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For my final culmination activity for AP Biology, I had to write a research paper focusing on a single, prominent area of biology. I chose to write about schizophrenia, and spent hours looking for numerous research and case studies, all binding them together in this paper.
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P a t e l | 1
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 (Bhugra, 2005). 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 (National Institute of Mental
Health, 2009).
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 (Lawrie, McIntosh, Hall, Owens, & Johnstone, 2008). 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.
P a t e l | 2
Diagnosis
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 (American Psychiatric
Association, 2000).
Causes
Evidence suggests that genetics and environmental factors can act in conjunction to result
in schizophrenia (Harrison & Owen, 2003). 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 (Owen &
O'Donovan, 2005). Schizophrenia has also been associated with rare deletions or duplications of
tiny DNA sequences occurring within genes involved with neural signaling and brain
development (McClellan, 2008). Schizophrenia is one of the most disabling conditions in the
world, just behind quadriplegia and dementia (Ustun & Rehm, 1999). 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
P a t e l | 3
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 (Van
Os, 2004). Social disadvantage also happens to be a risk factor, including poverty, racial
discrimination, family dysfunction, unemployment or poor housing conditions (Selten, Cantor-
Graae, & Kahn, 2007). Childhood memories and 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 (Moore, 2007).
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 (Gur, 2000). 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.
P a t e l | 4
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 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 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
Table 1. Sample characteristics of the test subjects used in this research
P a t e l | 5
thinking); avolition/apathy; anhedonia/asociality; and disturbance of attention.
Assessments are conducted on a six-point scale (0 = not at all to 5 = severe).
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.
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.
The Premorbid Adjustment Scale (PAS) is a widely used rating scale to assess premorbid
functioning retrospectively
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 1-
mm 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, Figure 1. Illustration of region placement for the subtemporal fields. HIP indicates hippocampus; AMG, amygdala; STG, superior temporal gyrus; and TP, temporal pole.
P a t e l | 6
and total cranial, brain, gray matter volumes, and age as sequential 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.
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 schizophrenia, compared with their healthy counterparts. The MANCOVA for
P a t e l | 7
STG showed a main effect of
diagnosis (F4,189 = 5.47;
P<.001), with patients having
lower volumes than the
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.
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.
Table 2. Mean Temporal Volumes for Patients with Schizophrenia and Healthy Controls
P a t e l | 8
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 significant for the
hippocampus in healthy men
(verbal, r39 = 0.30; P = .05;
spatial, r = 0.37; P = .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 (Gur, 2000).
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
P a t e l | 9
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.
Bhugra, D. (2005, May 31). The Global Prevalence of Schizophrenia. PLoS Medicine , pp. 372-373.
Gur, R. E. (2000, August). Temporolimbic Volume Reductions in Schizophrenia . Archives of General Psychiatry , pp. 769-775.
Harrison, P. J., & Owen, M. J. (2003, February 1). Genes for schizophrenia? Recent findings and their pathophysiological implications. The Lancet , pp. 417-419.
Lawrie, S. M., McIntosh, A. M., Hall, J., Owens, D. G., & Johnstone, E. C. (2008, January 27). Brain Structure and Function Changes During the Development of Schizophrenia: The Evidence From Studies of Subjects at Increased Genetic Risk. Schizophrenia Bulletin , pp. 330-340.
McClellan, J. M. (2008, April 25). Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia. Science , pp. 539-543.
Moore, T. e. (2007, August 3). Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review . The Lancet , pp. 319-328.
National Institute of Mental Health. (2009, January 21). Retrieved June 11, 2009, from National Institute of Mental Health Web Site: http://www.nimh.nih.gov/health/publications/schizophrenia/what-is-schizophrenia.shtml
Owen, M. J., & O'Donovan, M. (2005, September 6). Schizophrenia: genes at last? Trends in Genetics , pp. 518-525.
Selten, J.-P., Cantor-Graae, E., & Kahn, R. S. (2007, March). Migration and schizophrenia. Current Opinion in Psychiatry , pp. 111-115.
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Van Os, J. (2004). Does the urban environment cause psychosis? The British Journal of Psychiatry , pp. 287-288.
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