Attention-Deficit/Hyperactivity Disorder (ADHD) Brain Activity Changes to Psychostimulants
Condition: Attention Deficit Hyperactivity Disorder
MeSH terms: Hyperkinesis; Attention Deficit Disorder with Hyperactivity
Study type: Observational

Summary: 
      The purpose of this study is to examine the neural basis of response inhibition, working
      memory, and sustained attention in adolescents and adults with
      Attention-Deficit/Hyperactivity Disorder (ADHD), with particular emphasis on quantifying the
      effects of methylphenidate (i.e., treatment with psychostimulants) on neural function.
      Participants will undergo electrophysiological measurement of brain function during
      laboratory cognitive tasks. This research is aimed to develop a better understanding of how
      ADHD neural dysfunction relates to clinical presentation and medication response during the
      transition from adolescence to adulthood. The specific aims and hypotheses are:

      Specific Aim: To characterize the effect of Ritalin (methylphenidate) on neural activity
      underlying performance on the response inhibition task in ADHD adolescents and adults.
      Hypothesis 1) Methylphendiate will increase N2 and P3 amplitude in ADHD persons during
      medicated EEG sessions; Hypothesis 2) There will be a significant age × medication
      interaction such that ADHD teens will show increased amplitude of N2 while medicated,
      particularly at frontal sites, whereas ADHD adults will show differentially greater effect of
      medication on P3 amplitude and latency at central sites. Hypothesis 3) Brain activity
      assessed by fMRI will differ between unmedicated and medicated states.
    

Detailed description: 
      By conservative estimate, Attention-Deficit Hyperactivity Disorder (ADHD) is a common
      disorder that occurs in at least 3 to 6% of school-aged children (Barkley, 1990). It is
      marked by symptoms of inattention and hyperactive-impulsive behavior that are developmentally
      inappropriate. These symptoms must occur in multiple settings and impair functioning to a
      clinically significant degree (DSM-IV; American Psychiatric Association, 1994). ADHD is
      believed to be a developmental disorder that begins in early childhood, which distinguishes
      it from disorders of attention and behavioral control that arise later as consequence of
      brain injury. Although ADHD was once thought to affect only children, considerable evidence
      has accumulated to show that ADHD frequently continues into adulthood. Approximately 60% of
      ADHD youth (about 3-4% of all adults) have clinically significant residual problems as adults
      (Faraone, 1999; Hechtman, 2000; Mannuzza & Klein, 1999). Although inattention problems appear
      to persevere into adulthood unchanged, studies suggest that some persons' ADHD
      hyperactive/impulsive symptoms diminish following teenage years. However, the mechanism for
      this decrease is not currently known (Wender, 1987; Weiss & Hechtman, 1986, 1993; Brown,
      1995).

      Expert consensus holds that a deficit in response inhibition is a core feature of ADHD
      (Barkley, 1998). Supporting this, neuropsychological research suggests that ADHD persons'
      commonly perform poorly on tasks that require inhibition of response. These tasks, called
      Go/No-Go or Stop Signal tasks, require continual manual responding to successively presented
      stimuli and an occasionally withheld response following a predefined signal. Numerous
      neuropsychological studies have shown that ADHD children, teens, and adults respond more
      variably on Go trials on such tasks. They also have longer reaction times and more failures
      to inhibit responses on No-Go trials (Koshack et al., 2003; Oosterlaan, et al., 1998;
      Wodushek & Neumann, 1999). Psychostimulant medications like methylphenidate improve
      performance deficits (Bedard et al., 2003).

