Speer allergic tension-fatigue syndrome (SATFS) is a classic allergy syndrome characterized by allergy-like symptoms, muscle tension, headaches, chronic fatigue, and other particular behaviors that were initially described in the fifties. The particular behaviors displayed include symptoms such as hyperkinesis, hyperesthesia , restlessness, and distractibility, among others. Interestingly, these symptoms are very similar to descriptions of attention deficit hyperactivity disorder (ADHD), the most prevalent neurodevelopmental disorder worldwide, which is characterized by inattention, hyperactivity, and impulsivity. The clinical description of SATFS precedes the nomination of ADHD in 1960 by Stella Chess. In this conceptual paper, we stress that there is a gap in the research on the relationship between ADHD and allergic pathologies. The hypotheses of this conceptual paper are (1) SATFS is probably one of the first and best historical descriptions of ADHD alongside a common comorbidity  displayed by these patients; (2) SATFS (ADHD) is a systemic disease that includes both somatic and behavioral manifestations that may influence each other in a bidirectional manner; (3) The role of neuroinflammation and histamine is key for understanding the pathophysiology of ADHD and its frequent somatic comorbidities; (4) The deficiency of the diamine oxidase (DAO) enzyme, which metabolizes histamine extracellularly, may play a role in the pathophysiology of ADHD. Decreased DAO activity may lead to an accumulation of histamine, which could contribute to core ADHD symptoms and comorbid disorders. Further empirical studies are needed to confirm our hypotheses. Speer aSpeer was a pioneer of the psychosomatic approach. In 1954, he suggested a disruptive view of the psyche–soma relationship. At this time, the psychosomatic approach defended by alienists appeared to operate in just a single direction . On the contrary, Speer stressed that “this relationship may operate in the opposite direction, and that somatic disease may often be the cause of disorders of feeling and behavior rather than the effect” . In 1970In 1989, Paul Marshall recognized the absence of systematic studies testing the effects of allergies on ADHD behaviors . HoweverUnfortunately, none of these authors stressed the role of histamine as a potential mediator in the relationship between ADHD and the immune system (including inflammation) in general and allergies in particular. This is, at least, surprising, as histamine has played a core role in allergies since the use of antihistamine drugs since the beginning of the 20th century.The latest step in the liaison between allergies and ADHD took place in 2009 when Pelsser et al.  postulatTo sum up, there is a research gap that needs to address all these caveats regarding the relationship between allergies and ADHD: what happened with the concept of SATFS?; might the initial descriptions of SATFS be just a description of an emerging syndrome in the sixties, namely, ADHD?; if so, could histamine be the missing link between the classic ADHD symptomatology and the frequent somatic comorbidity reported in patients diagnosed with ADHD?The hypotheses of this conceptual paper areHypothesis 1.The clinical descriptions made by Speer in 1954 and 1958 about an “allergic tension-fatigue syndrome” is probably one of the first and best historical descriptions of patients with ADHD affected by a comorbidity  frequently displayed by these patients;Hypothesis 2.SATFS (ADHD) is indeed a systemic disease including both somatic and behavioral manifestations that may influence each other in a bidirectional manner ;Hypothesis 3.The role of histamine is key for understanding the pathophysiology of the typical medical comorbidities displayed by patients with ADHD and complements the cholinergic–adrenergic disbalance theory of the ADHD–allergy relationship; and finally,Hypothesis 4.The diamine oxidase (DAO) enzyme, which metabolizes histamine extracellularly, may play a key role in the pathophysiology of ADHD. A decreased DAO activity may lead to an accumulation of histamine, which could contribute to ADHD symptoms.We begin by describing the clinical picture  of SATFS . Next, IAs said before, SATFS includes behavioral and systemic constitutional manifestations.In his seminal works 1954, 1958), Speer reported that some allergic patients, either children or adults, tended to initially “overdo and overreact”, and then to become strongly fatigued 954, 1958. In otheIn his original description of the behavior of people with SATFS, Speer said, “While some victims of allergic fatigue may be said to be tired, others may more properly be regarded as torpid. Rather than muscular fatigue, there seems to be a depression of sensory and psychic function, and affected children may be described as sluggish, inactive, sleepy, and apathetic” .In addition to the disturbed (tension-fatigue) behavior typical of allergic children, Speer also considered the “constitutional allergic traits”. In other words, the original constitutional, systemic syndrome depicted by Speer included not only allergic and motor fatigue but also torpor, “asthma, gastrointestinal allergy, eczema, and nasal allergy” and a “less well defined and less well known phenomena” that he interpreted as “evidence of increased parasympathetic or cholinergic activity” which included hyperhidrosis, headaches , edema , lacrimation, (hyper)salivation, and increased bladder tone (increased urinary frequency and enuresis) . As we wThe first convincing hypothesis to explain SATFS in which children with atopic disorders developed hyperactivity and hyperesthetic behaviors was increased cholinergic activity at the cortical level triggered by the allergic stimulus, yet suggested by Speer ,5.In 1989, Marshall  expanded Speer’s cholinergic hypothesis by suggesting that the relationship between allergies and ADHD may be explained by a cholinergic/adrenergic activity imbalance in the central nervous system (CNS) . He streIn any case, what is quite surprising is that although Speer was describing a syndrome characterized by allergies, he did not mention either immunoglobulin E (IgE) or histamine, which are probably the most relevant biomarkers of allergies. Indeed, we had to wait until 2009, when Pelsser and colleagues hypothesized that suggested the relationship between allergies and ADHD was supported by a hypersensitive mechanism  . In otheIgE is an immunoglobulin that plays a crucial role in the immune response to allergens. When IgE binds to an allergen, it triggers the release of histamine and other mediators from mast cells, leading to an allergic response . FurtherAs we will defend later in point four (3rd hypothesis), histamine is critical for understanding the pathophysiology of both the behavior of ADHD and the typical medical comorbidities displayed by patients with ADHD. The human histaminergic system  is a complex system involved in basic physiological functions, such as the energy and endocrine homeostasis, digestion, sleep-wake cycle, cognition, attention, and immunoregulation, among others.Although our body synthesizes histamine, foods also contain varying amounts of histamine. Furthermore, histamine has the potential to be toxic. The deleterious effects of excessive histamine ingestion were initially referred to as scombrotoxicosis (histamine intoxication or histamine poisoning) more than 60 years ago . HistamiIn order to avoid potential intoxication or the deleterious effects of excessive histamine in the body, histamine is metabolized by two main enzymes: the DAO enzyme and histamine-N-methyltransferase (HNMT) ,12. HNMTBody histamine is mainly involved in local immune responses and the digestive system. The best-known histamine receptors, H1R and H2R, are low-affinity, classic drug targets for allergies and gastric ulcers, respectively. Lesser known but with high therapeutic potential, H3R and H4R “are high-affinity receptors in the brain and immune system, respectively” . H1R is Since its discovery in 1911, histamine has been involved in the pathophysiology of several somatic diseases. However, the role of body histamine is particularly relevant in regulating immunity. As a matter of fact, histamine has traditionally been recognized as a critical mediator in allergic diseases such as acute pruritus, atopic dermatitis, and allergic asthma Histamine is a potent inflammatory mediator with pleiotropic effects participating in the regulation of both innate and adaptive immunity . For insAntihistamines have been used to treat allergies mediated by H1R. Unfortunately, the use of first-generation antihistamines was limited because they penetrate the BBB and cause sedation, among other side effects. Second-generation anti-H1R drugs  do not penetrate the BBB and thus have improved tolerability . H4R alsRegarding the digestive system, H2R antagonists are yet considered traditional treatments for a variety of gastric diseases, such as gastritis or gastro-esophageal reflux, given their gastroprotective effect. One of the major uses is the prevention or treatment of peptic ulcers or bleeding associated with non-steroidal anti-inflammatory drug (NSAIDs) use . More reThe use of drugs targeting histamine receptors is increasingly used in migraine. Histamine has a vasodilative effect. There is reduced susceptibility for migraine attacks during the evening, which corresponds with less central histaminergic firing . FurtherHere, it is interesting to include a less-known pathology, histamine intolerance (HIT). HIT may be defined as a non-immunological disease characterized by an impaired ability to metabolize ingested histamine. Excessive body histamine can be secondary to (1) the ingestion of histamine-rich food that surpasses the catabolic capacity of the subject; (2) the intake of alcohol or other drugs that either release histamine and/or block the DAO; and (3) a genetic predisposition to a deleterious capacity for catabolizing histamine (genetic DAO deficiency). All three reasons may derive from the same clinical picture, but only the last two reasons are related to HIT. HIT may include both gastrointestinal and non-gastrointestinal non-specific symptoms such as food intolerance, allergies, and mastocytosis, among others . HIT symHIT symptoms are linked to the various physiological functions of histamine in the body, affecting the skin , the gastrointestinal tract , the respiratory , the cardiovascular , the reproductive , and neurological  bodily functions . Recall Currently, a positive response to a low-histamine diet is the most relevant for establishing the diagnosis. Similarly, following a low-histamine diet is the main therapeutic option for avoiding HIT symptoms . HoweverAn impaired histamine degradation based on reduced DAO activity is the most frequent cause of HIT. DAO activity may be the result of genetic DAO deficiency, environmental DAO deficiency , or both. DAO deficiency can lead to an excessive accumulation of histamine in the body, which has been linked to a number of symptoms and diseases, including  allergic diseases  and asthThere are several candidate tests to detect genetic DAO deficiency. However, their informative value is questionable, as the DAO expression and activity depend on the interplay between genes and the environment . FurtherTo treat DAO deficiency, dietary supplements containing the DAO enzyme have been developed. These supplements have been used successfully in reducing the symptoms of allergic diseases and asthma in some patients with DAO deficiency. However, food supplements should not replace a healthy, balanced diet. Indeed, a histamine-free diet is the treatment of choice for treating