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.

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.

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.

Amphetamine-based medications robustly suppress symptoms of attention-deficit/hyperactivity disorder (ADHD), but their exact mechanisms remain poorly understood. Recent hemodynamic imaging studies have suggested that amphetamines may modulate the prefrontal and anterior cingulate brain regions, although few studies have been published and the results have not been entirely consistent. Meanwhile, several electrophysiological studies have shown that abnormal fast oscillations (in the γ range) may be closely linked to inattention and other cardinal symptoms of ADHD. In this study, we utilized magnetoencephalography to examine how amphetamines modulate high-frequency brain activity in adults with ADHD. Participants performed an auditory attention task, which required sustained attention in one block and passive listening in a separate block. Participants completed the task twice in the on-medication and off-medication states. All data were analyzed using beamforming techniques to resolve cortical regions showing event-related synchronizations and desynchronizations. Our primary findings indicated that oral administration of amphetamine decreased γ-band event-related desynchronization activity significantly in the medial prefrontal area and decreased event-related synchronization in bilateral superior parietal areas, left inferior parietal, and the left inferior frontal gyrus. These results suggest that psychostimulants strongly modulate γ activity in frontal and parietal cortical areas, which are known to be central to the brain’s core attentional networks.

Psychostimulants are recognized for their role in managing attention-deficit/hyperactivity disorder (ADHD), but also have found a treatment niche in conditions such as apathy, fatigue, and depression. (1) Psychostimulants--methylphenidate, amphetamines, and their respective isomers--are known to promote wakefulness, increase energy, and help improve attention. Although these medications can provide much-needed relief to many older patients, clinicians need to be mindful of possible side effects and safety concerns when prescribing psychostimulants for geriatric patients. Most psychostimulant research has evaluated children and younger adults; however, geriatric patients (age >65) deserve special consideration. Although these patients' changing physiology often presents treatment challenges and may predispose individuals to adverse events, emerging evidence suggests that psychostimulants are valuable in treating motivational and attentional symptoms that do not respond to other treatments. Older adults' diminished treatment response to antidepressants, fatigue, and comorbid medical illness make stimulants an attractive treatment option. However, there is a paucity of research addressing psychostimulant use in geriatric patients. Moreover, psychostimulants should be used in older patients only after carefully considering potential side effects and general medical safety. This article will focus on clinical scenarios in late life-- such as apathy, ADHD, and depression in medically ill patients--when treatment with psychostimulants may be useful. Psychostimulants are FDA-approved primarily for use in ADHD and other uses are considered off-label. [ILLUSTRATION OMITTED] We will highlight research in this population and use case vignettes as examples to present a sensible approach to treating geriatric patients with psychostimulants (Table). Stimulants and apathy Apathy is a loss of motivation, interest, or initiative that is not attributable to cognitive impairment, diminished consciousness, or emotional suffering. (2) Considered a distinct entity from depression, apathy is common late in life, particularly in persons with dementia of the Alzheimer's type (DAT); 70% to 90% of patients may experience apathy at some stage of dementia. (3) Apathy is linked to impairment in activities of daily living and needing more assistance from caregivers, which increases caregiver burden. Treating apathetic symptoms may irnprove quality of life for the patient and caregivers. For a case study of an older patient with apathy treated with a psychostimulant, see Box 1 (page 26). Apathy has been treated successfully with a variety of stimulant medications. In an open-label study, patients with DAT who received methylphenidate, 10 to 20 mg/d, showed significant improvement in Apathy Evaluation Scale (AES) scores.(4) Similarly, Herrmann et al5 also demonstrated improvements in AES scores in DAT patients taking methylphenidate, 20 mg/d, compared with placebo. Although methylphenidate appears to have the strongest evidence for treating apathy, dextroamphetamine also has been shown to produce modest improvements in apathy scale measures. (6) A double-blind, placebo-controlled crossover study showed that dextroamphetamine, 20 mg/d, significantly improved scores on neuropsychiatric inventory scales that were driven by apathy sub-scales. (6 )However, this trial was small (N = 8). Preliminary evidence indicates that psychostimulants may improve apathetic symptoms in patients with dementia. In Mr. A's case (Box 1, page 26), he experienced apathy symptoms that affected his quality of life and that of those around him. He showed a clear lack of interest and motivation and indifference. This scenario is common among geriatric patients and may be misinterpreted as depression. Although the overlap may be considerable, screening for apathy may help determine a treatment course with psychostimulants instead of antidepressants, thus avoiding unnecessary medication trials. …