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O.k. Here is part of the results from the DNR Neurosciences division findings this is for the Behavioral Scientist with their degrees and not keeping up to date on present Neurological studies as well as the real ability to screen for ADD/ADHD using MRI and other brain scans. This renders observation of behavioral traits as pre-diagnosis of possible underlying neurological reasons for subject’s behavioral adaptation or lack thereof due to the premature administration of psychoactive drugs to treat a preconceived aliment that has zero physical cause to medicate. This creates an artificial dependency and pseudo-ADHD/ADD which then develops into a mental condition that has no physiological cause to pursue and perpetuate the drug abuse cycle that creates secondary sociological issues which develop into psychological issues such as victim syndrome which is exploited by the behavioral scientist in the United States at an alarming rate.The neurobiological basis of ADHDAbstractAttention-Deficit/Hyperactivity Disorder is not a single pathophysiological entity and appears to have a complex etiology. There are multiple genetic and environmental risk factors with small individual effect that act in concert to create a spectrum of neurobiological liability. Structural imaging studies show that brains of children with Attention-Deficit/Hyperactivity Disorder are significantly smaller than unaffected controls. The prefrontal cortex, basal ganglia and cerebellum are differentially affected and evidence indicating reduced connectivity in white matter tracts in key brain areas is emerging. Genetic, pharmacological, imaging, and animal models highlight the important role of dopamine dysregulation in the neurobiology of Attention-Deficit/Hyperactivity Disorder. To date, stimulants are the most effective psychopharmacological treatments available for Attention-Deficit/Hyperactivity Disorder. Currently only immediate release methylphenidate and atomoxetine are approved for the treatment of ADHD in Italy. Drug treatment should always be part of a comprehensive plan that includes psychosocial, behavioural and educational advice and interventions.Go to:IntroductionAttention-Deficit/Hyperactivity Disorder (ADHD) is a common, long-lasting, treatable childhood psychiatric disorder, characterized by a pattern of developmentally inappropriate inattention, motor restlessness, and impulsivity that affects approximately 3-7% of school-aged children [1].ADHD was first recognized 100 years ago as a childhood disorder found mainly in boys, and was initially described as "hyperactivity" or "hyperkinetic disorder of childhood". This abnormal behavior was found to be the result of a biological condition rather than a result of poor parenting [2]. In the 1960's and 70's much of the focus on what is now called ADHD was on hyperactivity. The presence of excessive movements in children was proposed to result from bilateral cortical activity secondary to a lack of transcallosal fiber tract-mediated interhemispheric inhibition [3]. Attention Deficit Disorder with or without Hyperactivity first featured in DSM-III in 1980 [4], and the more recent DSM-IV-TR provided updated ADHD criteria [5]. For a diagnosis of ADHD, symptoms need to occur often, have persisted for the past six months, and be maladaptive and incongruent with the individual's developmental level. Additionally, an ADHD diagnosis is only given if at least some of the behavioral symptoms were present before the age of 7 years, occur in more than one setting, and cause significant impairment in social and school functioning.The renaming of the disorder, the subsequent focus on attention, and the clarification of three subtypes led to a range of neurocognitive and neurobiological hypotheses regarding the etiology and pathophysiology of ADHD within a more specific brain localization. Furthermore, neurocognitive models of ADHD have become more refined, and one particular executive process, inhibition, is now considered to be a core deficit [6].Current theories emphasise the central role of attentional and executive dysfunctions in children [7,8], as well as affective components involving emotional control and motivational processes [9]. A growing body of evidence supports a model in which multiple genetic and environmental factors interact during early development to create a neurobiological susceptibility to the disorder; the expression of which is mediated by alterations within different and diverse neural networks and deficits in the neuropsychological functions that these subserve [10]. Individuals with ADHD present difficulties in several domains of attentional and cognitive functions: problem solving, planning, orienting, alerting, cognitive flexibility, sustained attention, response inhibition, and working memory [7,11]. Other domains involving affective components, such as motivation and delay aversion, are also affected [8,9]. Motor difficulties, such as problems with sensory motor coordination, including poor handwriting, clumsiness, and marked delays in achieving motor milestones [12], have also been reported and the prevalence of motor impairment in the ADHD population has been estimated to be approximately 50% [13]. Motor problems might be partially related to abnormalities in structure and/or function of the cerebellum and basal ganglia found in ADHD [14].Recently, neuroimaging has led to several important advances in the understanding of the neurobiology underlying the clinical picture of ADHD and demonstrates a clear brain basis to the disorder in regions involved in attention, and executive and inhibitory control [15,16]. Furthermore, transcranial magnetic stimulation (TMS) has provided evidence that intracortical inhibition, as indexed by the immature ipsilateral motor cortex, normalizes with psychostimulant treatment [17]. There is an exciting confluence between emerging studies in basic neurobiology and the genetic, neuroimaging, and neuropsychological analyses of ADHD. Knowledge of neurobiology can offer child neurologists, psychiatrists and other healthcare professionals a valuable framework for the interpretation of clinical findings of children meeting the criteria for the diagnosis of ADHD. In this article, we provide a brief overview of the salient neurological basis of the disorder.EtiologyADHD is not a single pathophysiological entity and appears to have a complex etiology. Multiple genetic and environmental factors act together to create a spectrum of neurobiological liability.The genetic basis for ADHDGenetic factors are implicated in ADHD, but the mechanism of action is not completely understood. Twin, family and adoption studies of ADHD have supported a strong genetic contribution to the disorder, with heritability ranging from 60-90% [18,19].Genes regulating neurotransmitter systems have been implicated in ADHD. Candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder, with meta-analyses supportive of a role of the genes coding for DRD4, DRD5, SLC6A3, SNAP-25, and HTR1B [20]. Genome scan studies on potential alleles for ADHD have demonstrated linkage on chromosomes 5p13, 6q12, 16p13, 17p11 and 11q22-25 [21,22]. However, genome-wide association studies have failed to report any associations that are significant after correction for multiple testing [23]. Therefore, a plausible genetic hypothesis for ADHD is a mixture of dominant and recessive major genes that act with complex polygenic transmission patterns [18]. An increased rate of large, rare, chromosomal deletions and duplications known as copy number variants have been reported in individuals with ADHD [24]. However, genetic testing in an individual child is not currently practical in normal clinical practice.Sometimes ADHD-like symptoms are exhibited by patients with established neurogenetic disorders such as Tuberous Sclerosis Complex, Neurofibromatosis I, Turner Syndrome, Williams Syndrome, Velocardiofacial syndrome, Prader-Willy syndrome, and Fragile × Syndrome. Although each syndrome may arise from different genetic abnormalities with multiple molecular functions, the effects of these abnormalities may give rise to common effects downstream in the biological pathways or neural circuits, resulting in the presentation of ADHD symptoms [25].The environmental basis of ADHDPre-, peri- and postnatal environmental factors play an important role in the pathogenesis of ADHD. Prenatal factors are associated with maternal lifestyle during pregnancy. For example, prenatal