1. In the movie, Nash consistently experiences visual hallucinations. In real life, this was not the case. Please describe which type of hallucinations are the most common in adult-onset schizophrenia. Which regions of the brain are believed to be involved in auditory hallucination (be specific)?
Hallucinations are a key feature of schizophrenia, affecting as many as many 80% of patients in one or more modalities (Lim et al., 2016). Whether the hallucinations occur unimodally, in which the hallucinations involve only one sensory modality, or multimodally, in which the hallucinations are a combination of sensory modalities experienced simultaneously, seems to be of some importance to both prognosis and treatment (Lim et al., 2016). In one study, of the 80% of schizophrenia patients who reported having experienced hallucinations in their lives, 27% reported having experienced only unimodal hallucinations, while the other 53% experienced multimodal hallucinations. Of the multimodal group, 29% experienced hallucinations in two modalities, 17% in three modalities and 8% experienced hallucinations of 4 or more modalities (Lim et al., 2016). Auditory hallucinations were reported as the most common form of hallucination in both the unimodal (present in 68% of cases) and multimodal (present in 88% of cases) groups (Lim et al., 2016). Thus, the most common presentation of hallucinations in schizophrenia is multimodal, involving 2 modalities, and the most common sensory modality for both unimodal and multimodal hallucinations is auditory (Lim et al., 2016).
Attempting to parse out which brain structures are involved in each modality of sensory hallucination is difficult, but by comparing schizophrenia patients with auditory hallucinations against those without, some insight to the neurological basis of auditory hallucinations can be found (Kim et al., 2018). The key areas of interest seem to be the superior, middle and inferior frontal gyri, as well as the putamen and the temporal lobe (Kim et al., 2018). Specifically, there is a significantly lower standardized uptake value ratio (SUVR) in the superior, middle and inferior gyri of patients who experience auditory hallucinations while the putamen shows higher SUVR (Kim et al., 2018). The superior frontal gyrus is thought to be key in cognitive functions like working memory, task-switching and self-focused reappraisal, meaning a weakening of this structure may lead to a weakening of top-down control on subcortical structures of the brain (Kim et al., 2018). The middle frontal gyrus is involved in reorienting attention to exogenous stimulus and the inferior frontal gyrus is important for inhibition and hierarchal organization of the brain, meaning the underactivity of these regions may contribute to a general defect in self-monitoring, causing further impairment in top-down control (Kim et al., 2018).
Perhaps most crucial for auditory hallucinations, however, is the overactivity observed in the temporal lobe, specifically, the inferior temporal gyri and the left middle gyri (Kim et al., 2018). The left middle temporal gyrus is associated with language processing, semantic memory and the perception of inner speech while the inferior temporal gyrus is associated with visual perception (Kim et al., 2018). Putting these all together it may be that auditory hallucinations are the result of overactivity in the temporal lobe, specifically the regions involved in processing internal speech, combined with the underactivity of top-down structures that grant executive control and are crucial for self-monitoring (Kim et al., 2018). This creates a situation wherein the person may generate internal speech that they cannot identify as their own, and will experience as an auditory hallucination (Kim et al., 2018).
2. Which of the symptoms that Nash experiences in the film are consistent with the experience of schizophrenia?
In the film, Nash experiences extremely vivid auditory and visual hallucinations in which he sees and carries on conversations with several people who in fact do not exist. These hallucinations persist even when he is put on Thorazine, and it is shown that the people he sees in fact “follow” him throughout the course of his entire life. In real life, John Nash did not experience visual hallucinations, but he did have auditory hallucinations and would have full conversations with the voices he was hearing, something not uncommon in people with schizophrenia (Farah, 2018).
Regardless of whether or not Nash personally experienced all of the symptoms in the film, many of the symptoms that are portrayed are accurate to the experience of living with schizophrenia. For one, the age of symptom onset is accurate as Nash begins to experience his first hallucinations in his early twenties, which is typical of schizophrenia (Farah, 2018). He has dramatic delusions that he is working as a codebreaker for the government on a secret mission to stop the Soviets from detonating a nuclear missile. Fantastic delusions like this are also common in schizophrenia, and in particular, paranoid and persecutory delusions are among the most prevalent (Farah, 2018). He makes strange associations between unrelated things, such as his obsession with deciphering hidden codes in innocuous newspaper articles, and as his condition progresses, his paranoias become more and more intense.
Nash experiences a number of negative symptoms of schizophrenia in the film as well, though they are perhaps more subtle than the positive ones. At the beginning of the film he has some friends and seems to enjoy their company, though as time goes on, he becomes more and more asocial, at one point commenting that he doesn’t really like people, and that people don’t really like him. Schizophrenia can cause emotional blunting, flattened affect and asociality, all of which are consistent with his experience in the film (Farah, 2018). Finally, he also experiences some cognitive symptoms of schizophrenia, such as an inability to hold attention and high distractibility (Farah, 2018).
3. Once diagnosed, Nash undergoes a number of different therapies, including pharmacotherapy. Which type of drugs do his doctors have him on and how do they work to reduce the symptoms of schizophrenia?
