Annette Conzelmann

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).

ADORA2A Gene variation, caffeine, and emotional processing: a multi-level interaction on startle reflex.

There is converging evidence for genetic, biochemical, and neuropsychological factors to increase the risk for anxiety and anxiety disorders. The pathogenesis of anxiety disorders is assumed to be influenced by a complex interaction of these individual risk factors on several levels, affecting intermediate phenotypes of anxiety such as the startle reflex. Thus, in the present double-blind, placebo-controlled study we attempted to paradigmatically investigate a multi-level pathogenetic model of anxiety by testing the effect of 300 mg caffeine citrate as an antagonist at the adenosine A2A receptor vs placebo on the emotion-potentiated (unpleasant, neutral, and pleasant International Affective Picture System pictures) startle reflex in 110 healthy individuals (male=56, female=54) stratified for the adenosine A2A receptor (ADORA2A) 1976T>C polymorphism (rs5751876). In addition to the expected main effect of picture category (highest startle amplitude for unpleasant, lowest for pleasant pictures) groups across all ADORA2A 1976T>C genotype and intervention (caffeine vs placebo) groups, an interaction effect of genotype, intervention, and picture category was discerned: In ADORA2A 1976TT risk genotype carriers, highest startle magnitudes were observed after caffeine administration in response to unpleasant pictures, with this effect arising particularly from the female subgroup. Our data point to a complex, multi-level, and potentially gender-specific pathogenetic model of anxiety, with genetic and biochemical factors interactively increasing the risk of maladaptive emotional processing and thereby possibly also anxiety disorders. The present findings may eventually aid in improving primary and secondary prevention by sharpening the risk profiles of anxiety-prone individuals.

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.

Methylphenidate normalizes emotional processing in adult patients with attention-deficit/hyperactivity disorder: preliminary findings.

Emotional-motivational dysfunctions may significantly contribute to symptoms of attention-deficit/hyperactivity disorder (ADHD). Hyperactive-impulsive symptoms and sensation seeking could be the result of a search for reinforcers, and cognitive dysfunctions might be due to a low motivational drive. Emotional-motivational dysfunctions could also explain social dysfunctions in ADHD patients because they may lead to misinterpretations of emotional and social clues. Since methylphenidate (MPH) is the first choice as a pharmacological treatment in ADHD, we examined its influence on dysfunctional emotional processes. 13 adult ADHD patients were examined twice, without and after intake of MPH according to their personal medication regimen. The affect-modulated startle paradigm was used to assess physiological (affect-modulated startle response) and subjective (valence and arousal ratings) responses to pleasant, neutral and unpleasant visual stimuli. Healthy controls displayed affective startle modulation as expected, with startle attenuation and potentiation while watching pleasant and unpleasant pictures, respectively. In contrast, unmedicated ADHD patients displayed deficient responses to pleasant stimuli; no startle attenuation during the exposure to pleasant pictures was observed. However, MPH reinstated a normal affective startle modulation, as indicated by attenuation and potentiation associated with pleasant and unpleasant pictures, respectively. Valence and arousal ratings of patients were not affected by MPH. The data suggest that MPH as first choice treatment in ADHD has a positive impact on emotional processes in adult ADHD patients and points to the clinical relevance of emotional-dysfunctions in ADHD.

A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional–motivational reactivity

RationaleThe endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional–motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional–motivational reactivity is complex and bidirectional due to upcoming compensatory processes.ObjectivesTherefore, we further investigated the relationship of the FAAH polymorphism and emotional–motivational reactivity in humans.MethodsWe assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385AC/C carriers and 45 A carriers.ResultsContrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence.ConclusionsOur findings emphasize the bidirectionality and thorough examination of the eCB system’s impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders.

Early Attentional Deficits in an Attention-to-Prepulse Paradigm in ADHD Adults

Adults with attention-deficit/hyperactivity disorder (ADHD) were examined for early and late attentional processes as a function of controlled attention. The test paradigm was the attentional modulation of prepulse inhibition (PPI; early controlled attentional processing) and prepulse facilitation (PPF; late controlled attentional processing). In 49 patients and 49 controls, the authors measured acoustic startle responses to 96-dB startle pulses preceded 120, 240 (for PPI), 2,000, and 4,500 (for PPF) ms by a 68-dB prepulse noise. Geometric figures signaled that prepulses were to be ignored or attended to (automatic vs. controlled attention). ADHD patients exhibited deficits in prepulse modulation, but these reflected an interaction of controlled attention and time of information processing. Normal PPI and PPF occurred under all conditions except for controlled attentional modulation of PPI. Attention deficits in ADHD patients may reflect not general derangements in information processing or ability to attend but, rather, selective disturbances of controlled attention during early information processing.

Effects of ADORA2A gene variation and caffeine on prepulse inhibition: A multi-level risk model of anxiety

The complex pathogenesis of anxiety and panic disorder in particular has been suggested to be influenced by genetic factors such as the adenosine A2A receptor gene (ADORA2A) 1976T>C polymorphism (rs5751876) as well as neuropsychological factors such as early information processing deficits. In 114 healthy individuals (males=57, females=57) controlled for anxiety sensitivity (AS), a multi-level risk model of the development of anxiety was applied: Genetic (ADORA2A 1976T>C variant) and biochemical (300 mg of caffeine citrate vs. placebo) factors were hypothesized to influence early information processing as measured by the prepulse inhibition/facilitation paradigm (stimulus onset asynchronies (SOAs) of 60, 120, 240, 480 and 2000ms between prepulses and startle stimuli). A fourfold interaction of genotype, intervention, gender, and SOAs was discerned. Stratification by SOAs revealed that at 120 ms and 240 ms SOAs in the caffeine condition, PPI was impaired in female ADORA2A 1976TT risk genotype carriers as compared to male ADORA2A 1976TT homozygotes, while no significant effects were observed in the ADORA2A 1976CC/CT non-risk genotype or placebo group. Only in high anxiety sensitive probands, a significant intervention effect was discerned with impaired prepulse facilitation (PPF) due to caffeine. The present results point to an impaired ability to selectively process very early information and to gate irrelevant sensory information, respectively, in female ADORA2A 1976TT homozygotes in response to caffeine, providing further evidence for the adenosinergic system to be involved in the pathogenesis of anxiety.

Autonomic hypoactivity in boys with attention-deficit/hyperactivity disorder and the influence of methylphenidate

Abstract Objectives. This study investigates an overall autonomic hypoactivity reflecting hypoarousal as important aetiological factor in ADHD at baseline during rest and in response towards stimuli. In addition, effects of methylphenidate (MPH) are examined. We further assessed whether this hypoarousal is a stable characteristic or ameliorated by arousing emotional stimuli. Methods. Boys with ADHD were examined with (n = 35) or without MPH (n = 45) and compared with healthy boys (n = 22) regarding skin conductance level (SCL) during rest and skin conductance responses (SCRs) as well as valence and arousal ratings in response to positive, neutral, and negative pictures. Results. ADHD children without MPH were characterized by reduced baseline SCL and overall reduced SCRs. ADHD children with MPH never differed from control children. All groups displayed normal valence and arousal ratings of the stimuli and enhanced SCRs to emotional in comparison to neutral pictures. Conclusions. This is the first study to unravel (1) a general autonomic hypoactivity in ADHD children at baseline and in response to low arousing neutral and highly arousing emotional stimuli, and (2) hints that MPH normalizes this hypoactivity. Results contribute to the understanding of ADHD aetiology and MPH functionality, and are consistent with the cognitive-energetic model of ADHD.