The results of this large-scale, population-based study supported the hypothesis that ADHD probands had the highest risk of subsequent TBI during the follow-up period, followed by unaffected siblings and healthy controls. In addition, we observed a counter-intuitive result that unaffected siblings had a higher risk of TBI requiring hospitalization than did healthy controls, whereas ADHD probands had a lower risk than controls. Furthermore, our findings suggest that the use of ADHD medications may reduce the risk of subsequent TBI requiring hospitalization, and the results demonstrated an earlier mean age at TBI diagnosis in ADHD probands and unaffected siblings than in controls.

As mentioned in the introduction, the potential relationship between ADHD and TBI has been suggested in several studies.21,22,23 However, a meta-analysis comprising 3023 mild TBI patients and 9,716 controls revealed a significant association between ADHD and mild TBI, and the association was significant in studies that have reported on ADHD subsequent to mild TBI, but not in studies that have reported mild TBI subsequent to ADHD.33 As TBI can exacerbate attention and impulsivity problems,34 the relationship between ADHD and TBI could become bidirectional and complicated. Moreover, both ADHD and TBI are associated with a wide range of negative outcomes; thus, clarifying the temporal association is essential for developing effective prevention and treatment measures. In a prospective longitudinal study that examined the TBI diagnosis records of 628 male patients from birth to the age of 34 years, Guberman et al. discovered that childhood inattention-hyperactivity assessed using teacher rating scales was significantly associated with an increased risk of TBI from the ages of 11–34 years.35 Asarnow et al. conducted a meta-analysis of 12,374 patients with TBI of all severity levels and 43,491 controls and reported that 16.0% of patients with TBI presented with ADHD before brain injury; the prevalence of severe TBI was considerably higher than that of 10.8% reported for the general population.36 As increasing studies have supported the relationship between ADHD and subsequent TBI,21,22,23,35,36 our study discovered a similar mean duration of 4.56 years between study enrollment and subsequent TBI development among ADHD patients. Therefore, because ADHD appears to be a risk factor for TBI, more attention should be paid to this high-risk population. Although studying whether TBI is a risk factor for ADHD is a crucial topic, it is not addressed in this study.

According to previous studies that have assessed ADHD patients, unaffected siblings of ADHD probands, and healthy controls using psychiatric interviews and different executive function tasks, unaffected siblings of ADHD probands may exhibit a common endophenotype with their ADHD siblings, and they may also exhibit some deficits in a wide range of neuropsychological functions.9,10,11,12,13 In addition, several neuroimaging studies have examined neuroanatomical abnormalities in ADHD patients and their unaffected siblings.10,37,38,39,40 Pironti et al. found an abnormal decrease in the gray matter volume in the right inferior frontal gyrus and an abnormal increase in the white matter volume in the caudal portion of the right inferior fronto-occipital fasciculus among ADHD patients and their unaffected first-degree relatives.10 Hoogman et al. compared unaffected siblings with healthy controls and demonstrated shared familial effects by showing a significantly smaller surface area in the caudal middle frontal, lateral orbital frontal, and superior frontal gyrus in unaffected siblings.37 Chiang et al. reported increased functional connectivity in the left insula and left inferior frontal gyrus among both ADHD probands and unaffected siblings compared with controls.38 These studies have provided evidence that neural profiles are shared between ADHD patients and their unaffected siblings, and the results suggest that some of the shared neuroanatomical abnormalities may be associated with the severity of ADHD symptoms in unaffected siblings.37,40 To summarize, neuropsychological and neuroanatomical abnormalities found in ADHD probands and unaffected siblings may lead to the partial expression of ADHD symptoms and further adversely affect their subsequent mental and physical health.6,7,24 Although the relationship between ADHD and TBI has been examined in previous research,21,22,23,33,35,36 the association between TBI and unaffected siblings of ADHD probands has been rarely discussed. Wei et al. reported that unaffected siblings of ADHD probands were more likely to develop TBI (OR: 1.24, 95% CI: 1.14–1.36) than controls.24 Our study data also revealed this finding. Consequently, unaffected siblings and ADHD probands appear to be a high-risk population for TBI; thus, increasing the awareness of the increased TBI risk for their families and caregivers is warranted.