      The link between abnormalities of brain structure/function and cognitive test performance in
      ADHD persons is well-established, if poorly understood. There is evidence for smaller right
      frontal lobe volume, abnormalities in basal ganglia size, and reductions in white matter
      tracts in persons with ADHD (Castellanos et al., 1994; Castellanos et al., 1996; Filipek et
      al., 1997; Hynd et al.,1993; Mataro et al., 1997). Prefrontal cortex and basal ganglia are
      involved in planning, initiation, execution, and supervision of ongoing cognitive and motor
      functions (Fuster, 1997). Structural brain abnormalities correlate with deficits in these
      cognitive functions and with impulsive behaviors that are symptoms of ADHD (Casey et al.,
      1997; Mataro et al., 1997; Semrud-Clikeman et al., 2000). Functional imaging techniques,
      which quantify neural systems operation with respect to cognitive processes, are particularly
      valuable tools used to characterize dysfunctional neural networks. The most frequently
      employed method is electrophysiology, in which small voltage changes on the scalp occurring
      during task performance are recorded and averaged into waveforms that depict brain function
      to events of interest. These average EEG waveforms are called event-related potentials
      (ERPs). ERPs to Go/No-Go tasks are well characterized in healthy, non-clinical samples
      (Logan, 1994). The most frequently observed component to No-Go trials is a large negative
      potential occurring approximately 275 msec following stimulus presentation (N2) that has a
      fronto-central distribution. The large N2 has been interpreted as a reflection of early
      response inhibition processes. Electrophysiological studies find that the large N2 often seen
      with successful inhibition is diminished in ADHD children and adolescents (Overtoom et al.,
      2002; Pilszka et al., 2000; Yong-Liang et al., 2000). A literature review reveals no
      comparable studies of ADHD adults, so the degree of N2 abnormality in older ADHD persons is
      not known.

      ERP source localization suggests that the No-Go N2 arises from activity in inferior
      prefrontal cortex (Bokura, 2001; Pliszka, 2000). The few FMRI studies of ADHD are consistent
      with this finding (Garavan et al., 1999; Liddle et al., 2001; Watanabe et al., 2002). Rubia
      et al. (1999) find less brain activity in right superior-lateral prefrontal cortex, right
      inferior prefrontal cortex, and left caudate nucleus in unmedicated ADHD adolescent boys
      relative to controls. Vaidya et al. (1998) report similar findings for ADHD children, and
      also showed that methylphenidate increased activity in the striatum for ADHD participants.
      These results support a fronto-temporal N2 decrease in ADHD in brain areas implicated by
      structural studies as abnormal.

      Durston and colleagues also found evidence that compared to non-ADHD, ADHD children also
      activate a more diffuse network of posterior and dorsolateral prefrontal cortex regions to
      subserve successful response inhibition (Durston et al., 2003). Increasing age also
      significantly alters the pattern of activity seen on Go/No-Go tasks for healthy, non-ADHD
      persons in these brain regions. Children activate more volume of prefrontal cortex compared
      to adults (Casey et al., 1997). There also is evidence that healthy adults and teenagers use
      different neural networks to achieve comparable response inhibition task performance (Rubia
      et al., 2000). Healthy adults show modulation of ventral prefrontal activity depending on
      task difficulty, whereas children appear to maximally activate these areas generally (Durston
      et al., 2002). In a sample of ADHD participants ages 8 to 20, age was found to correlate
      positively with left inferior frontal cortex, and correlate negatively with hemodynamic
      activity in left dorsolateral prefrontal cortex (Tamm et al., 2002). In other words, there
      was increasing use of cortex known to be a primary substrate of response inhibition, while
      reliance on cortex that is a primary substrate of working memory and other "on-line"
      cognitive processes decreased with age. These differences suggest that age is an important
      variable in understanding response inhibition neural activity in both ADHD and non-ADHD
      persons.

