Both attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have been linked to increased reaction time variability (RTV), a marker of attentional fluctuation. Here we test whether specificity to either trait emerges when we examine (1) detailed ex-Gaussian and frequency RTV subcomponents, (2) effects while controlling for the other trait and (3) improvement in the RTV measures following rewards or a faster event rate. 1110 children aged 7–10 years from a population-based sample completed a Go/No-Go task under three conditions . We measured RTV with standard deviation of RT (SDRT), ex-Gaussian distribution measures (Sigma and Tau), RT fluctuations in cycles of ~14–90 s in all conditions (Slow-4 and Slow-5), and RT fluctuations in cycles of 2–14 s in the fast condition (Slow-2 and Slow-3). Parent-rated ADHD and ASD traits were obtained. All refined RTV components were linked to ADHD traits only and not to ASD traits, while Sigma did not relate to either trait. Although both ADHD and ASD social-communication traits were associated with SDRT, the association with social-communication impairments disappeared when controlling for ADHD traits. A reward-induced improvement in RTV measures, indicating malleability, emerged in relation to ADHD traits but not ASD traits. Under closer inspection, specificity emerges of high RTV to ADHD traits. For the clinician, our findings indicate that attentional fluctuation in children with high ASD traits may be due to co-occurring ADHD traits and emphasise how the effectiveness of rewards does not generalise from ADHD to ASD traits.The online version of this article (10.1007/s10802-018-0457-z) contains supplementary material, which is available to authorized users. Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) show high rates of co-morbidity and significant overlap in genetic influences . However, SDRT represents an overall phenomenon; to better understand the association of ADHD and ASD with RTV, it may be informative to decompose SDRT into its components that capture the extremely slow RTs within the individual’s performance    .Parents also completed the Childhood Autism Spectrum Test (CAST)  and to react as quickly as possible, but to maintain a high level of accuracy. The proportion of ‘Go’ to ‘No-Go’ trials was 4:1. The participants performed the task under three conditions , matched for length of time on task. Seventy-two trials were presented with a fixed inter-stimulus interval of 8-s for the slow and incentive conditions; the fast condition, with an inter-stimulus interval of 1-s, consisted of 462 trials. The order of presentation of the slow and fast task conditions varied randomly across participants, whilst the incentive condition was always administered last. In the incentive condition, each correct response to the letter X and each correct nonresponse to the letter O earned the child 1 point. The child lost 1 point for each omission error (failure to respond to X) and for each failure to respond within 2-s. Each commission error (incorrect response to O) led to the loss of 5 points. The points were shown in a box, immediately right of the screen center, and were updated continuously throughout. The child started with 40 points to avoid the possibility of a negative tally. The child was asked to try to win as many points as possible and was told that the points will be exchanged for a real prize when the game ends. Due to technical issues, data were not available for 5, 6 and 7 children for the slow, fast and incentive conditions, respectively.RT data were included from children with accurate and plausible >150-ms) responses on ≥70% of Go trials in the slow condition and on ≥70% of Go trials in either the fast or the incentive condition, to only include participants with sufficient engagement in the task. The final sample consisted of 1110 children who had data from the slow condition. Among these, 1077 also had data from the fast condition, and 1105 also from the incentive condition. Table 50-ms resFor each dataset included in the analysis, we calculated the overall variability as the standard deviation of RT (SDRT).http://newcl.org/software/qmpe.htm). This algorithm measures the mean of the normal component of the RT distribution (mu) and divides the RTV into its normal (Sigma) and exponential (Tau) components. Here, we investigated the variability components Sigma and Tau.We applied ex-Gaussian deconvolution to RT data employing a maximum-likelihood algorithm , we evaluated the relationships between each RTV measure and each trait, as well as the effect of task condition, using a series of linear mixed-effects model analyses. Specifically, we modelled each RTV measure as a function of the participant’s rating on the ADHD or ASD trait, the task condition as a categorical factor and their interaction. To account for the non-independence of observations originating from within the same family  and expected within-subject correlations among datapoints collected from the same individual, the mixed models included random effects for participants and family. For analyses on the additional Slow-3 and Slow-2 frequency bands captured only by the fast condition, we used separate linear regression models (while controlling for family relatedness). Because the analyses were carried out using standardized scores, the β coefficients resulting from the regression models represent a standardized effect size measure such that a 1–standard deviation change in the ADHD/ASD trait leads to β change in standard deviation in RTV. The effect size is comparable to that of correlation coefficients.To account for positive skewness, we applied square root-transformation to Sigma and log-transformed all remaining measures prior to analysis, following the best approach suggested for each measure by the p values. Analyses were repeated to model the association between each measure and trait by controlling for the effect of both subdomains of the other trait, thus testing their specific associations with the measure. Second, when both ADHD and ASD symptoms were associated with a RTV measure or its change across conditions, we planned a hierarchical regression model for each RTV measure showing an association with both traits; by adding one of the two traits first, and the other trait second, we tested whether the addition of the second trait significantly improved the prediction of RTV beyond the first trait.To account for developmental effects and potential sex differences . We did not find a significant interaction between condition and SCI or RRBI on SDRT  but was positively, significantly associated with RRBI under incentives .For Tau, we found a significant main interaction of condition with ADHD-I and RRBI, but not with ADHD-HI or SCI Table . Increasp = 0.18; ADHD-HI: β = 0.01; 95% CI = −0.04,0.07; p = 0.58). No significant interaction emerged between SCI or RRBI and condition.For the Slow-5 RT fluctuations, we found a main trait x condition interaction with both ADHD traits: increasing levels of both ADHD traits were associated with a greater reduction in Slow-5 from slow to incentive condition only Table . FurtherFor Slow-4 RT fluctuations, we found a significant main interaction between condition and ADHD-I, but not with ADHD-HI; no significant interaction between condition and SCI or RRBI emerged Table . An incrIn post-hoc analyses, testing the effects of each trait by controlling for the subdomains of the other trait, interactions between the ADHD and ASD traits remained substantially unchanged ESM 2(DOCX 15 kb)ESM 3(DOCX 19 kb)


These guidelines do not aim to provide a comprehensive review of all the pertinent literature comprising the evidence base and, as such, should be utilised in conjunction with other guidelines as well as the responsibility of practitioners to maintain a high level of personal knowledge and expertise. Despite the known efficacy of treatment and the substantial costs of untreated attention-deficit/hyperactivity disorder (ADHD), access to healthcare and treatment is not a given for many patients in South Africa (SA). In SA, there is poor identification and treatment of common mental disorders at primary healthcare level and limited access to specialist resources with a service delivery and treatment gap of up to 75%. Medication options are also often limited in emerging markets and in SA psychiatrists, and patients do not have access to the medication armamentarium available in established markets. Furthermore, the majority of South Africans currently utilise the public healthcare sector and may not have access to treatment options referred to in these guidelines. These guidelines should therefore not be seen as a policy document.The South African Society of Psychiatrists’ Special Interest Group (SIG) for adult ADHD was launched on 25 September 2015, with doctors Rykie Liebenberg and Renata Schoeman as convenor and co-convenor, respectively. The overall objective of the ADHD SIG is to improve the basket of care available to patients with ADHD. This is only possible through a combined and concerted effort of individuals with a special interest in and passion for ADHD to improve knowledge about and funding for the care of individuals with the disorder. One of the specific aims of the ADHD SIG was to develop South African guidelines for the diagnosis and treatment of adult ADHD specifically and update guidelines for the treatment of child, adolescent and adult ADHD. Dr Schoeman has recently completed her MBA at the University of Stellenbosch Business School with a thesis entitled ‘A funding model proposal for private health insurance for adult attention-deficit/hyperactivity disorder in the South African context’. This is first South African study exploring the situation with regard to the prevalence and treatment of adult ADHD. Dr Schoeman was tasked by the SIG with the drafting of guidelines. Dr Liebenberg provided valuable input. The guidelines were then circulated to the SIG members, as well as the Chair of the Public Sector SIG, for written feedback and evidence-based suggestions which were then incorporated into the guidelines. The final guidelines were circulated for written approval by the SIG members, followed by formal approval at a SIG meeting held on 14 August 2016, after which it was submitted to the South African Society of Psychiatrists (SASOP) and Psychiatry Management Group (PsychMG) boards for recommendation and ratification. Associated symptoms of ADHD include behavioural, cognitive, emotional and social problems. Problems with planning, task initiation, task completion, impatience and impulsivity can cause numerous work-related and interpersonal problems.The notion that ADHD is a disorder of childhood prevailed until the 1990s. Rigorous research, including longitudinal studies, and public awareness highlighted the presence of ongoing symptoms in 65% of adult patients.6 The population prevalence for ADHD is estimated as 3.0% – 5.0%.7 It is now widely accepted that an estimated 60.0% – 70.0% of patients’ symptoms persist into adulthood,8 with estimates of the prevalence of adult ADHD between 2.5% – 4.3%.11 