Taken together, these data strongly implicate HGF in mediating hUC‐MSC‐induced improvements in functional recovery in AD models.Stem cells have emerged as a potential therapy for a range of neural insults, but their application in Alzheimer's disease (AD) is still limited and the mechanisms underlying the cognitive benefits of stem cells remain to be elucidated. Here, the effects of clinical‐grade human umbilical cord‐derived mesenchymal stem cells (hUC‐MSCs) on the recovery of cognitive ability in SAMP8 mice, a senescence‐accelerated mouse model of AD is explored. A functional assay identifies that the core functional factor hepatocyte growth factor (HGF) secreted from hUC‐MSCs plays critical roles in hUC‐MSC‐modulated recovery of damaged neural cells by down‐regulating hyperphosphorylated tau, reversing spine loss, and promoting synaptic plasticity in an AD cell model. Mechanistically, structural and functional recovery, as well as cognitive enhancements elicited by exposure to hUC‐MSCs, are at least partially mediated by HGF in the AD hippocampus through the activation of the cMet‐AKT‐GSK3 β signaling pathway.This study explores the effects of clinical‐grade hUC‐MSCs on the recovery of cognitive ability of Alzheimer's disease (AD). All results uncover that HGF secreted from hUC‐MSCs, mediates the beneficial effects of hUC‐MSCs on functional recovery of damaged neural cells by downregulating hyperphosphorylated tau, improving neurofibrillary tangles, reversing spine loss, and promoting synaptic plasticity in AD hippocampus through the cMet‐AKT‐GSK3 Recently, more new light has been shed on the possible interactions of Aβ and tau, and novel findings have shifted our understanding of the role of tau which acts downstream of Aβ or toward being a crucial partner of Aβ to induce neuronal death in the pathogenesis of AD, which prompts that targeting tau pathology might be a clinically effective therapy or targeting both tau and Aβ seems prudent. Current treatments for AD are solely symptomatic and pharmacological agents that are unable to attenuate disease progression. Thus, advancing our understanding of AD mechanisms is critical to improve the efficacy of current treatment strategies.Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by neuronal loss and cognitive decline. AD is rapidly becoming one of the leading causes of disability and mortality in the elderly.1, 2 In recent years, accumulating evidence indicates that the transplantation of adult stem cells such as bone marrow stem cells (BMSCs), adipose mesenchymal stem cells (ADMSCs) or neural stem cells (NSCs) into the lateral ventricles ameliorates cognitive deficits in AD animal models. Nevertheless, many factors limit their clinical applications, including low yield, ethical issues, and invasive procedures. Compared to the above stem cells, umbilical cord‐derived mesenchymal stem cells (hUC‐MSCs) maintain an earlier embryologic phase, are much younger, have a higher yield without ethical issues and invasive procedures, and can secrete a wide range of multifunctional factors; more importantly, only hUC‐MSCs can meet all these advantages at the same time. These factors suggest that hUC‐MSCs may be a better choice for clinical application compared to many other stem cells.Stem cell‐based therapy has emerged as a promising approach to treat neurodegenerative diseases.7, 8 We demonstrated that the intraperitoneal administration of clinical‐grade hUC‐MSCs could counteract cognitive aging of synaptic plasticity, neural networks, molecular regulation, and cognition in aged mice; these effects were systemic and integrated, suggesting that hUC‐MSCs may be a preferred resource to systematically regulate the aging brain and interpose the physiological processes of cognitive aging. However, whether the hUC‐MSCs are a better choice for treating pathological cognitive decline in the aging brain, especially for AD, still needs to be further addressed. Therefore, we hypothesized that hUC‐MSCs, as young stem cells, may be a superior source for interposing or reversing AD. More importantly, hUC‐MSCs can secrete a wide range of functional factors, including growth factors, cytokines, chemokines, and metabolites; so, there is still a valuable research topic that is which core functional factors secreted from hUC‐MSCs plays important roles in hUC‐MSC‐modulated recovery of cognition function.Recently, our group optimized transplantation parameters and established several benefits of hUC‐MSC‐based interventions for normal aging‐related cognitive decline.14 We β signaling pathway.Here, for the first time, we explored the effects of clinical‐grade hUC‐MSCs on the recovery of cognitive ability in SAMP8 mice, which is a senescence‐accelerated mouse model of AD; and we demonstrated that the core functional factor, hepatocyte growth factor (HGF), secreted from hUC‐MSCs plays important roles in hUC‐MSC‐modulated recovery of damaged neural cells by down‐regulating hyperphosphorylated tau, improving neurofibrillary tangles, reversing spine loss, and promoting synaptic plasticity in the aged hippocampus, which are all closely associated with memory deficits. Mechanistically, structural and functional recovery, as well as cognitive enhancements elicited by exposure to hUC‐MSCs, were at least partially mediated by HGF in the AD hippocampus through the activation of the cMet‐AKT‐GSK3β signaling pathway. Our study highlights a promising strategy for AD intervention based on the pleiotropic cytokine HGF, which could be used in isolation or in combination with hUC‐MSCs for AD treatment.Collectively, we demonstrate that HGF, a pleiotropic cytokine secreted by hUC‐MSCs, mediates the beneficial effects of hUC‐MSCs on functional recovery in AD related models via cMet‐AKT‐GSK322.1Figure Clinical‐grade hUC‐MSCs were prepared, and quality tests including morphology, phenotype, and differentiation potential were performed . 2 months after the transplantation of hUC‐MSCs, animals were tested in a series of behavioral experiments including Morris water maze (MWM), Shuttle box, Y‐maze, open field and object recognition for spatial learning and memory ability Figure 1A. In th2.2β (Tyr216), β‐amyloid precursor protein (APP) and presenilin 1 (PS1) were significantly decreased in the MSC‐treated group in hippocampus  , BACE1, pGSK3s Figure 2A,E and/  Figure ,F in the) Figure –D,F. In 2.3 According to different sensitivities to OA, primary neurons and SH‐SY5Y cells were induced by incubation with OA at a final concentration of 10 nm for 4 h and 20 nm for 24 h . We analyzed the cell morphology, mitochondrial function, cell viability, subcellular structure and phosphorylation level of tau protein to assess the degree of damage induced by OA and the restorative effects with conditioned medium (CM) of hUC‐MSCs. In terms of cell morphology, primary neurons in the Con group presented polygonal bodies, with longer axons and abundant dendrites; after induced by OA, cell bodies adopted a round morphology, and axons were shortened, bent, and fractured. In contrast, the cell morphology of the CM treatment group was restored and maintained  which we have established in a previous work.19 Accd Figure , right ad Figure . We subsd Figure . Both ned Figure . To verid Figure ,F. Dil‐fd Figure . The lend Figure . Based o2.4Figure After clarifying the effects of hUC‐MSCs in AD models in vivo and in vitro, we focused on the mechanism by which core functional factors secreted from hUC‐MSCs played important roles in hUC‐MSC‐modulated recovery of cognitive function and neurological damage. We used high throughput screening (HTS) to detect the quantity of expression of 174 known cytokines in the hUC‐MSC‐CM of four different generations  from three different umbilical cords ‐derived hUC‐MSCs. We obtained the cytokine expression spectrum of 12 samples and analyzed the overall quality control of the data. We found stable and reliable data through cluster analysis. From the results of the heat map Figure 4A, factoAb) was added into the MSC‐treated group. The repair capabilities of hUC‐MSCs were dramatically restrained compared with that of the CM group . Morphometric ultrastructural analyses with a transmission electron microscope indicated that the intracellular mitochondria of OA‐damaged SH‐SY5Y cells displayed collapse, swelling, and vacuoles with a large number of secondary lysosomes and residues. After treatment with HGF and CM, the intracellular mitochondria of treated SH‐SY5Y cells restored their shape to long ellipse, and mitochondrial cristae were arranged neatly. In contrast, the reparative effects of CM were dramatically restrained after the addition of HGFAb . These effects were partly associated with reversal of disease‐associated microglial neuroinflammation, as evidenced by decreased microglia‐induced proinflammatory cytokines (IL‐1β and TNF‐α) and increased anti‐inflammatory cytokine IL‐4, suggesting that both hUC‐MSCs and HGF produced sustained neuroprotective effects . Taken together, these data indicate that HGF improves cognitive function and regulates the expression of key AD‐related proteins in SAMP8 mice.The neuropathological hallmarks of AD and other tauopathies include senile plaques, neurofibrillary tangles, and/or neuroinflammation; these are evident in SAMP8 mice. SAMP8 brains over‐produce APP, have increased tau phosphorylation, accompanied with gliosis and neuroinflammation.22 Ind2.6ShHGF) and control cells (MSCCon)   Figure 6B. The e) Figure –E. Then,S Figure . SubsequS Figure –M. In thy Figure –H. Afterp Figure . In the y Figure . In the s Figure . In the s Figure  and objes Figure , the tim2.7 We used the HGF R/c‐Met antibody (cMetAb) that is able to block more than 90% of binding in OA‐induced primary neurons and SH‐SY5Y cells in vitro  in OA‐treated SH‐SY5Y cell model  in SAMP8 mice. Every group had four different hippocampal tissue samples. After obtaining the raw data from 16 hippocampal tissue samples, differentially expressed genes were identified. When a 1.5‐FC with respect to gene expression of the PBS group was used to filter our gene list, 19 different genes were obtained, which we subsequently focused on Figure 8A. With pathways.27 Paty Figure . We examl Figure ,H. Immunb Figure –I.