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Catecholamines in Attention-Deficit Hyperactivity Disorder: Current Perspectives
Abstract
To provide an update on the "catecholamine hypothesis" of attention-deficit hyperactivity disorder (ADHD).
Recent work examining the measurement of the norepinephrine, epinephrine, and dopamine systems in ADHD and normal subjects is reviewed and discussed in the context of recent neuroimaging and animal studies.
While data clearly indicate a role for all three of the above neurotransmitters in ADHD, a hypothesis suggesting "too much" or "too little" of a single neurotransmitter will no longer suffice. The central norepinephrine system may be dysregulated in ADHD, such that this system does not efficiently "prime" the cortical posterior attention system to external stimuli. Effective mental processing of information involves an anterior "executive" attention system which may depend on dopaminergic input. The peripheral epinephrine system may be a critical factor in the response of individuals with ADHD to stimulant medication.
A multistage hypothesis is presented which emphasizes the interaction of norepinephrine, epinephrine, and dopamine in modulation of attention and impulse control.
... It is known that patients with prefrontal DA hypofunction and striatal DA hyperfunction have difficulty differentiating the significance of the stimulus presented [25]. Dopamine and norepinephrine terminals coexist in the prefrontal cortex (PFC) [26] and their interactions seem to be crucial for controlling complex behaviors and, consequently, ADHD symptoms [27][28][29][30][31][32][33]. ...
... Data in the 0-0.8 range were excluded due to the abundance of artifacts. The following ranges for the electroencephalographic rhythms were used for analysis and interpretation (in Hz): delta (0.9-3), theta (4-8), alpha (9-11), lower beta (12)(13)(14)(15)(16)(17)(18)(19), higher beta (20)(21)(22)(23)(24)(25)(26)(27)(28)(29), lower gamma (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48), higher gamma (52-74). ...
... To analyze the power spectra of the neural activity in the prefrontal cortex (P dorsal striatum (Str), we used a traditional LFP analysis, based on the signal dec tion into simpler sinusoidal harmonics. We compare electroencephalographic rhy cording to the following ranges (in Hz): delta (0.9-3), theta (4-8), alpha (9-11), low (12)(13)(14)(15)(16)(17)(18)(19), higher beta (20)(21)(22)(23)(24)(25)(26)(27)(28)(29), lower gamma (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48), higher gamma . ...
Investigation of the precise mechanisms of attention deficit and hyperactivity disorder (ADHD) and other dopamine-associated conditions is crucial for the development of new treatment approaches. In this study, we assessed the effects of repeated and acute administration of α2A-adrenoceptor agonist guanfacine on innate and learned forms of behavior of dopamine transporter knockout (DAT-KO) rats to evaluate the possible noradrenergic modulation of behavioral deficits. DAT-KO and wild type rats were trained in the Hebb–Williams maze to perform spatial working memory tasks. Innate behavior was evaluated via pre pulse inhibition (PPI). Brain activity of the prefrontal cortex and the striatum was assessed. Repeated administration of GF improved the spatial working memory task fulfillment and PPI in DAT-KO rats, and led to specific changes in the power spectra and coherence of brain activity. Our data indicate that both repeated and acute treatment with a non-stimulant noradrenergic drug lead to improvements in the behavior of DAT-KO rats. This study further supports the role of the intricate balance of norepinephrine and dopamine in the regulation of attention. The observed compensatory effect of guanfacine on the behavior of hyperdopaminergic rats may be used in the development of combined treatments to support the dopamine–norepinephrine balance.
... MPD binds to dopamine (DA) transporter (DAT) and norepinephrine (NE) transporters (NET) at the synaptic cleft (Kuczenski and Segal 2002). This leads to an increase in NE and DA at the synaptic cleft, which has been shown to account for the observed rewarding therapeutic effects of MPD (Biederman and Spencer 1999;Drouin et al. 2006;Kuczenski and Segal 2002;Pliszka et al. 1996;Volkow et al. 1995Volkow et al. , 2005. ...
... Data on the NE system is limited. MPD treatment has been shown to increase extracellular NE levels by binding to NET in the CNS and specifically in the locus coeruleus (LC) (Biederman and Spencer 1999; Kidani et al. 2010;Segal 2001, 2002;Pliszka et al. 1996). Increases in NE concentration are known to affect attention and maintain arousal and alertness of the central nervous system (CNS) (Biederman and Spencer 1999;Drouin et al. 2006;Pliszka et al. 1996). ...
... MPD treatment has been shown to increase extracellular NE levels by binding to NET in the CNS and specifically in the locus coeruleus (LC) (Biederman and Spencer 1999; Kidani et al. 2010;Segal 2001, 2002;Pliszka et al. 1996). Increases in NE concentration are known to affect attention and maintain arousal and alertness of the central nervous system (CNS) (Biederman and Spencer 1999;Drouin et al. 2006;Pliszka et al. 1996). The locus coeruleus (LC) is the principal CNS site that synthesizes NE and thus changes in LC following MPD exposure are important to examine. ...
The objective of this study is to gain insight into the behavioral and neuronal changes induced by acute and chronic methylphenidate (MPD) administration. Specifically, there is limited knowledge of the effects of MPD on the locus coeruleus (LC), the main site of norepinephrine synthesis in the brain. In this study, LC neuronal firing rate was recorded simultaneously with locomotor activity in freely moving adolescent rats. Adolescent rats were chosen to mimic the age group in humans most affected by MPD exposure. Following acute dose of 0.6, 2.5 or 10 mg/kg MPD, all rats showed an increase in locomotor activity. However, in response to chronic MPD doses, individual rats showed either a further increase or decrease in their locomotor activity as compared to the effect initiated by the acute dose—expressing either behavioral sensitization or tolerance, respectively. The LC neuronal recordings from animals expressing behavioral sensitization showed that the majority of units responded to chronic MPD exposure by further increasing firing rates as compared to the initial response to the acute MPD exposure. For the LC neuronal units recorded from animals expressing behavioral tolerance, however, the majority of the units responded to chronic exposure by attenuating or no significant effect on their firing rate as compared to the acute MPD exposure. This observation indicates a correlation between the LC neuronal responses and behavioral activity to chronic MPD exposure. The study shows that LC participates in the effect of MPD and the behavioral expression of sensitization and tolerance to chronic exposure of MPD.
... If so, acute exercise may temporarily normalize baseline brain oscillations of individuals with ADHD by altering their state of arousal. Cortical hypo-arousal may impact several brain mechanisms including the anterior attentional network which controls sustained attention, and the fronto-striatal circuitry which governs inhibition of pre-potent and premature responses [30]. Medications generally used to treat ADHD symptoms are believed to increase arousal and alertness of the central nervous system through the stimulation of the noradrenergic and dopaminergic systems [30,31]. ...
... Cortical hypo-arousal may impact several brain mechanisms including the anterior attentional network which controls sustained attention, and the fronto-striatal circuitry which governs inhibition of pre-potent and premature responses [30]. Medications generally used to treat ADHD symptoms are believed to increase arousal and alertness of the central nervous system through the stimulation of the noradrenergic and dopaminergic systems [30,31]. The neurotransmitter changes induced by acute exercise may produce effects similar to those of stimulant medications. ...
This two stage study examined the effects of acute exercise on resting electroencephalographic (EEG) patterns of children with attention-deficit hyperactivity disorder (ADHD). The first stage compared the neural oscillatory patterns of children with and without ADHD. Resting EEGs were recorded under an open-eyes condition from 24 boys with ADHD and 28 matched controls. The second stage of the study employed a randomized cross-over trial design. The 24 boys with ADHD engaged in a 30-min intervention that consisted of either running on a treadmill or watching a video on alternative days, with resting EEGs recorded before and after treatment. The first stage found that children with ADHD exhibited significantly higher theta/beta ratios over the midline electrodes sites than controls. The second stage further indicated that children with ADHD displayed smaller theta/beta ratios following the exercise condition compared with the video-watching condition. This finding suggests that acute exercise normalizes arousal and alertness of children with ADHD, as reflected in resting EEG readings.
... Elevated theta power has been frequently observed in children and adults with ADD/ADHD, both in the EO and EC states (Janzen et al., 1995;Clarke et al., 1998Clarke et al., , 2001aClarke et al., ,b, 2002Lazzaro et al., 1998Lazzaro et al., , 1999Bresnahan et al., 1999;Barry et al., 2002Barry et al., , 2003Bresnahan and Barry, 2002;Loo and Makeig, 2012), as well as in dyslexia (Arns et al., 2007) and high-functioning autism (Yeung et al., 2016). This effect, found especially in the frontal area of the brain, may reflect poor concentration (Mann et al., 1992) and executive function deficits, such as difficulty in inhibiting inadequate reactions (Pliszka et al., 1996). Similar to individuals with ADHD, children with CAPD in our study showed increased theta power in the anterior region of the brain. ...
... Enhanced delta is thought to reflect reduced excitation level (Cannon, 2012) that may contribute to increased distractibility affecting the CAP tests execution. Similarly, increased theta may be related to poor concentration and executive functions deficits (Pliszka et al., 1996). To perform DDT, FPT, or DPT correctly, attention and short-term memory must be involved. ...
In this study, we showed an abnormal resting-state quantitative electroencephalogram (QEEG) pattern in children with central auditory processing disorder (CAPD). Twenty-seven children (16 male, 11 female; mean age = 10.7 years) with CAPD and no symptoms of other developmental disorders, as well as 23 age- and sex-matched, typically developing children (TDC, 11 male, 13 female; mean age = 11.8 years) underwent examination of central auditory processes (CAPs) and QEEG evaluation consisting of two randomly presented blocks of “Eyes Open” (EO) or “Eyes Closed” (EC) recordings. Significant correlations between individual frequency band powers and CAP tests performance were found. The QEEG studies revealed that in CAPD relative to TDC there was no effect of decreased delta absolute power (1.5–4 Hz) in EO compared to the EC condition. Furthermore, children with CAPD showed increased theta power (4–8 Hz) in the frontal area, a tendency toward elevated theta power in EO block, and reduced low-frequency beta power (12–15 Hz) in the bilateral occipital and the left temporo-occipital regions for both EO and EC conditions. Decreased middle-frequency beta power (15–18 Hz) in children with CAPD was observed only in the EC block. The findings of the present study suggest that QEEG could be an adequate tool to discriminate children with CAPD from normally developing children. Correlation analysis shows relationship between the individual EEG resting frequency bands and the CAPs. Increased power of slow waves and decreased power of fast rhythms could indicate abnormal functioning (hypoarousal of the cortex and/or an immaturity) of brain areas not specialized in auditory information processing.
... In a similar fashion, individuals with ADHD also have neurophysiological and neuroanatomical differences, which are associated with delayed cortical maturation, reduced selective and sustained attention, reduced prefrontal cortical function, and reduced brain volume when compared to healthy controls [24,25]. All currently available ADHD medications can improve the efficiency of signal transmission in brain regions responsible for attention, vigilance, impulsivity, and motoric response, based on their various effects on catecholamine neurotransmitters [26,27]. ...
... There are multiple stimulant and non-stimulant medications now FDA-approved for ADHD in patients at least 3-6 years of age. ADHD medications all have varying effects on dopamine and norepinephrine neurotransmitters in the brain, giving rise to so-called catecholamine hypothesis related to ADHD etiology [26,27]. As noted earlier, abnormal stress responses in PTSD patients are mediated in large part by catecholamine dysregulation. ...
Studies suggest a bidirectional association between the diagnoses of ADHD and post-traumatic stress disorders (PTSD). Multiple DSM-5 symptoms of PTSD (e.g., avoidance of stimuli, as well as alterations in cognitions, mood, arousal, and reactivity) overlap with symptoms of ADHD (e.g., inattention, hyperactivity, and impulsivity), as well as with other internalizing or externalizing disorders that may also be comorbid with ADHD. A careful assessment is needed for an accurate diagnosis and proper treatment. There are now multiple evidence-based psychotherapies for childhood PTSD and for ADHD, some potential useful for both conditions. There are many medications approved by the Food and Drug Administration (FDA) for pediatric and adult ADHD, and some for adult PTSD, but none for pediatric PTSD. Clinical practice guidelines are also available for ADHD and for PTSD, but not for when they co-occur. As such, clinical judgment and patient and family preferences must guide treatment decisions. In this chapter, we review the etiological aspects, assessment strategies, and psychosocial and pharmacological treatment approaches for patients with co-occurring ADHD and PTSD. We also highlight the need for more research within the field to inform better assessment and treatment of this comorbid combination in clinical practice.
