|
|
What are the causes of schizophrenia? The term schizophrenia was originally coined in 1908 by Eugen Bleuler, and literally means 'split mind' although schizophrenia is not a multiple personality disorder. Bleuler used the term to refer to a break from reality due to the disorganisation of various brain functions such as thoughts and emotions. Schizophrenia is a disorder that affects adolescents with a 1% prevalence, which is distributed very homogenously. Schizophrenia is characterised by two categories of symptoms, both positive and negative. The positive symptoms are evident by their presence and include thought disorders (irrational and disorganised), delusions (abnormal beliefs), hallucinations (usually auditory but sometimes olfactory) and mood disorders (disconnection of emotion and cognition). Delusions include those of grandeur, believing in your own power and self-importance, delusions of persecution, believing people are plotting against you and delusions of control. The negative symptoms are evident by the absence of normal, rational behaviour. This category includes flattened emotional responses, poverty of speech, a lack of initiative and persistence, anhedonia (inability to experience pleasure), and social withdrawal. The symptoms as they stand now were reported in 1931 by Hughlings-Jackson. The positive symptoms are seen as the hallmark of schizophrenia whilst the negative symptoms are less specific as they are shared with other mental disorders. Schizophrenia is often seen as a biological disorder due to the strong evidence that it is heritable. This evidence comes from two sources, both adoption and twin studies. Kety carried out one such adoption study in 1968 by examining Denmark's Folkregister. A list of adopted children was made, both those who had schizophrenia and those who didn't. The incidence rate was 5% in both the adoptive families who had schizophrenic children and those who did not. However the incidence in the biological families of those who developed the disorder was much higher (21%). This clearly suggests a genetic over environmental link. Gottesman and Shields (1972) carried out a study on 57 schizophrenics and their twins. They reported a 42% concordance rate for identical (monozygotic or MZ) twins and only a 9% concordance rate for DZ twins (non-identical). Studies have consistently supported this higher concordance rate in MZ rather than DZ twins (e.g. Rosanoff 1934; Slater 1953). However, if schizophrenia was purely genetic there would be 100% concordance and 75% of children with two schizophrenic parents (if dominant gene) would be schizophrenic (all children if the gene were recessive). The actual incidence is less than 50% in such cases, suggesting either a multiple gene influence or else a genetic susceptibility elicited by environmental factors. Furthermore, schizophrenia has been known to emerge with out any family history of the disorder. The schizophrenic gene or small group of genes are yet to be found but eventually if they exist geneticists will find them and research can turn to what role the genes play in normal function and their role in schizophrenia. A large amount of pharmacological evidence has suggested that the positive symptoms of schizophrenia are caused by a biochemical disorder. It appears that schizophrenia can be caused by an overactivity of dopamine synapses in the mesolimbic pathway (the dopamine hypothesis). Approximately fifty years ago, Laborit used a drug to prevent surgical shock and found that it reduced anxiety. A related compound was later developed called chlorpromazine that was found to have dramatic effects on schizophrenia. It was found to eliminate or at least diminish the positive symptoms such as hallucinations and delusions and lessened the need for indefinite hospitalisation. Following this discovery, other drugs have been developed and the common factor amongst them is that they all block dopamine receptors. In this way the positive symptoms of schizophrenia seem to be controlled by the antagonism of dopamine transmission. Dopamine agonists such as cocaine, amphetamine and L-dopa (stimulates the synthesis of dopamine) have the opposite effect i.e. the creation of schizophrenic-like symptoms. Most researchers believe the important dopamine site for schizophrenia is the mesolimbic pathway, i.e. the connection from the ventral tegmental area to the nucleus accumbens and the amygdala. The dopaminergic synapses in the nucleus accumbens and amygdala are involved in the process of reinforcement so it is suggested that when these synapses are overactive negative behaviours such as delusions are reinforced. The indiscriminate activity of these synapses may also explain disordered thinking; attentional processes become disorganised and sufferers struggle to follow an ordered thought sequence. In 1991 Fibiger suggested that paranoid delusions were elicited due to an increase in the dopaminergic input to the amygdala. There are several possible causes for the increased dopaminergic transmission in the brains of schizophrenics including increased dopamine release (possibly due to more excitatory input or fewer autoreceptors on dopamine neurons), increased postsynaptic response to dopamine receptors (more postsynaptic receptors or increased response in postsynaptic neuron to the activation of dopamine receptors) and the prolonged activation of postsynaptic receptors, possibly caused by the decreased reuptake of dopamine by dopamine terminals. Evidence for dopaminergic neurons releasing more dopamine was found by Breier et al. (1997) and Laruelle et al. (1996). Laruelle used a device like a PET scanner to estimate the release of dopamine caused by intravenous injection of amphetamine (stimulates the release of dopamine). More