The association of schizotypal traits with Prepulse Inhibition: a double approach exploration.

Introduction: According to the fully-dimensional approach, schizotypy is a personality trait present in the population in a continuous manner while the quasi-dimensional approach emphasises its extreme presentations. In this study we examined the relationship between sensorimotor gating, a core risk-index of the schizophrenia-spectrum, and four schizotypal factors in a dimensional-wise and a dichotomising-wise approach. Methods: Two-hundred and eighty-three participants were assessed with the Schizotypal Personality Questionnaire and were tested for Prepulse Inhibition (PPI). Associations between the schizotypal factors and startle measures were examined with stepwise regressions (dimensional-wise approach). Individuals in the lower 20% or the upper 20% for each schizotypal factor were identified and between-group comparisons were conducted (dichotomising-wise approach). Results: We found that with both approaches, only high paranoid or negative schizotypy were associated with reduced PPI. The low negative schizotypy group had prolonged onset and peak latencies, indicating that prolonged stimulus detection accompanies superior sensorimotor gating in this group. Conclusions: The findings suggest that although differentiating the effects of the various schizotypal factors is primary, the approach employed is secondary. The study also adds evidence in the literature supporting PPI as a useful endophenotypic marker of the schizophrenia-spectrum and highlights the contribution of specific aspects of schizotypy.

Meta-analysis on the association between genetic polymorphisms and prepulse inhibition of the acoustic startle response.

Sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) has been proposed as one of the most promising electrophysiological endophenotypes of schizophrenia. During the past decade, a number of publications have reported significant associations between genetic polymorphisms and PPI in samples of schizophrenia patients and healthy volunteers. However, an overall evaluation of the robustness of these results has not been published so far. Therefore, we performed the first meta-analysis of published and unpublished associations between gene polymorphisms and PPI of ASR. Unpublished associations between genetic polymorphisms and PPI were derived from three independent samples. In total, 120 single observations from 16 independent samples with 2660 study participants and 43 polymorphisms were included. After correction for multiple testing based on false discovery rate and considering the number of analyzed polymorphisms, significant associations were shown for four variants, even though none of these associations survived a genome-wide correction (P<5∗10-8). These results imply that PPI might be modulated by four genotypes - COMT rs4680 (primarily in males), GRIK3 rs1027599, TCF4 rs9960767, and PRODH rs385440 - indicating a role of these gene variations in the development of early information processing deficits in schizophrenia. However, the overall impact of single genes on PPI is still rather small suggesting that PPI is - like the disease phenotype - highly polygenic. Future genome-wide analyses studies with large sample sizes will enhance our understanding on the genetic architecture of PPI.

Cognitive and personality analysis of startle reactivity in a large cohort of healthy males.

Subjects with low/undetectable startle are usually excluded from startle studies but few reports not confounded by this factor, show reduced startle in healthy impulsive subjects, or clinical populations with disorders of affect and impulsivity but also in schizophrenia and its prodrome. We examined the relationship of startle reactivity including startle "non-responding" status to cognitive and affective personality traits in a large and ethnically/demographically homogeneous cohort of healthy males from the LOGOS study, Heraklion, Crete. Startle reactivity was monotonically related to sensitivity to reward (higher in "non-responders", lower in strong responders). In addition, "non-responders" had poorer strategy, working memory and sustained attention performance compared to responder tertile groups. More research in clinical and high risk populations is required to examine if low/undetectable startle reactivity is a valuable intermediate phenotype for disorders of affect and impulsivity. It is possible that the "non-responsive" status may capture disease related features such as executive dysfunction.

Dietary patterns during pregnancy and the risk of postpartum depression: the mother-child 'Rhea' cohort in Crete, Greece.

OBJECTIVE: To identify and describe dietary patterns in a cohort of pregnant women, and investigate whether dietary patterns during pregnancy are related to postpartum depression (PPD). DESIGN: The study uses data from the prospective mother-child cohort 'Rhea' study. Pregnant women completed an FFQ in mid-pregnancy and the Edinburg Postpartum Depression Scale (EPDS) at 8-10 weeks postpartum. Dietary patterns during pregnancy ('health conscious', 'Western') were identified using principal component analysis. Associations between dietary patterns categorized in tertiles and PPD symptoms were investigated by multivariable regression models after adjusting for confounders. SETTING: Heraklion, Crete, Greece, 2007-2010. SUBJECTS: A total of 529 women, participating in the 'Rhea' cohort. RESULTS: High adherence to a 'health conscious' diet, characterized by vegetables, fruit, pulses, nuts, dairy products, fish and olive oil, was associated with lower EPDS scores (highest v. lowest tertile: ß-coefficient = -1·75, P = 0·02). Women in the second (relative risk (RR) = 0·52, 95 % CI 0·30, 0·92) or third tertile (RR = 0·51, 95 % CI 0·25, 1·05) of the 'health conscious' dietary pattern were about 50 % less likely to have high levels of PPD symptoms (EPDS ≥ 13) compared with those in the lowest tertile. CONCLUSIONS: This is the first prospective study showing that a healthy diet during pregnancy is associated with reduced risk for PPD. Additional longitudinal studies and trials are needed to confirm these findings.

