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Repetitive Transcranial Magnetic Stimulation (rTMS) New ToolNew Therapy and New Hope for ADHD Maria T Acosta Fidias E Leon-Sarmiento

Curr Med Res Opin 200319(2)

Attention-deficit hyperactivity disorder (ADHD) is the most common developmental disorder that is associated with

environmental and genetic factors Neurobiological evidence suggests that fronto-striatum-cerebellum circuit

abnormalities mainly in the right hemisphere are responsible for most of the disturbed sensorimotor integration

dopamine seems to be the main neurochemical alteration underlying these morphological abnormalities Different

conventional treatments have been employed on ADHD however repetitive transcranial magnetic stimulation (rTMS) a

new and useful option for the clinicalresearch investigation of several neuropsychiatric disorders involving dopamine

circuits has yet to be considered as a therapeutic tool and possible drug-free option for ADHD Here the authors explore

the available evidence that makes this tool a rational therapeutic possibility for patients with ADHD calling attention to

safety issues while highlighting the potentials of such an approach and the new hope it may bring for patients parents

researchers and clinicians The authors advocate carefully conducted clinical trials to investigate efficacy safety

cost-effectiveness and clinical utility of rTMS for ADHD patients - in comparison to both placebo and standard

treatments

Attention-deficit hyperactivity disorder (ADHD) is the most common developmental disorder affecting at least 5 of

school-aged children with boys more frequently affected than girls[1]It persists into adulthood in up to 60 of the

cases [2 3] It is characterised by inattention impulsiveness and hyperactivity that impair normal daily life function

especially at home and school The long-term consequences of childhood ADHD include lower educational and

vocational outcomes as well as an increased risk for antisocial behavioural disorders and drug abuse in adulthood among other psychopathologies[4 5]

ADHD is a multifactorial disorder associated with environmental and genetic factors Variations in brain size and

morphology are present from early life with fronto-striatum-cerebellum circuit abnormalities mainly in the right

hemisphere considered responsible for most of the disturbed motor control and the abnormal sensory-motor

programme[3] dopamine seems to be the main neurochemical alteration underlying these morphological alterations

Based on these facts stimulants of the nervous system are to date the most successful as well as the most

controversial therapy employed[6] Nevertheless despite the enormous amount of research done clinicians and parents

are eagerly awaiting additional and better therapeutic options

Magnetic stimulation is a recent and powerful non-invasive tool developed for studying the nervous system with

promising findings on neural plasticity[7-9] It is also currently being used to treat brain diseases improving functional

deficits and achieving noteworthy results in recent years[9] This new tool has also been found useful in increasing the

understanding of ADHD pathophysiology[1011] however it has not been considered as a drug-free therapeutic option for

treating ADHD Therefore we anticipate that if the rTMS effects on the dopaminergic system found in normals can be

replicated in ADHD patients[12] it could be the first step in offering new hope to patients researchers and clinicians

Here we explore the available evidence that makes this option a viable possibility in the treatment of ADHD

Anatomical studies have shown significant prefrontal asymmetry in ADHD with smaller right-sided prefrontal brain

regionsl13] A decrease in grey matter in the right frontal gyrus the right posterior cingulate gyrus and the left central

white matter have been reportedP 11] Left-to-right asymmetry of the caudate nucleus[14 15] or volume abnormalities of

it[13] as well as a significant decrease in the right globus pallid us size16 or smaller posterior-inferior cerebellar vermis are also common features of this disease[3 17 18] The significance of these findings is still under debate[13] however

they do support the involvement of a circuit in the above-mentioned areas that are certainly hypofunctional in ADHD[3]

The pathophysiology of ADHD has been based on the catecholamine hypothesis[19 20] since the 1970s Unfortunately

after a quarter-century of research its role still remains unclear Dopaminergic dysfunction has been suspected in