... In a similar fashion, individuals with ADHD also have neurophysiological and neuroanatomical differences, which are associated with delayed cortical maturation, reduced selective and sustained attention, reduced prefrontal cortical function, and reduced brain volume when compared to healthy controls [24,25]. All currently available ADHD medications can improve the efficiency of signal transmission in brain regions responsible for attention, vigilance, impulsivity, and motoric response, based on their various effects on catecholamine neurotransmitters [26,27]. ...
... There are multiple stimulant and non-stimulant medications now FDA-approved for ADHD in patients at least 3-6 years of age. ADHD medications all have varying effects on dopamine and norepinephrine neurotransmitters in the brain, giving rise to so-called catecholamine hypothesis related to ADHD etiology [26,27]. As noted earlier, abnormal stress responses in PTSD patients are mediated in large part by catecholamine dysregulation. ...
... Several genetic markers of ADHD identified to date involve alterations in dopamine (DA) and noradrenaline signaling (NA) (Pliszka et al., 1996). There are certain similarities between dopaminergic and noradrenergic signaling and disruptions thereof in the brain. ...
For decades, psychostimulants have been the gold standard pharmaceutical treatment for attention-deficit/hyperactivity disorder (ADHD). In the United States, an astounding 9% of all boys and 4% of girls will be prescribed stimulant drugs at some point during their childhood. Recent meta-analyses have revealed that individuals with ADHD have reduced brain volume loss later in life (>60 y.o.) compared to the normal aging brain, which suggests that either ADHD or its treatment may be neuroprotective. Crucially, these neuroprotective effects were significant in brain regions (e.g., hippocampus, amygdala) where severe volume loss is linked to cognitive impairment and Alzheimer’s disease. Historically, the ADHD diagnosis and its pharmacotherapy came about nearly simultaneously, making it difficult to evaluate their effects in isolation. Certain evidence suggests that psychostimulants may normalize structural brain changes typically observed in the ADHD brain. If ADHD itself is neuroprotective, perhaps exercising the brain, then psychostimulants may not be recommended across the lifespan. Alternatively, if stimulant drugs are neuroprotective, then this class of medications may warrant further investigation for their therapeutic effects. Here, we take a bottom-up holistic approach to review the psychopharmacology of ADHD in the context of recent models of attention. We suggest that future studies are greatly needed to better appreciate the interactions amongst an ADHD diagnosis, stimulant treatment across the lifespan, and structure-function alterations in the aging brain.
... Dysregulated catecholamine secretion (mainly dopamine) is suggested to play an important mechanistic role. This is strongly supported by the fact that central nervous system stimulants (e.g., methylphenidate, by inhibiting central nervous system dopamine reuptake) are commonly used as the first-line long-term treatment options for patients with ADHD [2]. ...
Purpose
Attention-deficit/hyperactivity disorder (ADHD) is typically a chronic, often lifelong condition. Data suggest that ADHD itself and its treatment may be associated with dysregulated growth, including height and BMI. The reason for this association is yet unknown. The objective of this study was to examine differences in growth hormone (GH) response to exercise between children who had received a diagnosis of ADHD and age- and gender-matched controls. We reasoned that the normal increase in circulating GH seen in response to exercise would be blunted in children with ADHD.
Methods
We recruited 13 treatment-naïve children with newly diagnosed ADHD and 14 age-matched controls (all male) and measured GH response to an exercise test in which the work was scaled to each subject's physical capability.
Results
There was no difference in the peak heart rate achieved during exercise between controls and ADHD participants (196.6 ± 1.5 vs. 196.5 ± 2.1 bpm, respectively) and lactate response to exercise (53.8 ± 5.0 vs. 47.9 ± 3.8 mg/dl, respectively). After exercise, GH increased significantly in the control subjects (p < 0.005), while GH responses were substantially blunted in the ADHD group (p = NS) even though the work performed did not differ from controls.
Conclusions
Our data suggest that GH excretion after exercise challenge in children with ADHD is impaired. This can be detected using a minimally invasive, nonpharmacologic challenge and may link ADHD with growth impairment in some children.
Trial registration number: NCT00945971
... Furthermore, because brain attention dysfunction is usually more evident during cognitive tasks, electrophysiological recordings conducted during task conditions can act as discriminants for the diagnosis of ADHD [55]. Attention functions involve several brain areas, and altered parietal activity in ADHD may indicate abnormalities in the posterior visual attention system that affect performance monitoring, attention reallocation, and visuospatial attention, as well as motor mapping within the peripersonal space [56,57]. We infer that the K-CPT involves visual-input and motor-response tasks that require respondents' visual attention. ...
This study used a wireless EEG system to investigate neural dynamics in preschoolers with ADHD who exhibited varying cognitive proficiency pertaining to working memory and processing speed abilities. Preschoolers with ADHD exhibiting high cognitive proficiency (ADHD-H, n = 24), those with ADHD exhibiting low cognitive proficiency (ADHD-L, n = 18), and preschoolers with typical development (TD, n = 31) underwent the Conners’ Kiddie Continuous Performance Test and wireless EEG recording under different conditions (rest, slow-rate, and fast-rate task). In the slow-rate task condition, compared with the TD group, the ADHD-H group manifested higher delta and lower beta power in the central region, while the ADHD-L group manifested higher parietal delta power. In the fast-rate task condition, in the parietal region, ADHD-L manifested higher delta power than those in the other two groups (ADHD-H and TD); additionally, ADHD-L manifested higher theta as well as lower alpha and beta power than those with ADHD-H. Unlike those in the TD group, the delta power of both ADHD groups was enhanced in shifting from rest to task conditions. These findings suggest that task-rate-related neural dynamics contain specific neural biomarkers to assist clinical planning for ADHD in preschoolers with heterogeneous cognitive proficiency. The novel wireless EEG system used was convenient and highly suitable for clinical application.
... Among several genes associated with the pathogenesis of ADHD, the most noticeable is the gene encoding the dopamine transporter (DAT) (24,25). It is assumed that norepinephrine (NE) also plays an important role in the pathophysiology of ADHD (26)(27)(28). Recent investigations indicated the role of norepinephrine transporter (NET) in ADHD development (29). The NE system is involved in attention processes related to prefrontal cortex (PFC) functions. ...
Attention deficit hyperactivity disorder (ADHD) is manifested by a specific set of behavioral deficits such as hyperactivity, impulsivity, and inattention. The dopamine neurotransmitter system is postulated to be involved in the pathogenesis of ADHD. Guanfacine, a selective α2A-adrenoceptor agonist, is prescribed for ADHD treatment. ADHD also is known to be associated with impairment of multiple aspects of cognition, including spatial memory, however, it remains unclear how modulation of the norepinephrine system can affect these deficits. Hyperdopaminergic dopamine transporter knockout (DAT-KO) rats are a valuable model for investigating ADHD. The DAT-KO rats are hyperactive and deficient in spatial working memory. This work aimed to evaluate the effects of noradrenergic drugs on the fulfillment of spatial cognitive tasks by DAT-KO rats. The rats were tested in the Hebb – Williams maze during training and following noradrenergic drugs administration. The efficiency of spatial orientation was assessed as to how fast the animal finds an optimal way to the goal box. Testing in a new maze configuration allowed us to evaluate the effects of drug administration after the acquisition of the task rules. The behavioral variables such as the distance traveled, the time to reach the goal box, and the time spent in the error zones were analyzed. It has been observed that α2A-adrenoceptor agonist Guanfacine (0.25 mg/kg) had only a minimal inhibitory effect on hyperactivity of DAT-KO rats in the maze but significantly ameliorated their perseverative pattern of activity and reduced the time spent in the error zones. In contrast, α2A-adrenoceptor antagonist Yohimbine, at the dose of 1 mg/kg, increased the distance traveled by DAT-KO rats and elevated the number of perseverative reactions and the time spent in the error zones. Guanfacine caused minimal effects in wild-type rats, while Yohimbine altered several parameters reflecting a detrimental effect on the performance in the maze. These data indicate that modulation of α2A-adrenoceptor activity potently affects both dopamine-dependent hyperactivity and cognitive dysfunctions. Similar mechanisms may be involved in the beneficial effects of Guanfacine on cognitive deficits in ADHD patients. This study further supports the translational potential of DAT-KO rats for testing new pharmacological drugs.
... The exact mechanisms by which PA intervention is beneficial for inattentive symptom in ADHD patients are still unknown. Currently, the leading biological hypothesis of ADHD is based on the dysfunction of catecholamines (CAs, e.g., norepinephrine, epinephrine, or dopamine) (63). As one of the pathophysiology factors for ADHD, dopamine dysregulation in the brain dopamine reward pathway was suggested to be associated with inattentive symptoms in patients with ADHD, but not with hyperactive symptoms (64,65). ...
Objective: To assess the effectiveness of physical activity (PA) intervention on attention-deficit/hyperactivity disorder (ADHD)-related symptoms.
Method: Studies that investigated PA intervention for ADHD-related symptoms were identified through searching PubMed, Web of Science, Cochrane Library, and Embase databases from inception through June 2021. Standardized mean difference (SMD) with 95% confidence interval (CI) was used to assess the effectiveness of PA intervention on improving ADHD-related symptoms. The meta-analyses were conducted using fixed-effect or random-effect models according to the heterogeneity of the studies.
Results: Nine before–after studies (232 participants) and 14 two-group control studies (162 participants/141 controls) were included in this meta-analysis. Combined results for before–after studies indicated significant improvements on all studied ADHD-related symptoms (inattention: SMD = 0.604, 95% CI: 0.374–0.834, p < 0.001; hyperactivity/impulsivity: SMD = 0.676, 95% CI: 0.401–0.950, p < 0.001; emotional problems: SMD = 0.416, 95% CI: 0.283–0.549, p < 0.001; behavioral problems: SMD = 0.347, 95% CI: 0.202–0.492, p < 0.001). Meta-analyses for two-group control studies further confirmed that PA intervention significantly improved the inattentive symptom (SMD = 0.715, 95% CI: 0.105, 1.325, p = 0.022). Subgroup analyses suggested significant beneficial effect on inattention symptoms in children. Moreover, closed motor skills were beneficial for hyperactive/impulsive problems (SMD = 0.671, p < 0.001), while open motor skills were beneficial for attention problems (SMD = 0.455, p = 0.049). When excluding studies with combined medication, the studies in unmedicated participants in before–after studies still showed significant results in all studied ADHD-related symptoms as in the overall analysis. Given the limited sample size, the best frequency and intensity of PA intervention need further investigation.
Conclusion: Our results suggested that PA intervention could possibly improve ADHD-related symptoms, especially inattention symptoms. Closed-skill and open-skill activities could be beneficial for hyperactivity/impulsivity and inattention symptoms, respectively. Further high-quality randomized clinical trials with large sample size are needed.
... Methylphenidate and amphetamine salts (dextroamphetamine, mixed dextroamphetamine-amphetamine salts) are the two major drugs in this class. Stimulants work by increasing the release of catecholamines and acting at the noradrenergic and dopaminergic receptors in the CNS synapses [12]. Methylphenidate is available in short-acting, intermediate-acting, and long-acting forms. ...
Purpose of Review
Attention deficit hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder that is characterized by inattention, hyperactivity, and impulsivity along with a troubled functioning in family, social, occupational, and academic settings. A brief discussion of the management of ADHD including pharmacotherapy, behavioral interventions, multidisciplinary approach, and new advances in treatment is described.
Recent Findings
New developments in the management of ADHD including atypical drugs, neurostimulation, and druggable genomes.
Summary
The outline of the article includes dynamic advances in the treatment of ADHD with an emphasis on a multidisciplinary approach.
... Regarding brain regions, we observed that the significant EEG differences between groups were found not only in the central region but also in the parietal region, and these findings were similar to Kim's study [17]. It has been realized that the parietal region is critical for the process of disengaging from the current stimulus, moving the focus of attention to the new stimuli, and engaging attention on the new stimuli [66]. Reduced parietal activity in ADHD may indicate abnormality in neural activity affecting performance monitoring, attention reallocation, and visuospatial attention, as well as motor mapping in personal space [67]. ...
The present study aimed to characterize children at risk of attention-deficit/hyperactivity disorder (ADHD) during preschool age and provide early intervention. The continuous performance test (CPT) and electroencephalography (EEG) can contribute additional valuable information to facilitate diagnosis. This study measured brain dynamics at slow and fast task rates in the CPT using a wireless wearable EEG and identified correlations between the EEG and CPT data in preschool children with ADHD. Forty-nine preschool children participated in this study, of which 29 were diagnosed with ADHD and 20 exhibited typical development (TD). The Conners Kiddie Continuous Performance Test (K-CPT) and wireless wearable EEG recordings were employed simultaneously. Significant differences were observed between the groups with ADHD and TD in task-related EEG spectral powers (central as well as parietal delta, P <0.01), which were distinct only in the slow-rate task condition. A shift from resting to the CPT task condition induced overall alpha powers decrease in the ADHD group. In the task condition, the delta powers were positively correlated with the CPT perseveration scores, whereas the alpha powers were negatively correlated with specific CPT scores mainly on perseveration and detectability (P < 0.05). These results, which complement the findings of other sparse studies that have investigated within-task-related brain dynamics, particularly in preschool children, can assist specialists working in early intervention to plan training and educational programs for preschoolers with ADHD.