β in the hippocampus of P8 mice  was decreased in PBS‐treated P8 mice compared to that in R1 mice, and treatments with hUC‐MSCs and HGF restored the level of p‐AKT and p‐GSK3β in P8 mice compared to that in the PBS‐treated group . AD exerts a physical, psychological, social, and economical effects, on people with AD as well as their carers, families and society at large. Currently, there are no treatments to cure AD or alter its course of progression. As such, novel AD treatments are a critical unmet need.According to the WHO's latest top 10 global causes of death, deaths due to AD and other dementias more than doubled between 2000 and 2016, making it the fifth leading cause of global deaths in 2016 compared to 14th in 2000  in AD treatment, which could improve cognitive performance via diverse immunological, histological, and genetic measures. Nevertheless, these stem cells have many factors that limit their clinical application, including low yield, ethical issues, and invasive procedures. hUC‐MSCs have higher yield, and invasive procedures without ethical issues. Importantly, hUC‐MSCs maintain an earlier embryologic phase, are much younger, and can secrete a wide range of multifunctional factors. These features indicate that hUC‐MSCs may be a better choice for clinical application than many other MSCs.Recently, the transplantation of stem cells has been shown to be effective treating neurodegenerative diseases.7, 8 Indeed, while the use of animal components carries the risk of zoonoses and xenogeneic immune reactions, laboratory‐generated hUC‐MSCs do not undergo quality and safety testing that is required for clinical applications. Our group has established a Cell Factory and Biobank at the South China Institute of Biomedicine in Guangzhou that is currently producing clinical‐grade hUC‐MSCs, using methods that are fully compliant with current Good Manufacturing Practice guidelines, and conform to the quality standards of National Institutes for Food and Drug Control.However, the use of hUC‐MSCs derived from different sources and using various methods further confounds the direct comparison of findings from different labs. For clinical application, a standardized protocol that guarantees the reproducibility, safety, and efficacy of hUC‐MSCs is of utmost importance.28 Ind However, whether hUC‐MSCs have effects on pathological cognitive decline in AD, needs to be further addressed. Although some studies have showed positive effects of hUC‐MSCs in the treatment of AD, little is known about which core factor secreted from hUC‐MSCs plays important roles in hUC‐MSC‐modulated recovery of cognition function, which may be one of the key factors restricting the better clinical application of hUC‐MSCs. Therefore, it is very essential to clarify how hUC‐MSCs play a therapeutic role in AD from the perspective of hUC‐MSCs themselves, which may be the crux of both basic research and clinical application of hUC‐MSCs in the treatment of AD. Here, we comprehensively evaluated for the first time the effects of clinical‐grade hUC‐MSCs on AD and explored whether clinical‐grade hUC‐MSCs could improve cognitive ability in SAMP8 mice. We further demonstrated the core functional factor HGF secreted from hUC‐MSCs plays important roles in hUC‐MSC‐modulated recovery of damaged neural cells at least partially through the activation of cMet‐AKT‐GSK3β signaling pathway.Our past work has characterized beneficial effects of clinical‐grade hUC‐MSC‐based therapies for intervening with normal aging‐related cognitive dysfunction.14 How The majority of cases are most likely caused by complex interactions among multiple genetic, epigenetic, and environmental factors. Therefore, the spontaneous SAMP8 strain has several distinct advantages over gene‐modified models and is particularly well suited to study the “transitional switch” between aging and AD. The phenotypes of the SAMP8 mouse resemble the symptoms of late‐onset and age‐related sporadic AD patients. We therefore used SAMP8 mice as an animal model to study AD. SAMP8 mice that received clinical‐grade hUC‐MSC grafting exhibited improved performance, as assessed by five well characterized and widely used cognitive tasks , APP, PS1, pGSK3β (Ser9), and pAKT (Ser473) ; and the regeneration of endogenous neural stem cells  in multiple ways, including dendritic length and mitochondrial function. IL‐6 had some reparative ability, but ANG and GRO had no repair effects in the model. Therefore, we focused on HGF in subsequent studies. In order to verify whether HGF secreted from hUC‐MSCs could mediate hUC‐MSC‐modulated recovery of neurological damage, a neutralizing antibody against HGF (HGF‐Ab) was added into the MSC‐treated group. We observed that multiple repair capabilities  of hUC‐MSCs were dramatically restrained compared with that in the CM group  and certified that c‐Met could mediate the function of HGF for restoring neurological damage in vitro  and p‐GSK3β (Ser 9) were decreased in OA‐treated SH‐SY5Y cells compared to that of the control group. Both CM and HGF significantly increased the immunoblot reactivity of p‐AKT and p‐GSK3β in OA‐treated cells compared to that in OA‐treated cells alone. The positive effects of phosphorylation of AKT and GSK3β by CM and HGF were partly restricted after the addition of c‐Met Ab  was decreased in PBS‐treated SAMP8 mice compared to that in SAMR1 mice which was consistent with previous studies, and both hUC‐MSC and HGF treatment could restore the level of p‐AKT and p‐GSK3β in SAMP8 mice which may decrease the hyperphosphorylation of tau protein at Ser396, Thr181, and Ser404  of gene differential expression, 19 different genes were obtained and selected Figure ; then, K52 Theb Figure –I. Phosp4 Figure –L. Hence however, other studies have shown that IL‐6 could increase neurotoxicity caused by Aβ. Therefore, the regulation of inflammatory factors on the AD brain may be more complicated, and only through careful design and in‐depth research under specific time and space conditions can we further understand its function. In addition, there are some factors with the moderate expression, such as PDGF‐AA, ALCAM, FGF7, IGFBP6, FASLG, etc; although their expression intensity is relatively low, their roles in hUC‐MSC‐treatment of AD also need to be explored. Therefore, a further excavation on the exact roles of different core factors of hUC‐MSCs might be the key to delineate the therapeutic value of hUC‐MSCs in AD. AD is a complex disease characterized by multi‐pathological features, in which both Aβ plaques and NFTs are neurotoxic, and optimal approaches for AD treatment might be able to target the most toxic species of both Aβ and tau concurrently. Our ultimate goal is to develop various HGF combination therapies  for AD patients, including targeting of the Aβ and tau pathological changes and optimizing the existing regulatory methods for the inflammatory environment, to finally achieve a comprehensive therapy for AD; but all these speculations require further digging and verification, and we plan to explore more in future research.Although we have demonstrated that HGF secreted from hUC‐MSCs could mediate hUC‐MSC‐modulated recovery of neurological damage and cognitive function at least to some extent, we still believe that in addition to HGF, there may be other bioactive components that mediate hUC‐MSCs to play important roles. In fact, we are also concerned about the potential therapeutic effect of other highly expressed factors on AD and other cognitive dysfunction Figure ,B. For e42 how4β signaling pathway. Hence, we suggest that hUC‐MSC treatment could be a promising and effective neuroprotective candidate to prevent AD and other progressive age‐related neurodegenerative diseases. Crucially, these findings raise the possibility that HGF may be used in isolation or in combination with hUC‐MSCs for AD treatment.To our knowledge, this is the first study to use SAMP8 mice (a senescence‐accelerated mouse model of AD) to explore the effects and mechanisms of clinical‐grade hUC‐MSCs on the recovery of cognitive ability. Collectively, the data demonstrated that the core functional factor HGF secreted from hUC‐MSCs plays important roles in hUC‐MSC‐modulated recovery of damaged neural cells by down‐regulating hyperphosphorylated tau, improving the NFT, reversing spine loss, and promoting synaptic plasticity in the hippocampus of AD mice, which are all closely associated with memory deficits. Mechanistically, the structural and functional recovery, as well as cognitive enhancements elicited by exposure to hUC‐MSCs, were at least partially mediated by HGF in the AD hippocampus through the activation of cMet‐AKT‐GSK35 The entire link including isolation, cultivation, identification, quality control, and storage was conformed to the quality standards. The generation time of hUC‐MSCs used in this study was severely restricted from passage 3 (P3) to passage 5 (P5).All procedures involving human subjects in this study were approved by Ethics Committee at the Third Affiliated Hospital of Sun Yat‐sen University ; and all the patients gave their written informed consent to participate. Clinical‐grade hUC‐MSCs were used in this study which were greatly optimized in a previous research.14 The4 cells cm−2 in 10 cm dishes, cultured for 24 h, and the medium replaced with 8 mL of α‐MEM for additional 48 h, CM was centrifuged (2500 rpm for 5 min) to remove cell debris and used for experiments.hUC‐MSCs were seeded at initial density of 1 × 10−1 poly‐d‐lysine (Sigma) at a density of ≈350 000 cells per dish. Neurons were plated and maintained in Neurobasal medium supplemented with B27, N2, and GlutaMax (Invitrogen)in a humidified incubator at 37 °C with 5% CO2. SH‐SY5Y cells  were supplied with complete in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, 2 mm glutamine. To establish the in vitro model of tauopathy which was hyperphosphorylation of tau, SH‐SY5Y cells were induced by incubation with okadaic acid  at a final concentration of 20 nm for 24 h as a previous work, and neurons were induced by incubation with OA at a final concentration of 10 nm for 4 h, according to the different sensitivity to OA. For cell treatment, OA‐damaged SH‐SY5Y cells or neurons were replaced with CM or HGF, while Con and OA‐damaged groups were replaced with α‐MEM. To neutralize the function of HGF in CM and block the function of c‐Met of neural cells, HGF antibody (HGF Ab) (R&D) and HGF R/c‐Met antibody (R&D) were used in the experiment.Primary hippocampal neurons were prepared from embryonic day 18 rat embryos and plated on 25‐mm coverslips or 35‐mm glass bottom dishes pretreated with 0.1 mg mLlutamine.55 To −1).Neural stem cells (neurospheres) cultures were prepared from newborn rat cortex and grown in serum‐free medium containing EGF and bFGF  (data not shown). The average body weight of 4‐month‐old SAMP8 mice was about 30 g, and their whole blood was about 2 mL. In order to achieve the dose of human HGF in vivo after hUC‐MSCs injection, HGF alone was used at a dose of 100 ng. All animals received care according to the Guide for the Care and Use of Laboratory Animals. The protocol was approved by the Committee on the Ethics of Animal Experiments of Academy of Military Medical Sciences.The senescence accelerated mouse prone 8 (SAMP8), and senescence accelerated mouse resistant 1 (SAMR1) mice were purchased from Peking University Health Science Center. 4‐month‐old male SAMP8 and SAMR1 mice were used in this study. The vehicle‐treated mice were received with 500 µL phosphate buffered saline (PBS). the SAMP8 mice was treated with hUC‐MSCs  were used in this experiment. Signal intensity values representing detected cytokines were subtracted from the background and normalized to positive controls on the same membrane. Experimental steps and analyses were conducted according to the manufacturer's instructions. Signal intensity values of each cytokine were presented as mean ± standard deviation (SD).For signal pathway research, mRNA microarray was used to analyze and verify the probable pathway. Total RNAs was quantified by the NanoDrop ND‐2000 (Thermo Fisher Scientific) and the RNA integrity was assessed using the Agilent Bioanalyzer 2100 (Agilent Technologies). The sample labeling, microarray hybridization and washing were performed based on the manufacturer's standard protocols. After washing, the arrays were scanned by the Agilent Scanner G2505C (Agilent Technologies). Raw data were extracted using Feature Extraction . Next, quantile normalization and subsequent data processing were done using Genespring software . The microarray profiling, differential gene expression analysis and pathway analysis were conducted in the laboratory of the OE Biotech Company .t tests. Statistical significance was set at P < 0.05. All data were shown as means ± SEM or means ± SD.The intensity of IHC staining, were analyzed using Image‐Pro Plus 6.0 software . Statistical analyses were performed with GraphPad Prism 8.0 software  and expressed as mean plus or minus standard error of the mean. Multiple groups were compared using one‐way analysis of variance (ANOVA) followed by the Tukey test for post hoc comparisons based on single factor experiments. In behavioral study of MWM task, the data of the training trials were analyzed using a two‐way ANOVA with days as repeated measures factor and treatments as between subjects’ factor. For comparisons of the mean between two groups, statistical analysis was performed by applying Student's The authors declare no conflict of interest.Supporting InformationClick here for additional data file.


Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder in which patients present inattention, hyperactivity, and impulsivity. The etiology of this condition is diverse, including environmental factors and the presence of variants of some genes. However, a great diversity exists among patients regarding the presence of these ADHD-associated factors. Moreover, there are variations in the reported neurophysiological correlates of ADHD. ADHD is often treated pharmacologically, producing an improvement in symptomatology, albeit there are patients who are refractory to the main pharmacological treatments or present side effects to these drugs, highlighting the importance of developing other therapeutic options. Different non-pharmacological treatments are in this review addressed, finding diverse results regarding efficacy. Altogether, ADHD is associated with different etiologies, all of them producing changes in brain development, leading to the characteristic symptomatology of this condition. Given the heterogeneous etiology of ADHD, discussion is presented about the convenience of personalizing ADHD treatment, whether pharmacological or non-pharmacological, to reach an optimum effect in the majority of patients. Approaches to personalizing both pharmacological therapy and neurofeedback are presented. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder (NDD) presenting with inattention, hyperactivity, and impulsivity. It can be classified in three subtypes, depending on the intensity of the symptoms: predominantly inattentive, predominantly hyperactive–impulsive, and combined ,2. ADHD While most studies address ADHD in children from 7 to 17 years old, it is important to outline that this condition is also present in adults. It has been proposed that the number of adults with ADHD has increased over the last 20 years. A part of this increase is due to the permanence of ADHD symptoms in the adult age in 76% of diagnosed patients. ADHD implies important challenges for academic, personal, and job performance .As for any other condition affecting brain function, in order to find an adequate treatment for ADHD, it is important to first understand its physiological basis. As with other NDDs, the causes of ADHD are aberrant neural development, affecting neurogenesis, synaptogenesis, myelination, and neuronal and glial proliferation and migration. Even though symptoms begin to appear in childhood, neuronal development is affected from early embryogenesis .The etiology of ADHD is diverse—gestational, perinatal, and genetic factors have been associated with ADHD incidence. However, each patient presents only a few of them.The incidence of ADHD is associated with a number of environmental factors during different stages of central nervous system (CNS) development, such as gestational and perinatal periods. In this section, we will address some of the environmental factors that have been associated with ADHD.Premature birth is an important risk factor for ADHD, since it has been reported that it occurs 2.6 to 4 times more frequently in babies born with low weight or very low weight. Premature birth is associated with alterations in neurogenesis and cell death . One posPerinatal hypoxia is an environmental factor that increases the risk of developing AHDH, probably due to its effects on dopaminergic transmission and neurotropic signaling .The intake of nutrients during gestation is very important for proper brain development. An important element during neural development is the polyunsaturated fatty acid docosahexaenoic acid (DHA), promoting proliferation and neural differentiation of neural progenitor cells. Decreased levels of DHA during brain development have been associated with ADHD and other neurodevelopmental disorders , and decInterestingly, there is evidence in a rat model of the influence of preconceptional conditions on ADHD incidence. Offspring of Female rats administered with ethanol for 8 weeks before mating presented ADHD-like symptoms such as hyperlocomotive activity, impulsivity, and attention deficit. These rats also presented low levels of striatal DAT and increased presence of norepinephrine transporter (NET) in the frontal cortex . A laterAnother environmental factor associated with ADHD is pesticide exposure during development. A study addressing the issue, both at experimental and epidemiological levels, reported that exposure to the pesticide deltamethrin during gestation and lactation in rats led to ADHD-like symptoms, such as working memory and attention deficits, hyperactivity, and impulsive-like behavior. It also produced increased presence of DAT and D1 receptor in the striatum, as well as increased dopamine release and increased presence of D1 dopamine receptor in the nucleus accumbens. Interestingly, the authors also performed an epidemiological study in humans, revealing that children (6 to 15 years old) with detectable levels of pyrethroid metabolites in urine had more than twice the probability of being diagnosed with ADHD .One of the most reported environmental factors associated with ADHD is exposure to neurotoxic heavy metals. A study performed on school children revealed that children (6–7 years old) with ADHD presented higher levels of salivary mercury. However, when including all age groups studied (12–13 years and 15–16 years), no significant correlation was found between increased salivary mercury and ADHD, although a mild tendency was observed .In the case of manganese, both too high and too low blood levels are associated with cognitive deficits. High concentration of manganese in blood is associated with deficits in thinking, reading, and calculations, as well as with lower learning quotient (indicative of learning disability) and more errors in the continuous performance test (measuring attention and response inhibition). Conversely, low blood level of manganese is associated with a poorer performance in the Stroop test, which is used to assess cognitive inhibition . SimilarThe presence of lead in children’s deciduous teeth is positively associated with hyperactivity or impulsivity, as well as inattention and oppositional or defiant disorder . A studyA review on the effects of prenatal and childhood metal exposure on cognition found suggestive evidence of a relation between cadmium exposure and impaired cognitive ability in children. They did not find evidence of a relationship between cadmium exposure and ADHD . A more A recently published work reported that ADHD children present higher urine concentrations of chromium, manganese, cobalt, nickel, copper, molybdenum, tin, barium, and lead . A recenThus, there are a number of environmental factors associated with ADHD incidence. While environmental factors are not found in all ADHD cases, the data reviewed herein highlight the importance of environment in different developmental stages—and even before conception—in regard to the risk of developing ADHD.Sleep deprivation, either acute or chronic, produces decreased cognitive functioning (one of the main traits of ADHD). Interestingly, it also produces the externalizing symptoms observed in ADHD patients. For example, a very tired child might become hyperactive, while in a sleepy adult in a condition where it is not possible to sleep , the externalizing behavior will help them to remain awake. Thus, both of the core ADHD symptoms can be produced by sleep deprivation. Conversely, hyperactivity in children or high internal activity in adults in the evening might lead to sleep disruption .Among the sleep disorders found in ADHD patients are delayed sleep phase disorders, insomnia, sleep-disordered breathing, increased motor activity during the night, sleep anxiety, clenching teeth, periodic limb movement, restless legs, increased sleep onset latency and shorter sleep time, night awakenings, narcolepsy, and parasomnias ,37,38,39Sleep disturbance have an impact on daytime vigilance, producing excessive sleepiness ,37,39, aSleep disturbances in ADHD patients can produce significant impairments in attention, mood, and behavior ,35. PhysConversely, during wake time, sleep disturbances produces symptoms resembling those observed in ADHD patients ,41,42. IThe relationship between sleep disorders and ADHD is complex. While ADHD might produce sleep disorders, they could also be coincident conditions . MoreoveDifferent studies have revealed an important genetic influence in the etiology of ADHD . It is aBrain-derived neurotrophic factor (BDNF) is a neurotrophin with high expression in the brain that is highly concentrated in the hippocampus and cortex. It has an important role in neuronal development, being important for neuronal proliferation, migration, differentiation, and maturation, as well as for synaptogenesis . BDNF has been implied in ADHD pathophysiology. It has been proposed that low levels of this neurotrophin may explain the reduction in brain volume observed in ADHD patients, and it has also been implied in dopaminergic system homeostasis. Some pharmacological treatments for ADHD promote the regulation of plasma BDNF levels . Since BDNF is able to cross the blood–brain barrier and plasma concentrations of BDNF are highly correlated with its levels on cerebrospinal fluid, a number of studies have searched for a difference in plasma concentrations of BDNF in ADHD patients when compared against controls. There are reports indicating a lower concentration of BDNF in plasma of ADHD patients, both in children  and adulA recently published meta-analysis encompassing studies comparing BDNF levels in ADHD patients without any other comorbidity found no overall difference between ADHD patients and controls. However, when analyzing males and females separately, they found significantly higher levels of plasma BDNF in males with AHDH than in control males, while no difference was found between females with and without ADHD . Thus, different and even contrary results have been obtained regarding BDNF concentrations in plasma or sera of ADHD patients. While this suggests that the link between BDNF and ADHD is not completely clear, other alternatives should be considered. For example, fluctuations in serum BDNF concentrations in morning and evening samples have been reported , meaningThere are a number single nucleotide polymorphisms (SNP) of the BDNF gene that have been associated with ADHD. Among the most studied variations in the BDNF gene, there is a polymorphism called Val66Met , in which a change in codon 66 produces a substitution of the original amino acid  by methionine. The anatomical effects of this variation are more apparent in the hippocampus and cortex . While sAnother SNP of the BDNF gene whose association with ADHD is not conclusive is rs2030324, since some studies report an association between this polymorphism and ADHD ,58,59,64There are other SNPs of the BDNF gene that have been studied so far, with positive correlations being shown between ADHD and the presence of C270T rs27656701) ,61, rs116701 ,61,Moreover, rare single nucleotide variants of BDNF gen have also been associated with a higher risk of developing ADHD . HoweverAs observed with peripheral BDNF concentrations, genetic variants of the BDNF gene have been associated with ADHD in numerous cases, although in some cases there are contradictory results in different articles see . MoreoveFor rs6265 , there are many articles addressing the association of this SNP with different conditions, and in some of them it has been found. For example, some articles report an association of this SNP with major depressive disorder ,73, whilWhile BDNF has been widely studied in association with ADHD, it is not the only neurotrophin studied in relation with this condition, given the important role of neurotrophines in central nervous system development and synaptic plasticity. In this regard, there are studies addressing the participation of fibroblast growth factor (FGF), vascular endothelial growth factor, insulin-like growth factor (IGF2) , glial-dBDNF is a molecule highly involved in synaptic plasticity and has an undisputed role in central nervous system development. Therefore, it is not surprising to find a number of studies associating alterations in the presence of this neurotrophin in serum, or different SNPs of its gene, with ADHD. However, its role in ADHD development is not a constant for every sample of ADHD patients studied so far, and for many of the aspects of this molecule  there are reports indicating associations, with others finding no association at all. This does not mean that the alterations associated with this molecule are not important for ADHD, but rather highlight the variable etiology of this condition. The dopaminergic system emerges in early stages of CNS embryonic development, and an imbalance in this system might affect brain development. It is related with cell proliferation, neuronal differentiation and migration, synaptogenesis, and neurogenesis. Thus, it