Introduction
Schizophrenia and schizoaffective disorders include a disconnect from the real world in several manners, but how this disconnect is processed and where neural processing goes wrong is an area of increasing interest. Several biomarkers like MMN, P3a, and ASSR can show the differences in neural processing. One of the most well-established theories underlying schizophrenia is the dopamine hypothesis, which posits that excessive dopamine activity in certain brain regions contributes to psychotic symptoms. Elevated dopamine in the mesolimbic pathway is associated with hallucinations and delusions, as the brain assigns exaggerated significance to irrelevant stimuli (Howes & Kapur, 2009). This overactivity contrasts with reduced dopamine signaling in the mesocortical pathway, which contributes to cognitive deficits and negative symptoms, such as apathy and reduced emotional expression (Javitt & Sweet, 2015). While this occurs after a signal is received, there are many places that contribute to processing that malfunction along the way, cascading in the range of symptoms seen in related disorders.
Current Hypotheses
Schizophrenia and schizoaffective disorders feature impaired cognition, sensory processing, dysregulation of emotions, and daily functioning issues. Mismatch negativity (MMN) describes a brain response that filters out sensory information between what is important and unimportant. For example, if a louder sound occurs, most neurotypical brains respond by focusing on the louder noise, attributing that noise with some level of importance. In schizophrenia, psychosis, and schizoaffective disorders, this response is diminished, resulting in random sensory input to be attributed with deep significance. In this case, small shadows or noises will be interpreted as some bigger event, which leaves room to fill in the gaps on why that event occurred. Thus, it is hypothesized that because there is a need to signify sensory input, the brain comes up with related reasons and is then unable to distinguish those internal scenarios from reality. Studies show that mismatch negativity (MMN) response, which measures the brain's automatic detection of deviations in auditory patterns, is significantly reduced in schizophrenia patients (effect size d = 0.69) compared to healthy controls. This impairment suggests that the brain struggles to identify and adapt to changes in the environment, leading to a reduced ability to prioritize important stimuli (Koshiyama et al., 2021). Similarly, P3a, a related neural response that redirects attention to novel or salient events, is also diminished (d = 0.67), reflecting impaired attentional engagement. These deficits in sensory filtering create a chaotic sensory environment, where irrelevant stimuli compete with meaningful information for cognitive resources (Javitt & Sweet, 2015). These disruptions suggest the brain struggles to filter and prioritize sensory input, making it harder to focus on what’s relevant.
Gamma Oscillations in the Brain
Another key issue is gamma-band auditory steady-state response (ASSR), which measures how brain regions synchronize to process information over time. In schizophrenia, both phase coherence (d = 0.44) and power (d = 0.39) of gamma oscillations are reduced, indicating disrupted communication between neural circuits (Koshiyama et al., 2021). These disruptions hinder the brain’s ability to process sequences of information, affecting tasks that require temporal integration, such as understanding speech, following instructions, or paying attention. Gamma oscillations are critical for coordinating activity across neural circuits, and their disruption in schizophrenia reflects broader impairments in neural synchronization and communication across brain regions (Uhlhaas & Singer, 2010). Because the brain uses gamma ray oscillations to communicate with other parts of the brain, a reduced gamma-band auditory steady-state response signifies a lack of integration between thoughts and actions or a disorganized state of mind.
Biomarkers and Neurotransmitters
There are several connections with biomarkers and neurotransmitters that should be of notice. Dopamine dysregulation, which often occurs in schizophrenia-related disorders, interacts with other neurotransmitter systems, particularly glutamate. N-methyl-D-aspartate (NMDA) receptor hypofunction is a key mechanism in schizophrenia, impairing synaptic plasticity and predictive coding–the brain’s ability to distinguish between internal thoughts and external stimuli. Studies show that blocking NMDA receptors with drugs like ketamine induces schizophrenia-like symptoms, highlighting their role in psychosis (Krystal et al., 1994). NMDA receptor dysfunction also disrupts gamma oscillations, a key aspect of neural synchronization. Schizophrenia and schizoaffective disorders are highlighted by their lack of connectivity between different brain regions, which is undoubtingly a significant factor in the recurring clinical symptoms seen.
Ethical Considerations
Research is overwhelmingly lacking in severer mental disorders to begin with, as most theories and models were developed once and never elaborated upon. For example, the idea that hallucinations are simply internal thoughts that are perceived to be external is outdated, coming from a study done by Javitt and others in 1996. While some of their findings held truth, the lack of challenge to established ideas severely limits the scope of our understanding of schizophrenia and schizoaffective-related disorders. There also remains a lack of specificity, with many findings resulting in a generalized disorganization of thoughts rather than naming specifically what malfunctions. While this question remains unanswered, future research should focus on specifying the mechanisms underlying schizophrenia and related disorders instead of generally grouping these disorders as too disorganized or chaotic to research.
Conclusion
Schizophrenia and related disorders arise from a convergence of neurotransmitter imbalances, structural abnormalities, and connectivity disruptions. Dopamine and glutamate dysregulation, impaired gamma oscillations, and sensory processing deficits form the biological foundation of these disorders, which are amplified by stress and inflammation. Understanding these mechanisms provides insight into the complex interplay of symptoms and points to potential therapeutic targets, such as NMDA receptor modulation and interventions aimed at improving neural synchrony. By addressing these underlying biological and neurological disruptions, researchers hope to develop more effective treatments for schizophrenia and related conditions.
Works Cited
Howes, Oliver D., and Shitij Kapur. “The Dopamine Hypothesis of Schizophrenia: Version III—The Final Common Pathway.” Schizophrenia Bulletin, vol. 35, no. 3, 2009, pp. 549–562. doi:10.1093/schbul/sbp006.
Javitt, Daniel C., and Robert A. Sweet. “Auditory Dysfunction in Schizophrenia: Integrating Clinical and Basic Features.” Nature Reviews Neuroscience, vol. 16, no. 9, 2015, pp. 535–550. doi:10.1038/nrn4002.
Koshiyama, Daisuke, et al. “Hierarchical Pathways from Sensory Processing to Cognitive, Clinical, and Functional Impairments in Schizophrenia.” Schizophrenia Bulletin, vol. 47, no. 2, 2021, pp. 373–385. doi:10.1093/schbul/sbaa116.
Krystal, John H., et al. “Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans.” Archives of General Psychiatry, vol. 51, no. 3, 1994, pp. 199–214. doi:10.1001/archpsyc.1994.03950030035004.
Javitt, Daniel C., et al. “Role of Cortical N-Methyl-D-Aspartate Receptors in Auditory Sensory Memory and Mismatch Negativity Generation: Implications for Schizophrenia.” Proceedings of the National Academy of Sciences, vol. 93, no. 21, 1996, pp. 11962–11967. doi:10.1073/pnas.93.21.11962.
Uhlhaas, Peter J., and Wolf Singer. “Abnormal Neural Oscillations and Synchrony in Schizophrenia.” Nature Reviews Neuroscience, vol. 11, no. 2, 2010, pp. 100–113. doi:10.1038/nrn2774.
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