Methylphenidate and emotional-motivational processing in attention-deficit/hyperactivity disorder.

In line with the assumption that emotional-motivational deficits are one core dysfunction in ADHD, in one of our previous studies we observed a reduced reactivity towards pleasant pictures in adult ADHD patients as compared to controls. This was indicated by a lack of attenuation of the startle reflex specifically during pleasant pictures in ADHD patients. The first choice medical agents in ADHD, methylphenidate (MPH), is discussed to normalize these dysfunctions. However, experimental evidence in the sense of double-blind placebo-controlled study designs is lacking. Therefore, we investigated 61 adult ADHD patients twice, one time with placebo and one time with MPH with the same experimental design as in our study previously and assessed emotion processing during the presentation of pleasant, neutral and unpleasant pictures. We obtained startle reflex data as well as valence and arousal ratings in association with the pictures. As previously shown, ADHD patients showed a diminished startle attenuation during pleasant pictures while startle potentiation during unpleasant pictures was normal. Valence and arousal ratings unsuspiciously increased with increasing pleasantness and arousal of the pictures, respectively. There were no significant influences of MPH. The study replicates that ADHD patients show a reduced reactivity towards pleasant stimuli. MPH did not normalize this dysfunction. Possibly, MPH only influences emotions during more complex behavioural tasks that involve executive functions in adults with ADHD. Our results emphasize the importance for the use of double-blind placebo-controlled designs in psychopharmacological research.

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

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.

Neural responses to smoking stimuli are influenced by smokers' attitudes towards their own smoking behaviour.

An important feature of addiction is the high drug craving that may promote the continuation of consumption. Environmental stimuli classically conditioned to drug-intake have a strong motivational power for addicts and can elicit craving. However, addicts differ in the attitudes towards their own consumption behavior: some are content with drug taking (consonant users) whereas others are discontent (dissonant users). Such differences may be important for clinical practice because the experience of dissonance might enhance the likelihood to consider treatment. This fMRI study investigated in smokers whether these different attitudes influence subjective and neural responses to smoking stimuli. Based on self-characterization, smokers were divided into consonant and dissonant smokers. These two groups were presented smoking stimuli and neutral stimuli. Former studies have suggested differences in the impact of smoking stimuli depending on the temporal stage of the smoking ritual they are associated with. Therefore, we used stimuli associated with the beginning (BEGIN-smoking-stimuli) and stimuli associated with the terminal stage (END-smoking-stimuli) of the smoking ritual as distinct stimulus categories. Stimulus ratings did not differ between both groups. Brain data showed that BEGIN-smoking-stimuli led to enhanced mesolimbic responses (amygdala, hippocampus, insula) in dissonant compared to consonant smokers. In response to END-smoking-stimuli, dissonant smokers showed reduced mesocortical responses (orbitofrontal cortex, subcallosal cortex) compared to consonant smokers. These results suggest that smoking stimuli with a high incentive value (BEGIN-smoking-stimuli) are more appetitive for dissonant than consonant smokers at least on the neural level. To the contrary, smoking stimuli with low incentive value (END-smoking-stimuli) seem to be less appetitive for dissonant smokers than consonant smokers. These differences might be one reason why dissonant smokers experience difficulties in translating their attitudes into an actual behavior change.

An early attentional bias to BEGIN-stimuli of the smoking ritual is accompanied with mesocorticolimbic deactivations in smokers.

RATIONALE: Biased processing of drug-associated stimuli is believed to be a crucial feature of addiction. Particularly, an attentional bias seems to contribute to the disorder's maintenance. Recent studies suggest differential effects for stimuli associated with the beginning (BEGIN-smoking-stimuli) or the terminal stage of the smoking ritual (END-smoking-stimuli), with the former but not the later evoking high cue-reactivity. OBJECTIVE: The current study investigated the neuronal network underlying an attentional bias to BEGIN-smoking-stimuli and END-smoking-stimuli in smokers and tested the hypothesis that the attentional bias is greater for BEGIN-smoking-stimuli. METHODS: Sixteen non-deprived smokers and 16 non-smoking controls participated in an fMRI study. Drug pictures (BEGIN-smoking-stimuli, END-smoking-stimuli) and control pictures were overlaid with geometrical figures and presented for 300 ms. Subjects had to identify picture content (identification-task) or figure orientation (distraction-task). The distraction-task was intended to demonstrate attentional bias. RESULTS: Behavioral data revealed an attentional bias to BEGIN-smoking-stimuli but not to END-smoking-stimuli in both groups. However, only smokers showed mesocorticolimbic deactivations in the distraction-task with BEGIN-smoking-stimuli. Importantly, these deactivations were significantly stronger for BEGIN- than for END-smoking-stimuli and correlated with the attentional bias score. CONCLUSIONS: Several explanations may account for missing group differences in behavioral data. Brain data suggest smokers using regulatory strategies in response to BEGIN-smoking-stimuli to prevent the elicitation of motivational responses interfering with distraction-task performance. These strategies could be reflected in the observed deactivations and might lead to a performance level in smokers that is similar to that of non-smokers.

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.

Conditioned cues for smoking elicit preparatory responses in healthy smokers.

RATIONALE: Smoking cues are theorized to be conditioned stimuli (CSs) formed by repeated pairing with drug. Smoking paraphernalia can elicit subjective and physiological responses in smokers, indicative of positive affect and motivation to consume. Although these responses are probably the result of conditioning, direct evidence from human conditioning studies with physiological measures of motivational valence is rare. OBJECTIVE: The present study investigated the motivational properties of experimentally conditioned cues for smoking. METHODS: Thirty-nine smokers completed a differential conditioning protocol. Abstract pictures were used as CSs and single puffs on a cigarette as unconditioned stimulus (US). Skin conductance responses and facial electromyography of the zygomatic, corrugator, and orbicularis oris muscles were measured during conditioning. RESULTS: The conditioned cue for smoking (CS+) elicited stronger skin conductance responses and more activity of the zygomatic and orbicularis oris muscles than the CS-. CONCLUSIONS: These results support the notion that through pairing with smoking, neutral stimuli acquire the ability to elicit preparatory physiological responses, which are assumed to play an important role in the maintenance of addiction and relapse in the natural environment.

