Do blood plasma levels of oxytocin moderate the effect of nasally administered oxytocin on social orienting in high-functioning male adults with autism spectrum disorder?

OBJECTIVE: The study investigated whether baseline plasma oxytocin (OXT) concentrations might moderate the effects of nasally administered OXT on social orienting. METHODS: Thirty-one males with Autism spectrum disorder (ASD) and thirty healthy males participated in a double-blind placebo-controlled crossover trial. After administration of the compound, participants were viewing pictures from the International Affective Picture System that represented a systematic variation of pleasant, unpleasant and neutral scenes with and without humans. The outcome measures were a cardiac evoked response (ECR) and a cortical evoked long latency parietal positivity (LPP). RESULTS: Males with ASD had significantly higher plasma baseline levels than the controls. In the absence of general treatment effects, higher baseline concentrations were found to be associated with larger treatment effects, particularly in the group of males with ASD. Higher post-treatment plasma OXT concentrations were found to be associated with smaller treatment effects and larger orienting responses in the placebo situation in the group of controls. CONCLUSIONS: We interpret our findings as suggesting that it is the central availability of OXT determining how much of the nasally administered OXT will become centrally absorbed and how much of it will become released into the bloodstream.

Oxytocin microinjected into the central amygdaloid nuclei exerts anti-aggressive effects in male rats.

We recently demonstrated that acute and chronic intracerebroventricular enhancement of brain OXT levels induces potent anti-aggressive and pro-social explorative effects during social challenges. However, the exact anatomical location in the brain where OXT exerts its action is still elusive. In the present study, we targeted two critical brain areas, i.e. the central amygdala (CeA) and the dorsal raphe (DR), both containing high levels of OXT receptors (OXTRs) and constituting important nodes of the neural circuitry related to aggression. Behavioral effects of local micro-infusion of OXT and OXTR antagonist, L368.899, (alone and combined) were evaluated in resident male rats during confrontations with an unfamiliar male intruder. Our results show that OXT microinjected into the CeA markedly reduced resident's offensive behavior and facilitated social exploration, without affecting other non-aggressive behaviors. The receptor specificity of the behavioral effects was verified when a micro-infusion of a selective OXTR antagonist nullified the changes. Pharmacological blockade of CeA OXTRs per se was without clear behavioral effects suggesting that endogenous OXT within the CeA does not play a major inhibitory role on offensiveness. Anatomical specificity was also supported by the absence of relevant behavioral effects when OXT was microinjected into more medial sub-regions of the amygdala. Likewise, within the DR neither OXT nor OXTR exerted significant effects on offensive aggression, while microinjection of the 5-HT1A autoreceptor agonist in this region significantly suppressed aggression. In conclusion, our results point at the CeA as an important brain site of action for the anti-aggressive and pro-social explorative effects induced by exogenous enhancement of brain OXT levels.

Acute and repeated intranasal oxytocin administration exerts anti-aggressive and pro-affiliative effects in male rats.

Socio-emotional deficits and impulsive/aggressive outbursts are prevalent symptoms of many neuropsychiatric disorders, and intranasal administration of oxytocin (OXT) is emerging as a putative novel therapeutic approach to curb these problems. Recently, we demonstrated potent anti-aggressive and pro-social effects of intracerebroventricular (icv) OXT administration in male rats. The present study tested whether similar behavioral effects are induced when OXT is delivered intranasally. Heart-rate and blood-pressure responses were telemetrically monitored to investigate whether peripheral physiological effects were provoked after intranasal OXT administration. Intranasal OXT administration in resident animals reduced offensive aggression and increased social exploration toward an unfamiliar male intruder. Using a partner-preference test, intranasal OXT also strengthened the bonding between the male resident and its female partner. No changes in cardiovascular (re)activity were found, indicating an absence of direct peripheral physiological effects after intranasal OXT treatment. In conclusion, although the precise route and mechanisms of nose-to-brain transport/communication remain to be elucidated, our data demonstrated intranasal OXT to be an effective application method for suppressing intermale aggression and enhancing social affiliation.

Sex differences in orienting to pictures with and without humans: evidence from the cardiac evoked response (ECR) and the cortical long latency parietal positivity (LPP).