10f8 81182014833 AM

ADHD among other neuro-transmitters because symptoms respond favourably albeit temporarily to stimulant

medications such as dextroamphetamine and methylphenidate (MPH)[21] These medications increase the release and

inhibit the re-uptake of catecholamines especially dopamine whose modulatory influence is pervasive in frontalstriatal

regions This evidence suggests that the dysfunction in dopaminergic transmission is located in the frontal lobe and in

striatal structures[21 22] Genetic studies have also reported an association between ADHD and dopaminergic gene

dysfunction including associations between ADHD and variability of the dopamine transporter as well as D4 and D2 receptor gene abnormalities[23-25] Such receptors have an inhibitory effect on GABAergic synapsis and are found in the

relevant cortical basal ganglia thalamus and cerebellar vermis intemeurons related to ADHD pathophysiology[26]

From a neuropsychological perspective ADHD has commonly been defined by sustained attention deficits

impulsiveness and a high level of activity[27] More recently the nature of the disorder has been examined and is

undergoing further redefinition being considered a disorder of executive functions Although an extensive review of the

correlation between executive function and its anatomical substrates is beyond the scope of this article it can be said

that the location of executive functions implies activation of pre-frontal lobes basal ganglia structures and other cortical

and subcortical areas including cortico-striatal-thalamo-cortical circuits[28] which select initiate and execute complex

motor and cognitive responses[29] The cerebellum provides an on-line guidance of these functions[13-15]

Using functional magnetic resonance imaging Vaidya et al found differences between children with ADHD and healthy

controls in their fronto-striatal functioning during response inhibition tasks [3~] However changes in caudate and putamen

as well as prefrontal and striatal activation varied according to the task itself only in patients Interestingly MPH

enhanced activation in prefrontal and striatal areas in both patients and normals and decreased the latter in normals[31]

These findings suggest an atypical functioning of the fronto-striatal circuit in ADHD probably making a significant

contribution to striatal dysfunction In fact functional studies showed decreased blood flow in the striatum of ADHD

subjects[32] mostly in prefrontal regions with a frontal-cerebral decreased metabolism in adults with ADHD

demonstrated by positron-emission tomography with [18FJ-fluoro-2-deoxy-D-glucose 133xenon inhalation and singleshyphoton emission tomography [33]

While neurophysiological studies have been difficult to integrate into the physiopathology of ADHD P300 studies have shown smaller amplitude and longer latencies which correlated with attentional dysfunction[34] Steady-state visually

evoked potentials[35] were also strongly supportive of right prefrontal dysfunction in ADHD[13 36] The main findings with

magnetic stimulation are discussed below

Several pharmacological or non-pharmacological approaches have been considered in treating ADHD but no important

advances have been made since 1937 when Bradley first used stimulants to relieve ADHD symptoms[21] Today

psychostimulant medications in particular MPH are the most commonly prescribed drug for treating ADHD in children

and adults offering clinical benefits in up to 80 of cases[37 38] It is known that MPH captures the dopamine transporter

and is taken up primarily in the striatum of healthy adults[23] increasing striatal and frontal activation[30] Although there is

a large amount of evidence available on the beneficial effects safety and prognosis with short-term stimulant treatment

in children with ADHD many questions remain unanswered Parents and physicians still have concerns regarding safety

issues with the long-term use of stimUlants in children as well Needless to say new approaches to the treatment of this disease would be welcome

A multimodal treatment study of children with ADHD[38] concluded that medication alone was superior to medication plus

behavioural treatment or routine community care or if given in combination with any of the latter therapies for ADHD

symptoms These authors concluded that modifications in neurotransmitters carried out through non-conventional

pharmacological therapy would be an excellent alternative for treating ADHD[38] All of these facts therefore make room

for new therapies including those with TMS

Transcranial magnetic stimulation (TMS) is a newly developed tool for assessing functionality of the central nervous

system (eNS) After Baker et al demonstrated its value in humans in 1985 single and paired-pulse TMS have proven

useful in detecting clinical and subclinical abnormalities in a large array of neurological and neuropsychiatric disorders

including Tourettes syndrome obsessive compulsive disorder depression schizophrenia bipolar disorders and ADHD

