Christina G. Baehne

Influence of Functional Variant of Neuronal Nitric Oxide Synthase on Impulsive Behaviors in Humans

CONTEXT Human personality is characterized by substantial heritability but few functional gene variants have been identified. Although rodent data suggest that the neuronal isoform of nitric oxide synthase (NOS-I) modifies diverse behaviors including aggression, this has not been translated to human studies. OBJECTIVES To investigate the functionality of an NOS1 promoter repeat length variation (NOS1 Ex1f variable number tandem repeat [VNTR]) and to test whether it is associated with phenotypes relevant to impulsivity. DESIGN Molecular biological studies assessed the cellular consequences of NOS1 Ex1f VNTR; association studies were conducted to investigate the impact of this genetic variant on impulsivity; imaging genetics was applied to determine whether the polymorphism is functional on a neurobiological level. SETTING Three psychiatric university clinics in Germany. PARTICIPANTS More than 3200 subjects were included in the association study: 1954 controls, 403 patients with personality disorder, 383 patients with adult attention-deficit/hyperactivity disorder (ADHD), 151 with familial ADHD, 189 suicide attempters, and 182 criminal offenders. MAIN OUTCOME MEASURES For the association studies, the major outcome criteria were phenotypes relevant to impulsivity, namely, the dimensional phenotype conscientiousness and the categorical phenotypes adult ADHD, aggression, and cluster B personality disorder. RESULTS A novel functional promoter polymorphism in NOS1 was associated with traits related to impulsivity, including hyperactive and aggressive behaviors. Specifically, the short repeat variant was more frequent in adult ADHD, cluster B personality disorder, and autoaggressive and heteroaggressive behavior. This short variant came along with decreased transcriptional activity of the NOS1 exon 1f promoter and alterations in the neuronal transcriptome including RGS4 and GRIN1. On a systems level, it was associated with hypoactivation of the anterior cingulate cortex, which is involved in the processing of emotion and reward in behavioral control. CONCLUSION These findings implicate deficits in neuronal signaling via nitric oxide in moderation of prefrontal circuits underlying impulsivity-related behavior in humans.

Event-related functional near-infrared spectroscopy (fNIRS) based on craniocerebral correlations: Reproducibility of activation?

The purpose of the present study was to assess the retest reliability of cortical activation detected by event‐related functional near‐infrared spectroscopy (fNIRS) based on craniocerebral correlations. Isolated functional activation was evoked in the motor cortex by a periodically performed finger‐tapping task. During 44‐channel fNIRS recording, 12 subjects performed 30 trials of right and left index finger tapping in two sessions. The retest interval was set to 3 weeks. Simple correlations of the contrast t‐values supplemented by scatterplots, channel‐wise intraclass correlation coefficients (ICC), as well as reproducibility indices for the size and the location of the detected activation were calculated. The results at the group level showed sufficient single measure ICCs (up to 0.80) and excellent reproducibility of the size and the location (up to 89% were reproducible). Comparisons of the intersession group amplitudes demonstrate that the fNIRS signals were stable across time in a retest study design: the number of significant differences was less than randomly occurring false‐positive activated channels if an alpha level of 5% is chosen. Effect size analyses indicated that the intersession amplitude differences are small (mean < 0.25). For deoxyhemoglobin and oxyhemoglobin distinct statistical power profiles were revealed regarding the activation vs. baseline contrast as well as the intersession amplitude differences, indicating a higher sensitivity of deoxyhemoglobin for local hemodynamic changes. The results suggest that sensorimotor activation assessed by event‐related fNIRS based on craniocerebral correlations is sufficiently reproducible at the group level. Hum Brain Mapp, 2006.

Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals

Although therapeutic interventions in attention-deficit/hyperactivity disorder (ADHD) still focus on the dopaminergic system, recent studies indicate a serotonergic dysfunction in this disease as well. In that respect, several variants of the tryptophan hydroxylase gene (TPH2), which codes for the rate-limiting enzyme in the biosynthesis of serotonin (5-HT), have been associated with ADHD. The rs4570625 G-allele polymorphisms of the TPH2 gene have already been related to altered reactivity of the brain during perception tasks with emotional stimuli in healthy adults. Here we investigated the influence of the ADHD related risk alleles for rs4570625 and for rs11178997 on prefrontal brain function during cognitive response control in large samples of adult ADHD patients (n=124) and healthy controls (n=84). Response control was elicited with a Go-NoGo task (continuous performance test; CPT) performed during recording of an ongoing EEG. From the resulting event-related potentials in the Go- and NoGo conditions of the CPT, the NoGo-anteriorization (NGA) has been calculated as a valid neurophysiological parameter for prefrontal brain function. In the current study, ADHD risk alleles of both polymorphisms were found to be associated with a reduction in the NGA in both healthy controls and ADHD patients. These findings are in line with the notion that genetic variations associated with altered serotonergic neurotransmission are also associated with the function of the prefrontal cortex during response inhibition. This mechanism might also be relevant in the pathophysiology of ADHD.

Abnormal affective responsiveness in attention-deficit/hyperactivity disorder: subtype differences.

BACKGROUND Emotional-motivational dysfunctions likely contribute to attention-deficit/hyperactivity disorder (ADHD), especially to hyperactive and impulsive symptoms. This study examined the affective modulation of the startle reflex in a large sample of ADHD patients. The aim was to compare subtypes of ADHD. METHODS One hundred ninety-seven unmedicated adult ADHD patients (127 combined type [ADHD-C]; 50 inattentive type [ADHD-I]; 20 hyperactive-impulsive type [ADHD-HI]) and 128 healthy control subjects were examined. The affect-modulated startle response as well as valence and arousal ratings were assessed for pleasant, neutral, and unpleasant picture stimuli. RESULTS Control subjects exhibited startle response attenuation and potentiation by pleasant and unpleasant pictures, respectively. In ADHD-HI, startle response was not attenuated by pleasant and not potentiated by unpleasant stimuli. In ADHD-C, startle response was not attenuated by pleasant pictures, and ADHD-I responded similar to control subjects but startle response was attenuated to a lesser degree by pleasant stimuli. The ADHD-HI group rated all pictures as more positive, and male ADHD-HI rated unpleasant stimuli as less arousing. CONCLUSIONS This is the first study to assess the affect-modulated startle response in ADHD. It confirms emotional dysfunctions in these patients; all subtypes showed more or less diminished emotional reactions to pleasant stimuli. The hyperactive-impulsive type was also marked by blunted reactions to unpleasant stimuli. Results suggest that response patterns to emotional cues or reward may help to differentiate ADHD subtypes. Blunted emotional reactivity is especially pronounced in ADHD patients with symptoms of hyperactivity and impulsivity (ADHD-C, ADHD-HI).

Event-related visual versus blocked motor task: detection of specific cortical activation patterns with functional near-infrared spectroscopy.

The purpose of this study was to investigate the regional specificity of multi-channel functional near-infrared spectroscopy (fNIRS) in the detection of cortical activation in humans. Therefore, brain activation evoked by a visual as well as a motor task was examined using 52-channel fNIRS. Analyses demonstrated an isolated activation in the occipital area during visual stimulation, whereas other regions exhibited little or no activation. Analyses of the motor task data clearly identified a differential activation pattern. The observation of an extensive cortical area by multi-channel measurement during two different tasks made it possible to examine the extent to which fNIRS measurements detect regional specific activations. We conclude that fNIRS measurements can detect regionally isolated cortical activation.

Dopamine transporter (SLC6A3) genotype impacts neurophysiological correlates of cognitive response control in an adult sample of patients with ADHD.

