"Assessment 3 – Literature Review Assessment category – Submitted work Assessment Type – Literature Review Weighting: 40% Word count: 2000 words Description of assessment Students should choose a neuropsychiatric disorder of interest and investigate the ‘state-of-the art’in terms of preclinical diagnostics.- Identify one or two potential biological/physiological markers of the disorder and the relevantprobes or instrumentation used to detect its presence in vivo. Any modality that has beendiscussed in the lecture program may be discussed (e.g. MRI, fMRI, MRS, DTI or EEG). - The review should demonstrate understanding of how these techniques are applied to a specificdiagnostic problem. It should not be an open-ended background essay on well-establisheddetails of the technique or the pathology. Use primary research literature where possible. - Address each of the four key points below to give structure to your response and allow yourexaminer to follow the argument more easily. Assessment 3 marking criteria: Criterion 1 (~400 words)/15 - Provided a brief outline of a single neuropsychiatric disorder. - Explained what benefits a subclinical biomarker would provide in the context of thisparticular disorder, and what difficulties have been encountered in identifying a suitablecandidateCriterion 2 (~300 words)/10 - Described technique that has allowed better resolution of subclinical phenotypes in this disorder. In the case of MRI, for example, did not simply give a dry technical synopsis of howa scanner works but focused instead on what BOLD signals reveal about brain structure orfunction and why this was suited to detecting a signal of interest in the disorder.Criterion 3 (~800 words)/40 - Focused on the exact biomarker that has been associated with the disorder. Refered to the primary research literature that has demonstrated this association, commenting on thedesign and effectiveness of these studies.How strong and how replicable are the primary findings? What caveats might apply to thetechnique in regards to interpretation of these data? Criterion 4 (~500 words)/25 - Discussed the significance this biomarker has made or could make to clinical practice. - Is the technique reliable and applicable to all at-risk subjects or does it identify only asubsetof suffers and disease? What other barriers might exist to widespread uptake of thisdiagnostic technique, and what further research needs improve on this?Additional points/10 - Ability to make precise points of fact and a logical flowing argument. - Appropriate use of academic references. - The literature review is within the word limit.Introduction: Schizophrenia is one of the neuropsychiatric disorder which causes enormous socioeconomicand medical burden on both the patients and the society. Schizophrenia is a severe, chronicmental disorder associated with positive, negative and cognitive symptoms. It affects thethinking, feeling, and actions of a person. Schizophrenic patients lack the ability todistinguish between real and imaginary situation. They have difficulty expressing theiremotions and may be unresponsive or withdrawn from the society. Early symptoms ofschizophrenia are change in the personality, withdrawal from the social situations, lack ofsleep, poor concentration, bizarre behaviour, preoccupied with religious thoughts, lack ofpersonal hygiene, poor performance at work or academics, and irrational response to angerand fear towards loved ones (Frith, 2014). Most of the neuropsychiatric disorders are caused due to an imbalance in the neurotransmitterlevels. Neurotransmitters are the chemical messengers released from a neuron in the synapse.They bind to the receptors of the other neuron and initiate the neuronal activity. Excessamount of neurotransmitters in the synapse are reabsorbed by the first neuron. Schizophreniais caused due to an imbalance in the dopamine and glutamate neurotransmitters. Dopamine isresponsible for the transmission of impulses or signals related to movement and thoughts.The dopamine pathways in the brain are well developed and effects thinking or behaviour ofan individual. Hyperactivity of dopaminergic transmission at D2 receptor is identified as thefundamental pathogenesis of schizophrenia. High dopamine levels cause psychoticsymptoms, paranoid thinking, and symptoms of schizophrenia (Winter, et al., 2009).Illicit drugs such as cocaine, methamphetamine affect the dopamine levels in the brain andcause feeling of pleasure and well-being. Medications that block the dopamine receptors orthat decrease the secretion of dopamine are used for the treatment of schizophrenia. Inaddition to dopamine, glutamate a neurotransmitter also plays a role in symptoms ofschizophrenia. Low levels of glutamate cause learning deficits and cognitive symptoms in thepatients.A study has proved that high levels of dopamine receptors reduce the action ofglutamate. Biomarkers are the indicators of a disease traits and progression of a disease. They help toidentify the risk of developing an illness (antecedent biomarkers), screen the subclinicaldisease (Screening biomarkers), diagnose illness and determine the disease rate. They help todetermine a neurological disease in an early state (Weickert, et al., 2013). As mentionedearlier that the pathogenesis of the neurological disorders is associated with abnormalities inneurotransmitter pathways, monitoring the metabolism of the biogenic amines will act as anideal biomarker for the