HIT .In conclusion, DAO deficiency may be related to an increased susceptibility to allergic diseases and asthma, migraine, and several other medical comorbidities typically reported by patients diagnosed with ADHD. Excessive accumulation of histamine in the body can lead to more severe allergic reactions and worsen asthma symptoms. Dietary supplements containing the enzyme DAO may help reduce symptoms in some patients, but it is important to follow a healthy, balanced diet and seek medical attention if symptoms persist. Other therapeutic options, such as DAO supplementation, antihistamines, or probiotics, are considered complementary treatments.There is increasing evidence of the relevance of histamine in the CNS, where it acts as a neurotransmitter. In the brain, histamine is mainly produced by a group of tuberomammillary neurons concentrated in the posterior hypothalamus (TNM), which project practically to the whole CNS, and a limited number of mast cells throughout the CNS ,21,34. IBoth H1R and H2R are relevant postsynaptic receptors in the CNS, as they mediate some of the central effects of histamine, such as alertness and wakefulness. H3R is a pre- and postsynaptic receptor. H3R regulates the release of histamine and many other neurotransmitters. H4R is found in microglia and cerebral blood vessels. The expression of H4R in neurons is not yet well established . See TabA recent review focused on the role of the histaminergic system in neuropsychiatric disorders . CuriousFurthermore, there are several treatments for CNS disorders targeting histaminergic receptors: H1R antagonists have been used to treat insomnia. Unfortunately, the use of first-generation H1R antagonists capable of crossing the BBB is limited by sedation. H2R antagonists have shown some efficacy in schizophrenia, but their use is limited nowadays. An H3R antagonist, Pitolisant, is used to treat hypersomnia and narcolepsy. Finally, H4R ligands may play a role in neuroimmunological disorders and neurodegenerative disorders, but clinical tests are lacking .In theory, somatic (blood) histamine does not pass the BBB. However, during development, the BBB is permeable to histamine. Accordingly, DAO deficiency may influence not only a series of somatic alterations, such as gastric or allergic manifestations but also some manifestations in the brain, such as ADHD symptoms. Furthermore, as stated before, 85% of patients with migraine have DAO deficiency. Furthermore, “systemically given histamine may elicit, maintain, and aggravate headache” .Hypothesis 1: SATFS is probably one of the first and best historical descriptions of patients with ADHD;Hypothesis 2: SATFS (ADHD for me) is a systemic disease;Hypothesis 3: Histamine is key for understanding the pathophysiology of the typical medical comorbidities displayed by patients with ADHD; andHypothesis 4: The DAO enzyme may play a key role in the pathophysiology of ADHD. A decreased DAO activity may lead to an accumulation of histamine, which could contribute to ADHD symptoms.Here, I will defend the hypotheses stated in the introduction, namely:However, what is the evidence for these hypotheses?To our knowledge, there are no previous studies suggesting that SATFS is a good clinical description of some patients with ADHD. Speer ,2 stressAs stated in The hyperkinetic component of SATFS is clearly reminiscent of the hyperactivity component of ADHD, while the hypersensitive component clearly alludes to symptoms of the inattentive component of ADHD  .The fatigue sensory component of SATFS  clearly recalls either some inattentive symptoms or even the symptoms included within the concept of Sluggish Cognitive Tempo (SCT) . There iThe most plausible explanation is that, although several authors coined different terms for hyperactive children before 1950, including Franz Kramer and Hans Pollnow, it was not until the sixties, with the work by Stella Chess, that ADHD was nominated and began to become notorious in the scientific community . Indeed,In their original studies, Speer stressed that the behaviors of allergic children “constitute a primary allergic disorder of the nervous system” . In otheIn the second study, the authors tested whether or not ADHD polygenic risk scores (PRS) were associated with mid-to-late-life somatic diseases in the general population . They inThe third study focused on the phenotypic and etiological associations between ADHD and several somatic conditions across adulthood by doing a registered study with a final sample of nearly five million individuals in Sweden . StrongeIn conclusion, all these studies suggest that ADHD is particularly comorbid with other neuropsychiatric, cardiometabolic, and immune–inflammatory–autoimmune conditions. Psychiatric comorbidities that are commonly associated with ADHD include sleep disorders, such as obstructive sleep apnea and restless legs syndrome , depressGenerally speaking, the immune response can be defined as the body’s ability to stay safe by affording protection against harmful agents. The immune system plays a critical role in the body’s response to infection, injury, and disease. Immunity includes both a first-line line of defense, innate immunity , and highly specific responses to a particular offender (adaptive immunity). However, inflammation can be harmful if it becomes chronic or dysregulated . Indeed,All the allergic (atopic) symptoms included in SATFS are frequently reported by people diagnosed with ADHD. The first authors to draw attention to the high prevalence of autoimmune and atopic diseases in patients with ADHD were Geschwind (1985) ,49 and MSince the 1990s, several studies have emerged testing the association between atopia and ADHD. Regarding the relationship between atopic dermatitis and ADHD, most authors reported an association ,56,57,58Furthermore, patients with ADHD had a higher prevalence of autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and inflammatory bowel disease ,41,75. Cp < 0.001) [Although the study of the relationship between cancer and ADHD is still in its infancy, there are recent interesting studies linking both pathologies. For instance, a retrospective cohort study carried out in Taiwan reported that ADHD was associated with an increased risk of colorectal cancer  . Further< 0.001) . Moreove< 0.001) . However< 0.001) .Regarding the relationship between the immune system (including inflammation) and cardiovascular diseases, a recent prospective cohort study including 414,495 participants demonstrated a relationship between a total of 20 individual immune-mediated diseases and an increased risk of incident cardiovascular disease . FurtherIn conclusion, there is evidence to suggest a link between ADHD and immune-related diseases. The relationship between immunity and inflammation is complex and multifaceted, but a well-functioning immune system and balanced inflammatory response are essential for maintaining health and preventing disease . The rolAfter accepting Hypothesis 1 and 2, why histamine? As stated before, ADHD is a systemic condition in which the role of the immune system, particularly inflammation, is central. Histamine is a potent inflammatory mediator with pleiotropic effects derived from its activity through four different coupled protein receptors, which produces a fine-tuned regulation of the different immune cells, participating in the regulation of both innate and adaptive immunity, including the production and release of cytokines . HistamiHere, we also want to emphasize that by supporting the role of histamine on ADHD, we do not want to downplay the importance of the cholinergic system and the role of neurotransmitters such as dopamine or noradrenaline, which have a fundamental role in the pathophysiology of ADHD. We simply want to emphasize that histamine may be the missing link capable of explaining some aspects of the behavior, particularly the somatic comorbidities typically displayed by people with ADHD. In this respect, we again stress that it is awkward that, given the close relationship between ADHD and allergies, there is virtually no literature suggesting that histamine may play a role. In this section, we will review several lines of evidence suggesting a relationship between ADHD and histamine.As stated before, in 1989, Marshall postulated that a cholinergic/adrenergic activity imbalance in the CNS was critical to explain the relationship between ADHD and allergies . AcetylcIn 2009, Pelsser and colleagues suggested that the relationship between allergies and ADHD was supported by a hypersensitive mechanism, including both allergic (IgE- or non-IgE-mediated) and non-allergic alternatives . These aAlthough the step taken by Pelsser et al. was relevant, they did not take a final step to relate IgE to histamine. In other words, a potential exploratory model including inflammation remained unexplored. As a matter of fact, recent research suggests that inflammation is key in the pathogenesis of ADHD . ADHD isRegarding the relationship between left-handedness and migraine, the evidence is more controversial ,94,95. IMoreover, the evidence regarding an association between left-handedness and both dyslexia and ADHD is compelling ,99,100. As stated before, histamine is a biogenic amine that acts as a neurotransmitter in the CNS and is involved in a wide range of physiological and pathological processes. Histamine is synthesized in the brain and modulates several neurotransmitter systems, including the catecholaminergic system , which is the major neurotransmitter system associated with the pathophysiology of ADHD. Dopamine is a neurotransmitter that plays a crucial role in the regulation of the reward system, motivation, movement, and immune system . NoradreFurthermore, given the widespread use of antihistamines in allergic diseases and the well-known deleterious effect of traditional antihistamines, capable of crossing the BBB on attention and concentration, one might expect that the role of histamine on ADHD has extensively been explored, but this is not the case. The following data suggest that histamine is closely associated with ADHD and comorbid disorders.(1)One of the most relevant lines of evidence comes from the deleterious effects produced by some antihistaminergic drugs. Traditionally, first-generation antihistamines  were characterized by readily crossing the BBB, thus leading to significant CNS side effects such as altered mood, reduced wakefulness, drowsiness, and impaired psychomotor and cognitive performance  even in the absence of self-reported sleepiness . In othe(2)Histamine levels ,110, ser(3)Two frequently used drugs for treating ADHD (methylphenidate and atomoxetine) increase histamine availability in the pre-frontal cortex ,114. Thu(4)Antihistamine use has been associated with subsequent detection of ADHD ,118,119.