Schizophrenia: Neurophysiological Abnormalities

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Introduction Schizophrenia is a psychological diagnosis describing a severe disorder of the nervous system characterized by difficulties in the perception and recognition of reality. Such distortions in perception most commonly include auditory hallucinations, paranoid or bizarre delusions, or dysfunctional speech and/or thinking. People with schizophrenia may hear voices other people don’t hear or they may believe that others are reading their minds, controlling their thoughts, or plotting to harm them in some way. Symptoms usually manifest during young adulthood, with approximately 0.4-0.6% of the global population affected(). Schizophrenic experiences are terrifying and can cause fearfulness, withdrawal, or extreme agitation. People with schizophrenia may not make sense when they talk, may sit for hours without moving or talking much, or may seem perfectly fine until they talk about what they are really thinking. Because many people with schizophrenia have difficulty holding a job or caring for themselves, the burden on their families and society is significant as well(). Schizophrenia is known to be a highly genetic disorder and is associated with abnormalities of brain structure and function, along with other neuropathological differences in brain development(). Various types of equipment and devices have been used to demonstrate ventricular enlargement and a generalized loss of brain tissue in patients with schizophrenia. Global and regional cortical volume reductions, cortical development, and magnitude and extent of brain volume have also been explored. Temporolimbic irregularities and carum septum pellucidum prevalence, along with volume deficits in the prefrontal and temporal lobes, as well as the thalamus, have been detected in schizophrenic patients. This research paper focuses on the neuropathology of schizophrenia, specifically temporolimbic volume reductions compared to a healthy individual. The remainder of the introduction briefly explains the characteristics and diagnosis of schizophrenia, along with the suggested causes for the development of the disorder.

Diagnosis

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As of yet, there are no physical diagnostic tests which can absolutely diagnose the onset of schizophrenia. Rather, diagnosis is usually based on the self-reported experiences of the person, and abnormalities in behavior noticed by family, friends, or co-workers. This is then followed up by a clinical assessment by a mental health professional. Some form of mental status examination is administered, along with a test looking at a patient’s psychiatric tree. Characteristic symptoms of schizophrenia include delusions, hallucinations, disorganized speech, catatonic behavior, and negative symptoms. Negative symptoms are the loss or absence of normal traits or abilities, including affective flattening, alogia, and avolition, which are lack or decline in emotional response, speech, and motivation, respectively. Social or occupational dysfunction is defined as a significant decline in work, interpersonal relations, or self-care, since the onset of the disturbance. Continuous signs of a disturbance may persist for more than six months, indicating schizophrenia. There are five sub-types of schizophrenia: paranoid type, disorganized type, catatonic type, undifferentiated type, and residual type(). Causes Evidence suggests that genetics and environmental factors can act in conjunction to result in schizophrenia(). It has been suggested that schizophrenia is a condition of complex genetic inheritance, with several genes possibly interacting to generate risk for schizophrenia or the separate components that can occur leading to a diagnosis(). Schizophrenia has also been associated with rare deletions or duplications of tiny DNA sequences occurring within genes involved with neural signaling and brain development(). Schizophrenia is one of the most disabling conditions in the world, just behind quadriplegia and dementia (). Affected individuals have fewer offspring than the rest of the population. The central paradox of schizophrenia, which is one of the most interesting features of the disorder, focuses on one question: If the disease is linked with a biological disadvantage, why is this variation not selected out? To balance such a significant disadvantage, there must be a substantial advantage that exists, which continues to intrigue researchers since no answer has yet been found. An urban setting may also have something to do with schizophrenic development(). Social disadvantage also happens to be a risk factor, including poverty, racial discrimination, family dysfunction, unemployment or poor housing conditions(). Childhood memories and

