The neurobiology of schizophrenia

The neurobiology of schizophrenia

Schizophrenia is a complex, chronic brain disorder first discovered by German psychiatrist Emil Kraepelin in the early 1900s (Mueser & Jeste, 2008). This disorder affects approximately 1% of the population, typically presenting itself in adolescence or early adulthood (Jauhar et al. 2022). Symptoms of this disorder have been divided into three frameworks; positive, negative, and cognitive (Jauhar et al. 2022). Schizophrenia has been viewed as the result of a combination of factors making it difficult to develop a theory that encompasses all domains affected by the disorder such as thought, affect, and motor movement (Hanson & Gottesman, 2005). The dynamic view of this disorder has led to numerous theories aimed at explaining the origin and its impact on individuals. Research has yet to discover a definitive cause or cure (Mueser & Jeste, 2008). This paper will explore the neurobiological aspects of the disease by discussing the three symptomatic frameworks of schizophrenia and the areas of the brain that have been implicated in each. As well, it will address two central biological theories of schizophrenia: the dopamine theory and the theory of neurodevelopment.

Symptoms     

The symptomology of schizophrenia has changed over time. In 1973 a pilot study was conducted resulting in 12 symptoms that were present across the 811 participants with schizophrenia (Carpenter et al. 1973). These symptoms included restricted affect, poor insight, hearing thoughts aloud, not waking early, poor rapport, absence of sad appearance and elation, incoherent speech, and a variety of delusions. Although this pilot study narrowed down primary symptoms, the symptoms experienced in schizophrenia vary drastically. According to a study done by Cardno and Gottesman (2000) on monozygotic quadruplets concordant for the disease, symptoms vary not only between individuals with the disorder but also within an individual over time. When schizophrenia begins presenting itself approximately 75% of individuals experience prodromal symptoms such as indefinable feelings of change, anger, irritability, anxiety and depression, social withdrawal, or deterioration in social functioning (Moller & Husby, 2000). These symptoms can present intermittently before becoming more consistent over time. Diagnostic criteria and symptoms involved have changed over time and today the core symptoms are subdivided into three categories: negative, positive, and cognitive symptoms (Jauhar et al. 2022).

Negative Symptoms

The negative symptoms play a large role in the poor functioning and poor quality of life of patients with schizophrenia and evolve from prodromal symptoms to become acute negative symptoms (Ahmad et al., 2018). Currently there are five negative symptoms divided into two domains (Galderisi & Marder, 2017). The first domain is the Motivational Deficit domain, which includes lack of motivation, the inability to feel pleasure, and asociality. The second domain is the Expressive Deficit domain which includes blunted affect and speech issues (Giordano et al., 2023). A study using fMRI data to examine the neurobiological correlations of these domains was done to understand the impact of negative symptoms on different areas of the brain (Giordano et al., 2023). Researchers analyzed the resting brain states of 62 individuals with schizophrenia and compared them with the resting brain states of 46 healthy control individuals. The results of this study (Giordano et al., 2023) indicated that there was abnormal activity in a variety of brain areas which led to the negative symptoms presenting themselves.

Brain Areas Implicated in Negative Symptoms

There are many areas of the brain implicated in the negative symptoms of schizophrenia. The study conducted by Giordano and their peers (2003) showed increased brain activity in the parietal lobe and lower activity in the prefrontal cortex, the anterior cingulate cortex, and the caudate nucleus of the schizophrenia patients. The researchers found a relationship between the resting state activity of the left orbitofrontal cortex and negative symptoms of the Motivational Deficit domain as well as a relationship between the resting state activity of the left ventral caudate and the Expressive Deficit domain. The prefrontal cortex plays an important role in memory as well as motivational and reward behaviour and the anterior cingulate cortex is involved in processing cognition and emotion (Giordano et al., 2023). Both brain areas are involved in integrating motivational and cognitive information. Additionally, the caudate nucleus is important for cognition, motivation, and affect. Therefore, the study’s results showing that these areas of the brain have lower levels of activity support the idea that schizophrenia patients would express symptoms such as cognition issues, lack of motivation and inability to express their emotions appropriately (Giordano et al., 2023).

Positive Symptoms

The second framework of symptoms that can present itself in patients with schizophrenia is the positive symptoms. These symptoms involve alterations to an individual’s reality with the most prominent positive symptoms being hallucinations, delusions, and disturbed thought (Walton et al., 2017). These symptoms are often preceded by earlier symptoms that present in childhood that indicate a high risk for developing schizophrenia later in life (Maki et al., 2005). Antipsychotic treatments can be administered to diminish positive psychotic symptoms. However, treatment does not provide relief of these symptoms for approximately 20-30% of patients (Elkis, 2007). These symptoms can be incredibly distressing for patients, therefore understanding the neurobiological correlates of these symptoms is incredibly important (Walton et al., 2017).

Brain Areas Implicated in Positive Symptoms

            There are a number of brain regions that studies show to be implicated in positive symptoms of the disorder. Positive symptoms have been associated with dysfunctional activity and decreased volume of the superior temporal gyrus, which has been linked to auditory hallucinations and disturbed thought (Walton et al., 2017). Additionally, research has shown that the amygdala is dysfunctional by having reduced activity in schizophrenia patients. The amygdala plays an important role in determining and processing relevant stimuli. Therefore, when the amygdala is dysfunctional and less active than it should be it leads to individuals experiencing delusions because they are not able to determine which stimuli is relevant to their reality (Taylor et al., 2002).