(5)There is increasing evidence concerning the potential therapeutic use of drugs acting on the histaminergic system in patients diagnosed with ADHD. In 1985, a case study reported that an antihistamine, anti-motion sickness drug might exert some improvement in ADHD . While tAs stated previously, by stressing the role of histamine in ADHD, we do not want to downplay the role of the acetylcholine system. Both acetylcholine and histaminergic systems are important neurotransmitters that play a role in many physiological processes in the body. The interaction between them is complex, bi-directional, and involves multiple receptors and signaling pathways. Histamine mediates allergic responses and inflammation, but it is also involved in the regulation of neurotransmission. Histamine neurons project to many brain regions and can modulate the release of acetylcholine ,14. IndeFurthermore, several studies have shown that histamine and acetylcholine interact in many physiological processes, including sleep, cognitive function, and inflammation. For example, histamine and acetylcholine act together to regulate the sleep-wake cycle, with histamine promoting wakefulness and acetylcholine promoting REM sleep . In summOur last hypothesis should be understood as a corollary of the third hypothesis. It is probably the most disruptive of the four hypotheses, but it is also the most difficult to defend due to the scarcity of existing literature, mostly indirectly linking DAO activity and ADHD. What we defend here is that the DAO enzyme is probably closely related to ADHD symptoms and the somatic diseases frequently associated with ADHD.One of the major causes of an accumulation of histamine is decreased DAO activity. As stated before, SATFS included somatic symptoms that are frequently reported in patients with ADHD, but also in patients with either HIT or DAO deficiency See : (1) theFor instance, there is an increased risk of migraine among patients with ADHD patients ,131. IntFurthermore, the potential role of food additives in ADHD has long been debated, and the evidence appears to suggest such a relationship . This ishttps://www.aepap.org/sites/default/files/documento/archivos-adjuntos/878-texto_del_articulo-3110-2-10-20220623.pdf accessed on 1 Augutst 2023). Currently, we are writing a paper based on this set of data of 300 children and adolescents with ADHD.Finally, to our knowledge, there is not a single study addressing a direct relationship between DAO, the major catabolizing enzyme of histamine, and ADHD. If our hypothesis is that DAO deficiency is critically associated with ADHD, the prevalence of SNPs related to genetic DAO deficiency among patients diagnosed with ADHD should be high. As a matter of fact, in a pilot study, we have reported that nearly 80% of children and adolescents diagnosed with ADHD had a genetic DAO deficit, and in nearly 20% this deficit was severe  the SAFTS is indeed an initial description of the emerging concept of ADHD in the sixties. Furthermore, we have explained why Speer could have never suspected that he was describing an emerging psychiatric disorder, ADHD; (2) ADHD is a systemic disease in which the somatic comorbidities, yet described by Speer, are mainly affecting some specific body systems ; and the urinary/reproductive systems); (3) The role of histamine into the pathogenesis of ADHD has surprisingly been neglected. I suggested that histamine is critical to explain the overrepresentation of allergies in patients with ADHD; and (4) DAO deficiency may also be a critical factor in explaining both core ADHD symptoms and histamine-mediated  somatic comorbid disorders.The major limitation of the present study is its speculative nature. However, conceptual papers are important to attract the attention of the scientific community in neglected areas of research. Furthermore, I think that I have supported each of the hypotheses with scientifically sound literature. Another limitation is that I focused on the DAO enzyme deficiency and did not even hypothesize if the HNMT enzyme might also be involved in the pathogenesis of ADHD. As a matter of fact, a couple of articles stressed that the inhibition of HNMT may be used in the treatment of ADHD ,138. I tOverall, the relationship between histamine and ADHD is complex and multifaceted, and further research is needed to fully understand the mechanisms underlying this connection. Nevertheless, these preliminary findings highlight the potential importance of histamine-signaling in the pathophysiology of ADHD and suggest that histamine-based therapeutics may represent a promising avenue for the treatment of this systemic disorder. Future research is needed to fully understand the relationship between histamine, the DAO enzyme, and other major players in the pathophysiology of ADHD.


Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder whose primary symptoms are hyperactivity, impulsivity, and inattention. Historically, ADHD was recognized as a disease of childhood and adolescence. However, many patients are known to have persistent symptoms into adulthood. Many researchers consider the neuropathology of ADHD to be based on abnormalities in multiple parallel and intersecting pathways rather than a single anatomical area, but such alterations remain to be clarified.Using diffusion tensor imaging, we investigated differences in the global network metrics estimated by graph theory and the degree of connectivity between adjacent voxels within a white matter (WM) fascicle defined by the density of the diffusing spins (connectometry) between 19 drug-naive Japanese patients with adult ADHD and 19 matched healthy controls (HCs). In adult patients with ADHD, we examined the relationships between the symptomatology of ADHD and global network metrics and WM abnormalities.Compared with HCs, adult patients with ADHD showed a reduced rich-club coefficient and decreased connectivity in widely distributed WMs such as the corpus callosum, the forceps, and the cingulum bundle. Correlational analyses demonstrated that the general severity of ADHD symptoms was associated with several global network metrics, such as lower global efficiency, clustering coefficient, small worldness, and longer characteristic path length. The connectometry revealed that the severity of hyperactive/impulsive symptoms was associated with overconnectivity in the corticostriatal, corticospinal, and corticopontine tracts, the inferior fronto-occipital fasciculus, and the extreme capsule but dysconnectivity in the cerebellum. The severity of inattentive symptoms was associated with dysconnectivity in the intracerebellar circuit and some other fibers.The results of the present study indicated that patients with treatment-naive adult ADHD showed disrupted structural connectivity, which contributes to less efficient information transfer in the ADHD brain and pathophysiology of ADHD.UMIN Clinical Trials Registry (UMIN-CTR) UMIN000025183, Registered: 5 January 2017. Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disease that usually appears in childhood and is characterized by hyperactivity, increased impulsivity, and developmentally inappropriate inattention. ADHD is known to affect children; however, a recent World Health Organization (WHO) survey on global mental health found that the prevalence of patients with adult ADHD was 2.8% on average . Growingin vivo method that has made it possible to investigate white matter abnormalities in neuropsychiatric disorders  and 20 healthy controls (HCs) (M:F = 11:9) participated. From the Fukushima Medical University Hospital's outpatient service, we recruited participants with adult ADHD. At least two qualified psychiatrists diagnosed patients using the criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Participants with comorbid psychiatric disorders other than ADHD were excluded using the structured clinical interview for the DSM-5 clinical version. The healthy controls were recruited through local advertisements at Fukushima Medical University. Participants having neurological or medical conditions that could potentially affect the central nervous system, such as atypical headache, history of head trauma with loss of consciousness, thyroid disease, epilepsy, seizures, substance-related disorders, or mental retardation, were excluded. Participants with a history of illicit drug use, antidepressants (at least not over the last 3 months), or other psychoactive medication were excluded. The level of intellectual performance of the participants was evaluated with the Japanese version of the Wechsler Adult Intelligence Scale III (WAIS-III) test. The WAIS-III test provides a standardized full-scale intelligence quotient (IQ) based on subtests that measure the level of verbal [verbal IQ (VIQ)] and non-verbal knowledge and reasoning [performance IQ (PIQ)]. We obtained written informed consent from all participants before participation. The presence and severity of ADHD symptoms in both ADHD and HCs were assessed using the Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale (CAARS). The Research Ethics Committee of Fukushima Medical University approved this study . The study was organized and carried out in line with the Declaration of Helsinki.Due to the poor image quality of the diffusion tensor imaging, two participants (one ADHD and one HC) were excluded from the analyses.b = 0). The imaging parameters were set to the following values: TR = 10,100 ms, TE = 78 ms, average = 1, b-value = 1,000 s/mm2, slice thickness = 2.5 mm, and 60 slices. The matrix resolution was acquired at 96 × 96 and reconstructed to 96 × 96. The resolution was 2.5 × 2.5 × 2.5 mm3.The MRI data were acquired on a Siemens 3T Biograph mMR scanner with a 12-channel phased array coil. DTI acquisition involved a single-shot, spin-echo planar imaging sequence in contiguous axial planes that covered the whole brain. Diffusion-sensitizing gradients were applied in 30 non-collinear directions, together with acquisition without diffusion weighting  was extracted as the local connectome fingerprint .The chi-squared tests were used for gender and handedness, and independent two-sample The connectivity matrix (adjacency matrix) and graph theoretical analyses were conducted using DSI Studio and the brain connectivity toolbox , 17. Thet-test or a Mann–Whitney U-test was used to evaluate the diagnostic effect on each global network metric. Pearson's correlation coefficient or Spearman's rank-order correlation was computed to assess the relationship between scores of ADHD symptoms , and global network metrics. These statistical analyses were performed using R Statistical Software Version 3.1.0 .An independent two-sample Local connectometry was conducted using DSI Studio . To testThe Shapiro–Wilk test indicated that the data were consistent with a normal distribution at a significant level of 0.05. Levene's test indicated that the equality of the error variances was assumed at a significant level of 0.05. U-test, and a correlational analysis between the ADHD score and clustering coefficient was done with a Spearman's rank-order correlation. Other parameters were tested by parametric analysis . k = 15) . Patients with adult ADHD had significantly lower rich-club coefficients compared with HCs. Statistically significant differences between groups in the network density, global efficiency, clustering coefficient, characteristic path length, and small worldness were not found.Except for the clustering coefficient in the ADHD and HCs, the Shapiro–Wilk test indicated that the data were consistent with a normal distribution at a significant level of 0.05. Levene's test indicated that the equality of the error variances was assumed at a significant level of 0.05. Therefore, a comparison between adult ADHD and HCs in the clustering coefficient was done with a Mann–Whitney r = −0.481, 95% CI −0.768–−0.0346, P = 0.037)     were observed in the right corticostriatal tract, the right corticopontine tract, the right corticospinal tract, the right inferior fronto-occipital fasciculus, and the right extreme capsule  (body) and fibers near the corpus callosum, such as the forceps minor, the forceps major, the cingulum bundle, and the left fornix in patients with adult ADHD. In addition, the right corticospinal tract, the right corticopontine tract, the right medial lemniscus, and the right superior longitudinal fasciculus III (SLF III) also showed decreased connectivity in patients with adult ADHD. We speculated that widely distributed disrupted structural connectivity