Genetics of preparation and response control in ADHD: the role of DRD4 and DAT1.

BACKGROUND: Difficulties with performance and brain activity related to attentional orienting (Cue-P3), cognitive or response preparation (Cue-CNV) and inhibitory response control (Nogo-P3) during tasks tapping executive functions are familial in ADHD and may represent endophenotypes. The aim of this study was to clarify the impact of dopamine receptor D4 (DRD4) and dopamine transporter (DAT1) gene polymorphisms on these processes in ADHD and control children. METHODS: Behavioural and electrophysiological parameters from cued continuous performance tests with low and high attentional load were assessed in boys with ADHD combined type (N = 94) and controls without family history of ADHD (N = 31). Both groups were split for the presence of at least one DRD4 7-repeat allele and the DAT1 10-6 haplotype. RESULTS: Children with ADHD showed diminished performance and lower Cue-P3, CNV and Nogo-P3 amplitudes. Children with DRD4 7R showed similar performance problems and lower Cue-P3 and CNV, but Nogo-P3 was not reduced. Children with the DAT1 10-6 haplotype had no difficulties with performance or Cue-P3 and CNV, but contrary to expectations increased Nogo-P3. There were no Genotype by ADHD interactions. CONCLUSIONS: This study detected specific effects of DRD4 7R on performance and brain activity related to attentional orienting and response preparation, while DAT1 10-6 was associated with elevated brain activity related to inhibitory response control, which potentially compensates increased impulsivity. As these genotype effects were additive to the impact of ADHD, the current results indicate that DRD4 and DAT1 polymorphisms are functionally relevant risk factors for ADHD and presumably other disorders sharing these endophenotypes.

Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes.

22q11.2 deletion syndrome (22q11.2DS) is a common genetic risk factor for the development of schizophrenia. We investigated two neurophysiological endophenotypes of schizophrenia - P50 sensory gating and mismatch negativity in 22q11.2DS subject and evaluated their association with catechol O-methyltransferase (COMT) and proline dehydrogenase (PRODH) genetic variants. We also assessed the association of neurophysiological measures with schizophrenia-like symptomatology in 22q11.2DS. Fifty-nine subjects, 41 with 22q11.2DS and 18 typically developing controls, participated in the study. The participants with 22q11.2DS were genotyped for the COMT Val(158)Met (rs4680) and PRODH Gln(19)Pro (rs2008720) and Arg(185)Trp (rs4819756) polymorphisms. Following psychiatric evaluation, all the participants underwent neurophysiological recordings and executive function assessment. The 22q11.2DS group showed poorer sensory gating of the P50 response than the controls. Within the 22q11.2DS group, the COMT Met allele was associated with poorer sensory gating, while both the COMT Met allele and the PRODH Pro-Arg haplotype were associated with smaller mismatch negativity amplitudes. Smaller mismatch negativity amplitudes predicted greater impairment of executive functions and greater severity of schizophrenia-like negative symptoms in 22q11.2DS. The current study demonstrates that sensory gating impairments that are typical of schizophrenia are found in 22q11.2DS subjects. Our results further suggest that COMT and PRODH genetic variations contribute to sensory gating and mismatch negativity schizophrenia-like impairments in 22q11.2DS, possibly via dopaminergic/glutamatergic networks. The associations of mismatch negativity impairments with increased severity of schizophrenia-like negative symptoms and poorer executive functions performance in our 22q11.2DS sample suggest that mismatch negativity is a potential endophenotype for schizophrenia in 22q11.2DS.

Familiality of neural preparation and response control in childhood attention deficit-hyperactivity disorder.