is not surprising that a role of this neurotransmitter system has been reported in different neurological diseases, including ADHD .One of the most studied molecules of the dopaminergic system in relation to ADHD is DAT, a molecule responsible for dopamine reuptake, and the main target of two commonly used pharmacological treatments for ADHD, methylphenidate and amphetamines . GeneticIn humans, ADHD patients present lower DAT availability in the basal ganglia, caudate nucleus, and putamen . The DATAdditionally, the relevance of this VNTR has been studied in relation to cognitive function in healthy subjects. Again, mixed results were found. A meta-analysis published in 2016 addressing studies performed in healthy subjects did not find any association between DAT VNTR and different cognitive functions, such as executive functions, inhibition, attention, and long-term declarative memory . A studyThe participation of the dopaminergic system in the pathophysiology of ADHD has been widely reported . Herein,As an NDD, ADHD involves alterations of mechanisms such as neurogenesis and synaptogenesis. There are a number of possible mechanisms through which these alterations take place, both environmental and genetic, some of which have been mentioned in the present review. In the end, all of these altered mechanisms produce an altered brain function affecting attention and impulse control, functions regulated by the central nervous system. Understanding the changes in brain function associated with ADHD might shed some light not only on the functional causes of this condition, but also on possible ways to deal with it.Children with ADHD present atypical connectivity in reward circuitry when compared with control children. Increased connectivity of the nucleus accumbens with the prefrontal cortex was observed to be associated with greater impulsivity .Hypofunction and abnormal cortico-striatal pathways of the cortico-striato-thalamo-cortical (CSTC) circuit are associated with ADHD. Five different CSTC circuits have been reported: the sustained attention circuit, emotion circuit, selective attention circuit, hyperactivity circuit, and impulsivity–compulsivity circuit. Four of them (except emotion circuit) have been related with ADHD diagnostic criteria. However, pathogenesis of the emotion circuit is also related with ADHD A study on ADHD children reported significantly decreased white matter volume, as well as decreased volume in the cortex and caudate nucleus, although it did not reach statistical significance. Cortical thickness was reduced in ADHD patients bilaterally in the frontal cortex and in the right cingulate cortex, structures related with executive function and attention. Regarding default mode network, functional connectivity was reduced in ADHD children in the anterior and posterior cingulate cortexes, lateral prefrontal cortex, left precuneus, and thalamus. However, connectivity was increased in the bilateral posterior medial frontal cortex . A study on male adolescents with ADHD and controls reported decreased gray matter volume in the left anterior cingulate cortex and bilateral decreases in the occipital cortex, hippocampus–amygdala complex, and cerebellum in ADHD adolescents . Such deAn important issue with many of the imaging studies in ADHD patients has been small sample size. A large-scale study performed on children, adolescents, and adults with ADHD reported decreased surface area in children, mainly in the frontal, cingulate, and temporal regions. This effect was more pronounced in younger children (4–9 years old). Moreover, cortical thickness in ADHD children is also reduced in the fusiform gyrus and temporal lobe, an effect more prominent in children of 10 and 11 years old. No change in surface area or cortical thickness was observed in adolescent or adult ADHD patients .There are important changes in brain morphology in ADHD patients. An elegant study performed in ADHD patients and controls from 6 to 28 years of age analyzed differences in neurodevelopmental trajectories. This study reported that ADHD patients present overall reduced cortical volume, mainly in frontal lobes, and primarily due to a decrease in surface area and gyrification. Interestingly, although both groups presented maturational changes due to age, they presented different trajectories for these changes, suggesting that ADHD is associated with developmentally persistent changes in the whole cortex, mostly due to decreased surface expansion (reduced surface area and less convolution) .When comparing children with comorbid epilepsy and ADHD with control children, a widespread decrease in cortical thickness is observed, along with decreased volume in some subcortical structures and the brainstem. These alterations were observed early in the course of epilepsy, thus the authors suggested that neurodevelopmental changes occurred before epilepsy onset . In chilAll these changes lead to alterations in brain function. A frequently used technique for the study of brain activity is quantitative electroencephalography (qEEG), since it has a low cost, a high temporal resolution, and does not need special facilities to be performed. Furthermore, qEEG has also been used to determine the effects of pharmacological treatments on brain activity in order to assess effectiveness ,107, to During the last decades, several studies have performed qEEG analyses on ADHD patients. A review on the subject published in 2012 addressed the main associations between brain activity and ADHD, including increased frontocentral theta activity. Another frequently reported factor, although not always replicated, is an increased theta/beta ratio. For beta and alpha bands, most of the reports have indicated decreased activity, although there are also reports that have indicated increased activity in these frequency bands in ADHD patients . One of Another example of the influence of age on brain electrical activity associated with ADHD is a study comparing children with and without ADHD, as well as adults with and without ADHD. Interestingly, children with ADHD presented higher delta and theta activity than control children, while in adults no difference was found between ADHD group and controls in the frequency bands analyzed . Among tADHD patients often present comorbidities , which mIt is noteworthy that although a number of studies have been published regarding neurophysiological correlates of ADHD through qEEG, there are still some differences in the results reported by different authors. Beyond possible methodological differences, there are a number of factors reported to influence qEEG activity in ADHD patients, which might be responsible—at least in part—for the differences reported so far, and which might be of importance when using qEEG information to choose or design a therapeutic approach. These factors include comorbidities ,120 and Both stimulant and non-stimulant pharmacological treatments have proven to be effective in diminishing ADHD symptoms in children and adolescents ,133, altMethylphenidate is one of the most used drugs for ADHD treatment. It has been present in the market for 50 years and it reduces excessive hyperactivity, impulsivity, and inattention in children and adolescents with ADHD. In the United States, it is prescribed to 8% of children and adolescents under 15 years of age and to around 3% to 5% of the same population in Europe . Methylphenidate blocks DAT and NET, reducing reuptake and producing an increase in available dopamine and norepinephrine in the synaptic cleft ,136,137,Atomoxetine has been reported to be effective for ADHD treatment , being mAtomoxetine blocks norepinephrine reuptake, producing increased presence of norepinephrine and dopamine in prefrontal cortex . Since aBoth stimulant and non-stimulant pharmacological treatments for ADHD produce adverse effects in a percentage of treated patients. The main adverse effects found for these drugs (% of patients treated with stimulants/% of patients treated with non-stimulants) are decreased appetite (28.6%/14.2%), nausea (7.9%/10.3%), headache (14.5%/20.8%), insomnia (12.3%/8.6%), nasopharyngitis (6.0%/7.1%), dizziness (5.1%/10.0%), abdominal pain (7.8%/11.5%), irritability (9.3%/6.9%), and somnolence (4.4%/34.1%) .A systematic review on the adverse effects of methylphenidate in children and adolescents revealed that about 1 in 100 patients present serious adverse events after methylphenidate treatment , while more than half of the patients treated with methylphenidate suffer one or more adverse events. The authors concluded that it is important to identify subgroups of patients who might be harmed by methylphenidate treatment and highlight the importance of remaining alert to possible adverse events in patients with this treatment . There mA systematic review on possible adverse effects of atomoxetine, including decreased growth rate, cardiovascular and hepatic effects, aggression, psychosis, seizures, and suicidal ideation, determined that evidence indicates it is safe to use in ADHD patients . FurtherMethylphenidate and atomoxetine are known to increase heart rate and blood pressure, raising concern regarding possible cardiovascular effects of these drugs in ADHD patients. A review on the cardiovascular effects of these drugs in healthy subjects found the drug to be safe to use. Most of these studies were performed in children and adolescents, although there have also been some studies performed on adults, with no serious risk being reported in these subjects either. However, patient blood pressure and heart rate should be monitored on a regular basis. Moreover, careful follow-up should be performed for patients presenting certain cardiovascular conditions . Weight loss has also been reported after atomoxetine treatment, occurring during the first two years of treatment. However, evidence suggests this decrease begins to be compensated between 2 and 5 years after the beginning of treatment . SimilarA comparative study on short-term effects of methylphenidate and atomoxetine on ADHD reported significantly higher weight loss in children treated with atomoxetine . HoweverA meta-analysis on gastrointestinal adverse effects of methylphenidate reported increased risk of decreased appetite, weight loss, and abdominal pain in children and adolescents under this pharmacological treatment .A comparison between the presence of adverse effects after methylphenidate and atomoxetine treatments in ADHD children indicated methylphenidate as a safer option, since children under atomoxetine treatment presented higher incidence rates of anorexia, nausea, somnolence, dizziness, and vomiting than children under methylphenidate treatment . A more Long-term adverse effects of methylphenidate are the subject of intense study, given that it is the first-line stimulant drug used for ADHD treatment in children, adolescents, and adults ,151. A rGiven that ADHD is a chronic disorder and that many of the children presenting ADHD will still present symptoms in adulthood, it is particularly important to determine the long-term effectiveness of pharmacological treatments. However, very few studies address this issue, and no conclusion can yet be drawn regarding the long-term effects (years) of pharmacological treatment of ADHD on symptom reduction and quality of life. Thus, the long-term efficacy of drug treatment for ADHD remains under debate ,155,156Current pharmacological treatments for ADHD have proven to be safe and effective. The efficacy of these treatments on ADHD symptoms is clear, and thus pharmacological therapy is often used to treat ADHD patients ,141,152.Pharmacological therapy is effective although presents some inconveniences, including the existence of adverse effects in some patients and lack of effect in others. Therefore, there are also different non-pharmacological approaches for ADHD treatment.The goal of parent training is to equip parents with techniques that will be useful in managing ADHD-related behavior presented by their children. A systematic review published on 2011 found no reliable effect of ADHD children’s behavior, although it may lead to increased confidence and decreased stress in parents . Later sCognitive behavioral therapy (CBT) has also been used to treat ADHD. A review performed on the subject found CBT to be effective in reducing ADHD symptoms in adults, however only when improvement was evaluated by the patient and not when evaluated by the clinician , althougAttention training techniques are often used to improve life quality and increase well-being. Given the effect of these techniques on brain activity, as well as on attention and self-regulation, their use to reduce ADHD symptoms and improve life quality in these patients is currently under study . Mindfulness can be defined as paying attention to the present, an activity that implies sustained attention. A systematic review on the effects of