|Schizophrenia is a
disease of the brain. People with schizophrenia, more than 1% of
the world's population across all cultures, suffer from a socially
isolating and economically debilitating condition that usually begins
during late adolescence through mid-adulthood. People often confuse
schizophrenia with a split personality or a multiple personality,
but this is an incorrect description. People affected with schizophrenia
have difficulty differentiating what is generated by their imagination
and what is real.
Schizophrenia can be traced back as far Egypt in the second millennium
BC. Many of the clinical symptoms commonly used to describe schizophrenia
today, such as depression, dementia, and thought disturbances, were
described in detail in the Book of Hearts of the Eber papyrus.
In 1851 Falvet first described schizophrenia as a 'Folie Circulaire'
or cyclical madness. Twenty years later Hecker coined the term 'Hebephrenia',
or a silly, undisciplined mind. Kahlbaum documented both catatonic
and paranoid disorders. In 1878 Emil Kraepelin, combined these disorders
into a single disease, that he called dementia praecox, with four
subtypes - simple, marked by slow social decline and withdrawal;
paranoid, defined by persecutory delusions and fear; hebephrenic,
marked by rambling and incoherent speech and incongruous affect;
and catatonic, characterized by a severely limited movement and
expression. In 1911, Eugen Bleuler first used the term 'schizophrenia'
and described the four "A's" of schizophrenia; affect,
associations, ambivalence and autism. Each of the these A’s
identified a disturbance in the afflicted individual.
Schizophrenia remains an enigma that has fascinated the foremost
minds of psychiatry and neuroscience for more than a hundred years.
At stake is more than just the crucial welfare of the millions afflicted,
for schizophrenia research may represent the key to an understanding
of the mechanisms by which the brain filters, prioritizes and processes
the information gathered both internally and externally.
|A diagnosis of schizophrenia
is determined from behavioral observations by clinicians and from
self-reports by individuals about their abnormal mental experiences.
According to the American Psychiatric Association, symptoms that
must be present for diagnosis include a defined combination of delusions,
hallucinations, and characteristic disturbances in affect, goal
oriented behavior, form of thought and psychomotor behavior that
cannot be established as the result of an organic disturbance. Individuals
must also show continuous signs of the illness for at least six
months where occupational and social functioning have deteriorated
and an acute period of active symptoms must be present for at least
Typically, the clinical symptoms of schizophrenia are divided into
‘positive’ and ‘negative’ types.
- Positive symptoms include
delusions (irrational beliefs), hallucinations (sensory perceptions
with no outside stimulus), thought disorder (e.g., loosened
associations) and bizarre behavior.
- Negative symptoms include
flat affect, social withdrawal, lack of motivation and initiative,
impaired judgment and difficulty in planning.
Schizophrenia, however, is notably heterogeneous and the clinical
symptoms may vary considerably between patients, often with no
obvious overlap. Efforts have been made to characterize biologically
meaningful ‘subtypes’ of schizophrenia defined by
the cross-sectional clinical picture and by symptoms that co-occur.
Subtypes include paranoid, disorganized, catatonic, undifferentiated,
and residual types.
a Brain Disease
Early in the last
century, Emil Kraepelin described what is now known as schizophrenia,
as an organic brain disease. In recent decades, empirical evidence
from postmortem, in vivo imaging, neurochemical and neuropsychological
studies have confirmed that microscopic and macroscopic structural
brain abnormalities, biochemical abnormalities and impairments
in brain functioning are present in patients with schizophrenia.
People with schizophrenia show a generalized impairment with IQ
lower than normal and specific deficits in attention, memory,
abstraction, spatial working memory and executive functioning.
Structural brain abnormalities observed from postmortem and magnetic
imaging data are diverse, but suggest abnormalities in specific
cortical (e.g., frontal and temporal association areas) and subcortical
(e.g., lateral and third ventricles and medial-temporal regions)
brain regions with some consistency. Similarly, functional imaging
studies using PET and fMRI, have uncovered altered brain activity
in components of distributed neural circuitry in neocortical and
medial-temporal systems, as well as in other regions, in association
with specific cognitive tasks.
| As discussed above,
evidence supports that schizophrenia is highly heritable. That is,
individuals that are biologically related to a patient with schizophrenia
appear to possess a greater risk for developing the disease compared
to those that are unrelated. Shared environmental experiences, however,
could also account for the increased incidence of schizophrenia
within families compared to the general population. Twin and adoption
studies support that both genetic and harmful environmental events
are contributors to schizophrenia. Even though schizophrenia has
a large heritable component, investigators have had difficulty identifying
the genes involved. A single gene hypothesis does not appear to
explain the familial patterns of schizophrenia. A multi-factorial
genetic model is now more widely hypothesized to explain the genetic
contributions of schizophrenia. According to this hypothesis, schizophrenia
if the result of the additive effect of multiple genes and environmental
factors until a critical threshold is met whereupon an individual
|The genetic model alone
does not fully explain familial schizophrenia. Moreover, different
genotype-environmental interactions have been hypothesized to contribute
to the incidence and development of schizophrenia. Specifically,
it has been hypothesized that environmental factors have differing
effects on individuals with different genotypes, where some individuals
may have an increased genetic susceptibility towards developing
schizophrenia compared to others. Harmful environmental influences
that may contribute to cause schizophrenia may include psychosocial
factors, drug abuse, psychosis related to brain insults, and infections
and/or complications during pregnancy and birth.
|It is clear that both
genetic and environmental risk factors contribute to the incidence
and development of schizophrenia although how these factors interact
is less certain. Genetic factors and harmful environmental events
such as obstetric complications occur well before disease onset.
A neurodevelopmental model of schizophrenia helps to explain how
these factors add or interact to contribute to schizophrenia and
serves to explain the timing of genetic or environmental influences
that ultimately result in disease.