including the CC revealed by local connectometry could be related to the less efficient information transfer system revealed by graph theory in patients with adult ADHD and related to overall symptoms of ADHD. Except for median structure such as the CC and the cingulum, the white matter fiber abnormalities in adult ADHD in this study were found in the right hemisphere as in previous studies , suggestvia the splenium of the corpus callosum, and the forceps minor connects the lateral and medial surfaces of the frontal lobes via the genu of the corpus callosum  . The medvia the extreme and external capsules with the uncinate fasciculus. While the IFOF and extreme capsule are primarily associated with semantic language processing and transmission  in the right corticostriatal tract, the corticospinal tract, vextreme capsule, and the right inferior fronto-occipital fasciculus. The corticostriatal projections are critical components of forebrain circuits that are extensively involved in motivated behavior . Not onlsmission , researcsmission . We specDecreased connectivity in the cerebellum was associated with both hyperactive–impulsive and inattentive symptoms. As mentioned previously, cerebro-cerebellar communication should be an important component in cognitive processing . AlthougThe results for corticospinal and corticopontine tracts were ambiguous. Compared with HCs, these tracts showed significantly decreased connectivity in the adult ADHD group, but correlational analysis showed a positive correlation with the severity of hyperactive/impulsive symptoms. Furthermore, the corticospinal and corticopontine tracts showed opposite QA patterns in association with symptoms. As described earlier, higher QA in these areas was related to the severity of hyperactive–impulsive symptoms, whereas lower QA was related to the severity of inattentive symptoms. We have no clear explanation of these phenomena but speculate that different patterns of white matter abnormalities, decreased connectivity, and overconnectivity in the same region might be associated in different ways and might contribute to different symptoms in ADHD and patterns of the combination of overconnectivity/decreased connectivity of white matter fibers in each region, which might be associated with severity of clinical symptoms. However, there are no previous studies to support these speculations at this time, and further research is needed. Regarding other tracts, the inferior longitudinal fasciculus  , the medThe superior point of this study is the strict selection of treatment-naive patients with adult ADHD. Since WM integrity was affected by the treatment of MPH, it was important to evaluate DTI data in treatment-naive patients with adult ADHD.Meanwhile, there are some limitations in this study. First, as already mentioned in the Discussion section, the results for the corticospinal and corticopontine tracts were ambiguous, and we have no clear explanation for the phenomenon. Further research is needed to clarify such phenomena. The second limitation is a relatively small sample size of the study. Although Friston's loss-function analysis suggests that the optimal sample size for a neuroimaging study is 16 to 32 participants , 50, theTreatment-naive patients with adult ADHD showed lower rich-club coefficients and decreased connectivity of the corpus callosum and fibers near the corpus callosum and several fibers in the right cerebral hemisphere. The widely distributed abnormal WM would contribute to the abnormal rich club and consequently less efficient information transfer in the ADHD brain. The severity of overall ADHD symptoms was associated with several global network metrics and several fibers associated with the severity of the hyperactive–impulsive symptom and the inattentive symptom, suggesting the contribution of WM abnormalities in the adult ADHD brain to the pathophysiology of adult ADHD.tohnish8@its.jnj.com.The datasets presented in this article are not readily available because Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data is not available. Requests to access the datasets should be directed to The studies involving human participants were reviewed and approved by Research Ethical Committee of Fukushima Medical University. The patients/participants provided their written informed consent to participate in this study.TO: conceptualization, methodology, data analyses, writing—original draft preparation, and project administration. HY: writing—review and editing and supervision. HI, SIs, AS, and IM: data collection and writing—review and editing. JM: writing—review and editing. WT and SIt: conceptualization, data collection, and writing—review and editing.


Working memory (WM) deficits have frequently been linked to attention deficit hyperactivity disorder (ADHD). Despite previous studies suggested its high heritability, its genetic basis, especially in ADHD, remains unclear. The current study aimed to comprehensively explore the genetic basis of visual-spatial working memory (VSWM) in ADHD using wide-ranging genetic analyses.The current study recruited a cohort consisted of 802 ADHD individuals, all met DSM-IV ADHD diagnostic criteria. VSWM was assessed by Rey-Osterrieth complex figure test (RCFT), which is a widely used psychological test include four memory indexes: detail delayed (DD), structure delayed (SD), structure immediate (SI), detail immediate (DI). Genetic analyses were conducted at the single nucleotide polymorphism (SNP), gene, pathway, polygenic and protein network levels. Polygenic Risk Scores (PRS) were based on summary statistics of various psychiatric disorders, including ADHD, autism spectrum disorder (ASD), major depressive disorder (MDD), schizophrenia (SCZ), obsessive compulsive disorders (OCD), and substance use disorder (SUD).RAB11FIP1, whose encoded protein modulates several neurodevelopment processes and visual system, as significantly associated with DD scores . Candidate pathway enrichment analyses (N = 53) found that forebrain neuron fate commitment significantly enriched in DD , and dopamine transport enriched in SD . We also observed a significant negative relationship between DD scores and ADHD PRS scores .Analyses at the single-marker level did not yield significant results (5E−08). However, the potential signals with P values less than E−05 and their mapped genes suggested the regulation of VSWM involved both ocular and neural system related genes, moreover, ADHD-related genes were also involved. The gene-based analysis found Our results emphasized the joint contribution of ocular and neural genes in regulating VSWM. The study reveals a shared genetic basis between ADHD and VSWM, with GWAS indicating the involvement of ADHD-related genes in VSWM. Additionally, the PRS analysis identifies a significant relationship between ADHD-PRS and DD scores. Overall, our findings shed light on the genetic basis of VSWM deficits in ADHD, and may have important implications for future research and clinical practice. Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder in children, with an approximately 7.2% prevalence . Except , suggesting VSWM might serve as one promising endophenotype for ADHD [Working memory is the capacity to manipulate some information and maintain other information simultaneously, including auditory-verbal working memory and nonverbal working memory . Visual-for ADHD .The Rey-Osterrieth Complex Figure (RCFT) is a validated and widely used measure of VSWM, developed by Rey . The RCFDRD1) gene, in which SNPs rs4532 and rs265978 moderated working memory improvements over development, also predicted ADHD symptoms reduction [Visual-spatial working memory (VSWM) has been shown to be moderately to highly heritable by twin studies , 18. At eduction . The Asseduction –27.–6 significant level, with implications in several psychiatric disorders and adrenergic receptor signaling pathway [However, recent evidence suggests that causal variants involved in complex traits are not restricted to specific core pathways . Consist pathway , 30. A s pathway .The manipulation of VSWM involves coordinated interactions of a distributed neural network, with the frontal lobe playing a central role as a control structure –36 DopamThe prefrontal lobe and dopaminergic circuit also involved in WM treatment response. Prior evidence has shown that improvements of VSWM after behavioral training was associated with changes in the density of cortical dopamine D1 receptors in prefrontal lobe . MethylpIn conclusion, VSWM deficits in ADHD have a complex genetic basis that has not been fully understood. Previous candidate-gene based studies have identified that ADHD related genes involved in the dopaminergic circuit in frontal lobe are associated with VSWM deficits in TD and ADHD. As a primary neuropsychological function and endophenotype, VSWM is considered to be less genetically complex than clinical phenotypes. Thus, deconstructing the genetic basis underlying VSWM might shed light on illuminating the pathophysiological processes of ADHD, helps establish objective neurocognitive diagnostic modalities and holds promises for the development of precise behavioral therapies.The current study had two main objectives: (1) to identify genes associated with VSWM in individuals with ADHD using a genome-wide approach and explore the relevant biological processes, especially in dopaminergic circuit and forebrain development; (2) to disentangle overlapping and distinct genetic structures underlying different visuospatial processes involved in different parts of the RCFT task.The cohort, which consisted of 802 ADHD cases  aged between 6 and 16 (9.9 ± 2.4) was recruited from the Child and Adolescent mental health center at Peking University Sixth Hospital. All patients met the diagnostic criteria of the Statistical Manual of Mental Disorders-IV (DSM-IV) for ADHD. The diagnosis was first made by a child psychiatrist and then confirmed by semi-structural interview using the Chinese version of KSADS-PL . PatientAll subjects finished the RCFT to evaluate VSWM. Subjects were instructed to remember the RCFT figure within 30 s and subsequently draw what they remembered immediately (without intervening distraction) and then a 20–30 min' delay (other tests were conducted during this delay) . This te2 < 0.6 or SNPs with minor allele frequency < 0.05 were removed.The Omega DNA extraction Kit  was used to extract genomic DNA from peripheral blood. The genomic DNA was genotyped using the Affymetrix 6.0 array with standard protocol at Capital Bio Ltd (Beijing) . For qua2 < 0.05 for each pair of SNPs) that were outside the 5 long-range LD regions using the EIGENSOFT 4.2 software [Principle component analysis (PCA) was performed to check population stratification. It was conducted using the SNPs with low linkage disequilibrium . The Genecards website was used to check the function of genes [We used three methods for gene mapping: positional mapping, eQTL mapping, and chromatin interaction mapping. For positional mapping, we used a maximum distance of 10 kb . The eQTof genes , 56.We used Multi-marker Analysis of GenoMic Annotation (MAGMA)  for geneSince previous evidence emphasized the critical role of dopaminergic circuits and the frontal lobe in the regulation of VSWM; and the current GWAS results indicated participation of ocular system (described in the result section). The current study included 53 Gene ontology biological process (GOBP) pathways involved in frontal lobe/forebrain (n = 14), dopaminergic circuit (n = 15), and eye/visual perception (n = 24) as candidate pathways. Using MAGMA, we tested the association of candidate pathways with four RCFT scores. We