ADHD is more frequent in men than in women in the general population, with a ratio of approximately 1.6:1 in adults. Women are more likely than men to present primarily with inattentive features. The increased diagnosis of ADHD over the past decade seems to reflect improved criteria for the identification of ADHD in adults and female patients.16ADHD is the most common psychiatric disorder in children – affecting 2.0% – 16.0% of the school-age population.18The specific lifetime prevalence of ADHD in South Africa (SA) is unknown. The South African Stress and Health study, a nationally representative household survey of 4351 adults, conducted between 2002 and 2004, investigated the prevalence and treatment access and use for mental health disorders. Unfortunately, results were grouped as anxiety disorders, mood disorders, substance use disorders (SUD), and ‘any other disorder’. ADHD would be included within the last group, with a prevalence of 30.3%.19 extrapolating the known prevalence information to the South African context, the expected number of adults between the age of 20 and 50 years affected by ADHD was calculated to be between 771 264 (3%) and 1 285 439 (5%). In this triangulated study , the population prevalence of adult ADHD was estimated at 1.09%, whereas the prevalence in clinical psychiatric settings was as high as 52.5%, of which 13.68% were patients with newly-diagnosed ADHD. Conditions comorbid with adult ADHD are common with psychiatric conditions in up to 20.43% of individuals. In this study, lack of knowledge of adult ADHD and lack of funding for the treatment thereof were identified as the two main barriers to diagnosis and treatment. It is therefore possible that these prevalence rates are underestimating the true prevalence of adult ADHD in SA.In the first South African study exploring the situation with regard to the prevalence and treatment of adult ADHD,20 The economic burden of adult ADHD ($3020 per patient per annum) is less than those of depression and diabetes, but more so than seasonal allergy.21ADHD is a costly, chronic disorder, with significant impact on the quality of life of patients and their families. The burden of disease is significant, with the disability-adjusted life years (DALYs) calculated as 424 per 100 000.23Significant comorbidity, estimated at more than 50% with ADHD, contributes to the burden of disease and reduced quality of life of patients with ADHD. Adults with ADHD are more likely to suffer from comorbid medical disorders , as well as psychiatric disorders .31(Untreated) ADHD also impairs educational attainment and employment status, impairs work performance (reduced productivity and increased absenteeism), adversely affects interpersonal relationships (irritability and low frustration tolerance) and adds to significant societal costs (because of substance abuse and accidents).35Persons with ADHD have lower self-esteem and general happiness with life, higher divorce rates and problems keeping friends and are at risk of forensic contact.19 the presence of adult ADHD more than doubled the healthcare costs of medical scheme beneficiaries. However, the costs attributable to direct costs of ADHD formed only 0.56% of the total value of claims. Of this, medication was the largest expense , whereas psychiatric services formed only 3.27% of the direct costs. This is in agreement with international findings28 where the cost of medication for treatment of ADHD amounted to 7% of all direct and indirect costs. This would suggest that pharmacological treatment of ADHD is cost-effective.In a South African study,Individuals with untreated ADHD, their families and other caregivers must be made aware of the impact this disorder may have on them at every stage of life and, correspondingly, the improved outcomes that can be achieved with the successful management of ADHD.The Diagnostic and Statistical Manual of Mental Disorders (fifth edition) (DSM-5) criteria for ADHD).36The core triad of ADHD is a persistent pattern of inattention or hyperactivity–impulsivity that interferes with functioning. This is accompanied by associated behavioural, cognitive, emotional and social problems which can lead to work-related and interpersonal difficulties (see BOX 1DSM-5 criteria for ADHD.Inattention: Six (or more) of the following symptoms have persisted for at least 6 months to a degree that is inconsistent with developmental levels and negatively impacts directly on social and academic or occupational activities:Often fails to give close attention to details or makes careless mistakes in schoolwork, at work or during other activities .Often has difficulty sustaining attention in tasks or play activities .Often does not seem to listen when spoken to directly .Often does not follow through on instructions and fails to finish schoolwork, chores or duties in the workplace (e.g. starts tasks but quickly loses focus and easily side tracked).Often has difficulty organising tasks and activities .Often avoids, dislikes or is reluctant to engage in tasks that require sustained mental effort .Often loses things necessary for tasks or activities .Is often easily distracted by extraneous stimuli .Is often forgetful in daily activities .Note: The symptoms are not solely a manifestation of oppositional behaviour, defiance, hostility or failure to understand tasks or instructions. For older adolescents and adults (age 17 years and older), at least five symptoms are required:Hyperactivity and impulsivity: Six (or more) of the following symptoms have persisted for at least 6 months to a degree that is inconsistent with developmental levels and negatively impacts directly on social and academic or occupational activities:Often fidgets with or taps hands or feet or squirms in seat.Often leaves seat in situations when remaining seated is expected .Often runs about or climbs in situations where it is inappropriate. (Note: In adolescents or adults it may be limited to feeling restless.)Often unable to play or engage in leisure activities quietly.Is often ‘on the go’, acting as if ‘driven by a motor’ .Often talks excessively.Often blurts out an answer before a question has been completed .Often has difficulty waiting his or her turn (e.g. while waiting in line).Often interrupts or intrudes on others .Note: The symptoms are not solely a manifestation of oppositional behaviour, defiance, hostility or a failure to understand tasks or instructions. For older adolescents and adults (age 17 years and older), at least five symptoms are required.A persistent pattern of inattention and hyperactivity-impulsivity that interferes with functioning or development, as characterised by (1) and (2):Several inattentive or hyperactive-impulsive symptoms were present prior to 12 years of age.Several inattentive or hyperactive-impulsive symptoms are present in two or more settings .There is clear evidence that the symptoms interfere with or reduce the quality of social, academic or occupational functioning.The symptoms do not occur exclusively during the course of schizophrenia or another psychotic disorders and are not better explained by another mental disorders .Source: American Psychiatric Association (APA)36Inattention manifests behaviourally in ADHD as difficulty sustaining focus, wandering off tasks, lacking persistence, paralysing procrastination, poor time management, inefficiency and being disorganised.Hyperactivity refers to excessive motor activity when it is not appropriate or excessive fidgeting, tapping or talkativeness. In adults, hyperactivity may manifest as extreme restlessness or wearing others out with their activity, being a workaholic, excessive talkativeness, being overscheduled and feeling overwhelmed.Impulsivity refers to hasty actions that occur in the moment without forethought and could have a high potential for harm to the individual. This may reflect reward dependence and a need for immediate gratification. Impulsive behaviours may manifest as social intrusiveness, a low frustration tolerance, mood lability and losing one’s temper, making important decisions without consideration of long-term consequences  and addictive behaviours.These core symptoms should be evident since childhood, with evidence of several symptoms being present since before the age of 12 years. Also, substantial symptoms causing significant impairment should be present in more than one setting . Some of the impairments related to adult ADHD include job failure or under-employment, complications such as drug dependence, driving accidents, unwanted pregnancies and sexually transmitted diseases, and even a life of perpetual failure.Typically, symptoms vary depending on context within a given setting. Adult recall of childhood symptoms tends to be unreliable. Confirmation of the presence of symptoms and the impact thereof across various settings typically cannot be done accurately without consulting informants who have seen the individual in those settings. Obtaining collateral information is therefore beneficial – if not crucial.Symptoms often appear to decrease over time – in number and in severity. However, adults are often more adept at managing these symptoms. Some adults compensate for ADHD-related impairment by choosing lifestyles and careers that suit them. Although they may appear to function well, high amounts of energy and time are used to accomplish tasks.N = 4000) of 18–19-year-old adults15 indicated a 27% increase (from 2.8% to 3.55%) in the expected prevalence of ADHD when comparing DSM-IV to DSM-5 criteria. However, the study supported lowering the symptomatic threshold for diagnosing ADHD in adults, with the best symptomatic cut-off in the number of symptoms for predicting impairment being five symptoms of inattention and four symptoms of hyperactivity-impulsivity.A field trial in a representative large sample . If the clinician chooses not to specify the reason for partial fulfilment of criteria, or when there is insufficient information to make a more specific diagnosis, the diagnosis will be ‘unspecified attention-deficit/hyperactivity disorder’.37Recognition of adult ADHD as a chronic disorder which needs chronic treatment is crucial. ADHD is a clinical diagnosis, which should only be made by a specialist psychiatrist, paediatrician or other healthcare professional with training and expertise in the diagnosis of ADHD. Adults with suspected ADHD whom have previously been diagnosed with ADHD during childhood with symptoms suggestive to ongoing ADHD can consult general adult psychiatric service for confirmation of diagnosis and ongoing treatment. Adults with suspected ADHD without previous diagnosis during childhood should be assessed by a specialist psychiatrist with adequate training and experience in assessments of adults with suspected ADHD for confirmation of diagnosis and treatment initiation.It is important to consider the history of presenting complaints, but also to use (semi-)structured interviews, rating scales, school- or work-related assessments, social functioning assessments and collateral information in the diagnosis of the disorder.38 the Barkley adult ADHD rating