Remote neurocognitive interventions for attention-deficit/hyperactivity disorder - Opportunities and challenges.

Improving neurocognitive functions through remote interventions has been a promising approach to developing new treatments for attention-deficit/hyperactivity disorder (AD/HD). Remote neurocognitive interventions may address the shortcomings of the current prevailing pharmacological therapies for AD/HD, e.g., side effects and access barriers. Here we review the current options for remote neurocognitive interventions to reduce AD/HD symptoms, including cognitive training, EEG neurofeedback training, transcranial electrical stimulation, and external cranial nerve stimulation. We begin with an overview of the neurocognitive deficits in AD/HD to identify the targets for developing interventions. The role of neuroplasticity in each intervention is then highlighted due to its essential role in facilitating neuropsychological adaptations. Following this, each intervention type is discussed in terms of the critical details of the intervention protocols, the role of neuroplasticity, and the available evidence. Finally, we offer suggestions for future directions in terms of optimizing the existing intervention protocols and developing novel protocols.

Effect of Omega-3 Supplementation on Self-Regulation in Typically Developing Preschool-Aged Children: Results of the Omega Kid Pilot Study-A Randomised, Double-Blind, Placebo-Controlled Trial.

Supplementation of omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) may enhance self-regulation (SR) and executive functioning (EF) in children of preschool age. The aim of the Omega Kid Study was to investigate the effect of n-3 LCPUFA supplementation on SR and EF in typically developing preschool-aged children. A double-blind placebo-controlled pilot trial was undertaken, the intervention was 12 weeks and consisted of 1.6 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day compared to placebo. The HS-Omega-3 Index® was assessed by capillary blood samples at baseline and post-intervention. Seventy-eight children were enrolled and randomised to either the n-3 LCPUFA treatment (n = 39) or placebo (n = 39) group. Post intervention, there was a significant three-fold increase in the HS-Omega-3 Index® in the n-3 LCPUFA group (p < 0.001). There were no improvements in SR or EF outcome variables for the n-3 LCPUFA group post intervention compared to the placebo group determined by linear mixed models. At baseline, there were significant modest positive Spearman correlations found between the HS-Omega-3 index® and both behavioural self-regulation and cognitive self-regulation (r = 0.287, p = 0.015 and r = 0.242, p = 0.015 respectively). Although no treatment effects were found in typically developing children, further research is required to target children with sub-optimal self-regulation who may benefit most from n-3 LCPUFA supplementation.

The Feasibility of the "Omega Kid" Study Protocol: A Double-Blind, Randomised, Placebo-Controlled Trial Investigating the Effect of Omega-3 Supplementation on Self-Regulation in Preschool-Aged Children.

Self-regulation, the regulation of behaviour in early childhood, impacts children's success at school and is a predictor of health, wealth, and criminal outcomes in adulthood. Self-regulation may be optimised by dietary supplementation of omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs). The aim of the "Omega Kid" study is to investigate the feasibility of a protocol to investigate whether n-3 LCPUFA supplementation enhances self-regulation in preschool-aged children. The protocol assessed involved a double-blind, randomised, placebo-controlled trial of 12 weeks duration, with an intervention of 1.6 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day (0.3 g EPA and 1.3 g DHA) in a microencapsulated powder compared to placebo. Children (n = 78; 40 boys and 38 girls) aged 3-5 years old were recruited and randomly allocated to the treatment (n = 39) or placebo group (n = 39). The HS-Omega-3 Index® served as a manipulation check on the delivery of either active (n-3 LCPUFAs) or placebo powders. Fifty-eight children (76%) completed the intervention (28-30 per group). Compliance to the study protocol was high, with 92% of children providing a finger-prick blood sample at baseline and high reported-adherence to the study intervention (88%). Results indicate that the protocol is feasible and may be employed in an adequately powered clinical trial to test the hypothesis that n-3 LCPUFA supplementation will improve the self-regulation of preschool-aged children.

Effect of Neurocognitive Training for Children With ADHD at Improving Academic Engagement in Two Learning Settings.

