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Schizophrenia_ruth hannon.pdf

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Nancy Matthew- Maich

1 Schizophrenia Epidemiology ‐Schizophrenia has been described as a disconnection between thought and language  There is an interference with the filtering of stimuli from the environment  Which effects a persons thoughts feelings and overall behaviours  It is a complex disorder which occurs in about 1.3% of all Canadians  It occurs in all countries, and cultures and is equally distributed between men and women  Although there is a later onset of schizophrenia in women because estrogen is believed to be a protective factor and delays onset of symptoms  10 % of persons with schizophrenia will commit suicide Positive Symptoms  Positive symptoms can be remembe red as symptoms that exist but should not and are in excess or distortion of normal function  Positive symptoms of schizophrenia include delusions and hallucinations  Delusions are false fixed beliefs that usually involve a misinterpretation of an experience  The various types of delusions include:  Grandiose: where the person beliefs they have exceptional powers, wealth, skill, influence, or destiny  Nihilistic where the person believes they are dead or that a calamity is pending  Persecutory where the person believes they are being watched, ridiculed, harmed, or plotted against 2  Somatic where the person believes they have abnormalities in their bodily functions or structures  Hallucinations are perceptual experiences that occur without actual external sensory stimuli  Hallucinations involves any of the five senses but are usually visual or auditory  The person may see or hear things that are not in the external world but nevertheless are very real to the person that is experiencing them  Auditory hallucinations range from simple repetitive sounds to many voices speaking at once, and can be interpreted as pleasant to distressing by the person experiencing them  When visual hallucinations occur they often occur in conjunction to auditory hallucinations Negative Symptoms  Negative symptoms can be remembered as symptoms that don’t exist but should, they reflect the lessening or absence of normal social and interpersonal behaviours  Also important to note that a person with schizophrenia may have an increased tolerance to pain Neurocognitive Impairment  There are several areas of congitive function which may be impa ired in schizophrenia and this disfunction can occur even if the positive symptoms of schizophrenia are in remission  These areas of disfunction include : 3 Disorganized Symptoms  Disorganized thinking includes disturbed speech and thinking patterns involving thought content and thought process  Disturbances and thought content include various types of delusions  Other examples include depersonalization or the belief that one self and ones body is strange or unreal  Magical thinking which is a belief of ones thought, words, or actions have the power to cause or prevent things from happening  Examples of disturbances and thought process include loosening of association or there is a lack of a logical relationship between thoughts and ideas and conversation shifts from one topic to another in a completely unrelated matter  Another example is thought blocking where there is an upbrupt pause or interrpution in ones train of thought after which the individual cannot recall what they were saying  Disorganized perceptions include an oversensitivy to colours,shapes and background activities  Illusions include a misperception or an exaggeration of stimuli that exist in the external environment  Ancillary symptoms that may accompany schizophrenia but are by no means the main symptoms include anxiety, depression, and hostility 4  Disorganized behaviours of schizophrenia are coupled with disorganized speech and may for example include a slow rhythmic and ritualistic movement coupled with disorganized speech  Other examples include agression which often occurs if the person believes that someone is trying to harm them  Agitation involving an inability to sit still or attend to others which is accompanied by heightened emotion emotions intention  Catatonic excitement which involves a hyperactivity characterized by purposeless activities 5  Abdormal movements such as grimacing and posturing  Echoproxia which involves involuntary immitation of another persons movements and gestures  Regressed behaviour involving child like and immature behaviour  Stereoptypy involing repeptitive purposeless that are idocincratic to the individual and somewhat out of their control  Hypervigelence involivng sustained attention to external stimuli as if expecting something important of frightening to happen  Waxy flexibility involving holding a posture in an odd or unsually fixed position for an extended period of time Schizophrenia Subtypes  There are several of subtypes of schizophrenia which are currently recongized  The person with the paranoid subtype displays preoccupation with delusions or auditory hallucinations and absence of disorganized symptoms  The person with the disorganized subtype displays the disorganized type symptoms  The person with the catatonic subtype displays at least two of motor immobility or stuper, excessive purposless motor activity, extreme negativeism, posturing, stereotypy, prominent mannerisms , grimacing, and echolalia a parrot like repeptition of words, or echoproxia involuntary immitation of another persons imitations or chiidlike immature behaviour  The person with the undifferentiated subtype displays only characteristic symptoms but no criteria for other subtypes  The person with residual subtype displays an absence of prominent delusions, hallucinations, and disorgainzed symptoms, their negative sypmtoms persists, and