ANTERIOR CINGULATE CORTEX DYSFUNCTION AS A NEURAL SUBSTRATE OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER AND PAIN COMORBIDITY

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children and adults worldwide. It often coexists with anxiety, depression, or alterations in sensitivity. Patients with ADHD report sensitization to pain and the prevalence of generalized pain is higher in ADHD patients (up to 80%) compared to control population (17%) [Stray et al., 2013]. However, the mechanisms involved remain unknown. Neuroanatomical studies confirm that attentiveness and central mechanisms involved in pain transmission use identical neural networks (i.e., the anterior cingulate cortex -ACC- connection to insular cortex -IC-). Thus, alterations in these brain areas or their connectivity may underlie both attentional deficits and nociceptive sensitization.
We previously validated a mouse model of ADHD obtained by neonatal 6-hydroxydopamine (6-OHDA) lesion. We demonstrated that 6-OHDA mice exhibit increased nociception, showing higher sensitization to thermal and mechanical stimuli compared to sham animals. Using microendoscopic calcium imaging in freely moving mice, we monitored the neuronal population activity in ACC under ADHD-like conditions. Interestingly, when comparing both 6-OHDA and sham mice, the in vivo calcium imaging recordings showed different activity patterns under nociceptive stimulation. Using a photoconvertible calcium sensor (CaMPARI) combined with retrograde viruses, we tracked which ACC neurons activated during nociceptive stimulation project to other pain matrix areas, such as the posterior IC. Thus, we explored alterations in the ACC connectivity under ADHD-like conditions.
We provide functional evidence that nociceptive sensitization relies on ACC hyperexcitability. Our data indicate that ADHD and persistent pain are mutually worsening comorbid disorders with reciprocal worsening of nociceptive sensitization and hyperactivity.