The hypothesis that schizophrenia is of neurodevelopmental origin
is now the most widely accepted explanation for schizophrenia pathophysiology.
From the neurodevelopmental perspective, schizophrenia is assumed
an ongoing process, rather than the result of a specific static
event occurring sometime between conception and adulthood. A growing
amount of data supports that the pathophysiology of schizophrenia
involves abnormalities in normal brain development. Such evidence
comes from studies that have identified associations between viral
infections during pregnancy, obstetrical complications, and evidence
of childhood behavioral and neurological abnormalities before disease
onset in adulthood. Further, neuroimaging abnormalities that are
observed in patients with first episode schizophrenia, in first-degree
biological relatives and in schizotypal personality disorder, including
deficits in cortical gray matter and reduced volumes in mesiotemporal
regions, indicate that some anatomical abnormalities predate the
onset of schizophrenia further supporting a neurodevelopmental origination
and development of the disease.
|Distinct gender differences
are similarly observed in the clinical features of schizophrenia.
For example, negative symptoms appear more prominent in male patients
and males have an earlier age of onset, a worse course of illness
and more cognitive impairments. There is some evidence that structural
abnormalities such as ventricular enlargements and alterations in
callosal and temporal lobe shape are more apparent in male schizophrenia
groups. Gender and age are therefore considered important variables
when assessing structural brain alterations in patients with schizophrenia
and their biological relatives compared to normal controls.
|It is widely accepted
that neuroanatomic abnormalities are present in schizophrenic. To
investigate the regional specificity of abnormal neural systems
in schizophrenia, we have used magnetic resonance imaging (MRI)
and anatomical surface-based mesh modeling and brain atlasing approaches
to look for regional anatomical differences. We have also employed
standard statistical procedures to compare brain regions of interest
in patients with schizophrenia compared to normal control groups.
Experimental tests have concentrated on cortical and subcortical
regions widely implicated in schizophrenia neuropathology and on
the hypothesized alterations of normal cerebral asymmetries.
Enormous challenges exist in identifying neuroanatomic abnormalities
in schizophrenia that are potentially disease specific. Large inter-individual
variability in neuroanatomic structure in normal individuals, and
the notable clinical heterogeneity in schizophrenia all decrease
the likelihood of detecting disease-specific brain abnormalities.
The diffuse nature and varying magnitude of cerebral anomalies found
in schizophrenic populations further complicate localization strategies.
In our analyses of brain structure, however, we have benefited from
the improved spatial resolution of our imaging data and from the
development of sensitive image analysis techniques that can preserve
information on individual variability across many complex regions
in three dimensions.
To investigate the
neurodevelopmental and/or the progression of structural neuropathology
in schizophrenia we have studied some specific brain systems in
acute-onset patients as well as in chronic schizophrenia patients.
- Studies of drug-naïve first episode (FE) patients with
schizophrenia may confirm the presence of structural neuropathology
at the onset of the disease.
- Comparisons of brain abnormalities observed at disease onset
with those exhibited in chronic schizophrenia may reveal which
neural systems are most vulnerable in schizophrenia and implicate
which brain regions are susceptible to degenerative processes.
- Longitudinal MR data from first episode patients may confirm
which brain abnormalities are of a progressive nature and explain
how these abnormalities relate to a number of factors such as
different antipsychotic medication treatments.
To investigate the
genetic and/or environmental origins of structural neuropathology
in schizophrenia we have examined potentially vulnerable brain
regions in individuals who have an increased biological or environmental
risk for developing schizophrenia. We have hypothesized that neuroanatomic
abnormalities will manifest along a continuum of increased biological
relatedness of an individual to a patient with schizophrenia.
According to this model, structural brain abnormalities observed
in biological relatives of patients, who show no overt symptoms
of the disease, should by default, also be present at disease
onset and in chronic schizophrenia. Conversely, brain abnormalities
observed in acute onset patients or in patients that have experienced
a chronic course of illness, will not necessarily manifest in
healthy biological relatives.
In our investigations of structural neuropathology in schizophrenia,
we have assessed a number of widely implicated brain regions along
the continuum of genetic proximity, but only if these abnormalities
were first identified in chronic or first episode schizophrenia.
Specifically, we have included imaging data from monozygotic (MZ)
and dizygotic (DZ) twin pairs discordant for schizophrenia and
normal control twin pairs to dissociate genetic versus environmental
contributions to macroscopic structural brain abnormalities in
- By comparing brain abnormalities between MZ affected (schizophrenic)
and non-affected (non-schizophrenic) twins, the significance
and magnitude of disease specific (environmental) contributions
towards alterations in brain structure have been determined.
- By comparing regional brain abnormalities between non-schizophrenic
(healthy) co-twins of schizophrenic patients to normal twin
pairs, the genetic influences of schizophrenia on brain structure
have been ascertained.
- The contributions of shared environmental versus purely genetic
influences to regional brain abnormalities have been estimated
by comparing the patterns of structural brain abnormalities
between MZ and DZ affected and unaffected co-twins.
|To investigate hypothesized
alterations in functional and structural asymmetries in schizophrenia,
we have examined asymmetric brain regions and lateralized functional
systems in schizophrenia patients compared to normal controls. Structural
asymmetries in posterior temporo-parietal regions, previously established
as important for language processing, have been examined in patients
in their first episode and in chronic schizophrenia patients to
determine whether schizophrenia is related to pathophysiological
processes that may interfere with the specialization of the two
cerebral hemispheres. Behavioral paradigms have been employed simultaneously
in chronic schizophrenia patients and normal control groups to determine
whether functional lateralization and information transfer between
the two cerebral hemispheres through the corpus callosum, are disturbed.
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