two or more positive symptoms are displayed or attenuated for a less intense form such as odd beliefs or unusal perceptual experiences Risk Factors for Schizophrenia  These factors include stressors in the prenatal period of the mother for example: starvation, poor nutrition, and maternal infections. Which plays added stressors on the developing fetus  Some research has shown that the risk for schizophrenia worldwide is 5 to 8 percent higher for those born during the winter and spring when cold and viruses are more prevelant  The percise neurbiological mechanism in relation to maternal infections is not known, but it is believed that cytokines and an abnormal immune response to these infections interfer with normal fetal brain development during this period  Obestetrical complications may cause fetal hypoxia ischemic damage to the developing to the brain where premature cortical synaptic pruning may occur 6  Synaptic pruning in general terms means that connections between brain cells or neurons become disconnected or pruned prematurely  Older parental age including both the mother and fathers age has been found to double the risk for developing schizophrenia and this is thought to be related to impaired formation of sperm cells leading to an increased risk of genetic mutations  The risk for developing schizophrenia is higher for individuals born in urban settings and it is thought to be because the city is more of a stressful environment  Infants who have been effected by the previously stated maternal stressors have conditions that include their own risks such as: low birth weight, short gestation, early developmental difficulties, childhood CNS infections  First degree relatives of persons with schizophrenia have been found to be at a greater risk Schizophrenia: Cannabis Use  Cannabis use is associated with an increased risk for schizophrenia and early onset of psychosis and there is a dose response  Below is a link to a nature of things video – entitled the downside of high, which explores the increased risk for schizophrenia, related to marijuana use.  This video describes that the active ingredient in marijuana, delta nine tetrahydrocannabinol or THC has been shown to quadruple a teens chancing of developing this disorder  THC interacts with the cannabinoid system and deregulates the a cnnabinoids system.  This system serves a regulatory function in controlling the release of glutamate and gabba. Which has an effect on neuronal synaptic connections and on the dopamine system  Neuro pruning or untangling of brain cells happens to teenagers in their normal brain development and THC is believed to interfere with this normal developmental neuro pruning process.  Padromal symptoms are early symptoms of schizophrenia which often appear in adolescents and marijuana use has been seen to trigger and exacerbate these symptoms  This video also explores a genetic component of schizophrenia related to chromosomes 22. Where the person can have the Met or Val allele  An allele is an alternative form of a gene or one member of a pair and occurs at loci on chromosomes and people have two pairs for each trait  If the person has the Met and Met allele and smokes cannabis there is no effect on the risk for developing schizophrenia  If the person has one Met and one Val allele and smokes cannabis it doubles your risk  And if the person has two Vals and smokes cannabis it increases the risk of developing schizophrenia five times 7  Brain imaging studies has also shown that the hippocampus and amygdala are smaller in cannabis users than controls Etiology of Schizophrenia: Neurodevelopmental Model  The etiology of schizophrenia is influenced by many factors  Rapport in an update that he and his colleagues published in 2005 describes the model of schizophrenia simply has the behavioural outcome of an aberration in or abnormal neurodevelopmental processes that begins long before the onset of clinical symptoms and is caused by a combination of environmental and genetic factors  In simple terms this means that patients with schizophrenia have a biological predisposition or vulnerability that is exacerbated by environmental stressors  Environmental factors include: prenatal stressors, adolescent brain changes, and neurobiological challenges  Neurobiological changes involves some type of a lesion which causes anatomical and functional changes in the brain which are believed to begin in the prenatal period, continue to deteriorate during growth and developmental particularly the adolescent period but remain silent and begin to recognizable in late adolescent to early adulthood as behavioural changes and symptoms of schizophrenia Gene‐Environement Interaction ‐As you may recall from the pathophysiology module of depression there is a genetic environment interaction in the formation of depression and it is believed that a similar interaction also occurs in the formation of schizophrenia  First degree relatives including siblings and children are 10 times more likely to experience schizophrenia  Dizygotic twins share 50% of their genetic material and if one twin has schizophrenia the risk of the other is 10 to 15 % monozygotic share 100% of genetic material and if one twin has schizophrenia the risk of the other twin having schizophrenia in the other is about 40‐50 %  If both parents have schizophrenia the risk of their children developing schizophrenia is also about 40‐ 50 %  Genetic factors are thought to contribute to about 80% of the liability to develop schizophrenia in the population  And environmental factors are thought to contribute to 20% of the liability  Certain variations in genes called polymorphisms may increase the risk of schizophrenia  A polymorphism is an alternation in the sequence of DNA in the gene  Also from the depression module we talked about how genes help control the metabolism of neurotransmitters and their receptors, the numbers of particular types of neurons and their synaptic 8 connections, the intracellular transduction of neuronal signals and the speed in which all of these can change in response to environmental stressors.  