Background

This study examined the potential feasibility and utility of trigeminal nerve stimulation (TNS) for attention-deficit/hyperactivity disorder (ADHD) in youth.

Methods

Twenty-four participants ages 7-14 with ADHD enrolled in an 8-week open trial of TNS administered nightly during sleep, and were assessed weekly with parent- and physician-completed measures of ADHD symptoms and executive functioning as well as measures of treatment compliance, adverse events, and side effects. Computerized tests of cognitive functioning were administered at baseline and weeks 4 and 8.

Results

Significant improvements were seen on the ADHD-IV Rating Scale (P < .0001) and parent-completed Conners Global Index (P < .0001), as well as the majority of scales on the parent-completed Behavior Rating Inventory of Executive Functioning (BRIEF). Improvements were also noted on the computerized Attention Network Task (ANT) Incongruent Reaction Time (P = .006), suggesting that TNS has positive effects on response inhibition.

Conclusions

TNS therapy for youth with ADHD appears to be both feasible and without significant risk. Subjective improvements on rating scales and laboratory measures of cognition suggest a potential role for TNS in treating ADHD that merits further investigation. Future research in anticipation of designing definitive controlled efficacy trials should evaluate time to onset of TNS response and durability of treatment effects following TNS discontinuation, as well as validate an effective active sham comparator suitable for blinded studies.

Background

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous condition for which multiple efforts to characterize brain state differences are underway. The objective of this study was to identify distinct subgroups of resting electroencephalography (EEG) profiles among children with and without ADHD and subsequently provide extensive clinical characterization of the subgroups.

Methods

Latent class analysis was used with resting state EEG recorded from a large sample of 781 children with and without ADHD (N = 620 ADHD, N = 161 Control), aged 6-18 years old. Behavioral and cognitive characteristics of the latent classes were derived from semistructured diagnostic interviews, parent completed behavior rating scales, and cognitive test performance.

Results

A five-class solution was the best fit for the data, of which four classes had a defining spectral power elevation. The distribution of ADHD and control subjects was similar across classes suggesting there is no one resting state EEG profile for children with or without ADHD. Specific latent classes demonstrated distinct behavioral and cognitive profiles. Those with elevated slow-wave activity (i.e. delta and theta band) had higher levels of externalizing behaviors and cognitive deficits. Latent subgroups with elevated alpha and beta power had higher levels of internalizing behaviors, emotion dysregulation, and intact cognitive functioning.

Conclusions

There is population-level heterogeneity in resting state EEG subgroups, which are associated with distinct behavioral and cognitive profiles. EEG measures may be more useful biomarkers of ADHD outcome or treatment response rather than diagnosis.

Deficits in social communication are a core feature of autism spectrum disorder (ASD), yet significant social problems have been observed in youth with many neurodevelopmental disorders. In this preliminary investigation, we aimed to explore whether domains of social reciprocity (i.e., social communication, social cognition, social awareness, social motivation, and restricted and repetitive behaviors) represent transdiagnostic traits. These domains were compared across youth ages 7-17 with obsessive-compulsive disorder (OCD; N = 32), tic disorders (TD; N = 20), severe mood dysregulation (N = 33) and autism spectrum disorder (N = 35). While the ASD group was rated by parents as exhibiting the greatest social reciprocity deficits across domains, a high proportion of youth with severe mood dysregulation also exhibited pronounced deficits in social communication, cognition, and awareness. The ASD and severe mood dysregulation groups demonstrated comparable scores on the social awareness domain. In contrast, social motivation and restricted and repetitive behaviors did not appear to be transdiagnostic domains in severe mood dysregulation, OCD, or TD groups. The present work provides preliminary support that social awareness, and to a lesser extent social communication and cognition, may represent features of social reciprocity that are transdiagnostic across ASD and severe mood dysregulation.

Predictors of math achievement in attention-deficit/hyperactivity disorder (ADHD) are not well-known. To address this gap in the literature, we examined individual differences in neurocognitive functioning domains on math computation in a cross-sectional sample of youth with ADHD. Gender and anxiety symptoms were explored as potential moderators. The sample consisted of 281 youth (aged 8-15 years) diagnosed with ADHD. Neurocognitive tasks assessed auditory-verbal working memory, visuospatial working memory, and processing speed. Auditory-verbal working memory speed significantly predicted math computation. A three-way interaction revealed that at low levels of anxious perfectionism, slower processing speed predicted poorer math computation for boys compared to girls. These findings indicate the uniquely predictive values of auditory-verbal working memory and processing speed on math computation, and their differential moderation. These findings provide preliminary support that gender and anxious perfectionism may influence the relationship between neurocognitive functioning and academic achievement.

