Sensorimotor Gating in Schizophrenia
| Status: | Completed |
|---|---|
| Conditions: | Schizophrenia |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 2/17/2019 |
| Start Date: | June 2001 |
| End Date: | July 2013 |
This study is looking at problems people sometimes have taking in information from their
senses. Specifically, we are comparing the way in which people diagnosed with schizophrenia
process sound information, compared with people who have never been diagnosed with a
psychiatric disorder. When people hear a loud sound they sometimes feel startled, and when
they feel startled they usually blink their eyes. However, if they hear a softer sound
shortly before the loud one they may not blink their eyes - in other words, the eye-blink
response is smaller. When this happens it's called prepulse inhibition of startle. In this
study, we want to measure the startle response and prepulse inhibition of startle in
individuals diagnosed with schizophrenia versus individuals not diagnosed with schizophrenia.
We also want to find out whether people show the same amount of prepulse inhibition of
startle as other members of their family.
senses. Specifically, we are comparing the way in which people diagnosed with schizophrenia
process sound information, compared with people who have never been diagnosed with a
psychiatric disorder. When people hear a loud sound they sometimes feel startled, and when
they feel startled they usually blink their eyes. However, if they hear a softer sound
shortly before the loud one they may not blink their eyes - in other words, the eye-blink
response is smaller. When this happens it's called prepulse inhibition of startle. In this
study, we want to measure the startle response and prepulse inhibition of startle in
individuals diagnosed with schizophrenia versus individuals not diagnosed with schizophrenia.
We also want to find out whether people show the same amount of prepulse inhibition of
startle as other members of their family.
Patients with schizophrenia have difficulty screening out irrelevant stimuli, and often have
the experience of sensory flooding. These "gating deficits" may contribute to the thought
disorder, cognitive fragmentation and hallucinations which are so debilitating to these
individuals. The acoustic startle response is a reflex contraction of the skeletal muscles in
response to a sudden acoustic stimulus. It occurs across mammalian species and can be easily
measured. The modulation of this reflex by a preliminary nonstartling stimulus is termed
prepulse inhibition of acoustic startle (PPI), a paradigm which is used as an operational
measure of sensorimotor gating. In consonance with the schizophrenia symptoms that are
suggestive of gating deficits, many patients with schizophrenia have deficits in PPI when
compared to healthy controls. The brain regions that modulate PPI include the hippocampus and
prefrontal cortex, areas that are implicated as being abnormal in schizophrenia. Our prior
work and work from other labs suggests that PPI impairment in schizophrenia does not improve
with treatment and hence may be a trait related abnormality. Work from our current funding
period supports our original hypothesis, namely that impaired PPI exhibits familial
association. Specifically, we are finding that PPI in first degree family members of subjects
with schizophrenia is impaired. Further work is needed in order to establish that PPI
impairment is heritable.
An endophenotype is a measurable trait or phenotype detectable by a biological test. Using an
endophenotype rather than presence or absence of disease is a powerful tool in the study of
diseases with complex polygenic etiologies such as schizophrenia. Progress in the genetics of
schizophrenia is greatly confounded by the difficulty in identifying individuals who carry
genes contributing to schizophrenia. Incomplete penetrance and the fact that both heritable
and environmental factors interact to produce the disease add to this difficulty. This means
that some individuals carrying vulnerability genes for schizophrenia who fail to exhibit
robust symptoms will be classified erroneously as unaffected in genetic studies, confounding
attempts to reliably define the heritable phenotype. The phenomenon of incomplete penetrance
is exhibited by the finding that the risk of schizophrenia is the same for children of
affected and nonaffected monozygotic twins. The polygenic etiology of schizophrenia makes it
unlikely that a pooled sample of individuals defined by the presence of schizophrenia will
greatly overlap in the vulnerability genes that they carry. The goal of the endophenotype
approach is to narrow the defined phenotype so that a more homogeneous genotype is expected,
making it much more fruitful and to conduct genetic studies.
We hypothesize that impaired PPI will prove to be a heritable endophenotype in schizophrenia.
Based on our work accomplished during the current funding period, we now propose to further
develop this line of research by conducting a heritability analysis of PPI. Our field is
greatly in need of this work as a prelude to endophenotype-based genetic studies. We will
accomplish our important goal by collecting and characterizing a cohort of healthy controls
and their families, and by expanding our sample of schizophrenia subjects and their families.
We will collect diagnostic, symptom, cognitive, pedigree, and PPI data all subjects, and will
collect blood and extract DNA for future genetic analyses. We will use a family based
strategy to investigate the pattern and degree of heritability of impaired PPI in families of
schizophrenia and control probands.