... Besonders Dopamin, Serotonin und Noradrenalin scheinen in der Pathologie der ADHS eine wichtige Rolle zu spielen (Pliszka et al., 1996) (Krause et al., 2000;Volkow et al., 2005;Pei et al., 2016). Aber auch das in der Therapie genutzte Atomoxetin, als Noradrenalin-Wiederaufnahmehemmer, steigert die Konzentration von Noradrenalin und Dopamin im präfrontalen Kortex (Bymaster et al., 2002;Ratner et al., 2005 ...
Das Ziel der vorliegenden Arbeit war die Untersuchung der Impulsivität bei adulten Patienten mit ADHS. Es wurden 19 adulte Patienten mit ADHS und 20 gesunde Kontrollprobanden, die nach Alter, Geschlecht und Schulabschluss vergleichbar waren, untersucht. Wir nutzten ein kognitives Set Shifting Paradigma und erfassten die Verhaltensdaten (Reaktionszeit und Fehler) sowie hirnphysiologische Änderungen mittels funktioneller Nahinfrarotspektroskopie (fNIRS). Als „Region of Interest“ (ROI) legten wir den dorsolateralen präfrontalen Kortex (dlPFC) fest. Zusätzlich erfolgte eine Selbsterfassung der Impulsivität mittels BIS 11, SPSRQ und UPPS Fragebogen. Auf der Verhaltensebene zeigten die Patienten mit ADHS im Vergleich zu den gesunden Kontrollprobanden eine verlängerte Reaktionszeit. Die Bearbeitung einer Shift Aufgabe führte bei beiden Probandengruppen zu einer verlängerten Reaktionszeit sowie einer erhöhten Fehlerzahl im Verhältnis zu einer No Shift Aufgabe. In der Erhebung der funktionellen Daten konnten wir einen signifikanten Unterschied zwischen den Gruppen im Bereich der ROI feststellen. Die gesunden Kontrollprobanden wiesen eine erhöhte Hirnaktivität im dlPFC auf. In den Fragebögen zur Selbsterfassung der Impulsivität erreichten die Patienten in den meisten Unterskalen Werte, die mit erhöhter Impulsivität einhergehen.
... Our study showed a significant increase in the NGF levels in the treatment groups. Metal toxicity produces free radicals and in turn causes oxidative stress, which induces inflammation and thus IL-6 production [33]. Social isolation alters neroinflammatory response which can lead to decrease in IL-6 concentrations. ...
Objective: To explore the effect and mechanism of action of Celastrus paniculatus oil on the treatment of perinatal rats with attention deficit hyperactivity disorder.
Methods: In the perinatal stage, the rats were either isolated or administered with lead acetate to establish an animal model of attention deficit hyperactivity disorder. Atomoxetine served as the reference standard. Animals’ behaviours were assessed through Y-maze, novel object preference, fear conditioning and resident-intruder aggression tests. Oxidative stress parameters, bioamine concentration (dopamine, noradrenaline and 5-hydroxytryptamine), nerve growth factor, interleukin-6, nuclear factor-κB, and tumour necrosis factor (TNF)-α were estimated. Synaptophysin immunohistochemical assay was performed.
Results: Celastrus paniculatus oil significantly improved behavioural parameters in Y maze, novel object preference, discrimination index, fear conditioning and resident intruder aggressive tests. The treatment groups showed a decrease in malondialdehyde level. Changes in the levels of dopamine, noradrenaline, and serotonin were restored by Celastrus paniculatus oil. Celastrus paniculatus oil increased nerve growth factor and decreased interleukin-6, nuclear factor-κB, and TNF-α. Synaptophysin immunoreactivity was also improved by Celastrus paniculatus oil with alleviated reactive gliosis, degeneration, and vascular proliferation.
Conclusions: This research shows the therapeutic potential of Celastrus paniculatus oil for the treatment of attention deficit hyperactivity disorder.
... Our study showed a significant increase in the NGF levels in the treatment groups. Metal toxicity produces free radicals and in turn causes oxidative stress, which induces inflammation and thus IL-6 production [33]. Social isolation alters neroinflammatory response which can lead to decrease in IL-6 concentrations. ...
Mosquitoes belonging to the genus Aedes pose a significant threat to human health on a global scenario due to their role in transmission of dengue, chikungunya, zika, and yellow fever. In absence of specific medications and vaccines against these diseases, disease prevention relies on vector control. However, in today's world, vector control is facing major challenges due to the onset of insecticide resistance in mosquitoes. There are four main mechanisms of insecticide resistance, namely, behavioral resistance, reduced penetration/cuticular resistance, metabolic detoxification, and target site resistance; however, the latter two mechanisms have been studied widely in Aedes mosquitoes. Insecticide resistance in Aedes mosquitoes is widespread throughout the world. This review compiles the degree of insecticide resistance/susceptibility prevailing among different field populations of Aedes mosquitoes worldwide. In addition, the review has detailed the mechanisms providing the resistance phenomenon observed in nature in Aedes mosquitoes.
... Because brain attention dysfunction is usually more evident during cognitive tasks, electrophysiological recordings conducted during task conditions can act as discriminants for the diagnosis of ADHD [60]. Attention functions involve several brain areas, and altered parietal activity in ADHD may indicate abnormalities in the posterior visual attention system that affect performance monitoring, attention reallocation, and visuospatial attention as well as motor mapping within the peripersonal space [61,62]. We infer that the K-CPT involves visual-input and motor response tasks that require respondents' vision attention. ...
Background
Early diagnosis and intervention is essential for children at risk of attention deficit hyperactivity disorder (ADHD). For preschool-age children with ADHD, who have heterogeneous neurobehavioral deficits, the continuous performance test and quantitative electroencephalography (EEG) can facilitate clinical diagnosis. This study investigated EEG dynamics and task-based EEG coherence in preschoolers with ADHD, who exhibited varying cognitive proficiencies.Methods
The participants comprised 54 preschoolers (aged 5–7 years), 18 and 16 of whom exhibited high and low cognitive proficiency (ADHD-H and ADHD-L, respectively). The remaining 20 children had typical development (TD). All the children underwent the Conners’ Kiddie Continuous Performance Test and wireless EEG recording under different task conditions (rest, fast, and slow). ResultsIn the slow-rate task condition, the task-related parietal delta power of preschoolers with ADHD-L was significantly higher than that of their peers with TD. In the fast-rate condition, the preschoolers with ADHD-L exhibited higher parietal delta and theta/beta ratio as well as lower parietal beta power than those with ADHD-H. Unlike those in the TD group, the alpha power values of the participants in both the ADHD groups declined from rest to the task conditions. Task- related EEG beta coherence was decreased in both ADHD groups, which were distinct with TD groups. ConclusionThe aforementioned findings suggest that task-related brain oscillations were related to cognitive proficiency in preschool children with ADHD. The novel wireless EEG system used was demonstrated to be convenient and highly suitable for clinical use in preschool children. The EEG profiles in the present study may contain specific neural biomarkers that can assist early detection, diagnosis, and clinical planning for the treatment of ADHD in preschool children.
... Treatment overview Stimulant medications are generally the first-line treatment for ADHD (Wolraich et al., 2019). Although the exact mechanism of action of stimulants is unknown, it is established that stimulants affect the dopaminergic and noradrenergic systems (Pliszka, McCracken, & Maas, 1996). ...
Background
Given the prevalence of depression in persons with autism spectrum disorder (ASD), effective treatment is crucial; however, a systemic review on the topic has not been published in over a decade. This study aimed to systematically examine the efficacy of psychosocial and pharmacological treatments for depression in youth and adults with ASD to inform clinical practice.
Method
PsycINFO, PubMed, and CINAHL online databases were searched for peer-reviewed journal articles containing any combination of the following terms in the abstract: (1) autism, autistic, Asperger, or “pervasive developmental disorder,” (2) depression or depressive and (3) treatment, intervention, trial, therapy, medication, drug, or antidepressant. Evidence from studies meeting the predetermined criteria of inclusion was assessed for its strength to inform clinical decision-making.
Results
Twenty psychosocial treatment studies and five pharmacological treatment studies met the criteria of inclusion. Psychosocial interventions studied the effectiveness of cognitive remediation therapy, behavioral therapy, cognitive-behavioral therapy (CBT), combined psychosocial intervention, mindfulness-based therapy (MBT), and social, academic, and/or vocational skills training. Pharmacological interventions studied the effectiveness of anti-epileptic drug, norepinephrine reuptake inhibitor, stimulant, atypical antipsychotic, and NMDA receptor antagonist treatment.
Conclusions
Although much recent research has investigated potentially effective treatments for depression in individuals with ASD, the strength of the evidence remains generally poor. However, studies indicate preliminary efficacy for MBT. A number of investigations have examined the effect of CBT on depression in persons with ASD; however, the results are inconsistent. Further research is needed to advance clinical practice for individuals with ASD and comorbid depression.
... The current study observed a decrease in alpha power in the posterior region during AFC challenge. Alpha power may be an important factor in adult ADHD as it is connected to attentional self-control and active inhibition of external stimuli [24,31]. Interestingly, posterior alpha showed a significant negative correlation with hyperactive ASRS scores and overall ADHD symptoms, suggesting that posterior alpha may be associated with symptoms of ADHD. ...
Objectives: Removing artificial food coloring (AFC) is a common dietary intervention for children with Attention-Deficit/Hyperactivity Disorder (ADHD), but has not been tested in young adults. This pilot study examined the effects of AFC on ADHD symptoms and electroencephalography (EEG) in college students with and without ADHD.
Methods: At baseline, control and ADHD participants completed the Adult ADHD Self-Report Scale (ASRS), simple and complex attention measures, and resting-state EEG recordings. ADHD participants (n = 18) and a subset of controls (extended control group or EC, n = 11) avoided AFC in their diet for 2 weeks and then were randomized to a double-blind, placebo-controlled crossover challenge. Subjects received either 225 mg AFC disguised in chocolate cookies or placebo chocolate cookies for 3 days each week, with testing on the third day each week. Baseline comparisons were made using Student’s t-test or Wilcoxon rank sum tests and challenge period analyses were run using General Linear Modeling.
Results: The ADHD group had significantly greater scores on the ASRS (p < 0.001), confirming a symptom differential between groups; however, there were no differences in attentional measures or EEG at baseline. The AFC challenge resulted in an increase in posterior mean gamma power (p = 0.05), a decrease in posterior relative alpha power (p = 0.04), and a marginal increase in inattentive symptoms (p = 0.08) in the ADHD group. There were no effects of AFC in the EC group.
Discussion: This study indicates that AFC exposure may affect brainwave activity and ADHD symptoms in college students with ADHD. Larger studies are needed to confirm these findings.
... The current study observed a decrease in alpha power in the posterior region during AFC challenge. Alpha power may be an important factor in adult ADHD as it is connected to attentional self-control and active inhibition of external stimuli [24,31]. Interestingly, posterior alpha showed a significant negative correlation with hyperactive ASRS scores and overall ADHD symptoms, suggesting that posterior alpha may be associated with symptoms of ADHD. ...
Attention-Deficit Hyperactivity Disorder (ADHD) is the most common neurodevelopmental disorder in children, and over half of these individuals carry the diagnosis into adulthood. Dietary exposure to artificial food coloring (AFC) has been reported to worsen symptoms of ADHD in children, but the validity of these findings has been debated. Furthermore, no studies have been completed to date examining the potential effects of AFC on young adults with ADHD. The current study examined the effects of AFC on brainwave activity of college students with and without ADHD. Participants (mean (SD) age of 20 (1.3) yrs) with (n=18) and without (n=41) ADHD completed baseline testing, including the Adult ADHD Self-Report Scale (ASRS) and 4 minutes of eyes-closed resting-state EEG. After avoiding AFC in the diet for 2 weeks, the ADHD group and 11 controls (referred to as Extended Controls or EC) were randomized to a double-blind placebo-controlled crossover challenge lasting three days each over two consecutive weeks. The challenge materials consisted of either 225 mg of combined AFC disguised in chocolate cookies or placebo chocolate cookies. The ASRS and EEG measures were collected at the end of each 3-day exposure. ASRS scores significantly differed at baseline between the ADHD and control group (p<0.001), confirming significantly elevated symptoms in the ADHD group. There were no differences between the ADHD and control group in any EEG frequency band at baseline. The ADHD group experienced a significant decrease in relative
alpha power (p=0.04) and an increase in mean gamma power (p=0.05) in the posterior region (Pz, P3, P4, P7, P8, P9, P10, T7, T8, O1, O2) when challenged with AFC relative to placebo. There were no significant EEG changes in the EC group across challenge periods. Importantly, no changes were noted in ASRS scores across challenge periods in either group, but there was a marginally significant negative correlation between relative alpha power and the ASRS when exposed to AFC in the ADHD group (r= -0.49, p=0.06). These results indicate that AFC in the diet can change the brainwave activity of college students with ADHD, specifically in the mid and high frequency bands, but not in those without ADHD. More research is needed to better understand the underpinnings of how AFC changes brainwave activity, and if such changes are related to clinically meaningful symptom changes or more sensitive measures of attention not captured by the ASRS.