It is thought multiple genes are involved in the development of schizophrenia each appearing to have different regional brain expressions at different developmental stages  Research suggests that genes effecting brain development related to cognitive ability are operating more strongly in late adolescents which correlates with the onset of schizophrenia Candidate Genes  The short arm of chromosome 8 contains the gene neuroregulin which is involved in the neuronal migration and connectivity, cell signaling and myelination.  This gene is also related to a decreased activation of the temporal and frontal regions and in mouse research, neuroregulin has also found to be involved in structural brain abnormalities of lateral ventricle enlargement.  Research also suggests that alterations in neuroregulin can also lead to alter neuronal signaling of dopamine during development possibly leading to hyperdopaminerg ic states as an adult and to impact gabba and glutamatergic signaling  Calcineurin which is located on chromosome 2 is implicated in schizophrenia and in studies with mice Calcineurin has been known to be involved in the antisocial or isolative aspects of schizophrenia  DISC1 & DISC2 are located on chromosome 1 and DISC stands for disrupted in schizophrenia  This gene leads to neuronal migration problems involved in the development of schizophrenia and may play an important role in hippocampal development  Further research has shown that DISC1 may be linked with cognitive impairment, social anhedonia and reduced gray matter volume in the hippocampus and cortex of patients with schizophrenia  DISC 1 signaling during development may contribute to the alterations of dopaminergic and GABAergic signaling observed in the prefrontal cortex.  The dysbindin gene on chromosome 6 has also been found to be a risk gene for schizophrenia  It has been found to be related to Visual processing deficits ‐ Cognitive functioning ‐ Reductions in volume in the prefrontal and occipital cortex in persons with schizophrenia  Dysbindin has been found to have a major role in neuroplasticity and in mice studies creating mutations in dysbindin results in deficits in social interactions and poor performance in memory tasks has also been observed, also a link in dysbindin and NMDA which is a glutamate receptor has been observed 9  AKT1 a gene on chromosome 6 has found to be a susceptibility gene in schizophrenia with reduced levels of it in one of is substrates in the hippocampus and frontal cortex of people with schizophrenia  As well as a reduced gray matter volume in the caudate and right prefrontal cortex and reduced cognitive performance  AKT1 has also been found to be implicated in proper dopaminergic neurotransmission  Brain‐derived neurotrophic factor or BDNF in variance in the genes that encodes which are located on chromosome 11 have been implicated in schizophrenia  As you may recall from the depression module, BDNF is involved in the birth, survival and maturation of brain cells during development  And BDNF is also involved in the production of the alleles “met” and “val”  BDNF also plays a role in the GABAergic transmission, regulation of glutaminergic transmission, intracellular signaling and transmission.  Risk gene for schizophrenia has also been found in the NMDA receptor Summary  The best of our knowledge it is not clear whether genetic vulnerability is present in all cases of schizophrenia  Heritability of schizophrenia is high and genetic factors contribute to about 80% of liability for the illness  No major gene locus has been found that can explain this disorder  Currently we believe that a large number of candidate genes likely contribute for the illness Neuroplasticity  Introduce the idea that neurobiological changes in the brain occur as a result of these genetics and environmental factors  Some type of a lesion in the brain occurs which causes anatomical and functional changes in the brain  Which are believed to begin in the prenatal period, continue to develop during growth and development particularly the adolescent period but remain silent, and begin to be recognizable in late adolescent to early adulthood has behavioral changes and symptoms of schizophrenia  We are talking about the concept of neuroplasticity which you may recall during your depression module which can be defined as ability of the brain to change its structure and function in response to internal and external pressures  In neuroplasticity nerve signals may re‐rooted, nerve cells may learn new functions, the sensitivity of or number of nerve cells may increase or decrease, or nerve tissue may be regenerated 10  What happens in the brain of a person who develops schizophrenia in late adolescents to early adulthood is that when the person has the first psychotic break if they do not receive treatment first and foremost medication to block the D2 receptor and regulate levels of dopamine they can develop further neuroplastic changes and even neurotoxicological changes that can further and permanently effect the brain anatomically and functionally Neuroanatomical Changes Brain anatomical changes associated with schizophrenia are not the result of progressive brain deterioration or the effects psychiatric medications  But are caused by abnormalities and neural development that occur in prenatal and early postnatal life  These anatomical changes continue to deteriorate through the lifespan particularly in late adolescent to early adulthood, when the positive symptoms begin to occur and