OBJECTIVE: This study investigated the effect of social relevance in affective pictures on two orienting responses, i.e. the evoked cardiac response (ECR), and a long latency cortical evoked potential (LPP) and whether this effect would differ between males and females. Assuming that orienting to affective social information is fundamental to experiencing affective empathy, associations between self-report measures of empathy and the two orienting responses were investigated. METHOD: ECRs were obtained from 34 female and 30 male students, and LPPs from 25 female and 27 male students viewing 414 pictures from the International Affective Picture System. Pictures portrayed pleasant, unpleasant and neutral scenes with and without humans. RESULTS: Both the ECR and LPP showed the largest response to pictures with humans in unpleasant situations. For both measures, the responses to pictures with humans correlated with self-report measures of empathy. While we found a greater male than female responsiveness to the pictures without humans in the ECR, a greater female than male responsiveness was observed in the LPP response to pictures with humans. CONCLUSION AND SIGNIFICANCE: The sensitivity of these orienting responses to social relevance and their differential contribution to the prediction of individual differences underline the validity of their combined use in clinical studies investigating individuals with social disabilities.

Chronic enhancement of brain oxytocin levels causes enduring anti-aggressive and pro-social explorative behavioral effects in male rats.

Oxytocin (OXT) has been implicated in the regulation of social behaviors, including intermale offensive aggression. Recently, we showed that acute enhancement of brain OXT levels markedly suppressed offensive aggression and increased social exploration in resident rats confronted with an intruder in their home territory. Moreover, a different responsivity to the exogenous OXTergic manipulation was observed among individuals based on their baseline aggression. In this study we aimed at evaluating the behavioral response to chronically enhancing or attenuating central OXT levels, and at scrutinizing whether the trait-aggression moderates the treatment-induced behavioral changes. To this end, resident male wild-type Groningen rats were continuously (via osmotic minipumps) intracerebroventricularly infused with synthetic OXT or a selective OXT receptor (OXTR) antagonist for 7days. Changes in behavior were assessed performing a resident-intruder test before and at the end of the treatment period, as well as after 7days of withdrawal. Chronic infusion of OXT was found to selectively suppress aggression and enhance social exploration. Chronic blockage of OXTRs instead increased introductory aggressive behavior (i.e. lateral threat), yet without affecting the total duration of the aggression. The magnitude of the anti-aggressive changes correlated positively with the level of baseline aggression. Interestingly, OXT-induced behavioral changes persisted 7days after cessation of the treatment. In conclusion, these findings provide further evidence that enhanced functional activity of the central OXTergic system decreases social offensive aggression while it increases social explorative behavior. The data also indicate that chronically enhancing brain OXT levels may cause enduring anti-aggressive and pro-social explorative behavioral effects.

Local oxytocin expression and oxytocin receptor binding in the male rat brain is associated with aggressiveness.

We recently demonstrated in male wild-type Groningen rats that enhancing brain oxytocin (OXT) levels acutely produces marked pro-social explorative and anti-aggressive effects. Moreover, these pharmacologically-induced changes are moderated by the individual's aggressive phenotype, suggesting an inverse relationship between aggressiveness and tonic endogenous OXT signaling properties. Aim of the present study was to verify the hypothesis that variations in OXT expression and/or OXT receptor (OXTR) binding in selected brain regions are associated with different levels or forms of aggression. To this end, male resident wild-type Groningen rats that repeatedly contested and dominated intruder conspecifics were categorized as being low aggressive, highly aggressive or excessively aggressive. Their brains were subsequently collected and quantified for OXT mRNA expression and OXTR binding levels. Our results showed that OXT mRNA expression in the hypothalamic paraventricular nucleus (PVN), but not in the supraoptic nucleus (SON), negatively correlates with the level of offensiveness. In particular, the excessively aggressive group showed a significantly lower OXT mRNA expression in the PVN as compared to both low and highly aggressive groups. Further, the excessively aggressive animals showed the highest OXTR binding in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST). These findings demonstrate that male rats with excessively high levels and abnormal forms of aggressive behavior have diminished OXT transcription and enhanced OXTR binding capacities in specific nodes of the social behavioral brain circuitry.

Processing of continuously provided punishment and reward in children with ADHD and the modulating effects of stimulant medication: an ERP study.