scale,39 the Brown ADD Scale Diagnostic Form (BADDS),40 the ADHD Rating Scale,41 the Conner’s Adult ADHD Rating Scale (CAARS) (DSM–IV),42 the Wender Utah Rating Scale (WURS),43 and the Wender-Reimherr Adult Attention Deficit Disorder Scale.44 The WHO ASRS is the best researched, and the shortened 6-item version has a sensitivity of 68.7% and specificity of 99.5% with total classification accuracy of 97.9% evaluated using population survey data. However, specificity of this and other screening tools may be lower within clinical samples with high rates of other mental health disorders, and positive screens should always be followed by full diagnostic evaluations based on clinical interview data.Commonly used rating scales for screening adult ADHD include the World Health Organisation Adult ADHD Self-Report Scale (ASRS) Symptom Checklist,The clinical interview is one of the cornerstones of the assessment process in diagnosing adult ADHD. Although various standardised, structured interviews and rating scales are available, these cannot replace the clinical assessment, but can add some rigor, standardisation and a quantifiable dimension to the areas being evaluated.40 the Conners Adults ADHD Diagnostic Interview for DSM-IV (CAADID),45 or the Diagnostic Interview for ADHD in adults (DIVA).46For the main diagnostic assessment, the use of the following structured diagnostic interviews may be considered: the Brown Adult ADHD Diagnostic Interview,39 and the Weiss Functional Impairment Rating Scales (WFIRS)47 are useful measures to assess the impact of symptoms on clinically relevant domains of functioning.A thorough interview is needed, documenting present symptoms and functionality across all spheres of the patient’s life. An assessment of the following would be essential: exploring the presence of the core symptoms of ADHD , establishing the pervasiveness thereof throughout the individual’s lifespan and across different settings  and the presence of significant functional impairment throughout the lifespan and across different settings. It has to be noted that the expression of ADHD in adults differs to some extent from that in children, and the diagnostic descriptions of some of the features need to be adapted to adult expression of the disorder . The Barkley Functional Impairment Scale for adultsDifferential diagnoses  and other psychiatric or medical diagnosis (and treatment thereof) that can explain the symptoms should be excluded. Furthermore, a thorough evaluation for the presence of comorbid psychiatric disorders (including substance use) is essential.Comorbidity in individuals with adult ADHD is very common. Comorbid disorders can be the presenting problem in many adults and is a confounding factor in the diagnosis of ADHD, with a negative impact on treatment decisions and response. International studies indicated that the majority of adults with ADHD have complicating and clinically significant comorbid psychopathology, with more than one psychiatric disorder in up to 87%, whereas at least 57% of individuals have more than two psychiatric disorders.19 psychiatric comorbidity was also more prevalent in individuals with adult ADHD than in the general population for both anxiety disorders (13.1% vs. 8.1%) and mood disorders (13.8% vs. 4.5%). The presence of adult ADHD also more than tripled the prevalence of multiple comorbidity (9.09% vs. 3.9%). The most common psychiatric comorbidities were adjustment disorders in 29.5% of patients with comorbid psychiatric conditions (2.7% of the sample), followed by non-organic sleep disorders in 19.4% (1.8% of the sample) and anxiety disorders in 13.1% (1.2% of the sample). Mood disorders occurred as comorbid disorders in 13.8% of the patients (1.2% of the sample), whereas substance-related disorders occurred in 2.3% of adults with ADHD (0.2% of the sample).In a South African database analysis,19 psychiatrists indicated the presence of comorbid disorders in patients with adult ADHD as follows: anxiety disorders in 40.33% , SUD in 33.81% , major depressive disorder in 33.28% and bipolar mood disorder in 13.75%. Personality disorders as a group (mostly cluster B) were present in 28.26% of patients with adult ADHD.In clinical psychiatric practice settings,48 found that collateral report has no incremental value in the evaluation of childhood ADHD symptoms in adults with a self-reported history of ADHD assessed in clinical settings, obtaining collateral information from parents on childhood ratings protect against possible student and adult malingering to obtain ADHD medications or accommodations.49Although a diagnosis based only on self-report is possible, such an approach may lead to an under- or over-diagnosis of ADHD, and it may be more reliable to obtain collateral information from other sources. Whenever possible, corroborating information should be obtained from a living parent, or older relative for childhood behaviour and a partner, relative or close friend for current behaviour and symptoms. This should include additional information on developmental and family history. Although Breda et al.50 Brain mapping, event-related potentials and neuroimaging are also of limited clinical use. It lacks diagnostic specificity, is costly and is not readily available.It is important that each patient should have a thorough medical evaluation which would include a complete medical history and comprehensive physical examination with the purpose of excluding causative or comorbid medical disorders, and a baseline safety assessment. The minimum requirements are the documentation of vital signs, weight and height. Screening for visual and auditory deficits or processing and integration problems should be considered and appropriate referrals to specialist optometrists and speech and language pathologist considered. Special examinations are a significant cost-driver in the management of ADHD and should not be requested routinely. ECGs should be requested in any patient with personal or familial cardiac risk factors. Liver function tests should be requested in patients with a history of liver disease prior to initiating treatment with atomoxetine. A comprehensive neurological examination should be considered if any symptoms suspicious of neurological disorders, including head injuries or symptoms of epilepsy, are present, with an appropriate referral to a neurologist or for an EEG where indicated. There are at present insufficient data for the use of brain imaging modalities in the diagnosis of adult ADHD. Although the US Food and Drug Administration (FDA) has approved an electroencephalogram-based instrument as a diagnostic aid, demonstrating higher resting theta:beta waves, for ADHD in children , there is currently no evidence for the use thereof in the diagnosis of adults with ADHD.53 Although specific neuropsychological tests, especially those examining executive dysfunction, can be useful, it should not be used in isolation as a diagnostic tool in the absence of a comprehensive clinical evaluation by an experienced clinician, but as complementary to diagnostic assessments in order to determine individual deficits and to suggest individualised interventions.54 Current neuropsychological tests based solely on executive function are of limited value, whereas multi-domain assessments and computerised assessments ,55 the MOXO d-CPT,56 and the Test of Variable of Attention (TOVA)57 have not yet established utility and cost-effectiveness.There are currently no neuropsychological tests for ADHD with sufficient sensitivity and specificity to serve as an individual diagnostic test.50Neuropsychological assessments should be considered when the functional impairment the patient is experiencing is more than what would be expected from the core symptoms alone. Neuropsychological testing is also useful to supplement core treatment in the development of personalised treatment approaches and interventions for educational or work purposes, as well as monitoring treatment response and identifying areas which may need further interventions, but should not be used to establish treatment response.53 Appropriate referral to an educational psychologist should be considered.Sensitive use of general intelligence tests can be useful to ascertain potential attainment and to diagnose co-morbid learning disabilities for educational interventions.58Interest, reward and educational achievement are important complicating factors during the assessment of ADHD. A significant percentage of those making suspect effort during neuropsychological evaluation will be diagnosed with ADHD using the most commonly employed assessment methods: interview alone (71%), interview and behaviour rating scales combined (65%) and an interview, behaviour rating scale and Continuous Performance Test (CPT) test combined (57%). It is therefore essential to evaluate task engagement and possible symptoms amplification during clinical evaluation.59 mental health is ‘a state of well-being in which every individual realises his or her own potential, can cope with the normal stresses of life, can work productively and fruitfully, and is able to make a contribution to her or his community’. The initial goal of any intervention is therefore symptoms relief, followed by ongoing alleviation of symptoms accompanied by decreasing functional impairment and working towards optimal functioning. This will include the prevention and treatment of comorbid disorders, relapse prevention and the improvement of the quality of life of patients and their families.According to the WHO,50 Maudsley guidelines60 and Schoeman,19 a comprehensive assessment and diagnostic certainty prior to initiating pharmacological treatment is crucial and treatment should be initiated at specialist level.As highlighted by the British Association for Psychopharmacology (BAP) guidelines,Good long-term clinical care is contingent on adequate patient education about the nature of the disorder and effects of treatment. Once the diagnosis has been confirmed, clinicians should provide sufficient information to empower patients to make informed decisions with regard to treatment options and designing interventions that meet the patient’s individual needs.60 Drug treatment should be continued as long as clinically effective and should be reviewed at least annually. Effects of missed doses, planned dose reductions and periods of non-treatment should also be evaluated.50Pharmacotherapy remains the cornerstone of treatment. Contrary to the treatment of ADHD in children, pharmacological interventions are always first line in adults – based on the lack of efficacy of non-drug intervention in the absence of medical treatment.Although pharmacotherapy plays a primary role in the treatment of ADHD, psychosocial interventions form an integral part of a comprehensive, multi-modal, management approach for adults with ADHD. Meta-analysis and systematic reviews have confirmed the superiority of combination  interventions. A multi-modal approach is also encapsulated in international guidelines ) which recommend psychosocial treatments as complementary to psychopharmacological