BACKGROUND: Patients with attention deficit-hyperactivity disorder (ADHD) exhibit difficulties in multiple attentional functions. Although high heritability rates suggest a strong genetic impact, aetiological pathways from genes and environmental factors to the ADHD phenotype are not well understood. Tracking the time course of deviant task processing using event-related electrophysiological brain activity should characterize the impact of familiality on the sequence of cognitive functions from preparation to response control in ADHD. Method Preparation and response control were assessed using behavioural and electrophysiological parameters of two versions of a cued continuous performance test with varying attentional load in boys with ADHD combined type (n = 97), their non-affected siblings (n = 27) and control children without a family history of ADHD (n = 43). RESULTS: Children with ADHD and non-affected siblings showed more variable performance and made more omission errors than controls. The preparatory Cue-P3 and contingent negative variation (CNV) following cues were reduced in both ADHD children and their non-affected siblings compared with controls. The NoGo-P3 was diminished in ADHD compared with controls whilst non-affected siblings were located intermediate but did not differ from both other groups. No clear familiality effects were found for the Go-P3. Better task performance was further associated with higher CNV and P3 amplitudes. CONCLUSIONS: Impairments in performance and electrophysiological parameters reflecting preparatory processes and to some extend also for inhibitory response control, especially under high attentional load, appeared to be familially driven in ADHD and may thus constitute functionally relevant endophenotypes for the disorder.

Time-resolved influences of functional DAT1 and COMT variants on visual perception and post-processing.

BACKGROUND: Dopamine plays an important role in orienting and the regulation of selective attention to relevant stimulus characteristics. Thus, we examined the influences of functional variants related to dopamine inactivation in the dopamine transporter (DAT1) and catechol-O-methyltransferase genes (COMT) on the time-course of visual processing in a contingent negative variation (CNV) task. METHODS: 64-channel EEG recordings were obtained from 195 healthy adolescents of a community-based sample during a continuous performance task (A-X version). Early and late CNV as well as preceding visual evoked potential components were assessed. RESULTS: Significant additive main effects of DAT1 and COMT on the occipito-temporal early CNV were observed. In addition, there was a trend towards an interaction between the two polymorphisms. Source analysis showed early CNV generators in the ventral visual stream and in frontal regions. There was a strong negative correlation between occipito-temporal visual post-processing and the frontal early CNV component. The early CNV time interval 500-1000 ms after the visual cue was specifically affected while the preceding visual perception stages were not influenced. CONCLUSIONS: Late visual potentials allow the genomic imaging of dopamine inactivation effects on visual post-processing. The same specific time-interval has been found to be affected by DAT1 and COMT during motor post-processing but not motor preparation. We propose the hypothesis that similar dopaminergic mechanisms modulate working memory encoding in both the visual and motor and perhaps other systems.

Dopamine inactivation efficacy related to functional DAT1 and COMT variants influences motor response evaluation.

BACKGROUND: Dopamine plays an important role in orienting, response anticipation and movement evaluation. Thus, we examined the influence of functional variants related to dopamine inactivation in the dopamine transporter (DAT1) and catechol-O-methyltransferase genes (COMT) on the time-course of motor processing in a contingent negative variation (CNV) task. METHODS: 64-channel EEG recordings were obtained from 195 healthy adolescents of a community-based sample during a continuous performance task (A-X version). Early and late CNV as well as motor postimperative negative variation were assessed. Adolescents were genotyped for the COMT Val(158)Met and two DAT1 polymorphisms (variable number tandem repeats in the 3'-untranslated region and in intron 8). RESULTS: The results revealed a significant interaction between COMT and DAT1, indicating that COMT exerted stronger effects on lateralized motor post-processing (centro-parietal motor postimperative negative variation) in homozygous carriers of a DAT1 haplotype increasing DAT1 expression. Source analysis showed that the time interval 500-1000 ms after the motor response was specifically affected in contrast to preceding movement anticipation and programming stages, which were not altered. CONCLUSIONS: Motor slow negative waves allow the genomic imaging of dopamine inactivation effects on cortical motor post-processing during response evaluation. This is the first report to point towards epistatic effects in the motor system during response evaluation, i.e. during the post-processing of an already executed movement rather than during movement programming.

On the role of fronto-striatal neural synchronization processes for response inhibition--evidence from ERP phase-synchronization analyses in pre-manifest Huntington's disease gene mutation carriers.