neurological disorders. There is adequate evidence from variousstudies which suggest a role of aberrant neurotransmission particularly, dopamine,serotonergic and glutamatergic system in the pathogenesis of schizophrenia. Neuroimaging is another diagnostic or screening tool which helps to diagnose neurological orneuropsychiatric disorders. It can be used as a genetic probe to identify biological pathwaysin the underlying neuropsychiatric disorders. However, some of the difficulties faced whiledeveloping these biomarkers include lack of common language for clinical evaluation, lack ofinformation about the root cause of the disease, and lack of biomarkers that align with thedescriptors of the disease as per the definition of diagnostic frameworks.Magnetic resonanceimaging (MRI) and Functional Magnetic resonance imaging or functional (fMRI) help todiagnose and identify the risk of psychosis in the patients. They help the psychiatrist to examine the pathological changes in the brain and to determine best treatment options for thepatients by identifying the underlying neuropsychiatric disorder. Screening Methods: Development of high-resolution Magnetic resonance imaging (MRI) and sequential imagingenabled the scientist to study the neurodevelopmental and neurodegenerative processes inpatients with schizophrenia. MRI examination helps to identify neurodevelopmentalabnormalities in various regions of the brain. It helps to examine corpus callosal agenesis,cavum septum pellucidum, and hypoplasias/heterotopias in the schizophrenic patients. MRIstudies have shown that specific subcortical regions are affected in the patients withschizophrenia along with the reduction in the volume of hippocampus and thalamus. Incontrast, there is an increase in the size of the globuspallidus. It has also revealed changes inthe folding patterns in the cortex and decrease in the cortical volume and thickness in thefrontal and temporal lobes. On the other hand, fMRI helps to measure the neuronal activity of the brain by detecting thechanges in the blood flow and oxygenation that occur due to neural activity. The brainconsumes more oxygen when it is highly active in order to meet the increased demand ofoxygen, high amount of blood is supplied to the regions of the brain that are active. FMRIproduces the images of the brain regions that are active during a particular mental process.The fMRI is rapidly used in the diagnosis of schizophrenia as it detects the abnormal activityof the brain when the patient participates in a motor task, decision-making or other cognitivefunctions (Gur&Gur, 2010). We know that excess release of dopamine levels in the brain causes schizophrenia symptoms.A study was conducted by Watanble and his coworkers (2014) in which they have measuredthe activity of dopaminergic and noradrenergic neurons by using 3-T neuromelanin magnetic resonance imaging (MRI) in healthy and schizophrenic patients. Neuromelanin is a byproductformed during the synthesis of monoamine neurotransmitters, i.e., noradrenalin anddopamine. It is mainly concentrated within substantianigra or locus ceruleus neurons. It hasT1-shortening effects as that of cutaneous melanin. High field MRI such as 3T is highlysensitive to T1 tissue relaxation and therefore, depicts the tissues containing neuromelanin inthe substantianigra or locus ceruleus. The study was performed in 52 schizophrenic patientswho are = 35 years old. The signal intensity was measured in the substantianigra, midbraintegmentum, locus ceruleus, and pons of the brain. Following it, the contrast ratios werecalculated for substantianigra and locus ceruleus and were compared between healthy adultsand schizophrenic patients. The results suggest substantianigra and locus ceruleus are readilyidentified, and the posterior part of the cerebral peduncle and in the upper pontinetegmentumhave high signal intensity in both schizophrenic patients and healthy adults. However, thecontrast ratio for substantianigra was high in schizophrenic patients when compared tohealthy adults whereas there was no difference in contrast ratio for locus ceruleus in both thegroups. Hallucinations and delusions are the commonest symptoms of schizophrenia and are oftenused to detect schizophrenia in the patients. The fMRI studies suggest that ventricularenlargement and decrease in the volume of gray matter are the underlying pathological causefor auditory hallucinations.A study was conducted in 28 schizophrenia patients withpersistent hallucinations and 32 healthy adults using an automated voxel-wise analysis ofdual-echo spin-echo MRI. The results demonstrated a significant bilateral decrease in thegray matter in the following regions –insula, right superior temporal, fusiform gyri, and theleft inferior temporal gyrus. Therefore, this study suggests that structural changes in theneural circuits affect the processing of information in schizophrenia patients and causesauditory hallucinations in them (O'Daly, et al., 2007).Another neuroimaging study has suggested that neuroinflammation may cause earlysymptoms of schizophrenia and results in neurodegeneration. Positron emission tomography(PET) is a neuroimaging technique used to identify neuroinflammation in vivo (McGuire,2008). It produces 3D images by using ligand specific tracers, which are radionuclideschemically incorporated into the bioactive molecule and is introduced to the body. Theseimages represent the levels of gamma rays emitted by