Neurocognitive deficits in adult ADHD : preclinical and clinical studies

In this thesis the neurocognitive deficits in adult ADHD and the effects of ADHD medication have been investigated in animals and in humans. Firstly, by utilising a translational behavioural paradigm we have characterised of a novel animal model of the core symptoms of adult ADHD. In the first study, the 5-choice continuous performance task (5C-CPT) was used to examine different forms of attention and impulsivity in female Lister-hooded adult rats. Subsequently rats were separated into subgroups according to their baseline levels of attention and impulsivity in the 5C-CPT. The low-attentive; LA subgroup and the high-attentive; HA subgroup were selected based on levels of sustained attention and vigilance. The second subgroups include animals with varying levels of motor impulsivity and response inhibition (high-impulsive; HI and low-impulsive; LI subgroups). This allowed for examination of the effects of ADHD medication (methylphenidate and atomoxetine) on attention and impulsivity in the subgroups of animals modeling the inattentive subtype (ADHD-I), and the impulsive symptoms in the combined (ADHD-C) and impulsive-hyperactive (ADHD-IH) subtypes. Both drugs significantly improved sustained attention and vigilance in LA animals only. In HI animals methylphenidate decreased motor impulsivity, however in LI also increased motor impulsivity. Atomoxetine decreased motor impulsivity and response disinhibition in HI animals only. The second animal study extended this by selecting a group of animals with combined deficits in both attention and impulsivity (ADHD-C group). This separation (ADHD-C) allowed for the investigation of potential novel therapeutic targets, revealing the cognitive effects of tolcapone and A-412997. Tolcapone increased vigilance and sustained attention and reduced response disinhibition in ADHD-C animals only, while A-412997 increased vigilance and reduced response disinhibition also in ADHD-C animals only. The first clinical study evaluated the core neurocognitive deficits, including emotion recognition abilities in medicated and unmedicated adult ADHD patients, compared with a group of healthy controls. The back-translational cognitive tasks used for the evaluation were taken from the Cambridge Automated Neuropsychological Test Battery (CANTAB). Unmedicated adults with ADHD showed core deficits in sustained attention, attentional set-shifting, response inhibition and spatial working memory. Medicated patients showed no impairments compared with controls; highlighting the importance of ADHD medication for improving these cognitive deficits in ADHD. In the second study, the emotion recognition ability of each group was assessed and compared to each other. The second study also examined if the emotion recognition impairments were as a result of a general cognitive dysfunction or are a specific impairment in social perception. The unmedicated ADHD patients showed deficits in the correct recognition of the negative emotions including; fear, anger, sadness and disgust compared with controls. The group of patients followed-up after starting treatment with methylphenidate showed significant improvements in the recognition of all four negative emotions. This improvement was improved to a level comparable to healthy controls. Interestingly, in the unmedicated ADHD group, anger recognition proved to be a specific deficit in social perception whereas sadness, disgust and fear were influenced by deficits in attention and working memory. Following treatment with methylphenidate, improvements in attention accounted for the improvements in sadness, fear and disgust recognition but not anger recognition.In conclusion the animal studies have shown that animals from within a normal population could be selected according to variations in levels of attention and impulsivity. The ADHD drugs had different effects on attention and impulsivity depending on the natural baseline levels of behaviour of the adult rats. These findings highlight the need for a patient stratification approach in adult ADHD; as different responses are dependent of differences in symptom expression. They also show some potential new therapeutic targets in the animal model, which warrant further exploration. The clinical studies highlight the range of neurocognitive deficits, including emotion recognition deficits in adult ADHD. Together these results highlight the importance of pharmacotherapy in ADHD, not only to treat the core symptoms of ADHD (inattention, impulsivity and hyperactivity) but also to improve the disabling emotion recognition deficits of this disorder.