adopted a Bonferroni correction, setting the threshold of significance P < 9.43E−04.http://www.genemania.org) was adopted to construct the network of RCFT interactive proteins based on physical interactions, co-expression, predicted, co-localization, pathway, genetic interactions, and shared protein domains [GeneMANIA  GWAS statistics of six psychiatric disorders as base data, including ADHD, autism spectrum disorder (ASD), obsessive compulsive disorder (OCD), major depression disorder (MDD), schizophrenia (SCZ), bipolar disorder (BIP), and substance use disorder (SUD) –66. PRSiA total of 802 ADHD cases were included in the study, comprising 684 boys (85.3%) with an average age of 9.9 ± 2.4 years, and an average IQ was 104.5 ± 15.7. The average points for DD (9.1 ± 0.2), DI (9.5 ± 0.2), SD (2.7 ± 0.1), and SI (2.9 ± 0.1) were also measured (Table bon < 0.05), suggesting that VSWM functions undergo dynamic changes over time . However, we identified 26 potential risk loci with P < 1e−05 of DD, DI, SD, and SI  significantly associated with DD score .Gene-based analysis identified a gene Rab11-family interacting protein one . Genes of zinc protein family were also highlighted as top hub shared by DD and DI .Furthermore, in order to detect the genetic interaction networks between these four indexes, we constructed the protein networks connected by the mapped candidate genes Fig. A. Both dadj = 0.025), and the dopamine transport pathway was enriched in SD .We identified two pathways significantly involved in the RCFT. The forebrain neuron fate commitment pathway was enriched in DD ; dopamine transport, adenylate cyclase inhibiting dopamine receptor signaling pathway and forebrain neuron differentiation potentially enriched in SI  , which is critical for several neurodevelopmental process and visual pathways, associated with DD score. Dopaminergic circuit and forebrain development were suggested to be involved in SD and DD, respectively. Shared genetic basis between ADHD and VSWM were indicated, as the current study found the involvement of ADHD-related genes underlying VSWM and significant relationship between ADHD PRS and DD scores.Ocular and neural system related genes jointly modulate VSWM.The present study employed wide-range genetic analyses to explore the genetic basis underlying VSWM in ADHD. Although no SNP reached the genome wide significance, following the previous evidence demonstrated that missing heritability could be explained by the SNPs far below the genome-wide significance , we inveWorking memory is a complex and intricate system . NeurobiC8orf87, RPL13P, G3BP2, GABBR2, LINC01876, SEMA4B, RPN1 [NLRP1 enhancing in Muller glia cells, gene NR4A2 and gene IDH2 over-expressing in the eye (LifeMap), and genes TCL1B, TCL1A, TCL6, KLF7, FBN3, C1orf168, ADAMTSL1, MYOF, SEMA4B, CIB1, CREB1, CERS4 and NLRP1 being involved in eye diseases and eye measurements, such as myopia [In line with previous knowledge, the current study provided further evidence that ocular and neural genes jointly modulate visual-spatial working memory through a comprehensive set of genetic analyses. Using GWAS method (P < 1e−05) Table , we foun4B, RPN1 –85); Meas myopia –93glaucos myopia , 94, rets myopia , pinguecs myopia , uveitiss myopia , corneals myopia , and ints myopia .KLF7, FBN3, SEMA4B, CIB1, NLRP1, NR4A2 and MYOF, which were suggested only in immediate recall, were associated with visual system. However, in delayed recall task, only TCLs , which also related to immediate recall , which plays a crucial role in the Rab-11 mediated recycling of vesicles. Proteins in the Rab11-FIPs family are known to modulate various neurodevelopmental processes, such as dendritic arborization, neurite pruning, synaptic plasticity, and spatial memory formation [(2)Shared genetic basics between ADHD and VSWM.The results of gene-based analysis further support the current findings from GWAS analysis. Specifically, we identified an association between DD scores and the ormation , 100. Moormation , 102, phormation , 104.(2)C8orf87 (DD) [ZSCAN31  [RPL13P (DI) [FBN3  [LINC01876 (SD) [C8orf87 was identified in a meta-analysis of ADHD GWAS studies [ZSCAN31, a member of Zinc finger protein family, encodes a protein containing multiple C2H2-type zinc finger motifs that are critical for neurodevelopment [ZSCAN31 might underlie several neurodevelopmental disorders, including ADHD, ASD, Tourette syndrome, and SCZ [FBN3 encodes a member of the fibrillin protein family. Previous GWAS analysis have indicated associations between FBN3 and ADHD, brain morphology [The current studies identified genes shared by VSWM and ADHD, including f87 (DD) , ZSCAN31 , 83, RPL13P (DI) , FBN3  , and LIN876 (SD) , 83. C8o studies . ZSCAN31elopment , 77. Evi and SCZ , 83. FBNrphology , 106.(3)Shared genetic basis between different part of VSWM.Furthermore, our PRS analyses revealed ADHD PRS significantly predicted DD scores, providing additional evidence for a shared genetic basis between ADHD and short-term VSWM. Relationships between PRS and other three indexes failed to pass the permutation test, which might suggest the validity of DD, but not other indexes, as a neuropsychological endophenotype for ADHD. And this result was not surprising, because the delayed recall was one of the most consistent impaired functions reported in ADHD during RCFT task, and DD was supposed to demand the most WM load, able to reflect both encoding, maintenance, retrieval, organization, local and global processing , 14–16. TCL1A and TCL6 . Although evidence mainly focused on the involvement of TCLs in hematological diseases and cancers, a previous large-scale GWAS  study identified associations between myopia and TCLs [TCLs play in VSWM.Notably, one potentially shared genetic locus between DD, DI, and SI is rs56111147 located within the TCL1B gene, which encodes a T-Cell Leukemia/Lymphoma-1 family protein. In addition, the Hi-C data suggested that a chromatin loop can form between the genomic region  where rs56111147 is located and the promoter of and TCLs . FurtherFBN3 and KLF7 were also shared in structure scores, i.e., SD and SI. FBN3 encodes a member of the fibrillin protein family, mainly localized to extracellular microfibrils of developing skeletal elements, and responsible to Weill–Marchesani Syndrome and Marfan syndrome. Evidence also suggested its expression in the brain (UniProt/SwissProt) [FBN3 plays in nervous system, GWAS studies identified associations between FBN3 and ADHD, brain morphology, which implied its role in NDDs by altering brain development. KLF7 encodes kruppel-like transcriptional regulator family, which regulates cell proliferation, differentiation, survival and contains three C2H2 zinc fingers at the C-terminus that mediate binding to GC-rich sites. KLF7 plays a critical role in neuronal morphogenesis and survival of sensory neurons, and represses the corneal epithelium differentiation [KLF7 are also found to be associated with several psychiatric disorders, including ASD [KLF7 in human brain organoids caused dysregulation of 517 ASD risk genes. Moreover, an increase of KLF7 in the neural system in KLF7 ± adult mice significantly rescued ASD symptoms and the expression of majority of dysregulated ASD genes [KLF7 might provide protective effects to the brain through regulating the neural axon plasticity and activation of the JAK2/STAT3 signaling pathway [(4)Forebrain commitment and dopamine transport are involved with VSWM.Genes issProt) . Althougntiation . KLF7 arding ASD , 110, MDding ASD  and sleeding ASD , 113. A  pathway , 115. WhPAX6, BCL11B, GATA2, ASCL1, TBL1, NKX2.1 could result in abnormal GABAergic, dopaminergic, and glutamatergic neuron development [The current study identified that forebrain neuron fate commitment and dopamine transport were significantly associated with DD and SD, respectively. Forebrain neuron fate commitment refers to the process in which the developmental fate of a cell in frontal lobe becomes restricted, which mostly occurs prenatally , 117. Stelopment –124, andelopment , 125–128elopment –124, whielopment –131To conclude, our results indicated an early onset of altered neural substrates occurred during neuronal differentiation underlying VSWM and further emphasized the involvement of dopaminergic circuit.Our study should be interpreted in light of some limitations. Firstly, we solely utilized the RCFT to evaluate VSWM. As previous studies have demonstrated, the RCFT is more sensitive to active WM processes . BesidesIt is worth noting that, as highlighted by previous findings, complex traits are often influenced by thousands or more genetic variants that exert their effects cumulatively. The "nominal" variants are believed to contribute a considerable proportion of the overall heritability , 133. ThTCL1B, KLF7, and FBN3, were identified as potentially related to VSWM. In addition, the brain-expressed gene RAB11FIP1 was found to be significantly associated with DD. The results of polygenic risk score analyses provided evidence of shared genetic underpinnings between ADHD and VSWM, shedding light on the genetic basis of these conditions and potentially informing clinical practice in the future.This study represents a genome-wide association study of VSWM, in which several genes, including


Previous work demonstrated that, when creating metaphors, participants choose vehicles that are concrete, rather than abstract, and are also a moderate semantic distance away from the topic. However, little is known about the semantic representations underlying metaphor production beyond topic-vehicle semantic distance and vehicle concreteness. Here, we studied the role of two semantic richness variables in metaphor production – semantic neighborhood density (SND), which measures the proximity of a word and its associations in semantic space, and body-object interaction (BOI), which reflects the ease with which a human body can motorically interact with a word’s referent. In each trial, participants were presented with an abstract topic, such as miracle, and were instructed to make an apt and comprehensible metaphor by choosing a vehicle word . All of the topics were abstract but half were high-SND (from dense semantic neighborhoods) and half were low-SND (from sparse semantic neighborhoods). Similarly, half of the potential vehicle words were either high or low in SND and also differed on BOI such that half were high-BOI , whereas half were low-BOI . We observed a three-way interaction such that participants selected low-BOI, rather than high-BOI, vehicle words when topics or vehicles were high-SND. We interpret this finding to suggest that participants attempt to reduce the overall semantic richness of their created metaphors.In a metaphor, such as  MoreoveSociology is the ________ of sciences) by choosing the single best word from a list to serve as a vehicle . Two primary semantic variables of the selected vehicles were analyzed, word concreteness and semantic distance to the topic. Both concreteness and semantic distance effects were observed. Participants chose concrete vehicles more often than they did abstract vehicles, and the vehicles that were chosen were a moderate distance from the topic, rather than near or far. Therefore, Katz showed that a vehicle’s concreteness and its position among other concepts in semantic space both play a role in producing metaphors.In this paper, we extend on the work of bicycle, in as much as we interact with the referent motorically in many ways, whereas with others, such as butterfly we have less motoric interaction. Therefore, it is unclear if motoric interaction is the driver of concreteness effects in metaphor production. To