Objective

The current study applies a precision medicine approach to trigeminal nerve simulation (TNS), a Food and Drug Administration-approved neuromodulation treatment for attention-deficit/hyperactivity disorder (ADHD), by testing secondary outcomes of cognitive and electroencephalographic [EEG] predictors of treatment response among subjects from the original randomized controlled trial.

Method

Children aged 8 to 12 years with ADHD, were randomized to 4 weeks of active or sham TNS treatment, after which the sham group crossed over into 4 weeks of open-label treatment. TNS treatment responders (RESP) had an ADHD Rating Scale (ADHD-RS) Total score reduction of ≥25%, whereas nonresponders (NR) had <25% reduction posttreatment. Assessments included weekly behavioral ratings and pre-/posttreatment cognitive EEG measures.

Results

The final sample was 25 RESP and 26 NR comprising 34 male and 17 female children, with a mean (SD) age of 10.3 (1.4) years. Baseline measures that significantly differentiated RESP from NR included: lower working memory, lower spelling and mathematics achievement, deficits on behavioral ratings of executive function (BRIEF), and lower resting state EEG power in the right frontal (F4) region (all p values <.05). Compared to NRs, responders showed significantly increased right frontal EEG power with TNS treatment, which was predictive of improved executive functions and ADHD symptomatology (β = 0.65, p < .001). When EEG findings and behavior were modeled together, the area under the curve (AUC) for BRIEF Working Memory scale was 0.83 (p = .003), indicating moderate prediction of treatment response.

Conclusion

Children with ADHD who have executive dysfunction are more likely to be TNS responders and show modulation of right frontal brain activity, improved/normalized executive functions, and ADHD symptom reduction.

Clinical trial registration information

Developmental Pilot Study of External Trigeminal Nerve Stimulation for ADHD; http://clinicaltrials.gov; NCT02155608.

Objective

The Child Behavior Checklist-Dysregulation Profile (CBCL/DP) identifies youth at increased risk for significant psychopathology. Although the genetic architecture and several biological correlates of the CBCL/DP have been described, little work has elucidated its underlying neurobiology. We examined the potential utility of electroencephalography (EEG), along with behavioral and cognitive assessments, in differentiating individuals based on the CBCL/DP.

Method

Participants aged 7 to 14 years of age were categorized into 3 age- and sex-matched groups based on clinical assessment and CBCL/DP: typically developing controls without attention-deficit/hyperactivity disorder (ADHD) (n = 38), individuals with ADHD without the CBCL/DP (ADHD/DP-) (n = 38), and individuals with the CBCL/DP (CBCL/DP+) (n = 38). Groups were compared with EEG and measures of clinical phenomenology and cognition.

Results

ADHD/DP- and CBCL/DP+ groups had increased inattention, but the CBCL/DP+ group had increased hyperactive/impulsive symptoms, disruptive behavior, mood, and anxiety comorbidities compared with the group with ADHD alone. Cognitive profiles suggested that ADHD/DP-participants had fast impulsive responses, whereas CBCL/DP+ participants were slow and inattentive. On EEG, CBCL/DP+ had a distinct profile of attenuated δ-band and elevated α-band spectral power in the central and parietal regions compared to ADHD/DP- and controls. The low-δ/high-α profile was correlated with measures of emotion and behavior problems and not with inattentive symptomatology or cognitive measures. There were no EEG differences between the ADHD/DP- and control groups.

Conclusions

An EEG/cognitive profile suggests a distinct pattern of underlying neural dysfunction with the CBCL/DP that might ultimately serve as a biosignature. Further work is required to identify potential relationships with clinically defined psychiatric disorders, particularly those of dysregulated mood.

Objective

The combination of d-methylphenidate and guanfacine (an alpha-2A agonist) has emerged as a potential alternative to either monotherapy in children with attention deficit hyperactivity disorder (ADHD), but it is unclear what predicts response to these treatments. This study is the first to investigate pre-treatment clinical and electroencephalography (EEG) profiles as predictors of treatment outcome in children randomized to these different medications.

Method

181 children with ADHD (aged 7-14; 123 boys) completed an 8-week randomized, double-blind, comparative study with d-methylphenidate, guanfacine, or combined treatments. Pre-treatment assessments included ratings on ADHD, anxiety, and oppositional behavior. EEG activity from cortical sources localized within midfrontal and midoccipital regions was measured during a spatial working memory task with encoding, maintenance, and retrieval phases. Analyses tested whether pre-treatment clinical and EEG measures predicted treatment-related change in ADHD severity.