interventions to provide support, improve acceptance of diagnosis, and treat comorbidities and residual symptoms .61 (i.e. comparing treatment option A with treatment option B with regard to a certain outcome measure).Few economic evaluation studies could be traced – all of them cost-effectiveness studies in children with ADHD. In a cost-effectiveness study, costs are related to a single common effect that may differ in magnitude between the alternative options or programmes62 In this study, 579 children with ADHD were assigned to 14 months of medication management, behavioural treatment, both combined or community care. Services were tallied throughout the study, including medication, healthcare visits, behavioural treatments and rental costs. Provider specialty, total time and number of visits with providers were used to calculate costs, adjusted to FY 2000 dollars with the consumer price index. The authors found that treatment costs varied fourfold, with psychopharmacological management being the least expensive, followed by behavioural treatment, and then combined treatment. They concluded that medication only, although not as effective as combined treatment, is likely to be more cost-effective in routine treatment for children with ADHD.The first cost-effectiveness study in children with ADHD dates back to 2005.63 did a systematic literature review of 13 economic evaluations of pharmacotherapies for children and adolescents with ADHD conducted between 1990 and 2011 in North America, Europe, Australia or New Zealand. There was consistent evidence that pharmacotherapies are cost-effective compared with no treatment or behavioural therapy. However, the data were not comprehensive enough to draw conclusions regarding the relative cost-effectiveness of different pharmacological agents.Wu, Hodgkins, Ben-Hamadi, et al.64 The first double-blind placebo controlled trial in ADHD examining the efficacy of Dexedrine was done in 1967.65 Since then, many studies have been conducted and established the efficacy of both stimulant- and non-stimulant medications in the treatment of ADHD in children and adolescents, and more recently also in adults. Consistent with the catecholamine hypotheses of ADHD, the drugs that effectively treat the disorder are known to modulate catecholamine pathways.The first evidence for the effectiveness of stimulants in the treatment of ADHD dates back to 1937, when Bradley conducted a trial with Benzedrine in children with ADHD.2-adrenoceptor agonists (clonidine and guanfacine), tricyclic antidepressants (TCAs), bupropion, modafinil and venlafaxine]. Enhancement of dopaminergic and noradrenergic neurotransmission in the prefrontal cortex is probable critical to the therapeutic efficacy of ADHD medication66 (see Medications used in the treatment of ADHD include psychostimulants [e.g. methylphenidate (MPH) and amphetamines] and non-stimulants  are an integral part of management. Discussions on clinical efficacy are limited by the lack of head-to-head studies with adequate and unbiased methodology. In general, dopaminergic and noradrenergic agents can reduce the core symptomatology, though specific effects and side effects may vary between agents. Treatment choice would therefore also depend on factors such as patient preference and comorbid conditions, abuse potential, side effect profile and toxicity in overdose.67 The three stimulants – MPH, pemoline (withdrawn from the market because of liver toxicity) and dextroamphetamine – have similar effects, with an average response rate of 70%.8In terms of treatment, stimulants are by far the best studied (and most effective) treatment for ADHD across the lifespan.68 Meta-analyses of MPH in adults demonstrate similar drug response rates and effect sizes to those seen in children, although slightly lower. For direct comparison with placebo, effect sizes were calculated as 0.9 in favour of MPH.69 In a recent meta-regression analysis of 18 studies (2045 patients),70 MPH, at a mean dose of 57.4 mg/day, had a moderate effect on ADHD symptoms compared with placebo [standard mean difference (SMD) 0.57–0.58]. MPH improved ADHD symptoms in adults in a dose-dependent fashion, with an increase in efficacy (SMD 0.11–0.12) for every 10 mg increment of MPH. In another systematic review and indirect comparison meta-analysis of 22 placebo-controlled trials of 2203 adults with ADHD,71 conventional shorter-acting stimulants had a more favourable risk–benefit ratio than longer-acting stimulants and non-stimulants in adults. Short-acting stimulants also reach effect sizes of 4.32 versus an effect size of 1.35 for long-acting stimulants.Various controlled studies have confirmed the effectiveness of MPH in about 57% of adults with ADHD.67In addition to reducing the core symptoms of ADHD, stimulants improve associated features of ADHD, such as on-task behaviour, academic performance and social functioning. These effects appear to be dose-dependent and are evident across settings. In adults, emotional regulation, occupational problems and marital discord also tend to be reduced on treatment. Side effects  are usually mild and transitory.50 and the NICE guidelines37 recommend stimulants, specifically MPH as the first-line treatment choice in adults. The European Network Adult ADHD (ENAA) consensus statement67 specifically recommends the use of extended release stimulants as treatment of choice for adults with ADHD. Long-lasting, extended-release formulations are preferred because of non-adherence, a lower abuse potential, fewer rebound symptoms and frequent dosing with short-acting formulations. The Maudsley guidelines recommend the use of modified-release MPH (because of the convenience of single-day dosage – therefore improving adherence) or multiple doses of immediate-release  as the second-line treatment for adults with ADHD. The Canadian ADHD Practice (CAP) Guidelines indicates amphetamine mixed salts (not available in SA), MPH OROS® technology and atomoxetine as the first-line treatments, whereas other MPH preparations are considered second-line options.72The BAP guidelines73 The range of half-lives of medications suggest that it is more practical to consider maximum dose in terms of the maximum taken at each time point, the length of effect of each dose on the control of ADHD symptoms and the number of doses required to provide sufficient control throughout the day – rather than a maximum based on mg/kg per day.67Currently, combinations of immediate and extended release preparations are often prescribed in adults – where the immediate release formulations are used as ‘top-up’ when the extended release formula is wearing off. The dose of stimulants should be individually adjusted, based on efficacy and tolerability – with a general recommended dose of 1 mg/kg.74 A number of randomised, double-blind, placebo-controlled trials and open-able long-term studies have confirmed efficacy and tolerability for adults with ADHD,77 whereas a meta-analysis confirmed an effect size of 0.8.70 Furthermore, Jasinski and Krishnan78 documented a lower liability for recreational abuse – which would position this drug as one of the treatments of choice for patients with a dual diagnosis of ADHD and a substance abuse disorder. The NICE guidelines37 recommends dexamphetamine as the second-line treatment for adults who develop intolerable side effects to MPH. Common side effects of lisdexamphetamine include insomnia and irritability, whereas dizziness, appetite suppression with weight loss, headache and other gastrointestinal side effects have also been reported. There have been post-marketing reports of psychosis, aggression, depression, exacerbation of tics and cardiovascular side effects such as palpitations, hypertension and myocardial infarction with sudden death.Lisdexamphetamine is a prodrug metabolised by red blood cells to yield its active metabolite, d-amphetamine and L-lysine.67 The BAP guidelines50 and Maudsley guidelines60 recommend atomoxetine as the first-line treatment in patients with comorbid SUD and as the treatment of choice in patients with comorbid anxiety disorders, severe tics or when there is a risk of diversion of medication. The NICE guidelines37 as well as ENAA67 considers atomoxetine as a second-line agent for patients with insufficient response to, or those who cannot tolerate MPH.For adults who do not respond to stimulant treatment or who have a condition in which a stimulant is contra-indicated, the non-stimulant atomoxetine is an appropriate alternative.79 However, in a meta-analysis comparing pharmacotherapeutic options in adults with ADHD, the effect size of atomoxetine was 0.59 versus an effect size of 0.67 for stimulants. However, in a recent systematic review,80 criticism against previous studies was raised. When the duration of studies was increased, and treatment naïve patients analysed separately, the effect size of atomoxetine improved to 0.9, which is very similar to the effect size of 1.0 of MPH. In SA, atomoxetine is still being underutilised19 – which may be a reflection of lack of knowledge and experience with regard to efficacy and effectiveness. It may also reflect patients’ preference for a medication which leads to immediate results – which stimulants provide.In a meta-analysis of atomoxetine in the treatment of ADHD in children and adolescents, non-stimulants had a significant lower effect size than those of short-acting and long-acting stimulants .81Side effects of atomoxetine appear reflective of increased noradrenergic tone and include dry mouth, insomnia, nausea, decreased appetite, constipation, decreased libido, dizziness, sweating and rare cases of hepatotoxicity.72 none of these are registered for the treatment of adult ADHD in SA and use will be off-label – at the discretion of the treating physician. Anticonvulsants, mood stabilisers, selective serotonin reuptake inhibitors and antipsychotic drugs have not been shown to be effective for primary symptoms of ADHD. They may, however, be useful in treating some comorbid conditions that patients with ADHD have.Although other drugs such as clonidine, guanfacine, TCAs, modafanil and venlafaxine are mentioned in international guidelines as the third-line treatment for ADHD,2-noradrenergic agonists: Clonidine (Dixarit®) has demonstrated efficacy in childhood ADHD, especially for cases marked by severe hyperactivity and aggression.82 However, there is an absence of literature on efficacy and tolerability in adults with ADHD.