investigate this, we considered body-object interaction (BOI), which characterizes the ease with which one can interact with a word’s referent  of the topic and vehicle words, which characterizes the proximity of a word and its neighbors in semantic space . Second,referent . Below, bicycle are responded to faster than low-BOI words such as butterfly. Concepts that are high in BOI are argued to be semantically richer, such that they contain more semantic information, which facilitates their relatively rapid activation. However, BOI effects are task dependent; does the word refer to something that is touchable?), high-BOI and low-BOI concepts evoke distinct early electrophysiological effects , which is a measure of the average similarity between a word and its nearest associations . Semantisecrecy) and selected a vehicle word from a word-bank  to create novel metaphors . We opted to restrict the topics to abstract concepts because abstract concepts are typically grounded metaphorically with concrete concepts  = 1.0076, p = 0.32, or frequency, t (34) = 0.34, p = 0.74 but as expected, differed on SND, t (34) = 9.24, p < 001. See Abstract words, determined by their ratings in the The items chosen as potential vehicles are concrete nouns ; or frequency, (p = 0.952). Critically, the manipulation of BOI is significant, (p < 0.001), with Tukey-HSD tests confirming that the high-BOI items, across SND, do not significantly differ (p = 0.97) nor do the low-BOI items, across SND (p = 0.75), but the high and low BOI items differ from one another (both p’s < 0.001). The same can be said for the SND manipulation (p < 0.001), with Tukey-HSD tests confirming that high-SND items do not significantly differ (p = 0.99) nor the low-SND items (p = 0.90), but the high and low-SND items do (both p’s < 0.001).One-way ANOVAs were conducted to ensure the four vehicle conditions only differed on BOI and SND. The vehicles did not differ in concreteness,  = 31.297, p = <0.001, ηp2 = 0.395; participants chose low-BOI vehicles  56.4% of the time whereas they chose high-BOI vehicles  less frequently at 43.5% of the time; however, this main-effect was qualified by two interactions. First, a vehicle-BOI by vehicle-SND interaction was observed, F  = 9.883, p = 0.003, ηp2 = 0.171. As is depicted in The data from 11 participants were not included in the analysis, for one or more of the following reasons: they did not complete the study, created many similes despite the instructions given, or created extended metaphors. Thus, the analyses are based on 49 participants. The resulting participants created and interpreted nominal metaphors of the form A is B . A topic (high-SND vs. low-SND) by vehicle BOI (high vs. low) by vehicle SND (high vs. low) repeated measures ANOVA was conducted on the frequency of vehicles chosen from the four semantic conditions. A main effect of BOI was obtained, F  = 9.1, p = 0.004, ηp2 = 0.159. As F (1) = 40.74, p < 0.001 but not when the topic and vehicle were both high-SND, F (1) = 1.59, p = 0.21. Thus, for high-SND topics, participants relied more on low BOI – low SND vehicles to construct apt metaphors. We interpret this as an attempt by participants to reduce the overall semantic richness of the metaphor because the topic is already from a dense semantic neighborhood. Moreover, simple main effects analyses also revealed that when the topic was low-SND, the low-BOI effect was observed when participants selecting high-SND vehicles, F (1) = 8.27, p = 0.006, but no BOI effect was observed when both topic and vehicles were low-SND, F (1) = 2.17, p = 0.15. We interpret this to mean that when the topic is low SND, participants are drawn to low-SND vehicles, and higher semantic richness from BOI is tolerated. Moreover, when selecting a high-SND vehicle for a low-SND topic, participants preferred low-BOI words, again to reduce the richness from high-SND vehicles. Thus, when the topic is from a sparse semantic neighborhood, vehicle semantic richness does not matter as much as when the topic is from a dense semantic space.Most importantly, a three-way, topic SND by vehicle BOI by vehicle SND, interaction was observed, In sum, participants did not choose the semantically richest vehicles when creating novel metaphors. Rather, our findings demonstrate that semantic richness is detrimental to metaphor processing, and that, on average participants aim to reduce semantic richness of the metaphor when selecting an apt metaphor vehicle to create a metaphor.While lighting or tiger can trigger embodied simulations wherein one creates scenarios involving such concepts, even though one may not directly motorically interact with those words’ referents. Moreover, experimental work has demonstrated that bodily-actions related to concrete concepts are activated during metaphor processing  may be interpreted as evidence against embodied cognition, as such words are less amenable to motoric simulations than high-BOI counterparts. However, one must be cautious in such an interpretation, as the low-BOI words used in our study are nonetheless concrete concepts, and as such, can evoke sensory imagery. For example, low-BOI concepts such as ocessing . Therefoocessing  or thoseocessing . Howeverlemon, a conventional word that metaphorically refers to something of little value due to its faultiness . Initially, lemon would be processed concretely, evoking multimodal simulations of taste, smell and feel, and after repeated exposure in linguistic contexts, develops an abstraction that is the primary representation when used metaphorically . Moreover, our focus was on motoric interaction, but other modalities in concrete concepts may play a role in metaphor, such as concepts with salient auditory  or motion  properties (see toad whereas others, like guppy, have fewer features and are semantically less-rich. More broadly, however, we acknowledge that pragmatic context can, and often does, make virtually any concept metaphorical, and can also shape a word’s intended metaphorical meaning (Other work has demonstrated that metaphorical potential is captured in a word’s relationality . Accordimensions . That isties see . Some co meaning . It shouThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving humans were approved by the University of Western Ontario Research Ethics Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.HA-A conceived and designed the experiment, collected and analyzed the data, and wrote the first draft of the manuscript. ANK played a supervisory role in every step of the process and supported the project with grant funding. All authors contributed to the article and approved the submitted version.This research was supported by Natural Sciences and Engineering Research Council of Canada Operating Grant NSERC 06P007040 to ANK.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Developmental dyslexia (DD) and attention deficit/hyperactivity disorder (ADHD) are highly comorbid neurodevelopmental disorders. Individuals with DD or ADHD have both been shown to have deficits in white matter tracts associated with reading and attentional control networks. However, white matter diffusivity in individuals comorbid with both DD and ADHD (DD + ADHD) has not been specifically explored.rd and 4th graders  from three diagnostic groups ((DD (n = 40), DD + ADHD (n = 22), and typical developing (TD) (n = 20)). Behavioral measures of reading and attention alongside measures of white matter diffusivity were collected for all participants.Participants were 3DD + ADHD and TD groups differed in mean fractional anisotropy (FA) for the left and right Superior Longitudinal Fasciculus (SLF)-Parietal Terminations and SLF-Temporal Terminations. Mean FA for the DD group across these SLF tracts fell between the lower DD + ADHD and higher TD averages. No differences in mean diffusivity nor significant brain-behavior relations were found.Findings suggest that WM diffusivity in the SLF increases along a continuum across DD + ADHD, DD, and TD. Although reading occurs relatively easily for most children, the 5–17% of children who cannot learn to read proficiently may be affected by developmental dyslexia . DD is Research indicates that approximately 40% of children with DD also meet criteria for at least one additional disability , 11, witAlthough much research has characterized DD and ADHD as two separate and distinct disorders , 28, DD Research has deemed adequate attentional control as necessary for efficient executive functioning , 41, andThese distinct, yet overlapping, neural systems attributed to DD and ADHD may at times share a range of neural deficits between the two disorders, leading to the commonly occurring co-morbid DD and ADHD (DD + ADHD). Indeed, individuals with both a reading disability (encompassing DD) and ADHD have shown gray matter differences within regions of the frontal-striatal pathway partly comprising the attentional control network  and the  (DTI), which allows for the quantification of diffusion properties for white matter [These complex reading and attentional networks require effective and rapid communication between their connected regions to function effectively. Therefore, at a basic structural level, it is important to understand the quality and role of these network’s connecting white matter tracts and their relationship with specific behavioral outcomes in children with DD. Diffusion tensor imaginge matter , permitse matter . FA utile matter , 53. MD e matter  with hige matter .Four primary white matter tracts Fig.  – namelyThe ILF is a ventral associative tract consisting of long and short fibers that directly connect the occipital and anterior temporal lobes . ResearcThe UF is a ventral association bundle that connects the anterior temporal lobe with the orbitofrontal cortex, including the IFG . It is tThe CC is a major commissure that connects the left and right hemispheres of the brain and is mainly associated with interhemispheric connectivity . Based oResearchers have investigated the relations between white matter tract diffusivity of the CC, ILF, SLF, and UF as they relate to groups of individuals diagnosed with either DD or ADHD independently but have not evaluated their role in comorbid subjects who have DD + ADHD. The primary aim of this study was to explore potential differences in white matter tract diffusivity of the CC, ILF, SLF, and UF in children with DD only, DD + ADHD, and compared to typically developing, unimpaired readers (TD). We also sought to investigate the relations between measures of white matter diffusivity and behavioral measures of reading ability and attentional control in these groups. We hypothesized that white matter diffusivity for the tracts of interest would be significantly reduced in DD + ADHD compared to both DD and TD groups due to their shared underlying neural deficits, and based on the previous literature, that the DD only group would show reduced white matter diffusivity compared to the TD group. Furthermore, we hypothesized that white matter tract diffusivity would be positively correlated with measures of reading proficiency and attentional control.n = 40) scored at least one standard deviation below age-norm expectations on any of the following: Woodcock Johnson 3rd Edition  met the same criteria for DD and also exhibited high ADHD symptomology as defined by the Strengths and Weaknesses of ADHD symptoms and Normal Behavior  were recruited from the same schools but did not meet criteria for either DD or ADHD. All participants had a verbal and/or performance intelligence standard score at or above 80 on one of the subtests of the Wechsler Abbreviated Scale of Intelligence—II  Broad RTOWRE-2; ) subtestr  