OBJECTIVES: Current models of ADHD suggest abnormal reward and punishment sensitivity, but the exact mechanisms are unclear. This study aims to investigate effects of continuous reward and punishment on the processing of performance feedback in children with ADHD and the modulating effects of stimulant medication. METHODS: 15 Methylphenidate (Mph)-treated and 15 Mph-free children of the ADHD-combined type and 17 control children performed a selective attention task with three feedback conditions: no-feedback, gain and loss. Event Related Potentials (ERPs) time-locked to feedback and errors were computed. RESULTS: All groups performed more accurately with gain and loss than without feedback. Feedback-related ERPs demonstrated no group differences in the feedback P2, but an enhanced late positive potential (LPP) to feedback stimuli (both gains and losses) for Mph-free children with ADHD compared to controls. Feedback-related ERPs in Mph-treated children with ADHD were similar to controls. Correlational analyses in the ADHD groups revealed that the severity of inattention problems correlated negatively with the feedback P2 amplitude and positively with the LPP to losses and omitted gains. CONCLUSIONS: The early selective attention for rewarding and punishing feedback was relatively intact in children with ADHD, but the late feedback processing was deviant (increased feedback LPP). This may explain the often observed positive effects of continuous reinforcement on performance and behaviour in children with ADHD. However, these group findings cannot be generalised to all individuals with the ADHD, because the feedback-related ERPs were associated with the severity of the inattention problems. Children with ADHD-combined type with more inattention problems showed both deviant early attentional selection of feedback stimuli, and deviant late processing of non-reward and punishment.

Antiaggressive activity of central oxytocin in male rats.

RATIONALE: A substantial body of research suggests that the neuropeptide oxytocin promotes social affiliative behaviors in a wide range of animals including humans. However, its antiaggressive action has not been unequivocally demonstrated in male laboratory rodents. OBJECTIVE: Our primary goal was to examine the putative serenic effect of oxytocin in a feral strain (wild type Groningen, WTG) of rats that generally show a much broader variation and higher levels of intermale aggression than commonly used laboratory strains of rats. METHODS: Resident animals were intracerebroventricularly (icv) administered with different doses of synthetic oxytocin and oxytocin receptor antagonist, alone and in combination, in order to manipulate brain oxytocin functioning and to assess their behavioral response to an intruder. RESULTS: Our data clearly demonstrate that acute icv administered oxytocin produces dose-dependent and receptor-selective changes in social behavior, reducing aggression and potentiating social exploration. These antiaggressive effects are stronger in the more offensive rats. On the other hand, administration of an oxytocin receptor antagonist tends to increase (nonsignificantly) aggression only in low-medium aggressive animals. CONCLUSIONS: These results suggest that transiently enhancing brain oxytocin function has potent antiaggressive effects, whereas its attenuation tends to enhance aggressiveness. In addition, a possible inverse relationship between trait aggression and endogenous oxytocinergic signaling is revealed. Overall, this study emphasizes the importance of brain oxytocinergic signaling for regulating intermale offensive aggression. This study supports the suggestion that oxytocin receptor agonists could clinically be useful for curbing heightened aggression seen in a range of neuropsychiatric disorders like antisocial personality disorder, autism, and addiction.

Baroreflex sensitivity during rest and executive functioning in attention-deficit/hyperactivity disorder. The TRAILS study.

Children with attention-deficit/hyperactivity disorder (ADHD) often show executive function (EF) problems and neurophysiological hypoarousal. Baroreceptor activation, as part of the baroreflex short-term blood pressure regulatory mechanism, has been linked to cortical inhibition and attenuated cognitive-attentional functioning. We investigated the hypothesis that higher resting baroreflex sensitivity (BRS) predicts poorer EF performance in children with ADHD. EF measures of speed and accuracy were regressed upon resting BRS in 10-12-year-old children with ADHD from a clinic-referred sample (n=181) and healthy (n=194) and clinic-referred (n=260) comparison samples. Resting BRS was positively associated with poorer EF performance (e.g., response variability, working memory, response inhibition), especially in ADHD combined type, boys, and unmedicated children. Comparison samples partly suggested negative associations. We conclude that higher resting BRS is related to poorer cognitive performance in children with ADHD. Findings suggest afferent influences of the body's visceral state on higher-order cognitive functioning and imply energetic state dysregulation in ADHD.

Time-of-day effects on cognition in preadolescents: a trails study.

Cognitive performance fluctuates during the day due to diurnal variations in alertness level. This study examined: (1) whether cognitive performance in school-aged children is affected by time-of-day; (2) which functional domains are particularly vulnerable to time-of-day effects; and (3) whether the effects are more pronounced for cognitively more demanding tasks or task conditions. Children, aged 10-12 yrs, were randomly assigned to a test session starting either at 08:30 (n = 802), 10:00 (n = 713), or 13:00 h (n = 652). Speed and accuracy of information processing were evaluated by tasks that assess input-related cognitive processes (e.g., stimulus encoding), central cognitive processes (e.g., working memory, sustained attention), and output-related processes (e.g., response organization) using the Amsterdam Neuropsychological Tasks program. Time-of-day effects in children were identified in specific neurocognitive domains, such as visuospatial processing and working memory, but only under cognitively more demanding task conditions. Sustained attention showed a speed-accuracy tradeoff with increased slowness and lapses in the early morning, but with better feedback responsiveness and perceptual sensitivity than in the early afternoon. Furthermore, there was a significant interaction of time-on-task with time-of-day for tempo, with the afternoon group increasing in tempo with time-on-task, and the early-morning group first showing a slowing of tempo with time-on-task, followed at the end of the task by a speed increase towards the initial levels. To conclude, the authors found time-of-day effects in preadolescents, which were confined to cognitively more demanding tasks tapping input-related and central cognitive processes.

