Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent and controversial conditions in child psychiatry. Both clinical progress and basic research will benefit from the identification of endophenotypes — intermediate, quantifiable traits that predict an individual's risk of disease and can be linked to the underlying aetiology of the condition. Such endophenotypes should also be anchored in neuroscience.
One of the clearest symptoms of ADHD is locomotor hyperactivity. There is evidence for dopaminergic dysfunction in humans with ADHD and, in animals, hyperactivity can be seen in both hypodopaminergic and hyperdopaminergic models. Striatal abnormalities and alterations in dopamine transporter density have been measured in subjects with ADHD, and psychostimulants (which increase the levels of catecholamines at synapses) are effective in treating the symptoms of the disorder.
Subjects with ADHD appear to have a deficit in response inhibition. They also manifest delay aversion, including a tendency to choose a small, immediate reward over a larger, delayed one. This can be modelled as a shortened delay gradient (a decline in the effectiveness of reinforcement as the delay between behaviour and reward increases). At least three brain abnormalities that have been observed in ADHD could potentially lead to this endophenotype: striatal abnormalities, alterations in dopamine transporter expression and reduced volume of the cerebellar vermis.
Many data lead us to believe that subjects with ADHD show high response variability and inconsistency in performance. They also show deficits in the perception and reproduction of time intervals. Brain abnormalities that could lead to such a deficit include cerebellar dysfunction, striatal lesions and changes in catechol-O-methyltransferase (COMT) activity in the prefrontal cortex.
The last proposed endophenotype is an impairment in working memory, which could be linked to delay aversion, executive dysfunction, inattention and phonemic-awareness deficits in ADHD subjects. Potential brain abnormalities that could affect working memory include striatal lesions, alterations in COMT activity and changes in the electroencephalogram (EEG).
The endophenotype approach allows researchers and clinicians to avoid some of the problems associated with the use of symptom scales, and should facilitate large-scale collaborative projects that are aimed at clarifying the complex causes of ADHD.
Research on attention-deficit/hyperactivity disorder (ADHD), a highly prevalent and controversial condition, has, for the most part, been descriptive and atheoretical. The imperative to discover the genetic and environmental risk factors for ADHD is motivating the search for quantifiable intermediate constructs, termed endophenotypes. In this selective review, we conclude that such endophenotypes should be solidly grounded in the neurosciences. We propose that three such endophenotypes — a specific abnormality in reward-related circuitry that leads to shortened delay gradients, deficits in temporal processing that result in high intrasubject intertrial variability, and deficits in working memory — are most amenable to integrative collaborative approaches that aim to uncover the causes of ADHD.
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Encyclopedia of Life Sciences
attention deficit–hyperactivity disorder
MIT Encyclopedia of Cognitive Sciences
electrophysiology, electric and magnetic evoked fields
- WORKING MEMORY
The representation of items held in consciousness during experiences or after retrieval of memories. Working memory is short-lasting and associated with the active rehearsal or manipulation of information.
- BASAL GANGLIA
A group of interconnected subcortical nuclei in the forebrain and midbrain that includes the striatum, globus pallidus, subthalamic nucleus, ventral tegmental area and substantia nigra.
- EFFECT SIZE
A measure of effect that is adopted when different scales are used to measure an outcome. It is usually defined as the difference in means between the experimental and control groups, divided by the standard deviation of the control or both groups. As effect size is a standardized measure, it allows us to compare and/or combine the effects found in different studies of the same phenomenon.
Part of the subpallidum and one of the components of the striatopallidal complex. It comprises deep (caudate nucleus, putamen and nucleus accumbens) and superficial (olfactory tubercle) parts.
- SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY
A method in which images are generated by using radionuclides that emit single photons of a given energy. Images are captured at multiple positions by rotating the sensor around the subject; the three-dimensional distribution of radionuclides is then used to reconstruct the images. SPECT can be used to observe biochemical and physiological processes, as well as the size and volume of structures. Unlike positron emission tomography, SPECT uses many fewer detectors, resulting in the loss of many available photons and the degradation of the image.
- EXECUTIVE FUNCTION
A cluster of high-order capacities, which include selective attention, behavioural planning and response inhibition, and the manipulation of information in problem-solving tasks.
- ANTISACCADE TASKS
Tasks in which subjects are required to suppress the automatic response of making a saccade towards a target and, instead, produce an eye movement in the opposite direction.
- GO/NO-GO TASK
A task in which the subject must produce a motor response for one class of stimulus while ignoring others.
The simultaneous existence in the same population of two or more genotypes in frequencies that cannot be explained by recurrent mutations.
- VENTRAL TEGMENTAL AREA
A nucleus of the midbrain. The main supplier of dopamine to the cortex.
- LOCUS COERULEUS
A nucleus of the brainstem. The main supplier of noradrenaline to the brain.
- P300 COMPONENT
A positive-going waveform in the electroencephalogram that occurs approximately 300 ms after the onset of a stimulus, and is related to the attentional and working memory demands of a task.
- THETA/BETA POWER RATIO
A ratio that compares the power output in the theta (4–8 Hz) versus the beta (13–21 Hz) frequency bands of the electroencephalogram.
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Castellanos, F., Tannock, R. Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci 3, 617–628 (2002). https://doi.org/10.1038/nrn896
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