Sensorimotor Gating in Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Acoustic startle testing
Intervention type(s): Behavioral
Intervention description(s): recording of eyeblink component of acoustic startle reflex with small surface electrodes during presentation of acoustic stimuli through headphones
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Schizophrenia; Prepulse Inhibition; Acoustic Startle