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experiences of abuse and trauma have also been found to be risk factors later in life. Cannabis use is also linked with a risk of developing psychiatric disorders, such as schizophrenia(). Case Study Overview This research paper is the culmination of many case studies focusing on the neuropathology of the brain in schizophrenic patients compared with that of healthy individuals. Although many parts of the brain are affected by schizophrenia, the main focus of this paper is the temporolimbic regions. Neuroanatomic studies of schizophrenia have reported abnormalities in the temporolimbic region. Previous studies have reported volume reduction in the global temporal lobe, gray matter, but not white matter. Regional analysis has also revealed lower volume in the hippocampus, parahippocampal gyrus, and amyglada. Cortical temporal regions have also been examined, particularly the superior temporal gyrus (STG). Reduced volume that has been observed in the anterior, posterior, and total STG has been related to the severity of hallucinations and thought disorder. The hypotheses drawn included: 1) schizophrenia is associated with lower gray matter volumes across temporolimbic regions; (2) the reduction is more evident in men than women; (3) volume reduction is observed at initial clinical presentation; (4) higher volume is associated with better memory performance in patients and controls; and (5) no directional hypothesis is offered relating volume with symptom severity, but higher volumes are expected to be associated with better functioning (). The goal of this research was to evaluate differences between the two sexes in temporal lobe areas, relating volume with clinical and neurocognitive parameters. Temporal lobe structures control cognition and emotion, making them one of the most studied regions of the brain in patients with schizophrenia. Methods/Procedures Test Subjects The sample size used in this study involved 100 patients with schizophrenia (58 men, 42 women) and 110 healthy controls (51 men, 59 women) from the Schizophrenia Research Center in Philadelphia, PA. All participants were right-handed and aged 18 to 45 years old. Patients had a DSM-IV diagnosis of schizophrenia, as previously detailed in the Introduction. The healthy

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control individuals also underwent extensive assessment including medical, neurological, and psychiatric evaluations with laboratory tests. The test subjects had no previous history of any disorder or experience that might affect brain function. After complete description of the

Table 1. Sample characteristics of the test subjects used in this research

study, informed consent was obtained prior to experimentation and all clinical assessments, neurocognitive testing, and MRI studies were conducted within a week’s time. Clinical and Neurocognitive Assessments Clinical assessments, performed by research psychiatrics with established procedures, included the Scale for Assessment of Negative Symptoms (SANS), Scale for Assessment of Positive Symptoms (SAPS), the Hamilton Depression Scale (HAM-D), Premorbid Adjustment Scale (PAS), and Quality of Life Scale (QOLS). Abstraction-flexibility, attention, verbal memory, spatial memory, verbal abilities, and spatial abilities were also measured by trained fellows supervised by investigators. Descriptions of these clinical assessments are given below: ➢

SANS assesses five symptom complexes to obtain clinical ratings of negative symptoms in patients with schizophrenia. They are: affective blunting; alogia (impoverished thinking); avolition/apathy; anhedonia/asociality; and disturbance of attention. Assessments are conducted on a six-point scale (0 = not at all to 5 = severe).

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SAPS is a measure of psychosis which rates severity of psychotic positive symptoms on a scale from 0 to 176–the highest number represents more severe disease.

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The HAM-D is a 21-question multiple choice questionnaire that clinicians may use to rate the severity of a patient's major depression, where scores range from 0 to 54 in increasing depression.

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The Premorbid Adjustment Scale (PAS) is a widely used rating scale to assess premorbid functioning retrospectively

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The QOLS is a 16-item instrument that measured five conceptual domains of quality of life: material and physical well-being, relationships with other people, social, community and civic activities, personal development and fulfillment, and recreation.

MRI Measurements Magnetic resonance imaging scans were acquired: a GE Signa (General Electric Co.) 1.5-T system was used, along with a spoiled gradient-recalled echo sequence; a 35° flip angle was used; repetition time was 35 milliseconds; echo time was 6 milliseconds; field of view was 24 cm; there was 1 repetition, a 1mm slice thickness, no gaps, transaxial images, and 0.9375 x 0.9375-mm resolution. The brain volume was extracted semiautomatically and segmented into gray and white matter using the optimal thresholding and morphological operations. Statistical Analysis Brain volumes in milliliters were the dependent measures in the analyses. Since the hippocampus and amyglada only had gray matter, they were each analyzed using univariate analyses of covariance, or ANCOVA with diagnosis and sex as grouping factors, hemisphere as a repeated-measures (within-group) factor, and total cranial, brain, gray matter volumes, and age as sequential

Figure 1. Illustration of region placement for the subtemporal fields. HIP indicates hippocampus; AMG, amygdala; STG, superior temporal gyrus; and TP, temporal pole.

covariates. For the temporal cortex (STG and TP), where since both GM and WM were present, a multivariate analysis of covariance, or MANCOVA, was conducted where a compartment (GM, WM) was added as a repeated-measures factor. These analyses tested hypotheses 1 and 2. Analyses of variance were performed within the patient group, contrasting first-episode neuroleptic-naive to previously treated patients (hypothesis 3) and comparing deficit with nondeficit subtypes (W.T., Heinrichs, & Wagman, 1988) As these analyses did not show group effects or interactions, these results are not detailed.

