Test–retest stability of the oral niacin test and electrodermal activity in patients with schizophrenia

In schizophrenia, well-replicated findings support an attenuated niacin skin-flush response. We have previously reported a delayed skin-flush after niacin ingestion and also an association between niacin non-responding and electrodermal non-responding in schizophrenia. The stability of the niacin and electrodermal tests was now studied in a test–retest design. An additional aim was to assess the association previously found.Twenty-three patients with schizophrenia underwent two sessions 3 months apart during which an oral niacin test was conducted and electrodermal activity was measured. Despite similar values for niacin outcome variables at the group level, there was high intraindividual variation. Test–retest stability for the oral niacin test was thus low, although a trend toward correlation for the dichotomous response criterion was found. Most electrodermal measures correlated between baseline and retest. A significant association between the tests was again found; niacin non-responding implied electrodermal non-responding, providing further support for a common underlying aberration in schizophrenia.     

Relationship between the niacin skin flush response and essential fatty acids in schizophrenia

The skin flush response to niacin is selectively mediated by the release of vasodilatory prostaglandins from the skin. The normal skin flush response to niacin is attenuated in many individuals with schizophrenia (SCZ). This finding suggests abnormal prostaglandin signaling in SCZ. Since prostaglandins are derived from arachidonic acid (AA), the finding of an abnormal skin flush response is consistent with biochemical data suggesting relative depletion of AA, and other essential fatty acids (EFAs), in a substantial portion of people with SCZ. This paper will describe the mechanism of the skin flush response to niacin, and will review evidence that the response to niacin is abnormal in SCZ, that this abnormality is not related to psychotropic medications, and that it may be a marker of the EFA deficiency which has been documented to be present in many patients with SCZ.     

Comparison between monorhinal and birhinal olfactory stimulations in bilateral electrodermal recordings

The study of olfactory lateralization in human subjects has given rise to many publications, but the findings have often been contradictory. Most research used either birhinal or monorhinal stimulations, but rarely a comparison between these two types of olfactory input. The aim of this study was to investigate variations in psychophysiological measurements and test each side of the nose and binasal performances. This work used bilateral electrodermal recordings and compared the skin conductance responses (SCRs) for a pleasant odorant (isoamyl acetate) and an unpleasant odorant (triethylamine) in a suprathreshold concentration on 30 dextral subjects (16 females and 14 males). First, the results reported no differences between the two nostrils but differences in electrodermal activity (EDA) in relation to the odorant: 1) higher amplitude in response to unpleasant versus pleasant odorant; 2) no differences between monorhinal and birhinal stimulations for the unpleasant odour but higher amplitude in response to birhinal versus monorhinal for the pleasant odour. Second, the results showed constant bilateral differences in EDA recordings and are discussed in terms of hemispheric asymmetry activation.     

The impact of PLA2G4A and PTGS2 gene polymorphisms,and red blood cell PUFAs deficit on niacin skin flush response in schizophrenia patients

We investigated the etiology of the attenuated niacin skin flush response in schizophrenia patients. Skin response to topical niacin of 0.1 M, 0.01 M, 0.001 M, and 0.0001 M concentrations was rated using method of volumetric niacin response (VNR) and correlated to two functional A/G polymorphisms in genes: phospholipase A2 group IVA (BanI of the PLA2G4A), and rs689466 of the prostaglandin synthase-2 (PTGS2). We further tested the possible correlation between niacin response and fatty acid (FA) content of red blood cells (RBCs). We detected statistically significant but weak impact of both polymorphisms on niacin flush response in schizophrenia patients. The dosage of the G alleles of both polymorphisms was associated with higher VNR values, although each polymorphic variant accounted for only 1% of the overall flush response variability. Regarding FA content, both n?3 and n?6 polyunsaturated FAs (PUFAs) were significantly reduced in the patient group, but an association with niacin sensitivity was not detected.     