Fronto-striatal loops play an important role action selection processes, especially when discordant sensory and contextual information has to be integrated to allow adequate selection of actions. Neurodegeneration weakens neural inter-connectivity, which compromises the precision of neural synchronization processes. Yet, it is widely unknown how far changes in the precision of neural synchronization processes are induced by only slight dysfunctions of striatal neural inter-connectivity and in how far such slight changes may affect action selection processes. We investigated these processes in a sample of 25 pre-HDs and case-matched controls in a modified Go/Nogo task, while assessing neural synchronization processes by means of phase-locking factors (PLFs) as derived from event-related potentials (ERPs). The results show that pre-HDs only encounter problems in response inhibition, when discordant contextual information and sensory input have to be integrated. No deficits were evident, when response inhibition can be based on more habitual stimulus-response mappings, i.e., when contextual and sensory information were congruent. While 'habitual' action selection is unaffected by changes in striatal structures influencing reliability of neural synchronization processes, efficient 'controlled' processes of action seem to be closely dependent upon highly reliable neural synchronization processes. The neurophysiological analysis suggests that especially pre-motor inhibition processes (Nogo-N2) are affected. This was most strongly reflected in a decline in the degree of phase-locking in the Nogo-N2 range. Deficits in pre-HDs seem to emerge as a consequence of phase-locking-behavioural decoupling. Of clinical interest, declines in the precision of phase-locking depended on the amount of the individual's mutant huntingtin exposure and predicted the probability of disease manifestation in the next five years. This suggests that phase-locking parameters may prove useful in future studies evaluating a possible function as a biomarker in Huntington's disease.

Individual differences in reward-prediction-error: extraversion and feedback-related negativity.

Medial frontal scalp-recorded negativity occurring ∼200-300 ms post-stimulus [known as feedback-related negativity (FRN)] is attenuated following unpredicted reward and potentiated following unpredicted non-reward. This encourages the view that FRN may partly reflect dopaminergic 'reward-prediction-error' signalling. We examined the influence of a putatively dopamine-based personality trait, extraversion (N = 30), and a dopamine-related gene polymorphism, DRD2/ANKK1 (N = 24), on FRN during an associative reward-learning paradigm. FRN was most negative following unpredicted non-reward and least-negative following unpredicted reward. A difference wave contrasting these conditions was significantly more pronounced for extraverted participants than for introverts, with a similar but non-significant trend for participants carrying at least one copy of the A1 allele of the DRD2/ANKK1 gene compared with those without the allele. Extraversion was also significantly higher in A1 allele carriers. Results have broad relevance to neuroscience and personality research concerning reward processing and dopamine function.

First genome-wide association scan on neurophysiological endophenotypes points to trans-regulation effects on SLC2A3 in dyslexic children.

Dyslexia is one of the most common learning disorders affecting about 5% of all school-aged children. It has been shown that event-related potential measurements reveal differences between dyslexic children and age-matched controls. This holds particularly true for mismatch negativity (MMN), which reflects automatic speech deviance processing and is altered in dyslexic children. We performed a whole-genome association analysis in 200 dyslexic children, focusing on MMN measurements. We identified rs4234898, a marker located on chromosome 4q32.1, to be significantly associated with the late MMN component. This association could be replicated in an independent second sample of 186 dyslexic children, reaching genome-wide significance in the combined sample (P = 5.14e-08). We also found an association between the late MMN component and a two-marker haplotype of rs4234898 and rs11100040, one of its neighboring single nucleotide polymorphisms (SNPs). In the combined sample, this marker combination withstands correction for multiple testing (P = 6.71e-08). Both SNPs lie in a region devoid of any protein-coding genes; however, they both show significant association with mRNA-expression levels of SLC2A3 on chromosome 12, the predominant facilitative glucose transporter in neurons. Our results suggest a possible trans-regulation effect on SLC2A3, which might lead to glucose deficits in dyslexic children and could explain their attenuated MMN in passive listening tasks.

Lack of association between the 5-HTTLPR and the error-related negativity (ERN).