dopamine was found to be released in the striatum of schizophrenics. A positive correlation was also found between an increase in dopamine levels in the brain and more positive symptoms. However more emphasis has been put on the idea that the brains of schizophrenics have more dopamine receptors. The earliest drugs known to help in schizophrenia treatment worked by blocking D2 receptors. Two types of analysis have been used with mixed results. Post mortem measurements of the brains of deceased schizophrenics have been taken. The second type of analysis is PET scans after treatment with radioactive ligands for dopamine receptors. It would appear that too much time has been spent looking in the neostriatum where lots of dopamine receptors are found but this region is involved in motor control so is not really a factor when looking at schizophrenia. A more recent drug that has been used in the treatment of the positive symptoms is clozapine; it does not act in the neostriatum or on D2 receptors. It mainly works in the nucleus accumbens, blocking D4 receptors. Research is therefore beginning to turn to these receptors as well as D3 receptors as there is a high concentration of them in the nucleus accumbens. High concentrations of these two types of receptor have been found in the brains of deceased schizophrenics. Murray (95) found double the normal concentration of D4 receptors in the nucleus accumbens. Gurevich found the same for D3 receptors in 1997. However it is not yet definite that these receptors have a role in schizophrenia; clozapine blocks them but the real cause may still be elsewhere. A problem with the dopamine hypothesis is that it is unable to account for the negative symptoms, they may not be specific to schizophrenia but they are still important. It has been suggested that the negative symptoms may be due to brain damage. There is a long list of symptoms that suggest this including catatonia, higher or lower than normal rates of blinking, staring and avoiding eye contact. A large amount of neuroimaging evidence to support this has come from CT and MRI scans. Weinberger and Wyatt (1982) looked at the CT scans of 80 schizophrenics and 66 normal people of the same mean age (29 years). Without knowing whether each scan belonged to a schizophrenic or control participant, the areas of lateral ventricles were measured. It was found that the ventricles in schizophrenics were more than twice the size of the ventricles in the control participants. The most likely reason for this increase in ventricle size is loss of brain tissue. Abnormalities in the brains of schizophrenics are commonly found in the medial temporal lobes, lateral temporal cortex, prefrontal cortex and the medial diencephalon. It has been suggested that a high proportion of the brain damage found in schizophrenics comes from prenatal problems. These factors include seasonal effect, viral epidemics and prenatal malnutrition. The seasonality effect suggests that you have an increased chance of developing schizophrenia if you are born in the late winter or spring. It is more possible in this time frame for the mother to contract a viral infection in a crucial stage of the pregnancy. The foetal brain may be affected by the viral toxins or by the mother's antibodies. The winter flu season coincides with the second trimester of pregnancy that is crucial in the brain development of the baby. Several studies have found an increased incidence of schizophrenia following flu epidemics for example in Finland in 1957. The increased incidence was found only if the epidemic had struck during the second trimester. As I have already mentioned, schizophrenia is associated with damage to the frontal lobes, medial temporal lobes, lateral temporal lobes and the diencephalon due to experimental CT and MRI scanning. In 1988 Weinberger suggested that the negative symptoms of schizophrenia are caused by hypofrontality, a decrease in the activity of the frontal lobes especially the dorsolateral prefrontal cortex (PFC). The activity of this area can be tested using the Wisconsin Card Sorting Test (WCST). A set of cards that differ in colour, number of items and pattern are shown to the participant in different combinations e.g. four blue squares. The participant is asked to categorise the cards according to pattern, number or colour but is not given the criterion for doing so, the experimenter simply says 'right' or 'wrong'. Once the participant has responded correctly the criterion are randomly changed and the participant must categorise the cards in a new way. If a person has a damaged dorsolateral PFC then he/she learns the first criterion as quickly as a normal person but then finds it difficult to adapt to new criterion. This suggests that one function of this area is related to behavioural flexibility. Weinberger et al. (1986) carried out a computerised version of the test with schizophrenics and normal participants whilst recording regional cerebral blood flow. The schizophrenics performed poorly as though they had a damaged dorsolateral PFC. Further more, the lateral PFC of normal participants showed increased blood flow that wasn't present in the brains of the schizophrenics. This finding has been confirmed by other research. The PFC of schizophrenics show decreased blood flow and decreased activity. The cause appears to be a decrease in dopamine release in the PFC. Daniel et al. (1991) injected amphetamine into schizophrenics and found an increase in blood flow in the PFC and an improvement on WCST tasks. The drug
PCP, 'angel dust' has suggested a link between positive and negative
symptoms and between the increased dopamine activity in the mesolimbic
system It appears
that there is no single factor involved in the causation of schizophrenia.
