Brain Morphology and Schizophrenia

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Neuroimaging is a nascent research tool in neuroscience that allows studying the brain structurally and functionally. Since the development of this technique there has been increased amount of research done to suggest that schizophrenia patients have alterations in brain connectivity[1]. There are two forms of schizophrenia: acute and chronic. In acute onset outbreak takes place rapidly, usually triggered by some sort of event. On the other hand, chronic schizophrenia takes place over time, where the signs start to accumulate over years and finally leading to being diagnosed as schizophrenic. This difference between two forms is important to point out because brain abnormalities are associated with the chronic onset.

Changes in the Brain Morphology

Schizophrenic patients experience delusions, loss of motivation, social isolation, and thinking disorders[3]. Causes of these symptoms are yet unknown, however new technology has given some clues as to what brain structure changes lead to these terrifying symptoms[2]. Analyzing the structural change in the brain can explain the functional changes seen in a schizophrenic patient. Furthermore, looking at changes in the brain morphology and its relation to age, gender, and variety of other factors, can really define at what age the disease originates[1]. In addition, looking at brain morphology and usage of antipsychotic treatments can also show the possible negative effects of the treatment on brain morphology. Therefore, by being able to look at changes in the brain structure over the age and gender can lead us to early diagnosis of this illness therefore improving treatment and hopefully finding a cure.

Myelin Dysfunction Hypothesis

White matter plays an important role in maintaining the neural circuit in order to support the function of the neuron [1]. Neurons need a certain amount of myelination around their axons to function optimally and maintain the neural system that controls mood, thought and various other activities. Defects in myleination are seen when a patient shows reduction in social functioning, changes in emotion and behaviour [4] [1]. The appearance of schizophrenic patients’ brains has myelin reduction and changes in the white matter volume[5]. This white matter reduction most likely plays an important role in cognitive disabilities in schizophrenia, and therefore it means that this illness is a result of dysfunction of brain regions failing to function properly, not because of any lesion in the brain[3]. Changes in the white matter tract are seen in schizophrenic patients in vivo by performing a diffusion tensor imaging. In addition, there is less oligodendroglial cells and untrastructural abnormalities seen in post-mortem analysis. Disruptions in the white matter of the frontostriatal pathway (decision-making pathway) cause worse executive function[1].

Enlarged Ventricles

Enlarged Ventricles
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left (unaffected) and right (affected)

Ventricles of the brain are cavities containing cerebrospinal fluid (CSF) which help remove waste and provide nutritive products to the brain, prevent damage to brain by absorbing shock and produces chemical stability in the brain[6]. There are 4 ventricles in the brain, and largest one is the lateral ventricle. Enlargement of the ventricular size in patients with schizophrenia was first reported in 1976 by Johnstone and colleagues by using computerized tomography (CT) scanning. Latter Weinberger in 1979 showed the same results of enlarged lateral ventricles in schizophrenics when compared to controls[((bibcite example 8))]. Many discoveries like these lead many scientists to discover the causes of ventricular enlargement in schizophrenia.

Ventricle size can be measured in various ways (like according to area or performing volumetric measures) however, most often ventricle: brain ratio (VBR) is used by performing a CT scan or magnetic resonance image (MRI). Using VBR allows for adjusting the whole brain volume[9].
Enlarged ventricles mean that the brain is shrinking leading to build up of extra CSF in the ventricles[10]. This data is collected from new imaging techniques and postmortem investigations. Typically entire lateral ventricle, left side of the temporal horn (in the lateral ventricular system) and also the third ventricle seem to be enlarged. It is seen that schizophrenics have 15% larger ventricles than non-schizophrenics (measured in the case oftype 2 schizophrenia) [10]. It is suggested that the cause of schizophrenia is not ventricular enlargement, rather the decrease in the brain tissue. A non-schizophrenic brain composes of roughly 97% brain tissue and 3 % ventricle. On the other hand, in a patient suffering from schizophrenia brain tissue makes up about 82% and 18% is taken up by the ventricles. This difference is very huge and therefore schizophrenia shows increased VBR from 20 to 75% [9].

Many reasons are given to explain the enlargement of ventricles in the brain. Shrinkage in the frontal and temporal lobe causes more free space that can be occupied by the enlarged ventricles because of disease related changes [10]. On the other hand it is thought that size of the ventricle is changed based on genetic basis according to monozygotic studies [12]. In a longitudinal study schizophrenics had larger ventricles filled with increased CSF when compared with control group that had no history of schizophrenia. During the follow up study after a year it was concluded that as the ventricles get enlarged the patients have a harder time managing their condition[11]. This means that the as the size of ventricles increases it means the disease has progressed so the changes in ventricle can be thought of as disease related. However, the studies with monozygotic twin shows those ventricles in the schizophrenic twin are larger in size when compared to non-schizophrenic twin, confirming that increased ventricle: brain ratio is somehow correlated to schizophrenia [13]. Also the non-schizophrenic sibling has smaller ventricles compared to the schizophrenic patient, but when you compare the non-schizophrenic sibling to healthy population, they appear to have enlarged ventricles[12]. This shows that there is some genetic association with enlarged ventricles [12].