Information processing differences and similarities in adults with dyslexia and adults with Attention Deficit Hyperactivity Disorder during a Continuous Performance Test: a study of cortical potentials.

Twenty male adults with ADHD, 16 dyslexic adults, 15 comorbid adults, and 16 normal controls were compared on performance and underlying brain responses, during a cued Continuous Performance Test (O-X CPT), with the aim of discovering features of information processing differentiating between the groups. The study evaluated both cue- and target-related processes by analysing performance measures (errors, reaction time, and variability of reaction time), and event-related potentials (ERPs). Cue-related ERP components included the Cue-N2, Cue-P3, contingent negative variation (CNV) consisting of the CNV1, related to cue orienting, and the CNV2, related to response preparation. For targets, a distinction was made between response-related (Go), and inhibitory (Nogo) processing. Target-related components included the Go-P3, Nogo-N2, and Nogo-P3. Performance deficits were found only for the ADHD group, who demonstrated a faster decline in response speed with time-on-task and greater overall within-subject variability. No group differences were found for cue-related ERP components. Yet, controlling for group differences in internalising problems, inhibitory control was reduced in all clinical groups compared to controls, as demonstrated by an absence of frontal amplification of P3 in the Nogo condition, relative to the Go condition. For the ADHD group, in contrast to the comorbid and the dyslexic group, this effect remained after controlling for externalising symptoms, indicating that only for the ADHD group deficiencies in inhibitory control were not explained by externalising behaviour.

Reproducibility of heart rate variability and baroreflex sensitivity measurements in children.

Despite their extensive use, the reproducibility of cardiac autonomic measurements in children is not well-known. We investigated the reproducibility of short-term continuous measurements of heart rate (HR), heart rate variability (HRV, time and frequency domain), and spontaneous baroreflex sensitivity (BRS, frequency domain) in the supine and standing position in 57 children (11.2+/-0.7 years, 52.6% boys). Reproducibility between two sessions within a two-week interval was evaluated by intraclass correlation coefficients (ICCs), standard error of measurement, coefficients of variation (CVs), limits of agreement, and Bland-Altman plots. HR and HRV were moderately-to-highly (ICC=.63-.79; CV=5.7%-9.7%) and BRS moderately (ICC=.49-.63; CV=11.4%-14.0%) reproducible. While the BRS measurements were slightly less reproducible than the HR and HRV measurements, all can be reliably applied in research, thus implicating sufficient capacity to detect real differences between children. Still, clinical studies focusing on individual changes in cardiac autonomic functioning need to address the considerable random variations that may occur between test-retest measurements.

Variants of the SLC6A3 (DAT1) polymorphism affect performance monitoring-related cortical evoked potentials that are associated with ADHD.

Although the 10-repeat (10R) variant of the dopamine transporter gene (DAT1 or SLC6A3) is suggested to be a risk allele for Attention Deficit Hyperactivity Disorder (ADHD) no relationships between DAT1 and measures of cognition in children with ADHD have yet been demonstrated. We studied neurophysiological correlates of performance monitoring during a feedback-based learning task by measuring cortical event-related potentials (ERPs) in a group of 65 10-13-year-old children half of whom were diagnosed as ADHD. The first part of the study investigates correlations between parent-reported behaviour problems and several performance monitoring components, while the second part investigates the relationship between DAT1 and these components. Specifically ADHD problems correlated significantly with an error-related positivity (Pe) and a feedback-anticipatory negativity (the SPN). Only these two components discriminated between the DAT1 10/10R and 9R carriers. The 10/10R carriers showed a smaller Pe to errors and a smaller SPN in anticipation of negative feedback, particularly with learning.

Reduced interhemispheric coherence in dyslexic adults.