... In humans, dysfunctional catecholaminergic neurotransmitter systems contribute to the symptoms of attention deficit hyperactivity disorder (ADHD) (Sontag et al., 2010). The use of animal models for ADHD was evaluated and validated by Mefford & Potter (1989) and Pliszka et al. (1996). Arnsten et al. (1996) emphasized the role of norepinephrine in focusing on stimuli or tasks. ...
Animal temperament and individual animal personalities in combination with an animal's ability to cope with stressful situations have been studied in the past. There are clear differences between cattle breeds in urinary catecholamine concentration. Individual differences in behaviour exist in a large number of species and breeds within species. This review gives an overview of the involvement of catecholamines in the expression of stress in animals. Domestication, the heritability of stress and terms currently used in animal personality research are discussed. This includes animals used for production. The aim of this review is to consolidate and present current knowledge on the function of an activated catecholamine system and to question whether behavioural changes of animals are tending towards increased aggressiveness or towards mproved coping mechanisms.
... Whereas, increase in CA via MAO inhibition is highlighted as an efficient avenue in the treatment of various mental disorders such as depression, anxiety disorders, ADHD, Parkinson's disease (PD) and Tourette's syndrome (Bortolato et al., 2008). Therefore, it is evident that CA enhancement have been used as a strategy for the treatment of various neurological ailments such as Segawa Syndrome (Segawa et al., 1971), PD (Singh et al., 2007), Huntington's disease (HD) (Ondo et al., 2002;Marshall, 2006), depression (Nutt et al., 2007) and ADHD (Pliszka et al., 1996). ...
Background: Catecholamines (CAs) have been reported to be involved in numerous functions including central nervous system. CA release from the intra neuronal storage vesicles aid in the therapy of various neurological and neuropsychiatric disorders where the catecholaminergic neurotransmission is compromised. Bioavailability of CA at the synapse can be increased through stimulated neurotransmitter release, monoamine oxidase and CA reuptake inhibition. Plant based galenicals are reported to have similar CA enhancement activities and have been used for the management of neurological disorders. Aim: To review evidence-based literature with plant extracts, bioactive compounds, and composite extracts that modulate central catecholaminergic system, thereby enhancing CA activity for beneficial neurological effect. Methods: Electronic databases such as PubMed, Scopus, and ScienceDirect were used to search scientific contributions until January 2018, using relevant keywords. Literature focusing plant-derived CA enhancing compounds, extracts and/or composite extracts were identified and summarized. In all cases, dose, route of administration, the model system and type of extract were accounted. Results: A total of 49 plant extracts, 31 compounds and 16 herbal formulations have shown CA activity enhancement. Stimulated CA release from the storage vesicles, monoamine oxidase and CA reuptake inhibition were the major mechanisms involved in the increase of CA bioavailability by these phytoconstituents. Conclusion: This review provides an overview on the phytoconstituents with CA enhancement property that have been used for neuropsychiatric disorders. Such herbal remedies will provide an avenue for cost effective and easily available medication which have holistic approach towards disease management. There is also scope for alternate medicines or prototype drug development utilizing these phytomedicines for treating neurodegenerative diseases. However, hurdles are to be met for analyzing the mode and mechanism of action associated with these phytomedicines and their proper scientific documentation.
... We did, however, find a group-by-condition interaction close to the PCC and MFG. Both regions are part of an attention network (Pliszka, McCracken, & Maas, 1996), and associated with DD, either as a self-control region (MFG), or as a reward valuation region (PCC) (Scheres, de Water & Mies 2013a). Our Fig. 3 e Group (ADHD, control) x condition (delay, effort) interaction during decision phase in white matter close to the splenium of the corpus callosum/posterior cingulate cortex (A), and white matter close to the anterior corona radiate/middle frontal gyrus (B), and the corresponding mean beta values extracted for 8 mm-radius spheres surrounding the peak coordinates of these regions (on the basis of the contrasts delay > control and effort > control). ...
... In particular, in contrast to the essential effects of moderate levels of catecholamines, very high levels of catecholamine release in the PFC during stress exposure markedly impair working memory function through network collapse and suppression of PFC cell firing. However, as already observed by Pliszka et al. 63 , it seems unlikely that ADHD is related to a simple hypo-functioning of the dopamine system, Indeed, the complex multistage hypothesis of ADHD suggested by Pliszka et al. remains a plausible model of the complex interactions involved in ADHD ethiology. ...
We propose a novel semi-automatic approach to design biomarkers for capturing pharmacodynamic effects induced by pharmacological agents on the spectral power of electroencephalography (EEG) recordings. We apply this methodology to investigate the pharmacodynamic effects of methylphenidate (MPH) and atomoxetine (ATX) on attention deficit/hyperactivity disorder (ADHD), using rodent models. We inject the two agents into the spontaneously hypertensive rat (SHR) model of ADHD, the Wistar-Kyoto rat (WKY), and the Wistar rat (WIS), and record their EEG patterns. To assess individual EEG patterns quantitatively, we use an integrated methodological approach, which consists of calculating the mean, slope and intercept parameters of temporal records of EEG spectral power using a smoothing filter, outlier truncation, and linear regression. We apply Fisher discriminant analysis (FDA) to identify dominant discriminants to be heuristically consolidated into several new composite biomarkers. Results of the analysis of variance (ANOVA) and t-test show benefits in pharmacodynamic parameters, especially the slope parameter. Composite biomarker evaluation confirms their validity for genetic model stratification and the effects of the pharmacological agents used. The methodology proposed is of generic use as an approach to investigating thoroughly the dynamics of the EEG spectral power.
... It is characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity that impairs both academic performance and interpersonal relationships. 1 Prevalence rates were estimated to be about 3-7% of school age children. 2 The level of severity ADHD is specified as mild, moderate or severe. 1 Evidence suggests that dysregulation of biogenic amines, especially of both norepinephrine and dopamine, is involved in the pathophysiology of ADHD. 3,4 In addition, dopaminergic and noradrenergic agonists as well as other stimulants are used as firstline medications in the treatment of patients with ADHD. 5 Toxoplasma gondii is a widespread protozoon, which can infect any warm-blooded vertebrate. ...
Background:
Evidence suggests that Toxoplasma gondii, which causes toxoplasmosis, changes the metabolism of neurotransmitters, especially dopamine, resulting in both neurologic and psychiatric disorders. On the other hand, the dysregulation of catecholamines, especially of both norepinephrine and dopamine, has been proposed in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The aim of the present study was to investigate anti-toxoplasma antibodies in children and adolescents with ADHD and compare it with a control group, to determine whether toxoplasmosis is a risk factor for ADHD.
Methods:
A total of 200 children and adolescents (117 patients with ADHD and 83 individuals without ADHD) participated in the study. Participants were tested for the presence of anti-T. gondii antibodies by enzyme-linked immunosorbent assay. A Parent ADHD Rating Scale and Clinical Global Impression-severity Scale were also completed. Data were analyzed using a χ test and Fisher exact test.
Results:
Anti-toxoplasma antibodies were detected in 18.1% of patients with ADHD disorder and 24% of individuals without ADHD. There was no significant difference in seropositivity between the 2 groups (P > 0.05). The number of patients with T. gondii infection in the 3 subgroups was 0, 9 and 12, respectively. The differences in infection rate among subgroups were not statistically significant (P > 0.05).
Conclusion:
Although not conclusive, the present study does not support the theory that T. gondii is a risk factor for ADHD.
... Beberapa studi yang menggunakan populasi klinis epilepsi, melaporkan 40% anak dengan epilepsi mempunyai masalah inatensi, hiperaktivitas dan distraktibilitas serta agresif dan mood lability. 11 Beberapa alasan dapat menjelaskan kenapa ADHD dan gangguan atensi sering dijumpai pada anak dengan epilepsi. Attention-Deficit / Hyperactivity Disorder (ADHD) merupakan gangguan neurobehavioral akibat kerusakan dari frontalstriatal networks. ...
Attention-deficit / hyperactivity disorder (ADHD) has been associated with childhood epilepsy. Epilepsy are themost common neurologic disturbance in child age. Children with epilepsy tend to get one or more ADHD symptoms,its related to lack of norepinephrine neurotransmitter in brain, that cause attenuate the effect of GABA and disruptionto fronto-striatal brain networks, these same brain networks are disrupted by seizures or the structural brainabnormalities that can cause seizures. Children with epilepsy especially absance, tend to get inattentive type ofADHD more than other types. Abnormalities of electro-encephalography found in inattentive type of ADHD withhigh focus activities in all lobe area. No data published that methylphenidate can lower seizure threshold or act asproconvulsant. Children with epilepsy tend to get one or more symptoms of ADHD in the following days.
... Although in many studies, epinephrine and norepinephrine levels, or their metabolites in ADHD children's plasma or urine has increased relative to control group, (5)(6)(7)(8) there are no constant findings in review studies that indicate the decrease or lack of any changes in environmental levels of monoamines or their metabolites. Considering the role of the central noradrenergic system and peripheral automatic sympathetic system in arousal state, and considering the noradrenergic effects of stimulant drugs, this theory formed that the noradrenergic system plays a role in ADHD (9)(10)(11)(12). Of other physiologic disorders, available in this disease is the reduced response of the adrenaline moderator (5). ...
Background
In some children with ADHD, sub-optimal levels of various nutrients including PUFA especially omega-3 has been observed, and contradictory reports exist on the results of studies conducted on the positive therapeutic effects of PUFA in patients with ADHD.
Objective
The aim of this study was to investigate the effectiveness of methylphenidate and PUFA on treatment of patients with ADHD in Zahedan, Iran.
Methods
In this clinical trial, 40 children between 6 and 12 years of age with ADHD were investigated in Zahedan in 2014. Patients were randomly divided into two groups of methylphenidate plus PUFA and methylphenidate plus placebo. ADHD rating scale was filled before and after the study for patients of both groups. Finally, data were analyzed using SPSS18, paired-samples t-test and chi-square.
Results
Mean age of patients was 2.9±1.8 years. Thirty-three children (82.5%) were boys and seven children (17.5%) were girls. Mean severity of signs in the group under methylphenidate plus PUFA treatment was 39.9±4.9 before treatment and 20.1±6.0 after 8 weeks of treatment (p<0.001). Mean severity of signs in the group under methylphenidate plus placebo treatment was 41.2±2.7 before treatment and 26.1±9.0 after 8 weeks of treatment (p<0.001). Mean reduction in the severity of symptoms in the group under methylphenidate therapy was 19.7±5.9 and in PUFA and placebo group it was 15.1±9.3 (p<0.067). Response to treatment (a reduction of at least 25% in the signs) in the group taking methylphenidate plus PUFA was 90% (18 patients) and in methylphenidate plus placebo group, it was 60% (12 patients) (p=0.028).
Conclusion
This study shows that PUFA is an efficient nutrient to treat ADHD and it can be used to treat patients. However, definitive conclusion requires repeating the study with a larger sample and longer study period.
Trial registration
The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the Irct ID: IRCT2015092724209N2.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
... This was supported by the findings of animal studies, e.g., a rise in brain noradrenaline leads to an increase in focused behaviour, while a reduction in noradrenaline increases the reaction to irrelevant stimuli (Aston- Jones et al. 1997). Pliszka et al. (1996) postulated a dysfunction in both noradrenergic and dopaminergic neurotransmission and described a posterior system, in which a noradrenergic dysfunction results in attention deficits, and an anterior system, in which a hypofunctional dopamine system causes impaired executive functions. Another hypothesis suggests a reduced noradrenaline activity inducing a changed alpha-2 receptor activity in the prefrontal cortex and resulting in a dysfunctional inhibition control in children with ADHD (Arnsten et al. 1996;Arnsten and Dudley 2005). ...