Objective: This preliminary study investigated effectiveness of neurocognitive training on academic engagement (AET) for children with ADHD. The training approach targeted working memory, inhibitory control, and attention/relaxation (via brain electrical activity). Method: A reversal design with a 2-week follow-up was used to assess the effectiveness of the treatment on two children with diagnosed ADHD in two learning settings. Direct observation was used to collect academic-related behavior. Results: Improvements in on-task expected behavior (ONT-EX) and general AET, as well as reductions in off-task motor activity (OFF-MA) and off-task passive behavior (OFF-PB) were observed for both students over baselines and across the settings. Moreover, differences in behavioral change were found between participants and settings. Conclusion: These findings support using the treatment for improving academic performance of children with ADHD. Future studies may investigate influences of contextual differences, nontreatment variables, or adult's feedback during the training session on treatment effectiveness.

EEG coherence during subjectively-rated psychological state variations.

BACKGROUND: Neurofeedback training aims to develop awareness and control of psychological states in order to self-regulate brain activity and while used widely therapeutically, important questions remain unanswered. Central to these aims is an assumed association between the live EEG-based feedback and the subjective experience of a psychological state. To date, there is little evidence to support this relationship. Previous studies examining the association between an EEG index and subjective experience have explored only the presence or absence of the state, or merely assumed state variations. The current study aims to examine this association by considering how different levels of a psychological state (i.e., attention) are reflected in EEG coherence. METHODS: Our approach aims to allow comparisons of EEG coherence between psychological states (attention vs. rest), and also within subjectively-rated levels of a psychological state (attention) through a purpose-designed questionnaire. Thirty healthy adult participants performed a resting eyes-open (REO) and attention modulation task, while 28 channels of EEG were recorded. Levels within the psychological state were subjectively-attested by participants on a trial-by-trial basis. RESULTS: The main analyses examined the effect of subjectively-rated attention levels (SRALs) on EEG coherence, with results suggesting that high and low SRALs may be represented by: 1) different levels of alpha and theta coherence at anterior and posterior electrodes of the frontal lobe bilaterally, and 2) different levels of alpha coherence between central and parietal lobes, also bilaterally. DISCUSSION: These findings provide partial, preliminary evidence for EEG correlates of SRALs. These findings may have implications for understanding underlying mechanisms of NFT, which is an underdeveloped area.

Game-based combined cognitive and neurofeedback training using Focus Pocus reduces symptom severity in children with diagnosed AD/HD and subclinical AD/HD.

Previous studies report reductions in symptom severity after combined working memory (WM) and inhibitory control (IC) training in children with AD/HD. Based on theoretical accounts of the role of arousal/attention modulation problems in AD/HD, the current study examined the efficacy of combined WM, IC, and neurofeedback training in children with AD/HD and subclinical AD/HD. Using a randomized waitlist control design, 85 children were randomly allocated to a training or waitlist condition and completed pre- and post-training assessments of overt behavior, trained and untrained cognitive task performance, and resting and task-related EEG activity. The training group completed twenty-five sessions of training using Focus Pocus software at home over a 7 to 8-week period. Trainees improved at the trained tasks, while enjoyment and engagement declined across sessions. After training, AD/HD symptom severity was reduced in the AD/HD and subclinical groups according to parents, and in the former group only according to blinded teachers and significant-others. There were minor improvements in two of six near-transfer tasks, and evidence of far-transfer of training effects in four of five far-transfer tasks. Frontal region changes indicated normalization of atypical EEG features with reduced delta and increased alpha activity. It is concluded that technology developments provide an interesting a vehicle for delivering interventions and that, while further research is needed, combined WM, IC, and neurofeedback training can reduce AD/HD symptom severity in children with AD/HD and may also be beneficial to children with subclinical AD/HD.

Mismatch Negativity and P50 Sensory Gating in Abstinent Former Cannabis Users.