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.

Neural responses to BEGIN- and END-stimuli of the smoking ritual in nonsmokers, nondeprived smokers, and deprived smokers.

Drug-associated stimuli (cues) have a prominent role in addiction research because they are able to provoke craving and relapses. Generally, drug cues are seen as conditioned excitatory stimuli, which elicit drug seeking and usage. However, newer data suggest differential effects for smoking stimuli depending on their stage in the smoking ritual. Specifically, stimuli associated with the terminal stage of smoke consumption (END-stimuli) may evoke reactivity opposite to the reactivity evoked by stimuli associated with the beginning of smoke consumption (BEGIN-stimuli). This fMRI study compared 20 nondeprived smokers with 20 nonsmokers to unravel the influence of smoking-related pictures displaying the beginning (BEGIN-stimuli) and termination (END-stimuli) of the smoking ritual on neural activity in the addiction network. In addition, 20 deprived smokers (12 h deprivation) were investigated to explore the effects of deprivation on the processing of these stimuli. In nondeprived smokers, BEGIN-stimuli reliably activated the addiction network (for example, the ventral striatum, orbitofrontal cortex, and anterior cingulate cortex (ACC)). In contrast, END-stimuli triggered a differential pattern of activations as well as deactivations; deactivations were found in the ventral striatum and the ACC. Deprivation had no clear effect on the responses triggered by BEGIN-stimuli, but affected the reactivity to END-stimuli. Our data clearly suggest that stimuli associated with different stages of the smoking ritual trigger differential neuronal responses. While BEGIN-stimuli generally seem to activate the addiction network, END-stimuli presumably have some inhibitory properties. This new finding might add to a more differentiated understanding of cue reactivity and addiction.

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.

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).

Smoking stimuli from the terminal phase of cigarette consumption may not be cues for smoking in healthy smokers.

BACKGROUND: Stimuli from the terminal phase of smoke or drug intake are paired with drug effect but have surprisingly low cue reactivity. Smoking terminal stimuli were compared to cues under conditions of different perceived smoke intake to probe whether (1) terminal stimuli are only weak cues, (2) any effect is an artifact of rigid test conditions, and (3) terminal stimuli have a unique function during the intake ritual. MATERIALS AND METHODS: Nonabstinent, healthy smokers were tested in three experiments with one-session, within-subject cue reactivity tests. Smoking terminal stimuli and cues were compared using pictures depicting events after completion (END) and before start of smoke inhalation (BEGIN). Test pictures were presented alone and in combination with no-go symbols (from no-smoking signs) or with extra cues to decrease and to increase perceived smoke availability, respectively. Measured were subjective effects and affect modulation of the startle reflex. RESULTS: END stimuli relative to BEGIN stimuli evoked less subjective craving and pleasure but more arousal. A no-go stimulus, which reduced reports of intention to smoke, reduced the reactivity to BEGIN but only marginally affected responses to END stimuli. This was confirmed with different sets of test pictures and using tests with the startle response. An extra cue did not affect reactivity to a BEGIN stimulus but increased craving and pleasure to the END stimulus, although not to the level of BEGIN stimuli alone. CONCLUSIONS: This first systematic study of terminal stimuli found their effects to be robust and have test generality. They are probably not weak cues but evoke reactivity, which may oppose reactivity of cues. They may signal poor availability of drug. Methodological, clinical, and theoretical implications were noted.

Electromyographic activity of the lip muscle as a measure of puffing on a cigarette.

The electromyographic activity (EMG) of the upper lip muscle (m. orbicularis oris) during sucking on a cigarette was examined as a potential new measure of smoking behaviour. This parameter was examined under conditions of actual smoking, sham smoking and sucking on a straw. We applied psychophysical procedures (methods of magnitude production), normal and paced smoking, two conventional means to confirm puffing (video recording and changes in air pressure in a cigarette holder) on different groups of smokers (heavy and light). The data revealed that lip-EMG is a valid and reliable means to quantify sucking on a cigarette in a variety of situations common to the study of smoking. It was concluded that lip-EMG may be a sensitive and selective measure of motor activity associated with smoking. The lip-EMG may also be applied together with hand activity and breathing to identify individual puffing, particularly in heavy smokers and during actual smoking. Discussed were several applications of this method to the study of smoking and other motivated behaviour such as consumption of water and palatable fluids.

Pavlovian conditioning of opioid and nonopioid pain inhibitory mechanisms in humans.

Learning processes such as respondent or Pavlovian conditioning are believed to play an important role in the development of chronic pain, however, their influence on the inhibition of pain has so far not been assessed in humans. The purpose of this study was the demonstration of Pavlovian conditioning of stress-induced analgesia in humans and the determination of its opioid mediation. In a differential classical conditioning paradigm two different auditory stimuli served as conditioned stimuli and mental arithmetic plus white noise as unconditioned stimulus. Subsequent to four conditioning trials naloxone or placebo was applied in a double-blind fashion on two test days. Both pain threshold and pain tolerance showed conditioned stress-induced analgesia. Pain tolerance was affected by naloxone whereas pain threshold was not. The data of this study show that stress analgesia can be conditioned in humans and that it is at least partially mediated by the endogenous opioid system. Learning processes also influence pain inhibitory processes in humans and this effect might play a role in the development of chronic pain.