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.

Ustun, T., & Rehm, J. e. (1999, July 10). Multiple-informant ranking of the disabling effects of different health conditions in 14 countries. The Lancet , pp. 111-115.

Van Os, J. (2004). Does the urban environment cause psychosis? The British Journal of Psychiatry , pp. 287-288.

W.T., C., Heinrichs, D., & Wagman, A. (1988). Deficit and nondeficit forms of schizophrenia: the concept. The American Journal of Psychiatry , pp. 578-583.