Neural chaos and schizophrenia

Recent data indicate that random-like processes are related to the defects in the organization of semantic memory in schizophrenia which is more disorganized and less definable than those of controls with more semantic links and more bizarre and atypical associations. These aspects of schizophrenic cognition are similar to characteristics of chaotic nonlinear dynamical systems. In this context, the hypothesis tested in this study is that dynamic changes of electrodermal activity (EDA) as a measure of brain and autonomic activity may serve as a characteristic which can be used as an indicator of possible neural chaotic process in schizophrenia. In the present study, bilateral EDA in rest conditions were measured in 40 schizophrenic patients and 40 healthy subjects. Results of nonlinear and statistical analysis indicate left-side significant differences of positive largest Lyapunov exponents in schizophrenia patients compared to the control group. This might be interpreted that the neural activity during rest in schizophrenic patients is significantly more chaotic than in the control group. The relationship was confirmed by surrogate data testing. These data suggest that increased neural chaos in patients with schizophrenia may influence brain processes that can cause random-like disorganization of mental processes.     

The hypothesis of the nature of electrodermal reactions

Long-term studies of electrodermal activity (EDA) in the activation-relaxation cycles, including simultaneous recording of skin resistance and temperature, were conducted. The new facts observed (a rapid drop in conductance after electrodermal response (EDR), a frequent absence of a correlation between skin resistance and EDR frequency, the conditions for correlation between the dynamics of resistance and temperature) are difficult to explain within the framework of the most generally accepted hypothesis of the formation of all EDA components by the secretory region of the eccrine sweat glands. They testify in favor of the hypothesis of the existence of two systems of EDA regulation that are largely independent. According to the hypothesis, the thermoregulation function is mainly mediated by the continuous release of a secretion resulting in tonic changes in resistance. EDR occur in response to emotions and are associated with thermoregulation, but only slightly. They are determined by the properties of the excretory region of the gland. The phase of decrease in resistance is accompanied by narrowing of the ducts caused by myoepithelial cells on activation, possibly adrenergic, of the sympathetic nervous system.     

Niacin skin test response in dyslexia

The niacin skin test reflects a flush and oedema owing to the production of prostaglandin D2 from arachidonic acid. A diminished response may indicate abnormalities in the phospholipid metabolism, which has been shown in schizophrenia. There is evidence that dyslexia might also involve phospholipid abnormalities, therefore we examined the skin response in 51 dyslexics and 45 controls. Four concentrations of aqueous methyl nicotinate were applied topically to the forearm. Flushing was rated using a seven-point scale at 3 min intervals over 21 min. Repeated measures ANOVA for the four concentrations across all seven time-points showed no significant effect of subject group, but when analyses were confined to the first 9 min, flushing was reduced in dyslexics. Significant group differences were also found for the lowest niacin concentration (0.0001M) across six out of seven time-points. The results indicate a slightly reduced and delayed response to niacin in dyslexia.     

Negative correlation between cerebral inorganic phosphate and the volumetric niacin response in male patients with schizophrenia who have seriously and dangerously violently offended: a (31)P magnetic resonance spectroscopy study

The aim of the study was to examine the association of arachidonic acid-related signal transduction with cerebral metabolism in patients with schizophrenia who have violently and dangerously offended while psychotic. Cerebral 31-phosphorus magnetic resonance spectroscopy was carried out in 11 male patients with schizophrenia who had violently offended (homicide, attempted murder, or wounding with intent to cause grievous bodily harm) while psychotic. Spectra were obtained from 70 x 70 x 70 mm(3) voxels using an image-selected in vivo spectroscopy pulse sequence. Niacin flush testing results were quantified as the volumetric niacin response. There was a strong, and negative, correlation between the volumetric niacin response and the metabolite concentration of inorganic phosphate expressed as a ratio of the total 31-phosphorus signal (p<0.005). Our results suggest that patients with schizophrenia who have violently offended and have poor phospholipid-related signal transduction may have higher levels of cerebral energy metabolism.     

Impaired niacin sensitivity in acute first-episode but not in multi-episode schizophrenia

Niacin (vitamin B3) flushing--a marker of altered prostaglandin signaling--is indirectly linked to the phospholipid-prostaglandin metabolism. Diminished skin flushing was repeatedly found in schizophrenia, but has not been systematically investigated at different stages of disorder as yet. We compared niacin sensitivity of 32 first-episode and 32 multi-episode patients (mainly on stable medication) with age and gender matched healthy controls. Methylnicotinate was applied in three concentrations onto the inner forearm skin. Flush response was assessed in 3 min intervals over 15 min using optical reflection spectroscopy. Whereas first-episode patients showed significantly diminished flush response as compared to controls, comparable differences were not found between multi-episode patients and controls. Comparison of niacin sensitivity at different stages of schizophrenia support the notion of altered prostaglandin signaling primarily at the onset of disorder. Longitudinal studies have to rule out possible long-term effects of neuroleptic medication.     

