26 December 2006. In a world where we are constantly bombarded with information, sensory overload can take its toll. Luckily, most of us unconsciously filter out much of the extraneous noise. The startle response is a prime example. Give a sneak blast of a foghorn to an unsuspecting “volunteer” and the reaction will be spectacular (if not downright hostile—don’t try this at home!). But if the blast is preceded a fraction of a second earlier by even a barely audible "click," the response will be considerably muted. This prepulse inhibition (PPI) of the startle response is a well documented phenomenon and one that has aroused considerable interest among the schizophrenia research community because testing consistently shows that schizophrenia patients are deficient in it—they react more strongly to the second stimulus than do control subjects.
On that point most people in the field seem to agree. Where consensus breaks down, however, is in deciding whether PPI deficits are related in any meaningful way to other symptoms of schizophrenia, or to deficits in cognition and function. A paper in this month’s Archives of General Psychiatry suggests that they are. In the largest study to date on PPI in schizophrenia, Neal Swerdlow, David Braff, and colleagues at the University of California, San Diego, report that PPI deficiency is not only related to gender, medication, and smoking, but that it also correlates with impaired functional status.
Swerdlow and colleagues studied the startle response in occulomotor muscles in 103 schizophrenia patients and 66 normal comparison subjects. They found that in both patient and control groups, PPI to acoustic stimuli is higher in men than in women (the gender difference in control subjects has been well documented) and that the magnitude depends on the prepulse interval (120ms interval elicits greater inhibition, followed by 60, then 30ms intervals). Though the researchers found no main effect of diagnosis on PPI, post-hoc analysis of the data showed that schizophrenia patients are deficient in PPI specifically when 60 ms prepulse intervals were used. Though the deficit was small, it was statistically significant.
Because of the large sample size, the authors were able to glean statistically meaningful data from a variety of subgroup analyses. Interestingly, when they looked at patients who were not taking antipsychotic drugs (APs), they found that PPI was deficient at all prepulse intervals (30, 60 and 120 ms). The finding confirms what many have postulated previously, that antipsychotic medications increase and normalize PPI in schizophrenics. The data also suggest that the 60ms interval is least sensitive to the effects of these drugs, but the reason for this is unclear. The authors point out that the 60ms interval sits in that transition between time scales where information is processed automatically and consciously. “Theoretical models have proposed that this transitional zone between consciously accessible and unconscious processing is of particular importance for regulating the contents of consciousness and may also be an epoch of particular vulnerability in psychopathological states,” note the authors. In short, the finding that 60ms PPI remains deficient in patients taking APs suggests that this time interval may be particularly relevant to the pathology of the disease.
Swerdlow and colleagues found that compared to non-smoking control subjects, patient non-smokers were statistically deficient in PPI across all prepulse intervals as well. Though the effects of smoking and nicotine are hard to control for (time between last cigarette and testing, smoking history, level of smoking and individual differences in nicotine receptor sensitivity all vary) the results support the premise that nicotine increases PPI. Incidentally, PPI was also significantly greater in heavier smokers.
As for the relationship between PPI and other symptoms, the researchers compared PPI using the most sensitive 60ms interval with a variety of clinical test scores and found no significant correlation with symptom domains, either positive (using the SAPS, Scale for Assessment of Positive Symptoms) or negative (using SANS, Scale for Assessment of Negative Symptoms). The researchers sub-grouped this analysis, too, to try to weed out any significant correlations, looking at PPI across gender, highest and lowest quartiles of SAPS and SANS scores, or combined SAPS and SANS scores. None of these comparisons yielded any significant relationship. Similarly, they found no significant link between PPI and measures of neurocognitive function, such as the California Verbal Learning Test, and the Wisconsin Card Sorting Test.
However, analysis turned up a significant relationship between PPI and the Global Assessment of Functioning (GAF) scale—GAF scores were higher in patients with the highest PPI. Comparing patients by PPI response, the researchers found that those in the highest quartile had significantly higher GAF and LIL scores (Level of Independent Living scale) than those in the lowest. The results support the assertion that PPI may be a useful surrogate, or endophenotype, for studying schizophrenia, particularly functional ability. But there’s one rather large catch, which is the finding in this study and others that atypical APs are more effective than typical APs in "normalizing" the startle response. “Because an overwhelming number of patients with schizophrenia are currently treated with atypical APs, it is possible that PPI deficits in this population are a vanishing biomarker,” write the authors. —Tom Fagan
Swerdlow NR, Light GA, Cadenhead KS, Sprock J, Hsieh MH, Braff DL. Startle gating deficits in a large cohort of patients with schizophrenia. Arch Gen Psych. December, 2006;63:1325-1335. Abstract