The severity of TBI has often been considered when exploring the relationship between TBI and subsequent ADHD.33,36,41 However, fewer studies have considered the severity of TBI because more studies are focusing on the association between ADHD and subsequent TBI development. In this study, we also considered the severity of TBI by identifying TBI requiring hospitalization. The results revealed that when compared with controls, unaffected siblings were at a higher risk of TBI requiring hospitalization, whereas ADHD probands were at a lower risk. By using the German Pharmacoepidemiological Research Database, Lindemann et al. performed a large-scale retrospective cohort study to assess the risk of hospitalization due to injury diagnoses in children and adolescents with newly diagnosed ADHD compared with those without ADHD,42 and the results were different from our findings. Moreover, they reported that the incidence of TBI hospitalization was 1.87% (95% CI: 1.71–2.04) in male ADHD patients, 1.32% (95% CI: 1.19–1.47) in male controls, 1.38% (95% CI: 1.15–1.65) in female ADHD patients, and 0.91% (95% CI: 0.73–1.13) in female controls, with an increased adjusted HR of TBI hospitalization for patients with ADHD compared with those without. By contrast, our study reported that the incidence of TBI requiring hospitalization was 1.1% in ADHD patients and 1.3% in healthy controls, with a decreased adjusted HR of TBI requiring hospitalization for ADHD probands compared with controls. To explain the differences, we proposed the following possible reasons. The differences may be attributed to some biological, psychological, and sociological factors that were not investigated but could influence the incidence rates. For instance, Lindemann et al. did not consider the ADHD medication treatment as a possible protective factor against TBI in ADHD patients; however, the factor was discussed further in the study. Consequently, the results are potentially confounded by the fraction of patients receiving ADHD medications. In addition, other unmeasured potential prognostic factors, such as socioeconomic status, psychological stress, and environmental safety, may influence the results and contribute to the differences. Due to the limited relevant literature, further studies are required to reveal more details. Moreover, our study discovered a counter-intuitive and surprising result that ADHD probands had a decreased risk of TBI requiring hospitalization compared with healthy controls, which might be because ADHD probands may be in a safer setting, be under more protection, and receive more care from caregivers given their diagnosis of ADHD than other healthy individuals. The aforementioned reasons may also explain our finding of the longest duration between enrollment and TBI occurrence in the ADHD probands compared with the other two groups. Nevertheless, these measures to prevent ADHD patients from physical injuries have some limitations because of the increased TBI risk among ADHD patients shown in this study, but they may play an important role in reducing their risk of TBI hospitalization. The beneficial effect of the use of ADHD medications on subsequent TBI requiring hospitalization could also explain the difference. However, the result should be interpreted with caution, and further studies are needed to confirm the hypothesis. Additionally, our study reported that the unaffected siblings of ADHD probands were more likely to develop both TBI and TBI requiring hospitalization than healthy controls. Hence, we recommend that more attention be paid to preventing subsequent TBI development in this population.

Previous studies have revealed that ADHD medications are related to decreases in the risks of a wide range of ADHD-associated functional outcomes, including TBI and accidents and injuries.23,43,44,45,46,47 Mikolajczyk et al. demonstrated a 34% risk reduction for hospitalization due to brain injury diagnoses during the periods with ADHD medication compared with nonmedicated periods.45 Liou et al. examined 72,181 ADHD patients and 72,181 age-and sex-matched non-ADHD controls and reported the association between the long-term use of ADHD medications and a reduced risk of subsequent TBI.23 Boland et al. conducted a meta-analysis of 21 studies in 2020 and revealed a robust protective effect of ADHD medications on academic outcomes, accidents and injuries, and mood disorders, along with a statistically insignificant protective effect on TBI.46 More recently, Brunkhorst-Kanaan et al. conducted a systematic review and suggested that stimulant medication appeared to be effective for injury prevention in ADHD patients over their lifespan.47 Compatible with the results of previous studies, our study results suggest that the use of ADHD medications may reduce the risk of subsequent TBI requiring hospitalization. Therefore, early diagnosis and optimal treatment for individuals with ADHD are critical in clinical practice to minimize the risk of subsequent TBI requiring hospitalization. In addition, further well-designed clinical studies may be needed to quantify the protective effects of ADHD medications on subsequent TBI risk.

Age at TBI diagnosis may influence neurocognitive, academic, and behavior outcomes following TBI and is a topic worth exploring.48,49,50,51,52,53 However, previous studies have reported mixed results. Some studies have supported the theory of neuroplasticity describing that children injured at an earlier age have better outcomes due to the ability for neuronal circuits in the young brain to undergo adaptive changes on structural and functional levels,51,52 whereas other studies have supported the theory of vulnerability stating that children injured at an earlier age have poorer outcomes because of the incomplete development of the brain after TBI.48,49,50,53 The impact of age at TBI diagnosis on the results is difficult to assess because of the increasing difficulty of detecting neurocognitive impairments in younger children, the lack of large-scale studies, and variations in the distribution of age categories and the timing of follow-up evaluations in various studies.54,55 In this study, we collected a wide range of demographic data on age at TBI diagnosis from a considerably large-sized sample. In addition, we observed an earlier mean age at TBI diagnosis in ADHD probands and unaffected siblings compared with controls. However, the impact of age at injury on outcomes following TBI remains controversial; therefore, further studies are necessary to corroborate this finding.

However, this study has several limitations. First, the incidence of TBI and TBI requiring hospitalization may have been underestimated because only those who seek medical help are registered in the NHIRD. Second, information on the severity of ADHD and TBI is unavailable in the NHIRD. Therefore, we did not account for the severity of ADHD and identified TBI requiring hospitalization as an alternative way to assess the severity of TBI. Further studies would be required to clarify the association of ADHD diagnosis and trait with the exact severity, which was defined by the TBI neuroimaging criteria and Glasgow Coma Scale, of TBI. Finally, because the NHIRD does not provide information on factors such as psychosocial stress, family relationships, personal lifestyle, and environment, we could not explore their influence. Therefore, these limitations should be considered when interpreting the results.

In conclusion, this large-scale, population-based study suggested that ADHD probands had the highest risk of subsequent TBI, followed by their unaffected siblings and controls. We also found that unaffected siblings had a higher risk of TBI requiring hospitalization than controls, whereas ADHD probands had a lower risk. Hence, we recommend that more attention should be paid in order to prevent subsequent TBI development in the unaffected siblings of ADHD probands. In addition, this study demonstrated that the use of ADHD medications may reduce the risk of subsequent TBI requiring hospitalization, which supports the importance of early diagnosis and optimal treatment for individuals with ADHD.