mindfulness-based interventions on ADHD found that such approaches were popular among adults with ADHD, finding improvements in attention, although the effects of such approaches in children and adolescents are still unclear . A recenAdult ADHD patients that underwent an 8-week mindfulness awareness practice period presented decreased ADHD, depression, and anxiety symptoms . SimilarNeurofeedback (NFB) is a therapy in which patients learn to modify EEG patterns through operant conditioning. There are articles reporting the induction of plastic changes after NFB training ,182,183,Specific NFB protocols have been developed over the decades. These protocols were designed based on articles reporting specific qEEG variations in neurological patients or qEEG patterns associated with cognitive function. Some of these standardized protocols have been studied in terms of their ability to treat ADHD .Several articles have addressed the use of NFB in ADHD patients. The results have been mixed and numerous meta-analyses have been published on the subject. The conclusions of these meta-analyses have also been mixed. There are meta-analyses reporting good effects of NFB on ADHD ,186,187,An overview of recent publications gave the same impression. Some reports found effects of NFB theta/beta or theta/alpha protocols on ADHD, measurable at follow-up 8 weeks or 12 months after treatment completion ,193. OthNFB is a therapeutic approach widely studied for ADHD treatment. The results so far have been mixed. However, given the absence of side effects and its ability to induce synaptic plasticity , it is aThe use of non-pharmacological supplementations, such as polyunsaturated fatty acids, peptides, amino acids, plat extracts, probiotics, micronutrients, and herbal supplementation, is currently being studied in order to determine their usefulness in treating ADHD. However, further research is still needed in this area .A study performed in ADHD children under methylphenidate treatment for whom zinc supplementation was added reported no significant effect of zinc supplementation on the total score for a parent’s questionnaire for ADHD or in the hyperactivity and impulsivity subscales. However, zinc-supplemented children present improvements in inattention scores .A meta-analysis on non-pharmacological interventions for ADHD patients found that physical exercise produced a good effect on ADHD cognitive symptoms, especially aerobic exercise targeting executive functions .In the first sections of this review, we addressed some of the factors associated with ADHD incidence, ranging from a variety of environmental factors to the presence of different genetic polymorphisms. However, these different etiologies are not always present, since patients might present one or another see . SimilarSince the etiology of ADHD could be very different from patient to patient, the precise nature of the physiological changes underlying the clinical manifestations of ADHD in each case could be slightly different, affecting the effectiveness of the chosen treatment and possibly explaining the variation in the effect of the same treatment on different patients. This can be observed in the variations in qEEG activity observed in different studies ,116,121.Selecting the appropriate pharmacological treatment and the dose to be used takes some time, given the large inter-individual variability regarding treatment efficacy, leading to a delay in reaching a therapeutic effect, and in some cases producing an early termination of treatment due to frustration, either by the provider or the family . MoreoveTreatment resistance has been reported for both atomoxetine  and methMost of the reports on the use of NFB for ADHD use a standardized protocol, either equal for all participants or adapted to each patients after qEEG analysis. However, there is another more personalized approach known as qEEG-informed (or qEEG-guided) NFB. In this variant of NFB, rather than selecting a particular protocol  and applying it to all participants, subjects receive a NFB protocol selected for them after qEEG analysis. This type of NFB has been successfully used in schizophrenia , obsessiThere are so far only two studies applying qEEG-informed NFB in ADHD patients, so it is not yet possible to perform a meta-analysis on the effects of this type of NFB on ADHD. However, a positive effect of NFB has been reported in both published studies ,210. ADHD is an NDD with a complex etiology. While it is clear that its main cause is alterations in neurodevelopmental processes such as synaptogenesis, myelination, and neurogenesis , the cauThe purpose of this review is not to fully describe all factors associated with ADHD appearance, but rather to address some of the main etiologies described so far, in order to clarify the high diversity of factors associated with this NDD. When analyzing the different sections of this review, one thing becomes evident—that ADHD patients are diverse regarding the etiology of their condition and their responses to treatment. This heterogeneity outlines the high variability in patients’ particular conditions regarding ADHD symptom manifestation and treatment, since it is probable that the underlying neurophysiological alterations for each patient are at least slightly different. Thus, standardized treatment  may not be equally efficient in all cases. Moreover, there could be other factors that are usually disregarded in relation with ADHD incidence, but which might play an important role in this condition. Recently, the gut microbiome has been the subject of intense research as an ADHD-associated factor, and even though further research is needed in order to determine its precise influence on ADHD, there are already reports indicating a possible link between them ,213,214.In the end, all of these factors produce changes in brain structure and function ,114,115,Pharmacological treatments, both stimulants and non-stimulants have proven to be effective and safe for ADHD patients ,133, andThe search for other therapeutic options has led to the assessment of the effects of other drugs on ADHD , as wellThe effects of behavioral parent training on ADHD symptoms in children are not consistent, with some articles finding effects  and otheAttention training techniques are still under intense study. There is some evidence regarding the effect of this technique on ADHD in adults ,175, whiA number of studies on the effect of NFB on ADHD symptoms have yielded different results, either finding a positive effect ,192,193,In the present review, we have gone through some of the factors associated with ADHD, and it is clear that a great heterogeneity exists in the etiology of this condition. Therapeutic approaches, although functional in many cases, also show heterogeneity in their effects in certain groups of patients. The diverse range of effects of the therapeutic approaches used should not be a surprise, given the diversity of etiologies found in ADHD. Even though clinical manifestations of this condition might be similar (diagnosis is based on the presence certain symptoms), the same clinical manifestations could occur with different underlying physiological changes, considering the variations in qEEG activity in different groups of patients ,116,121.Regarding non-pharmacological options, the use of qEEG-informed NFB has been proposed for personalized treatment in ADHD patients. The studies carried out to date have shown positive results ,210, alt


Background: Attention deficit and hyperactivity disorder (ADHD) is one of the most common mental disorders in childhood. Recently, several studies showed the high suicide risk of patients with ADHD; however, most of these studies had a cross-sectional design.Aims: The aim of the current research is to complete a systematic review of published studies which investigate the suicide risk of ADHD patients with longitudinal design.Methods: The systematic search was made on OVID Medline, PsychInfo, PubMed, Scopus, and Web of Science. The search terms were (ADHD OR attention deficit hyperactivity disorder) AND  AND . The inclusion criteria were as follows: written in English; the participants were under 18 years at baseline; longitudinal, prospective studies; ADHD population at baseline and at follow-up; and suicide behavior as a primary outcome. The exclusion criteria were as follows: the study did not contain empirical data and reviews/meta-analyses and studies which aimed to investigate the drug treatment efficacy of ADHD.Results: After the screening process, 18 papers were included in the systematic review. Ten articles were altogether published in the last 5 years. The range of follow-up periods varied between 2 and 17 years. Several different assessment tools were used to investigate the symptoms and/or the diagnosis of ADHD and the suicidal risk. Nine studies enrolled children aged under 12 at baseline, and three studies used birth cohort data, where there was no strict age-based inclusion criteria. A total of 17 studies found a positive association between ADHD diagnosis at baseline and the presence of suicidal behavior and/or attempts at the follow-up visits.Limitations: The main limitation of this review is the methodological heterogeneity of the selected studies. A further limitation is the relatively low number of studies that examined a population with balanced gender ratios. Additionally, only one study published data about the treatment of ADHD. Finally, though we carefully chose the keywords, we still may be missing some relevant papers on this topic.Conclusions: In spite of the methodological diversity of the included studies, the results of the current systematic review highlight the importance of screening suicidality in the long term in patients with ADHD. Therefore, further studies that compare the suicidal risk of treated and untreated groups of ADHD patients in the long term are needed. Attention deficit and hyperactivity disorder (ADHD) is one of the most common child and adolescent psychiatric disorders, with a prevalence rate of 3.4% CI 95% 2.6–4.5) . The cor.6–4.5 . Suicide deaths are the second most common cause of death among females and third among males in the ages 15–29 years worldwide . RecentlAll these previous reviews and meta-analyses focusing on the topic of ADHD and suicidality mainly included studies with a cross-sectional design. A very recent systematic review and meta-analysis by Septier et al.  collecteThe main aim of the current study was to identify all previously published studies which investigated the connection between ADHD and suicide thought and behavior with a longitudinal design, where the baseline data were available from age under 18 and that assessed ADHD participants. Furthermore, our aim was to provide a systematic overview about these identified studies according to findings, methods, and design.The literature search was made on the 24th of March 2019 on the following scientific electronic databases: OVID Medline, OVID PsychInfo, PubMed, Scopus, and Web of Science. The following search terms were calculated using a Boolean operator : (ADHD OR attention deficit hyperactivity disorder) AND  AND . To organize the articles and to manage the filtration, we used EndNote X8 software. The inclusion criteria of the systematic search were the following: written in English; the participants were under 18 years at baseline; longitudinal, prospective studies; a group of ADHD population at baseline and at follow-up; and suicide thought and behavior as a primary outcome. The exclusion criteria were if the study did not contain empirical data and reviews/meta-analyses and studies which aimed to investigate the drug treatment efficacy of ADHD. Using the inclusion and the exclusion criteria, we screened the titles and the abstracts of the articles found with the search terms. After this initial screening, the relevant full texts of the papers that passed were read, and the ones that met the inclusion criteria were collected. The title, abstract, and full text of the eligible studies were measured by the first author, a process which was carefully reviewed and supervised by the second author, i.e., all included and excluded articles were double-checked according to the inclusion and the exclusion criteria. In case of disagreement, the paper was carefully read again by both authors. The final selection of the relevant studies was based on the agreement of the two authors. The reference lists of the retrieved papers were screened, and papers that possibly met the inclusion criteria were retrieved and studied as well. After the systematic search method, the current literature was screened continuously for eligible studies to include in the review. The reporting of this systematic descriptive review follows the PRISMA statements. Due to the clinical and methodological heterogeneity of the included studies, a narrative approach to data synthesis and presentation