Juergen Brinkmeyer

Neurocognitive impairments in non‐deprived smokers—results from a population‐based multi‐center study on smoking‐related behavior

The aim of the present study was to examine neurocognitive function associated with chronic nicotine use. A total of 2163 healthy participants (1002 smokers, 1161 never‐smoking controls) participated in a population‐based case‐control design. The main outcome measures were six cognitive domain factors derived from a neuropsychological test battery. In smokers, the battery was administered after controlled smoking of one cigarette. Analyses included age, sex and education as covariates. Results demonstrated small, but significant deficits in smokers for visual attention (P < 0.001) and cognitive impulsivity (P < 0.006), while verbal episodic memory, verbal fluency, verbal working memory, and Stroop‐interference did not differ between groups. These attention/impulsivity deficits were also present in smokers with only a low amount of cigarette consumption. Lifetime nicotine use (pack‐years) was not correlated with cognition in smokers. In conclusion, this study confirmed subtle and specific cognitive deficits in non‐deprived smokers. The independence of these deficits from consumption intensity may argue for an a priori deficit of some cognitive abilities in smokers. These specific deficits may constitute intermediate phenotypes for genetic research on nicotine use.

The val158met polymorphism of human catechol-O-methyltransferase (COMT) affects anterior cingulate cortex activation in response to painful laser stimulation

BackgroundPain is a complex experience with sensory, emotional and cognitive aspects. Genetic and environmental factors contribute to pain-related phenotypes such as chronic pain states. Genetic variations in the gene coding for catechol-O-methyltransferase (COMT) have been suggested to affect clinical and experimental pain-related phenotypes including regional μ-opioid system responses to painful stimulation as measured by ligand-PET (positron emission tomography). The functional val158met single nucleotide polymorphism has been most widely studied. However, apart from its impact on pain-induced opioid release the effect of this genetic variation on cerebral pain processing has not been studied with activation measures such as functional magnetic resonance imaging (fMRI), PET or electroencephalography. In the present fMRI study we therefore sought to investigate the impact of the COMT val158met polymorphism on the blood oxygen level-dependent (BOLD) response to painful laser stimulation.Results57 subjects were studied. We found that subjects homozygous for the met158 allele exhibit a higher BOLD response in the anterior cingulate cortex (ACC), foremost in the mid-cingulate cortex, than carriers of the val158 allele.ConclusionThis result is in line with previous studies that reported higher pain sensitivity in homozygous met carriers. It adds to the current literature in suggesting that this behavioral phenotype may be mediated by, or is at least associated with, increased ACC activity. More generally, apart from one report that focused on pain-induced opioid release, this is the first functional neuroimaging study showing an effect of the COMT val158met polymorphism on cerebral pain processing.

Functional Polymorphism in the Neuropeptide Y Gene Promoter (rs16147) Is Associated with Serum Leptin Levels and Waist-Hip Ratio in Women

Objective: The neuropeptide-Y (NP-Y) gene is a strong candidate gene in the pathophysiology of obesity-linked behavior, and several single-nucleotide polymorphisms of NP-Y have already been linked to body weight and appetite. However, the results from current studies remain inconclusive. The aim of the present study was to test whether a certain functional genetic variant (SNP rs16147) in the NP-Y promoter gene is associated with serum leptin levels and body fat distribution. Method: We genotyped and measured the serum leptin levels of the NP-Y rs16147 polymorphism in 1,097 Caucasian subjects in the context of a population-based, case-control multicenter study. We measured weight, height and waist circumference, from which we then calculated BMI and waist-to-hip ratio (WHR). Results: We found the CT-genotype of the SNP rs16147 to be significantly associated with lower WHRs and higher serum leptin levels in women, compared to homozygote gene carriers. No association between rs16147, WHR and serum leptin levels was found in men. Conclusion: Our results provide evidence that the functionally relevant SNP in the NP-Y promoter gene affects body fat distribution and serum leptin levels in women, pointing towards possible behavioral effects of NPY in obesity.