This project will provide the necessary next step in advancing the use of impaired PPI as a
powerful tool for the discovery of vulnerability genes contributing to schizophrenia.
Currently available treatments for this devastating disorder are sadly inadequate. Our
medications are virtually ineffective for a subset of our patients. The discovery of
vulnerability genes and of a method for biological subtyping of patients will allow our field
to develop genetically informed new treatments that specifically target particular subtypes
of patients. This approach is our best hope for bringing relief to patients suffering from
this disease.
the experience of sensory flooding. These "gating deficits" may contribute to the thought
disorder, cognitive fragmentation and hallucinations which are so debilitating to these
individuals. The acoustic startle response is a reflex contraction of the skeletal muscles in
response to a sudden acoustic stimulus. It occurs across mammalian species and can be easily
measured. The modulation of this reflex by a preliminary nonstartling stimulus is termed
prepulse inhibition of acoustic startle (PPI), a paradigm which is used as an operational
measure of sensorimotor gating. In consonance with the schizophrenia symptoms that are
suggestive of gating deficits, many patients with schizophrenia have deficits in PPI when
compared to healthy controls. The brain regions that modulate PPI include the hippocampus and
prefrontal cortex, areas that are implicated as being abnormal in schizophrenia. Our prior
work and work from other labs suggests that PPI impairment in schizophrenia does not improve
with treatment and hence may be a trait related abnormality. Work from our current funding
period supports our original hypothesis, namely that impaired PPI exhibits familial
association. Specifically, we are finding that PPI in first degree family members of subjects
with schizophrenia is impaired. Further work is needed in order to establish that PPI
impairment is heritable.
An endophenotype is a measurable trait or phenotype detectable by a biological test. Using an
endophenotype rather than presence or absence of disease is a powerful tool in the study of
diseases with complex polygenic etiologies such as schizophrenia. Progress in the genetics of
schizophrenia is greatly confounded by the difficulty in identifying individuals who carry
genes contributing to schizophrenia. Incomplete penetrance and the fact that both heritable
and environmental factors interact to produce the disease add to this difficulty. This means
that some individuals carrying vulnerability genes for schizophrenia who fail to exhibit
robust symptoms will be classified erroneously as unaffected in genetic studies, confounding
attempts to reliably define the heritable phenotype. The phenomenon of incomplete penetrance
is exhibited by the finding that the risk of schizophrenia is the same for children of
affected and nonaffected monozygotic twins. The polygenic etiology of schizophrenia makes it
unlikely that a pooled sample of individuals defined by the presence of schizophrenia will
greatly overlap in the vulnerability genes that they carry. The goal of the endophenotype
approach is to narrow the defined phenotype so that a more homogeneous genotype is expected,
making it much more fruitful and to conduct genetic studies.
We hypothesize that impaired PPI will prove to be a heritable endophenotype in schizophrenia.
Based on our work accomplished during the current funding period, we now propose to further
develop this line of research by conducting a heritability analysis of PPI. Our field is
greatly in need of this work as a prelude to endophenotype-based genetic studies. We will
accomplish our important goal by collecting and characterizing a cohort of healthy controls
and their families, and by expanding our sample of schizophrenia subjects and their families.
We will collect diagnostic, symptom, cognitive, pedigree, and PPI data all subjects, and will
collect blood and extract DNA for future genetic analyses. We will use a family based
strategy to investigate the pattern and degree of heritability of impaired PPI in families of
schizophrenia and control probands.
This project will provide the necessary next step in advancing the use of impaired PPI as a
powerful tool for the discovery of vulnerability genes contributing to schizophrenia.
Currently available treatments for this devastating disorder are sadly inadequate. Our
medications are virtually ineffective for a subset of our patients. The discovery of
vulnerability genes and of a method for biological subtyping of patients will allow our field
to develop genetically informed new treatments that specifically target particular subtypes
of patients. This approach is our best hope for bringing relief to patients suffering from
this disease.
Inclusion Criteria:
- Diagnosis of a Schizophrenia Spectrum disorder OR no history of Psychiatric Illness
Exclusion Criteria:
- History of head injury with loss of consciousness of more than 5 minutes
- History of neurological disease (ex. meningitis, encephalitis)
- Drug or alcohol abuse within the last 3 months
- Hearing loss
- Non-correctable vision problems
- Current cancer treatment (radiation or chemotherapy currently ongoing)
- History of Post Traumatic Stress Disorder
- Diagnosis of HIV or AIDS
- Uncontrolled diabetes
- History of seizures
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