20f8 81182014833 AM

among others[39-43] Regarding ADHD specifically TMS seems to be an ideal method for studying the maturational

process of the motor pathways since it clearly excites the corticomotoneuronal system presumed to be involved in this disorder [10]

Ucles et al[10] using single stimulation in children with ADHD found a prolongation of central motor conduction time as

well as some side-to-side stimulation differences compared with those found in age- and sex-matched controls These

findings demonstrated a delay in the maturation of the corticomotoneuronal system in patients with ADHD Moll et a[11]

reported that children with ADHD had significantly reduced intracortical inhibition (ICI) with a normal intracortical

facilitation compared to healthy controls and such ICI showed improvement after giving 10 mg of MPH However most

of the morphophysioneurochemical hallmarks of ADHD involving prefrontal-caudate-cerebellar pathways with noteworthy

dopaminergic abnormalities have not yet been taken into account Therefore we consider that they should be the current

focus if rTMS is to be employed as a therapeutic option

rTMS has been found effective in Parkinson disease depreSSion obsessive-compulsive disorder Tourettes syndrome

and some types of tic[42-44] With regard to children rTMS has been tried with a small number of patients with action

myoclonus progressive myoclonic epilepsy bipolar disorder major depression and schizophrenia45 with some

promising albeit short-lasting positive results Some of these disorders are due to dopamine abnormalities and share

some genetic clinical biochemical neuranatomical and neuro-behavioural similarities with ADHD Even though a complete understanding of the mechanism of action of rTMS has not been developed [42] it is now clear that rTMS at low

frequencies could cause long-term depression of cortico-cortical transmission in normals43 as well as improvement of

symptoms of some neuropsychiatric disorders commented on above including the modulation of several

neurotransmitters such as dopamine and its metabolites (eg homovanilic acid) mainly after prefrontal cortex stimulation [46]

It should also be noted that modulation of dopamine release could be due to GABAergic and glutamatergic

corticostriatal projection the latter being spared in ADHD In fact the recent reduced ICI found in patients with ADHD and demonstrated by TMS is known to be modulated by GABAergic synapsis[47] suggesting that a cortical instability in

the excitatory and inhibitory signals interexchange is present in this disease[48]It is therefore likely that parasitic foci of

autonomous electrical or magnetic neuronal activity modifying the input-output neural shortcuts and decreasing the

appropriate integration and complex dynamics of the CNS as suggested elsewhere[48] seem also to be present in

ADHD patients and perhaps associated conditions Such cortical instability with an imbalance between the so-called

direct and indirect cortical pathways mediating sensory-motor integration might be the most important target for applying the appropriate rTMS treatment in this disorder[12 34]

Because of this the recent findings reported by Strafella et al[12] may may be significant in ADHD cases These authors

showed that rTMS applied to the left mid-dorsolateral prefrontal cortex (MDL-PFC) induced the release of endogenous

dopamine from the left caudate as a consequence of direct corticostriatal axon stimulation increasing the extracellular dopamine concentration measured by the [11C]raclopride binding method[49] These findings are more than interesting

because the clinical benefits of MPH seem to be due to an increase in the resting extracellular levels of dopamine

lowering the levels of pulsatile release of it as well These pharmacological effects also produce a decreased activation of postsynaptic dopamine receptors involved in psychomotor activity modulation[50] making it possible to suggest that a

similar mechanism of action leading to the improvement of clinical symptoms might be considered in ADHD after

applying rTMS The fact that in depressed patients some forms of rTMS also produce similar effects to those described

with the use of conventional pharmacological antidepressants[51] adds strength to the concepts expressed above and

encourage us to apply it to ADHD patients

We concede that rTMS can produce not only a release of amines but also an increase in the production of growth or other trophic factors[43] leading to gene induction modulation and expression[42] and even a release of nitric oxide due

to blood flow changes produced by rTMS[52] The actions of these co-factors could also playa role in leading to the

expected clinical benefits of applying rTMS

Some safety issues must be considered in some of patients since there is a limited experience of possible side-effects

