The relationship between prepulse detection and prepulse inhibition of the acoustic startle reflex

Prepulse inhibition (PPI) of the startle reflex is defined as the attenuation of the startle response to a startling stimulus (pulse), when such a stimulus is briefly preceded by a stimulus of subthreshold intensity (prepulse). PPI is thought to be neither learned nor due to conscious response inhibition, as it occurs at stimulus onset asynchronies (SOAs) too short to enable the activation of a volitional response. The present study explored the latter of these assertions by investigating (a) the degree to which human subjects are able to detect prepulses at SOAs of 30, 60 and 120 ms, and (b) whether such detection is related to inhibition. Startle eyeblink reflex and detection were measured in 39 participants subjected to an acoustic startle paradigm. Results revealed a significant trend in prepulse detection according to SOA, with highest detection rates at the 120-ms SOA (75%). However, trials on which detection occurred did not differ from trials without detection on measures of startle inhibition. This suggests that PPI is independent of awareness of the prepulse.     

Relationship between prepulse inhibition of acoustic startle response and schizotypy in healthy Japanese subjects

Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) is the most common psychophysiological index of sensorimotor gating. Several studies have investigated the relationship of PPI of ASR to schizotypy in Caucasians. However, little has been reported on this relationship in Asians. We investigated a possible relationship between PPI of ASR and schizotypy in 79 healthy Japanese subjects. Schizotypy was assessed by the Schizotypal personality Questionnaire (SPQ). PPI was evaluated at signal‐to‐noise ratios (SnRs: difference between background noise intensity and prepulse intensity) of +12, +16, and +20 dB. The total SPQ score, cognitive/perceptual score, and interpersonal score correlated negatively with PPI at SnR of +16 and +20 dB. We conclude that PPI is associated with the trait of schizotypy in healthy Asian subjects.     

Age, sex and strain comparison of habituation of the startle response in the rat

Habituation and sensitization of the acoustic startle response were studied in young (3 month) and aged (26 month) male and female Fischer 344 rats and in young (3 month) and aged (32 month) male Sprague Dawley rats. Tones were presented on 25 consecutive trials for a session, one session on each of four consecutive days. An air puff stimulus immediately preceded trial 20 on each day to test sensitization. All aged rats demonstrated greater short-term (within session) relative habituation than their younger counterparts. Across sessions, aged male rats of both strains habituated more quickly than younger males. Aged female rats habituated more slowly. Sensitization was more likely to occur in younger rats.     

Attenuation of the prepulse inhibition of the acoustic startle response within and between sessions

Prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR) are widely used biological markers in the study of psychiatric disorders and have been shown to be homologous across species. Previous studies in humans suggested that PPI is a stable and reliable measure between test sessions, but that PPI decreases within sessions. The purpose of this study was to explore the short- and long-term decrease in PPI as a potential confound in the measurement and interpretation of PPI. We investigated the progression of PPI and habituation of ASR in three test sessions spaced 4 weeks apart in a group of 20 healthy participants. Analysis revealed a significant decrease in the percent PPI within and between the test sessions. Nevertheless, PPI was reliable across three test sessions, indicating that the significant attenuation of PPI over time was a consistent phenomenon. These results suggest that PPI exhibits short- and long-term attenuation.     

Temperament in preweanling horses: development of reactions to humans and novelty, and startle responses

The purpose of this study was to investigate the development and the stability across situations and over time of three temperament traits in young foals: propensity to react to humans, propensity to react to novelty, and propensity to react to suddenness. In a comparative study, we examined the reactions of animals in three independent groups (N = 27) tested at 3, 12, and 24 weeks of age, respectively. We observed that human avoidance and novel object approach behaviors are quasi inexistent in the group tested at 3 weeks, but are more and more present in the groups tested at subsequent ages. In a longitudinal study, we tested 48 foals successively at 3, 6, 12, and 24 weeks of age. Since reactions appear progressively with time, no stability over time or across situations was found. However, once a foal manifests a behavioral reaction at a given age, it will always reproduce this reaction subsequently.     