      Age-related changes to behavior or cognitive functioning are typically interpreted within a
      developmental framework. Researchers hypothesize that age-related improvements in neural
      function (i.e., increased neural connectivity or functional specialization) are responsible
      for improvements in ADHD hyperactive/impulsive symptomatology. A body of evidence indirectly
      supports such contentions. Adults and adolescents are developmentally distinct with regard to
      brain structure and function. Structural MR studies consistently show increases in white
      matter volume throughout early childhood to early adulthood (Caviness et al.,1996; Giedd et
      al., 1999) reflecting increasing connectivity among cortical areas, especially in reciprocal
      connections between prefrontal and posterior brain areas (Goldman-Rakic, 1987). Gray matter
      is seen to increase in a linear fashion until puberty and decrease during adolescence in most
      brain regions. These curves peak in the frontal and parietal lobes at about age 12, the
      temporal lobes at age 16, and the occipital lobes at increase until 20 (Giedd et al., 1999).
      These findings are paralleled by histological animal and in vivo studies of human brain
      development that show a sharp reduction in syntapogenesis at puberty, followed by an period
      of synaptic pruning that continues at a similar rate throughout middle adulthood (Bourgeois,
      2001). These changes presumably reflect the shaping of brain structure/function following
      experience (Purves, 1988), and such changes likely reflect continuing performance
      improvements on some cognitive tests throughout adolescence.

      The juxtaposition of changes in brain structure/function and ADHD behavior from adolescence
      to adulthood raises the possibility that the two might be linked. Furthermore, if these
      factors are directly related, a link should be observable in a study that focuses on a core
      impairment of ADHD (i.e., response inhibition) across different age groups. Two positions
      have arisen in the field of developmental neurobiology to explain how ADHD symptoms diminish.
      First, some researchers hold that brain areas crucial for behavioral inhibition (i.e.,
      ventral prefrontal cortex) may continue to mature, albeit at a delay. Second, it is possible
      that other, unimpaired cognitive mechanisms develop to compensate for behavioral inhibition
      system impairment. Among others, some candidate compensatory mechanisms include stimulus
      evaluation or working memory processes. Because of the lack of research, neither of these
      positions have great support at the current time; moreover, the two possibilities are not
      incompatible. However, this question is crucial in understanding the pathophysiology of ADHD.
      Figure 2 (right) depicts a two possible relationships of response inhibition development in
      terms of ERP N2 amplitude. In Figure 2A, the diminished N2 seen in ADHD youth could be
      hypothesized to resolve with increasing age. Alternatively (Figure 2B), there may be no such
      gains in response inhibition N2 neural function. Rather, other cognitive processes that can
      be measured with different ERP indices may reflect the development of compensatory neural
      mechanisms in older ADHD persons, such as those reflected by the P3.

      Summary Previous research shows that response inhibition measured on Go/No-Go tasks is
      abnormal in all ages of ADHD persons, and that methylphenidate improves performance and
      alters neural function. When electrophysiological indices of response inhibition (i.e., the
      N2 ERP) are compared between No-Go success and failure trials, ADHD persons show differences
      related to automatic processes involved with response inhibition thought to involve
      prefrontal brain activity. This conclusion is supported by fMRI studies that localize No-Go
      hemodynamic response to inferior lateral prefrontal cortex and medial cortex (i.e., anterior
      cingulate and premotor cortex). Therefore, the N2 measures the strength of inhibitory neural
      processing, likely reflecting activity in brain structures known to be abnormal in ADHD with
      respect to both structure and hemodynamic function. However, electrophysiology has not yet
      been used to measure behavioral inhibition in ADHD adults, or to compare ADHD adults and
      youth.

      This study will use electrophysiology to determine whether age-related differences in ADHD
      symptom expression are related to differences in brain activity involved with response
      inhibition. Furthermore, by quantifying ADHD brain function both on and off psychostimulant
      medication, it will be possible to determine how age influences ADHD persons' neural response
      to methylphenidate. We broadly hypothesize that methylphenidate will affect each groups' ERPs
      differently. Medication-related differences also will be observed in ADHD symptom severity
      and neuropsychological test performance. Innovations include that this will be the first
      electrophysiology study 1) of response inhibition in ADHD adults, 2) that attempts to
      directly link brain function changes to symptomatology changes in maturation, and 3) that
      examines medication effects on cognition and behavior across age groups in ADHD.
    

Observational model: Case-Crossover
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Participants will be recruited from the community and referred from psychiatric outpatient
        clinics.
      
Biospecimen description: 
      Saliva samples for genotyping