The aim of this study was to assess the effects of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) on attention in rats as measured using the 5-choice-serial-reaction-time task (5CSRTT) and to investigate whether methylphenidate has effects on DSP4-treated rats. Methylphenidate is a noradrenaline and dopamine reuptake inhibitor and commonly used in the pharmacological treatment of individuals with attention deficit/hyperactivity disorder (ADHD). Wistar rats were trained in the 5CSRTT and treated with one of three doses of DSP4 or saline. Following the DSP4 treatment rats were injected with three doses of methylphenidate or saline and again tested in the 5CSRTT. The treatment with DSP4 caused a significant decline of performance in the number of correct responses and a decrease in response accuracy. A reduction in activity could also be observed. Whether or not the cognitive impairments are due to attention deficits or changes in explorative behaviour or activity remains to be investigated. The treatment with methylphenidate had no beneficial effect on the rats' performance regardless of the DSP4 treatment. In the group without DSP4 treatment, methylphenidate led to a reduction in response accuracy and bidirectional effects in regard to parameters related to attention. These findings support the role of noradrenaline in modulating attention and call for further investigations concerning the effects of methylphenidate on attentional processes in rats.
Genetic studies on attention have mainly focused on children with attention-deficit/hyperactivity disorder (ADHD), so little systematic research has been conducted on genetic correlates of attention performance and their potential brain mechanisms among healthy individuals. The current study included a genome-wide association study (GWAS, N = 1145 healthy young adults) aimed to identify genes associated with sustained attention and an imaging genetics study (an independent sample of 483 healthy young adults) to examine any identified genes' influences on brain function. The GWAS found that TTLL11 showed genome-wide significant associations with sustained attention, with rs13298112 as the most significant SNP and the GG homozygotes showing more impulsive but also more focused responses than the A allele carriers. A retrospective examination of previously published ADHD GWAS results confirmed an un-reported, small but statistically significant effect of TTLL11 on ADHD. The imaging genetics study replicated this association and showed that the TTLL11 gene was associated with resting state activity and connectivity of the somatomoter network, and can be predicted by dorsal attention network connectivity. Specifically, the GG homozygotes showed lower brain activity, weaker brain network connectivity, and non-significant brain-attention association compared to the A allele carriers. Expression database showed that expression of this gene is enriched in the brain and that the G allele is associated with lower expression level than the A allele. These results suggest that TTLL11 may play a major role in healthy individuals' attention performance and may also contribute to the etiology of ADHD.
This volume represents a burgeoning perspective on the origins of psychopathology, one that focuses on the development of the human central nervous system. The contemporary neurodevelopmental perspective assumes that mental disorders result from etiologic factors that alter the normal course of brain development. Defined here in its broadest sense, neurodevelopment is a process that begins at conception and extends throughout the life span. We now know that it is a complex process, and that its course can be altered by a host of factors, ranging from inherited genetic liabilities to psychosocial stressors. This book features the very best thinking in the converging fields of developmental neuroscience and developmental psychopathology. The developmental window represented is broad, extending from the prenatal period through adulthood, and the authors cover a broad range of etiologic factors and a spectrum of clinical disorders. Moreover, the contributors did not hesitate to use the opportunity to hypothesize about underlying mechanisms and to speculate on research directions.
ADHD is a clinically heterogeneous neuropsychiatric disorder with a childhood onset and is often accompanied by comorbidities. Symptoms consisting of inattention with or without hyperactivity or impulsivity may result from disturbances of higher cognitive control, involving multiple regions of the brain which are functionally connected. Although the value of PET and SPECT in establishing diagnosis is limited, it has added to understanding the neurobiological basis of ADHD. Investigations of cerebral perfusion and glucose metabolism during resting conditions and specific tasks have led ADHD to be associated with reduced functionality of the prefrontal cortex and the anterior cingulate cortex, as well as the basal ganglia, cerebellum and parietal lobe. In addition, there is a growing body of literature assessing the dopamine transporter, endogenous levels of dopamine, response to treatment with methylphenidate and the relationship with genotypes in ADHD with few studies having assessed serotonergic and noradrenergic functioning.
Lisdexamfetamine dimesylate (hereinafter referred to as “lisdexamfetamine”; brand name, Vyvanse®), was developed for the treatment of attention-deficit/hyperactivity disorder (ADHD). This drug, which is classified as a central nervous system (CNS) stimulant for once-daily oral administration, received marketing approval in March 2019 and was launched in December 2019 in Japan. Lisdexamfetamine is a prodrug that is hydrolyzed to its active form d-amphetamine in the blood following oral administration. Pharmacologically, d-amphetamine competitively inhibits the dopamine transporter (DAT) and the noradrenaline transporter (NAT) to increase dopamine (DA) and noradrenaline (NA) concentrations in the synaptic cleft. In addition to inhibiting the reuptake of DA and NA, d-amphetamine has also an effect in promoting the release of these neurotransmitters by being taken up into neuronal cells and then acting on the vesicular monoamine transporter. The mechanisms of action by which d-amphetamine exerts a therapeutic effect on ADHD may be based on the above-described effects. Clinical studies conducted in Japan and overseas have demonstrated the efficacy of lisdexamfetamine over placebo in the treatment of pediatric ADHD patients. The most of the adverse events with a higher incidence than in the placebo were mild, and long-term administration of the drug was not associated with an increase in the incidence of adverse events or the rate of treatment discontinuation. Lisdexamfetamine, which is designated as raw material for stimulants and therefore requires strict distribution control in Japan, is expected to be effective in the treatment of ADHD patients with inadequate responses to existing therapeutic agents.
Purpose of Review
Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders characterized by inattention, impulsivity, diminished executive functions, and hyperactivity. Objective criteria can be used to assess the diagnosis and response of the disease to medications.
Recent Findings
Several biomarkers belonging to electrophysiological, genetic, peripheral, and miRNA-based biomarkers have shown promise in studies to be an objective aid to clinical diagnostic criteria for the diagnosis of ADHD.
Summary
This review article focuses on summarizing the existing evidence for different biomarkers that have been studied in the past for diagnosing ADHD.
This book contains a comprehensive theory about subgroups of people and their problem-solving characteristics. The theory and data from 95 different studies by the author and others incorporate information about personality, interests, and cognition integrated around various kinds of numerical, verbal, and spatial problems. Using a developmental perspective, the research illustrates how children, adolescents, adults and different subgroups of people apply knowledge to everyday problems and, at times, become stymied, slowed, or adept in the problem-solving process. Individual differences are characterized through a classification system of 36 problem-solving subgroups via machine learning-Naïve Bayes, support vector machine, and decision making trees.
Genetic and environmental factors play a role in the cause and development of attention-deficit/ hyperactivity disorder (ADHD). Recent studies have suggested an important role of the gut-brain axis (GBA) and intestinal microbiota in modulating the risk of ADHD. Here, the authors provide a brief overview of the clinical and biological picture of ADHD and how the GBA could be involved in its cause. They discuss key biological mechanisms involved in the GBA and how these may increase the risk of developing ADHD. Understanding these mechanisms may help to characterize novel treatment options via identification of disease biomarkers.
Using the following link (https://authors.elsevier.com/a/1ZUyR3AL6MDLaQ) before September 21, 2019 will take you directly to the final version of our article on ScienceDirect.
Análisis de las relaciones entre el Trastorno en el Desarrollo de la Coordinación (TDC/DCD) y el Trastorno por Déficit de Atención e Hiperactividad (TDAH) en la edad escolar Resumen: Los Trastornos en el Desarrollo de la Coordinación (TDC), en inglés, Developmental Coordination Disorder (DCD), son una problemática relativamente reciente, cuya prevalencia se sitúa en torno a un 5-8% de la población infantil. Afecta a niños que no presentan ningún déficit cognitivo aparente, pero que muestran un desarrollo motor deficiente para su edad con limitaciones de coordinación y dificultades para la realización de actividades cotidianas. Los problemas de coordinación, suelen coexistir con otras dificultades. Por ello, en el presente estudio se ha realizado una revisión sistemática de la literatura científica más relevante, que analiza la comorbilidad del Trastorno en el Desarrollo de la Coordinación (TDC/DCD), con el Trastorno por Déficit de Atención e Hiperactividad (TDAH). Los resultados han destacado las relaciones que existen entre ambos trastornos en los escolares estudiados. La importancia de una intervención temprana en niños diagnosticados con TDC/DCD+TDAH se hace latente, ya que estas dificultades pueden entorpecer la vida cotidiana de los mismos (escolar, deportiva, relaciones) que pueden causar efectos colaterales. Palabras Clave: Atención, hiperactividad, coordinación, trastorno, escolares. Abstract: Motor Coordination Problems (Developmental Coordination Disorder-DCD) deal with a relatively recent problem that affects around 5-8% of the child population. It affects children who do not present any apparent cognitive deficit, but who show a deficient motor development for their age, with limitations of coordination and difficulties for the accomplishment of daily activities. DCD often coexists with other diseases. Therefore, this study presents a systematic review of the most relevant scientific literature analyzing the comorbidity of these difficulties with the Attention Deficit Disorder and Hyperactivity (ADHD). The results have shown that there are relationships between both types of difficulties among children. The importance of an early intervention in children diagnosed as DCD + ADHD is evident when analyzing the motor and attentional difficulties that hinder the normal development of their daily life (school, sport, relationships), which can be the cause of collateral problems. Introducción Los problemas evolutivos de coordinación en la edad escolar Existe un consenso en aceptar que la competencia motriz es el eje dinamizador de las clases de educación física, y el que permite comprender la existencia de los problemas evo-lutivos de coordinación en las edades escolares (Ruiz, 1995, 2005). A lo largo del pasado siglo, la literatura científica evi-dencia una amplia discusión sobre cuáles son las descrip-ciones más apropiadas para los niños con problemas de co-ordinación motora. En primer lugar, uno de los primeros autores en tratar este asunto, fue Gubbay (1975), que empleó el término dispraxia infantil para definir este tipo de trastorno, ya que teóricamente, hacía referencia a la apraxia constructiva de los adultos. Sin embargo, la apraxia es un trastorno adquiri-do, asociado a daños cerebrales localizados en el lóbulo parietal izquierdo, la corteza premotora, el área motora temporal o el área motora suplementaria (Buxbaum, Shaìro & Coslett, 2014). Progresivamente, fueron surgiendo diferen-tes términos para definir este problema. Términos como tor-peza motriz, discapacidad motora, torpeza física, apraxia del desarrollo y dificultades perceptivo-motrices, comenzaron a ser empleados por médicos, terapeutas o educadores (Barnhart, Davenport, Epps y Nordquist, 2003).
Dans de nombreuses activités physiques et sportives, la performance dépend de l’efficacité des processus physiologiques et cognitifs sollicités dans l’action. Plus précisément, il semblerait que celle-ci soit fréquemment influencée par l’efficacité des processus décisionnels qui s’effectuent sous pression temporelle. A ce titre, ce travail de thèse s’intéresse à l’effet de l’administration de trois supplémentations nutritionnelles classiquement consommées par les athlètes (hydrates de carbone, caféine et guarana) sur le fonctionnement cognitif au cours d’un exercice. Nos résultats indiquent que l’ingestion isolée de ces trois composés améliore la vitesse du traitement de l’information lors d'une tâche décisionnelle dès la fin d’un exercice. Par ailleurs, l’utilisation de la caféine en rinçage de bouche semble aussi pertinente, puisque nos résultats suggèrent une amélioration probable de l’efficacité des processus relatifs à la gestion d’un conflit au cours de l’exercice. Enfin, une diminution de la perception de l’effort est aussi rapportée lors de l’ingestion de caféine et de guarana, ou de l’utilisation d’hydrates de carbone en rinçage de bouche. L’ensemble de ces résultats indique une potentialisation de l’effet de l’exercice sur la performance cognitive. Il suggère aussi que la mise en place de supplémentations nutritionnelles lors d’un exercice améliore l’efficacité de processus cognitifs qui s’avèrent être essentiels à la performance sportive.