Genetic association study of GABRA2 single nucleotide polymorphisms and electroencephalography in alcohol dependence

The gamma aminobutyric acid (GABA) system has been implicated in the susceptibility to develop alcohol dependence and in determining electroencephalogram (EEG) beta activity. The role of the GABA receptor alpha-2 gene (GABRA2) in human alcohol dependence was determined in a genetic and electrophysiological study. The study population comprised 586 white UK individuals with alcohol dependence but a very low prevalence of co-morbid drug dependence, and 603 ancestrally matched healthy controls. Genotyping for seven GABRA2 single nucleotide polymorphisms (SNPs), identified from the literature as positively associated with alcohol dependence, was performed with success rates of 90% or greater. EEGs were available in 32 selected patients who had been abstinent from alcohol for a minimum of 24 months and in 138 ancestrally matched healthy controls. None of the SNPs showed allelic or haplotypic association with alcohol dependence. All markers were in Hardy Weinberg equilibrium (HWE) in the controls. HWE for marker rs279841 in the alcohol dependent sample was p=0.0199 and combined p=0.0166. Linkage disequilibrium patterns appear to be very similar to that observed in the HapMap CEU data. A significantly higher prevalence of excess EEG fast activity was found in the patients (31 vs. 14%, p=0.018). A significant relationship was found between the presence of excess EEG fast activity and GABRA2 SNPs rs548583, rs279871 and rs279841. This allelic association study provides no evidence for an association between GABRA2 polymorphisms and alcohol dependence. However, a significant relationship was identified between GABRA2 and excess EEG fast activity. This dissociation of effect may reflect the fact that the EEG is a more direct marker of phenotypic GABRA2 expression than the more heterogeneous alcohol dependence phenotype.     

Family-based and case-control study of DRD2, DAT, 5HTT,COMT genes polymorphisms in alcohol dependence

The paper focuses on such candidate gene polymorphisms that alter alcoholism-related intermediate phenotypes including: dopaminergic system polymorphic variants (DRD2 -141C Ins/Del in promoter region, exon 8 and DRD2 TaqI A and DAT 40bp VNTR genes polymorphisms) that cause predisposition to severe alcoholism (haplotype Ins/G/A2); COMT Val158Met gene polymorphism related to differences in executive cognitive function and 5-HTT gene promoter polymorphism, which alters stress response and affects anxiety and dysphoria. The transmission disequilibrium test (TDT) was used in the study. One hundred Polish families with alcohol dependence were recruited. The control subjects for the case-control study were 196 ethnically and gender matched healthy individuals. It was found that DRD2 TaqIA and DAT gene polymorphisms contained statistically significant differences in allele transmission. In the homogenous subgroups of patients with early onset and with withdrawal complications a statistically significant preferential A2 allele transmission was found in DRD2 TaqIA gene polymorphism. The alleles and genotypes distribution of the investigated polymorphisms did not differ significantly between the alcoholics and the controls in the case-control study. The results confirmed the fact that the candidate genes (DRD2 and DAT) are partially responsible for the development of alcohol dependence. The results are also in agreement with the hypothesis that there are various subtypes of alcohol dependence, which differ depending on their genetic background. Meanwhile, the currently available pharmacological therapies for alcoholism treatment are effective in some alcoholics but not for all of them. Some progress has been made in elucidating pharmacogenomic responses to drugs, particularly in the context of Clonninger and Lesch typology classification system for alcoholics.     