The error-related negativity (ERN) is a negative waveform that occurs approximately 50ms after an incorrect response. Pharmacological manipulations and theoretical accounts suggest that the ERN reflects reward-related dopamine activity; however, it is likely that several neurotransmitters contribute to the generation of the ERN. Two studies have found an association between the ERN and the serotonin transporter-linked promoter region (5-HTTLPR) polymorphism. In order to investigate this further, 86 participants performed an arrow version of the flanker task and were genotyped for the 5-HTTLPR and the A/G SNP (rs25531) located within the L allele. Despite using multiple methods to group subjects by genotype and score the ERN, no reliable associations between the ERN and the 5-HTTLPR were found. The current study casts doubt on the relationship between ERN and 5-HTTLPR; reasons for this discrepancy with previous work are discussed.

Catechol-O-methyltransferase Val158Met genotype affects neural correlates of aversive stimuli processing.

It was previously shown that variation of the catechol-O-methyltransferase (COMT) gene modulates brain activity during the processing of stimuli with negative valence, but not for pleasant stimuli. Here, we tested whether the COMT genotype also modulates the electrophysiological correlates of emotional processing and explored whether the environmental factor of life stress influences this effect. Using the early posterior negativity (EPN) paradigm, event-related brain potentials were measured in 81 healthy individuals during the processing of pictures that evoked emotions of positive and negative valence. As was hypothesized, the COMT genotype affected the EPN amplitudes for unpleasant stimuli, but not for pleasant ones. Specifically, Met/Met carriers respond more sensitively to unpleasant stimuli, as compared with Val/Val carriers. We did not find evidence that life stress moderates the effect of the COMT genotype on emotional stimuli processing.

Are auditory P300 and duration MMN heritable and putative endophenotypes of psychotic bipolar disorder? A Maudsley Bipolar Twin and Family Study.

BACKGROUND: Impaired P300 auditory response has been reported in patients with psychotic bipolar disorder (BPD) and unaffected relatives of psychotic bipolar patients. Deficits in mismatch negativity (MMN), however, have not been observed in bipolar patients. To our knowledge, no family study of MMN in BPD has been reported. The current study combined the Maudsley twin and bipolar family samples using genetic model fitting analyses to: (1) assess the relationship between BPD and MMN, (2) substantiate the association between psychotic BPD and P300 variables, (3) verify the genetic overlap of BPD with P300 amplitude previously reported in the twin sample, and (4) examine the shared genetic influences between BPD and bilateral temporal scalp locations of P300 components. METHOD: A total of 301 subjects were included in this study, including 94 twin pairs, 31 bipolar families, and 39 unrelated healthy controls. Statistical analyses were based on structural equation modelling. RESULTS: Both P300 and MMN are heritable, with heritability estimates of 0.58 for MMN, 0.68-0.80 for P300 amplitude, and 0.21-0.56 for P300 latency. The bipolar patients and their relatives showed normal MMN. No significant association, either genetic or environmental, was found with BPD. BPD was significantly associated with reduced P300 amplitude and prolonged latency on midline and bilateral temporal-posterior scalp areas. Shared genetic factors were the main source of these associations. CONCLUSIONS: The results confirm that MMN is not an endophenotype for psychotic BPD whereas P300 amplitude and latency components are valid endophenotypes for psychotic BPD.

The error-related negativity (ERN) and psychopathology: toward an endophenotype.

The ERN is a negative deflection in the event-related potential that peaks approximately 50 ms after the commission of an error. The ERN is thought to reflect early error-processing activity of the anterior cingulate cortex (ACC). First, we review current functional, neurobiological, and developmental data on the ERN. Next, the ERN is discussed in terms of three psychiatric disorders characterized by abnormal response monitoring: anxiety disorders, depression, and substance abuse. These data indicate that increased and decreased error-related brain activity is associated with the internalizing and externalizing dimensions of psychopathology, respectively. Recent data further suggest that abnormal error-processing indexed by the ERN indexes trait- but not state-related symptoms, especially related to anxiety. Overall, these data point to utility of ERN in studying risk for psychiatric disorders, and are discussed in terms of the endophenotype construct.

Influence of MTHFR genotype on contingent negative variation and MRI abnormalities in migraine.

