Collicular dysfunction in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder characterised by (inter alia) an increase in distractibility. The current front-line pharmacotherapies for the treatment of ADHD, namely the psychostimulants methylphenidate and amphetamines, have clear abuse potential, hence there is a strong need to develop new drug treatments for this disorder. Central to this process is the identification of the pathophysiological changes which underlie ADHD. Given the heterogeneity of the disorder, multiple loci are probably involved, providing multiple potential therapeutic targets. Here, we hypothesise (Hypothesis 1) that one such locus is the superior colliculus (SC), a sensory structure intimately linked with distractibility and the production of eye and head movements. It is proposed that in ADHD, the colliculus is hyper-responsive, leading to the core symptom of increased distractibility. Hypothesis 1 is supported by: 1. ADHD patients show increased distractibility in tasks which are sensitive to collicular function; 2. ADHD patients have a general problem inhibiting saccades, the generation of which involves the SC; 3. Saccadic deficits in ADHD include defects in the production of saccadic types (anti-saccades and express saccades) which are particularly associated with the colliculus; 4. Covert shifts in attention (which also have been argued to involve the SC) are also impaired in ADHD; 5. Reading disorders are frequently co-morbid with ADHD; dyslexia (which is associated with eye movement problems) is linked to a specific visual perceptual deficit in the M pathway, a major recipient of which is the colliculus. Whether or not the SC is indeed hyper-responsive in ADHD as Hypothesis 1 suggests, the SC may well represent an important therapeutic target for drugs. In fact current psychostimulant therapies, which reduce distractibility, may already work at that level (Hypothesis 2), a contention which is supported by: 1. The colliculus and structures immediately afferent to it contain the neurochemical machinery necessary to respond to these drugs; 2. d-Amphetamine depresses visually evoked activity in the rat colliculus in a dose-dependent manner. Fortunately, again, even if psychostimulants do not achieve their therapeutic effects on distractibility in ADHD by acting on the SC, then the development of drugs which dampen stimulus-related activity in the colliculus could still represent an important novel path for drug development to take. Pharmacological manipulations of this structure are able to decrease distractibility. As a consequence, sensory responsiveness in the SC may represent a new model system for use in the development of non-addictive pharmacotherapies for ADHD.