Cognitive Symptoms

Although not all patients with schizophrenia experience cognitive symptoms they have become a prominent feature of this disorder. There are seven key functions affected by this symptom framework: working memory, attention, verbal and visual learning and memory, reasoning, problem solving, processing speed, and social cognition (Kaneko, 2018). These symptoms are thought to present themselves prior to the onset of the disorder (Caspi et al., 2003). Caspi and colleagues (2003) conducted a study to observe if poor cognitive functioning was present prior to the onset of the disease and analyze how it persisted after the patients first schizophrenic episode. To do this, they compiled a sample of 44 individuals and conducted a series of tests to analyze their aptitude of various cognitive skills including mathematics, verbal reasoning, and abstract and verbal intelligence (Caspi et al., 2003). The results of this study indicated that participants with schizophrenia performed significantly worse on these cognitive tests than the healthy control groups. This study supports the idea that cognitive deficits exist prior to the first psychotic episode and there is an additional decline when the disorder presents itself. (Caspi et al., 2003).

Brain Areas Implicated in Cognitive Symptoms

            The area of the brain that is highly correlated with the poor cognitive functioning of schizophrenia patients is the prefrontal cortex (Minzenberg et al., 2009). Specifically, the dorsolateral prefrontal cortex is shown to have decreased activity compared to healthy control patients (Glahn et al., 2005). Studies have found cortical thickness deficits across the whole cortex, temporal and frontal areas of the brain, with the deficits in these regions being 4.4% to 5.7% thinner than healthy controls (Schultz et al., 2010). Additionally, the decreased volume of the hippocampus is shown to correlate to memory issues in patients with cognitive symptoms (Goldberg et al., 1994). It is the dysregulation and thinning of the gray matter in these regions that causes schizophrenia patients to experience dysfunctional working memory and other behavioural control issues (Glahn et al., 2005).

Central Biological Theories of Schizophrenia

Dysfunctional Dopamine Activity Theory

Schizophrenia is an elusive disorder making it difficult to pinpoint an exact cause within one theory (Hanson & Gottesman, 2005). One dominant hypothesis for the cause of schizophrenic symptoms is the dopamine hypothesis (Howes & Kapur, 2009). This hypothesis is commonly used to explain a number of the symptoms associated with this disorder, especially the psychosis related positive symptoms (Pankow et al., 2012). The basis of this theory is that the dopaminergic neurons fire in a dysfunctional, chaotic manner to the ventral striatum which leads to irrelevant stimuli becoming significant. The main finding of a study done by McCutcheon and their colleagues (2018) using PET scans to analyze dopaminergic functioning in individuals with schizophrenia was that the there is an increase in presynaptic dopamine functioning in the dorsal striatum of individuals with the disorder. It is theorized that hyperactivity within the striatum (Stahl, 2018) leads to the creation of hallucinations and delusions (Pankow et al., 2012). While there is hyperactivity in the striatum, PET scans have shown decreased dopamine activity in the rest of the brain, which leads to cognitive and negative symptoms such as decreased cognition and social functioning (Abi-Dargham, 2020). The constant revisions that are made to this theory over time illustrate how difficult it can be to develop one theory for the origin of schizophrenia.

Neurodevelopmental Theory

A second theory that has been put forward to explain the origin of schizophrenia is the neurodevelopmental theory. This theory involves the idea that there are small disturbances to an individual’s early brain development that will lead to the development of schizophrenia once synaptic pruning has ended (Weinberger, 1995). A twin study found that there is a 60-80% chance of schizophrenia being inherited (Sullivan et al., 2003). However, it is sometimes viewed as an epigenetic disorder (Popovic et al., 2019). Researchers now believe that epigenetic risk factors interact in a variety of ways during critical periods of neurodevelopment that leads to symptoms later in life when stress triggers a vulnerability created during neurodevelopment (Popovic et al., 2019). An example of this would be if there is a genetic abnormality such as a dysregulation of the hypothalamic-pituitary-adrenal axis which leads to a reduction in the size of the hippocampus and frontal lobe it may result in negative and cognitive symptoms of schizophrenia such as trouble with memory and social functioning (Popovic et al., 2019). A competing theory involves the idea that Schizophrenia is actually a problem of neurodegeneration. One study found that there was an association between the age individuals reached important neurodevelopmental milestones such as standing and the age their cognitive decline began (Kobayashi et al., 2014). This supports the theory that neurodevelopmental issues can lead to neurodegeneration and possibly negative and cognitive symptoms of schizophrenia later in life, suggesting that these two opposing theories are interrelated (Kobayashi et al., 2014).

Conclusion

Through the discussion of the various symptoms of schizophrenia, the brain areas impacted, and various theories of the disorder, there is one recurring theme and that is that there is no singular way of looking at schizophrenia. Over time the criteria and symptoms of schizophrenia have changed until they reached the current three frameworks of negative, positive, and cognitive symptoms (Jauhar et al. 2022). However, these symptoms do not look the same across individuals or within an individual over time (Cardno & Gottesman, 2000). This disorder affects both structure and activity levels in numerous areas of the brain depending on the symptoms experienced (Glahn et al., 2005; Walton et al., 2017; Giordano et al., 2023). It becomes clear why it is difficult to pinpoint one theory of schizophrenia. The theories of dopamine dysfunction and neurodevelopment consider how abnormal brain activity and structure can lead to the development of symptoms (Popovic et al., 2019; Weinberger, 1995). Although there is no cure to this disorder yet, the constant development of new theories and revisions of old ones gives hope that future researchers will be able to find a treatment or cure that can help individuals suffering from the intrusive symptoms of this complex disorder.

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