BACKGROUND: The MTHFR C677T genotype has been associated with increased risk of migraine, particularly of migraine with aura (MA) in selected clinical samples and with elevated homocysteine. The hyper-homocysteinemia may favor the vascular and neuronal mechanism underlying migraine, and the risk of stroke. OBJECTIVE: The first aim of the present study was to examine the Contingent Negative Variation (CNV) amplitude and habituation pattern in a migraine sample versus non-migraine subjects, at the light of the MTHFR genotype, according to an unrelated and clinical based case-control panel. The second aim was to compare the frequency of Magnetic Resonance Imaging (MRI) subclinical brain lesions across the different C677 genotypes in the same migraine sample, selected for the young age and the absence of any cardiovascular risk factor. METHODS: One hundred and five 18-45 year old out-patients, 90 affected by migraine without aura (MO) and 15 by MA, and 97 non-migraine healthy subjects, age and sex matched, were selected for the genetic analysis. All subjects had a common ethnic origin from Puglia. Sixty-four migraine subjects and 33 control subjects were submitted to the recording of the CNV. All migraine subjects underwent the MRI evaluation. RESULTS: The frequency of homozygosis was 14.33% in normal subjects, versus 25.7% in MA + MO group (chi2-test: 10.80 P= .001). The frequency of homozygosis in MO patients, was 25.5% (MA versus N: chi2-test: 9 P= .003), in MA group it was 26.6%. Considering the MTHFR genotype in migraine patients and controls, the C677TT subjects exhibited a reduced habituation index of the early CNV (iCNV), in respect with both C677TC and C677CC; in the migraine group, there was a significant decrease of CNV habituation in patients with homozygosis and a positive correlation between the habituation index values and the homocysteine levels. Nineteen migraine patients exhibited subclinical brain lesions (18.05%): patients with C677T homozygosis did not exhibit a higher risk for MRI abnormalities. CONCLUSIONS: This unrelated and clinical based case-control study showed that genetically induced hyper-homocysteinemia may favor the neuronal factors predisposing to migraine, while it does not influence the presence of subclinical vascular brain lesions probably linked with increased risk of stroke.

[Mismatch negativity in schizophrenia research. An indicator of early processing disorders of acoustic information]. / Die Mismatch-Negativität (MMN) in der Schizophrenieforschung. Ein Indikator früher Störungen der akustischen Informationsverarbeitung.

Mismatch negativity (MMN) represents an event-related component of the auditory evoked potentials at about 100-250 ms, evoked by discernible changes in an ongoing uniform acoustic stimulation. The current paper reviews all recently published MMN studies in the field of schizophrenia research. A reduced MMN in schizophrenic patients is found in the majority of the studies. This deficit is likely to be related to the disorder, since antipsychotic medication seems to have little influence on these results. Interestingly, a reduced MMN is also found in first-degree relatives of patients. Clear evidence for a hemispheric lateralization of the MMN reduction in schizophrenic patients is lacking. A hypofunction of the N-methyl-D-aspartate (NMDA) receptor is discussed as a possible explanation of this deficit.

Genetic analysis of IQ, processing speed and stimulus-response incongruency effects.

Psychometric IQ (WAIS-III), onset and peak latency of the lateralized readiness potential (LRP), decision time, and accuracy were assessed during an Eriksen Flanker task in a young (149 families) and in an older (122 families) cohort of twins and their siblings. Stimulus-response incongruency effects were found on all measures of processing speed and accuracy. The effects on the percentages of wrong button presses and too slow (>1,000 ms) responses were larger in the older than in the younger age cohort. Significant heritability was found for processing speed (33-48%), accuracy (41%), and stimulus-response incongruency effects (3-32%). Verbal and performance IQ correlated significantly with stimulus-response incongruency effects on accuracy (-0.22 to -0.39), and this correlation was completely mediated by an underlying set of common genes. It is concluded that measures of the ability to perform well under conditions of stimulus-response incongruency are viable endophenotypes of cognitive ability.

[Role of family in development of neurophysiological manifestations in children with migraine]. / Die Rolle der Familie in der Entstehung neurophysiologischer Auffälligkeiten bei Kindern mit Migräne.