alcohol exposure is known to induce brain structural anomalies, especially in the cerebellum [26]. Children exposed prenatally to alcohol can become hyperactive, disruptive, impulsive, and are at an increased risk of a range of psychiatric disorders [27,28]. Maternal smoking produces a 2.7-fold increased risk for ADHD [29], and a dose-response relationship between maternal smoking during pregnancy and hyperactivity has been reported [30]. This may be due to an effect on nicotinic receptors, which modulate dopaminergic activity. Dopaminergic disruption is believed to be involved in the pathophysiology of ADHD [31,32].Peri-natal factors have also been implicated, with a two-fold increase in ADHD in very-low-birthweight children and an increased rate of pregnancy and birth complications in mothers of children later diagnosed with ADHD [33].Among postnatal factors, a role for malnutrition and dietary deficiency in ADHD has been proposed. An imbalance of essential fatty acid (omega-3 and omega-6) intake has been suggested to be potentially involved in the development of ADHD [34], although further evidence is required to establish a role. Iron deficiency has been implicated in some cases [35]. Early deprivation of social environment during the postnatal period may also have significant effects.Gene-environment interactionsMore complex models of the etiology of ADHD incorporating gene-environment interplay need to be considered. Recent studies have focused on the joint effects of gene variants (of DRD4 and DAT1) and prenatal substance exposures on subtypes of ADHD children, demonstrating that smoking during pregnancy is associated with the combined ADHD type in genetically susceptible children [36]. A significant interaction between DAT1 genotype and prenatal smoke exposure was found in males. Men homozygous for the DAT1 10-repeat allele had higher hyperactivity-impulsivity than males from all other groups [37]. Despite the heterogeneity of the etiology and pathophysiology of ADHD, abnormal DAT density seems to be common among subjects with ADHD [38].NeuroimagingGrowing evidence points to the involvement of the frontostriatal network as a likely contributor to the pathophysiology of ADHD. This network involves the lateral prefrontal cortex, the dorsal anterior cingulate cortex, and the caudate nucleus and putamen. In ADHD patients, reductions in volume have been observed in total cerebral volume, the prefrontal cortex, the basal ganglia (striatum), the dorsal anterior cingulate cortex, the corpus callosum and the cerebellum [39]. A developmental trajectories study in ADHD patients showed a delay in cortical maturation and demonstrated that different clinical outcomes may be associated with different developmental trajectories in adolescence and beyond [40]. In studies of cortical development in children with ADHD, a marked delay in brain maturation was seen; the grey matter peaks were about 3 years later than in healthy controls [41]. The delay was most prominent in prefrontal regions important in the control of cognitive processes including attention and motor planning [41,42]. Compensatory networks including basal ganglia, insula and cerebellum have been implicated for relative lower cognitive load tasks in ADHD patients [43].Neuroimaging studies have also reported reduced white matter (WM) volumes [43], midsagittal corpus callosum (CC) areas [44], and cortical thickness [43] in ADHD patients compared with controls. One of the most replicated alterations is a significantly smaller CC, but there are conflicting reports regarding the affected callosal segments [45]. Recent magnetic resonance imaging (MRI) structural investigations have shown that WM alterations are present in children, adolescents, and adults with ADHD [46]. In 15 young males with ADHD, Silk et al. (2008) found WM abnormalities in several distinct regions underlying the inferior parietal, occipito-parietal, inferior frontal, and inferior temporal cortex [47]. Tractography methods showed that these regions form part of WM pathways connecting prefrontal and parieto-occipital areas with the striatum and the cerebellum. The authors also demonstrated anomalous WM development in ADHD in distinct cortical regions that they had previously shown to be dysfunctional or hypoactive in a functional MRI study of subjects with ADHD [47].Diffusion tensor imaging (DTI) is an MRI modality that provides information about the direction and integrity of neural fibre tracks in the brain in vivo. DTI studies have revealed developmental changes in cortical WM pathways in prefrontal regions and in pathways surrounding the basal ganglia and cerebellum in patients with ADHD, which presumably reflect decreasing myelination of axons. It is believed that these changes cause a decrease in the speed of neuronal communication [48]. Moreover, the neural networks serving the corticostriatal and corticocerebellar circuits could represent putative biomarkers for ADHD. Indeed, in this disorder their quantification using DTI could be relevant for both diagnostic and therapeutic purposes [46].As well as offering new data to map the brain systems involved in ADHD, and to integrate these findings with clinical symptoms, functional neuroimaging studies allow us to understand the mechanisms of treatment response [42,49]. Positron emission tomography (PET) studies have shown that methylphenidate hydrochloride (MPH) blocks dopamine active transporters (DAT) and that extracellular dopamine (DA) increases in proportion to the level of blockade and to the rate of DA release. This process is associated with an enhanced perception of the external stimulus as salient in subjects with ADHD [50].Clinical diagnosis and comorbiditiesClinical presentation of ADHD may vary according to age and stage of development and there are cultural differences in the level of activity and inattention that are regarded as a problem [51]. Diagnosis requires that there should be clear evidence of clinically significant impairment in social, academic, or occupational functioning [5]. The predominantly inattentive type is relatively more common in females. Children with the predominantly hyperactive-impulsive type are aggressive and impulsive, and tend to be highly rejected by their peers. The combined type causes more impairment in global functioning, in comparison with the other two types. Adolescents with ADHD often report low self-esteem and poor peer relationships; and are at high risk of smoking and substance abuse early in life [52,53].Endophenotypes can be used as trait markers for disease susceptibility, to identify more genetically homogeneous subgroups, to highlight distinct pathophysiological mechanisms or etiological pathways, or to define "spectrum" phenotypes suitable for quantitative trait analyses [54]. Cognitive deficits and motor response inhibition are the prime endophenotype candidates in ADHD [55].The co-existence of several other types of psychopathology along with ADHD, such as oppositional defiant disorder, mood and anxiety disorders, learning disorders, tics, and mental retardation, is very common [56].TreatmentBefore starting treatment, it is important to identify the target outcomes to guide the therapy decision. Drug treatment should be based on a thorough assessment and should always be part of a comprehensive treatment plan that includes psychosocial, behavioural, and educational advice and interventions. Psychotherapy combined with medication may play a role in treating behavioural problems, organisational issues and psychiatric comorbidities [57]. In Italy, an ADHD diagnosis can only be made at a regional referral centre approved by the Italian Ministry of Health. Treatment guidelines put forward by the Ministry of Health and based on European guidelines, specify that pharmacological treatment can only be initiated after failure of cognitive behavioural therapy over a period of 6 months or longer has been demonstrated. Patients must first be enrolled in the ADHD medication registry before treatment with MPH or atomoxetine (ATX) can be prescribed.Behavioural therapy and pharmacological treatment have both been shown to benefit ADHD patients. A longitudinal study of the efficacy of different treatments (an intensively monitored medication program, behavioural therapy, combination of medication and behavioural therapy or treatment as usual by community care) showed after 8-year follow-up that all four of the original treatment groups had a similar outcome: all showed improvement in comparison