Although the diagnostic criteria for attention-deficit hyperactivity disorder (ADHD) were originally intended for children [1, 2], the criteria are the same for adults and can be reliably used to diagnose individuals who are currently experiencing symptoms of the disorder and have a history of these symptoms since early childhood [3, 4]. It is also necessary to document impairment in professional, academic, and personal settings and that the symptoms are due primarily to ADHD and not to another psychiatric condition or other environmental or personal circumstances. Rating scales can be quite helpful for documenting symptoms (ADHD symptom scales) or for more structured evaluations which can be used in fully establishing the diagnosis. A further utility of ADHD adult symptom scales can be in monitoring the response to treatment. There are several diagnostic interviews and symptom rating scales that can be used in the clinical evaluation of adults for ADHD (Tables 18.1 and 18.2), which are generally economical and effective in obtaining a large amount of data quickly, including symptom severity and response to treatment. Many of these measures include adult-specific prompts and probes designed to assess the impact and severity of ADHD symptoms using a semi-structured interview, which is particularly advantageous for clinicians who have limited experience in working with adult ADHD patients. There are also measures that assess ADHD-related impairments in executive function (EF), emotional regulation (ER), occupational, and quality-of-life domains.
The volume is based on the papers that were presented at the international conference Model-Based Reasoning in Science and Technology (MBR09_BRAZIL), held at the University of Campinas (UNICAMP), Campinas, Brazil, December 2009. The presentations given at the conference explored how scientific cognition, but several other kinds as well, use models, abduction, and explanatory reasoning to produce important or creative changes in theories and concepts. Some speakers addressed the problem of model-based reasoning in technology, and stressed the issue of science and technological innovation. The various contributions of the book are written by interdisciplinary researchers who are active in the area of creative reasoning in logic, science, and technology: the most recent results and achievements about the topics above are illustrated in detail in the papers. The book is divided in three parts, which cover the following main areas: part I, abduction, problem solving, and practical reasoning; part II: formal and computational aspects of model based reasoning; part III, models, mental models, representations.
Animal welfare has become an important determinant of meat quality with poor animal temperament leading to huge economic losses to the meat industry due to carcass bruising and condemnation. Handling and transport of live animals is a stressful experience for animals. The temperaments of cattle affect their behaviour and differ between breeds, i.e. studies have shown that Bos indicus types are more temperamental than Sanga and Bos taurus types. Catecholamines (CAT's) are considered as indicators of stress, because higher concentrations of CAT's in brain tissue were noted in animals that are better adapted to stressful situations. In the present study, urinary CAT's of three beef breeds were determined immediately post mortem. Brahman cattle represented Bos indicus types, Simmentaler cattle represented Bos taurus types and Nguni cattle represented the Sanga type. Nguni steers showed higher urinary norepinephrine (NE) and epinephrine (E) concentrations than Brahman and Simmentaler steers. Simmentaler steers showed a higher concentration of urinary dopamine (DA) than Br and Ng. The results suggest that Nguni cattle are less stress sensitive compared to the other beef breeds studied. These observations may be due to the process of domestication and selection for specific genes that influence tameability and consequently resulting in a shift in circulating concentrations of urinary CAT's.
The aim of the present study was to assess the effects of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), which allows a depletion of noradrenergic terminals in a dose-dependent manner, on attention in rats as measured using the five-choice serial-reaction time task (5CSRTT). In addition, we investigated whether the effects of DSP4 treatment can be reversed by atomoxetine. Atomoxetine is a selective noradrenaline reuptake inhibitor and has been shown to be effective in the treatment of attention deficit hyperactivity disorder. Wistar rats were trained in the 5CSRTT and treated with one of the three doses of DSP4 (10, 20 or 50 mg/kg) or saline. Following DSP4 treatment, rats were injected with three doses of atomoxetine (0.1, 0.5 or 1 mg/kg) or saline and tested in the 5CSRTT. The treatment with DSP4 caused a reduction in activity and a decline of performance in parameters related to attention in the 5CSRTT. Whether or not these impairments are due to attention deficits or changes in explorative behaviour and activity remains to be investigated. The treatment with atomoxetine had no beneficial effect on the rats’ performance regardless of the DSP4 treatment. The present findings support the role of noradrenaline in modulating attentional processes and call for future studies regarding the effects of atomoxetine on attention in rats.
This chapter summarizes the empirical literature on attention-deficit/hyperactivity disorder (ADHD) in African American youth. ADHD, characterized by age-inappropriate levels of inattention and/or hyperactivity and impulsivity, causes significant impairment for children in three major areas of their lives: at home, at school, and with peers. Given the family discord, academic struggles, and difficulties with friendships that may plague youth with ADHD, evidence-based treatments have been developed. This review will discuss those interventions, including both psychosocial and pharmacological treatments, with a specific focus on the literature to date with regard to African American children and adolescents. Significant treatment disparities exist in this area of child psychopathology, with African American youth being less likely to obtain appropriate diagnoses and treatment. Several possible explanations for the disparities, such as culturally bound attitudes about mental health, are presented. There is much work to be done to better understand and serve African American youth with ADHD and their families. However, the literature to date offers some pointed directions for clinicians (e.g., including extended family members in treatment) as well as researchers (e.g., investigating the acceptability of the different components of psychosocial treatments). Thus we conclude the chapter by providing several guidelines for clinicians working with African American families of children with ADHD as well as suggestions for future research in this area.
A vast body of research and clinical experience about the pharmacological treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) has been gathered over several decades. In this chapter’s review of this literature, we particularly emphasize the role and effects of psychostimulants, the most commonly prescribed medications for children with ADHD and the most extensively studied. We examine the current role of medication in the treatment of ADHD, summarize the contemporary concepts of the neurochemical rationale for the effects of the various drugs used to treat ADHD, and comment on the benefits and limitations of each class of medication. Although we emphasize the clinical implications of existing knowledge about drug effects, we do not provide a guide to clinical practice for the treatment of children with ADHD.
PET images of blood flow change that were averaged across individuals were used to identify brain areas related to lexical (single-word) processing, A small number of discrete areas were activated during several task conditions including: modality-specific (auditory or visual) areas activated by passive word input, primary motor and premotor areas during speech output, and yet further areas during tasks making semantic or intentional demands.
We review 22 neuropsychological studies of frontal lobe functions in children with attention deficit disorder with and without hyperactivity (ADD/+H, ADD/-H). Some measures presumed to assess frontal lobe dysfunctions were not reliably sensitive to the deficits occurring in either form of ADD. Tests of response inhibition more reliably distinguished ADD/+H from normal children. Where impairments were found on other tests between ADD and normal subjects, they were highly inconsistent across studies and seemed strongly related to age of the subjects and possibly to the version of the test employed. Other methodological differences across studies further contributed to the discrepant (LD) and conduct problems, with ADD may be an additional confounding factor in some, though not all, of these studies. In a separate reports. The co-morbidity of other disorders, such as learning disabilities (LD) and conduct problems, with ADD may be an additional confounding factor in some, though not all, of these studies. In a separate study, children with ADD/+H (n = 12) were then compared on frontal lobe tests to three other groups: ADD/-H (n = 12), LD but no ADD (n = 11), and normal children (n = 12) statistically covarying for differences in conduct problems across groups. Most measures did not distinguish among these groups. Both ADD groups made more omission errors on a Continuous Performance Test (CPT) than the normal group. All three clinical groups performed more poorly on the word and interference portions of the Stroop Test. Thus, while both types of ADD share some apparent similarities in deficits on a few frontal lobe tests in this study, the totality of existing findings suggests an additional problem with perceptual-motor speed and processing in the ADD/-H group.
: The concept of attention as central to human performance extends back to the start of experimental psychology, yet even a few years ago, it would not have been possible to outline in even a preliminary form a functional anatomy of the human attentional system. New developments in neuroscience have opened the study of higher cognition to physiological analysis, and have revealed a system of anatomical areas that appear to be basic to the selection of information for focal (conscious) processing. The importance of attention is its unique role in connecting the mental level of description of processes used in cognitive science with the anatomical level common in neuroscience. Sperry describes the central role that mental concepts play in understanding brain function. As is the case for sensory and motor systems of the brain, our knowledge of the anatomy of attention is incomplete. Nevertheless, we can now begin to identify some principles of organization that allow attention to function as a unified system for the control of mental processing. Although many of our points are still speculative and controversial, we believe they constitute a basis for more detailed studies of attention from a cognitive-neuroscience viewpoint. Perhaps even more important for furthering future studies, multiple methods of mental chronometry, brain lesions, electrophysiology, and several types of neuro-imaging have converged on common findings.
To compare the effects of the stimulant drugs dextroamphetamine and methylphenidate on urinary and plasma monoamines and metabolites within the same clinical sample, thirty-one children with attention-deficit disorder with hyperactivity were treated with dextroamphetamine (up to 1.5 mg/kg/day), methylphenidate (up to 3.0 mg/kg/day), and placebo in an 11-week double-blind crossover trial. As expected, both drugs showed striking clinical efficacy, and within a subsample of the group, earlier findings were confirmed, that dextroamphetamine but not methylphenidate lowered urinary and plasma 3-methoxy-4-hydroxyphenylglycol and whole body norepinephrine turnover, and that urinary and plasma concentration of homovanillic acid was unaltered by either drug. Methylphenidate but not dextroamphetamine increased plasma norepinephrine. Urinary epinephrine and metanephrine were increased with both drugs, but this increase did not correlate significantly with clinical improvement.
The cause of childhood hyperactivity (attention deficit-hyperactivity disorder) is unknown. We investigated the hypothesis that cerebral glucose metabolism might differ between normal adults (controls) and adults with histories of hyperactivity in childhood who continued to have symptoms. Each patient was also the biologic parent of a hyperactive child. None of the adults had ever been treated with stimulant medication. To measure cerebral glucose metabolism, we administered 148 to 185 MBq (4 to 5 mCi) of [18F]fluoro-2-deoxy-D-glucose intravenously to 50 normal adults and 25 hyperactive adults while they performed an auditory-attention task. Images were obtained for 30 minutes with a Scanditronix positron-emission tomograph with a resolution of 5 to 6 mm. Whole-brain and regional rates of glucose metabolism were measured with computer assistance by two trained research assistants, working independently, who were blinded to the subjects' status (control or hyperactive).
Global cerebral glucose metabolism was 8.1 percent lower in the adults with hyperactivity than in the normal controls (mean +/- SD, 9.05 +/- 1.20 mg per minute per 100 g vs. 9.85 +/- 1.68 mg per minute per 100 g; P = 0.034). In the adults with hyperactivity, glucose metabolism was significantly reduced, as compared with the values for the controls, in 30 of 60 specific regions of the brain (P less than 0.05). Among the regions of the brain with the greatest reductions in glucose metabolism were the premotor cortex and the superior prefrontal cortex. When the seven women with hyperactivity or the six patients with learning disabilities were omitted from the analysis, the results were similar.
Glucose metabolism, both global and regional, was reduced in adults who had been hyperactive since childhood. The largest reductions were in the premotor cortex and the superior prefrontal cortex--areas earlier shown to be involved in the control of attention and motor activity.
From W.B. Cannon's identification of adrenaline with "fight or flight" to modern views of stress, negative views of peripheral physiological arousal predominate. Sympathetic nervous system (SNS) arousal is associated with anxiety, neuroticism, the Type A personality, cardiovascular disease, and immune system suppression; illness susceptibility is associated with life events requiring adjustments. "Stress control" has become almost synonymous with arousal reduction. A contrary positive view of peripheral arousal follows from studies of subjects exposed to intermittent stressors. Such exposure leads to low SNS arousal base rates, but to strong and responsive challenge- or stress-induced SNS-adrenal-medullary arousal, with resistance to brain catecholamine depletion and with suppression of pituitary adrenal-cortical responses. That pattern of arousal defines physiological toughness and, in interaction with psychological coping, corresponds with positive performance in even complex tasks, with emotional stability, and with immune system enhancement. The toughness concept suggests an opposition between effective short- and long-term coping, with implications for effective therapies and stress-inoculating life-styles.
This chapter will be mote empirical than theoretical. There are two interconnected reasons for making the empirical studies primary. First, the results may be of some interest in themselves, and second, careful observation and analyses of the phenomena studied precede (and indeed form the best basis for) sound theorizing about the lawful principles of individual functioning that we are researching.
Twenty-four hyperactive or unsocialized-aggressive children participated in an exploratory double-blind crossover study comparing the cognitive effects of methylphenidate hydrochloride (0.3 mg/kg), two doses (0.25 and 0.05 mg/kg) of haloperidol, and inert placebo. Each subject received each of four drug conditions, drug order being randomized by a Latin square design. At the end of each 18-day trial period, attention, immediate recognition memory, reaction times, and seat activity were tested.
While drug effects were small, methylphenidate and, to a lesser extent, the low dose of haloperidol, facilitated performance, whereas there was some suggestion that the high dose of haloperidol may have caused a slight deterioration In performance. These results are contrasted with effects on social behavior where the latter improved behavior. No differences attributable to diagnosis were found.