30f8 81182014833 AM

in children and adolescents using TMS particularly rTMS[45] Even though muscle-tension headache that resolved

promptly is the only only side-effect found in children receiving rTMS there is still concern in applying it with pulse

frequencies of 50 Hz or more for periods of several seconds because of the possiblity of seizures[42] At present there

is no reason for applying rTMS at higher frequencies intensities or with longer train durations than those employed in

clinical or research studies Thus frequencies lower than 50 Hz might be used with some confidence in humans until

new safety guidelines on rTMS applications can be published[53] The use of other pharmacological treatment (eg

neuroleptics antidepressants etc) should also be borne in mind when using this tool since such drugs may change cortical excitability and lower seizure thresholds with further increase of the risk of seizures[45]

Some technical considerations should be taken into account as well For example the recent study carried out by Strafella et al[12] demonstrating dopamine release after MDL-PFC stimulation was performed with the subjects eyes

closed This condition modulates the release of dopamine modifies cortical excitability itself[54 55] and could produce a

natural deafferentation that might modify final outcomes Stimulation parameters such as frequency intensity train duration coil size and sham conditions among others must also be considered[42] The individual variations cited with

blood flow and brain metabolism after applying TMS[56] should also be borne in mind when applying rTMS to patients

with ADHD who have been found to have a decreased blood flow and metabolism in the frontal prefrontal and striatum

regions[33 57] Additionally patients with decreased metabolism seem to respond better to higher frequency stimulation

(10 or 20 Hz) with those possessing baseline hypermetabolism responding better to 1 Hz stimulation[42]

If the evidence-based science and experimental effects of rTMS (mostly dopamine modulation) can be replicated in

children with ADHD after systematic clinical research trials to investigate efficacy safety cost-effectiveness and clinical

utility - in comparison to both placebo and standard treatments - we anticipate that this tool and the like might become

an effective and secure treatment to be employed for this neuropsychiatric condition targeting the specific cortical

systems affected Since the available evidence suggests this is a safe and well-tolerated technique for children[58]

rTMS application on ADHD patients is worth trying and we advocate carefully conducted clinical trials the results of which

are awaited with much and obvious interest

References

1 Acosta MT Clinical epidemiological and therapeutical aspects in ADHD Rev Neuro1200031 221

2 Acosta MT Neurobiological aspects in ADHD an update Rev Neuropsicol Neuropsiquiat Neuroc 20001 3-19

3 Castellanos XC Acosta MT ADHD as expression of functional organic disorder Rev Neurologia 2002351-11

4 Mannuzza S Klein RG Bessler A Malloy P Hynes ME Educational and occupational outcome of hyperactive

boys grown up J Am Acad Child Adolesc Psychiatry 1997361222-7

5 Acosta MT Leon-Sarmiento FE ADHD and alcohol abuse in parents Ann NeuroI200252(SuppI1)127

6 Jensen PS Bhatara VS Vitiello B Hoagwood K Feil M Burke LB Psychoactive medication prescribing

practices for US children gaps between research and clinical practice JAm Acad Child Adolesc Psychiatry 199938557-5

7 Acosta MT Montanez P Leon-Sarmiento FE Half brain but not half function Lancet 2002360643

8 Hallett M Functional reorganization after lesions of the human brain studies with transcranial magnetic stimulation Rev Neurol (Paris) 2001 157822-6

9 Leon-Sarmiento FE Electrodiagnostico EEG PE EMG Estimulacion Magnetica In Uribe CS Arana A

Lorenzana P eds Neurologia Medellin CIB 200234-66

10 Ucles P Serrano JL Rosa F Central conduction time of magnetic brain stimulation in attention-deficit

40f8 81182014833 AM

hyperactivity disorder J Child NeuroI200015723-8

11 Moll GH Heinrich H Trott G Wirth S Rothenberger A Deficient intracortical inhibition in drug-naive children with

attention-deficit hyperactivity disorder is enhanced by methylphenidate Neurosci Lett 2000284121-5