α84 In adults, the effect size was comparable to placebo.85 Potentially problematic side effects include hypotension, bradycardia, dizziness, somnolence, sedation, fatigue, dry mouth, nausea and abdominal pain. Guanfacine is the only ADHD medication which is associated with moderate weight gain.Results from clinical trials have demonstrated efficacy for guanfacine (not available in SA) in combined (hyperactive-impulsive-inattentive) ADHD in children and adolescents, but it appears to be less effective in the inattentive subtype of ADHD. The response rate in children was 50% – 60%.Tricyclic antidepressants: Most studies of TCAs found a moderate to robust reduction in ADHD symptomatology in children with a moderate to strong treatment effect. The more selective noradrenergic drugs, that is, imipramine  and the active metabolite desipramine, are more effective and better tolerated. A target dose of 200 mg/day is indicated. TCAs have negligible abuse liability and efficacy for comorbid anxiety and depression.86Modafanil (Provigil®): Although efficacy for this wake-promoting drug in the treatment of ADHD in children has been demonstrated,87 studies in adults failed to demonstrate efficacy in reducing ADHD symptoms.89Selective serotonergic and noradrenergic reuptake inhibitors: Venlafaxine  appears to be mildly efficacious in moderating ADHD symptom, with studies indicating a measurable reduction in symptoms at doses of 75 mg/day – 150 mg/day.91Noradrenergic dopaminergic reuptake inhibitors: Bupropion hydrochloride (Wellbutrin®) has demonstrated moderate effect in the treatment of ADHD with a 42% reduction in ADHD rating, with 52% of subjects considered responders at a mean dose of 362 mg/day.95 Dosing appears to be optimal at 400 mg/day – 450 mg/day and there is a delay in onset of action. In a meta-analysis96 found the number needed to treat 4.6 with a discontinuation rate no higher than placebo. In a systematic search of studies, Peterson, McDonagh and Fu71 found the pooled effect size for bupropion to be 1.87. Side effects include insomnia, edginess and a low risk for seizures. Bupropion should be considered in adults with comorbid mood disorders (depression or bipolar disorder) or SUD.Monoamine oxidase inhibitors: Some studies98 have suggested effectiveness of monoamine oxidase inhibitors  in the treatment of adult ADHD, but their potential to cause hypertensive crisis and the dietary restrictions pertaining to tyramine-containing foods, seriously limit their use.10068 The multimodal treatment study in ADHD101 has confirmed definitive evidence for the beneficial effect of psychotherapeutic interventions in childhood ADHD. However, evidence in adult ADHD is sparse. Various forms of structured, intensive and skills-based treatment may improve the likelihood of attaining remission, especially when combined with medication.53 The effects of therapy on the core symptoms of ADHD seem substantial, with potential effects on comorbid symptoms.Pharmacotherapy alone is not sufficient to stabilise the many problems of adults with ADHD, nor does current research support the efficacy of psychotherapeutic treatments as sole treatment for adult ADHD.37 ENAA67 and BAP guidelines50 recommend a multi-modal treatment approach with psychosocial treatments as complementary to psychopharmacological interventions to provide support, improve acceptance of diagnosis, and treat comorbidities and residual symptoms .The NICE guidelines,103 CBT strategies are focused on improving the core symptoms of ADHD through self-instructional training and memory aids to improve attention, techniques to reduce impulsivity (e.g. ‘stop and think’), diaries and time schedules to improve organisational skills, and assertiveness and social skills training to improve communication skills. Group and individual CBT demonstrated similar outcomes.104Although different approaches have been used, the majority of evidence is for structured CBT interventions, with modified CBT plus medication demonstrating greater benefits than psychotherapy or medication alone particularly on the core symptoms of ADHD, with lesser effect on anxiety and depression.105 There is also some evidence for the use of dialectical behaviour therapy,106 psychoeducation and organisational skills teaching107 and cognitive remediation programmes.108 Cognitive remediation provides techniques focussing on retraining cognitive function, teaching internal and external compensatory strategies, and restructuring the physical environment to maximise functioning. However, it is important to note that skills-based therapy and psychodynamic therapy109 may have a negative effect on self-esteem.Mindfulness awareness therapy is a complementary intervention that not only improves affect and mood regulation in adults with ADHD, but also sustained attention and quality of life.Formal studies of the effectiveness of coaching and psychoeducation have not been performed, but many adults with AHDD report that they gain benefit from these approached. Coaching is a structured, supportive therapy that can be offered individually or by group sessions. The purpose of coaching is to learn new problem-solving skills for identified practical problems.It is optimal to pursue an individually tailored problem-oriented approach to psychosocial interventions. This may include individual, family, and group therapy, social skills training, occupational therapy and liaison with employees and academic institutions, and coaching.110 NF is thought to reduce behavioural problems associated with the core symptoms of ADHD through enabling the patient to acquire skills to self-regulate certain brain activity patterns. In a meta-analysis, large effect sizes for impulsivity and inattention, and a medium effect size for hyperactivity were reported for theta and beta, sensorimotor rhythm and slow cortical potentials (SCP) protocols in ADHD.111 A recent study112 has evaluated the effectiveness of 30 sessions of SCP NF in 24 adults with ADHD. In this study, significant symptom reduction (self-rated and third-party rated) was observed with medium to large effect sizes after treatment and 6 months post treatment with regard to clinical symptoms, as well as reaction time, reaction time variability and contingent negative variation. Fourteen participants experienced a symptom reduction of over 25% and symptoms of six participants remitted, that is, they did not meet criteria for an ADHD diagnosis anymore. However, in a systematic review and meta-analyses of randomised controlled trials,113 NF did not demonstrate any statistically significant improvement on ADHD measures with blinded assessment in placebo- and non-placebo controlled trials.Neurofeedback (NF) has been investigated as a possible alternative treatment for ADHD in children.114 In humans and in animal models, exercise has been found to have wide-ranging cellular, structural, functional and cognitive benefits. These include enhanced frontal lobe volume, executive functioning, brain-derived neurotrophic factor (BDNF) levels, cerebral blood flow, and dopamine and other monoamine modulation.115A recent meta-analysis investigating the effects of acute exercise on cognitive performance in healthy adults revealed that cognitive performance, particularly executive functioning tasks, was improved after 20 minutes of exercise.119 whereas acute high intensity physical activity can improve sustained attention independent of stimulant treatment.120There is also growing body of research indicating positive effects of acute aerobic activity and longer-term activity on neuropsychological function in ADHD. Existing studies examining effects of physical activity on ADHD have generally studied children and adolescents, with some emerging work in adults with ADHD. Studies have shown that in children with ADHD, moderate-to-vigorous physical activity improves planning, and working memory, inhibitory control, novel problem-solving, processing speed and academic performance,18 whereas acute moderate intensity exercise facilitated performance on executive functioning.122 Although specific recommendations regarding frequency, intensity or duration of exercise in ADHD have not been established,123 there is growing consensus that regular exercise engagement is a powerful nonpharmacological treatment for management of ADHD symptoms and promotion of cognitive health.In adults with ADHD, there is preliminary evidence that individuals who report more frequent physical activity experience reduced impulsivity, worry and intrusive thoughts,113 2904 published randomised controlled trials of dietary  and psychological interventions  for ADHD were screened. Of these, 54 trials met inclusion criteria for the analysis. Two different analyses were performed: one where the outcome measure based on ADHD assessments was completed by parents or teachers, and the other where the best possible blinded assessments  of improvement on ADHD measures were included. Although all dietary and psychological interventions produced statistically significant effects, in the latter group only free fatty acid supplementation and artificial food colouring exclusion remained significant. It therefore seems that free fatty acid supplementation produced small but significant reductions in ADHD symptoms even with probably blinded assessments, although the clinical effects of these effects remain to be determined. Artificial food colouring exclusion produced larger effects but often in individuals selected for food sensitivities.In a systematic review and meta-analyses of randomised controlled trials of dietary and psychological interventions,124 only marginal evidence was found for n-3 PUFA supplementation in those who are n-3 PUFA deficient. No significant benefit was found for the general population, nor those with ADHD.N-3 omega-3 polyunsaturated fatty acids (n-3 PUFAs) are promoted as cognitive enhancers in the general population, as well as for patients with neurocognitive deficits such as ADHD. In a recent systematic review and meta-analysis,67Although many individuals, with and without ADHD, report benefits from ‘brainsmart food’ such as mentat, zinc, l-carnitine, vitamin B6, magnesium, ginkgo biloba, ginseng, passionflower, acetyl l-carnitine(ALCAR), dimethylethanolamine (DMAE), L-theanine, dosahexaenoic acid (DHA), citicoline, curcumin, phosphatidylserine, vincopetine, L-alpha-glycerylphosphorylcholine, bacopa monnieri and huperzine A, formal studies of the effectiveness of these agents are lacking. At present, there is no consistent evidence from randomised control trials for the use of any food supplements.See The order of treatment of ADHD and comorbid disorders depends on the severity of the different disorders and clinical judgement on which disorder is driving the current level of behavioural impairments or mental state changes. The presence of comorbidity increases the likelihood of the need for combination therapy – both in terms of psychopharmacological agents and psychotherapeutic approaches. In initiating medication for comorbid conditions, an individualised approach with regard to effectiveness, risk-benefit profile and tolerance should be considered.67 A sequential approach to initiating medication is recommended. In the case of psychotic disorders or severe bipolar disorders, stimulants should be used with caution.In the presence of comorbid disorders, a risk assessment should be done. Severe mood disorders, severe anxiety disorders (with panic attacks) and psychotic disorders should be treated prior to treating ADHD. Milder disorders (e.g. mild depression and anxiety) may be deferred until after treatment of ADHD as treating the ADHD might alleviate other symptoms.Patients with ADHD and comorbid SUD often present with more