Genetic susceptibility does seem to play a major role but it is not
the only cause as shown by schizophrenics with no family history of
the disorder. Environmental factors also must play a role such as prenatal
stress or malnutrition and the seasonality effect. Brain damage does
also play a key role especially in the prefrontal cortex where dopaminergic
release is affected and then the regulation of dopaminergic release
in the mesolimbic system is also disrupted. Dopamine does play a main
role in schizophrenia, if levels are unbalanced in the PFC and mesolimbic
pathway then schizophrenia can be elicited. Parkinson's disease is a degenerative neurological disease that was first described by James Parkinson in 1817. Although this first description was nearly 200 years ago, understanding of the causes and effects of Parkinson's disease is still relatively recent. The treatment of the disease has developed in parallel to our understanding and within the last 50 years a number of important discoveries have been made, primarily the use of L-dopa as a treatment. It is important to carry out more research into this disease as it affects 0.5% of the population over 50 years of age and as it stands there is no cure. The characteristic symptoms of Parkinson's disease are hypertonia (rigidity of muscles), resting tremor and bradykinesia (slowness in initiating movements) or akinesia (loss of movement). These problems are usually in the initiation of movement rather then in their execution. There are also some problems in control of movements, typically, once some one with Parkinson's starts walking, they are very slow in getting started but speed up, go forward onto the balls of their feet and have problems stopping themselves. People with Parkinson's are often said to be wearing a 'Parkinsonian mask' meaning they carry a blank expression. This is due to the loss of the motor ability to quickly produce an expression. When asked to make an expressive face they can, but it takes some time. Sufferers may also have some difficulty with posture as they have problems counteracting the force of gravity. Parkinson's underlying cause is damage to the nigrostriatal pathway in the basal ganglia. (That is the pathway from the pars compacta of the substantia nigra to the striatum, which uses dopamine as its transmitter substance.) In the brains of people with Parkinson's disease the substantia nigra, which is usually dark due to the presence of melanin, is pale. Melanin is produced when dopamine is broken down so this again points out the huge loss of dopamine in patients with Parkinson's disease. This pathway normally inhibits the (inhibitory) indirect pathway of the basal ganglia, and facilitates the direct pathway, (which promotes movement). The onset of Parkinson's disease is in later life (usually at around 60 years old). The late beginning of this disease is because the symptoms are only obvious after 60% of nerve cells and 80% of dopamine is lost in the brain. Up until this point it seems the brain naturally compensates for the reduced dopamine and cell levels. It is still not known why the nigrostriatal pathway starts to break down. There is not thought to be a genetic predisposition for Parkinson's, although some people argue that mitochondrial genes (inherited from the mother's egg cell mitochondria) may carry a susceptibility to Parkinson's. Environmental factors probably play a role in the cause of Parkinson's. Toxins similar to MPTP can be found in heavy metals (e.g. aluminium), food and pesticides. MPTP is a chemical that has significantly aided the understanding of the causes of Parkinson's. In the 1980's a group of young drug users took a synthetic form of heroin (MPTP) and developed an accelerated form of Parkinson's disease. It was found that the MPTP was being broken down into MPP+; this destroys the mitochondria of dopaminergic cells which eventually kills them. Although this incident was tragic, it did give researchers a very useful tool to use in their study of the causes and treatments of Parkinson's disease. It is now though that damage to different parts of the basal ganglia cause the different symptoms of Parkinson's disease. This fits with the fact that not all symptoms are always present in everyone suffering from Parkinson's. Bradykinesia (and akinesia) are thought to be caused by loss of dopamine in the caudate nucleus of the nigrostriatal system. Tremor and rigidity are now thought to be due to loss of neurons in other pathways of the basal ganglia, associated with the nigrostriatal pathway. Research carried out on animals has shown that damage to the substantia nigra