• Depressed patients as a group have been found to excrete greater amounts of catecholamines (CAs) and metabolites than healthy control subjects, but these differences were not uniform for all metabolites. Patients may differ from controls in the metabolism and/or disposition of CAs. We analyzed the suggested metabolic-dispositional differences by determining 24-hour urine values for norepinephrine (NE), epinephrine (E), normetanephrine (NM), metanephrine (M), vanillylmandelic acid (VMA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). For each subject, we calculated ratios of CAs or metabolites to an estimate of CA synthesis and determined ratios of CAs and metabolites to each other based on a precursor-product paradigm. The results indicate that (1) as a group, patients have modestly but significantly greater CA synthesis rates than controls; (2) patients excrete disproportionately more NE and E and disproportionately less MHPG relative to estimated CA synthesis, as well as other metabolites, than do controls; (3) in contrast to NE, E, and MHPG, the increased NM, M, and VMA excretion rates by patients are proportional to each other as well as to the increase in CA synthesis; and (4) the differences in NE, E, and metabolite excretion in the patients as a group are due principally to unipolar rather than bipolar depressives. The differences would be expected if patients, relative to controls, released more NE and E into the circulation. These data indicate the need to measure several CAs and metabolites when evaluating differences between groups since the significance of any given metabolite value needs to be examined in the context of total CA and metabolite production and excretion.
• Cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, a metabolite of serotonin, were measured in relation to aggression, impulsivity, and social functioning in 29 children and adolescents with disruptive behavior disorders. The cerebrospinal fluid 5-hydroxyindoleacetic acid level was low compared with that of age-, sex-, and race-matched patients with obsessive-compulsive disorder. Within the disruptive group, significant negative correlations with age-corrected 5-hydroxyindoleacetic acid level were seen for the child's report of aggression toward people and the expressed emotionality of the child toward his or her mother; other correlations of age-corrected 5-hydroxyindoleacetic acid level with measures of aggression were in the expected negative direction but did not reach statistical significance. Impulsivity per se and socioenvironmental factors were not significantly related to cerebrospinal fluid 5-hydroxyindoleacetic acid concentration.
The dopamine innervation of the prefrontal cortex is functionally as well as anatomically specific. Dopamine-immunopositive terminals form symmetrical, presumed inhibitory, synapses on the spines of pyramidal neurons usually in conjunction with input from other afferent sources. In addition, different subsets of prefrontal neurons appear to bear different complements of D1 and D2 receptors. The cognitive deficits associated with dopamine deficiency in the prefrontal cortex are equally selective: they are expressed in performance which is memory-guided and not in tasks which are guided by external stimuli. Evidence from studies of experimentally induced dopamine deficits in nonhuman primates as well as in patients with Parkinson's disease supports the view that short-term (working) memory is a mnemonic process especially vulnerable to dopamine loss. This dependence can be understood if dopamine afferents modulate the responses of prefrontal neurons to excitatory input, particularly via axospinous synapses on projection neurons that participate in mnemonic coding and/or influence motor outflow and feedback to the cortex. It is possible that different subsets of pyramidal neurons bearing the majority of D1 and D2 receptors, respectively, mediate different aspects of memory-guided behaviours.
Our knowledge of dopamine receptor diversity has markedly increased during the past few years as a result of discovery of five distinct genes and splice variants. These genes can be classified into two subfamilies: the intronless genes that encode the D1 and D5 receptors positively linked to adenylyl cyclase and genes with introns that encode the two isoforms of the D2 receptor and the D3 and D4 receptors. The various dopamine receptor subtypes can be distinguished by their sequence, intracellular signalling systems, pharmacology and localization.
place three broad-band childhood disorders—Attention Deficit Disorder with Hyperactivity (ADDH), Conduct Disorder (CD), and Anxiety-Withdrawal Disorder (AW)—within Gray's REW [reward system] and BIS [behavioral inhibition system] model
propose a number of investigations, utilizing both learning paradigms and psychophysiologic measures to test those proposed relationships (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The central question concerns the relationship between aspects of behaviour and physiological reactions. Measures of sympathetic-adrenal activity in terms of adrenaline excretion in a normal and a stressful situation as well as teacher ratings of behaviour were analysed for a representative group of 86 boys aged 13. Adrenaline excretion was in both situations significantly negatively related to ratings of aggressiveness, motor restlessness, and concentration difficulties and also to the sum of the latter two, used as an indicator of hyperactive behaviour. The association between hyperactive behaviour and adrenaline excretion persisted in the stressful situation when aggressiveness was controlled, whereas there was no significant relationship between aggressiveness and adrenaline output when hyperactive behaviour was controlled. Furthermore, hyperactive boys differed significantly from non-hyperactive boys in displaying lower adrenaline excretion in both situations. The results are discussed in terms of low sympathetic-adrenal reactivity to external demands as a risk factor and as a possible indicator of vulnerability for social and/or pervasive conduct disturbances.
The influence of neurotic instability as manifested by functional somatic complaints (neurosomatism) and aerobic fitness on responses to mental stress and to intravenous adrenaline infusions were investigated in 44 university students. Adrenaline-induced changes from resting levels in state anxiety and somatic anxiety were significantly more pronounced in high than in low neurosomatic subjects and all anxiety ratings were generally negatively related to aerobic fitness. Cardiovascular reactivity was induced by mental stress and by adrenaline infusions, but was not altered by neurosomatism. In individuals assumed to be characterized by a susceptibility to adrenergic effects, interference of adrenaline-induced arousal with cognitive performance may not occur. In contrast, a further increase in performance may occur when adrenaline is infused. Performance measures correlated negatively with anxiety during the baseline task and the placebo task, but this negative relation was absent during the adrenaline infusion and was replaced by positive relations between performance and aerobic power. The complex relations between bodily symptoms of anxiety, aerobic fitness and mental stress are discussed.
The repeatedly observed strong positive correlation between 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in human cerebrospinal fluid (CSF) prompted an investigation to see if conclusions concerning possible interactions between brain serotonin and dopamine turnover could be reached from human CSF concentrations of these acid metabolites. CSF data from patients with depressive disorders diagnosed according to the RDC from Sweden (n=140) and from the National Institute of Mental Health (n=35) were used to test structural hypotheses by two statistical approaches—LISREL analysis and logistic regression. Results from both men and women were unequivocal: 5HIAA “controls” HVA, interpretable as a regulatory action of serotonin turnover on dopamine turnover. In women, only 5HIAA was affected by age, height and body size (higher in elderly, short and stout women); no similar relationships were seen in males. The concept of a serotonergic regulation of dopamine turnover was tested on brain punch analyses of serotonin and dopamine and their metabolites in two sets of dogs in a large number of brain areas. Results confirm a facilatory effect of serotonin on indices of dopamine turnover in many brain regions, especially brain stem and hypothalamus. The animal data validate the data analytic approach in humans.
Cerebrospinal fluid (CSF), plasma, and urinary monoamine metabolites were determined for 29 boys, aged 6–12, with attention-deficit hyperactivity disorder (ADHD). Levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), the metabolites of serotonin, dopamine, and norepinephrine, respectively, correlated significantly with behavioral measures of aggression and impulsivity/hyperactivity. However, these correlations were in the unexpected direction; for example, CSF 5-HIAA correlated positively with the Brown-Goodwin Lifetime History of Aggression Scale. HVA in CSF was positively correlated with several measures of hyperactivity. The replicability of these findings, as well as possible socioenvironmental effects, and the predictive value of CSF monoamines in prepubertal hyperactivity are the subjects of ongoing study.
Activity of neurons in the hippocampus (HPC) was recorded in awake, freely moving rats. Most cells were inhibited by either a loud auditory stimulus (tone) or by electrical stimulation of the nucleus locus coeruleus (LC). The inhibitory responses to the tone were antagonized by drugs that interfere with central noradrenergic transmission. When LC stimulation was used as the unconditioned stimulus in a classical conditioning paradigm, previously inhibitory responses to the tone were reinstituted. When behaviorally subthreshold LC stimulation preceded a tone which was correlated with food, the existing conditioned response to the tone was potentiated. These data suggest that the generalized inhibitory response of HPC neurons to a tone is modulated by the noradrenergic pathway and that experimental activation of LC can potentiate HPC responses to behaviorally significant conditioned stimuli.
Lumbar cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid, the major metabolites of dopamine and serotonin, respectively, in hyperactive children did not differ significantly from those of age-matched controls. Dextroamphetamine treatment substantially reduced the spinal fluid content of homovanillic acid but not of 5-hydroxyindoleacetic acid. No change in levels of either monoamine metabolite occurred with placebo therapy. In hyperactive children receiving dextroamphetamine, the amount of homovanillic acid decline correlated closely with the degree of clinical improvement. These results support the view that an alteration in central dopamine-mediated synaptic function may occur in children manifesting the hyperactive syndrome.
Twenty-four hyperactive or unsocialized-aggressive children participated in an exploratory double-blind crossover study comparing the cognitive effects of methylphenidate hydrochloride (0.3 mg/kg), two doses (0.25 and 0.05 mg/kg) of haloperidol, and inert placebo. Each subject received each of four drug conditions, drug order being randomized by a Latin square design. At the end of each 18-day trial period, attention, immediate recognition memory, reaction times, and seat activity were tested. While drug effects were small, methylphenidate and, to a lesser extent, the low dose of haloperidol, facilitated performance, whereas there was some suggestion that the high dose of haloperidol may have caused a slight deterioration in performance. These results are contrasted with effects on social behavior where the latter improved behavior. No differences attributable to diagnosis were found.
Clinical, animal and neuroanatomical studies of differential isomer and dosage effects of CNS stimulant medications on behaviour are reviewed. Wender's hypothesis that an underlying biochemical abnormality and a disorder of reinforcement was the primary deficit in "MBD" children is restated in terms of a disorder of polysynaptic dopaminergic circuits, between prefrontal and striate centres. Wender's notion of a disorder of reinforcement is broadened to include a disorder of planning and correction of behaviour, including capacity for cortical control of automatic instinctual motor programmes. The dopamine hypothesis of Attention Deficit Hyperactivity Disorder (ADHD) is examined from the point of view of differential dose effects of CNS stimulant medications, and theories of neural control. Clinical, animal and neuropharmacological studies are reviewed. Implications of the findings for understanding clinical and side effects in ADHD children of stimulants are discussed.
Experiments were conducted to examine the hypothesis that increased neuronal discharge activity of noradrenergic neurons of the locus coeruleus (LC) above resting discharge rates can alter forebrain electroencephalographic (EEG) activity. Small infusions (70-135 nl) of the cholinergic agonist bethanechol within 500 microns of the LC were used to activate this nucleus reversibly in halothane-anesthetized rats. A combined recording-infusion probe allowed verification of this electrophysiological activation. Simultaneously, EEG activity was recorded from sites in the frontal cortex and hippocampus and subjected to power-spectrum analyses. The findings were (1) LC activation was consistently followed, within 5 to 30 sec, by a shift from low-frequency, high-amplitude to high-frequency, low-amplitude EEG activity in frontal neocortex and by the appearance of intense theta-rhythm in the hippocampus; (2) forebrain EEG changes followed LC activation with similar latencies whether infusions were made lateral or medial to the LC; (3) infusions placed outside the immediate vicinity of the LC were not followed by these forebrain EEG effects; (4) following infusion-induced activation, forebrain EEG returned to preinfusion patterns with about the same time course as the recovery of LC activity (10-20 min for complete recovery). These infusion-induced effects on EEG activity were blocked or severely attenuated by pretreatment with the alpha 2-agonist clonidine, which inhibits LC discharge and norepinephrine release, or the beta-antagonist propranolol. These observations indicate that enhanced LC discharge activity is the crucial mediating event for the infusion-induced changes in forebrain EEG activity observed under these conditions and suggest that LC activation may be sufficient to induce EEG signs of cortical and hippocampal activation.
The pathophysiology of Attention-Deficit Hyperactivity Disorder (ADHD) forms the subject of the two papers in this section. Dr. James McCracken of the University of California, Los Angeles, reviews current ideas about the psychopharmacology of ADHD. He takes as his starting point the undoubted efficacy of stimulant drugs in this condition and constructs a model of catecholamine abnormality to account for disordered attention and activity. Dr. Katya Voeller, from the University of Florida in Gainesville, takes a different approach. Attention is abnormal in neglect and related phenomena, well studied in adult patients with identifiable brain lesions. She proposes a model of attention and intention based on these disorders and cites her own work to place ADHD within this framework. The two papers present ideas that are not at all mutually exclusive. We hope the reader can use them to develop a working theory of ADHD for clinical practice.
