Prepulse inhibition in fragile X syndrome: feasibility, reliability, and implications for treatment
David Hessl1, Elizabeth Berry-Kravis, Lisa Cordeiro
1Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California-Davis, Medical Center, Sacramento, California 95817, USA. david.hessl@ucdmc.ucdavis.edu
Abstract:
Pharmacological rescue of behavioral, cognitive and synaptic abnormalities in the animal models of fragile X syndrome (FXS) has prompted the initiation of clinical trials of targeted treatments in humans with this condition. Objective, well-validated outcome measures that are reflective of FXS deficits and can be modeled similarly in animal and human studies are urgently needed. A protocol measuring prepulse inhibition (PPI) of the startle reflex, including measures of test-retest stability, was evaluated in 61 individuals with the fragile X full mutation (40 males and 21 females; 19.18 +/- 7.18 years) and 63 age-matched normal controls (35 males and 28 females; 20.83 +/- 6.96 years) across two laboratory sites with identical equipment and protocols. Relative to controls, the fragile X group had PPI impairment of 26%, 22%, and 28% for 60, 120, and 240 ms prepulse interval trial types, respectively, P = 0.000002. PPI test-retest reliability in 29 of the participants was excellent for the 120 ms prepulse interval trials (intraclass correlations: FXS, 0.85; controls, 0.88, 0.89 overall). This study demonstrates the feasibility and reliability of PPI measurement in a developmentally disabled population and highlights its potential as an outcome measure to test the efficacy of targeted neurotherapeutic agents.
Insights
Fragile X syndrome (FXS) patients show significant prepulse inhibition (PPI) deficits. This study confirms PPI as a reliable outcome measure for FXS clinical trials, aiding the development of targeted neurotherapeutics.
Area of Science:
- Neuroscience
- Genetics
- Clinical Trials
Background:
- Fragile X syndrome (FXS) is a genetic disorder causing cognitive and behavioral abnormalities.
- Animal model studies show promise for pharmacological treatments, necessitating human clinical trials.
- Validated outcome measures are crucial for assessing treatment efficacy in FXS.
Purpose of the Study:
- To evaluate the prepulse inhibition (PPI) of the startle reflex as a reliable outcome measure in individuals with FXS.
- To assess the test-retest stability of PPI measurements across different prepulse intervals.
- To determine the feasibility of using PPI in clinical trials for FXS.
Main Methods:
- A standardized PPI protocol was administered to 61 individuals with FXS and 63 age-matched controls across two sites.
- PPI was measured using three different prepulse intervals (60, 120, and 240 ms).
- Test-retest reliability was assessed in a subset of participants.
Main Results:
- Individuals with FXS exhibited significant PPI impairment across all tested prepulse intervals (P = 0.000002).
- PPI measurements demonstrated excellent test-retest reliability, particularly for the 120 ms interval (intraclass correlations ranging from 0.85 to 0.89).
- The protocol proved feasible in a population with developmental disabilities.
Conclusions:
- Prepulse inhibition (PPI) is a reliable and feasible neurophysiological measure for individuals with fragile X syndrome.
- PPI shows potential as a sensitive outcome measure for evaluating targeted neurotherapeutics in FXS clinical trials.
- This study supports the use of PPI to track treatment effects in FXS.
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