tracers. The estimated binding potentialwas found to be high in the hippocampus of the schizophrenic patients. The trend levelincreased the binding potential in the basal ganglia, midbrain, cerebellum, and pons of thebrain, suggesting the presence of subtle neuroinflammatory effect during the early stages ofschizophrenia (Pasternak, et al., 2016).Apart from memory defects and hallucination, patients with schizophrenia have deficits inbasic information processing which results in sensory gating. Sensory gating is thesubconscious filtering of sensory information received through the senses. Patients withschizophrenia have impaired sensory gating which may cause sensory information overloadin the cortical regions of the brain and may cause psychotic symptoms. Concurrent use ofelectroencephalography (EEG)/functional magnetic resonance imaging (fMRI) methodologywith P50 paradigm helps to assess the sensory gaiting in schizophrenia. A P50 paradigm hastwo identical stimuli, i.e., S1 – conditioning and S2- testing stimuli. They are presented with500 msinterstimulus interval and 1,000 ms of the intertrial interval. The results demonstratedsignificant P50 suppression in the 500 ms trials only in the control group. The scientists haveobserved that negative correlations between P50 ratios and the BOLD response were presentbilaterally in the hippocampus, thalamus, anterior and posterior superior temporal gyrus(STG), and in the left inferior frontal gyrus pars opercularis (Bak, et al., 2014). Antipsychotic medications are used as the first-line drugs for the treatment of schizophrenia. They act as dopamine D2 receptor antagonist and alleviate positive symptoms of schizophrenia but they have some extrapyramidal side effects.A neuroimaging study hasproved that antipsychotic treatment may cause progressive brain changes in the patients withschizophrenia. A thirty longitudinal MRI studies in schizophrenic patients who are onantipsychotic medications has reported the progressive shifts in the brain. The study wasconducted on 1046 schizophrenia patients and 780 healthy adults. At baseline, a significantreduction in the volume of the whole brain and enlargement of the lateral ventricle wasobserved in the patients when compared to control group. However, no volumetricabnormalities were observed in the grey matter volumes (GMV), white matter volume,cerebrospinal fluid and the caudate nucleus. GMV decrease and an increase in lateralventricles were found in the patients as the treatment progressed. The study suggests that theantipsychotic medications may cause neuroanatomical alternations in the patients. Therefore,careful monitoring of patients is required to identify the early side-effects of antipsychoticmedications (Fusar-Poli., et al., 2013). Dopamine is an inhibitory neurotransmitter which is involved in the pathology ofschizophrenia. Dopaminergic projects are present in the nigrostriatal, mesolimbic, andmesocortical systems. Changes in the dopamine levels in the mesolimbic and prefrontalregions of the brain cause various symptoms of schizophrenia. Dysfunctioning of thesubstantianigra, ventral tegmental region, striatum, prefrontal cortex, and hippocampusresults in impaired functioning of the dopamine system. The increase in the subcorticalrelease of dopamine and disturbed cortical pathway causes activation of the D2 receptor andresults in positive symptoms of schizophrenia such as hallucinations and delusions. Thedecrease in activation of the D1 receptor in the prefrontal cortex region of the brain, decreasein the activity of the nucleus caudatus, and alternation in D3 receptors causes negativesymptoms such as anhedonia, lack of motivation, and poverty of speech.MRI and fMRI techniques help to identify the changes in the particular regions of the brainand help to diagnose the neurological disorder. These neuroimaging techniques provide real- time feedback about the activity of specific regions of the brain. They also help to comparethe pathological changes in the regions of the brain in the patients and healthy subjects. Ithelps to identify the early symptoms that a patient may experience. It aids in planningappropriate treatment to prevent progression of the disease.It takes a lot of time to identify, validate and market the biological test. Moreover, high costand use of highly sophisticated equipment limit its use. However, it is essential to develop acost-effective and easily implementable diagnostic tool that can be used in broad-based scalesto reduce the risk of neurological diseases. Further, these screening methods should notrequire highly specialized equipment that would restrict its use. Reference:Bak, N., Rostrup, E., Larsson, H. B., Glenthøj, B. Y., &Oranje, B. (2014).Concurrentfunctional magnetic resonance imaging and electroencephalography assessment of sensorygating in schizophrenia.Human Brain Mapping, 35(8), 3578– 3587.http://doi.org/10.1002/hbm.22422Frith, C. D. (2014). The cognitive neuropsychology of schizophrenia.Psychology Press.Fusar-Poli, P., Smieskova, R., Kempton, M. J., Ho, B. C., Andreasen, N. C., &Borgwardt, S.(2013). Progressive brain changes in schizophrenia related to antipsychotic treatment? Ameta-analysis of longitudinal MRI studies.Neuroscience &Biobehavioral Reviews, 37(8),1680-1691. https://doi.org/10.1016/j.neubiorev.2013.06.001Gur, R. E., &Gur, R. C. (2010).Functional magnetic resonance imaging in schizophrenia.Dialogues in Clinical Neuroscience, 12(3), 333–343. "