with pretreatment baseline scores, but none demonstrated superiority [58].The fronto-subcortical circuits (lateral prefrontal cortex, dorsal anterior cingulate cortex, caudate, and putamen) associated with ADHD are rich in catecholamines, which are involved in the mechanism of action of medications used to treat this disorder. Neuropharmacological studies have provided evidence that ADHD involves dysregulation of both noradrenaline (NE) and DA neurotransmitter systems [59]. MPH treatment causes an increase in DA signalling through multiple actions, including blockade of the DA reuptake transporter, amplification of DA response duration, disinhibition of the dopamine D2 receptor and amplification of DA tone [60]. MPH is also an inhibitor of NE re-uptake. ATX is a selective inhibitor of synaptic re-uptake, and in vivo, it specifically increases extracellular levels of DA in the prefrontal cortex but not in the striatum; probably by modulating cortical synaptic DA uptake via the NE transporter [61]. Dextroamphetamine increases the synaptic activity of DA and NE by increasing the release of the neurotransmitters into the synaptic cleft, decreasing reuptake back into the presynaptic neuron, and inhibiting their catabolism [62]. Strong evidence exists indicating that stimulant medications, such as MPH and dextroamphetamine, and the non-stimulant ATX, are effective in improving ADHD symptoms [63]. Guanfacine is a selective alpha2A adrenergic receptor agonist, which improves working memory by stimulating postsynaptic alpha2A adrenoceptors, strengthening the functional connectivity of prefrontal cortex networks [64]. Guanfacine has also been shown to be effective in reducing ADHD symptoms [65,66]. Table ​Table11 summarises the most important characteristics of these pharmacological treatments for ADHD. Only ATX and immediate release MPH are currently approved for the treatment of ADHD in Italy.Table 1Clinical characteristics of ADHD pharmacotherapiesPharmacotherapyMolecular mechanisms [59-66]FormulationsEfficacy(meta-analysis effect size) [74,70]Common adverse events[75-79]StimulantsMethylphenidateBlocks DA reuptake transporter, amplifies DA response duration, disinhibits D2 receptor, inhibits NE re-uptakeImmediate release0.92 (0.80, 1.05)Decreased appetite, insomnia, abdominal pain, headache dizziness, reduced weight gain, affective symptomsOsmotic release0.90 (0.76, 1.05)Decreased appetite, abdominal pain, headacheExtended release0.85 (0.65, 1.05)Decreased appetite, headache, abdominal painLong-acting0.96 (0.75, 1.16)Headache, insomnia, upper abdominal pain, decreased appetite, anorexiaTransdermal patchNot availableAppetite, nausea, vomiting, insomniaDexmethylphenidate0.76 (0.45, 1.08)Decreased appetite, headache, abdominal pain, nauseaDextroamphetamineIncreases release of DA and NE into synaptic cleft, decreases reuptake into presynaptic neuron, inhibits catabolismImmediate release1.24 (0.88, 1.60)Decreased appetite, insomniaExtended release1.13 (0.57, 1.69)Palpitations, tremor, insomnia, decreased appetite, headache, dizziness, dry mouth, weight loss, abdominal symptomsProdrug1.52 (1.34, 1.71)Decreased appetite, headache, insomnia, abdominal pain, irritabilityMixed amphetamine saltsIncreases release of DA and NE into synaptic cleft, decreases reuptake into presynaptic neuron, inhibits catabolismImmediate release1.34 (0.95, 1.72)Decreased appetite, agitation, insomniaExtended release0.77 (0.59, 0.94)Decreased appetite, headache, insomniaNon-stimulantsAtomoxetineSelectively inhibits synapticDA re-uptakeImmediate release0.63 (0.57, 0.69)Upper abdominal pain, decreased appetite, vomiting, somnolence, irritability, fatigueGuanfacineSelective alpha2A adrenergic receptor agonistImmediate releaseNot availableSedation, insomnia, decreased appetite, dry mouth, constipationExtended release0.8 (0.53, 1.07)Somnolence, fatigue, upper abdominal pain, sedationOpen in a separate windowADHD pharmacological therapies are generally well-tolerated (Table ​(Table1).1). However, concerns surrounding the cardiovascular safety of some of these drugs has prompted a recent examination of the effects of ATX and MPH on blood pressure (BP), heart rate (HR), and ECG parameters. MPH appears to cause minor increases in BP and HR, with no strong data to suggest that itincreases the QT interval. Limited data suggest that ATX may increase BP and HR in the short term; in the long term it appears to only increase BP. The effects of ATX on QT interval remain uncertain. Because the current evidence is based on research that has not been specifically designed to investigate the cardiovascular effects of these drugs, it is difficult to draw firm conclusions [67].Both MPH and ATX significantly increase activation in key cortical and subcortical regions subserving attention and executive functions. Therefore, alterations in dopaminergic and noradrenergic function are apparently necessary for the clinical efficacy of pharmacological treatment of ADHD [68]. However MPH and ATX have both common and distinct neural effects, consistent with the observation that while many children respond well to both treatments, some respond preferentially to one or the other. Although pharmacotherapy for ADHD appears to prepare and facilitate the brain for learning, experiential programs need to elicit compensatory development in the brain. The clinical amelioration of some children after environmental experiential inputs and early cognitive/behavioural treatment could indicate outcome-associated plastic brain response [69]. One year of treatment with MPH may be beneficial to show enduring normalisation of neural correlates of attention. However, little is known about the long-term effects of stimulants on the functional organisation of the developing brain [70]. Recent findings have shown that chronic MPH use in drug-naive boys with ADHD enhanced neuropsychological functioning on "recognition memory" component tasks with modest executive demands [71]. Patients receiving pharmacological treatment for ADHD should always be closely monitored for both common and unusual potentially severe adverse effects.Go to:ConclusionsConvergent data from neuroimaging, neuropsychology, genetics and neurochemical studies consistently point to the involvement of the frontostriatal network as a likely contributor to the pathophysiology of ADHD. This network involves the lateral prefrontal cortex, the dorsal anterior cingulate cortex and the caudate nucleus and putamen [39]. Functional neuroimaging has provided new ways to examine the pathophysiology of ADHD, has shown widespread dysfunction in neural systems involving the prefrontal, striatal, and parietal brain regions, and has led to a brain model of deficits in multiple developmental pathways [72]. Molecular genetic studies support dysregulation of neurotransmitter systems as the basis of genetic susceptibility to the disorder, and it is becoming clear that the genotype may influence the response to medications [73]. Hopefully, advances in understanding the underlying neurobiology of ADHD will contribute to identifying more specific and targeted pharmacotherapies, and will help child neurologists to better manage their patients.Go to:Competing interestsProfessor Paolo Curatolo has served as an Advisory Board Member for Eli Lilly and Shire, and has received research grants from Eli Lilly and Shire. The other authors have no conflicts of interest to declare.Go to:Authors' contributionsPC proposed and designed the study, and revised the final draft. EDA and RM reviewed all the relevant articles on the literature, and prepared the first draft under the supervision of Prof. Paolo Curatolo. All authors contributed to the intellectual content and approved the final version.Go to:AcknowledgementsEditing of the manuscript and table preparation was performed by Rachel Wright of Fishawack Communications, supported by Shire Development Inc.Go to:ReferencesPolanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007;164:942–948. doi: 10.1176/appi.ajp.164.6.942. [PubMed] [Cross Ref]Still G. The Coulstonian lectures on some abnormal physical conditions in children. Lecture 1. Lancet. 1902. pp. 1008–1012. 1077-1082, 1163-1168.Denckla MB, Rudel RG. Anomalies of motor development in hyperactive boys. Ann Neurol. 1978;3:231–233. doi: 10.1002/ana.410030308. [PubMed] [Cross Ref]American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3 (DSM-III) Washington: American Psychiatric Association; 1980.APA. Diagnostic and Statistical Manual of Mental Disorders. 