The relationship between mental and physical health: Insights from the study of heart rate variability

Here we review our recent body of work on the impact of mood and comorbid anxiety disorders, alcohol dependence, and their treatments on heart rate variability (HRV), a psychophysiological marker of mental and physical wellbeing. We have shown that otherwise healthy, unmedicated patients with these disorders display reduced resting-state HRV, and that pharmacological treatments do not ameliorate these reductions. Other studies highlight that tricyclic medications and the serotonin and noradrenaline reuptake inhibitors in particular may have adverse cardiovascular consequences. Reduced HRV has important functional significance for motivation to engage social situations, social approach behaviours, self-regulation and psychological flexibility in the face of stressors. Over the longer-term, reduced HRV leads to immune dysfunction and inflammation, cardiovascular disease and mortality, attributable to the downstream effects of a poorly functioning cholinergic anti-inflammatory reflex. We place our research in the context of the broader literature base and propose a working model for the effects of mood disorders, comorbid conditions, and their treatments to help guide future research activities. Further research is urgently needed on the long-term effects of autonomic dysregulation in otherwise healthy psychiatric patients, and appropriate interventions to halt the progression of a host of conditions associated with morbidity and mortality.     

Habituation and sensitization of the acoustic startle response during cortical spreading depression in rats

Habituation of the acoustic startle response was tested in 8 groups of rats which received different CSD-treatments on 3 successive days. Both short-term habituation and long-term habituation were investigated. Bilateral CSD did have a significant effect on short-term habituation, but not unilateral CSD. This effect was interpreted as a temporary increment of sensitization in the beginning of the session. Neither unilateral CSD nor bilateral CSD had an effect on long-term habituation as long as no treatment change took place. Treatment change resulted in an increased startle amplitude if it was a change from no CSD to unilateral or bilateral CSD. The reverse change had no such effect. These results were interpreted as evidence for a gradual compensation over sessions for the initial CSD-induced sensitization increment. The results were discussed in connection with the results of earlier experiments on CSD and habituation.     

Influence of functional tryptophan hydroxylase 2 gene variation and sex on the startle response in children, young adults, and older adults

Serotonin, a key regulator of emotional behavior, is synthesized by tryptophan hydroxylase (TPH). Allelic variation of TPH2 gene expression influences serotonin synthesis in the brain and therefore may modulate emotional processing. Here, we investigated the influence of the −703 G/T polymorphism in the regulatory promoter region of the TPH2 gene on the startle response in three different age samples: children (N = 110), young adults (N = 209), and older adults (N = 95). Startle magnitudes to intense noise bursts were recorded during baseline and while participants viewed unpleasant, pleasant or neutral pictures. There was a significant TPH2 × sex interaction effect in young adults with male T allele carriers showing stronger overall startle responses compared to male G/G homozygotes while in young women this effect appeared to be reversed. The difference between TPH2 genotype groups also reached significance in the female subsample when including menstrual cycle phase. In contrast, there was no effect of TPH2 or a TPH2 × sex interaction effect in children or in older adults.     

Family-based and case-control association studies of glutamate receptor GRIK3 Ser310Ala polymorphism in Polish patients and families with alcohol dependence

The aim of this study was to evaluate the role of the GRIK3 functional polymorphism (Ser310Ala) in the pathogenesis of alcoholism. This polymorphism was investigated in two types of studies: (1) the association study in a whole group of alcoholics (116 patients fulfilling ICD-10 alcohol dependence (AD) criteria and 255 controls, Polish descent) and homogenous overlapping subgroups of patients with: a history of delirium tremens and/or alcohol seizures, early age of onset of alcoholism (AOO<26 years), a co-occurrence of dissocial personality disorder, a history of familial alcoholism; (2) the family-based study (using Transmission Disequilibrium Test (TDT) in 100 Polish families with alcohol dependence). The history of alcoholism was obtained using SSAGA (Polish version). GRIK3 functional polymorphism was determined using PCR. TDT revealed an adequate transmission of both alleles to the affected offspring in the whole group of alcohol families (29 x Ser, 24 x Ala; chi2=0.472; d.f.=1; p=0.492) and in the homogenous subgroups of families. No significant associations between any of the above mentioned alcohol phenotypes and Ser310 allele were observed (the whole AD group: p=0.66 AD with delirium and/or seizures: p=0.521; early onset AD: p=0.868; AD with familial history of alcoholism: p=0.798 and AD with dissocial personality disorder: p=0.618). These findings do not seem to support the hypothesis of the role of this polymorphism in the pathogenesis of alcoholism.     

