The first brain image of an individual with psychosis was completed as far back as 1935 using a technique called pneumoencephalography (a painful and now obsolete procedure where cerebrospinal fluid is drained from around the brain and replaced with air to allow the structure of the brain to show up more clearly on an X-ray picture).
The purpose of the brain is to collect information from the body (pain, hunger, etc), and from the outside world, interpret it to a coherent world view, and produce a meaningful response. The information from the senses enter the brain in the primary sensory areas. They process the information and send it to the secondary areas where the information is interpreted. Spontaneous activity in the primary sensory areas may produce hallucinations which are misinterpreted by the secondary areas as information from the real world.
For example, a PET or fMRI scan of a person who claims to be hearing voices may show activation in the primary auditory cortex, or parts of the brain involved in the perception and understanding of speech.
Tertiary brain cortex collects the interpretations from the secondary cortexes and creates a coherent world view of it. A study investigating structural changes in the brains of people with psychosis showed there was significant grey matter reduction in the right medial temporal, lateral temporal, and inferior frontal gyrus, and in the cingulate cortex bilaterally of people before and after they became psychotic.
Findings such as these have led to debate about whether psychosis itself causes excitotoxic brain damage and whether potentially damaging changes to the brain are related to the length of psychotic episode. Recent research has suggested that this is not the case although further investigation is still ongoing.
Studies with sensory deprivation have shown that the brain is dependent on signals from the outer world to function properly. If the spontaneous activity in the brain is not counterbalanced with information from the senses, loss from reality and psychosis may occur already after some hours.
A similar phenomenon is paranoia in the elderly when poor eyesight, hearing and memory causes the person to be abnormally suspicious to the environment.
On the other hand, loss from reality may also occur if the spontaneous cortical activity is increased so that it is not longer counterbalanced with information from the senses. The 5-HT2A receptor seems to be important for this, since drugs which activate them produce hallucinations.
However, the main feature of psychosis is not hallucinations, but the inability to distinguish between internal and external stimuli. Close relatives to psychotic patients may hear voices, but since they are aware that they are unreal they can ignore them, so that the hallucinations do not affect their reality perception. Hence they are not considered to be psychotic.
Psychosis has been traditionally linked to the neurotransmitter dopamine. In particular, the dopamine hypothesis of psychosis has been influential and states that psychosis results from an overactivity of dopamine function in the brain, particularly in the mesolimbic pathway.
The two major sources of evidence given to support this theory are that dopamine receptor D2 blocking drugs (i.e., antipsychotics) tend to reduce the intensity of psychotic symptoms, and that drugs which boost dopamine activity (such as amphetamines and cocaine) can trigger psychosis in some people.
However, increasing evidence in recent times has pointed to a possible dysfunction of the excitory neurotransmitter glutamate, in particular, with the activity of the NMDA receptor. This theory is reinforced by the fact that dissociative NMDA receptor antagonists such as ketamine, PCP and dextromethorphan/detrorphan (at large overdoses) induce a psychotic state more readily than dopinergic stimulants, even at "normal" recreational doses.
The symptoms of dissociative intoxication are also considered to mirror the symptoms of schizophrenia, including negative psychotic symptoms, more closely than amphetamine psychosis.
Dissociative induced psychosis happens on a more reliable and predictable basis than amphetamine psychosis, which usually only occurs in cases of overdose, prolonged use or with sleep deprivation, which can independently produce psychosis. New antipsychotic drugs which act on glutamate and its receptors are currently undergoing clinical trials.
The connection between dopamine and psychosis is generally believed to be complex. While dopamine receptor D2 suppresses adenylate cyclase activity, the D1 receptor increases it. If D2-blocking drugs are administered the blocked dopamine spills over to the D1 receptors.
The increased adenylate cyclase activity affects genetic expression in the nerve cell, a process which takes time. Hence antipsychotic drugs take a week or two to reduce the symptoms of psychosis.
Moreover, newer and equally effective antipsychotic drugs actually block slightly less dopamine in the brain than older drugs whilst also blocking 5-HT2A receptors, suggesting the 'dopamine hypothesis' may be oversimplified. Soyka and colleagues found no evidence of dopaminergic dysfunction in people with alcohol-induced psychosis and Zoldan et al. reported moderately successful use of ondansetron, a 5-HT3 receptor antagonist, in the treatment of levodopa psychosis in Parkinson's disease patients.
Psychiatrist David Healy has criticised pharmaceutical companies for promoting simplified biological theories of mental illness that seem to imply the primacy of pharmaceutical treatments while ignoring social and developmental factors which are known to be important influences in the aetiology of psychosis.
Some theories regard many psychotic symptoms to be a problem with the perception of ownership of internally generated thoughts and experiences. For example, the experience of hearing voices may arise from internally generated speech that is mislabeled by the psychotic person as coming from an external source.
One clear finding is that persons with bipolar disorder seem to have increased activity of the left hemisphere compared to the right hemisphere of the brain, while persons with schizophrenia have increased activity in the right hemisphere.
Increased level of right hemisphere activation has also been found in healthy people who have high levels of paranormal beliefs and in people who report mystical experiences.
It also seems to be the case that people who are more creative are also more likely to show a similar pattern of brain activation. Some researchers have been quick to point out that this in no way suggests that paranormal, mystical or creative experiences are in any way ''by themselves'' a symptom of mental illness, as it is still not clear what makes some such experiences beneficial and others distressing.
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