Improvement of prepulse inhibition and executive function by the COMT inhibitor tolcapone depends on COMT Val158Met polymorphism.

Recent evidence suggests that prepulse inhibition (PPI) levels relate to executive function possibly by a prefrontal cortex (PFC) dopamine (DA) link. We explored the effects of enhanced PFC DA signaling by the nonstimulant catechol-O-methyltransferase (COMT) inhibitor tolcapone, on PPI and working memory of subjects homozygous for the Val (low PFC DA) and the Met (high PFC DA) alleles of the COMT Val158Met polymorphism. Twelve Val/Val and eleven Met/Met healthy male subjects entered the study. Tolcapone 200 mg was administered in two weekly sessions, according to a balanced, crossover, double-blind, placebo-controlled design. PPI was assessed with 5 dB and 15 dB above background prepulses, at 30-, 60-, and 120 ms prepulse-pulse intervals. Subjects also underwent the n-back and the letter-number sequencing (LNS) tasks. PPI was lower in the Val/Val compared to the Met/Met group in the placebo condition. Tolcapone increased PPI significantly in the Val/Val group and tended to have the opposite effect in the Met/Met group. Baseline startle was not affected by tolcapone in the Val/Val group but it was slightly increased in the Met/Met group. Tolcapone improved performance in the n-back and LNS tasks only in the Val/Val group. Enhancement of PFC DA signaling with tolcapone improves both PPI and working memory in a COMT Val158Met genotype-specific manner. These results suggest that early information processing and working memory may both depend on PFC DA signaling, and that they may both relate to PFC DA levels according to an inverted U-shaped curve function.

The dopamine D(3) receptor Ser9Gly polymorphism modulates prepulse inhibition of the acoustic startle reflex.

BACKGROUND: The dopamine D(3) receptor (DRD(3)) is suspected to modulate prepulse inhibition (PPI) in animals and humans, but definite conclusions cannot be drawn due to lack of selective DRD(3) ligands. The Ser9Gly polymorphism is a common variant of the DRD(3) gene and determines the gain of function of the D(3) receptor. This is the first study to examine the influence of the DRD(3) Ser9Gly polymorphism on human PPI. METHODS: Prepulse inhibition was measured in 101 healthy male subjects presented with 75-dB and 85-dB prepulses at 30-, 60-, and 120-msec prepulse-pulse intervals. Subjects were grouped according to their DRD(3) status into a Gly/Gly, a Ser/Gly, and a Ser/Ser group. RESULTS: Analyses of variance showed that at all prepulse and interval conditions, Gly/Gly individuals had the lowest PPI and the greatest onset latency facilitation and Ser/Ser individuals had the highest PPI and the lowest onset latency facilitation, while Ser/Gly individuals were intermediate. CONCLUSIONS: These results suggest that PPI is modulated by the D(3) receptor and its levels depend on the Ser9Gly polymorphism.

Evidence of disrupted prepulse inhibition in unaffected siblings of bipolar disorder patients.

BACKGROUND: Prepulse inhibition (PPI) of the startle response refers to a reduction in the response to a strong stimulus (pulse) if preceded shortly by a weak stimulus (prepulse). Disrupted PPI is thought to reflect abnormalities in the inhibitory control of information processing. Reduced PPI has been reported in mania, although it is not clear whether it represents a trait feature of bipolar disorder (BD). To address this issue, the present study examined whether disrupted PPI is present in individuals at high risk for BD. METHODS: Twenty-one remitted BD patients and 19 of their unaffected siblings were compared with 17 age- and gender-matched healthy volunteers on tests of acoustic startle reactivity and PPI of the startle response. RESULTS: There were no group differences in startle reactivity. Compared with healthy individuals, BD patients and their unaffected siblings showed lower PPI. In the patient group, no significant correlations were found between PPI and measures of symptom and disease severity or medication. CONCLUSIONS: This is the first study to report reduced PPI in remitted BD patients and their unaffected first-degree relatives. This finding, although in need of replication, suggests that PPI disruption may represent a trait deficit in BD associated with genetic predisposition.

