Contents

1 How minimal?

Historically, when the term Minimal Brain Damage was in use, it meant brain damage that could not at that time be detected on current scanning technology, nor even in post-mortem gross anatomy examination. Modern brain imaging studies now detect the presence of abnormalities in structure (smaller size) and function (hypoactivation) of critical brain regions related to dopamine (DA) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) [13].

2 Specific Deficits

Lou [8] and Volpe [14] suggest an excitotoxicity hypothesis to explain how ‘minimal brain damage’ may not be detected by earlier brain imaging techniques: the damage might preferentially affect late-developing granular cells and other interneurons and pathologically reduce the population of neurons that will later differentiate into specific brain structures. Thus, the morphology of the structure and overall brain will be normal, but smaller. The striatum was specifically highlighted because it is rich in dopaminergic synapses, is vulnerable to perinatal hypoxic complications, and if damaged, produces hyperactivity and poor inhibitory control [8].

This hypothesis has gained further support with modern structural and functional neuroimaging studies showing ADHD subjects to have small volume reductions in frontal–subcortical regions [5, 11]. This is consistent with studies of brain anatomy of children with ADHD, which reported a 5 % reduction in overall cerebral volume [3].

Jin et al. [6] used neuroimaging in medication-naïve ADHD children, and suggests that 20 % to 25 % of neurons in the globus pallidus had died or were severely dysfunctional, and reported a mild hyperactivity of the cholinergic system in the striatum. Other reports implicate reductions in specific areas of the prefrontal cortex, basal ganglia, cerebellum, and corpus callosum [9, 11, 12], some of which are outside the frontal–subcortical circuits, but are involved in coordinating activities of multiple brain regions.

3 Mild Abnormalities of Anatomy and Activity

This hypothesis also fits a curious pattern observed in follow-up studies of premature infants by Krägeloh-Mann et al. [7]: A 5 year follow up of a cohort of babies born prematurely and had MRI performed at time of birth found a correlation between later incidence of ADHD-like symptoms and more mild abnormalities in the neonate MRI. Damage to a frontal–subcortical network important for coordinating motivation and cognition in decision-making processes, like learning from mistakes and delaying gratification to maximize short- and long-term benefits of choices [1] may lead ADHD sufferers to have dysfunctional responses to reward and punishment [2], including severe delay aversion [10].

Functional MRI studies have found frontal hypoactivity affecting the anterior cingulate, dorsolateral, and inferior prefrontal cortex, portions of parietal cortex, basal ganglia, and thalamus [4]. Recent studies have shown disruptions in ADHD affect not only the activity in these brain regions, but also the way in which they connect with one another to form networks [11].

Acronyms

ADHD

attention-deficit/hyperactivity disorder

DA

dopamine

References

Contents

1 Theories

Most drugs used to treat hyperactivity have action at the dopamine transporter (DAT) and norepinephrine transporter (NET), indirectly increasing the concentration of synaptic and extrasynaptic catecholamines dopamine (DA) and norepinephrine (NE) [7, 8]. Dysregulation of DA and NE circuits has been postulated as the major pathophysiology of attention-deficit/hyperactivity disorder (ADHD) [1, 4]. Through neuromodulation of fronto–striatal–cerebellar circuits, both DA and NE have critical roles in prefrontal-dependent executive functions thought to underlie clinical symptoms of ADHD, and are a key target for pharmacological manipulation [5].

Most studies looking at DAT and DA receptor densities are restricted to the striatum because of the extremely high density there, and the use of radiotracers with low affinity. Very few studies measure receptor densities in prefrontal cortex, which is more often implicated in the deficits found in ADHD [2]. Berridge and Devilbiss [3] used microdialysis to demonstrate that low, and clinically relevant methylphenidate (MPH) doses preferentially increase extracellular catecholamines in the prefrontal cortex relative to subcortical regions.