Prolonged heavy exposure to cannabis is associated with impaired cognition and brain functional and structural alterations. We recently reported attenuated mismatch negativity (MMN) and altered P50 sensory gating in chronic cannabis users. This study investigated the extent of brain functional recovery (indexed by MMN and P50) in chronic users after cessation of use. Eighteen ex-users (median 13.5 years prior regular use; median 3.5 years abstinence) and 18 nonusers completed (1) a multifeature oddball task with duration, frequency, and intensity deviants and (2) a P50 paired-click paradigm. Trend level smaller duration MMN amplitude and larger P50 ratios (indicative of poorer sensory gating) were observed in ex-users compared to controls. Poorer P50 gating correlated with prior duration of cannabis use. Duration of abstinence was positively correlated with duration MMN amplitude, even after controlling for age and duration of cannabis use. Impaired sensory gating and attenuated MMN amplitude tended to persist in ex-users after prolonged cessation of use, suggesting a lack of full recovery. An association with prolonged duration of prior cannabis use may indicate persistent cannabis-related alterations to P50 sensory gating. Greater reductions in MMN amplitude with increasing abstinence (positive correlation) may be related to either self-medication or an accelerated aging process.

Clarifying the functional process represented by P50 suppression.

P50 suppression refers to the amplitude-reduction of the P50 event related potential to the second (S2) relative to the first (S1) of identical auditory stimuli presented 500ms apart. Theory suggests that refractory periods (RPs) and/or inhibitory inputs (II) underlie P50 suppression. The present study manipulated interval between stimulus pairs (IPI: 2, 8s) and direction of participants' attention (Attention, Non-Attention) in order to determine which theory best explains P50 suppression. The rationale is that: 1/ RP and II predict opposite effects of manipulating the functionality of the mechanism responsible for S2P50 suppression (e.g. reducing function would increase S2P50 according to the II and decrease S2P50 according to the RP hypothesis); 2/ IPI2 (relative to IPI8) will reduce functionality of the mechanism responsible for S2P50 suppression, as it results in less recovery of (and a greater challenge to) that mechanism - RP would thus predict reduced S2P50, whereas II would predict enhanced S2P50 amplitude; and 3/ where the mechanism responsible for S2P50 suppression is challenged (i.e. at IPI2, due to insufficient recovery), Attention (relative to Non-Attention) will enhance functionality of this mechanism - RP would thus predict increased S2P50, whereas II would predict reduced S2P50 amplitude. In the Non-Attention paradigm, reducing IPI from 8 to 2s tended to increase S2P50 amplitude (and consequently impaired P50 suppression), and in the 2s IPI paradigm, directing attention towards the stimuli reduced S2P50 amplitude (and improved P50 suppression), with both effects supporting the II hypothesis only.

Chronic effects of cannabis on sensory gating.

Chronic cannabis use has been associated with neurocognitive deficits, alterations in brain structure and function, and with psychosis. This study investigated the effects of chronic cannabis use on P50 sensory-gating in regular users, and explored the association between sensory gating, cannabis use history and the development of psychotic-like symptoms. Twenty controls and 21 regular cannabis users completed a P50 paired-click (S1 and S2) paradigm with an inter-pair interval of 9s. The groups were compared on P50 amplitude to S1 and S2, P50 ratio (S2/S1) and P50 difference score (S1-S2). While cannabis users overall did not differ from controls on P50 measures, prolonged duration of regular use was associated with greater impairment in sensory gating as indexed by both P50 ratio and difference scores (including after controlling for tobacco use). Long-term cannabis users were found to have worse sensory gating ratios and difference scores compared to short-term users and controls. P50 metrics did not correlate significantly with any measure of psychotic-like symptoms in cannabis users. These results suggest that prolonged exposure to cannabis results in impaired P50 sensory-gating in long-term cannabis users. While it is possible that these deficits may have pre-dated cannabis use and reflect a vulnerability to cannabis use, their association with increasing years of cannabis use suggests that this is not the case. Impaired P50 sensory-gating ratios have also been reported in patients with schizophrenia and may indicate a similar underlying pathology.