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To examine the relationship between volumes and neurocognitive functioning, we computed the correlations between GM volume in the subregions and performance on the 6 neurocognitive domains. Two domains, verbal and spatial memory, are hypothesized to relate to temporal lobe functioning (hypothesis 4). This was tested with a Pearson correlation coefficient with level set at 0.05. The other 4 correlations were considered exploratory and the P value was Bonferroni adjusted so that a P value of .01 (0.05/4) was considered statistically significant at P = .05. Similarly, the possible link between volumes and clinical variables was examined by correlating the temporal subregions' GM with global measures of function (PAS and Quality of Life Scale), where positive correlations are expected with volumes (hypothesis 5) and severity of symptoms (SANS, SAPS, HAM-D), where we make no directional hypothesis. Here P values were Bonferroni adjusted using the 5 measures in the denominator, so that a P value of .01 was considered statistically significant at P = .05. Results Magnetic Resonance Imaging The ANCOVA for the hippocampus showed a main grouping effect of diagnosis (F2,191 = 3.53; P = .03), indicating that patients had overall smaller hippocampal volumes. The ANCOVA for the amygdala showed no main effects of diagnosis or sex, but a diagnosis x sex interaction was significant (F1,192 = 4.21; P = .04). This reduced volume in men relative to increased volume in women with

Figure 2. Means ± SEMs for gray matter volume of healthy men (n = 59) and patients with schizophrenia (58 men and 42 women) for temporolimbic regions. HIP indicates the hippocampus; AMG, amygdala; STG, superior temporal gyrus; and TP, temporal pole.

schizophrenia, compared with their healthy counterparts. The MANCOVA for STG showed a main effect of diagnosis (F4,189 = 5.47; P<.001), with patients having lower volumes than the

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controls. There was a main effect of compartment (F1,192 = 4.12; P = .04) showing overall higher GM than WM, and a diagnosis x compartment interaction (F1,192 = 21.70; P = .001), indicating that the reduction in STG volume seen in patients was specific to gray matter. Assessment Measurements Since the differences between patients and controls were in GM, only GM volumes were correlated with the clinical symptoms. In men with schizophrenia, lower hippocampus volume correlated with poorer PAS scores (r56 = -0.34; P = .02). No other correlations were significant. There were no correlations between volumes and illness duration. Neurocognitive results were more successful. The hypothesized correlations between volumes and memory were Table 2. Mean Temporal Volumes for Patients with Schizophrenia and Healthy Controls

significant for the hippocampus in healthy men (verbal, r39 = 0.30; P = .05; spatial, r = 0.37; P =

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.02), healthy women (spatial, r54 = 0.35; P<.007), men with schizophrenia (verbal, r56 = 0.35; P<.02), and women with schizophrenia (verbal, r40 = 0.26; P = .05; spatial, r = 0.29; P = .05). Amygdala volume did not correlate that significantly with performance on any neurocognitive domain. STG volume correlated significantly with spatial memory in healthy women (r = 0.36; P = .005). Temporal pole volume correlated with verbal and spatial memory in healthy women (r = 0.27; P = .04 and r = 0.36; P = .005, respectively). Other correlations that withstood Bonferroni adjustment included STG with attention in healthy men (r = 0.38; P = .05) and TP with abstraction (r = 0.45; P = .009) and spatial abilities (r = 0.38; P = .004) in healthy women (). Conclusion Schizophrenic patients suffer from a severe mental disorder, in which the brain struggles to maintain a grasp on reality as its perception of what’s real and what’s not becomes distorted. There are also significant neuropathological abnormalities in brain development and structure in those afflicted with schizophrenia. The temporolimbic system, playing a key role in cognition and emotion, is reduced slightly in schizophrenic patients, along with other structures. Although schizophrenia still remains mostly a mystery – its direct causes and genetic inheritance still remain blotted. However, promising and forthcoming research will one day erase these blots.

References/Sources American Psychiatric Association. (2000). Schizophrenia. In Diagnostic and statistical manual of mental disorders: DSM-IV. Washington D.C.: American Psychiatric Publishing, Inc.

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