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No there is no cure for ADHD neurologyThe neurobiological basis of ADHDAbstractAttention-Deficit/Hyperactivity Disorder is not a single pathophysiological entity and appears to have a complex etiology. There are multiple genetic and environmental risk factors with small individual effect that act in concert to create a spectrum of neurobiological liability. Structural imaging studies show that brains of children with Attention-Deficit/Hyperactivity Disorder are significantly smaller than unaffected controls. The prefrontal cortex, basal ganglia and cerebellum are differentially affected and evidence indicating reduced connectivity in white matter tracts in key brain areas is emerging. Genetic, pharmacological, imaging, and animal models highlight the important role of dopamine dysregulation in the neurobiology of Attention-Deficit/Hyperactivity Disorder. To date, stimulants are the most effective psychopharmacological treatments available for Attention-Deficit/Hyperactivity Disorder. Currently only immediate release methylphenidate and atomoxetine are approved for the treatment of ADHD in Italy. Drug treatment should always be part of a comprehensive plan that includes psychosocial, behavioural and educational advice and interventions.Go to:IntroductionAttention-Deficit/Hyperactivity Disorder (ADHD) is a common, long-lasting, treatable childhood psychiatric disorder, characterised by a pattern of developmentally inappropriate inattention, motor restlessness, and impulsivity that affects approximately 3-7% of school-aged children [1].ADHD was first recognised 100 years ago as a childhood disorder found mainly in boys, and was initially described as "hyperactivity" or "hyperkinetic disorder of childhood". This abnormal behaviour was found to be the result of a biological condition rather than a result of poor parenting [2]. In the 1960's and 70's much of the focus on what is now called ADHD was on hyperactivity. The presence of excessive movements in children was proposed to result from bilateral cortical activity secondary to a lack of transcallosal fibre tract-mediated interhemispheric inhibition [3]. Attention Deficit Disorder with or without Hyperactivity first featured in DSM-III in 1980 [4], and the more recent DSM-IV-TR provided updated ADHD criteria [5]. For a diagnosis of ADHD, symptoms need to occur often, have persisted for the past six months, and be maladaptive and incongruent with the individual's developmental level. Additionally, an ADHD diagnosis is only given if at least some of the behavioural symptoms were present before the age of 7 years, occur in more than one setting, and cause significant impairment in social and school functioning.The renaming of the disorder, the subsequent focus on attention, and the clarification of three subtypes led to a range of neurocognitive and neurobiological hypotheses regarding the etiology and pathophysiology of ADHD within a more specific brain localisation. Furthermore, neurocognitive models of ADHD have become more refined, and one particular executive process, inhibition, is now considered to be a core deficit [6].Current theories emphasise the central role of attentional and executive dysfunctions in children [7,8], as well as affective components involving emotional control and motivational processes [9]. A growing body of evidence supports a model in which multiple genetic and environmental factors interact during early development to create a neurobiological susceptibility to the disorder; the expression of which is mediated by alterations within different and diverse neural networks and deficits in the neuropsychological functions that these subserve [10]. Individuals with ADHD present difficulties in several domains of attentional and cognitive functions: problem solving, planning, orienting, alerting, cognitive flexibility, sustained attention, response inhibition, and working memory [7,11]. Other domains involving affective components, such as motivation and delay aversion, are also affected [8,9]. Motor difficulties, such as problems with sensory motor coordination, including poor handwriting, clumsiness, and marked delays in achieving motor milestones [12], have also been reported and the prevalence of motor impairment in the ADHD population has been estimated to be approximately 50% [13]. Motor problems might be partially related to abnormalities in structure and/or function of the cerebellum and basal ganglia found in ADHD [14].Recently, neuroimaging has led to several important advances in the understanding of the neurobiology underlying the clinical picture of ADHD, and demonstrates a clear brain basis to the disorder in regions involved in attention, and executive and inhibitory control [15,16]. Furthermore, transcranial magnetic stimulation (TMS) has provided evidence that intracortical inhibition, as indexed by the immature ipsilateral motor cortex, normalises with psychostimulant treatment [17]. There is an exciting confluence between emerging studies in basic neurobiology and the genetic, neuroimaging, and neuropsychological analyses of ADHD. Knowledge of neurobiology can offer child neurologists, psychiatrists and other healthcare professionals a valuable framework for the interpretation of clinical findings of children meeting the criteria for diagnosis of ADHD. In this article we provide a brief overview of the salient neurological basis of the disorder.EtiologyADHD is not a single pathophysiological entity and appears to have a complex etiology. Multiple genetic and environmental factors act together to create a spectrum of neurobiological liability.The genetic basis for ADHDGenetic factors are implicated in ADHD, but the mechanism of action is not completely understood. Twin, family and adoption studies of ADHD have supported a strong genetic contribution to the disorder, with heritability ranging from 60-90% [18,19].Genes regulating neurotransmitter systems have been implicated in ADHD. Candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder, with meta-analyses supportive of a role of the genes coding for DRD4, DRD5, SLC6A3, SNAP-25, and HTR1B [20]. Genome scan studies on potential alleles for ADHD have demonstrated linkage on chromosomes 5p13, 6q12, 16p13, 17p11 and 11q22-25 [21,22]. However, genome-wide association studies have failed to report any associations that are significant after correction for multiple testing [23]. Therefore, a plausible genetic hypothesis for ADHD is a mixture of dominant and recessive major genes that act with complex polygenic transmission patterns [18]. An increased rate of large, rare, chromosomal deletions and duplications known as copy number variants have been reported in individuals with ADHD [24]. However, genetic testing in an individual child is not currently practical in normal clinical practise.Sometimes ADHD-like symptoms are exhibited by patients with established neurogenetic disorders such as Tuberous Sclerosis Complex, Neurofibromatosis I, Turner Syndrome, Williams Syndrome, Velocardiofacial syndrome, Prader-Willy syndrome, and Fragile × Syndrome. Although each syndrome may arise from different genetic abnormalities with multiple molecular functions, the effects of these abnormalities may give rise to common effects downstream in the biological pathways or neural circuits, resulting in the presentation of ADHD symptoms [25].The environmental basis of ADHDPre-, peri- and postnatal environmental factors play an important role in the pathogenesis of ADHD. Prenatal factors are associated with maternal lifestyle during pregnancy. For example, prenatal alcohol exposure is known to induce brain structural anomalies, especially in the cerebellum [26]. Children exposed prenatally to alcohol can become hyperactive, disruptive, impulsive, and are at an increased risk of a range of psychiatric disorders [27,28]. Maternal smoking produces a 2.7-fold increased risk for ADHD [29], and a dose-response relationship between maternal smoking during pregnancy and hyperactivity has been reported [30]. This may be due to an effect on nicotinic receptors, which modulate dopaminergic activity. Dopaminergic disruption is believed to be involved in the pathophysiology of ADHD [31,32].Peri-natal factors have also been implicated, with a two-fold increase in ADHD in very low-birthweight children and an increased rate of pregnancy and birth complications in mothers of children later diagnosed with ADHD [33].Among postnatal factors, a role for malnutrition and dietary