This study identified significantly diminished SICI in dominant motor cortex in 8- to 12-year-old children with ADHD. We identified this finding after comprehensive assessments of cognition, learning, and behavior, including screening for and statistically analyzing IQ, reading ability, and socioeconomic status, in a cohort in which other neurologic, psychiatric, developmental, or medical problems that might act as confounders were excluded. This finding was statistically robust in both univariate and multivariate analyses. Correlation with parent-rated hyperactivity symptoms was more substantial than that for inattention. This is the largest and most completely characterized sample of children to undergo TMS testing. Our results suggest that motor cortex SICI is a quantitative, biologically based marker of both the categorical diagnosis of ADHD and the severity of ADHD symptoms in children at an age during which rapid motor and physiologic development is occurring.
SICI also correlated, although less strongly, with development of motor skills. The more modest degree of SICI/motor function correlation is not surprising. The neural substrate for the PANESS is diffuse, involving not only frontal lobes but also other cerebral cortical, basal ganglia, and cerebellar structures. In contrast, SICI probably reflects more localized inhibitory neurons in or adjacent to the motor cortex. These are more anatomically proximate to prefrontal regions involved in attention, impulse control, and behavioral regulation. In relating a physiologic marker to behavioral or motor scales, it is important to keep in mind that rating scales are only semiquantitative. More importantly, behavioral diagnoses are syndromes that may result from many processes and in which symptoms will overlap with typical peer behavior. Therefore, there will always be overlap between case patients and control subjects and at most modest correlations.21
SICI is believed to result from γ-aminobutyric acid (GABA)A
-mediated inhibition at the level of the primary motor cortex.22
The surround inhibition produced by GABAergic interneurons and modulated by dopamine is believed to provide an increased signal-to-noise ratio in the frontal cortex.23
This finding may be important for refining cortical signals involved in the accurate selection and control of motor responses. Because in healthy adults SICI is upregulated by both dopaminergic agonists24
and because psychostimulants also alter SICI (although in complex ways influenced possibly by age, dose, diagnosis, and genetic factors), we speculate that SICI may provide a window into further investigations to the role of both GABA and GABA/dopamine interactions in frontal cortex behavioral and motor dysfunction in ADHD. Studies of SICI in healthy adults suggest that this may be relevant to motor task inhibition25
and reward expectation.26
Difficulties with response selection and control (including increased inhibitory failure and variability) are hallmarks of ADHD,27
as are alterations in reward motivation.28
Refinement of neural signals critical to developing appropriate response selection and control, particularly in response to reward, may be critical to development of appropriate control of impulsive, hyperactive, and off-task behavior. Decreased SICI may thereby reflect a mechanism critical to the pathophysiology of hyperactive impulsive behavior.
SICI appears to be heritable.29
ADHD also tends to run in families, and our findings show SICI to be robustly predictive of its core diagnostic features. Still, SICI reflects processes important in other brain disorders as well. Diminished SICI has been described in Tourette syndrome,30
and juvenile myoclonic epilepsy in the morning.34
However, to date, the only strong correlation between SICI and symptom severity has been demonstrated with ADHD, as we have previously noted in smaller samples of children with Tourette syndrome.5
A novel and important contribution of the present study is characterization of a relationship between SICI and a highly relevant, developmental motor function, the PANESS score. The diversity of associations between neurologic diagnoses and SICI suggests that SICI may reflect fundamental problems in the frontal lobe–based executive function shared in many neurologic and psychiatric conditions, possibly in some cases as they relate to dopamine or to GABA neurotransmission.
Both ADHD and TD cohorts were samples of convenience and may include some unknown referral biases. We found no evidence that the SICI/ADHD effect is accounted for by use of stimulant medication or medication withdrawal, because, after subdividing the ADHD group by current stimulant treatment status, both groups remained robustly different from the non-ADHD group. Based on our sample size and detailed phenotypic analysis, we believe that our findings are probably generalizable. An additional possible confounder in this or any hyperkinetic disorder is activity level during the TMS study. Movement or premovement preparation increases MEP amplitudes and decreases SICI.25,35
If children with ADHD were more likely to move during the study, this movement would increase the group differences. We do not think increased ADHD-related fidgeting and movement explain our findings, however, based on the measures we took, as described in greater detail in appendix e-1.
Methodologic decisions about TMS stimulus intensities as well as interstimulus intervals probably affected paired-pulse ratios but did not substantially affect group differences or correlations in this study. The conditioning pulse intensity affects the magnitude of SICI and ICF in healthy adults.36
However, because the ADHD vs TD group differences and correlation with symptom severity we found were similar to those in prior studies,5,6
and, in addition, demonstrated correlation with PANESS scores, we think this conditioning pulse intensity yields valid, generalizable results for children.
Facilitatory effects in paired-pulse studies are also of some relevance. In this study, neither group generated much ICF. This observation means that early ICF effects probably did not “contaminate” the SICI result, but higher conditioning intensity would probably have been a better choice for evaluating ICF.36
Likewise, short interval cortical facilitation, which can occur at 3-ms interstimulus intervals, tends to occur more efficiently at far higher conditioning stimulus intensities.37,38
Therefore, our study was not optimal for assessing paired-pulse facilitation but probably yielded SICI data that were relatively uncontaminated by facilitatory processes.
High resting thresholds reduced our final sample size and may have reduced the precision of our results in the youngest children. In addition, although the comprehensive evaluation and strict exclusions in this study may have enhanced our ability to detect ADHD-related differences, it is possible that some components of our findings will not generalize well to a broader ADHD population with more complex emotional or learning problems. In addition, it is not known to what extent, if any, psychostimulants affect SICI after washout. We do not think that this effect is likely to be profound, because our results are similar to those in small studies of treated patients with more complex conditions5
as well as untreated populations.39
This study was cross-sectional, and a longitudinal study might provide more readily interpretable insights into the relationship between age-related motor development, motor physiology, and ADHD. Given that ADHD symptoms are well established by age 8 years, it would be helpful to evaluate children at a much younger age. This work will probably have to wait for advances in coil design and comfort. Large longitudinal studies might clarify the extent to which SICI or other measures indicate compensatory processes40
In addition, studies in which SICI is evaluated during tasks may be important. For example, a recently published, small study in healthy adults showed that SICI is reduced when an individual is attending to a task and then increases in response to anticipation of reward during this task.26
This finding suggests that mechanisms measured by SICI may engage in attention and reward processing. Such studies in ADHD in children might further enhance our understanding of SICI as a quantitative, biologically based marker of ADHD symptoms.