Effects of Gender on Brain Morphology

Variability in frontal lobe by gender
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brain morphology of schizophrenic males compared to females.

The rate of schizophrenia in male and female is about the same but there are some differences in the gender that cause changes in the age of onset, response to treatment. Men develop schizophrenia at about 18 to 25 year old, where as women will develop it around 25 to 25 year old [22] [23]. Studies have demonstrated that there is reduction of coronal brain part, lefthippocampus formation and larger ventricles in schizophrenic males but it is not found in females[24] [25]. Furthermore, there are many MRI studies that suggest that sexual dimorphism does play a role in abnormal brain morphology[24]. It has also been proven that women seem to have a greater ratio of grey matter in the caudate, hippocampus, and temporal gyrus because these parts involve functions with language, thinking and memory. Therefore it is thought that this sexual dimorphism is useful for women because it can prevent them from gaining serious cognitive dysfunction due to brain abnormality[24]. These results can be justified by the level of estrogen which might reduce the morphological changes in women with schizophrenia, females under hormonal protection seem to have decrease in some brain morphological changes. A study shows that grey matter is mostly reduced in male patients and this maybe because of the low estrogen levels causing the change in the brain area[26].

Effects of Anti-psychotics on Brain Morphology

Neuroleptic-induced changes in cortical-striatal motor circuitry
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Anti- psychotics (also known as neuroleptic) are medication used to treat psychosis which include hallucinations or delusions[14]. There are typicaltypical (first generation anti-psychotics) and atypicalatypical (second generation) anti psychotics[14]. Some of the first generation medications like chlorpromazine and haloperidol are still used today to treat schizophrenia [15]. Anti-psychotic medication block dopamine’s effects and that can seize the neuron hence called neuroleptics.

Treatments with these anti-psychotics cause many short term side effects like weight gain or dry mouth, however using anti-psychotics for a prolonged period of time might be considered as a confounding factor when it comes to looking at changes in brain morphology[16]. It is hard to know if the structural abnormalities are caused by the disease itself or by the usage of anti-psychotics[16]. Increasing research suggest that there are some affects of anti-psychotic medication on the brain morphology.

According to a recent study patients who use anti-psychotic medication lose some brain tissue over a period of time[17]. It is shown that the more usage of anti-psychotics is associated with more decrease in brain’s grey and white matter[17]. Many studies have also shown that the loss of grey matter volume is caused by atypical anti-psychotics, but not by haloperidol [18] [19] [20] which is a typical anti-psychotic. However current research shows that 2 hours after the administration of haloperidol (which is usually prescribed to schizophrenics) healthy subjects faced impairment in their motor abilities due to decrease in grey matter volume in striatum [21]. Striatum is the brain region which coordinated movement. This change is also viewed in the functional magnetic resonance (fMRI) scans where the motor circuit is changed in the brain [21. Effect of this reduction in grey matter was seen when their reaction times slowed in a computer based testing.


Structure of haloperidol
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Haloperidolhas been widely used in treating schizophrenic patients, and it works by blocking D2 receptors therefore blocking the sensitivity to dopamine in the brain [21]. As the drug works on blocking these D2 receptors, it also alters the brain morphology of the striatum, because it contains large amount of D2 receptors [21].

Duration of Untreated Illness:

Schizophrenic patients like many other patients suffering from a mental illness take many years to figure out where to seek help and often present symptoms many years after the onset of the illness. It is noted that the longer the duration of untreated illness the worse a person’s mental state is [27]. In a longitudinal follow up study longer DUP is correlated with less grey matter in limbic area, mostly the hippocampus. Other studies show that longer DUP is related to gray matter reduction in, temporal lobe, occipital cortices [28], reduced volume of the caudate [29]. This leads to the neurotoxicity hypothesis, which states that longer DUP may lead to structural changes in brain due to toxicity[30]. However, all these brain changes are not caught earlier in a person’s life, and the relationship between DUP and brain changes stresses the need for early detection. For better understanding please view the flow chart, this shows the events that take place secretly before the psychosis onset[31]. Currently the focus of schizophrenia has shifted to early intervention, where one author suggests that cognitive remediation should be used as a tool for early intervention [31]. However there is still a lot of research that needs to be done, and better technology to view the brain changes at their earliest stage, or hopefully find a biomarker. There are some plans that have been put together for providing better services and awareness about mental illness which may lead to earlier diagnosis (view the image).

Structure of haloperidol
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