Nicotine effects on anterior cingulate cortex in schizophrenia and healthy smokers as revealed by EEG-informed fMRI

Nicotine can have beneficial effects on attention performance and corresponding brain function in both schizophrenia patients and healthy controls, but it remains controversial whether nicotine affects brain function differentially in patients vs. controls. The effects of nicotine on brain activity elicited by attention-requiring oddball-type tasks have not been studied in schizophrenia patients. In this study we sought to investigate the impact of nicotine on the p300 evoked potential component and corresponding fMRI (functional magnetic resonance imaging) activation measures in schizophrenia patients and controls. Applying a double-blind, placebo-controlled cross-over design, the effects of 1mg nasal nicotine on brain activity elicited by a visual oddball-type task in N=14 schizophrenia and N=15 control smokers were studied with simultaneous EEG-fMRI. EEG single trial amplitudes were used to inform the fMRI analysis. We found a nicotine-associated increase in P300-informed fMRI activation in schizophrenia patients and controls, mainly in the anterior cingulate and adjacent medial frontal cortex. No group differences in the response to nicotine were found. Remarkably, averaged EEG and fMRI activation measures considered in isolation were largely unaffected by nicotine. Taken together, the effects of nicotine on P300 amplitude-associated brain activation do not seem to be fundamentally different in schizophrenic smokers and healthy controls.

Dynamic EEG-informed fMRI modeling of the pain matrix using 20-ms root mean square segments.

Previous studies on the spatio‐temporal dynamics of cortical pain processing using electroencephalography (EEG), magnetoencephalography (MEG), or intracranial recordings point towards a high degree of parallelism, e.g. parallel instead of sequential activation of primary and secondary somatosensory areas or simultaneous activation of somatosensory areas and the mid‐cingulate cortex. However, because of the inverse problem, EEG and MEG provide only limited spatial resolution and certainty about the generators of cortical pain‐induced electromagnetic activity, especially when multiple sources are simultaneously active. On the other hand, intracranial recordings are invasive and do not provide whole‐brain coverage. In this study, we thought to investigate the spatio‐temporal dynamics of cortical pain processing in 10 healthy subjects using simultaneous EEG/functional magnetic resonance imaging (fMRI). Voltages of 20 ms segments of the EEG root mean square (a global, largely reference‐free measure of event‐related EEG activity) in a time window 0–400 ms poststimulus were used to model trial‐to‐trial fluctuations in the fMRI blood oxygen level dependent (BOLD) signal. EEG‐derived regressors explained additional variance in the BOLD signal from 140 ms poststimulus onward. According to this analysis, the contralateral parietal operculum was the first cortical area to become activated upon painful laser stimulation. The activation pattern in BOLD analyses informed by subsequent EEG‐time windows suggests largely parallel signal processing in the bilateral operculo‐insular and mid‐cingulate cortices. In that regard, our data are in line with previous reports. However, the approach presented here is noninvasive and bypasses the inverse problem using only temporal information from the EEG. Hum Brain Mapp, 2010.

Lack of Association of a Functional Catechol-O-Methyltransferase Gene Polymorphism With Risk of Tobacco Smoking: Results From a Multicenter Case–Control Study

BACKGROUND The catechol-O-methyltransferase (COMT) modulates dopaminergic neurotransmission in the prefrontal cortex as well as in the mesolimbic reward system. Since the reward system mediates addictive behavior, the COMT gene is a strong candidate gene regarding the pathophysiology of tobacco dependence and smoking behavior. Because of rather conflicting results in previous studies, the purpose of the present study was to test for association between a functional genetic variant in the COMT gene (single nucleotide polymorphism [SNP] rs4680) and tobacco smoking behavior. METHODS In a population-based case-control multicenter study designed for tobacco addiction research, a total of 551 current smokers of European ancestry and 548 age-matched healthy volunteers (never-smokers) were genotyped for SNP rs4680 and extensively characterized concerning their smoking behavior. RESULTS We found no association between smoking status and SNP rs4680 genotype nor did we find a significant association to the degree of tobacco dependence. CONCLUSIONS Although prefrontal cortical and ventral striatal activity are highly relevant for addictive behavior, and under partial control of COMT rs4680 genotype, no association between COMT and smoking behavior was observed. Other genetic variants may account for the high heritability of behavioral smoking phenotypes.