In spatial navigation, the striatum and hippocampus are two critical parts of the brain that support two different navigational strategies. The striatum is used for stimulus-response memory to navigate (e.g. using landmarks to find your way home), while the hippocampus supports a virtual map to navigate (e.g. the relative spatial positions of various locations). Most people switch back and forth between these two navigation strategies. However, in patients with schizophrenia, the hippocampus appears to be dysfunctional. Wong plans to explore how hippocampal navigation is altered in patients with schizophrenia, using a VR cityscape environment that his research team has developed in collaboration with Sheridan College in Oakville, Ontario. The VR cityscape is meant to simulate the experience of exploring an unfamiliar city for the first time. Preliminary results have shown that patients with schizophrenia take more time to navigate in the VR city compared with healthy participants, suggesting that abnormalities in brain regions that control navigation (hippocampus and striatum) exist in this psychiatric population.10 The next phase of their study will incorporate functional magnetic resonance imaging to study hippocampal and striatal activity in patients with schizophrenia in a VR environment.

Between his work in Disc1 mutant mice and VR schizophrenia studies, Wong is at the forefront of exciting and cutting-edge neuropsychiatric research. Neuroscience is reaching a “golden age” era where recent major breakthroughs are starting to unravel mysteries of the brain. From brain-computer interface technology, memory storage on microchips, and the Brain Mapping Project led by President Obama, to name a few, neuroscientists are furiously working to better understand the brain and what causes psychiatric illness. While Wong currently has two separate roles of “psychiatrist” and “neuroscientist,” his research in the lab may one day directly influence the way he and his colleagues diagnose and treat patients.

 References

1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354:1231-42.

 2. Kapur S, Phillips AG, Insel TR. Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? Mol Psychiatry. 2012;17:1174-9.

3. Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain. 1999;122:593-624.

4. Lee FH, Fadel MP, Preston-Maher K, et al. Disc1 point mutations in mice affect development of the cerebral cortex. J Neurosci. 2011;31:3197-206.

5. Lipina TV, Haque FN, McGirr A, et al. Prophylactic valproic acid treatment prevents schizophrenia-related behaviour in Disc1-L100P mutant mice. PLoS One. 2012;7:e51562.

6. Ressler KJ, Rothbaum BO, Tannenbaum L, et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004;61:1136-44.

7. Gerardi M, Rothbaum BO, Ressler K, et al. Virtual reality exposure therapy using a virtual Iraq: case report. J Trauma Stress. 2008;21:209-13.

8. Maguire EA, Burgess N, Donnett JG, et al. Knowing where and getting there: a human navigation network. Science. 1998;280:921-4.

 9. Ekstrom AD, Kahana MJ, Caplan JB, et al. Cellular networks underlying human spatial navigation. Nature. 2003;425:184-8.

10. Zawadzki JA, Foussias G, Rodrigues A, et al. Spatial navigation in schizophrenia using a realistic virtual city. Schizophr Bull. 2013;39:S254.