Eicosapentaenoic acid in the treatment of schizophrenia and depression: rationale and preliminary double-blind clinical trial results

It has been hypothesised that polyunsaturated fatty acids (PUFA) play an important role in the aetiology of schizophrenia and depression. Evidence supporting this hypothesis for schizophrenia includes abnormal brain phospholipid turnover shown by 31P Magnetic Resonance Spectroscopy, increased levels of phospholipase A2, reduced niacin skin flush response, abnormal electroretinogram, and reduced cell membrane levels of n-3 and n-6 PUFA. In depression, there is strong epidemiological evidence that fish consumption reduces risk of becoming depressed and evidence that cell membrane levels of n-3 PUFA are reduced. Four out of five placebo-controlled double- blind trials of eicosapentaenoic acid (EPA) in the treatment of schizophrenia have given positive findings. In depression, two placebo-controlled trials have shown a strong therapeutic effect of ethyl-EPA added to existing medication. The mode of action of EPA is currently not known, but recent evidence suggests that arachidonic acid (AA) if of particular importance in schizophrenia and that clinical improvement in schizophrenic patients using EPA treatment correlates with changes in AA.     

慢性心力衰竭患者心脏再同步化治疗的疗效及其影响因素分析

目的:观察慢性心衰患者经心脏再同步化治疗(cardiac resynchronization therapy,CRT)的临床疗效,并分析CRT无应答的影响因素。方法:入选2010年1月至2015年7月上海长海医院心血管内科因心衰接受CRT的患者共47例,收集病史资料、手术资料、术后资料以及随访,比较CRT有无应答患者的临床特征,并通过多因素回归分析CRT无应答的危险因素。结果:纳入病例数共47例,其中CRT应答34例(72.3%),CRT无应答13例(27.7%)。CRT无应答组中心房颤动和冠脉问题发生率明显高于CRT应答组(P0.05);CRT应答组中左心房容积、右心房容积、左心室容积以及二尖瓣返流量均明显低于CRT无应答组(P0.05)。多因素回归分析显示患者合并心房颤动或冠脉问题是CRT无应答可以影响CRT的应答。结论:CRT对慢性心衰患者具有较好的疗效,而合并心房颤动或冠脉问题是预测慢性心衰患者CRT无应答的独立影响因素。     

The characteristics of the electrodermal activity during changes in the level of human wakefulness

The wake-drowsiness transition during the performance of a monotonous psychomotor test was studied using polygraphic recording, with particular emphasis on changes in the electrodermal activity (EDA) and occurrence of electrodermal reactions (EDR). It was found that decrease in wakefulness was accompanied by a drop of the EDA. The EDR gradually disappeared for several minutes and did not reappear without activation; their dependence on sex and individual features of a subject significantly increased. It is suggested that discrepancies in the experimental results of psychophysiological studies with EDA may be explained by an insufficient control of the subject's alertness throughout the experiment. Examples of such discrepancies are given: disagreement of sex differences in the EDA, differentiation between EDA-labile and EDA-stable persons, on a possibility of recording the "emotional" EDA from different parts of human body etc. The ways of reproducibility of the results are discussed including the recording of several wake-drowsiness transitions and better recognition of the EDR.     

Niacin Skin Sensitivity Is Increased in Adolescents at Ultra-High Risk for Psychosis

Background

Most studies provide evidence that the skin flush response to nicotinic acid (niacin) stimulation is impaired in schizophrenia. However, only little is known about niacin sensitivity in the ultra-high risk (UHR) phase of psychotic disorders.

Methods

We compared visual ratings of niacin sensitivity between adolescents at UHR for psychosis according to the one year transition outcome (UHR-T n = 11; UHR-NT n = 55) with healthy controls (HC n = 25) and first episode schizophrenia patients (FEP n = 25) treated with atypical antipsychotics.

Results

Contrary to our hypothesis niacin sensitivity of the entire UHR group was not attenuated, but significantly increased compared to the HC group, whereas no difference could be found between the UHR-T and UHR-NT groups. As expected, niacin sensitivity of FEP was attenuated compared to HC group. In UHR individuals niacin sensitivity was inversely correlated with omega-6 and -9 fatty acids (FA), but positively correlated with phospholipase A₂ (inPLA₂) activity, a marker of membrane lipid repair/remodelling.

