Dysfunction of cingulate, frontal and parietal cortical regions has been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) by convergent data from a variety of sources, including neuroimaging, neuropsychological neurochemical and genetics studies (1
). Earlier in this special issue, the groundwork has been laid which shows how cingulate, frontal and parietal cortical regions interact with striatal, cerebellar and other brain regions in healthy humans and animals during cognitive processes relevant to ADHD. This review will highlight studies that have found functional and structural abnormalities of the cingulo-frontal-parietal (CFP) cognitive-attention network in ADHD. However, at no time should the narrow focus of this review be taken to suggest that CFP network abnormalities are the only factors responsible for ADHD. Clearly, they are only part of the pathophysiology of ADHD. To fully characterize the disorder, the findings herein will need to be integrated with the wider literature on neurocircuitry models of ADHD—such as data on possible dysfunction of a proposed “default mode” network of the brain and/or reward/motivation networks—as reviewed in this issue and elsewhere (8
CFP Network Interactions and Conclusions
Advances have been made in identifying hypofunction within the CFP in ADHD. Specifically, it should be noted that while the data reviewed here strongly support the premises that (1
) the CFP neural circuitry supports attention, cognition, motor control and motivation/reward processes in healthy humans, and (2
) dysfunction of components of the CFP neural circuitry likely contributes to the pathophysiology of ADHD, the exact mechanisms by which such dysfunction leads to the symptoms of ADHD has yet to be determined.
In broad terms, the multiple functions of daMCC, DLPFC, VLPFC and parietal cortical regions alone provide a great many possibilities. Simplistically, it could be the case that for healthy humans, DLPFC is more responsible for overall planning and goal-setting, VLPFC and daMCC are responsible for inhibiting excessive or inappropriate motor behavior, heteromodal parietal cortex assists with target detection and attention shifts, and daMCC integrates information from these inputs and helps to execute such plans by modifying behavior on a trial-by-trial basis. Dysfunction within components of the CFP network in ADHD could therefore lead to inattention by failing to detect targets or inadequately filtering noise within the system. Such dysfunction could also lead to hyperactivity by failing to adequately inhibit motor activity that is not in line with motivated goals, or by failing to use reward and error feedback to modify behavior. Similarly, impulsivity could be produced by insufficient encoding of motivational goals and/or the impaired ability to preferentially pursue long-term goals over short-term goals.
Of course, the reality is much more complex. Beyond just the CFP intranetwork communications, it has been shown how the CFP network interacts with striatum, premotor cortex, cerebellum, superior temporal sulcus, thalamus, and the brain stem reticular activating system to support cognitive-motor processing. Also, reward/motivational information (encoded by striatum, daMCC, nucleus accumbens and orbitofrontal cortex) is integrated with information from default mode network regions (perigenual ACC, medial PFC, portions of VLPFC, amygdala and posterior cingulate cortex).
Interactions within such networks and the specific roles of each region are starting to be parsed out experimentally. For example, Corbetta and colleagues have postulated that a “reorienting response” relies on the coordinated action of a dorsal frontoparietal network that links stimuli and responses and helps select actions, along with a predominantly right hemispheric ventral frontoparietal network which serves to interrupt and reset ongoing activity. Further, they hypothesize that when attention for a specific task is required, the ventral network is suppressed to prevent reorienting to distracting events (78
). Distinct and separable roles for DLPFC, daMCC and parietal cortex in cognitive processing have also been suggested by Liston et al. (79
). Dosenbach and colleagues have suggested that parallel “hybrid” control systems are possible in which transient activity of a fronto-parietal network reflects trial-by-trial adjustments, while sustained activity of cingulo-opercular regions throughout trials may indicate that it is more responsible for set maintenance (80
). Recent work has utilized event-related fMRI and functional connectivity analyses to identify how different elements of proposed interacting networks are responsible for the maintenance of attention on a target, cued shifts of attention, and reorienting to an unexpected target (82
Translations of such network models into testable predictions about ADHD network circuitry have commenced. For example, it has been hypothesized (83
) that in ADHD, abnormal activity in “default mode” brain systems that normally subserve resting state and vigilance functions (85
) may interfere with CFP-modulated attention systems. Castellanos and colleagues (87
) have reported abnormal connectivity within default network structures (VMPFC, precuneus, and posterior cingulate cortex) and furthermore altered functional connectivity between the daMCC and default network areas (precuneus and posterior cingulate cortex). Finally, Liston and colleagues recently reported that psychosocial stress reversibly and selectively impairs attention control and disrupts functional connectivity within a frontoparietal network that mediates attention shifts (89
). While admittedly speculative, it would be interesting to extend beyond these findings to determine if the chronic stress within those with ADHD could (1
) parametrically contribute to the disruption of functional attention network integrity in ADHD and (2
) if stress-reduction techniques such as relaxation response training, meditation or yoga could be used to alleviate some portion of ADHD morbidity by strengthening CFP network connections. For the interested reader, fuller explanations for how such observed CFP cognitive-attention network abnormalities described here might lead to specific ADHD symptoms appear elsewhere within this special issue and also in other sources (8
Lastly, although this narrow review focuses on CFP network abnormalities, it is important to recall that many other systems have been implicated, Most prominently, studies of subcortical dysfunction and dopaminergic modulatory functions have been reported and must be integrated with CFP neurocircuitry models. The interested reader can find reviews of dopaminergic imaging relevant to ADHD (90
) as well as the roles various neurotransmitters may play in the pathophysiology of ADHD (92
). Dopamine plays roles on attention, cognition and reward processes (92
) and can increase the neuronal signal-to-noise ratio both by boosting signal and dampening background noise (98
). Dopamine also displays an inverted-U influence such that it optimizes neural transmission within a range but may adversely affect performance at lower or higher levels (92
). Volkow and colleagues showed specific activity of methylphenidate in basal ganglia (99
), that it blocks the dopamine transporter (DAT) (100
), and that methylphenidate increases extracellular dopamine in striatum (101
). Spencer et al (102
) confirmed how striatal effects of methylphenidate match behavioral effects using immediate and extended release formulations. Studies of the dopamine transporter (DAT), which is primarily responsible for presynaptic reuptake of dopamine, have shown that methylphenidate blocks striatal DAT and increases extracellular dopamine (90
). These studies dovetail nicely with imaging studies that illustrate striatum dysfunction in ADHD by Durston, Casey, Vaidya, Epstein and colleagues (7
In conclusion, functional, structural, biochemical and connectionist imaging data have identified abnormalities of brain regions within CFP networked functional systems, and pharmacoimaging has helped to identify ways that medications used to treat ADHD exert their effects. It remains to be determined how the CFP network functions during cognitive and reward processing, and more specifically how dysfunction of the component regions contribute to the pathophysiology of ADHD.