and thee  as rateWASI-II; ) in ordeThe composite score of the Sight Word Efficiency and Phonological Decoding Efficiency subtests of the TOWRE-2 was used as a measure of word reading fluency (TOWRE-CST). The TOWRE-2 requires participants to read aloud words and pseudowords, respectively, as quickly and as accurately as possible. A higher TOWRE-CST reflects better word reading efficiency.The Behavior Rating Inventory of Executive Function (BRIEF) measured executive function via an 86-item questionnaire answered by a parent or guardian . The Glon = 13). Data acquisition and scan parameters were kept consistent throughout the duration of the study and processed data was harmonized to account for inter-scanner differences  to a PRIMSA-Fit (20-channel) during the final year of data collection  after outlier removal and for all data analyses. The Tukey–Kramer post hoc test was used to test for significant group differences for all analyses. Pearson bivariate correlations were run for mean FA and MD of the tracts of interest and the following behavioral measures: TOWRE-CST, BRI-T, and GEC-T. The False Discovery Rate (FDR) was applied to all correlations to correct for multiple comparisons.A separate one-way between subjects analysis of variance compared the TOWRE-CST, BRI-T, and GEC-T on three levels: DD + ADHD, DD, and TD. Likewise, separate one-way between subject analysis of variance models compared the harmonized means for FA and MD for each of the tracts of interest individually on three levels: DD, DD + ADHD, and TD. Mean FA and MD data were assessed for extreme outliers via box-and-whisker plots, which resulted in the removal of two outliers that were present in more than one white tract of interest. p < 0.001), WASI-II  = 31.0, p < 0.001), TOWRE-CST  = 93.5, p < 0.001), BRI-T  = 7.42, p < 0.001), and GEC-T  = 23.3, p < 0.001). For diagnostic measures, TD significantly differed from DD and DD + ADHD on the WJ-3- Basic (p < 0.001) and WASI-II (p < 0.001) showing the highest reading and intelligence scores, respectively; however, DD and DD + ADHD showed no significant differences. Likewise, TD significantly differed from DD and DD + ADHD on the TOWRE-CST (p < 0.001) showing the highest reading score; however, DD and DD + ADHD showed no significant differences. Moreover, DD + ADHD significantly differed from both TD (p < 0.001) and DD (p = 0.026) on the BRI-T showing the lowest behavioral attentional score; however, TD and DD showed no significant difference. On the GEC-T, TD significantly differed from DD (p = 0.014) and DD + ADHD (p < 0.001), while DD significantly differed from DD + ADHD ( p < 0.001) with DD + ADHD showing the lowest and TD showing the highest executive functioning score.The one-way analysis of variance revealed significant differences between groups on all behavioral measures of reading, attention, and intelligence Tables  and 2: Wp = 0.024), L SLFt  = 3.13, p = 0.003), R SLFp  = 3.33, p = 0.041), and R SLFt  = 3.72, p = 0.029). There were significant differences in the mean FA of the L SLFp (p = 0.018), L SLFt (p = 0.002), R SLFp (p = 0.036), R SLFt (p = 0.029), such that the DD + ADHD group had significantly lower FA than the TD group in all tracts  and L SLFt (r (80) = 0.269, p = 0.015); BRI-T and L UF (r (80) = 0.229, p = 0.036); GEC-T and L SLFp (r (80) = -0.240, p = 0.030), L SLFt (r (80) = -0.232, p = 0.036), and R SLFp (r (80) = -0.263 p = 0.017). For mean MD, correlations were found between the GEC-T and L UF (r (80) = -0.233, p = 0.035); BRI-T and L UF (r (80) = -0.234, p = 0.034). However, no significant correlations were maintained after correction for multiple comparisons  = 0.220, The current study investigated white matter tracts associated with reading and attentional/executive functioning between three groups: DD + ADHD, DD, and TD. As expected, measures of reading and attentional control were significantly different between groups, with TD showing the highest scores on all measures, while DD and DD + ADHD showed no difference in reading but differed significantly in attentional control Tables  and 2. MAs expected, our results support the TD group as superior readers with the strongest attentional control and highest white matter diffusivity bilaterally in the parietal and temporal regions of the SLF , 58. TheAccordingly, previous research also has suggested that children with comorbid DD and ADHD may exist as a third phenotype independent from sole DD or ADHD conditions –16. ResuGiven the profound reading impairment within individuals with DD, the highly demanding task of reading may be further impeded by a dysfunctional attentional control network that moderates top-down and bottom-up processing. This suggests that the SLF, critically employed within both the reading and attentional control networks, may be a main contributor for the successful integration of top-down and bottom-up processing necessary for efficient reading and attentional control. Therefore, one of the primary deficits associated with the comorbid DD and ADHD (particular to ADHD-I) phenotype may be attributed to this additive effect of reduced diffusivity of the SLF, constituting the continuum of FA found within our sample. The consequences of differential white matter integrity in the SLF may be a fundamental factor in attentional control, with DD + ADHD exhibiting poor attentional control and TD exhibiting superior attentional control. Accordingly, a conjunction analysis of studies assessing grey matter differences within ADHD and DD populations found reduced grey matter volume only within the right caudate nucleus of the striatum , which cSimilarly, white matter diffusivity of the ILF has been associated with both attentional control and reading. Encompassing language systems of logographic phonological alphabets, adults with ADHD  and childecrease in FA within the UF [increase in FA within the same tract [Contrary to previous findings concerning white matter diffusivity for individuals with DD , 78, 79,n the UF , whereasme tract , 73; howme tract , 15 may Although decreased white matter diffusivity in the CC has been considered an integral component underlying the DD phenotype , 76 and Similarly, there were no significant differences observed in MD between groups for any of the tracts of interest. Although changes in MD have been reported in individuals with ADHD, there is less evidence of difference in MD associated with DD. Differences between ADHD and typically developing controls is most frequently reported in adult ADHD populations , 68. TheFinally, the absence of an ADHD-only comparison group is a potential limitation of the current study. However, our primary aim was to investigate the differences in DD populations with and without ADHD to better understand the differences and similarities of the co-morbid condition in comparison to the’pure’ DD. Due to the nature of the overarching study, we were unable to collect a pure ADHD sample, which prevented us from directly assessing the impact of attentional deficits alone on white matter diffusivity. Future research will benefit from the inclusion of all four potential groups: TD, DD only, ADHD only, and DD + ADHD co-morbid samples. Similarly, future research should further evaluate the contribution of comorbidity to DD observed in ideographic language.Our results indicate that neurostructural differences in the SLF may occur in children with DD + ADHD in comparison to TD. Results suggest that differences in white matter diffusivity may exist on a continuum, with DD + ADHD having the lowest mean FA compared to DD only or TD groups. Differences in FA in these specific tracts may underlie the severity of specific behavioral impairments seen in comorbid DD + ADHD when compared to those children with only DD exclusively.


Attention-deficit/hyperactivity disorder (ADHD) is characterized by an inappropriate, pervasive and persistent pattern of inattention, hyperactivity, and/or impulsivity and associated with substantial functional impairment. Despite considerable advances in the understanding and management of ADHD, some patients do not respond well to methylphenidate (MPH), the first-choice pharmacological treatment. Over the past decades, among non-invasive brain stimulation techniques, transcranial direct current stimulation (tDCS) has proven to be an effective and safe technique to improve behavior and cognition in children with neurodevelopmental disorders, including ADHD, by modifying cortical excitability. However, the effect of tDCS has never been directly compared with that of the MPH. The present randomized sham-controlled trial evaluated the effect of a single session of anodal tDCS compared with the administration of a single dose of MPH in children and adolescents with ADHD.After completing baseline assessment (T0), 26 children and adolescents with ADHD were exposed to 3 conditions with a 24-h interval-sessions: (A) a single session of anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC); (B) a single session of sham tDCS over the left DLPFC; (C) a single dose of MPH.Our results showed that after administering a single dose of MPH, children and adolescents with ADHD improved inhibitory control and visual–spatial WM compared with baseline, anodal, and sham tDCS. However, a single session of active tDCS over the left DLPFC was not effective compared with either baseline or sham tDCS.In conclusion, our protocol in ADHD involving a single tDCS session did not demonstrate consistent improvements in neurocognitive features compared with baseline, sham tDCS, or single MPH administration. Different protocols need to be developed to further test the effectiveness of tDCS in improving ADHD symptoms. Attention-deficit/hyperactivity disorder (ADHD) is characterized by an inappropriate, pervasive and persistent pattern of severe inattention, hyperactivity, and/or impulsivity  with a wMost people with ADHD have impairments in high-level cognitive functions necessary for goal-directed behaviors, such as inhibitory control, working memory (WM), and cognitive flexibility . NeuroimMethylphenidate (MPH) is the most commonly used drug for ADHD . AlthougMore than 100 randomized placebo-controlled clinical trials ascertain that MPH is one of the most successful interventions for ADHD, reducing symptoms of inattention, hyperactivity, and impulsivity  as well For example, transcranial direct current stimulation (tDCS) directly and non-invasively modulates cortical excitability and, consequently, associated behavior and cognitive functions via a weak electrical current  delivered through one or more electrodes placed on the scalp . SpecifiThe application of tDCS in pediatric population is an emerging area of intensive research, supported by promising results in a wide range of neurodevelopmental disorders . Over thFurther studies are still needed to understand the actual potential of this technique in the treatment of ADHD. In addition, direct comparison between tDCS and MPH could provide interesting insights into the magnitude of the effect on cognitive function of brain stimulation compared with MPH treatment.The aim of the present study is to test whether tDCS can induce improvement in inhibitory control and WM of children and adolescents with ADHD and to explore whether the effect of a single session of tDCS can be comparable to that obtained after a single dose of MPH.All participants received a comprehensive neuropsychiatric assessment at the Child and Adolescent Neuropsychiatry Unit of the Bambino Gesù Children’s Hospital (Rome). Neuropsychiatrists and development psychologists conducted clinical eligibility screenings, evaluating cognitive level, ADHD symptoms