Pharmaco-MEG evidence for attention related hyper-connectivity between auditory and prefrontal cortices in ADHD.

The ability to attend to particular stimuli while ignoring others is crucial in goal-directed activities and has been linked with prefrontal cortical regions, including the dorsolateral prefrontal cortex (DLPFC). Both hyper- and hypo-activation in the DLPFC has been reported in patients with attention-deficit/hyperactivity disorder (ADHD) during many different cognitive tasks, but the network-level effects of such aberrant activity remain largely unknown. Using magnetoencephalography (MEG), we examined functional connectivity between regions of the DLPFC and the modality-specific auditory cortices during an auditory attention task in medicated and un-medicated adults with ADHD, and those without ADHD. Participants completed an attention task in two separate sessions (medicated/un-medicated), and each session consisted of two blocks (attend and no-attend). All MEG data were coregistered to structural MRI, corrected for head motion, and projected into source space. Subsequently, we computed the phase coherence (i.e., functional connectivity) between DLPFC regions and the auditory cortices. We found that un-medicated adults with ADHD exhibited greater phase coherence in the beta (14-30Hz) and gamma frequency (30-56Hz) range in attend and no-attend conditions compared to controls. Stimulant medication attenuated these differences, but did not fully eliminate them. These results suggest that aberrant bottom-up processing may engulf executive resources in ADHD.

Estimating the passage of minutes: deviant oscillatory frontal activity in medicated and unmedicated ADHD.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a common and extensively treated psychiatric disorder in children, which often persists into adulthood. The core diagnostic symptoms include inappropriate levels of hyperactivity, impulsivity, and/or pervasive inattention. Another crucial aspect of the disorder involves aberrations in temporal perception, which have been well documented in behavioral studies and, recently, have been the focus of neuroimaging studies. These functional magnetic resonance imaging studies have shown reduced activation in anterior cingulate and prefrontal cortices in ADHD using a time-interval discrimination task, whereby participants distinguish intervals differing by only hundreds of milliseconds. METHOD: We used magnetoencephalography (MEG) to evaluate the cortical network serving temporal perception during a continuous, long-duration (in minutes) time estimation experiment. Briefly, medicated and unmedicated persons with ADHD, and a control group responded each time they estimated 60 s had elapsed for an undisclosed amount of time in two separate MEG sessions. All MEG data were transformed into regional source activity, and subjected to spectral analyses to derive amplitude estimates of gamma-band activity. RESULTS: Compared to controls, unmedicated patients were less accurate time estimators and had weaker gamma activity in the anterior cingulate, supplementary motor area, and left prefrontal cortex. After medication, these patients exhibited small but significant increases in gamma across these same neural regions and significant improvements in time estimation accuracy, which correlated with the gamma activity increases. CONCLUSION: We found deficient gamma activity in brain areas known to be crucial for timing functions, which may underlie the day-to-day abnormalities in time perception that are common in ADHD.

Atypical coupling between posterior regions of the default mode network in attention-deficit/hyperactivity disorder: a pharmaco-magnetoencephalography study.

BACKGROUND: Dysfunction in the default mode network (DMN), a group of cortical areas more active during the resting state, has been linked to attentional deficits and symptoms associated with attention-deficit/hyperactivity disorder (ADHD). Prior imaging studies have shown decreased functional connectivity between DMN nodes in patients with ADHD, primarily between anterior and posterior regions. Using magnetoencephalography (MEG), we evaluated phase coherence (i.e., functional connectivity) among regions of the DMN in healthy controls and adults with ADHD before and after stimulant therapy. METHODS: We obtained a resting-state MEG recording for all participants. Magnetoencephalography data were transformed into a ~30 node regional source model using inverse spatial filtering, including regions corresponding to the DMN. We computed the zero-lag phase coherence between these regions pairwise for 5 distinct frequency bands, and we assessed group and medication effects. RESULTS: Twelve adults with and 13 without ADHD participated in our study. Functional connectivity was stronger between particular node pairs and showed frequency-specific effects. Unmedicated patients showed reduced phase locking between posterior cingulate/precuneus regions (PCC) and right inferior parietal cortices (RIPL), and between medial prefrontal regions (MPFC) and the left inferior parietal region (LIPL) and the PCC. Unmedicated patients had increased phase locking between the RIPL and LIPL regions compared with controls. Administration of stimulants improved phase locking abnormalities along the MPFC-PCC and LIPL-RIPL pathways in patients with ADHD. LIMITATIONS: Modest sample size and lack of duration of patient treatment history may limit the generalizability of our findings. CONCLUSION: Adults with ADHD exhibit hyper- and hypoconnectivity between regions of the DMN during rest, which were suppressed after stimulant medication administration.