Results

Higher pre-treatment hyperactivity-impulsivity and oppositional symptoms and lower anxiety predicted greater ADHD improvements across all medication groups. Pre-treatment event-related midfrontal beta power predicted treatment outcome with combined and monotherapy treatments, albeit in different directions. Weaker beta modulations predicted improvements with combined treatment, whereas stronger modulation during encoding and retrieval predicted improvements with d-methylphenidate and guanfacine, respectively. A multivariate model including EEG and clinical measures explained twice as much variance in ADHD improvement with guanfacine and combined treatment (R²=.34-.41) as clinical measures alone (R²=.14-.21).

Conclusion

We identified treatment-specific and shared predictors of response to different pharmacotherapies in children with ADHD. If replicated, these findings would suggest that aggregating information from clinical and brain measures may aid personalized treatment decisions in ADHD.

Background

Abundant work indicates ADHD abnormal posterior brain structure and function, including abnormal structural and functional asymmetries and reduced corpus callosum size. However, this literature has attracted considerably less research interest than fronto-striatal findings.

Objective

To help address this imbalance, the current study replicates and extends our previous work showing abnormal parietal brain function in ADHD adults during the Conner's Continuous Performance Test (CPT).

Method

Our previous study found that ADHD adults had increased rightward EEG beta (16-21 Hz) asymmetry in inferior parietal brain regions during the CPT (p = 0.00001), and that this metric exhibited a lack of normal correlation (i.e., observed in controls) with beta asymmetry at temporal-parietal regions. We re-tested these effects in a new ADHD sample and with both new and old samples combined. We additionally examined: (a) EEG asymmetry in multiple frequency bands, (b) unilateral effects for all asymmetry findings, and (c) the association between EEG asymmetry and a battery of cognitive tests.

Results

We replicated our original findings by demonstrating abnormal rightward inferior parietal beta asymmetry in adults with ADHD during the CPT, and again this metric exhibited abnormal reduced correlation to temporal-parietal beta asymmetry. Novel analyses also demonstrated a broader pattern of rightward beta and theta asymmetry across inferior, superior, and temporal-parietal brain regions, and showed that rightward parietal asymmetry in ADHD was atypically associated with multiple cognitive tests.

Conclusion

Abnormal increased rightward parietal EEG beta asymmetry is an important feature of ADHD. We speculate that this phenotype may occur with any form of impaired capacity for top-down task-directed control over sensory encoding functions, and that it may reflect associated increase of attentional shifting and compensatory sustained/selective attention.

Objective

The combination of d-methylphenidate and guanfacine (an α-2A adrenergic agonist) may be an effective alternative to either agent as monotherapy in children with attention-deficit/hyperactivity disorder (ADHD). This study investigated the neural mechanisms underlying medication effects using cortical source analysis of electroencephalography (EEG) data.

Method

A total of 172 children with ADHD (aged 7-14; 118 boys) completed an 8-week randomized, double-blind, comparative study with 3 treatment arms: d-methylphenidate, guanfacine, or their combination. EEG modulations of brain oscillations at baseline and end point were measured during a spatial working memory task from cortical sources localized within the anterior cingulate (midfrontal) and primary visual cortex (midoccipital), based on previously reported ADHD and control differences. Linear mixed models examined treatment effects on EEG and performance measures.

Results

Combined treatment decreased midoccipital EEG power across most frequency bands and task phases. Several midoccipital EEG measures also showed significantly greater changes with combined treatment than with monotherapies. D-methylphenidate significantly increased midoccipital theta during retrieval, while guanfacine produced only trend-level reductions in midoccipital alpha during maintenance and retrieval. Task accuracy improved with combined treatment, was unchanged with d-methylphenidate, and worsened with guanfacine. Treatment-related changes in midoccipital power correlated with improvement in ADHD severity.

Conclusion

These findings show that combined treatment ameliorates midoccipital neural activity associated with treatment-related behavioral improvements and previously implicated in visuo-attentional deficits in ADHD. Both monotherapies had limited effects on EEG measures, with guanfacine further showing detrimental effects on performance. The identified midoccipital EEG profile may aid future treatment monitoring for children with ADHD.

Clinical trial registration information

Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); https://clinicaltrials.gov/; NCT00429273.

Diversity & inclusion statement

We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. We actively worked to promote sex and gender balance in our author group.