Kurt P. Schulz

Revisiting the Role of the Prefrontal Cortex in the Pathophysiology of Attention-Deficit/Hyperactivity Disorder.

Most neural models for the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) have centered on the prefrontal cortex and its interconnections with the striatum and other subcortical structures. However, research only partially supports these models, and they do not correspond with the development of the prefrontal cortex and its interrelated neurocircuitry. The neural and functional development of the prefrontal cortex more closely parallels recovery from ADHD as indicated by the developmental remission of symptomatology. The authors hypothesize that ADHD is due to noncortical dysfunction that manifests early in ontogeny, remains static throughout the lifetime, and is not associated with the remission of symptomatology. Data supporting this neurodevelopmental model of prefrontal cortex function in ADHD are reviewed. Research and treatment implications are discussed.

Brain dopamine transporter levels in treatment and drug naïve adults with ADHD

Attention deficit hyperactivity disorder (ADHD) is the most frequent psychiatric disorder in children, yet data are sparse on its pathophysiology. Particularly relevant are the dopamine transporters since these are the main targets of stimulant medications used for ADHD treatment. Though some imaging studies have shown increases in dopamine transporters in ADHD others have not and their role in the neurobiology of ADHD remains unclear. Here we investigate dopamine transporters in ADHD subjects with control of potentially confounding factors (previous medication and/or drug histories, comorbidity) and their association with clinical symptoms. Positron emission tomography and [11C]cocaine were used to measure dopamine transporters in 20 never medicated adults with ADHD and 25 controls. Dopamine transporters were lower in left caudate (13%, p < 0.05) and in left nucleus accumbens (p < 0.005) in ADHD subjects than in controls. In putamen dopamine transporters did not differ between groups but were associated with scores of inattention (Conners Adult Attention Rating Scale) both in ADHD subjects (p < 0.005) and in controls (p < 0.005). Thus, for a given transporter level the scores for inattention were on average five times greater in ADHD subjects than in controls. These results do not corroborate increases in dopamine transporters in ADHD subjects and show that in some they are reduced. It also provides evidence that dopamine transporter levels modulate attention but suggest that additional pathology (e.g., prefrontal or cingulostriatal pathways, noradrenergic neurotransmission) is necessary to account for the large differences in inattention observed between controls and ADHD subjects.

Plasma Cortisol and Aggression in Boys With ADHD

OBJECTIVE The results of several studies suggest an inverse relationship between cortisol secretion and aggressive behavior. This study examined basal plasma cortisol levels in aggressive and nonaggressive boys with attention-deficit hyperactivity disorder (ADHD). METHOD The subjects were 23 aggressive and 27 nonaggressive boys with ADHD, aged 7 to 11 years. After 3 days of a low monoamine diet and an overnight fast, an indwelling catheter was inserted into a forearm vein. Samples for plasma cortisol levels were obtained 105 and 115 minutes after insertion of the catheter. RESULTS A one-way analysis of covariance (ANCOVA) controlling for body mass revealed no significant difference in plasma cortisol between the aggressive and nonaggressive boys. Furthermore, when the children were alternatively divided on the basis of the presence or absence of a DSM-III-R diagnosis of conduct disorder, a one-way ANCOVA again revealed no significant difference in cortisol levels. CONCLUSIONS The hypothesized inverse relationship between cortisol secretion and aggressive behavior in boys with ADHD was not found. These findings are consistent with a large body of literature indicating that the biological substrate of aggression is complex and that the identification of biological laboratory markers of aggressive behavior is not a clinically useful strategy at this time.

Common and Unique Therapeutic Mechanisms of Stimulant and Nonstimulant Treatments for Attention-Deficit/Hyperactivity Disorder

CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing psychiatric disorder that affects both children and adults. There are Food and Drug Administration-approved stimulant and nonstimulant medications for treating ADHD; however, little is known about the mechanisms by which these different treatments exert their therapeutic effects. OBJECTIVE To contrast changes in brain activation related to symptomatic improvement with use of the stimulant methylphenidate hydrochloride vs the nonstimulant atomoxetine hydrochloride. DESIGN Functional magnetic resonance imaging before and after 6 to 8 weeks of treatment with methylphenidate (n = 18) or atomoxetine (n = 18) using a parallel-groups design. SETTING Specialized ADHD clinical research program at Mount Sinai School of Medicine, New York, New York. PARTICIPANTS Thirty-six youth with ADHD (mean [SD] age, 11.2 [2.7] years; 27 boys) recruited from randomized clinical trials. MAIN OUTCOME MEASURES Changes in brain activation during a go/no-go test of response inhibition and investigator-completed ratings on the ADHD Rating Scale-IV-Parent Version. RESULTS Treatment with methylphenidate vs atomoxetine was associated with comparable improvements in both response inhibition on the go/no-go test and mean (SD) improvements in ratings of ADHD symptoms (55% [30%] vs 57% [25%]). Improvement in ADHD symptoms was associated with common reductions in bilateral motor cortex activation for both treatments. Symptomatic improvement was also differentially related to gains in task-related activation for atomoxetine and reductions in activation for methylphenidate in the right inferior frontal gyrus, left anterior cingulate/supplementary motor area, and bilateral posterior cingulate cortex. These findings were not attributable to baseline differences in activation. CONCLUSIONS Treatment with methylphenidate and atomoxetine produces symptomatic improvement via both common and divergent neurophysiologic actions in frontoparietal regions that have been implicated in the pathophysiology of ADHD. These results represent a first step in delineating the neurobiological basis of differential response to stimulant and nonstimulant medications for ADHD.

Differential Prefrontal Cortex Activation During Inhibitory Control in Adolescents With and Without Childhood Attention-Deficit/Hyperactivity Disorder.

The authors examined inhibitory control processes in 8 adolescents diagnosed with attention-deficit/ hyperactivity disorder (ADHD) during childhood and in 8 adolescent control participants using functional MRI with the Stimulus and Response Conflict Tasks (K. W. Nassauer & J. M. Halperin, 2003). No group differences in performance were evident on measures of interference control and/or response competition created by location and direction stimuli. However, the ADHD group demonstrated significantly greater activation of the left ventrolateral prefrontal cortex during interference control as well as greater activation of the left anterior cingulate cortex, right ventrolateral prefrontal cortex, and left basal ganglia during the dual task of interference control and response competition. The magnitude of the prefrontal and basal ganglia activation was positively correlated with severity of ADHD. Response competition alone did not yield group differences in activation.

Inhibitory Control Deficits in Childhood and Risk for Substance Use Disorders: A Review

Identification of neurobiological factors that confer risk for the development of addiction may substantially advance development of new prevention and treatment strategies to combat substance use disorders. This review focuses on the relationship between impulsivity—a behavior that is common to the clinical picture of both substance use disorders (SUD) and childhood disruptive behavior disorders—and neurobiological risk for SUD. It further examines various behaviors within the over-arching domain of impulsivity, ultimately focusing on the more narrowly defined and measurable construct of inhibitory control, and concluding that underlying deficits in inhibitory control may be central to many of the behaviors associated with high risk for SUD. Targeted cross-sectional study of the neural basis of inhibitory dyscontrol in subjects at high risk for SUD, who have not yet begun to abuse drugs, has the potential to generate important hypotheses regarding the neurobiological underpinnings of SUD risk. Hypotheses developed using this approach can be more definitively evaluated in longitudinal studies with these same populations, extending through the period of maximal risk for SUD in adolescence and early adulthood.

Dissociable neural effects of stimulus valence and preceding context during the inhibition of responses to emotional faces

Socially appropriate behavior requires the concurrent inhibition of actions that are inappropriate in the context. This self‐regulatory function requires an interaction of inhibitory and emotional processes that recruits brain regions beyond those engaged by either processes alone. In this study, we isolated brain activity associated with response inhibition and emotional processing in 24 healthy adults using event‐related functional magnetic resonance imaging (fMRI) and a go/no‐go task that independently manipulated the context preceding no‐go trials (ie, number of go trials) and the valence (ie, happy, sad, and neutral) of the face stimuli used as trial cues. Parallel quadratic trends were seen in correct inhibitions on no‐go trials preceded by increasing numbers of go trials and associated activation for correct no‐go trials in inferior frontal gyrus pars opercularis, pars triangularis, and pars orbitalis, temporoparietal junction, superior parietal lobule, and temporal sensory association cortices. Conversely, the comparison of happy versus neutral faces and sad versus neutral faces revealed valence‐dependent activation in the amygdala, anterior insula cortex, and posterior midcingulate cortex. Further, an interaction between inhibition and emotion was seen in valence‐dependent variations in the quadratic trend in no‐go activation in the right inferior frontal gyrus and left posterior insula cortex. These results suggest that the inhibition of response to emotional cues involves the interaction of partly dissociable limbic and frontoparietal networks that encode emotional cues and use these cues to exert inhibitory control over the motor, attention, and sensory functions needed to perform the task, respectively. Hum Brain Mapp, 2009.