Studies provide ample evidence for a dysfunction in dopaminergic neurotransmission in Attention-Deficit/Hyperactivity Disorder (ADHD). In that respect, a common variable number of tandem repeats (VNTR) polymorphism in the 3′ untranslated region (UTR) of the dopamine transporter gene (SLC6A3) has been repeatedly associated with the disorder. Here, we examined the influence of the common 9- and 10-repeat alleles of SLC6A3 on prefrontal brain functioning and cognitive response control in a large sample of adult ADHD patients (n=161) and healthy controls (n=109). To this end, we inspected a neurophysiological marker of cognitive response control (NoGo anteriorization, NGA) elicited by means of a Go-NoGo task (continuous performance test, CPT). Within the group of ADHD patients, nine-repeat allele carriers showed significantly reduced NGA, whereas no influence of SLC6A3 genotype was observed in the control group. In contrast to previous association studies of children, the nine-repeat—not the 10-repeat—allele was associated with functional impairments in our sample of adult ADHD patients. Our findings confirm a significant effect of the SLC6A3 genotype on the neurophysiological correlates of cognitive response control in ADHD, and indicate that still to-be-identified age-related factors are important variables modulating the effect of genetic factors on endophenotypes.

The time course of temporal discrimination: An ERP study

OBJECTIVE The question of how temporal information is processed by the brain is still a matter of debate. This study aimed to elucidate the brain electrical activity associated with a visual temporal discrimination task. METHODS For this purpose, 44 participants were required to compare pairs of sequentially presented time intervals: a fixed standard interval (1000ms), and an equal-to-standard, longer (1200ms) or shorter (800ms) comparison interval. Behavioural data and event-related potentials (ERPs) were analyzed. RESULTS Long intervals were more rapidly identified than short intervals. The amplitude of the contingent negative variation (CNV) found at frontocentral sites before the end of the comparison interval was significantly affected by the difference between its duration and the standard one. The amplitude and the scalp distribution of ERPs registered after the offset of the comparison interval were linearly modulated by its absolute duration. CONCLUSIONS ERP components associated with the offset of the comparison intervals clarified the involvement of working memory processes and different brain structures in temporal discrimination. SIGNIFICANCE This study further improves our understanding of the cognitive processes and neural substrates underlying temporal discrimination in healthy subjects and lays the ground for the investigation of clinical samples with time processing deficits.

Affect-modulated startle reflex and dopamine D4 receptor gene variation.

The affect-modulated acoustic startle response (ASR) might be a promising indicator for emotional reactivity as an endophenotype (an intermediate level between genetics and phenotypes), which we expected to be associated with the DRD4 polymorphism. Therefore, the affect-modulated ASR was examined in 114 healthy volunteers, 74 lacking the DRD4 7R allele (7R-absent group) and 41 with at least one DRD4 7R allele (7R group). Results revealed the well-known affect-modulated ASR in the 7R-absent group. The 7R group, however, was characterized by a blunted affect-modulated ASR, especially by a reduced startle potentiation toward unpleasant pictures. Associations between the exploratory assessed 5-HTT, COMT, and DAT polymorphisms and affect-modulated ASR were not found. Results speak for the importance of the DRD4 polymorphism in modulating emotional responses and also for the usefulness of the affect-modulated ASR as an endophenotype.

Reduced NoGo-anteriorisation during continuous performance test in deletion syndrome 22q11.2

Deletion syndrome 22q11.2 (DS22q11.2) is a high-risk factor for psychiatric disorders. Alterations in brain morphology and function including the anterior cingulate cortex (ACC) are suggested to underlie the increased psychiatric disposition. We assessed response-inhibition in patients with DS22q11.2 (n=13) and healthy controls (n=13) matched for age, sex, and handedness by means of a Go-NoGo-Task during recording of a multi-channel electroencephalography (EEG). Analysis of event-related potentials (P300) resulted in an aberrant topographical pattern and NoGo-anteriorisation (NGA) as a parameter of medial prefrontal function was significantly reduced in patients with DS22q11.2 compared to controls. Differences in IQ between groups did not account for the findings. Source localization analysis (LORETA) revealed diminished left temporal brain activation during the Go-condition, but no altered ACC activation in DS22q11 during the NoGo-condition. Despite recent reports of structural alterations of the ACC in DS22q11.2 our findings suggest that response-inhibition mediated by the ACC is not impaired in DS22q11.2.

Brain activation in the visual and the motor cortex assessed with event-related functional near infrared spectroscopy (fNIRS): are the results reproducible

Human brain activation was recorded in two sessions on a CW-system to investigate the reproducibility of its spatial extent, location and magnitude. Reproducibility of the size and the location was excellent at the group level.