was undertaken. To assess the methodology quality of the selected cohort studies, we used the Newcastle–Ottawa Scale Cohort Studies supplement   was usedBarbaresi et al.  and YoshBiederman et al.  collecteGoldston et al.  applied Ljung et al.  identifiHurtig et al.  used a tIn the study by Forte et al., the teacher version of the Behavior Questionnaire (BQ) was used to evaluate ADHD symptoms. The BQ was developed with the incorporation of items from the Child Behavior Checklist (CBCL) , the OntGaléra et al.  used theThe assessment of suicidality focused on suicidal thoughts, suicidal attempts, or both. Two articles investigated suicidal thoughts , 33, sixOnly two studies investigated on suicide thoughts exclusively. Strandheim et al.  used onlMajority of the selected articles, which investigated only suicide attempts, obtained data from medical records , 28–30.Huang et al.  and Lan By contrast, Barbaresi et al.  used medIn another study, several Swedish nationwide registers were used in the research of Ljung et al. ; among tBeyond the medical record-based studies, Caye et al.  investigMiller et al.  did not Gordon and Hinshaw , GuendelChronis-Tuscano et al.  used theIn the study of Forte et al. , a two-sHurtig et al.  evaluateIn the study of Galera et al. , informaGoldston et al.  investigYoshimasu et al.  used theAlthough the number of follow-up visits varied in a wide range among the selected studies, the vast majority of the studies collected data after more than a 5-years follow-up period.Firstly, we present the articles which investigated the long-term risk of suicidal thoughts , 33, aftN = 448). After 17 years of follow-up, the gender-adjusted odds ratio was 1.3 (CI = 1.0–1.7). This odds ratio was lower compared to the anxiety/depressive, conduct problems, and insomnia subgroups.Strandheim et al.  followedp < 0.05).In an adolescent and young adults female sample, Biedermann et al.  investigN = 3 from 367) and the controls  .In a large birth cohort study, Barbaresi et al.  focused p = 0.003] and in young adults with ADHD than in young adults without ADHD . The data assessment did not show a correlation between the number of suicide attempts and parental distress (p = 0.13) or stress-inducing dysfunctional parent–child interactions (p = 0.11).Gordon and Hinshaw  focused 2  = 6.59, OR = 1.85, 95% CI = 1.14, 3.00; p = 0.01]. Additionally, this group showed a greater impairment in internalizing symptomatology (anxiety and depression), eating disorder symptomatology, and self-esteem. The analyses of covariance  revealed that the difference between maltreated and non-maltreated suicide attempts was significant .Guendelman et al.  investigF = 17.01; p < 0.001). In the pairwise comparisons, the partial (OR = 5.0) and the persistent (OR = 5.8) groups showed higher rates in suicide attempt than the comparisons. However, a relatively large odds ratio showed in partial vs. desisters (OR = 9.0) and persisters vs. desisters (OR = 10.6); there was no significant difference because of the small sample size.Owens et al.  performeb = 0.28, standard error = 13, t(195) = 4.12, p < 0.001, R2 = 0.08] and in the 5-years follow-up. The authors reported the internalizing symptoms as a partial mediator between baseline ADHD status and future suicide attempts .Swanson et al.  assessedn = 53/104 vs. n = 40/169), with 6.1 OR (95% CI 2.34–16.0). On the other hand, the number of suicidal acts was low in both groups, without a significant difference .In another longitudinal study, Hurtig et al.  investigp < 0.001, OR = 2.42; 95% CI = 1.51–3.86).Finally, Yoshimasu et al.  followedRegarding gender differences, we overviewed the included studies which investigated a mixed-gender population.The objective of the study by Forte et al.  focused By contrast to these findings, in the study of Strandheim et al. , the oddp = 0.17) in the case of a concrete suicide plan, but the girls showed a greater risk  for suicide attempt than the boys in the same group at 1-year follow-up period in a Cox modeling method. It was notable that the participants were only 5–7 years old at the first year of follow-up.Chronis-Tuscano et al.  reportedp = 0.02) in a lifetime period than HI-s girls. Neither in male nor in female groups was there a higher risk of suicide ideation in the lifetime and the 12-months period. It was noted that the authors measured just the presence of hyperactivity symptoms; the participants had no established ADHD diagnosis.In the study of Galéra et al. , the HI-2 = 1,271.0; p < 0.001)].Following was a register-based study of Ljung et al. , where fIn our review, we found that four of the selected studies included measures of comorbidities in the data analysis.n = 80) vs. 21% (n = 23)]. The ADHD group showed more than double the risk  for lifetime MD than the control group after adjustment for comorbid conditions. Following a symptom-level analysis, the ADHD group had a higher rate of suicidal ideation . For a broader view, MD combined with ADHD showed a greater duration of MD, with more severe MD-related impairment than in controls with MD only.Biedermann et al.  investigp = 0.005) than the group with bipolar disorder. Based on the Kaplan–Meier survival analysis, the risk of suicide attempts is greater (p = 0.002) in the group of patients with ADHD and bipolar disorder than in patients with bipolar disorder only.In the study by Lan et al. , data shp < 0.001, OR = 2.58, 95% CI = 1.54–4.31). Based on the data, the three most prominent comorbid disorders that have a direct effect as a percent change of the total effect were as follows: MDD (25.7%), hypomanic episode (18.3%), and dysthymia (18.1%). They also calculated an expected joint effect to evaluate the synergic (OR exceed the expected OR) or independent effect of ADHD and other psychiatric comorbidities. The data showed a significant synergic effect between generalized anxiety disorder , hypomanic episode , and substance-related disorder .The effect of the psychiatric comorbidities in relation to childhood ADHD diagnosis and suicide thought and behavior was the objective of the study of Yoshimasu et al. . In obsep = 0.003] and in young adults with ADHD than in young adults without ADHD . These differences remained significant after excluding the comorbidities from young adults with and without ADHD .Finally, Caye et al., in their birth cohort study, reported a higher rate of comorbidities in young adulthood in those participants who had an ADHD diagnosis in childhood. A significantly higher number of self-reported suicide attempts was found in children with ADHD than those without [35 (10%) vs. 213 (6%), To our knowledge, this is the first systematic review on the topic of ADHD and suicidality including studies with follow-up design exclusively. By this method, our objective was to summarize the current literature findings to provide an additional perspective and a better understanding of the long-term cause–effect relationship between ADHD and suicidality.In spite of the methodological heterogeneity of the included studies, which limits conclusions about the suicide risk of ADHD patients, there have clearly been major advances in the available studies with follow-up design. Based on these studies, there is now strong evidence that there is a positive association between the presence of ADHD diagnosis at baseline and having suicidal thoughts and/or attempts at follow-up visits.In our systematic review, we could identify 18 studies with follow-up design which investigated the suicidal risk of ADHD patients , 20–36. For suicide measuring instruments, only half of the studies investigated both suicide thoughts and attempts , 34, 35.Regarding our descriptive findings, the majority of the studies 10/18) are from North America; however, four of them collected data from the same population sample. The selected studies investigated only 10 separate populations. The data were derived from clinical samples , 32, 34,/18 are fThe majority of the studies (12/18) assessed population from both sexes , 35, 36;Although ADHD is more prevalent among boys than girls, none of the selected studies investigated a male population only; however, one-third (6 of 18) of the studies followed up female participants only , 32, 34.Although the age of the study populations at baseline was mostly (10/18) under 12 years, the included studies covered a wide age range at the final follow-up visits.Although the higher retention rate in child or adolescent longitudinal studies challenges the long-term design and an eligible sample size, except for one study , the folIn the case of measurement of suicidality, the most assessed domain was suicide attempt. Altogether 14 of the selected 18 articles assessed suicide attempts, of which 13 of them reported a significant association with baseline ADHD symptoms. Despite the fact that, among these studies, 12 used available data from detailed statistical probes, our results highlighted the growing evidence of the elevated risk of ADHD for later suicide attempt.Regarding suicidal thoughts and plans, six studies published data, of which five reported a significant risk context of the baseline ADHD symptoms. Childhood ADHD diagnosis is deemed to be a significant risk factor for future suicide deaths; however, only a few , 30 longThese results are consistent with the recently published systematic reviews and meta-analyses, which mainly focused on a wide range of population of adults, adolescents, and children with ADHD and a cross-sectional design, and found a positive correlation between ADHD and suicidality , 17.The selected studies showed a significant range in terms of the heterogeneity of different methodologies. However, the majority of the studies used standardized ADHD diagnostic tools or medical data , 34–36; A selective review by Giupponi et al.  suggesteAmong the risk factors of suicidality, in this review, we focused on psychiatric comorbidities in two ways: We evaluated the risk for developing comorbid disorders in ADHD population. Two studies , 35 repoHowever, there are no clear data on the role of comorbidities in suicide in ADHD population. James et al.  estimateAmong the selected articles of the current review, two studies investigated the effect of comorbid conditions in suicidal thought and behavior in an ADHD population. Yoshimasu et al.  evaluateA further important topic among the objectives of this review was to investigate the risk of suicide in patents with symptoms of ADHD in the context of sex differences. Previously, Nigg et al.  reportedFocusing on the persistence of ADHD, two studies were included in our review , 34; howIn the case of ADHD subtypes, Chronis-Tuscano et al.  found a These limited findings raise the possibility that children with ADHD may form an inhomogeneous group as a possible suicide risk factor. Our findings suggest that ADHD comorbidities, especially MD, combined type of ADHD, and persistence of the symptoms play a significant role in future suicide thought and behavior.Long-term data about the effect of ADHD treatment on suicidality in childhood or adolescence are limited. Only one study  examinedBased on our review, we have the following methodological suggestions for future studies:  monitoriAmong the selected studies, only one published data about the treatment of ADHD highlighted the importance of ADHD treatment which could even decrease the symptoms of depression and the number of harmful outcomes , includiFurther limitations are derived from the method of the study selection. Firstly, among the search terms that we used, the ADHD terms to find the relevant articles with participants who met the ADHD diagnosis did not minimize the symptoms-only related articles. Secondly, we performed the database search with terms of suicidal behavior. We did not add the terms “self-harm” or “self-injury” to focus on suicidal topics and minimize the articles that investigated non-suicidal self-harm or self-injury. These limitations are the cause that we may be missing some relevant studies on this topic.In conclusion, our results, based on follow-up studies, underline the growing evidence of higher later suicidal risk of children and adolescents with ADHD. In the future, there is an additional need to clarify the role of treatment, comorbidities, subtypes, and persistence of ADHD in suicide thought and behavior. We would like to highlight the importance of the early diagnosis and treatment of ADHD, and during treatment, we need to pay special attention to comorbid conditions, especially anxiety and depression symptoms in boys.All datasets generated for this study are included in the article/supplementary material.PG: article selection process, presentation of the results, and discussion. JB: supervising the selection process and the presentation of the results and discussion. All authors contributed to the article and approved the submitted version.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.