As DAT is a major target for ADHD stimulant medications, and medication-naïve ADHD subjects have reduced levels of DAT, DA D2 and D3 receptor availability in subcortical regions (including nucleus accumbens (NAcc), caudate nucleus, and midbrain) [9–11], whereas ADHD patients who had previous medication history showed an increased DAT density [6], it seems long-term treatment with MPH causes long-term changes in DAT and DA receptor expression. Possible alterations to endogenous DA levels in ADHD are likely to trigger complex pre- and post-synaptic compensatory changes to restore balance in the system, which may include changes in DA synthesis, release, receptor sensitivity, and neuronal responsiveness [5]. In order to better understand the DA dysfunction underlying ADHD, abnormal markers of DA signaling need to be understood in the presence of powerful counteracting regulatory influences.

ADHD

attention-deficit/hyperactivity disorder

DAT

dopamine transporter

DA

dopamine

MPH

methylphenidate

NAcc

nucleus accumbens

NET

norepinephrine transporter

NE

norepinephrine

References

Contents

1 ADHD symptoms

Individuals with attention-deficit/hyperactivity disorder (ADHD) experience tasks that require sustained mental effort as unpleasant and markedly aversive. Avoidance of these tasks and failure to complete tasks must be due to difficulties with attention, and not a primary oppositional attitude, although secondary oppositionalism is common, and therefore, hard to distinguish. Approximately half of clinic-referred children with ADHD are also diagnosed with Oppositional Defiant Disorder or Conduct Disorder [1]. Individuals diagnosed with ADHD are easily distracted by irrelevant stimuli and more frequently interrupt ongoing tasks to attend to trivial noises or events (i.e. a car alarm outside while in a classroom setting) that are normally ignored by others. When a person with ADHD is in a novel environment, in a one-to-one situation, engaged in interesting activities, or is receiving frequent rewards or remuneration for appropriate behavior, signs and symptoms of the disorder are often minimal or absent [4]. Situations that require sustained attention and mental effort, or lack intrinsic novelty and appeal, typically reveal a worsening of symptoms. Symptoms and features of the disorder vary by developmental stage. As children age into adolescents and adults, previous symptoms of hyperactivity more commonly take the form of feelings of restlessness and difficulty engaging in quiet, sedentary activities [1].

Other associated features of ADHD may include low frustration tolerance, temper outbursts, stubbornness, excessive and frequent insistence that requests be met, mood lability, demoralization, dysphoria, rejection by peers, and poor self-esteem [1]. Academic achievement is often impaired and devalued by the individual with ADHD, leading to conflict with family and school authorities. Variability in individual symptoms often leads family and teachers to believe that the troublesome behavior is willful, often leading to family discord, negative parent/child interactions, and resentment and antagonism in family relationships [1].

Children with ADHD show a great range in intellectual level, as assessed by individual IQ tests, although on average they are slightly below non-ADHD cohorts, also, individuals with ADHD obtain less schooling and have poorer vocational achievement than their peers on average [1].

2 ADHD subtypes

ADHD is currently split into three subtypes: primarily inattentive, primarily hyperactive/impulsive, and a combined subtype. All three subtypes are associated with significant impairment not only in scholastic achievement, but also in familial and social adjustment [1].

2.1 Impulsivity

Impulsivity commonly manifests as impatience, difficulty in delaying responses, difficulty awaiting one’s turn, and frequently interrupting or intruding on others. Peer rejection, and to a lesser extent, accidental injury are more pronounced in the subtypes marked by hyperactivity and impulsivity.

2.2 Inattentive

Individuals with predominantly inattentive subtype have more typical academic deficits and school-related problems, they also tend to be socially passive and appear neglected, rather than rejected by peers [1].

3 ADHD comorbidity with other disorders

Many patients with other disorders, e.g. Tourette’s Disorder, show a high prevalence of ADHD symptoms, although most individuals with ADHD do not have accompanying Tourette’s Disorder [1]. ADHD-like symptoms are also commonly exhibited by patients with established neurogenetic disorders such as Tuberous Sclerosis Complex, Neurofibramatosis I, Turner Syndrome, Williams Syndrome, Velocardiofacial Syndrome, Prader-Willy Syndrome, and Fragile X Syndrome [2]. This suggests that presentation of ADHD symptoms are a common downstream effect of multiple disruptions in biological pathways or neural circuits, though each syndrome arises from different genetic abnormalities with multiple molecular functions [2].