Migraine is a familial disorder. The aim of this study was to compare the relationship between specific neurophysiologic pathogenetic mechanisms of migraine such as abnormal information processing and enhanced cortical excitability on the one hand, and parent-child-interactions and personality traits such as neuroticism and extraversion on the other hand in migraine and healthy families. The correlation and factor analyses demonstrated that the stronger the control over a child and the more intensive the suppression of a child's independence by a parent during a stressful situation in migraine families, the more pronounced the loss of habituation of the contingent negative variation (CNV), and the greater the neuroticism in a migraine child. The CNV amplitude was independent of psychosocial conditions in the family but represented similarities in information processing between parents and their children suffering from migraine. This could be possibly explained by genetic influences on information processing in migraine. In healthy families only the relationship between parameters of parent-child-interaction could be observed. This investigation demonstrates that the neurophysiological disposition to a migraine attack as well as personality traits in migraine could be influenced by psychosocial factors such as parent-child interactions and that different parameters of information processing in headache patients are related to either non-genetic familial conditions (habituation) or functional genetic factors (amplitude).

Slow cortical potentials in migraine families.

Amplitude and habituation of event-related potentials are abnormal in migraine. We investigated 43 migraine and 41 healthy families to evaluate the influences of age, sex and familial contribution on the variance of amplitude and habituation of the contingent negative variation (CNV). Analysis of individual differences in relation to the CNV habituation was performed. The study demonstrated that habituation of the early CNV component characterizes migraine considerably better than the CNV amplitudes. Habituation, however, is strongly influenced by age. Migraine adults and children generally showed reduced habituation. Surprisingly, more than 30% of the healthy adults demonstrated a marked loss of habituation. The reduced CNV habituation represented a high sensitivity but low specificity to migraine, especially in children. CNV amplitude and habituation parameters revealed a considerable familial contribution associated with migraine. No familial influence on either morphology or habituation of the CNV in healthy families or between healthy members of migraine families was observed. The low specificity and familial transmission of CNV parameters in members of migraine families suggest that increased amplitudes and reduced habituation of CNV do not constitute a primary risk factor for migraine, but rather represent a predisposition. Genetic components probably affect variation of the CNV amplitude and habituation.

Mismatch negativity in young children of alcoholics from high-density families.

The mismatch negativity (MMN) component of event-related potentials was recorded from a group of young children of alcoholics (n = 19, 8 females) with a high-density family history of alcoholism and from a control group (n = 23, 12 females), between 8 and 15 years of age. A dichotic listening task was used, and subjects had to pay attention to an oddball paradigm in one ear and ignore the stimuli in the other ear. The event-related potentials elicited by the standard unattended tones were subtracted from those elicited by the infrequent deviant unattended tones, and the MMN was measured at 10 frontal and central electrodes. No group differences were observed in peak latency, peak amplitude, and mean amplitude of the MMN. These results indicated that preattentive mechanisms of mismatch detection were not impaired in young subjects at high risk for alcoholism. Results are discussed in relation to differences in electrophysiological indexes of automatic versus controlled information processing and in relation to the characteristics of the sample.

No electrocortical evidence of automatic mismatch dysfunction in children of alcoholics.

The mismatch negativity (MMN) event-related potential (ERP) component is an automatic, attention-independent brain response to auditory stimulus change, which has been reported to be smaller in alcoholics relative to nonalcoholic controls. To determine whether MMN decrements might be a trait marker of alcoholism that is also present in nonalcoholic individuals at high risk for developing alcoholism, we investigated MMN in 9- to 18-year-old children of alcoholics (n = 20) and control children (n = 20) in three different stimulus conditions using a passive auditory oddball paradigm. There were no statistically significant between-group differences observed in amplitude, scalp topography, and peak latency of MMN. These findings, if replicated, suggest that reported MMN decrements in alcoholics most likely represent a state marker, and not a trait marker, of alcoholism. Also, inasmuch as another ERP component, the P300, is attention-dependent and reported to be smaller in children of alcoholics, the present results implicate that deviations in attentive, but not in automatic, information processing are associated with alcoholism vulnerability.