An evaluation of P50 paired-click methodologies.

The utility of P50 paired-click measures is limited by their unestablished reliability, unknown effects of time, and long protocol. This study measured within-session reliability, temporal course, effect of varying interpair interval (IPI), and peak definition and ratio calculation methods on P50 paired-click measures in healthy participants. Results indicate higher reliability for difference (ICC=.72) than ratio (ICC=.44) method; when P50 peaks are defined as baseline-to-peak than peak-to-peak; time-related changes; and comparable P50 paired-click measures at long (9 s) and short (3-7 s) IPIs. After controlling for time effects, P50 paired-click measures are relatively reliable within-session and are best measured using the difference method and defined as baseline-to-peak amplitude; time effects must be taken into account when measuring P50 paired-click measures in a long paradigm; and IPI can be shortened in studies with healthy samples.

Movement-related potentials in the Go/NoGo task: the P3 reflects both cognitive and motor inhibition.

OBJECTIVE: The contribution of movement-related potentials (MRPs) to the Go/NoGo N2 and P3 'inhibitory' effects is controversial. This study examined these components in overt and covert response inhibition tasks. METHODS: Twenty adult participants counted or button-pressed in response to frequent (60%) and rare (20%) Go stimuli in a Go/NoGo task with equiprobable rare (20%) NoGo stimuli. RESULTS: The N2 NoGo effect did not differ between Count and Press responses, but the P3 NoGo effect was amplified during the Press task. Additionally, subtraction of the ERP waveform for Count NoGo from Press NoGo trials revealed a positivity between 200 and 400ms, occurring maximally over the central region, contralateral to the responding hand. This difference wave became significant at 210-260ms, close to the estimated time taken to stop an overt response. CONCLUSIONS: The N2 NoGo effect may reflect a non-motoric stage of inhibition, or recognition of the need for inhibition, while the NoGo P3 may overlap with a positive MRP occurring specifically on trials where overt motor responses must be inhibited. SIGNIFICANCE: The study confirms that the N2 and P3 NoGo effects are not solely due to movement-related potentials, and posits the NoGo P3 as a marker of motor inhibition.

Effects of varying stop-signal probability on ERPs in the stop-signal task: do they reflect variations in inhibitory processing or simply novelty effects?

The aim of the present study was to determine whether ERP modulations associated with varying the probability of the stop-signal in the stop-signal task reflect variations in inhibitory processing, or whether they simply reflect general arousal associated with novel stimuli. This was achieved by examining the effects of probability on a control "ignore-signal" stimulus in addition to the stop-signal. ERP findings revealed large fronto-central N1 and P3 components that were larger in amplitude for stop-signals than ignore-signals, and when stimuli were rare (30%) compared to frequent (70%). However, probability effects were not greater for stop-signals compared to ignore-signals, discounting an interpretation exclusively in line with inhibitory processing. A principal components analysis (PCA) revealed a slow-wave ERP component that partially accounted for these probability effects. Together, the present findings indicate that ERP differences between rare and frequent stop-signals did not primarily reflect varying inhibitory requirements, but rather may be confounded by novelty effects.

Caffeine effects on ERPs and performance in an auditory Go/NoGo task.

OBJECTIVE: Previous research has shown that caffeine produces a general increase in arousal. The present study examined caffeine-induced arousal effects on performance and auditory ERPs. We sought components showing amplitude changes without topography changes, as would be expected of a pure arousal amplification of source activity. METHODS: The effects of a single oral dose of caffeine (250 mg) were examined in a randomised double-blind placebo-controlled repeated-measures cross-over study. Subjects abstained from caffeine for 4h before the testing sessions, which were conducted, in the afternoon, one week apart. A simple auditory Go/NoGo task was used, with a random mix of 75 tones at 1000 Hz and 75 at 1500 Hz. All tones were 60 dB SPL, 50 ms duration (rise/fall time 5 ms), with SOA 1100 ms. RESULTS: There was a reduction in RT, but no effects on omission or commission errors. The major ERP effects of caffeine were focal rather than global increases in P1, P2 and P3b amplitudes to Go stimuli, with no changes in latency. There were no effects on N1 or N2 to Go stimuli, and no effects on any components in response to NoGo stimuli. CONCLUSIONS: The results suggest that caffeine differentially improves aspects of the processing related to response production and task performance, contrary to the widespread amplification of ERP component amplitudes, and latency reductions, expected of an increase in general arousal. SIGNIFICANCE: These results add auditory ERP data to the list of complex effects of caffeine on brain function and behaviour. They appear to rule out a simple arousal interpretation, and suggest directions for future research.