Cerebrospinal fluid levels of 5-hydroxyindoleacetic acid, a metabolite of serotonin, were measured in relation to aggression, impulsivity, and social functioning in 29 children and adolescents with disruptive behavior disorders. The cerebrospinal fluid 5-hydroxyindoleacetic acid level was low compared with that of age-, sex-, and race-matched patients with obsessive-compulsive disorder. Within the disruptive group, significant negative correlations with age-corrected 5-hydroxyindoleacetic acid level were seen for the child's report of aggression toward people and the expressed emotionality of the child toward his or her mother; other correlations of age-corrected 5-hydroxyindoleacetic acid level with measures of aggression were in the expected negative direction but did not reach statistical significance. Impulsivity per se and socioenvironmental factors were not significantly related to cerebrospinal fluid 5-hydroxyindoleacetic acid concentration.
Recordings from noradrenergic locus coeruleus (LC) neurons in behaving rats and monkeys revealed that these cells decrease tonic discharge during sleep and also during certain high arousal behaviors (grooming and consumption) when attention (vigilance) was low. Sensory stimuli of many modalities phasically activated LC neurons. Response magnitudes varied with vigilance, similar to results for tonic activity. The most effective and reliable stimuli for eliciting LC responses were those that disrupted behavior and evoked orienting responses. Similar results were observed in behaving monkeys except that more intense stimuli were required for LC responses. Our more recent studies have examined LC activity in monkeys performing an "oddball" visual discrimination task. Monkeys were trained to release a lever after a target cue light that occurred randomly on 10% of trials; animals had to withhold responding during non-target cues. LC neurons selectively responded to the target cues during this task. During reversal training, LC neurons lost their response to the previous target cue and began responding to the new target light in parallel with behavioral reversal. Cortical event-related potentials were elicited in this task selectively by the same stimuli that evoked LC responses. Injections of lidocaine, GABA, or a synaptic decoupling solution into the nucleus paragigantocellularis in the rostral ventrolateral medulla, the major afferent to LC, eliminated responses of LC neurons to sciatic nerve stimulation or foot- or tail-pinch. This indicates that certain sensory information is relayed to LC through the excitatory amino acid (EAA) input from the ventrolateral medulla. The effect of prefrontal cortex (PFC) activation on LC neurons was examined in anesthetized rats. Single pulse PFC stimulation had no pronounced effect on LC neurons, consistent with our findings that this area does not innervate the LC nucleus. However, trains of PFC stimulation substantially activated most LC neurons. Thus, projections from the PFC may activate LC indirectly or through distal dendrites, suggesting a circuit whereby complex stimuli may influence LC neurons. The above results, in view of previous findings for postsynaptic effects of norepinephrine, are interpreted to reveal a role for the LC system in regulating attentional state or vigilance. The roles of major inputs to LC from the ventrolateral and dorsomedial medulla in sympathetic control and behavioral orienting responses, respectively, are integrated into this view of the LC system. It is proposed that the LC provides the cognitive complement to sympathetic function.
The prefrontal cortex is involved in the cognitive process of working memory. Local injections of SCH23390 and SCH39166, selective
antagonists of the D1 dopamine receptor, into the prefrontal cortex of rhesus monkeys induced errors and increased latency
in performance on an oculomotor task that required memory-guided saccades. The deficit was dose-dependent and sensitive to
the duration of the delay period. These D1 antagonists had no effect on performance in a control task requiring visually guided
saccades, indicating that sensory and motor functions were unaltered. Thus, D1 dopamine receptors play a selective role in
the mnemonic, predictive functions of the primate prefrontal cortex.
Nineteen children and adolescents with attention-deficit hyperactivity disorder were treated with fluoxetine hydrochloride. The drug was administered in an open-label fashion for 6 weeks. At completion of the study, nearly 60% were judged to be at least moderately improved. No effects on appetite or weight were observed, and side effects were minimal. These findings suggest that fluoxetine may prove to be an alternative treatment for some attention-deficit hyperactivity disorder patients.
Attention deficit hyperactivity disorder is a heterogeneous disorder of unknown etiology. Little is known about the comorbidity of this disorder with disorders other than conduct. Therefore, the authors made a systematic search of the psychiatric and psychological literature for empirical studies dealing with the comorbidity of attention deficit hyperactivity disorder with other disorders.
The search terms included hyperactivity, hyperkinesis, attention deficit disorder, and attention deficit hyperactivity disorder, cross-referenced with antisocial disorder (aggression, conduct disorder, antisocial disorder), depression (depression, mania, depressive disorder, bipolar), anxiety (anxiety disorder, anxiety), learning problems (learning, learning disability, academic achievement), substance abuse (alcoholism, drug abuse), mental retardation, and Tourette's disorder.
The literature supports considerable comorbidity of attention deficit hyperactivity disorder with conduct disorder, oppositional defiant disorder, mood disorders, anxiety disorders, learning disabilities, and other disorders, such as mental retardation, Tourette's syndrome, and borderline personality disorder.
Subgroups of children with attention deficit hyperactivity disorder might be delineated on the basis of the disorder's comorbidity with other disorders. These subgroups may have differing risk factors, clinical courses, and pharmacological responses. Thus, their proper identification may lead to refinements in preventive and treatment strategies. Investigation of these issues should help to clarify the etiology, course, and outcome of attention deficit hyperactivity disorder.
Attention deficit disorder with hyperactivity (ADDH) is characterized by a high level of inappropriate activity, distractability and impulsivity as well as learning deficits. In mammals, the protective mechanism for acquisition of sensory information, processed for its survival value, can be termed "vigilance". In ADDH, a low threshold for novel or sensory stimuli, results in a "hard wired" mammalian response, orienting, followed by exploratory behavior, the orienting reaction. This behavior is mediated in the brainstem through sensory neurons in the reticular formation regulating the discharge of locus coeruleus noradrenergic neurons. It is proposed that adrenaline acts as a tonic inhibitor of these neurons, modulating the level of sensory stimulation necessary to elicit locus coeruleus excitation. An imbalance in adrenaline formation or alpha-2 adrenergic receptor number (or affinity) leads to the inability to maintain the appropriate threshold for discharge of locus coeruleus neurons. The consequences are inability to maintain focused attention, difficulty in falling asleep or light levels of sleep, inattention to consumptive behavior, and probable inappropriate response for reward as all these behaviors require disruption of processing of sensory stimuli. Cognitive deficits may occur secondarily.
It has previously been demonstrated that monkeys exhibit certain event-related potential (ERP) components showing latency, polarity, and contingency similarities to those observed in humans. In the present study, monkey P300-like components were studied in order to evaluate the hypothesis that the noradrenergic locus coeruleus (LC) system participates in their generation or modulation. ERPs were recorded from untrained squirrel monkeys (Saimiri sciureus) twice a week for 4 weeks before and after bilateral LC lesions and interruption of dorsal bundle (DB) fibers. Stimuli consisted of 2 and 6 kHz tone pips (40 msec duration, 60 dB above nHL) presented once a second in random order. In most sessions, one tone constituted 90% of the stimuli and the other tone 10%, while in some sessions tones were made equiprobable to test the effects of manipulating stimulus probability. LC and DB lesions were made by first localizing the nucleus and creating an electrolytic lesion. Then, the electrode was placed at the anterior pole of the nucleus and a knife cut effected. The extent of damage to LC perikarya and ascending axons was assessed by reconstructing lesions from Nissl-stained sagittal sections through the brain stems. The effect of lesions on cortical noradrenergic axons was immunohistochemically verified utilizing antisera directed against dopamine-B-hydroxylase and tyrosine hydroxylase to label noradrenergic and dopaminergic axons, respectively. The prelesion ERP results replicated previous findings of P300-like components recorded in response to low-probability tones. The postlesion ERP data indicated that following damage to LC cell bodies, combined with interruption of histochemically detectable ascending noradrenergic axons, monkey P300-like potentials exhibited decreased areas, altered brain-surface distribution, and reduced sensitivity to stimulus probability. The correlation between the extent of cell body lesions and percentage reduction in the magnitude of P300-like responses was significant. However, interruption of DB fibers alone did not have similar effects. Neither type of lesion had any effect on amplitudes, latencies, or brain-surface distributions of P52, P172, or N250-900. There was, however, a significant effect on N106. Stimulus probability effects on the frontally distributed P52 and N106 were not altered by the lesions. These data support the hypothesis that the integrity of the LC nucleus and its ascending fibers is important in the generation and modulation of surface-recorded P300-like activity.
Children with attention deficit disorder with hyperactivity were given either methylphenidate hydrochloride or dextroamphetamine sulfate to compare the effects on urinary excretion of catecholamines, indoleamines, and phenylethylamine (PEA). Methylphenidate's effects were distinctly different from those of dextroamphetamine. After methylphenidate administration, both norepinephrine (NE) and normetanephrine (NMN) concentrations were significantly elevated, and there was a 22% increase in excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG). In contrast, after dextroamphetamine treatment, MHPG excretion was significantly reduced and NE and NMN values were unchanged. Excretion of dopamine and metabolites was unchanged by either drug. Urinary PEA excretion was not significantly changed after methylphenidate treatment, but increased 1,600% in response to dextroamphetamine. Methylphenidate treatment did not significantly alter serotonin or 5-hydroxyindoleacetic acid excretion. Effects of dextroamphetamine were not tested.
Twenty boys (mean age, 9 +/- 2 years) with attention deficit disorder with hyperactivity received three weeks each of dextroamphetamine sulfate (0.5 mg/kg/d), fenfluramine hydrochloride (0.6 mg/kg/d increased to 2.0 mg/kg/d), and placebo in a double-blind, random-order, crossover design. Half the boys also met criteria for conduct disorder. Dextroamphetamine produced immediate and marked improvement in disruptive, overactive behaviors. Fenfluramine had no effect on any behavioral measure at either the low or high dosage. Both drugs decreased levels of urinary norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid. Fenfluramine, however, also produced a significant decrease in plasma MHPG levels and a larger decrease in urinary norepinephrine levels. It reduced urinary epinephrine levels as well, an effect opposite to that of dextroamphetamine. These findings suggest that different mechanisms of action are involved in the ability of the two drugs to reduce levels of MHPG and vanillylmandelic acid. Fenfluramine increased plasma prolactin levels and decreased platelet serotonin levels. Despite the structural similarity of the two drugs, some common overall effects on catecholamine metabolism, and similar effects on weight, fenfluramine had none of the motor activity or therapeutic effects of dextroamphetamine.
The effect of methylphenidate (0.3 mg/kg) on the performance of vigilance tasks after a prior treatment with haloperidol (0.04 mg/kg) was investigated to see whether haloperidol changed the response on vigilance tasks. The subjects were 12 attention deficit disorder with hyperactivity boys aged 64 to 122 months. Methylphenidate was shown to diminish attention deficits in the hyperactive group, but when methylphenidate was preceded by haloperidol, this effect was blocked on all the vigilance subtests. The implications of these findings for a primarily dopaminergic action of methylphenidate in attention-disordered children is discussed.
Marmosets, shown to have comparable levels of spontaneous locomotor activity, assessed in cages equipped with infra-red photocell units, could be separated into "high", "moderate" and "low activity" responders on the basis of their locomotor hyperactivity response to peripherally administered (-)N-n-propylnorapomorphine [(-)NPA]. Animals selected as "low" and "high activity" responders to (-)NPA were subjected to chronic infusion of dopamine, or its solvent, bilaterally into the nucleus accumbens for 13 days through Alzet osmotic minipumps. Both "low" and "high activity" responders exhibited an increased locomotor activity which peaked on days 6-7 of the infusion. This hyperactivity, caused by infusion of dopamine was antagonised by small doses of sulpiride and fluphenazine. After the infusion, the level of spontaneous locomotor activity of the marmosets was unchanged from pre-infusion values. However, 2-3 weeks after discontinuing the infusion, the animals initially classified as "low activity" responders showed markedly enhanced activity when challenged with (-)NPA, and conversely, animals initially classified as "high activity" responders showed a reduced responsiveness to (-)NPA. It is concluded that the consequences of a persistent increase in the activity of dopamine in the nucleus accumbens of the brain of the marmoset are to (a) enhance locomotor activity during infusion and (b) after discontinuing infusion, to modify the locomotor responsiveness to challenge with a dopamine agonist, with the direction of the change dependent on the initial basal locomotor responsiveness to (-)NPA.
Over 20 neuropharmacological agents have been used for the study and treatment of children with Attention Deficit Disorder with Hyperactivity since Charles Bradley first described the effects of benzedrine in 1937, now 50 years ago. Although an array of drugs are superior to placebo, the stimulants are still the treatment of choice. The large number of efficacious drugs do not support any single neurotransmitter defect hypothesis, and no current model can account for the abundance of “positive” findings. The most promising areas for research at this time appear to be in-depth studies of response to stimulants and more physiological studies using brain imaging techniques.