Abstract
Attention deficit/hyperactivity disorder (ADHD) is a pervasive neurodevelopmental disorder which in many individuals is characterised by response inhibition and working memory deficits, underpinned by abnormalities in brain activation within ventrolateral frontal, cingulate, parietal, and striatal regions, as well as the default mode network. Methylphenidate and atomoxetine are clinically effective and commonly used treatments for ADHD, which both improve cognitive deficits and neural abnormalities. Nonetheless, few studies have explored the longer-term effects of methylphenidate on brain function or the effects of common ADHD medications on task-related functional connectivity. Given the mixed evidence for long-term efficacy of stimulants, investigations of neurocognitive effects of chronic stimulant use can provide valuable insights into the drugs’ mechanism of action. Furthermore, functional connectivity techniques allow the study of complex inter-regional interactions in the brain, likely better reflecting the dynamic nature of neural processing.A systematic review of studies exploring task-based functional connectivity in ADHD was conducted to appraise the current state of the literature, identifying studies of ADHD aetiology and the effects of interventions in patients. Across cognitive domains, ADHD individuals exhibited abnormalities in functional connectivity in cingulo-opercular, sensorimotor, visual, subcortical, and executive control networks. Interventions were found to modulate those dysfunctional networks, with most consistent effects on the functional connections with the striatum, anterior cingulate cortex, occipital, and midline default mode network regions.
Longer-term neurocognitive effects of methylphenidate on response inhibition were investigated by comparing boys with ADHD receiving methylphenidate through their standard clinical care for an average of two and a half years and medication-naıve boys with ADHD. Boys treated with methylphenidate showed lower variability of reaction time, greater successful inhibition-related connectivity changes between the right supramarginal gyrus and the right striatum/insula, and greater failed inhibition-related connectivity changes between the right supramarginal gyrus and left sensorimotor areas, right visual regions, as well as between the right insula and left sensorimotor areas and superior parietal lobule relative to medication-naıve participants. No differences, however, were observed in brain activation between the two groups.
The effects of acute methylphenidate and atomoxetine on inhibition were sub-sequently explored in a separate group of medication-naıve boys with ADHD in a randomised, double-blind, placebo-controlled, cross-over study. Under methylphenidate, individuals with ADHD showed shorter stop-signal reaction time and post-error reaction time relative to age-matched neurotypical controls, along with greater right frontal pole activation during failed inhibition relative to placebo. No effects of atomoxetine were ob-served during failed inhibition and no effects of either drug were detected during successful inhibition. Under placebo, boys with ADHD showed elevated failed-inhibition connectivity between the right supramarginal gyrus and sensorimotor areas relative to controls. This hyperconnectivity was no longer observed when individuals with ADHD were under methylphenidate or atomoxetine, but full neurofunctional normalisation was not achieved. Additionally, atomoxetine was associated with faster reaction time and post-error reaction time relative to controls, as well as widespread increases in functional connectivity in sensorimoto-occipito-cerebellar and fronto-parieto-occipital networks relative to placebo, and insulo-occipito-thalamic networks relative to methylphenidate.
Acute effects of methylphenidate and atomoxetine on working memory-related functional connectivity were explored in the same sample. No effects of either medication on performance were observed. Under placebo, higher parieto-operculo-insular connectivity was observed in boys with ADHD compared to controls. While these abnormalities were no longer observed under methylphenidate and atomoxetine, full neurofunctional normalisation was ruled out. However, methylphenidate led to increases of fronto-striato-thalamic, fronto-parieto-temporal, and cingulo-parietal connectivity relative to neurotypical controls. No effects of atomoxetine were observed.
Altogether, the results of this thesis suggest that methylphenidate may exert its long-term effects through modulation of task-positive functional networks. They further suggest that acute neurofunctional effects of methylphenidate and atomoxetine are modality-specific, with greater effects of atomoxetine on response inhibition and of methylphenidate on working memory. Finally, the lack of complete normalisation effects together with widespread increases of functional connectivity suggest that methylphenidate and atomoxetine may trigger compensatory neurofunctional mechanisms, rather than rely solely on normalisation of neural abnormalities.
| Date of Award | 1 Nov 2021 |
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| Original language | English |
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| Supervisor | Owen O'Daly (Supervisor), Mitul Mehta (Supervisor) & Marion Criaud (Supervisor) |