Increased prepulse inhibition of the acoustic startle response is associated with better strategy formation and execution times in healthy males.

Prepulse inhibition (PPI) refers to the attenuation of the amplitude of the startle reflex in response to sudden intense stimuli (pulse) if preceded by a weaker sensory stimulus (prepulse). PPI reflects the ability to filter out irrelevant information in the early stages of processing so that attention can be directed to more salient environmental features. Inhibition at this early stage of information processing appears modulated by the prefrontal cortex in a "top-down" fashion and this may account for the normal inter-individual variability in PPI and in cognitive performance. PPI data were calculated from 82 healthy male subjects who were also tested in problem solving (Stockings of Cambridge; SoC), spatial working memory (SWM) and 5-choice reaction time (RT) tests from the Cambridge Neuropsychological Test Automated Battery. Correlations between PPI scores and cognitive test variables were examined. In addition PPI scores were divided in quartiles which were used as grouping factors in examining cognitive test performance. Compared to individuals in the lowest quartile those in the highest had (a) shorter execution but not reaction times on the 5-choice RT, (b) shorter subsequent but not initial thinking times in the SoC where they also solved more problems correctly with the minimum number of moves, and (c) better strategy but not errors scores in the SWM. Our findings suggest that greater PPI is associated with superior abilities in strategy formation and execution times. We suggest that this is due to more efficient early information processing.

The level of prepulse inhibition in healthy individuals may index cortical modulation of early information processing.

This study examined whether baseline PPI levels reflect individual efficiency in tasks associated with routine versus supervisory attentional systems (SAS). PPI and neuropsychological data were collected from 30 healthy male subjects. High PPI was associated with shorter movement times on the 5-choice Reaction Time and shorter Subsequent Thinking Times in the Stockings of Cambridge test. These data suggest that high-PPI status reflects greater efficiency in tasks that engage SAS.

Parametric exploration of the fear-inhibited light reflex.

The effect of various parameters on the mediation of the fear-inhibited light reflex was examined. The light reflexes of 16 healthy men were measured across four light probe intensities, either in the presence of white noise alone or when the white noise was associated with the threat of either an electric shock or an acoustic sound blast. The white noise alone did not affect the light reflex amplitude. Both types of threat were subjectively anxiogenic and inhibited the light reflex across all light probe intensities, the threat of shock being more potent than the threat of sound blast. Importantly, the effect of either type of threat on the light reflex amplitude was found to increase with increasing light probe intensity, suggesting that brighter light probes may become more relevant motivationally in the threat condition, thus attracting greater allocation of attentional/cognitive resources.

The effects of dopamine agonists on prepulse inhibition in healthy men depend on baseline PPI values.

RATIONALE AND OBJECTIVES: Dopamine (DA) agonists reliably disrupt prepulse inhibition (PPI) of the startle reflex in animals but less so in humans despite cross-species similarities in the neural regulation of PPI. This study examines whether individual variation in baseline PPI may account for the inconsistencies in DA agonist-induced PPI disruption in humans. METHODS: Baseline PPI measures were obtained from 32 healthy adult men. Subjects were subsequently tested in three sessions after ingestion of placebo or active drug in a balanced double-blind design. Seventeen subjects were given 0.05 and 0.1 mg of pergolide (a direct DA agonist) and 15 subjects were given 100 and 200 mg of amantadine (an indirect DA agonist). In each treatment group, subjects were assigned to "high" and "low" PPI subgroups based on the median split of their baseline PPI. RESULTS: Amantadine and pergolide disrupted PPI in high- but not in low-PPI subjects. In contrast, low-PPI subjects showed a trend towards PPI facilitation especially with pergolide. CONCLUSIONS: Our results suggest that baseline PPI is an important determinant of the effect of DA agonists on PPI.

Relationship of prepulse inhibition of the startle reflex to attentional and executive mechanisms in man.

Prepulse inhibition (PPI) of the startle reflex at short lead intervals is thought to reflect the operation of a preattentive "sensorimotor gating" mechanism, which suggests that processing of the prepulse stimulus should not be modulated prior to its inhibitory effects on startle. To test this hypothesis, we examined whether PPI is affected following habituation to the prepulse. PPI was measured in two sessions associated with either the presence (habituation condition) or the absence (control condition) of prepulse repetition. There was a trend for prepulse repetition to reduce the effectiveness of that prepulse in inhibiting the startle response. We also explored the relationship of PPI to scores in tests of selective and sustained attention and planning ability. Overall PPI performance was correlated to performance indices of planning ability and there was a trend level correlation with scores in selective but not sustained attention tests. These preliminary results merit further investigation.