deficiency in ADHD has been proposed. An imbalance of essential fatty acid (omega-3 and omega-6) intake has been suggested to be potentially involved in the development of ADHD [34], although further evidence is required to establish a role. Iron deficiency has been implicated in some cases [35]. Early deprivation of social environment during the postnatal period may also have significant effects.Gene-environment interactionsMore complex models of the etiology of ADHD incorporating gene-environment interplay need to be considered. Recent studies have focused on the joint effects of gene variants (of DRD4 and DAT1) and prenatal substance exposures on subtypes of ADHD children, demonstrating that smoking during pregnancy is associated with the combined ADHD type in genetically susceptible children [36]. A significant interaction between DAT1 genotype and prenatal smoke exposure was found in males. Men homozygous for the DAT1 10-repeat allele had higher hyperactivity-impulsivity than males from all other groups [37]. Despite the heterogeneity of the etiology and pathophysiology of ADHD, abnormal DAT density seems to be common among subjects with ADHD [38].NeuroimagingGrowing evidence points to the involvement of the frontostriatal network as a likely contributor to the pathophysiology of ADHD. This network involves the lateral prefrontal cortex, the dorsal anterior cingulate cortex, and the caudate nucleus and putamen. In ADHD patients, reductions in volume have been observed in total cerebral volume, the prefrontal cortex, the basal ganglia (striatum), the dorsal anterior cingulate cortex, the corpus callosum and the cerebellum [39]. A developmental trajectories study in ADHD patients showed a delay in cortical maturation, and demonstrated that different clinical outcomes may be associated with different developmental trajectories in adolescence and beyond [40]. In studies of cortical development in children with ADHD, a marked delay in brain maturation was seen; the grey matter peaks were about 3 years later than in healthy controls [41]. The delay was most prominent in prefrontal regions important in the control of cognitive processes including attention and motor planning [41,42]. Compensatory networks including basal ganglia, insula and cerebellum have been implicated for relative lower cognitive load tasks in ADHD patients [43].Neuroimaging studies have also reported reduced white matter (WM) volumes [43], midsagittal corpus callosum (CC) areas [44], and cortical thickness [43] in ADHD patients compared with controls. One of the most replicated alterations is a significantly smaller CC, but there are conflicting reports regarding the affected callosal segments [45]. Recent magnetic resonance imaging (MRI) structural investigations have shown that WM alterations are present in children, adolescents and adults with ADHD [46]. In 15 young males with ADHD, Silk et al. (2008) found WM abnormalities in several distinct regions underlying the inferior parietal, occipito-parietal, inferior frontal, and inferior temporal cortex [47]. Tractography methods showed that these regions form part of WM pathways connecting prefrontal and parieto-occipital areas with the striatum and the cerebellum. The authors also demonstrated anomalous WM development in ADHD in distinct cortical regions that they had previously shown to be dysfunctional or hypoactive in a functional MRI study of subjects with ADHD [47].Diffusion tensor imaging (DTI) is an MRI modality that provides information about the direction and integrity of neural fibre tracks in the brain in vivo. DTI studies have revealed developmental changes in cortical WM pathways in prefrontal regions and in pathways surrounding the basal ganglia and cerebellum in patients with ADHD, which presumably reflect decreasing myelination of axons. It is believed that these changes cause a decrease in the speed of neuronal communication [48]. Moreover, the neural networks serving the corticostriatal and corticocerebellar circuits could represent putative biomarkers for ADHD. Indeed, in this disorder their quantification using DTI could be relevant for both diagnostic and therapeutic purposes [46].As well as offering new data to map the brain systems involved in ADHD, and to integrate these findings with clinical symptoms, functional neuroimaging studies allow us to understand the mechanisms of treatment response [42,49]. Positron emission tomography (PET) studies have shown that methylphenidate hydrochloride (MPH) blocks dopamine active transporters (DAT) and that extracellular dopamine (DA) increases in proportion to the level of blockade and to the rate of DA release. This process is associated with an enhanced perception of the external stimulus as salient in subjects with ADHD [50].Clinical diagnosis and comorbiditiesClinical presentation of ADHD may vary according to age and stage of development and there are cultural differences in the level of activity and inattention that are regarded as a problem [51]. Diagnosis requires that there should be clear evidence of clinically significant impairment in social, academic, or occupational functioning [5]. The predominantly inattentive type is relatively more common in females. Children with the predominantly hyperactive-impulsive type are aggressive and impulsive, and tend to be highly rejected by their peers. The combined type causes more impairment in global functioning, in comparison with the other two types. Adolescents with ADHD often report low self-esteem and poor peer relationships; and are at high risk of smoking and substance abuse early in life [52,53].Endophenotypes can be used as trait markers for disease susceptibility, to identify more genetically homogeneous subgroups, to highlight distinct pathophysiological mechanisms or etiological pathways, or to define "spectrum" phenotypes suitable for quantitative trait analyses [54]. Cognitive deficits and motor response inhibition are the prime endophenotype candidates in ADHD [55].The co-existence of several other types of psychopathology along with ADHD, such as oppositional defiant disorder, mood and anxiety disorders, learning disorders, tics, and mental retardation, is very common [56].TreatmentBefore starting treatment, it is important to identify the target outcomes to guide the therapy decision. Drug treatment should be based on a thorough assessment and should always be part of a comprehensive treatment plan that includes psychosocial, behavioural, and educational advice and interventions. Psychotherapy combined with medication may play a role in treating behavioural problems, organisational issues and psychiatric comorbidities [57]. In Italy, an ADHD diagnosis can only be made at a regional referral centre approved by the Italian Ministry of Health. Treatment guidelines put forward by the Ministry of Health and based on European guidelines, specify that pharmacological treatment can only be initiated after failure of cognitive behavioural therapy over a period of 6 months or longer has been demonstrated. Patients must first be enrolled in the ADHD medication registry before treatment with MPH or atomoxetine (ATX) can be prescribed.Behavioural therapy and pharmacological treatment have both been shown to benefit ADHD patients. A longitudinal study of the efficacy of different treatments (an intensively monitored medication program, behavioural therapy, combination of medication and behavioural therapy or treatment as usual by community care) showed after 8-year follow-up that all four of the original treatment groups had a similar outcome: all showed improvement in comparison with pretreatment baseline scores, but none demonstrated superiority [58].The fronto-subcortical circuits (lateral prefrontal cortex, dorsal anterior cingulate cortex, caudate, and putamen) associated with ADHD are rich in catecholamines, which are involved in the mechanism of action of medications used to treat this disorder. Neuropharmacological studies have provided evidence that ADHD involves dysregulation of both noradrenaline (NE) and DA neurotransmitter systems [59]. MPH treatment causes an increase in DA signalling through multiple actions, including blockade of the DA reuptake transporter, amplification of DA response duration, disinhibition of the dopamine D2 receptor and amplification of DA tone [60]. MPH is also an inhibitor of NE re-uptake. ATX is a selective inhibitor of synaptic re-uptake, and in vivo, it specifically increases extracellular levels of DA in the prefrontal cortex but