severe SUD characterised by early onset, extended duration of the SUD, greater impairment and shorter transition from substance use to dependence. In cases of comorbid SUD, the SUD can be treated either before initiating treatment for ADHD, or simultaneously. Close supervision is advised when treating ADHD patients with SUD with stimulants and in cases where diversion or abuse is a particular concern, atomoxetine may be selected as the first-line treatment. The concerns of some professionals that use of stimulants in ADHD may lead to drug abuse either by sensitisation or as a gateway to other drugs is not supported by evidence. Long-acting stimulants with a lower abuse potential, lisdexamphetamine and bupropion are preferred over short-acting stimulants. Concomitant psychosocial interventions are crucial.125 Although continuation of treatment during pregnancy may therefore pose a risk to the child, discontinuation may increase harmful behaviours related to the mother’s mental state.50 It is therefore important to consider the risk–benefit profile of not treating the mother, for example, poor risk management, dangerous driving, illicit drug use, alcohol and tobacco use, increased levels of distress and self-injurious behaviour. Non-pharmacological strategies should be explored, and liaison with the obstetrician is important.All the stimulants, atomoxetine, bupropion, modafinil and other pharmacological agents discussed in these guidelines  are considered ‘category C’ by the FDA, that is, animal studies have reported some harm, without having any robust evidence in human studies.Adult ADHD is a chronic, costly and debilitating disorder – if untreated. Recognition of adult ADHD as a chronic disorder which needs chronic treatment is crucial.A comprehensive diagnostic assessment and diagnostic certainty prior to initiating drug treatment are crucial. This is not possible during the average 15-min general practitioner consultation, and it is therefore strongly advised that the diagnosis of adult ADHD and treatment initiation should be made by a psychiatrist well versed in the complexities of ADHD and the comorbidity thereof. Raising the diagnostic bar for adult ADHD will also prevent the scripting of medication for patients who use the medication for reasons other than the treatment of ADHD (e.g. cognitive enhancement) which artificially escalates the prevalence and costs of ADHD.19 Ongoing treatment (which includes compliance to treatment) is crucial in preventing complications and long-term costs.Once a proper treatment plan has been established, and a patient is contained within a multi-disciplinary and multi-modal  basket of care, follow-up can take place on primary healthcare level – leading to further cost savings to schemes and reducing pressure on resources  at specialist level.


Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder associated with a range of mental health, neurocognitive and functional problems. Although the diagnosis is based on descriptions of behaviour, individuals with ADHD characteristically describe excessive spontaneous mind wandering (MW). MW in individuals with ADHD reflects constant mental activity which lacks topic stability and content consistency. Based on this review of the neural correlates of ADHD and MW, we outline a new perspective on ADHD: the MW hypothesis. We propose that altered deactivation of the default mode network, and dysfunctional interaction with the executive control network, leads to excessive and spontaneous MW, which underpins symptoms and impairments of ADHD. We highlight that processes linked to the normal neural regulation of MW  are deficient in ADHD. MW-related measures could serve as markers of the disease process, as MW can be experimentally manipulated, as well as measured using rating scales, and experience sampling during both cognitive tasks and daily life. MW may therefore be a potential endophenotype. ADHD isDespite considerable progress in understanding the symptoms and impairments of ADHD and the availability of effective treatments , key clinical issues remain to be resolved. ADHD, particularly in adults, remains a disorder that often goes undiagnosed and untreated. One explanation is diagnostic uncertainty due to the high rates of psychiatric comorbidity and overlap of ADHD symptoms with other common mental health disorders . The diaHere we propose a novel approach that focuses on a measurable component of ADHD psychopathology: excessive, spontaneous mind wandering (MW) . We put We propose this as a promising new avenue for research as MW has been linked to ADHD and ADHD-associated impairments, and unlike ADHD symptoms such as inattention, MW can be measured using a range of direct and indirect measures. These include rating scale state and trait measures, experience sampling in daily life, experience sampling during experimental paradigms, and the neural correlates of MW. Potentially these may provide new clinical and neural biomarkers of ADHD that could provide new insights into the neurobiological basis of ADHD, which can be used for diagnosis and prediction and monitoring of treatment effects, and could lead to novel treatments targeting the regulation of MW in ADHD.22.1Mind wandering (MW) occurs when one’s mind drifts away from the primary task and focuses on internal, task-unrelated thoughts and images. MW is a universal experience that represents up to 50% of daily thinking time . While s2.2The first study of MW in ADHD was conducted using an experience sampling technique to measure on-task and off-task thoughts during a simple attention task .The freqA further study, using the MW Deliberate and Spontaneous scales  found thIn our own studies, we developed a clinical scale reflecting ADHD patient reports of excessive spontaneous MW . The 12-Overall, these findings suggest that asking about the subjective experience of MW alone, provides a better prediction of ADHD associated impairment than the traditional ADHD inattention and hyperactive/impulsive symptoms. Moreover, as we will discuss, MW may reflect the primary deficit arising directly from dysregulated neural network activity in ADHD that underpins the symptoms and impairments currently used to define ADHD.2.3The neural basis of MW has generated considerable interest since 2006 . The DMNAmong the first investigations of MW-associated neural activity were two functional magnetic resonance imaging (fMRI) studies using tasks with low cognitive demand , or highA limitation of these early studies was that the frequency of task-unrelated thoughts was measured outside the scanning sessions. To provide a more direct investigation of neural activity during periods of MW, The finding of co-activation of both executive and default networks during periods of task-unrelated thoughts in control subjects was subsequently confirmed by meta-analysis of fMRI studies . ExaminiHowever, not all studies have reported co-activation of DMN and executive control regions during periods of MW. 2.4Overall the findings discussed above confirm the association of DMN activity with the frequency of task-unrelated thoughts. However, the role of executive control networks may depend on task conditions or type of MW and other forms of spontaneous thought. Typically, executive control and DMN function in an anti-correlated manner. Early work showed increased activation in executive control and decreased activation in DMN regions with increasing attentional demands, and vice versa . LikewisHowever, as discussed, fMRI research has been inconclusive on the role of executive control on MW, which sparked off a debate. One argument is that MW results from a failure in executive control to prevent automatic task-unrelated thoughts from becoming conscious . For exaTo investigate the relative role of different neural networks, an activation likelihood estimation (ALE) meta-analysis was conducted on different types of internal thoughts, including experimentally directed episodic future thinking, and spontaneous MW . The resTo address the various findings, recent models of MW better reflect the complexity of internally generated thoughts. They clarify that MW is not a unitary construct, but rather an umbrella term that captures different types of MW experiences in the general population. A key conceptual paper proposes a dynamic framework in which MW is understood as a subtype of spontaneous-thought phenomena that also includes creative thought and daydreaming . The aut2.5Resting state connectivity studies of ADHD in children and adults have examined interactions between the DMN and executive control network, as well as connectivity within the DMN itself. These studies consistently find that anti-correlation between the executive control  network and DMN is attenuated, and that resting state connectivity within the DMN itself is reduced . ADHD isThe observation of DMN abnormalities in ADHD led to a hypothesis known as the DMN interference model . This moRelated to the default mode interference hypothesis, it has also been proposed that activation of DMN hubs will depend on motivation, cognitive load, attentional demands and individual state regulation/capacity . This isThe DMN interference hypothesis also proposed that a certain threshold of DMN activity needs to be reached before DMN interference occurs . In rela3So far, we have outlined studies that link ADHD to MW, MW to DMN activity, and DMN activity to ADHD. These studies raise the possibility that deficient regulation of DMN activity leads to excessive spontaneous MW in individuals with ADHD, which might underpin the inattentive symptoms of ADHD and deficits in cognitive task performance. Further support for this hypothesis comes from several observations that draw parallels between processes that underlie the regulation of MW in neurotypical controls, and processes found to be deficient in ADHD. These parallels include: (1) context regulation of MW in controls, and deficient context regulation of neural activity in ADHD; (2) perceptual decoupling of somatosensory processing during MW, and in ADHD; (3) sensitivity of MW and MW-associated neural processes to task salience and rewards; (4) impairments in cognitive task performance, and function in daily life. Below we outline these areas in more detail.3.1The context regulation hypothesis states that an adequate capacity to self-regulate mind wandering within a context will reduce a potential negative impact on the primary task performance . ContextRegarding the potential role of executive control and working memory capacity, individuals with both low and high working memory capacity report greater levels of MW under low cognitive demand conditions . HoweverFurthermore, higher working memory capacity predicted greater frequency of task-unrelated thoughts in a low demand breath-awareness task  but feweIn summary, these findings indicate that higher working memory/executive control capacity moderate frequency of MW according to task demands. In general, greater working memory capacity is predictive of more MW during low demand conditions, whereas it is predictive of less MW during high