The influence of frontal alpha‐asymmetry on the processing of approach‐ and withdrawal‐related stimuli—A multichannel psychophysiology study

The approach‐withdrawal model of hemispheric activation suggests that left frontal cortical areas mediate approach, while right frontal cortical areas mediate withdrawal motivation. Within this framework, the present study investigates the association of frontal cortical asymmetry with attentional and emotional responses toward approach‐ and withdrawal‐related emotional stimuli. Resting frontal asymmetry was measured from 43 students before they passively viewed negative, neutral, and positive emotional pictures. The startle reflex, skin conductance response, and subjective ratings of valence and arousal were assessed to quantify emotional responding, while attention was assessed with ERPs. We also assessed frontal asymmetry in response to the pictures. Results indicated that relatively stronger right frontal cortical activation was associated with increased N1 amplitudes and more negative subjective emotional evaluation of all stimuli. Furthermore, enhanced right frontal asymmetry (state and trait) was associated with diminished emotional modulation of the late positive potential. In contrast, no association of frontal asymmetry with defensive reflex physiology or activation of sympathetic nervous system activity was found. The current data suggest dissociable influence of resting frontal brain asymmetry on attentional and physiological processing of withdrawal‐ and approach‐related stimuli. That is, asymmetrical frontal cortical brain activation might not modulate approach‐/withdrawal‐related motor responses and sympathetic arousal directly, but instead enhances allocation of attentional resources to subjectively significant stimuli. The results are discussed in terms of their potential importance for emotion perception in anxiety disorders and their contribution to the understanding of frontal asymmetry.     

Association of alcohol dehydrogenase 2*1 allele with liver damage and insulin concentration in the Japanese

The Japanese have a polymorphism in the alcohol dehydrogenase 2 gene (ADH2). The alleles of ADH2 (ADH2*1 and ADH2*2) encode more active and less active forms for ethanol metabolism, respectively. We examined whether liver damage and the insulin–glucose axis vary according to ADH2 genotype in the Japanese. The 2,232 subjects (1,126 men and 1,106 women) were recruited from a population-based prospective cohort study. Clinical evaluations including alcohol consumption, percentage of alcohol drinkers, plasma glucose, HbA1c, insulin, AST, ALT, -GTP, and prevalence of diabetes were compared among the ADH2 genotypes. The percentage of drinkers, alcohol consumption, AST, ALT, and -GTP were higher in group ADH2*1/1 than in group ADH2*1/2 or ADH2*2/2 (all P<0.05). Hence, ADH2*1/1 is associated with excess alcohol intake and liver disorders. However, the prevalence of diabetes did not differ among the three groups. For the glucose–insulin axis, we examined subjects who did not receive insulin therapy or oral anti-diabetes medication. While amounts of alcohol consumed and glucose levels were nearly the same between ADH*1/2 and ADH2*2/2, insulin concentrations were lower in ADH2*2/1 than in ADH2*2/2 (P<0.05 in men). This finding suggests that the ADH2*1 allele is associated with a lower insulin concentration when alcohol intake is light or moderate. It also suggests that the genetic effect of ADH2*1 plays an important role in alcohol drinking behavior and in the occurrence of liver injury, but the effect is so mild that it does not influence the glucose–insulin axis or prevalence of diabetes.     

DRD2/ANKK1 TaqIA and SLC6A3 VNTR polymorphisms in alcohol dependence: association and gene-gene interaction study in a population of Central Italy