4 ADHD in Adulthood.

ADHD persists into adulthood in about half of children diagnosed with the disorder, is still significantly more prevalent among men than women, and clinician-assessed adult ADHD was significantly higher in non-Hispanic whites, previously married, and people in the ‘other’ employment category (mostly unemployed and disabled) [5], with a total overall prevalence of 3.5 % to 4.5 % of adults [3, 5]. Adults with ADHD were even less likely than ADHD children to have received treatment for ADHD within the past year (< 11% [5]).

ADHD

attention-deficit/hyperactivity disorder

APA

American Psychiatric Association

References

Contents

1 Attention-Deficit/Hyperactivity Disorder

ADHD is a behavioral disorder characterized by inattention, hyperactivity, and impulsivity. Sir Alexander Crichton appears to be the first to describe a disorder among boys of ‘mental restlessness’ in 1798, which has since been described by many others with many names, including most recently: hyperkinetic disorder of childhood, minimal brain damage (i.e. not obvious by then current scanning technology or gross anatomy), attention deficit disorder, and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) term ADHD [2, 5]. The essential feature of ADHD is a “persistant pattern of inattention and/or hyperactivity-impulsivity that is more frequently displayed and more severe than is typically observed in individuals at a comparable level of development” [2]. Diagnosis with ADHD is associated with higher incidence of criminal behavior, alcohol abuse, and problematic drug use [6, 7].

Over the years, critics have suggested that ADHD and other previous diagnostic terms are used to label difficult children whose behavior is at the extreme end of the normal range, but are not ill [5]. Current diagnostic requirements state that some symptoms must be present before age 7, although many are first diagnosed after symtoms have been present a number of years. Symptoms must be considered impairing in multiple settings, and there should be evidence of interference with developmentally appropriate social, academic, or occupational functioning, which is not better accounted for by another mental disorder [2].

2 How big is ADHD?

ADHD affects 8 % to 12 % of children worldwide [3, 4].

2.1 Male/Female disparity

The disorder is more frequent among males than in females, with male-to-female ratios ranging from 2:1 to 9:1 depending on the subtype and setting [2, 4]. The male-to-female ratio is greater in clinical studies than in community studies, indicating that females are less likely to be referred for treatment than male individuals [3].

2.2 Under- and Over-Diagnosis

If diagnosed on symptom load alone, the prevalence of ADHD is as high as 16.1 %, but only 6.8 % if functional impairment was required, as is now the case in the DSM-IV. Community studies commonly find a large percentage of children who meet DSM-IV criteria for ADHD, but who have never been diagnosed nor treated, and usually a similar percentage (3 % to 5 %) who did not meet criteria for ADHD, yet had been treated with stimulants [1, 4].

2.3 Demographics

National studies in the USA have not observed a difference in rates of ADHD by income, or have identified income-related differences among boys but not girls; however, the poorest children were least likely to receive ADHD medication treatment [4]. While these national studies have shown lower rates of reported ADHD diagnoses in children from minority backgrounds, other studies found no difference in DSM-IV-based ADHD rates in non-Hispanic white and African American children [4]. Mexican American children had lower overall rates of ADHD, and non-Hispanic white children had higher rates of ADHD inattentive subtype than Mexican American or African American children [4]. Female sex, minority status, and low income predict failure to diagnose and treat children with the disorder. While minority children with ADHD were less likely to be pharmacologically treated, pharmacological treatment rates were not different in minority children with other psychiatric disorders [8]. Among those meeting DSM-IV criteria, less than half of caregivers reported that their child had received an ADHD diagnosis by a health-care professional. Significant predictors of prior ADHD recognition included non-Hispanic white race, male sex, older age, and health insurance coverage of the child. Income and ADHD subtype were not associated with prior diagnosis among children meeting DSM-IV criteria [4]. Of the children who met DSM-IV criteria, 38.8 % had received medication to treat inattention, hyperactivity, or overactivity within the past year [4].

ADHD

attention-deficit/hyperactivity disorder

APA

American Psychiatric Association

DSM-IV

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

References