Although behavioral studies have repeatedly demonstrated that individuals with attention-deficit/hyperactivity disorder (ADHD) have deficits in alertness, little is known about its underlying neural basis. It is hypothesized that pupil diameter reflects the firing of norepinephrine (NE) neurons in the locus coeruleus (LC), and that the LC-NE neuromodulatory system for regulating alertness may be dysfunctional in ADHD. To clinically and non-invasively examine this hypothesis, we monitored the kinetics of pupil diameter in response to stimuli and compared them between adults with ADHD (n = 17) and typically developing (TD) adults (n = 23) during an auditory continuous performance task. Individuals in the ADHD group exhibited a significantly larger tonic pupil diameter, and a suppressed stimulus-evoked phasic pupil dilation, compared to those in the TD group. These findings provide support for the idea that the aberrant regulatory control of pupil diameter in adults with ADHD may be consistent with a compromised state of alertness resulting from a hyperactivated LC-NE system. Attention-deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and hyperactivity . While iAlertness is one of the specific types of attentional functions compromised in ADHD . AttenuaBased on this concept, excessive exploratory-mode activity may result in disturbed alertness due to the implicit capture of too much irrelevant information. Thus, the attenuated alertness in ADHD could be attributed to relatively higher LC activity at the baseline than occurs in typically developing (TD) controls. To verify this hypothesis, pupillometry can be utilized as an indirect but non-invasive approach, because pupil diameter reflects LC firing on time –17. SomePupillometry has already been employed for some studies of children and adolescents with ADHD and revealed a decreased phasic pupil dilation after stimulus onset during working memory tasks including a N-back task –23. ThesFig 1A) in which the performance of adults with ADHD was found to be worse than that of TD [The present study aims to address this deficit by monitoring pupil diameter during an auditory continuous performance test , as Fig 1B shows , the ADHD group exhibited increased tonic pupil diameter compared to the TD group both in the aCPT (mean 3.39 mm (TD), 3.84 mm (ADHD)) and the passive-viewing task (mean 3.63 mm (TD), 4.16 mm (ADHD)). To test for group differences in tonic pupil diameter, we conducted a repeated-measures analysis of covariance (ANCOVA) with group as a between-participants factor, task as a within-participants factor, and age as a covariate. We used age as a covariate because tonic pupil diameter is thought to become smaller with increasing age [p = .08) in the present study  = 8.1, p < .01) and task  = 7.3, p < .01), but no interaction between factors  = 0.17, p = .68).First, we examined if there were differences in tonic pupil diameter and phasic pupil dilation during the task between the two groups. Tonic pupil diameter indicates prestimulus baseline pupil diameter. On the other hand, phasic pupil dilation indicates a difference between a peak pupil diameter after stimulus onset and prestimulus baseline pupil diameter. sing age , and becnt study 1. The anFig 2B). A mixed-model analysis of variance (ANOVA) with the factors group and stimulus (target vs. nontarget) demonstrated that there was no main effect of group  = 3.7, p = .06), but a significant main effect of stimulus  = 146.0, p < .001). Furthermore, there was a significant interaction between group and stimulus  = 9.6, p < .005). When the responses were subgrouped according to target vs. nontarget trials, only responses to target trials were significantly different  = 6.3, p < .05; nontarget, F = 0.5, p = .48). Thus, target tones evoked a greater phasic pupil dilation than nontarget tones as previously reported [Both the TD and ADHD groups had transient dilatory responses in pupil diameter after stimulus onset. We compared the phasic pupil dilation in response to the stimulus tones between groups , 0.12 mm , 0.20 mm , 0.11 mm ) .We also examined the possibility that the ADHD group had reduced phasic pupil dilation simply due to any limitations in pupillary responses caused by elevated tonic pupil diameter. We examined whether there was a linear relationship between phasic pupil dilation and tonic pupil size using regression analysis. We found that tonic pupil diameter had no significant predictive power for phasic pupil dilation  and phase . As shown in Fig 3, although detection accuracy was lower in the ADHD group compared to the TD group in the practice trials (hit rate: .91(TD), .72(ADHD); false alarm rate : .08(TD), .19(ADHD),), it reached a ceiling in the test trials (hit rate: .98(TD), .96(ADHD); false alarm rate: .01(TD), .01(ADHD)). To test for group differences in the hit rate, we used a mixed-model ANOVA with the factors group and phase (practice vs. test). This demonstrated that there were main effects of group  = 9.23, p < .01) and phase  = 17.19, p < .001) with a two-way interaction between these factors  = 5.97, p < .05)). Follow-up ANOVAs revealed that the ADHD group had a significantly lower hit rate compared to the TD group in the practice phase  = 7.91, p < .05) but not in the test phase  = 1.0, p = .32). The same analysis for the false alarm rate showed no main effect of group  = 2.52, p = .12), but a significant main effect of phase  = 15.70, p < .001) and no significant two-way interaction between these factors  = 2.44, p = .13). The RT and RT variability data were also analyzed by using mixed-model ANOVAs with the factors group and phase. Results showed neither main effects of group  = 0.83, p = .38, σRT: F = 0.09, p = .77), or phase  = 1.22, p = .28, σRT: F = 0.01, p = .93) and that there was no two-way interaction between these factors  = 0.81, p = .38, σRT: F = 0.05, p = .83). Both groups had comparable RTs (practice: 1073.2(TD), 1063.6(ADHD), test: 1068.7 ms (TD), 1026.4 ms (ADHD)) and RT variability (practice: 196.9(TD), 198.9(ADHD), test: 192.6 (TD), 209.1 (ADHD)).Next, we evaluated behavioral variables . The behavioral variables represent the speed and accuracy of the button press (the participant’s response). Fig 4 shows, phasic pupil dilation was positively correlated with the hit rate in every group, regardless of whether the trials were target or nontarget , ρ = .46, p < .05 (ADHD)); nontarget trials: r = .71, p < .0001(TD), r = .45, p < .05 (ADHD).We also evaluated the relationships between pupillary and behavioral variables by using Spearman’s rank order test. As Fig 2B), when compared to those in the TD group. Second, the ADHD group exhibited a significantly increased tonic pupil diameter . To our knowledge, this is the first demonstration of the relationship between tonic and phasic pupil regulation in adult ADHD. These data suggest that in adults, ADHD presents as a relatively hyperarousal state in combination with compromised phasic responses to target stimuli. In addition, the ADHD group consistently showed higher tonic pupil diameter in both the passive viewing task and the aCPT. These differences in pupillary response in adult ADHD are consistent with a compromised alerting condition and hyperactive LC-NE system that would be in line with the adaptive gain theory [Fig 2B). In accordance with basic findings in pupillometry [This study aimed to clarify atypical pupillary responses during an aCPT in adults with ADHD. Children and adolescents with ADHD have been previously reported to exhibit decreased phasic pupil dilation after stimulus onset –23. Thisn theory . On the llometry , we showllometry , 27. TheFig 4). Some earlier studies have shown that attenuated phasic pupil diameter is associated with worse performance in working memory tasks in children and adolescents with ADHD [We also found associations between pupillary and behavioral variables; there was a positive correlation between the magnitude of phasic pupil dilation and the hit rate (ith ADHD –23. Takeith ADHD ). There Fig 3C). Although a meta-analysis of CPT-related studies found small or moderate effect sizes for performance over time [The results of this study should be considered in light of several study limitations. First, despite our expectation based on the adaptive gain theory that higher NE tone in ADHD should be correlated to lower performance, the ADHD group performed worse in the practice period but not in the test period , these factors can confound between-participant baseline measures. Further research is necessary to establish a reliable method for between-participant comparisons based on pupillary responses.Second, pupil diameter can be regulated not only by LC-NE, but also by the cholinergic system , but thewww.accessdata.fda.gov), and there are some previous studies that employed similar paradigms [Fourth, in this study we defined one-day medicine-free as being almost equal to drug-naïve. Although the average half-lives of methylphenidate and atomoxetine are 3.5 and 5 hrs, respectively  might be associated with atypical attentional functions . For exaIn conclusion, adults with ADHD demonstrated elevated tonic and attenuated phasic pupil dilations during an aCPT compared to TD adults. These observations may reflect dysfunction of the LC-NE system in adult ADHD, as well as the theoretically exploratory-biased alert system representative of ADHD. Future research will be necessary to clarify the underlying mechanisms of the atypical pupillary responses in individuals with ADHD.All of the experiments reported here were conducted in accordance with the ethical standards stipulated in the 1964 Declaration of Helsinki and approved by the Research Ethics Committee of Showa University. The participants consisted of 23 TD adults  and 17 adults with ADHD . p = .38), VIQ (p = .50), and PIQ (p = .19). As a screening tool, we used the Japanese version of the adult attention-deficit hyperactivity disorder (ADHD) Self-Report Scale (ASRS-J) [The participants in the TD group were selected to closely match the ADHD group in terms of their demographic features as noted above. There were no significant differences between the ADHD and TD groups in terms of age , FIQ ((ASRS-J) . The dia(ASRS-J) ) by authThe exclusion criteria for all participants were having a current major depressive or manic-depressive episode, a history of psychosis, FIQ < 80, a history of head injury with loss of consciousness, sensory-motor handicap, and neurological illness. No TD adult displayed clinically significant levels of ADHD symptomatology, as indexed by the ASRS-J. All participants had normal or