Event-related FMRI of inhibitory control in the predominantly inattentive and combined subtypes of ADHD.

To examine the neurophysiological basis for the pronounced differences in hyperactivity and impulsiveness that distinguish the predominantly inattentive type of attention‐deficit/hyperactivity disorder (ADHD‐PI) from the combined type of the disorder (ADHD‐C).

Preparatory activity and connectivity in dorsal anterior cingulate cortex for cognitive control.

Dorsal anterior cingulate cortex (dACC) is composed of functionally distinct subregions that may contribute to the top-down control of response selection and preparation. Multiple motor areas have been identified in dACC, including an anterior zone implicated in conflict monitoring and a caudal zone involved in movement execution. This study tested the involvement of a third cingulate area, the posterior zone of dACC, in the top-down control of response selection and preparation. Sixteen healthy young adults were scanned with event-related functional magnetic resonance imaging while performing a cued go/no-go task that was designed to minimize response conflicts. The activation and functional connectivity of dACC were tested with standard convolution models and psychophysiological interaction analyses, respectively. Ready cues that informed the direction of the impending response triggered preparatory neural activity in the posterior zone of dACC and strengthened functional connectivity with the anterior and caudal zones of dACC, as well as perigenual anterior cingulate cortex, frontal operculum, dorsolateral prefrontal cortex, sensory association cortices, and extra-pyramidal motor areas. The preparatory cues activated dACC above and beyond the general arousing effects common to cues despite negligible conflict in the go/no-go task. The integration of cognitive, sensorimotor, and incentive signals in dACC places the region in an ideal position to select and prepare appropriate behavioral responses to achieve higher-level goals.

Adolescent outcome of ADHD: impact of childhood conduct and anxiety disorders.

OBJECTIVE This study examines the impact of comorbidity of attention-deficit/hyperactivity disorder (ADHD) with disruptive and anxiety disorders in childhood on clinical course and outcome. We consider the relative contribution of each comorbid symptom constellation, and also their interaction, to assess the following questions: (1) Does early comorbidity with conduct disorder (CD) and anxiety disorders define specific developmental trajectories?; (2) Is comorbid anxiety disorders in childhood continuous with anxiety disorders in adolescence?; (3) Does comorbid anxiety disorders mitigate the negative behavioral outcome of youth with ADHD?; and (4) Is there an interaction between comorbid CD and anxiety disorders, when they occur simultaneously, that predicts a different outcome than either comorbid condition alone? METHOD Thirty-two 15- to 18-year-old adolescent males, diagnosed with ADHD between 7 and 11 years of age, were re-evaluated for assessment of adolescent outcome 4.3-9.2 years later. Hierarchical regression analyses were run with each of the eight Child Behavior Checklist and Youth Self-Report problem scales, and the four anxiety symptom subscales of the Multidimensional Anxiety Scale for Children serving as outcome variables. RESULTS Findings indicate that comorbid CD at baseline predicted parent reports of behavior problems in adolescence, while comorbid anxiety disorders in childhood predicted youth reports of anxiety and social problems. Anxiety disorders without CD did not predict poor behavioral outcome. Children with both comorbid CD and anxiety disorder had the highest levels of parent-rated symptoms on follow up. In particular, adolescent social problems were best predicted by the combination of comorbid CD and anxiety disorder in childhood. CONCLUSION These data provide evidence that children with ADHD plus anxiety disorder do in fact have anxiety disorders, and that the combination of anxiety disorder and CD predicts a more rather than less severe course.