Behavioural and ERP indices of response inhibition during a Stop-signal task in children with two subtypes of Attention-Deficit Hyperactivity Disorder.

Previous research has shown that children with Attention-Deficit Hyperactivity Disorder of the Combined Type (AD/HDcom) have problems with response inhibition, with poorer task performance and atypical inhibition-related ERPs relative to control subjects, while little is known about response inhibition in children with Attention-deficit Hyperactivity Disorder of the Predominantly Inattentive Type (AD/HDin). In this study children with AD/HDin (N=12), AD/HDcom (N=13) and age-matched controls (N=13) aged between 8 and 14 years completed a Stop-signal task, with visual Go and auditory Stop-signal stimuli, while EEG was recorded. The results indicated that the groups did not differ on any inhibitory task performance measure, but the AD/HD groups showed more errors of omission to Go stimuli than controls. ERPs to the visual Go stimuli differed between children with AD/HDin and controls (increased central N1 and N2, decreased central P2 and increased parietal P3), while the AD/HDcom group showed only minor scalp distribution differences for N2 and P3. The AD/HDin group showed amplitude differences from controls to Stop signals (larger central N1 and parietal P3; reduced midline N2) and did not show a Successful vs. Failed inhibition effect for P3. The AD/HDcom group showed reduced parietal P3 to Stop signals, with the Trial Type effect present for N2 but not P3. These data suggest that the apparent atypical inhibitory processing at N2 and P3 may stem, at least in part, from atypical early sensory/alerting processing of all stimuli in children with AD/HDin.

The development of stop-signal and Go/Nogo response inhibition in children aged 7-12 years: performance and event-related potential indices.

The present study examined the development of response inhibition during the Stop-signal and Go/Nogo tasks in children using performance and ERP measures. Twenty-four children aged 7 to 12 years completed both tasks, each with an auditory Nogo/Stop-signal presented on 30% of trials. On average, response inhibition was more difficult in the Stop-signal than Go/Nogo task. Response inhibition performance did not develop significantly across the age range, while response execution varied significantly in a task dependent manner (Go/Nogo: increasing accuracy and reducing response variability with age; Stop-signal: reducing Go mean reaction time and response variability with age). The N1, P2, N2 and P3 components showed different scalp distributions, with N1 and P2 peaking earlier, and P3 later, in Nogo compared to Stop stimuli. N2 and P3 amplitude were positively correlated with successful inhibition probability in the Go/Nogo task only. N2 amplitude and latency to both Nogo and successful Stop stimuli decreased linearly with age, but not in the frontal regions. N1 and P3 amplitude in the parietal region increased with age for Stop-signals. An age-related reduction in P3 latency to Nogo stimuli correlated significantly with reduced RT and variability in Go responding, indicating a relationship between efficient Nogo and Go processing. Together the behavioural and ERP results suggest little development of the response inhibition process as measured via the Stop-signal and Go/Nogo tasks across the 7 to 12 year age range, while response execution processes develop substantially.

Event-related potentials in the auditory oddball as a function of EEG alpha phase at stimulus onset.

