We have shown that prepulse inhibition (PPI) deficits can be reliably measured in children and adults with FXS and mental impairment. To our knowledge, this is the first study demonstrating the test-retest reliability of PPI measurement in a developmentally disabled population, and replicates an earlier study showing PPI deficits in boys with FXS (Frankland and others 2004
). The lack of FXS group differences in baseline EMG startle magnitude suggests that the PPI deficits are not simply due to abnormality in the startle response pathway but are more specifically related to inhibitory control mechanisms.
We provide the first evidence that females with FXS have substantial sensorimotor gating deficits, despite their typically less severe phenotypic and cognitive involvement. The PPI measurement may be especially sensitive to inhibition problems that are seen even in high functioning females. Indeed, of the 9 females with FXS with IQ scores in the average range, 6 had PPI measures one standard deviation or more below the control group. These findings are surprising, given that females with FXS typically express higher levels of FMRP as a result of X chromosome inactivation; measures that are deficient in FXS are therefore typically more abnormal in males. We are conducting studies to correlate FMRP level with various clinical and physiological measures, including PPI, to better address this question.
While the participants with FXS had substantial PPI deficits, on average ranging from 22% to 28% below controls, sensorimotor gating problems are not specific to this condition. Indeed, FXS is one of many neurodevelopmental and neurodegenerative disorders having major disruptions in inhibitory control and sensorimotor gating, including schizophrenia, ADHD, autism spectrum disorder, obsessive compulsive disorder, and Huntington's disease. The deficit in FXS measured here is not as large as was estimated by the prior smaller study (47% difference; (Frankland and others 2004
), but it does exceed that of schizophrenia (based on weighted means of 12 studies − 20% difference; (Hamm and others 2001
). Although there is little overlap in the clinical aspects of FXS and schizophrenia, both conditions appear to have a common deficit in glutamatergic signaling, sensorimotor gating, and brain systems involved with executive function and inhibition.
Functional MRI studies of both males and females with FXS demonstrate frontostriatal dysfunction during a Go/NoGo inhibitory control task that is correlated with the degree of FMRP deficit (Hoeft and others 2007
; Menon and others 2004
). PPI is clearly modulated by the GABAergic and glutamatergic frontal-striatal circuits that are implicated in FXS. Therefore, PPI may offer an alternative, less expensive method for indexing CNS dysfunction from a broader range of individuals, in age and level of functioning, than is possible with functional MRI.
The PPI test-retest reliabilities reported here, at least for the 120 ms interval, were excellent and similar to other studies reporting these data from other populations. For example, Cadenhead and colleagues (Cadenhead and others 1999
) studied PPI across three sessions, each one month apart, in healthy adult men, and found excellent test-retest and within-session stability, with intraclass correlations in the 0.90 range. Ludewig and colleagues (Ludewig and others 2002
) conducted a study of PPI reliability, also at three time points across 3 months, in normal controls as well as patients with schizophrenia and found PPI to be highly and equally reliable in both groups, especially for the 60 ms and 120 ms prepulse trial duration, with correlations in the 0.80 range. Given the challenges associated with physiological testing of patients with FXS who demonstrate significant hyperactivity and anxiety problems, our data suggest that slight modifications to typical PPI procedures and analysis techniques, such as allowing participants to view an engaging silent movie, using an adaptation procedure (a series of startle stimuli of increasing intensities) before the PPI trials, and carefully excluding trials with movement or other artifact, can lead to reliable measures even in these challenging participants. Furthermore, the higher reliability obtained for the 120 ms prepulse interval suggests that use of this trial type may be more sensitive to changes associated with treatment, and should be more strongly considered in future intervention studies.
Frankland and colleagues (Frankland and others 2004
) found strong correlations between PPI and clinical measures in young males with FXS. Within our subgroup children with FXS, we found a similar positive association between PPI and IQ, but no significant association in the larger group of patients including adults. These inconsistent results raise a concern that PPI deficiencies in FXS may not reflect clinical deficits. However, a weakness of the current study was that IQ scores were derived from several different instruments, and were not available for all participants, perhaps leading to more error and less accurate estimates of these correlations. Studies are needed that compare PPI to consistent and more sensitive cognitive testing, and more specific neuropsychological constructs associated with inhibitory control. In addition, it would be informative to compare PPI in FXS and a group of individuals with another developmental disability in order to separate the impact of the FMR1
mutation from general developmental effects. Finally, the sensory sensitivity, anxiety, and hyperarousal problems experienced by individuals with FXS are well-documented and may be associated with and influenced the PPI deficits observed.
There were several important limitations of the present study. First, we found a significant effect of laboratory site on PPI, especially within the FXS sample, with somewhat lower values from participants seen at Rush. However, we subsequently compared baseline startle magnitude data between the two sites, within each group, and found no significant differences (data not shown), and we found that one participant had very similar startle and PPI results when tested at each site. Together, these data suggest that the site effect may be more related to FXS cohort PPI effects than methodological or equipment differences, although it is also possible that differences in the testing environment may have influenced the findings. While previous studies suggest that males have increased PPI relative to females (Swerdlow and others 1999
) we found no significant gender effects within the FXS or control groups. Third, unfortunately we were unable to examine the effect of specific medication types on PPI in FXS patients. Given the finding of improved PPI in children with ADHD treated with methylphenidate (Hawk and others 2003
), as well as the reported success of stimulant medications in patients with FXS (Berry-Kravis and Potanos 2004
), a controlled trial of the effect of stimulant treatment on PPI and ADHD symptoms in FXS could be fruitful. Fourth, we did not measure hearing threshold in the participants, although we did screen individuals for hearing loss by history. Recurrent otitis media infections are common in early childhood but they typically resolve by age 5 in children with FXS so it is unlikely that this interfered with our study. Frankland and colleagues did obtain normal audiometric data on their subjects. Future PPI studies in FXS should also check for hearing loss directly. Finally, in addition to varying the prepulse interval, it may be useful to evaluate the level of inhibition with different prepulse sound levels, and to demonstrate that participants do not respond to prepulse sounds alone.
In summary, we show that males and females with FXS have abnormal sensorimotor gating that can be reliably measured using classic prepulse inhibition methodology. We believe that PPI is an excellent candidate for an objective treatment outcome measure to be used to test the efficacy of future novel therapeutic agents such as mGluR5 antagonists aimed at normalizing brain function and behavior in patients with FXS, and perhaps other neurodevelopmental disorders characterized by executive and inhibitory dysfunction.