demand conditions.3.2Context regulation of MW in ADHD has yet to be investigated. However, there is consistent evidence for deficient neural adaptation to task demands in ADHD compared to controls, with deficient upregulation of executive control regions, accompanied by deficient deactivation of the DMN. Thus, the neural networks that show deficient context regulation in ADHD are the same networks associated with context regulation of MW in neurotypical controls.For example, deficient context regulation was seen in ADHD compared to controls using electroencephalography EEG recordings during the Flanker Task. This task contrasts a low cognitive demand (no conflict) with a high cognitive demand (conflict) condition. In contrast to the ADHD group, controls showed a significantly greater increase in frontocentral theta amplitude and decreased phase variability  in response to the higher cognitive demands of the conflict condition , 2014. LSimilarly, there was greater RTV in ADHD compared to controls, under high demand (very fast or very slow event rates), compared to low demand (medium event rates) conditions  reflectifMRI studies also demonstrate deficient context regulation in ADHD. Compared to controls, ADHD is associated with under-activation of the FPN  during on-task conditions  and reduTaken together, the evidence from cognitive-EEG and fMRI studies points to a reduced ability to modulate task positive and negative neural processes in ADHD. Since the networks involved are the same as those linked to context regulation in neurotypical controls, deficient context regulation in individuals with ADHD may explain the high frequency of task-unrelated thoughts. This hypothesis has yet to be formally tested.3.3A key characteristic of MW is the association with attenuated somatosensory processing, referred to as perceptual decoupling. This means that during periods of MW there is a reduced somatosensory response to sensory stimuli . One hypEEG research has consistently reported that event-related potential (ERP) components (P1), markers of early visual information processing within 100 ms, are attenuated during periods of task-unrelated compared to task-related thoughts . Phase-lCortical source activity analyses during a visual Sustained Attention to Response Task (SART) also confirm the attenuation of early visual information processing, during periods of MW . In thisCollectively, these findings suggest a switch from active cognitive processing to MW, which is facilitated by a state of perceptual decoupling, or detachment of perception from attention. Consequently, a reduced P1 amplitude is regarded as a marker of perceptual decoupling during episodes of MW.3.4Somatosensory responses are far less studied in ADHD, and the association between sensory decoupling and ADHD is not well established. Furthermore, there have been no studies that directly investigate the relationship of perceptual decoupling to periods of MW in ADHD. Yet, the few studies that have focused on early sensory processing in ADHD find deficits that are similar to those seen during periods of MW in neurotypical controls.Initial reports found decreased slow frequency fluctuations within the left sensorimotor cortex  and suppUsing ERP, a larger P1 (100 ms post-stimulus) amplitude has been seen in children with ADHD compared to controls; a finding that was interpreted as a compensatory mechanism in the absence of performance differences . In cont3.5Several studies find that the frequency of MW is related to task salience or incentives designed to increase motivation. This is not surprising, since almost everyone finds it easier to remain focused on tasks that are inherently interesting, compared to mundane or boring tasks. A high degree of task-related motivation and interest were both associated with lower frequency of MW during the SART , 2016 asA related phenomenon is the response to unexpected infrequent stimuli, which tend to be of high salience in auditory oddball paradigms. Infrequent and deviant auditory stimuli were associated with an increased mismatch negativity amplitude, which is a marker of attention allocation to these stimuli, during episodes of task focus compared to a decreased amplitude during MW . TherefoIn another study, monetary incentives increased the number of reports of self-caught MW compared to conditions that were unrewarded . The inc3.6There are numerous examples of enhanced sensitivity to the effects of task salience and rewards in children and adults with ADHD. Here we discuss some of the most pertinent studies related to MW-associated task performance and neural activity.In a key fMRI investigation, a sample of children with ADHD and controls completed a Go/No-go task under low- and high-incentive conditions . In the In a series of publications from Kuntsi and colleagues, fast-rewarded (high incentive) conditions compared to slow-unrewarded (low incentive) conditions on tasks requiring sustained attention reduced or abolished ADHD case-control differences for arousal measures using skin conductance , RTV An and omisBased on the findings that enhancing task saliency alters neural responses, task performance and frequency of MW, we hypothesise that adequate rewards will modulate the frequency of MW in both neurotypical and ADHD populations. In particular, a decrease in MW will lead to better early attentional orienting in ADHD, or successful detection of visual information early on at presentation. Despite similar effects on DMN activity of task saliency (reward) and stimulants in ADHD , differe3.7MW has an adverse impact on both cognitive task performance and daily life in control populations. Measured performance deficits associated with MW include greater stimuli-response error rates , slower Similarly, attenuation in the amplitude of ERPs reflecting late cognitive analysis of stimuli  has been observed during periods of MW. Examples include reduced N400, mismatch negativity  and P3 aMW has also been associated with several daily life impairments, including deficits in reading comprehension , negativ3.8Similar impairments in cognitive task performance and daily life associated with MW are also seen in ADHD. Examples include attentional orienting, performance monitoring, response preparation and inhibitory processes; manifesting in increased error rates, reaction time variability and attenuation in Cue-P3 and No-Go N2 and P3 amplitudes .ADHD is also associated with impairments in daily life including poorer psychosocial, educational and global function . IndividIn summary, the findings on impairment show that both ADHD and MW in non-ADHD controls appear to be linked to similar performance deficits. This is consistent with our MW hypothesis for ADHD since we propose that episodes of MW in controls and excessive spontaneous MW in individuals with ADHD lead to similar functional and cognitive impairments. Potentially, excessive spontaneous MW in ADHD can be expected to lead to typical impairments experienced by people with ADHD in their daily lives. Examples could include problems following a conversation, reading and watching a film; maintaining a coherent train of thought for problem solving and holding thoughts in mind; difficulties falling asleep due to constant mental restlessness associated with excessive MW; and feeling exhausted by the mental effort required to sustain focus on daily activities. Further research is required to investigate the extent to which impairment seen in individuals with ADHD can be explained by excessive, spontaneous MW.3.9As discussed extensively in this review, deficient deactivation of the DMN during cognitive task performance has been consistently reported in ADHD. However, ADHD is associated with a wide range of cognitive and neural deficits, anyone of which could be contributing to the generation of ADHD symptoms, and be potential targets for treatment. Indeed, the range of deficits associated with ADHD has led many to argue that the neuropathological basis for ADHD is highly heterogeneous .Key additional processes highlighted in the literature include: deficits in the dorsal attention network of dorsolateral prefrontal cortex, basal ganglia and parietal regions during tasks of selective and sustained attention ; inhibitDespite the findings linking various neural functions to ADHD, it remains unclear which of these play a direct causal role in the generation of the inattentive and hyperactive/impulsive symptoms currently used to define ADHD. This is a critical point, because numerous non-causal associations are expected to arise through the process of pleiotropy, in which shared genetic  risks can lead to multiple different phenotypic outcomes at the level of brain structure, function, cognitive performance and behaviour. Yet, only a subset of the associated neural deficits may reflect underlying causal processes in ADHD . There a3.10In relation to ADHD, important new insights have come from longitudinal outcome studies that investigate the cognitive and neural correlates of remission and persistence in ADHD . A central question in causal models of ADHD has been the separation of executive control measures (e.g. inhibition and working memory) from preparation-vigilance measures. Earlier work showed that measures reflecting these processes are both associated with ADHD in children, but are genetically largely uncorrelated, reflecting distinct aetiological pathways .Regarding developmental change, in a 6-year longitudinal outcome study of children with DSM-IV ADHD, adolescents and young adults who no longer met ADHD criterial (ADHD remitters), but not those who still had ADHD (ADHD persisters), showed a similar profile to controls without ADHD on cognitive and neural measures. These measures indicated response preparation, attention and vigilance processes  and were significantly correlated to the severity of inattention at outcome. In contrast, executive control measures of working memory, and inhibitory processes did not distinguish in persisters and remitters, and did not correlate with ADHD symptoms at outcome; including commission errors, digit span backwards, and ERP activity of inhibitory control (No-go P3) and conflict monitoring (N2) .Similarly, in another follow-up study there was no an association between ADHD remission and improvements in executive functioning , interfeA recent study reported increased resting-state fMRI connectivity in ADHD remitters compared to controls in the executive control network, with intermediate connectivity profiles in persisters . Two othHowever, in a resting study fMRI, only ADHD persisters showed reduced positive functional correlation between DMN hubs  . ReducedFrom these findings we conclude that, potentially, DMN activity and preparation-vigilance processes (associated with MW) may have direct aetiological significance in ADHD since they track the symptoms of ADHD during child to adult development. In contrast, deficits in executive control functions appear to dissociate from the clinical course of ADHD symptoms during development and are therefore less likely to play a direct causal role in the ongoing