OBJECTIVE: We aimed to examine the relation between the phase of electroencephalogram (EEG) alpha activity at stimulus onset and event-related potentials (ERPs) in a fixed-inter-stimulus interval auditory 'oddball' task, using a novel conceptualisation of orthogonal phase effects (cortical negativity versus positivity, negative driving versus positive driving, waxing versus waning). METHODS: EEG responses to button-press targets, from 14 subjects presented with 4 blocks of 150 stimuli (50% target probability), were examined. Pre-stimulus alpha activity (8-13 Hz) at Pz was assessed for each trial by digital filtering of the EEG. The alpha cycle at Pz, starting from a negative-going zero crossing, was used to sort trials into 4 phases, for which ERPs were derived from both the filtered and unfiltered EEG activity at Fz, Cz, and Pz. RESULTS: Preferred brain states in this paradigm were indicated by an 8% greater occurrence of negative driving than positive driving, and a 33% greater occurrence of waxing than waning phases. Negative driving phases were associated with increased N1 latencies and decreased N2 amplitudes. Latencies of N1 and P2 were reduced in waxing phases. These reflected systematic changes in alpha frequency and amplitude at stimulus onset. CONCLUSIONS: In a fixed-inter-stimulus interval paradigm, component frequencies of the EEG are dynamically adjusted in order to provide brain states at the moment of stimulus presentation which differentially affect the EEG correlates of stimulus processing. SIGNIFICANCE: The results add to our understanding of the genesis of the ERP, indicating the importance of the dynamic interplay between instantaneous EEG activity and stimulus processing reflected in the ERP.

Inhibitory motor control in children with attention-deficit/hyperactivity disorder: event-related potentials in the stop-signal paradigm.

BACKGROUND: The aim of the study was to investigate the inhibitory control of an ongoing motor response and to identify underlying neural deficiencies, manifested in event-related potentials, that cause poorer inhibitory performance in children with attention-deficit/hyperactivity disorder. METHODS: A stop-signal paradigm with a primary visual task and auditory stop signal was used to compare performance in 13 children with attention-deficit/hyperactivity disorder and 13 control children, while event-related potentials were recorded simultaneously. RESULTS: Children with attention-deficit/hyperactivity disorder showed poorer inhibitory performance through a slower inhibitory process. Inhibitory processing of auditory stop signals was marked by a frontal N2 component that was reduced in the attention-deficit/hyperactivity disorder group relative to controls. A central positive component (P3) was associated with the success of inhibiting a response, but there were no group differences in its amplitude or latency. CONCLUSIONS: Findings support the hypothesis of deficient inhibitory control in children with attention-deficit/hyperactivity disorder. Slower inhibitory processing appears to be due to a specific neural deficiency that manifests in the processing of the stop signal as attenuated negativity in the N2 latency range.

Preferred EEG brain states at stimulus onset in a fixed interstimulus interval auditory oddball task, and their effects on ERP components.

Previous work has indicated the importance of ongoing EEG activity in the elicitation of the event-related potential (ERP), supporting the conceptualisation of the ERP in terms of amplification and attenuation of component frequencies in the EEG. We investigated the importance of the phase of narrow-band EEG activity in generating N1 and P2 components in the auditory ERP. An auditory oddball paradigm requiring a button-press response to targets, with fixed interstimulus interval (ISI) and 15% target probability, was utilised. The continuous EEG at Cz was recorded from 16 subjects as the raw data set. Offline digital filtering was used to separate the EEG into 13 narrow bands from 1 to 13 Hz. For each band, the phase at the onset of each non-target stimulus was determined. These were used to sub-average the unfiltered data stream at each of four phases for each of 13 frequencies for each subject. Phase effects were examined in terms of two orthogonal dimensions of electrical brain activity: Cortical negativity and negative driving. Stimulus onset varied as a function of these dimensions in a non-random fashion across frequency, indicating the preferential occurrence of particular phases, interpretable as preferred brain states. Large differential effects were also apparent in N1 and P2 amplitudes. These data indicate important aspects of brain dynamics, suggesting that in a fixed-ISI paradigm the component frequencies of the EEG are dynamically adjusted in order to provide particular brain states at stimulus occurrence to facilitate the brain's processing of the stimulus.