Broadband neurophysiological abnormalities in the medial prefrontal region of the default-mode network in adults with ADHD.

Previous investigations of the default-mode network (DMN) in persons with attention-deficit/hyperactivity disorder (ADHD) have shown reduced functional connectivity between the anterior and posterior aspects. This finding was originally demonstrated in adults with ADHD, then in youth with ADHD, and has been tentatively linked to ultra low frequency oscillations within the DMN. The current study evaluates the specificity of DMN abnormalities to neuronal oscillations in the ultra low frequency range, and examines the regional specificity of these DMN aberrations in medicated and unmedicated adults with, and those without ADHD. An individually matched sample of adults with and without ADHD completed 6-minute sessions of resting-state magnetoencephalography (MEG). Participants with ADHD were known responders to stimulant medications and completed two sessions (predrug/postdrug). MEG data were coregistered to the participant's MRI, corrected for head motion, fitted to a regional-level source model, and subjected to spectral analyses to extract neuronal population activity in regions of the DMN. The unmedicated adults with ADHD exhibited broadband deficits in medial prefrontal cortices (MPFC), but not other DMN regions compared to adults without ADHD. Unmedicated patients also showed abnormal cross-frequency coupling in the gamma range between the MPFC and posterior cingulate areas, and disturbed balance within the DMN as activity in posterior regions was stronger than frontal regions at beta and lower frequencies, which dissipated at higher γ-frequencies. Administration of pharmacotherapy significantly increased prefrontal alpha activity (8-14 Hz) in adults with ADHD, and decreased the cross-frequency gamma coupling. These results indicate that neurophysiological aberrations in the DMN of patients with ADHD are not limited to ultra slow oscillations, and that they may be primarily attributable to abnormal broadband activity in the MPFC.

Gamma-frequency neuronal activity is diminished in adults with attention-deficit/hyperactivity disorder: a pharmaco-MEG study.

Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder affecting approximately 4-7% of children and persisting in 2-5% of adults. The core symptoms include pervasive inattention and inappropriate levels of hyperactivity-impulsivity. High-frequency gamma activity has been implicated in the temporal binding of stimulus properties across cortical areas, and is known to be crucial for complex information processing and attentional processes in particular. Thus, we evaluated the amplitude of gamma-frequency neural responses in adults with and those without ADHD, and tested whether stimulant medications, the most common treatment for ADHD, modulate gamma activity in affected adults. Participants underwent two sessions (~75 min apart) of auditory stimulation using stimuli known to elicit 40 Hz gamma-band responses as magnetoencephalography data were acquired. Between sessions, the ADHD group (who were in maintenance therapy) were administered their daily stimulant medication and both groups were told to relax. The primary results indicated that gamma activity was weaker in the ADHD group during session one (pre-drug), but not session two (post-drug), and that gamma activity significantly increased following stimulant administration in adults with ADHD. These results suggest that ADHD is associated with reduced cortical gamma activity and that stimulants may ameliorate this abnormality.

Beyond the 'typical' patient: treating attention-deficit/hyperactivity disorder in preschoolers and adults.

Attention-deficit/hyperactivity disorder (ADHD), typically affects school-aged children, but can present during the preschool years and persist into adulthood. Accurate diagnosis for preschoolers and adults requires adaptation of the current diagnostic criteria to account for differences in symptomatology across the age span. The differential diagnosis of ADHD and the pattern of psychiatric comorbidity vary with each age group and complicate diagnosis and management. To maximize outcomes clinicians must be able to accurately identify ADHD across the lifespan, and develop comprehensive, collaborative treatment plans. The Preschool ADHD Treatment Study (PATS) demonstrated the potential utility of methylphenidate for treating ADHD in preschoolers, and trials of psychostimulants and atomoxetine have shown some benefits for adults. Behavioural interventions likely have an adjunctive role in ADHD treatment for both groups. More research, however, is needed to determine the safest and most effective pharmacotherapies and psychosocial interventions for these non-typical patients.