not in the striatum; probably by modulating cortical synaptic DA uptake via the NE transporter [61]. Dextroamphetamine increases the synaptic activity of DA and NE by increasing the release of the neurotransmitters into the synaptic cleft, decreasing reuptake back into the presynaptic neuron, and inhibiting their catabolism [62]. Strong evidence exists indicating that stimulant medications, such as MPH and dextroamphetamine, and the non-stimulant ATX, are effective in improving ADHD symptoms [63]. Guanfacine is a selective alpha2A adrenergic receptor agonist, which improves working memory by stimulating postsynaptic alpha2A adrenoceptors, strengthening the functional connectivity of prefrontal cortex networks [64]. Guanfacine has also been shown to be effective in reducing ADHD symptoms [65,66]. Table ​Table11 summarises the most important characteristics of these pharmacological treatments for ADHD. Only ATX and immediate release MPH are currently approved for the treatment of ADHD in Italy.Table 1Clinical characteristics of ADHD pharmacotherapiesPharmacotherapyMolecular mechanisms [59-66]FormulationsEfficacy(meta-analysis effect size) [74,70]Common adverse events[75-79]StimulantsMethylphenidateBlocks DA reuptake transporter, amplifies DA response duration, disinhibits D2 receptor, inhibits NE re-uptakeImmediate release0.92 (0.80, 1.05)Decreased appetite, insomnia, abdominal pain, headache dizziness, reduced weight gain, affective symptomsOsmotic release0.90 (0.76, 1.05)Decreased appetite, abdominal pain, headacheExtended release0.85 (0.65, 1.05)Decreased appetite, headache, abdominal painLong-acting0.96 (0.75, 1.16)Headache, insomnia, upper abdominal pain, decreased appetite, anorexiaTransdermal patchNot availableAppetite, nausea, vomiting, insomniaDexmethylphenidate0.76 (0.45, 1.08)Decreased appetite, headache, abdominal pain, nauseaDextroamphetamineIncreases release of DA and NE into synaptic cleft, decreases reuptake into presynaptic neuron, inhibits catabolismImmediate release1.24 (0.88, 1.60)Decreased appetite, insomniaExtended release1.13 (0.57, 1.69)Palpitations, tremor, insomnia, decreased appetite, headache, dizziness, dry mouth, weight loss, abdominal symptomsProdrug1.52 (1.34, 1.71)Decreased appetite, headache, insomnia, abdominal pain, irritabilityMixed amphetamine saltsIncreases release of DA and NE into synaptic cleft, decreases reuptake into presynaptic neuron, inhibits catabolismImmediate release1.34 (0.95, 1.72)Decreased appetite, agitation, insomniaExtended release0.77 (0.59, 0.94)Decreased appetite, headache, insomniaNon-stimulantsAtomoxetineSelectively inhibits synapticDA re-uptakeImmediate release0.63 (0.57, 0.69)Upper abdominal pain, decreased appetite, vomiting, somnolence, irritability, fatigueGuanfacineSelective alpha2A adrenergic receptor agonistImmediate releaseNot availableSedation, insomnia, decreased appetite, dry mouth, constipationExtended release0.8 (0.53, 1.07)Somnolence, fatigue, upper abdominal pain, sedationOpen in a separate windowADHD pharmacological therapies are generally well-tolerated (Table ​(Table1).1). However, concerns surrounding the cardiovascular safety of some of these drugs has prompted a recent examination of the effects of ATX and MPH on blood pressure (BP), heart rate (HR), and ECG parameters. MPH appears to cause minor increases in BP and HR, with no strong data to suggest that itincreases the QT interval. Limited data suggest that ATX may increase BP and HR in the short term; in the long term it appears to only increase BP. The effects of ATX on QT interval remain uncertain. Because the current evidence is based on research that has not been specifically designed to investigate the cardiovascular effects of these drugs, it is difficult to draw firm conclusions [67].Both MPH and ATX significantly increase activation in key cortical and subcortical regions subserving attention and executive functions. Therefore, alterations in dopaminergic and noradrenergic function are apparently necessary for the clinical efficacy of pharmacological treatment of ADHD [68]. However MPH and ATX have both common and distinct neural effects, consistent with the observation that while many children respond well to both treatments, some respond preferentially to one or the other. Although pharmacotherapy for ADHD appears to prepare and facilitate the brain for learning, experiential programs need to elicit compensatory development in the brain. The clinical amelioration of some children after environmental experiential inputs and early cognitive/behavioural treatment could indicate outcome-associated plastic brain response [69]. One year of treatment with MPH may be beneficial to show enduring normalisation of neural correlates of attention. However, little is known about the long-term effects of stimulants on the functional organisation of the developing brain [70]. Recent findings have shown that chronic MPH use in drug-naive boys with ADHD enhanced neuropsychological functioning on "recognition memory" component tasks with modest executive demands [71]. Patients receiving pharmacological treatment for ADHD should always be closely monitored for both common and unusual potentially severe adverse effects.Go to:ConclusionsConvergent data from neuroimaging, neuropsychology, genetics and neurochemical studies consistently point to the involvement of the frontostriatal network as a likely contributor to the pathophysiology of ADHD. This network involves the lateral prefrontal cortex, the dorsal anterior cingulate cortex and the caudate nucleus and putamen [39]. Functional neuroimaging has provided new ways to examine the pathophysiology of ADHD, has shown widespread dysfunction in neural systems involving the prefrontal, striatal, and parietal brain regions, and has led to a brain model of deficits in multiple developmental pathways [72]. Molecular genetic studies support dysregulation of neurotransmitter systems as the basis of genetic susceptibility to the disorder, and it is becoming clear that the genotype may influence the response to medications [73]. Hopefully, advances in understanding the underlying neurobiology of ADHD will contribute to identifying more specific and targeted pharmacotherapies, and will help child neurologists to better manage their patients.Go to:Competing interestsProfessor Paolo Curatolo has served as an Advisory Board Member for Eli Lilly and Shire, and has received research grants from Eli Lilly and Shire. The other authors have no conflicts of interest to declare.Go to:Authors' contributionsPC proposed and designed the study, and revised the final draft. EDA and RM reviewed all the relevant articles on the literature, and prepared the first draft under the supervision of Prof. Paolo Curatolo. All authors contributed to the intellectual content and approved the final version.Go to:AcknowledgementsEditing of the manuscript and table preparation was performed by Rachel Wright of Fishawack Communications, supported by Shire Development Inc.Go to:ReferencesPolanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry. 2007;164:942–948. doi: 10.1176/appi.ajp.164.6.942. [PubMed] [Cross Ref]Still G. The Coulstonian lectures on some abnormal physical conditions in children. Lecture 1. Lancet. 1902. pp. 1008–1012. 1077-1082, 1163-1168.Denckla MB, Rudel RG. Anomalies of motor development in hyperactive boys. Ann Neurol. 1978;3:231–233. doi: 10.1002/ana.410030308. [PubMed] [Cross Ref]American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3 (DSM-III) Washington: American Psychiatric Association; 1980.APA. Diagnostic and Statistical Manual of Mental Disorders. 