and the occurrence of comorbid psychiatric disorders.Cognitive level was assessed using the Wechsler Intelligence Scale for Children Fourth Edition   or the RThe diagnosis of ADHD and psychiatric comorbidities was based on the developmental history, a thorough clinical examination, the semi-structured interview Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version for DSM-5 (K-SADS-PL DSM-5)  and pareChildren and adolescents with the following characteristics were considered for the inclusion in the study:1) diagnosis of ADHD (combined presentation) according to the DSM-5 criteria (1);2) Intelligence Quotient (IQ): higher than or equal to 85 (IQ ≥ 85);3) age between 8 years to 13 years and 11 months;4) normal or corrected-to-normal vision;5) being drug naïve and needing drug treatment for ADHD symptoms.Patients were excluded if they presented:6) autism spectrum disorders or specific psychiatric disorders  as comorbid conditions;7) a history of neurological  or medical  or genetic conditions;8) a pre-existing medical condition  contraindicated for the administration of MPH.After clinical eligibility screening, 26 children and adolescents  with combined presentation of ADHD were included in the study. All participants and their parents were fully instructed about the procedures and the purpose of the study, and both parents and adolescents aged 12 years and older provided written consent before entering the study.ClinicalTrials.gov (ID: NCT04964427) on the 13th of July 2021. The rationale and design of this trial was discussed in a published Study Protocol  and was registered at Protocol . The stuA randomized, single-blind, within-subjects, and sham-controlled design was conducted.After clinical eligibility screening at baseline (Day 0), participants were exposed to three conditions with a 24-h interval-sessions . Outcome measures were recorded at Day 0, Day 1, Day 2, and Day 3.2) saline sponge electrodes held in place by elastic bands. The anodal electrode was placed over the left DLPFC, in accordance with the International System 10–20, on the sites corresponding to F3, while the cathodal electrode was located over the contralateral supraorbital area (OFC), corresponding to Fp2.Direct current was delivered by a battery-operated direct current stimulator  through a pair of identical square  and, at the end of stimulation, the current slowly decreased to 0 mA during the last 30 s (ramp-down). Based on previous studies conducted on children and adolescents with neurodevelopmental disorders , a curre2.Between ramp-up and ramp-down, constant current was delivered for 20 min, with a density of 0.04 mA/cmDuring the sham tDCS condition, stimulation was delivered the same positioning as active tDCS, respectively left anodal on DLPFC and right electrode reference on OFC. The stimulation intensity was set to 1 mA, but the current was applied for 30 s and was reduced without participant awareness. This placebo condition induces sensations  associated with tDCS and, is therefore indistinguishable by participants from the active condition .tDCS set-up was based on previous studies in children and adolescents with ADHD  demonstrDepending on the age and weight of the child, a single dose of 5–10 mg of immediate-release MPH  was administered by a neuropsychiatrist in accordance with NICE and AIFA  guidelines for the treatment of ADHD. Neuropsychiatric preventive and naturalistic assessment  according to the AIFA guidelines for ADHD was conducted by a neuropsychiatrist before recruitment. At that time, cardiovascular risk factors associated with MPH assumption  were excluded by clinicians. After this first evaluation, the participants underwent medical examinations. Specifically, the electrocardiogram and the correction of the QT segment were preventively evaluated by a cardiologist. Moreover, blood exams were carried out to exclude any other medical condition associated with ADHD and that may mime this disorder’s symptoms .The primary outcome measure was response inhibition , SSRT, RTs, VRTs.In n − 2. When the accuracy was higher than 80%, the difficulty of the N-Back task increased . The N-Back index was determined based on the last unachieved span . For example, if the participant reached the 1-Back span (accuracy percentage ≥ 80%) and achieved only 30% accuracy in the 2-Back span, the N-Back index would be 2.3. The task took about 2 min to complete.The N-Back task is one of the most frequently used culture-free instruments to assess WM. The visual–spatial condition consists of presenting a series of visual stimuli (blue boxes) at a given position on the screen. After a training phase, participants had to indicate whether the position of each box presented was the same as that presented in previous trials. For example, in 2-Back task, participants had to indicate whether the current position was the same as the position in trial Outcome measures were collected at Day 0 and 10 min after the start of stimulation  or 90 miN-back and SST tasks were administered during tDCS, in agreement with studies  that havThe order of N-back and SST was counterbalanced across sessions.Overall, the evaluation took about 20 min to complete.Safety and tolerability are important dimensions for validating and translating a treatment in the daily clinical routine. Therefore, symptoms and side effects were evaluated by using a standard questionnaire  completea priori analysis in G*Power, version 3.1.9.7 , and β = 0.80 .Sample size was calculated using  3.1.9.7 . As prev 3.1.9.7 , the samPost-hoc comparisons were run using Tukey’s honest significance test. Partial eta square (ηp2) was used as a measure of effect size.Repeated-measures ANOVAs were conducted separately on SSRT, VRTs and Accuracy of SST with Condition  as a within-subjects factor. Post-hoc analyses were conducted by using Wilcoxon signed-rank tests to check for potential differences among conditions . Cohens’ d was used as a measure of effect size.The Friedman’s ANOVAs were employed to conduct nonparametric tests on the RTs of the SST and the visual–spatial N-Back index, as they did not follow a normal distribution. To exclude sequences effect, non-parametric analysis was run for each outcome measure  in the primary outcome, the SSRT (see Post-hoc comparisons showed a significant reduction of SSRT after a single dose of MPH compared with Day 0 (p = 0.006). However, no significant differences were found between MPH and anodal tDCS (p = 0.11) or between MPH and sham tDCS (p = 0.15).Repeated-measures ANOVA documented a significant Condition Effect .No further significant differences were found  = 0.88, p = 0.83) among the conditions  in VRTs (see Post-hoc documented a significant reduction of VRTs after a single dose of MPH compared with Day 0 (p = 0.001), anodal tDCS (p = 0.0002), and sham tDCS (p = 0.047). No further significant differences were found .Repeated-measures ANOVA showed a significant Condition effect  in the Accuracy of SST (see Repeated-measures ANOVA showed no significant Condition effect (F SST see  panel D.χ2(3) = 17.75, p = 0.0005). Wilcoxon signed-rank tests documented a significant increment of visual–spatial N-Back index after a single dose of MPH compared with Day 0 , anodal tDCS  and sham tDCS . No further significant differences were found   see .Regarding the safety questionnaire used to assess post-stimulation adverse effects , most paThe present study is the first attempt to compare the effects of tDCS with those of established pharmacological treatment.In this randomized, single-blind, sham-controlled study, children and adolescents with ADHD were exposed to a single session of anodal tDCS, sham tDCS, and a single dose of MPH.After a single dose of MPH, results showed a significant improvement in inhibitory control (in terms of VRTs and SSRT) and visual–spatial WM compared with baseline, one session of anodal tDCS and sham tDCS. These findings corroborate previous evidence, showing MPH beneficial effects on inhibitory control and visual–spatial WM .However, several explanations could be proposed for the lack of results on cognitive variables examined after left anodal tDCS on DLPFC. First, a possible reason may lay into the stimulated brain region – i.e., DLPFC. The choice of stimulating this brain region was based on previous studies demonstrating that the DLPFC abnormalities are physiologically associated with the cognitive deficits of ADHD . For theSecond, a potential explanation could be due to the specificity of the neurophysiological actions associated with tDCS. Indeed, it is well-known that tDCS can induce the alteration of cortical excitability that depends on the dendro-axonic orientation of the pyramidal cells . HoweverThird, a single stimulation of the anodal tDCS may not have been sufficient to give an effect. Although a single dose of MPH has been shown to affect brain network connectivity and cognitive symptoms , evidencThe current results have helped confirm the safety and feasibility of tDCS in the pediatric population , 2020b aFinally, online administration of tDCS may have influenced the results. Although tDCS during task performance has been shown to increase the synaptic strength of neural networks already activated by concurrent tasks , some stOur study has some limitations. The first refers to the absence of a placebo pharmacological-control intervention to compare the effects obtained after MPH administration. Future studies involving four conditions  could be useful to clarify the contribution of a single dose of MPH compared with placebo and the non-invasive brain stimulation conditions in the same group of children with ADHD.The number of participants can also be considered a limitation of the present study. To confirm the superiority of the effects of MPH over tDCS, it will be necessary to collect data from larger groups.In addition, neurophysiological and neuroimaging studies, such as EEG and/or MRI studies, could help explain the reduced effect of a single non-invasive brain stimulation session.In conclusion, our protocol involving a single tDCS session in ADHD did not demonstrate consistent improvements in neuropsychological measures. Different protocols could be developed that provide significant effects. Different montages should be implemented to target other potential brain regions involved in inhibitory control and visual–spatial WM  beyond DLPFC. Other transcranial electrical stimulation techniques  could be used so as to reach more deeply and focally the brain structures involved in ADHD symptoms. In addition, multi-session tDCS protocols could make more significant changes than a single session for ADHD, possibly in combination with usual treatments such as cognitive-behavioral psychotherapy and medication. However, our study has the merit of directly comparing tDCS with a pharmacological intervention , whereasIn light of previous considerations, it should not be therefore excluded that tDCS could represent a promising treatment for ADHD-associated executive dysfunctions, and it is still an open area of research which merits to be further investigated.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of the Bambino Gesù Children Hospital (2185_OPBG_2020). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.BD, DM, and SV: conceptualization. BD, DM, GL, PP, and SV: methodology. SV and DM: supervision. BD, GL, and AB: writing original draft. BD, DM, GL, AB, PDR, SDV, IP, FC, and SV: writing review and editing. All authors have read and agreed to the published version of the manuscript.This work was supported by the Italian Ministry of Health with “Current Research” funds.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.