Conclusions

Increased niacin sensitivity in UHR states likely indicates an impaired balance of eicosanoids and omega-6/-9 FA at a membrane level. Our findings suggest that the emergence of psychosis is associated with an increased mobilisation of eicosanoids prior to the transition to psychosis possibly reflecting a “pro-inflammatory state”, whereas thereafter eicosanoid mobilisation seems to be attenuated. Potential treatment implications for the UHR state should be further investigated.     

Endophenotype properties of niacin sensitivity as marker of impaired prostaglandin signalling in schizophrenia

BACKGROUND: Disruption of arachidonic acid pathways and prostaglandin signalling has been implicated in the pathophysiology of schizophrenia. AIMS: We intended to study prostaglandin signalling in groups of young schizophrenia patients, first-degree relatives, and healthy controls in order to assess effects of heritability on this biological marker-one important endophenotype criterion. METHOD: Namely, we assessed intensity of methylnicotinate skin flushing using optical reflection spectroscopy. Tests were applied to 19 adolescent first-episode schizophrenia patients, 21 first-degree relatives, and groups of age and gender matched healthy controls. RESULTS: Compared to healthy controls, attenuation of skin flushing at low niacin concentrations was found only in schizophrenia patients, but not in first-degree relatives. CONCLUSION: While our results indicate niacin hyposensitivity as reliable biological marker in schizophrenia, they do not provide clear evidence for its heritability. Particularly, the results in adolescent schizophrenia patients are suggestive for the perception of attenuated niacin flushing as secondary to the pathophysiology at the onset of schizophrenic illness, namely increased oxidative stress, alterations of unspecific immune-response or inflammation-like processes.     

Liver fat reduction with niacin is influenced by DGAT-2 polymorphisms in hypertriglyceridemic patients

Niacin reduces plasma triglycerides, but it may increase free fatty acids and insulin resistance during long-term treatment. We examined the effect of extended-release niacin on liver fat content in Chinese patients with dyslipidemia and whether the common diacylglycerol acyltransferase-2 (DGAT2) polymorphisms influenced this effect. The 39 patients (baseline liver fat content: 12.8 ± 7.6%, triglycerides: 3.30 ± 1.67 mmol/l) were treated with niacin, gradually increasing the dose to 2 g/day for a total of 23 weeks. The liver fat content and visceral/subcutaneous fat was measured before and after treatment. Subjects were genotyped for the DGAT2 rs3060 and rs101899116 polymorphisms. There were significant (P < 0.001) reductions in plasma triglycerides (-34.9 ± 37.6%), liver fat content (-47.2 ± 32.8%), and visceral fat (-6.3 ± 15.8%, P < 0.05) after niacin treatment. Mean body weight decreased by 1.46 ± 2.7% (1.17 ± 2.44 kg, P < 0.001) during the study, but liver fat changes remained significant after adjustment for age, gender, and body weight changes [mean absolute change (95% CI): -6.1% (-8.0, -4.3), P < 0.001]. The DGAT2 variant alleles were associated with a smaller reduction in liver fat content in response to niacin after adjustment for other covariates (P < 0.01). These findings suggest that niacin treatment may reduce liver fat content in Chinese patients with dyslipidemia and that the mechanism may involve inhibition of DGAT2. However, the findings might have been confounded by the small but significant reductions in body weight during the study. Future large randomized controlled trials are needed to verify these findings.     

Instrumental conditioning of skin potential responses in curarized cats: non specific effects of a punishment procedure

This study evaluates the effects of a punishment paradigm upon electrodermal activity (EDA) in curarized cats. In ten experimental subjects, any skin potential response (SPR) exceeding threshold value was punished by an electric shock. Ten control subjects received an electric shock or an electric stimulation of the mesencephalic reticular formation unrelated to the EDA. The results show that: a) No significant modifications of EDA occurred in subjects characterized by low initial activity; b) The frequency of SPR significantly decreased in high activity subjects used both for the experiments and the controls. Therefore, this diminution, in experimental subjects, cannot be due to a learning process. Neither can it be related to level of curarization or to rate of artificial ventilation. It is suggested that this effect results from a non-specific cortical inhibitory mechanism acting on the reticular activating system. The results obtained in three decorticated cats submitted to a punishment procedure are in accordance with such an hypothesis. Consequently the existence of operant autonomic learning remains unproven.     