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What is the proof of the conceptual and mathematical collapse of the foundation of quantum mechanics?This question can have three answers:1. This question is asked by an ignorant person who does not know anything about the quantum mechanics, there is no question of any failure or collapse, therefore, no such proof exists.2. The quantum mechanics is here for almost a century and its derivative theories are also here for more than several decades, there are continuously mounting experimental supports in favour of these theories, in spite of accepting its mysterious characteristics the journals are full of papers supporting these theories and claims of further advancing these theories, the mainstream physicists accepts these theories, therefore there is no question of any failure or collapse of the quantum mechanics and its derivative theories, at the same time nobody has ever claimed and produced any failure of foundation of the quantum mechanics, therefore, no such proof exists.3. By any means this is not a usual normal question related to physics; this is an extra-ordinary question and therefore requires an extra-ordinary answer, because the stack value is extremely high, one half of the whole modern physics is on stack, the other half is covered by the theory of relativity. If the proof exists then it must be established with utmost clarity, beyond any shadow of doubt. I claim that such proof exists and it is given in my paper“Are Dual nature of electron, Uncertainty principle, Schrodinger’s equation and Born’s rules & interpretation based on scientific foundations?”Since this paper is long contains about 63 pages therefore I am posting its link below:IPKR HIRWANIThis paper can be downloaded from the above link. If somebody is interested in detailed scientific discussion then please join me in Academia.Having claimed to have researched, found and compiled the proof of collapse of the foundation of the quantum mechanics and its all derivative theories, in the above paper, it becomes important to give some more information about the above paper.This paper contains the proofs of complete conceptual and mathematical collapse of the foundation of the quantum mechanics on many counts by showing that the main pillars of the quantum mechanics/the main basic concepts are developed on absolutely wrong physical concepts and their mathematical derivation/foundation are based on grave mathematical errors.These four main pillars of the quantum mechanics are:a. The de Broglie’s hypothesis of dual nature of sub atomic particlesb. The Heisenberg’s uncertainty principlec. The Schrodinger’s equationd. The Born’s rule and interpretationThis paper contains lot of mathematics, for those who do not want to go into the details can skip the mathematical part, the errors in every mathematical part is explained in a clear non-mathematical way. Those who want to know what the grave mistakes are can go through at least two chapters,chapter VIISummary of Non-Scientific Steps Taken In the Formulation of the Pillar Concepts Principlesand the Chapter VIIIConclusionI am providing these chapters at the end of this answer, for details please go through the paper.This is the first scientific paper ever produced in the whole century which provides the complete conceptual and mathematical collapse of the foundation of the quantum mechanics and therefore, all its derivative theories. If you don’t agree, please show my claim is wrong; I welcome every refutation, every criticism, and every discussion, provided they are scientific in nature.I have listed more than 30 grave errors / mistakes, if anybody goes through this paper then it will be found that the errors are made absolutely clear, they can’t be denied, they can’t be explained in any other way, it’s like 2 + 3 = 7, once known they cannot be ignored.It is a request to all the viewers of Quora who would reply and participate in the discussion to please keep the discussion scientific, I like healthy criticism, I will answer every question. A big event is being unfolded with you as a witness and participant, please make it graceful.This is an open invitation to any physicist or anybody within the Quora and beyond it to scientifically criticize my paper, to ask questions about my paper, to point out the scientific errors in the analysis and the claims, but I would request to please avoid the minor grammatical and cosmetic mistakes which does not affect the heart of the arguments and the paper, because we have been going through lots of such papers with zero grammatical and cosmetic mistakes but completely devoid of the heart. Let us focus on the heart of the physics and avoid the cosmetics.Some more details about this paper which also shows how the mainstream physics community is behaving, this was perfectly anticipated by the author because this is a natural human reaction but if our aim is understanding the Nature, understanding the Physics then we must be guided by the scientific principles and keep the influence of all the non-scientific factors and emotions to the minimal.This paper is first presented to the American Physical Society’s (APS) journal the Physical Review X on 5th Nov 2019, this paper received the referee approval for the publication in the journal but its managing editor declined the publication without providing any scientific reason, but suggested to put in the arXiv or try to other places.I sent this paper to the Nature Physics, they asked for the previous correspondence to other journals, they were aware that this paper has received the referee approval of PRX, still they declined without providing any reason.This paper was sent again to the American Physical Society’s another journal the Physical Review Research, after taking long time finally this paper is rejected by the Editorial Director of the American Physical Society again without providing any reason.This paper was then sent to the journal Science, here again this paper is rejected by the editor without giving any proper reason.I tried to post this paper in the arXiv, but I could not get the membership because of their non-scientific criteria of endorsement and it is almost impossible to get an endorsement for an independent researcher and finally they clearly declined and asked to come through their endorsement system which was impossible for me to get through.I tried many other journals also, but returned without any proper reason.I have posted one of the paper in Academia, I have also posted on of my book there, if interested, please go through the paper first.I understand it is very difficult for any journal to publish this paper because it contains the proof of failure of the foundation of the quantum mechanics and therefore all its derivative theories, which is against the prevailing mainstream accepted views, all the physics journals are publishing lots of papers in the support of the quantum physics, in this reference I am thankful that the APS at least considered this paper and rejected from their highest authority, this itself tells a lot of story, the other journals attitude are clearly non-professional and non-scientific.Contents from my paper:VII. SUMMARY OF NON-SCIENTIFIC STEPS TAKEN IN THE FORMULATION OF THE PILLAR CONCEPTS PRINCIPLESIt is important to summarize the non-scientific steps taken in the formulation of the above fundamental principles of the quantum mechanics, which invalidates them as a scientific theory.A. Dual nature of electrona. Use of the same formulafor an electron which is valid for a photon but invalid for an electron. There is no empirical evidence of its validity for an electron. Violation of physics.b. Use of the relation E = hν and E = mv^2 for electron in the derivation of the de Broglie’s wavelength relation. There is no empirical evidence of their validity for an electron. Violation of physics.c. A photon is electrically neutral but an electron is charged, the properties of a photon cannot be applied to an electron. Violation of physics.d. The assumption 2 π r = n lambda, the quantized use of the wavelength. There is no empirical evidence. Violation of physics.e. Acceptance of Davison Germer experiment and Compton experiments as proof of wave nature of electron. Insufficient evidence.B. Uncertainty principlea. In the thought experiment Heisenberg’s microscope use of single photon cannot measure position or momentum of an electron. Violation of physics.b. Self-contradictory thought experiment set up, the position of the electron is known precisely, the photon can be aligned with the electron.c. All the uncertainties are not taken into account, like the dimensional uncertainty of the object; the time lag of the refracted photon etc., these shows uncertainty principle is not complete, therefore invalid for fundamental theory.d. Misuse of the uncertainty principle, forcing the parameters to assume values. There is no scientific evidence; there are many contradictory evidence available, therefore absolutely wrong. Violation of physics.e. Assumption of uncertainty in momentum as total momentum of the photon. Invalid. Violation of physics.f. Assumption of uncertainty in position equal to one wavelength. Violation of physics.g. Invalid use of frequency time-period ambiguity relation. Valid for a single wave, but used for wave packet. Violation of physics.h. Invalid use of frequency time-period ambiguity relation. ∆ν and ∆T are