negative symptoms become enhanced  In summary the anatomical changes include an enlargement of lateral and third ventricles  Reduction in frontal lobe, a reduction in the temporal lobe particularly in the medial aspect, a whole brain volume reduction ( gray matter)  Diminished neuronal content in both the thalamus and hippocampus  Prominent sulci ( superior temporal gyrus)  Increased activity in limbic system 11  Increased generally in D2 receptors (basal ganglia) Ventricular System  Total brain volume is reduced and lateral and ventricle spaces are larger  Remember that the ventricle system is part of the brain that houses the cerebral spinal fluid and that an increase in the size of the ventricular system is a result of a reduced overall brain volume  So as the brain shrinks as a result of that abnormal pruning and neuroplasticity the ventricles enlarge. Hypofrontality  You may remember from the depression module that the prefrontal cortex is part of the cerebral cortex which is the most evolved portion of our brain  It is described as the chief administrator of the brain and is responsible for planning, problem solving, intellectual insight, judgment, and expression of emotion  The prefrontal cortex is part of the frontal lobe which contains most of the dopamine sensitive neurons  The dopamine system is associated with reward, attention, short term memory tasks, planning and drive  Dopamine tends to limit and select sensory information arriving from the thalamus to the forebrain  A PET scan of the frontal lobe in this slide shows Hypofrontality or reduced blood flow in glucose metabolism in the prefrontal cortex of people with schizophrenia  Also MRI studies have shown a reduced neuronal volume in the frontal lobes  This Hypofrontality of the frontal lobe perhaps relates o negative symptoms and neurocognitive impairment in schizophrenia as has been previously described  For example there is a poverty of thought and speech and the person has trouble functioning and may have unusual movements and postures  Including when a person becomes locked in a posture in a catatonic state  It has been suggested that this cognitive impairment may be related to a dopamine 1 receptor deficit in the prefrontal cortex Medial Aspects of Temporal Lobe ‐ The temporal lobe is responsible for processing auditory information and language, visual and spatial information, emotion and memory. ‐ Limbic system structures buried within the temporal lobe are responsible for emotional responses 12 ‐ A volume reduction occurs in schizophrenia in the temporal lobe and results in formal thought disorders in this part of the brain. ‐ People with schizophrenia who have damage in the temporal lobe experience a disconnection between their thinking and their language and this will be expressed in symptoms such as a loosening of associations between thoughts as previously described to absolute non sensical expression which is called “word salad”. ‐ Damage to Broca’s and Wernicke’s area in the auditory processing centre in the frontal and temporal lobe is thought to be expressed as hallucinations for the person with schizo ‐ You will remember that Broca’s area is responsible for the production of and expression of speech. ‐ Wernicke’s area is responsible for the comprehension of speech and spoken language. ‐ And it is believed that the person with schizo may be hearing voices that don’t actually exist, which are stimulated in these damaged areas ‐ The temporal lobe also stores auditory and verbal and visual information or memories. ‐ The amygdala being involved in emotional memory and the hippocampus taking short term memory and storing them as LT memory in the temporal lobe ‐ The hippocampus interacts with the amygdala and stores the emotional attributes of the memories. These stored memories are then the basis for dreams and hallucinations. ‐ It makes sense then, that if there is damage to these structure s which is what occurs in schizo, there will be trouble with verbal and visual memory. ‐ These verbal and visual memories which are stored in the temporal lobe can become stimulated in schizo without an external stimulus. And this is believed to be the basis of verbal and visual hallucinations and delusions which can become quite bizarre and complex. ‐ When you dream, these areas and memories are also stimulated and this is what makes up the verbal and visual content of our dreams. ‐ Most of the time when we dream, it is as if it is really happening to us. When we wake up, we realize that it was only a dream. ‐ For the person with schizo, it is as if the dream occurs upon wakefulness and there is no convincing that person that what has happened is not real. Because of damage in these areas, a person may lose their ability recognize faces of family members and believe that they have been replaced by imposters. Or may begin to recognize strangers as people they know. And they may become quite paranoid and frightened. ‐ A person may experience seeing or hearing God or the devil who may be commanding them to take certain actions. And these are called command hallucinations and they can be come quite frightening and dangerous for the person ‐ If the person experiences voices which seem to be coming from within their head, they are thought to be less severely ill than the person who experiences voices coming from outside of their head 13 ‐ The most severe form of hallucinations is when the person experiences both voices and visual hallucinations which come from the external environment. The Hippocamus and Thalamus ‐ As was discussed in the previous slide, the hippocampus plays important roles in the consolidation of information from ST memory to LT memory and spatial navigation ‐ Again, in MRI studies, reduced neuronal volume
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