Dopamine is a neurotransmitter whose functions are mediated by five receptors expressed in several organs and tissues. Dopaminergic system dysfunctions are involved in the etiology or treatment of several pathological conditions, including drug addiction. Alcohol dependence (AD) is a widespread psychiatric disorder, affecting 5.4% of the general population lifetime. Family and twins studies support the role of a genetic component in AD. Since dopamine neurotransmission has been shown to be involved in drug reward, related genes are plausible candidates for susceptibility to AD. Here, we evaluated both the DRD2/ANKK1 TaqIA (rs1800497) and SLC6A3 40 bp-VNTR SNP and gene-gene interaction analysis in AD patients from a population of Central Italy. The study design was a case-control. In total, 280 alcoholic subjects (213 men and 67 woman) and 280 age- and sex-matched control subjects were recruited for this study. Case subjects met the DSM-IV criteria for AD and they are free from any psychiatric co-morbidities. Controls were subjects who had non-alcohol problem either never drank; those who have smoked at least one pack of cigarettes per day for at least 1 year were excluded. Genotyping was performed by allele-specific PCR and RFLP-PCR. SLC6A3 40 bp 3'UTR-VNTR displays no association with AD. DRD2/ANKK1 TaqIA genotype distribution is significantly associated to AD (O.R.=1.551, p=0.023), with A1* allele displaying an O.R.=1.403 (p=0.029). Gene-gene interaction analysis using three-way contingency table analysis by a log-linear model yielded no significant result. Our study in a population of Central Italy extends and confirms previous results and, for the first time, tested the gene-gene interaction between SLC6A3 and DRD2 in AD.     

Effect of alcohol on the development of hepatocellular carcinoma in patients with hepatitis B virus-related cirrhosis: a cross-sectional case-control study

Background/Aims

Whether alcohol intake increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection remains controversial. The aim of this study was to determine the effect of alcohol intake on the development of HCC.

Methods

Between January 2006 and August 2008, 146 patients with an initial diagnosis of HCC who were hospitalized in 3 major hospitals in the Incheon area were enrolled as cases. Another 146 cirrhotic patients, who matched the cases by age and sex, were enrolled as controls. All cases and controls were HBsAg positive, and had a history of lifetime alcohol intake.

Results

The cases and controls were aged 53±8 and 53±9 years (mean±SD), respectively, with each group comprising 118 males and 28 females. The basal laboratory data, distribution of Child-Pugh class, HBeAg positivity (31.5% vs. 37.7%), HBV DNA level (5.74±2.35 vs. 5.98±2.29 log₁₀ copies/mL), and proportion with a lifetime alcohol intake of more than 292 kg (30.8% vs. 34.9%) did not differ between cases and controls. The cumulative alcohol intake and the proportion of heavy drinkers did not differ between the two groups in male patients.

Conclusions

Alcohol intake might not increase the risk of HCC in patients with HBV infection.     

The alterations in alcohol dehydrogenase and aldehyde dehydrogenase activities in the sera of patients with renal cell carcinoma

Purpose

In a previous study we showed that the total activity of alcohol dehydrogenase (ADH) and its isoenzyme class I was significantly higher in renal cancer (RCC) cells compared to normal kidney. The aim of this study was to compare the activities of ADH isoenzymes and aldehyde dehydrogenase (ALDH) in the sera of patients with different stages of RCC and healthy subjects.

Mutation screening of the dopamine D1 receptor gene in tourette's syndrome and alcohol dependent patients

We report a single stranded conformational polymorphism (SSCP) analysis of the coding region of the dopamine D1 receptor (DRD1) in Tourette's syndrome (n = 50) and control (n = 50) subjects. Tourette's syndrome populations with comorbidity for attention deficit-hyperactivity disorder (AD-HD) (n = 35) and obsessive compulsive disorder (OCD) (n = 30) were also screened. As a related study, we also screened patients diagnosed with alcohol dependence (n = 72). The present study discovered no DRD1 coding region mutations in any of the Tourette's syndrome or alcohol dependent patients. One silent mutation, a C for a T at Ile49, was discovered in one control subject. The non-polymorphic structure of the DRD1 gene among the Tourette's syndrome, Tourette's syndrome comorbid with AD-HD and OCD and the alcohol dependent populations screened by SSCP suggests that coding region mutations of the DRD1 gene are unlikely to contribute to the inheritance of these disorders. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:241–244, 1998. © 1998 Wiley-Liss, Inc.