considered independent, they cannot be. Violation of physics.i. Use of the relation ∆E = ∆ν h, which is valid only for a photon, but is generalized for any energy which does not obey the above relation. Violation of physics.j. Use of the relation ∆E ∆T = h, which is valid only for a photon, where ∆T is the dependent change in ‘time period’ of the photon but is generalized for any ‘time’ which does not obey the above relation. Violation of physics.k. Use of the relation ∆E = ∆p v, this is an absolutely invalid substitution. Here ∆E is the change in energy of a photon which is derived from ∆ν h, but this change in energy ∆E is generalized for any energy. Violation of physics.l. Use of relation ∆T = ∆x / v, where ∆T is the change in time period of a photon and ∆x is the distance traveled by a particle with velocity v. This substitution is impossible. Absolute violation of physics.m. Arbitrary changing the equality to inequality. Violation of mathematics and physics.n. Changing the words from “a small change of parameter” to “measurement uncertainty” without any reason and justification.o. Elevation of the principle to the level of fundamental principle without any scientific reason and empirical evidences. Violation of physics.p. There are several empirical evidences available for the violation of the uncertainty principle for example, confinement of an electron in the nucleus, electron capture, precise atomic spectral lines. These are empirical proofs of the failure of the uncertainty principle.C. Schrodinger’s equationa. Use of an abstract non-physical concept Y, to describe the physical reality. Violation of physics.b. The concept of 3-dimensional transverse wave. Physically impossible, violation of physics.c. How an electron generates or gets converted into a wave. No understanding. Violation of physics.d. How the mass of an electron, which is an elementary particle of mass, can be distributed in a much larger 3-dimensional volume than its own volume. Violation of known physics.e. How the charge of an electron, which is an elementary particle of charge, can be distributed in much larger 3-dimensional volume than its own volume. Violation of physics.f. How a stationary wave can be created without any boundary, what makes the wave bend and confined in the orbitals. Violation of physics.g. The incompleteness of the Schrodinger’s equation, only 3 out of 4 quantum numbers emerge from the Schrodinger’s equation.h. Failure of quantum mechanics to predict the spin quantum number.i. Use of complex numbers, which does not have any relation with the physical reality. Violation of physics.j. Use of special method of getting the square of the wave function. Violation of mathematics.k. Use of Hermitian equation, Eigen function and Eigen values. Abstract mathematics, no empirical evidence. Violation of physics.l. Use of 1-dimensional oscillation equation as multi-dimensional wave equation. Violation of physics and mathematics both.m. Use of de Broglie’s dual nature of electron. Violation of physics.n. The problem of partial derivative w.r.t. space for deriving Helmholtz’s equation. Violation of mathematics.o. The problem of momentum, replacing the momentum of a photon by the momentum of an electron in the Helmholtz’s equation. Grave violation of physics.p. Substitution of total energy of the electron E by hν. This relation is valid only for photon and absolutely invalid for an electron. Grave violation of physics.q. Replacing the wave function Y in the middle of the derivation. Violation of mathematics.r. Claiming the ‘general form’ of the Schrodinger’s equation as general equation which can accept any value of a wave function Y. Violation of mathematics.s. Use of imaginary number which flips real number and the imaginary number in deriving the quantum numbers, this is one of the biggest reason to invalidate the Schrodinger’s equation and therefore the whole Quantum mechanics.t. Use of imaginary numbers to manipulate the equation, Violation of physics.u. Substitution of the value of Y with two entirely different wave functions as equals. Violation of mathematics and physics.v. The general form of the Schrodinger’s equation contains only potential energy. Sign of failure. Violation of physics.w. The general form of the Schrodinger’s equation does not contain any wavelength term. Sign of failure. Violation of physics.x. Use of method of separation of variables in solution of the Schrodinger’s equation. Invalid in context of wave equations. Violation of physics.y. Use of more than one form of Schrodinger’s equation in single derivation. Violation of physics and mathematics.z. Considering the potential energy of an electron as a function of only r, this is a classical concept, invalid in quantum mechanics. Violation of its own law, violation of physics.aa. The problem of imposed quantization. Violation of physicsbb. The problem of derivation of magnetic quantum numbers, the claim that the constant can have both positive and negative angles. This leads to invalid extraction of the magnetic quantum numbers. Violation of mathematics and physics.cc. The problem of derivation of the angular momentum quantum numbers. Partial substitution of boundary conditions. Violation of mathematics.dd. Treating the same parameteras a constant, independent of variable q, then treating it as a function of cosq at different situation. Violation of mathematics and physics.ee. Neglecting the constant for determination of the angular momentum quantum numbers. Violation of mathematics.ff. Forcing the constantto some value to avoid ¥/¥ term during the extraction of the angular momentum quantum numbers. Invalid extraction of the quantum number. Violation of mathematics and physics.D. Born’s rules and interpretationa. There is absolutely no scientific basis of the Born’s rule and interpretation; it is based on arbitrary belief and arguments. It is still being searched if they can be derived from some fundamental principles.b. Born’s claim that the orbitals represent the probability of finding an electron is an absolute non-scientific claim.c. There is no scientific evidence that the Hermitian equation, Eigen functions and the Eigen values represent the physical reality. The claims are erratic and are based on the concept of normalisation, which itself is one of the biggest non-scientific concept.d. Born’s hypothesis are based on the acceptance of the Heisenberg’s non-scientific postulatee. The relation defined to find the probability of an electron is non-mathematical and wrong because of the concept of probability density. Uniform probability density at a constant radius is impossible practically as well as theoretically.f. Probabilistic concept of Born cannot explain the empirical bond ionization of polar molecules; it cannot explain the stable and precise bond energy, bond length and bond angles of the molecules.g. It is not possible for electrons in an atom to exist as Probability cloud with discrete energy. This violates the very basic conservation of energy principle.VIII. CONCLUSIONIt is clear from the above analysis that the pillar/basic concepts, the Dual nature of subatomic particles, particularly electrons, the Uncertainty principle, the Schrodinger’s equation and the Born’s rules & interpretations are based on non-scientific principles; there are grave violations of the laws of physics and mathematics on many counts in the formulation and derivation of these concepts. The analysis reveals the biggest mystery of the quantum mechanics that why quantum mechanics is so weird, it is weird because the basic concepts are developed on non-scientific and wrong physics and mathematics. The basic concepts and equations are completely disconnected from the physical reality, they are incapable to represent any physical reality therefore their predictions cannot and do not match with the empirical findings, but neglecting all the failure, they are justified by declaring them as weird to prove the quantum mechanics correct.The analysis leaves no doubt that the quantum mechanics never was a correct scientific theory to explain the physical reality, its failure at the fundamental level is blatant now, the best and only defence of the quantum mechanics “…but it works” has clearly failed, it shows the complete conceptual and mathematical collapse of the quantum mechanics.In the light of the conceptual and mathematical collapse of quantum mechanics at the fundamental levels pointed out in this paper, it becomes necessary to discard the quantum mechanics and look beyond it.