Sex differences, activation level, and bilateral electrodermal activity

The effects of the activation level and subject's sex on bilateral skin conductance measures were studied. Thirty right-handed subjects (15 males and 15 females) were exposed to three types of stimulus conditions: rest-period, verbal task and spatial task. Results showed that no relationship was observed between EDA asymmetry and the increase in the activation level induced by the verbal and the spatial tasks. Males showed both higher SCRs and greater frequency of responses on the left than on the right hand. The direction of electrodermal asymmetry remained constant regardless of the stimulus conditions. It was concluded that sex differences are important in the study of EDA asymmetry and that this asymmetry appeared to depend on peripheral variations.     

Epileptiform activity in alcohol dependent patients and possibilities of its indirect measurement

Background

Alcohol dependence during withdrawal and also in abstinent period in many cases is related to reduced inhibitory functions and kindling that may appear in the form of psychosensory symptoms similar to temporal lobe epilepsy frequently in conditions of normal EEG and without seizures. Because temporal lobe epileptic activity tend to spread between hemispheres, it is possible to suppose that measures reflecting interhemispheric information transfer such as electrodermal activity (EDA) might be related to the psychosensory symptoms.

Methods and Findings

We have performed measurement of bilateral EDA, psychosensory symptoms (LSCL-33) and alcohol craving (ACQ) in 34 alcohol dependent patients and 32 healthy controls. The results in alcohol dependent patients show that during rest conditions the psychosensory symptoms (LSCL-33) are related to EDA transinformation (PTI) between left and right EDA records (Spearman r = 0.44, p<0.01).

Conclusions

The result may present potentially useful clinical finding suggesting a possibility to indirectly assess epileptiform changes in alcohol dependent patients.     

No evidence for association between DRD3 and COMT with schizophrenia in a Malay population

Molecular components of the dopamine D3 receptor (DRD3) may play an important role in the pathophysiology of schizophrenia. Previous studies have demonstrated an association between DRD3 Ser9Gly and cathechol-o-methyltransferase (COMT, SNP = rs165656) polymorphisms and schizophrenia but the results were inconclusive. We investigated this apparent association between Ser9Gly (A/G) polymorphism and an intronic SNP (dbSNP or rs165656) in 261 Malay patients diagnosed with schizophrenia and 216 controls, using PCR-RFLP. The genotype distribution of the polymorphism DRD3 Ser9Gly was in Hardy-Weinberg equilibrium (HWE) for patients (P = 0.1251) and out of HWE for controls (P = 0.0137). However, both healthy controls and schizophrenia patients were out of HWE for the polymorphism COMT rs165656. Based on allele and genotype frequencies in both groups, we found no significant association of DRD3 Ser9Gly polymorphisms and COMT (rs165656) with schizophrenia in Malays. Further studies should examine the association between other dopamine-related genes and the behavioral phenotypes of schizophrenia.     

The PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophrenia

Several putative schizophrenia susceptibility genes have recently been reported, but it is not clear whether these genes are associated with schizophrenia in general or with specific disease subtypes. In a previous study, we found an association of the neuregulin 1 (NRG1) gene with non-deficit schizophrenia only. We now report an association study of four schizophrenia candidate genes in patients with and without deficit schizophrenia, which is characterized by severe and enduring negative symptoms. Single-nucleotide polymorphisms (SNPs) were genotyped in the DTNBP1 (dysbindin), G72/G30 and RGS4 genes, and the relatively unknown PIP5K2A gene, which is located in a region of linkage with both schizophrenia and bipolar disorder. The sample consisted of 273 Dutch schizophrenia patients, 146 of whom were diagnosed with deficit schizophrenia and 580 controls. The strongest evidence for association was found for the A-allele of SNP rs10828317 in the PIP5K2A gene, which was associated with both clinical subtypes (P = 0.0004 in the entire group; non-deficit P = 0.016, deficit P = 0.002). Interestingly, this SNP leads to a change in protein composition. In RGS4, the G-allele of the previously reported SNP RGS4-1 (single and as part of haplotypes with SNP RGS4-18) was associated with non-deficit schizophrenia (P = 0.03) but not with deficit schizophrenia (P = 0.79). SNPs in the DTNBP1 and G72/G30 genes were not significantly associated in any group. In conclusion, our data provide further evidence that specific genes may be involved in different schizophrenia subtypes and suggest that the PIP5K2A gene deserves further study as a general susceptibility gene for schizophrenia.