In the film as well as in real life, Nash was prescribed Thorazine, which is a brand of chlorpromazine, the most common typical antipsychotic on the market at the time. Chlorpromazine is an antipsychotic that acts on all levels of the central nervous system, a number of organ systems, and also has a mild antihistaminic and antiserotonin effect as well (NCATS, 2020). Chlorpromazine acts as an antagonist that blocks postsynaptic dopaminergic receptors, in addition to some serotonergic, histaminergic, alpha1/alpha2 and cholinergic receptors (NCATS, 2020). The main receptors chlorpromazine block are D2 dopamine receptors, though they also act on D1, D3 and D4 dopamine receptors as well (NCATS, 2020). By blocking out these receptors, chlorpromazine is effective at reducing the psychotic symptoms of schizophrenia such as bizarre delusions and hallucinations, but it is relatively ineffective at reducing the negative and cognitive symptoms when compared with the later-developed atypical antipsychotics (PubChem, 2020).
4. In real life, Nash lived without medications for most of his life. Many patients also will also stop taking the drugs as soon as possible. Why does this happen? Which side effects does Nash exhibit? Are these consistent with this type of drug? What are other side effects that people may experience?
Many patients with schizophrenia choose to stop taking their antipsychotic medication due to the severity of side-effects resulting from the drugs (Adams et al., 2005). There are sedative effects to chlorpromazine that may cause weight gain, vertigo and drops in blood pressure (Adams et al., 2005), as well as reflex tachycardia (rapid heartbeat to compensate for low blood pressure), hypersalivation, incontinence and sexual disfunction such as the inability to ejaculate (NCATS, 2020). There are also anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty urinating, sinus tachycardia, ECG-changes and loss of memory (NCATS, 2020).
Perhaps the most troubling side-effect of chlorpromazine is Parkinsonism (sometimes called pseudoparkinsonisim) in which the reduced dopamine activity in the brain causes changes to the basal ganglia, resulting in symptoms typical of Parkinson’s disease such as dystonia (muscle spasms and/or contractions), akathisia (restless legs) and dyskinesia (involuntary movements) (Shin & Chung, 2012). In some patients who had been taking antipsychotics for an extended period of time and were exhibiting the symptoms of Parkinsonisim, it was found that more than 80% of the D2 receptors in the substantia nigra were occupied, which seems to correlate with the finding that most clinical symptoms of Parkinson’s Disease occur when 80% of the nigral neurons have deteriorated (Shin & Chung, 2012).
5. Schizophrenia is often considered a disconnection syndrome. Why is this the case? List at least one region (each) of the frontal lobe, limbic system and midbrain that are thought to be altered in this disease and describe how/why they are altered or not functioning properly.
Schizophrenia is often considered a disconnection syndrome, as it is not a disorder located in a single section of the brain but rather a spectrum of symptoms and defects affecting multiple systems and the way in which they connect and communicate with one another (Bányai et al., 2011). Essentially, schizophrenia is a disorder wherein connection and coordination of neural circuitry is dysfunctional, a condition sometimes known as cognitive dysmetria (Calhoun et al., 2009).
While schizophrenia is a heterogeneous disorder with many different presentations in terms of both symptoms experienced and neurological functioning, impaired dopamine-related prefrontal function and impaired glutamate-related hippocampal functioning seem to be critical in explaining disordered fronto-hippocampal connectivity (Bányai et al., 2011). This impaired connectivity in the fronto-hippocampal region is thought to be a part of the basis for the difficulties people with schizophrenia often have learning as well as maintaining attention and working memory (Bányai et al., 2011).
There is also reduced prefrontal connectivity with a number of other areas that relate to some of the defects involved in schizophrenia, such as the temporal lobe and the basal ganglia (Calhoun et al., 2009). This lack of prefrontal control over subcortical structures, in particular the reduced activity of the superior and inferior frontal gyri means there is a lack of executive control, hierarchal brain structure and self-reflection that may lead to many of the cognitive symptoms of schizophrenia, as well as the inability to distinguish what is real and what is not (Kim et al., 2018). Using PET scans during a working memory task, a lack of interaction between the right anterior cingulate and other brain regions was observed, causing a disruption in integration between the medial superior frontal gyrus and both the anterior cingulate and the cerebellum, in addition to reduced functional connectivity in frontotemporal regions (Calhoun, 2009).
Dopamine has also long been associated with schizophrenia, as well as the structures that take part in the dopamine circuit, such as the striatum and the substantia nigra in the tectum of the midbrain (Howes et al., 2013). Schizophrenia is associated with elevations in striatal dopamine synthesis capacity and heightened baseline and stimulated striatal dopamine levels (Howes et al., 2013). These alterations in dopamine function are most prominent in the associative subdivision of the striatum, which receives a large number of connections from the substantia nigra (Howes et al., 2013). Greater nigral F-DOPA uptake is also linked to greater symptom severity in schizophrenia, and there is evidence of increased dopamine synthesis capacity in both the nigral cell bodies of dopamine neurons as well as their striatal terminals (Howes et al., 2013).
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