INTRODUCTION: Developmental dyslexia has been associated with reduced interhemispheric neural connectivity in children. The present study investigated functional interhemispheric connectivity in male dyslexic adults. METHODS: A group of 19 dyslexic men were compared to a group of 15 controls on interhemispheric coherence of the dominant frequency in the power spectrum during a visuo-spatial attention task. The coherence between a left hemisphere central-parietal electrode and the respective right hemisphere electrode and surrounding sites was analysed. RESULTS: Compared to controls, the dyslexic group demonstrated reduced, and more diffuse, interhemispheric coherence of alpha activity in the central-parietal cortex. No group differences in interhemispheric coherence were found on frontal, temporal or central sites. CONCLUSIONS: The deviant pattern of functional connectivity in dyslexics is suggestive of an altered development of neural circuitry that may lead to deficits in magnocellular processing.

Methylphenidate improves diminished error and feedback sensitivity in ADHD: An evoked heart rate analysis.

Attention Deficit Hyperactivity Disorder (ADHD) is a developmental disorder that has previously been related to a decreased sensitivity to errors and feedback. Supplementary to the traditional performance measures, this study uses autonomic measures to study this decreased sensitivity in ADHD and the modulating effects of medication. Children with ADHD, on and off Methylphenidate (Mph), and typically developing (TD) children performed a selective attention task with three feedback conditions: reward, punishment and no feedback. Evoked Heart Rate (EHR) responses were computed for correct and error trials. All groups performed more efficiently with performance feedback than without. EHR analyses, however, showed that enhanced EHR decelerations on error trials seen in TD children, were absent in the medication-free ADHD group for all feedback conditions. The Mph-treated ADHD group showed 'normalised' EHR decelerations to errors and error feedback, depending on the feedback condition. This study provides further evidence for a decreased physiological responsiveness to errors and error feedback in children with ADHD and for a modulating effect of Mph.

Differential effects of 5-HTTLPR and DRD2/ANKK1 polymorphisms on electrocortical measures of error and feedback processing in children.

OBJECTIVE: Applying a probabilistic learning task we examined the influence of functional polymorphisms of the serotonin transporter gene (5-HTTLPR) and the D2 dopamine receptor gene (DRD2/ANKK1) on error and feedback processing by measuring electrocortical event-related potentials (ERPs) in 10- to 12-year-old children. METHODS: Three pairwise group comparisons were conducted on four distinguishable ERP components, two of which were response-related, the other two feedback-related. RESULTS: Our ERP data revealed that children carrying the short (S) variant of the 5-HTTLPR gene process their errors more intensively while exhibiting less habituation to negative feedback with task progression compared to children who are homozygous for the 5-HTTLPR long (L) variant. Children possessing the Taq1 A variant of the DRD2 gene showed greater sensitivity to negative feedback and, as opposed to Taq1 A non-carriers, a diminishing sensitivity to positive feedback with task progression. Regarding error processing, children possessing both the S variant of the 5-HTTLPR and the Taq1 A allele of the DRD2 gene showed a picture quite similar to that of the 5-HTTLPR S carriers and regarding feedback processing quite similar to that of the DRD2 Taq1 A carriers. CONCLUSIONS: Our findings support the hypotheses that the 5-HTTLPR S allele may predispose to (performance) anxiety, while DRD2 Taq1 A allele may predispose to the reward deficiency syndrome. SIGNIFICANCE: The results may further enhance our understanding of known associations between these polymorphisms and psychopathology.

Do children with ADHD and/or PDD-NOS differ in reactivity of alpha/theta ERD/ERS to manipulations of cognitive load and stimulus relevance?

OBJECTIVE: We examined whether the method of event-related (de-)synchronization (ERD/ERS) revealed differential effects of selective attention and working memory load in children (8-11 years) with pervasive developmental disorder - not otherwise specified (PDD-NOS) or attention-deficit/hyperactivity disorder (ADHD). METHODS: Fifteen healthy controls and three equally large groups of children with symptoms of PDD-NOS, ADHD or both (PDD/HD) performed a visual selective memory search task. The EEG was recorded from which occipital alpha and frontal theta were derived. RESULTS: The effects of the overall task manipulations of task load, relevance and target/nontarget were clearly present in the overall analyses of alpha and theta ERD/ERS. However, no significant differences with respect to these manipulations existed between any of the subject groups. CONCLUSIONS: The results supply no evidence for a distinction in information processing abilities of selective attention and working memory as reflected by alpha and theta ERD/ERS between children diagnosed with either ADHD, PDD-NOS or healthy controls. SIGNIFICANCE: Alpha and theta ERD/ERS are sensitive to manipulations of task load, relevance and target/nontarget, but supply no additional information on possible group differences in comparison to the more frequently used method of event-related potentials.