causes hyperactivity not rigidity. It is possible that tremors originate in a malfunction of a feedback circuit from the ventral thalamus to the motor cortex and back to the thalamus. It has been observed that neurons in the thalamus fire in time with tremors. This discovery lead to the development of the treatment thalamotomy which lesions the thalamus. This does in fact reduce or eliminate the rigidity and tremor but does not get rid of bradykinesia. Other types of surgery are now possible due to technological advances that allow surgeons to specifically target deep areas of the brain. One of these is a pallidotomy which lesions the globus pallidus thereby reducing its inhibition on the thalamus. This type of surgery is very affective in the treatment of Parkinson's disease. However, due to its expense it is not widely used. The most common treatment for Parkinson's disease is the drug L-dopa. L-dopa is the metabolic precursor of dopamine. As dopamine does not cross the blood-brain barrier it cannot be administered directly. Instead L-dopa is teamed with a drug to prevent its uptake in the periphery and administered orally. L-dopa is then converted by the remaining dopaminergic cells into dopamine. PET scans have shown a return to almost normal brain levels of dopamine once L-dopa treatment has started. However, as with many treatments L-dopa carries side effects. It is very difficult to get the amount administered to the correct level and too much dopamine leads to symptoms often seen in Huntington's disease such as chorea (rapid, jerky movements). Sometimes anticholinergic drugs are used to treat the tremors of Parkinson's disease (Bannister, 1992). These drugs attempt to redress the imbalance between dopaminergic and cholinergic systems in the nigrostriatal pathway. However, they also carry side effects. In extreme cases treatment using L-dopa or anticholinergic drugs can lead to depression, disruption of a person's thought patterns or delusions. These symptoms go away if treatment is stopped. A balance must therefore be struck between the side effects of drug treatments and the symptoms of the disease itself. Another major problem with these treatments is that they stop being effective after a number of years of use. This is because so many cells have died there are not enough to produce a suitable level of dopamine. A more preferable situation would be someway of stopping the degeneration of the dopaminergic cells of the substantia nigra, or creating a permanent source of dopamine within the brain itself. Recently steps towards this have been made, specifically in the field of neural transplants. In this surgery tissue containing very high numbers of dopamine producing cells are grafted onto the substantia nigra of the affected person. These tissue grafts can come from a number of sources. Experiments have been carried out (usually on animals who have previously been given MPTP) where a graft is taken from the medulla of their own adrenal gland. However, although these do seem to work they only last for a year at most. Another source of tissue comes from foetal substantia nigra cells. These are used as they are quite unlikely to be rejected by the recipient of the donor. However, again these are not a permanent solution and the use of foetuses in treatment or research is an ethical dubious issue. Recent research has focused on glomus cells in the carotid organ as another type of donor cell. However, these treatments are still under research so L-dopa remains as the most widely used treatment for Parkinson's disease. Parkinson's disease is caused by degeneration of the dopamine pathway between the pars compacta of the substantia nigra and the striatum. Why this pathway decays is unknown, but what is known can be use to guide the treatment of this disease (for which at present there is no cure). The most common treatment is L-dopa; this is a precursor to dopamine and is converted into dopamine by the remaining dopaminergic cells of the substantia nigra. As our understanding of how Parkinson's disease progresses new treatments can be created. Now the specific parts of the pathway have been identified treatment targeting them have been formed. Surgery such as pallidotomy's or thalamotomy's target specific parts of the pathway and have proved to be effective (but expensive) treatments. A more permanent treatment is also being researched; tissue transplants are in theory a way of halting the disease and returning dopamine levels to near normal. However, although they do seem to work for a time they are still not a cure for this progressively degenerative disease.
|
|
|