corrected normal vision and normal hearing and provided written and informed consent before inclusion in the study. Participants were restricted from using caffeine and/or nicotine on the experimental day, as well as any medication that could affect eye movements . They wehttp://www.mathworks.com/) and presented on a 23-inch LCD monitor (1920×1080 pixels at 60 Hz) driven by a PC (Windows 7).The participants sat in a lit room facing a monitor screen, subtending 50.9 × 28.6 degrees of visual angle at 57 cm distance. A chin-rest was used to stabilize the participants' head position. Each task was preceded by a calibration procedure for which the participants were required to saccade to nine red dots that were presented sequentially in a square array. Stimuli were generated with the Psychophysics Toolbox routines , 47 for During the whole experiment including the practice and test phases of the aCPT, the participant’s eye position and pupil diameter were monitored with a remote type eye tracker  with a sampling rate of 300 Hz. This device enabled us to measure the pupil diameter of the participants over time, based on the distance between the eyes and the sensor.2) subtending 0.5×0.5 degrees of visual angle. This was done to obtain baseline information before engaging the task.Before the auditory CPT task, the participants were instructed to maintain a steady fixation for 2 minutes on a black cross  at the center of a gray background (25.65cd/m2). The area subtended 10 × 10 degrees of visual angle.The present study employed an acoustic consecutive performance test (aCPT ) that isEach participant ran three blocks. Each block consisted of 100 trials and lasted about 8.5 minutes. Before starting the test blocks, the participants ran a practice block  in which the target and nontarget tones were presented equally to familiarize the stimulus tones to the participants. Then either of the tones was presented for 250 ms followed by a random interstimulus interval (ISI) ranging from 3 to 5 seconds. After each block (8.5 min) a short break was given. It took about 40 min to complete the whole task.MATLAB was used to process and analyze pupil data. As pupil diameter data contained missing values as well as noise  induced by eye blinks, we first looked for missing data and eliminated irregular samples surrounding the gaps. Next, we estimated putative correct pupil diameter using linear interpolation . Data frTo estimate pupillary responses in the aCPT, we averaged pupillary fluctuations that were time-locked to the stimulus onset, separately per participant. To estimate tonic pupil diameter, we calculated an average pupil diameter in the period from -1 to 0 s before the stimulus presentation. Phasic pupil diameter was defined as a difference between pupil diameter maxima in a time window between after stimulus onset and 4 s after stimulus  onset and tonic pupil diameter. We calculated phasic pupil dilation by subtracting the averaged tonic pupil diameter from the pupil diameter maxima after stimulus onset.S1 File(XLSX)Click here for additional data file.S2 File(XLSX)Click here for additional data file.


Low birth weight (LBW) is an important general health indicator. The present study was conducted to evaluate the prevalence and risk factors of LBW in Iran.This meta-analysis was reported based on the PRISMA guidelines. All stages were independently performed by two authors. This review is registered with PROSPERO (CRD42020163446). We searched epidemiological studies at international databases of Scopus, Embase, Science Direct, PubMed/Medline, CINAHL, EBSCO, Cochrane Library, Web of Science, and Google Scholar search engine, as well as Iranian databases of SID, IranDoc, Iranian National Library, Barakat Knowledge Network System, RICST and Magiran using MeSH keywords without time limit until 2019. After selecting the studies, applying the inclusion and exclusion criteria, data extraction and qualitative assessment, the data were analyzed based on random effects model using Comprehensive Meta-Analysis Software version 2. P < 0.05 was considered significant.The prevalence of LBW in Iran was 7.95%  in 62 studies with a sample size of 301,839 newborns. The prevalence of LBW in girls and boys was 8.41% (95%CI: 7.47–9.45) and 6.67% (95%CI: 5.86–7.59), respectively. The girls-to-boys odds ratio of LBW was 1.25  very LBW and extremely LBW prevalence was estimated to be 0.61% (95%CI: 0.40–0.93) and 0.29% (95% CI: 0.18–0.45), respectively. The risk factors for LBW were age of >35 versus [vs.] ≤35 (P = 0.024), age of <18 vs. ≥18 (P < 0.001), education of middle school and lower vs. high school and higher (P < 0.001), weight under 50 kg (P = 0.001), employed vs. housekeeper (P < 0.001), inadequate prenatal care (P = 0.046), interval with previous pregnancy <2 vs. >2 (P < 0.001), prematurity (P < 0.001), history of LBW (P < 0.001), multiple birth (P < 0.001), abortion (P < 0.001), vaginal bleeding (P < 0.001), hypertension (P = 0.001) and preeclampsia (P < 0.001).The results of this meta-analysis showed that LBW is prevalent in Iran. This study can be a national database for LBW that would be of interest to Iranian health policy-makers and planners. Public health; Pediatrics; Prevalence; Iran; Risk factors; Low birth weight; Meta-analysis. It is eLBW is one of the main causes of neonatal mortality, accounting for about 40% of all mortality among children under five years of age, and the mortality rate in LBW infants is approximately twenty times higher than heavier infants , 4. The LBW imposes an economic burden on the health care system, which is equal to one-third of the world's medical expenses . In addiSeveral studies have been conducted in Iran on LBW , 23, 24.22.1https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020163446.This meta-analysis was reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses . The stu2.2http://www.sid.ir/), Iranian Research Institute for Information Science and Technology (IranDoc) (https://irandoc.ac.ir), Iranian National Library (http://www.nlai.ir/), Barakat Knowledge Network System , and Regional Information Center for Science and Technology (RICST) (http://en.ricest.ac.ir/), and Magiran (http://www.magiran.com/) using MeSH and non MeSH keywords including “prevalence”, “Incidence”, “epidemiology”, “frequency”, “newborn”, “Infant”, “neonate”, “underweight”, “abnormal birth weight”, “birth outcome”, “low birth weight”, “preterm birth” and “Iran” without time limit until 2019. To perform a combined search, the "AND" and "OR" functions were used. An example of the PubMed search strategy were  AND  AND (Iran). The manual search was also done using the list of references in the selected or review articles.We searched epidemiological studies at nine international databases of Scopus, Embase, Science Direct, PubMed/Medline, CINAHL, EBSCO, Cochrane Library, Web of Science, and Google Scholar search engine, as well as six Iranian databases of Scientific Information Database (SID)  that examined the prevalence and risk factors of LBW; 2) Intervention: Weight less than 2500 g to confirm LBW and subcategories include very low birth weight (VLBW), which is less than 1500 g, and extremely low birth weight (ELBW), which is less than 1000 g; 3) Comparison: Evaluation of the demographic, medical diseases, obstetrics and gynecology variable in infants with LBW and without LBW for risk factors; 4) Outcome: Estimating the prevalence and risk factors of LBW.The inclusion criteria according to PICO (based on Evidence Based Medicine)  were: 1)The exclusion criteria were: 1) Non-Iranian studies; 2) Studies with non-random sample size to estimate the prevalence of LBW; 3) Non-related studies; 4) Duplicate studies; 5) Case reports, Case series, Letter to Editor, Editorial, Commentary and review; and 6) Low quality studies.2.5LBW defined by the WHO as weight at birth less than 2500 g. Subcategories include VLBW, which is less than 1500 g, and ELBW, which is less than 1000 g , 6–11 month aOR: 1.23 , moderate preterm birth , low birthweight , stillbirth  . A revieIn the present study, the relationship between caesarean section and LBW was not significant. Some studies show that LBW is higher in women with CS delivery. However, this conclusion is controversial, while in other studies, the risk of LBW was not reported to be higher in CS delivery .The medical risk factors in the present study were LBW, hypertension and preeclampsia. The association between LBW and preeclampsia has been confirmed in other countries , 132. OtThe strengths of this study: 1. We used a comprehensive search strategy to maximize the identification of all relevant literature, 2. Following the PRISMA protocol, we were able to provide the largest data on LBW in Iran to date, 3. We contacted the first author or the corresponding author to eliminate the ambiguity of the articles, 4. We used random effects model to integrate the data to provide a conservative estimate of the prevalence of LBW, and subgroup analysis and meta-regression model were performed to detect the cause of heterogeneity and to evaluate the publication bias. Limitations of the present study: 1. Search in national databases was limited due to limitations in combined search in these databases, 2. Studies on specific infants such as preterm infants, etc. or non-random sample sizes were excluded and the resulting estimate may be attributable to the general public, 3. In addition, there was a high heterogeneity between studies in the meta-analysis, and based on available data, we could attribute this difference to the provinces under study (P < 0.001), but there appears to be other causes, including differences in lifestyle, dietary habits, ethnicity (given that Iran has different ethnicities with different customs ) may als5The results of this meta-analysis showed that LBW is prevalent in Iran. Effective risk factors in LBW in Iranian population include low and high maternal age, low level of education, low maternal weight, maternal occupation, inadequate prenatal care, short interval with previous pregnancy, prematurity, LBW history, multiple sclerosis, abortion, vaginal bleeding, hypertension and preeclampsia, while many of these risk factors are manageable. Therefore, controlling these factors before and during pregnancy by health policymakers may lead to the birth of healthy infants and reduce the incidence of LBW.All authors listed have significantly contributed to the development and the writing of this article.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.The authors declare no conflict of interest.No additional information is available for this paper