generation of symptoms. Since, the neural processes tracking the clinical disorder are closely aligned to those thought to underpin MW, we propose that targeting the regulation of MW or MW-associated neural dysfunctions could potentially lead to reductions in ADHD symptoms and remission of the disorder.44.1Finally, we provide a developmental perspective on the neural processes linked to MW, since the frequency and impact of MW may vary throughout development. “Small-world” properties represent quantifiable metrics of topographic properties of large-scale/global brain organisation . These pAn increase in long-range connections, as well as a decrease in short-range connections (segregation) and strengthening of within-network interactions (integration), are thought to govern functional brain development and functional specialisation . The chiWithin-network integration of DMN hubs  and segr4.2Related to the findings on typical functional brain development, With regard to the development of MW in ADHD, to date there has been only one published study, which compared the frequency of MW in children and adults with ADHD . Using aOverall, the developmental studies suggest that understanding the cortical maturation of key networks leading to aware/unaware and spontaneous/deliberate forms of MW, may be important to understanding the onset, course and development of ADHD.5This review sets out to draw parallels between MW and ADHD, and guide new insights into ADHD psychopathology. The theoretical conceptualisations outlined are designed to set the scene for further hypothesis testing. The basis for this work is the observation that a spontaneous and poorly controlled type of MW is strongly associated with ADHD, and ADHD-related impairments. Currently, there are only a small number of studies that measure MW in ADHD, and none that simultaneously measure ADHD, MW and neural functions associated with both ADHD and MW. The relationship of MW to ADHD symptoms such as inattention is therefore not yet well understood. We therefore set out to summarise what is known about the links between ADHD, MW and their neural correlates.At the level of neural networks, there are strong parallels in the association of both ADHD and MW with DMN activity during task conditions. Reduced deactivation of DMN activity during tasks requiring sustained attention is associated with the frequency of MW in controls, and is also associated with ADHD compared to controls. Since ADHD is also linked to a specific pattern of spontaneous and poorly controlled MW, a simple hypothesis can be proposed that the normal neural processes that regulate MW are disturbed in ADHD, leading to excessive levels of spontaneous and uncontrolled MW. Furthermore, cognitive and functional impairments that are associated with periods of MW in controls are comparable to the range of impairments associated with ADHD, suggesting that excessive spontaneous MW may underpin functional deficits in ADHD.In support of our hypothesis we draw on evidence that the usual processes regulating MW are disrupted in ADHD. First, we see that the usual context regulation of DMN and executive control network activity to increasing task demands is associated with MW, and deficient in ADHD. Furthermore, deficient regulation of these processes appears to be reversed by stimulant medications used to treat ADHD. Second, we see that the processes associated with both MW and ADHD are sensitive to the salience of task conditions. In ADHD increasing the salience of task conditions may “normalise” performance and associated neural processes. Finally, we see that both MW and ADHD may be associated with sensory decoupling such as the reduced early P1 response of the occipital cortex to a visual stimulus. We therefore propose that by understanding the processes of normal regulation of MW in the general population, we can identify with more precision aberrant processes in ADHD.One question that arises from this model is whether measures of MW can be considered distinct from the inattentive symptoms of ADHD. For example, measures of MW may merely reflect alternative measures of the same underlying construct. Currently, there is almost no evaluation of the incremental information provided by measures of MW, although we did report that a rating scale measure of MW was an independent predictor of impairment in ADHD after controlling for ADHD inattention and hyperactivity/impulsivity symptoms . FurtherIf there is a very close relationship of MW with ADHD-inattention, this would open new avenues for research. MW has the advantage that it can be measured using simple rating scale trait measures, but also experience sampling data in daily life ; and experience sampling during experimental paradigms such as sustained attention tasks, which have been used to investigate the neural correlates of MW in control samples. Measures of MW may also be less dependent than the inattentive symptoms of ADHD on behavioural adaptation, which is influenced by learnt coping strategies, so perhaps a better reflection of the underlying neural condition.The model we propose views the inattentive symptoms of ADHD as outcomes of MW , and MW in ADHD may be a direct outcome of altered neural regulation of internal thought processes. Cognitive performance deficits seen in ADHD may also be a direct outcome of MW. We propose that dysregulated neural functions (DMN overactivity during task conditions for example), are reflected in excessive spontaneous MW, and that such internal distractibility explains behavioural symptoms such as losing track during conversations, avoiding tasks that require sustained attention, not completing tasks, and misplacing things.Further research is required to investigate heterogeneity the range of internally generated thoughts, and understand the regulatory processes involved. A key question is to fully understand the differences in studies which find that episodes of MW are associated with both reduced or absent  co-recruSpontaneous, unaware (‘zone-off’) MW was associated with decreased functional connectivity  and a neIn our review, we identified three existing fMRI accounts proposing specific dynamics of MW. The dynamic framework  proposesFuture research could focus on the use of EEG, which can capture fast and covert cognitive processes such as MW. The increased use of state-of-the-art EEG approaches that provide improved source localisation of EEG signals, combined with EEG’s millisecond temporal resolution, has already demonstrated their better potential to explain the dynamics of MW compared to more traditional scalp-level EEG analyses .6The MW hypothesis proposes that altered interaction between the four large scale networks , and that deficient DMN deactivation during task activities will lead to excessive spontaneous MW, lacking in coherence and topic stability, which in turn will lead to ADHD symptomatology.To investigate this hypothesis, future work could apply experimental designs that have been successfully applied to manipulate and measure MW and measures the neural correlates of MW in controls samples, to ADHD case-control studies, or by investigating correlations to dimensional measures of ADHD symptoms. Examples include sustained attention and inhibitory control tasks, varying cognitive load by using manipulations such as altering the stimulus presentation rate  or introInferring causal directions may be difficult because of the close temporal timing of neural, cognitive performance and MW events if they covary strongly with each other. One approach to infer causal relationships is to use treatment interventions such as stimulant mediation, to bring about change in the various outcome measures . Then thTo guide future work, we outline specific predictions derived from this hypothesis.6.1We propose that individuals with ADHD will experience greater perceptual decoupling driven by the proposed ADHD-specific MW, compared to controls during long-lasting (>30 min) sustained attention paradigms. A potential neural correlate is absent or reduced inter-regional synchronisation or positive functional correlation between DMN and visual networks. Using EEG, reduced mean P1 and N1 amplitudes will reflect inefficient early perceptual processes in ADHD.6.2We propose that individuals with ADHD will be unable to adapt to increasing cognitive  demands both at the neural level, and behaviourally; and that deficient context regulation of neural activity in ADHD will be related to the frequency of MW. Regarding neural correlates of these processes, we propose that a reduced positive functional connectivity between DMN and salience network will reflect the deficit in switching from rest to task, task to rest and from a low to high demand condition. Another neural correlate will be an absent change in frontal midline theta power from rest to task, hypoactivation in the DMN from task to rest and hypoconnectivity or reduced positive functional connectivity within the DMN  during rest.6.3We propose that variable reaction times will stem from MW and serve as a behavioural correlate of reduced negative functional correlation (or even disconnection) between default mode and executive control network and hyperactivation within the DMN during cognitive paradigms.The neural inefficiency in the large-scale networks will manifest in increased phase inconsistency/variability of parietal or frontal theta in response to task-related stimuli, which will coincide with excessively frequent episodes of MW.Changes in the content and context of MW is likely to reflect differential recruitment of DMN regions . For instance, depressive thoughts might result in greater connectivity between the core DMN and salience network, and a weaker connectivity between these two networks with the FPN and the medial temporal lobe (DMN hub). Excessive MW was correlated with the highest degree of DMN activation, suggesting that overactivity of the DMN might reflect the frequency rate of MW . Therefo7Converging evidence indicates that both MW  and ADHDFuture studies should focus on understanding whether completely different neural processes underlie MW in ADHD compared to controls, or there is simply neural attenuation in ADHD. Understanding context regulation requires the use of conditions varying in cognitive demand. Another necessary study is to measure effects of reward, or whether reward ‘normalsies' MW in ADHD compared to controls. Importantly, validation across different MW measures and conceptualization of different types of MW will enable the investigation of neural activity underlying specific types of MW.Professor Jonna Kuntsi has given talks at educational events sponsored by Medice: all funds are received by King’s College London and used for studies of ADHD. Kings College London research support account for Professor Philip Asherson received honoraria for consultancy to Shire, Flynn-Pharma, Eli-Lilly, Novartis, Lundbeck and Medice; educational/research awards from Shire, Lilly, Novartis, Flynn Pharma, Vifor Pharma, GW Pharma and QbTech; speaker at sponsored events for Shire, Lilly, Novartis, Medice and Flynn Pharma.