12 Strafella AP Paus T Barrett J Dagher A Repetitive transcranial magnetic stimulation of the human prefrontal

cortex induces dopamine release in the caudate nucleus J Neurosci 2001 21 RC157

13 Castellanos FX Giedd IN Marsh WL Hamburger SO Vaituzis AC Dickstein DP et al Quantitative brain

magnetic resonance imaging in attention-deficitlhyperactivity disorder Arch Gen Psychiatry 199653607-16

14 Hynd GW Hern KL Novey ES Eliopulos D Marshall R Gonzalez JJ et al Attention deficit hyperactivity disorder

and asymmetry of the caudate nucleus J Child NeuroI19938339-47

15 Matara M Garcia-Sanchez C Junque C Estevez-Gonzalez A Pujol J Magnetic resonance imaging

measurement of the caudate nucleus in adolescents with attention-deficit hyperactivity disorder and its

relationship with neuropsychological and behavioral measures Arch NeuroI199754963-8

16 Overmeyer S Bullmore ET Suckling J Simmons A Williams SC Santosh PJ et al Distributed grey and white

matter deficits in hyperkinetic disorder MRI evidence for anatomical abnormality in an attentional network

Psychol Med 2001 31 1425-35

17 Mostofsky SH Reiss AL Lockhart P Denckla MB Evaluation of cerebellar size in attention-deficit hyperactivity

disorder J Child NeuroI199813434-9

18 Castellanos FX Giedd IN Berquin PC Walter JM Sharp W Tran T et al Quantitative brain magnetic resonance

imaging in girls with attention-deficitlhyperactivity disorder Arch Gen Psychiatry 2001 58289-95

19 Wender PH Some speculations concerning a possible biochemical basis of minimal brain dysfunction Ann NY

Acad Sci 197320518-28

20 Pliszka SR McCracken JT Maas JW Catecholamines in attention-deficit hyperactivity disorder current

perspectives J Am Acad Child Adolesc Psychiatry 199635264-72

21 Acosta MT Neurobiological and neuropsychological implications from pharmacological treatment of attention

deficit hyperactivity disorder Thesis for obtaining the degree of specialist in child neuropsychology European

Graduate School of Child Neuropsychology and Vrije University Duivendrechtl Amsterdam Netherlands 1997

22 Ernst M Zametkin AJ Matochik JA Jons PH Cohen RM DOPA decarboxylase activity in attention deficit

hyperactivity disorder adults A [fluorine-18]fluorodopa positron emission tomographic study J Neurosci

1998185901-7

23 Krause KH Dresel SH Krause J Kung HF Tatsch K Increased striatal dopamine transporter in adult patients

with attention deficit hyperactivity disorder effects of methylphenidate as measured by Single photon emission

computed tomography Neurosci Lett 2000285107-10

24 Faraone SV Doyle AE Mick E Biederman J Meta-analysis of the association between the 7 -repeat allele of the

dopamine 0(4) receptor gene and attention deficit hyperactivity disorder Am J Psychiatry 2001 1581 052-57

25 Gill M Daly G Heron S Hawi Z Fitzgerald M Confirmation of association between attention deficit hyperactivity

disorder and a dopam ine transporter polymorphism Mol Psychiatry 19972 311-3

26 Swanson JM Flodman P Kennedy J Spence MA Moyzis R Schuck S et al Dopamine genes and ADHD

Neurosci Biobehav Rev 20002421-5

50f8 81182014833 AM

27 Barkley RA Behavioral inhibition sustained attention and executive functions constructing a unifying theory of

ADHD Psychol Bull 1997121 65-94

28 Alexander GE Delong MR Strick Pl Parallel organization of functionally segregated circuits linking basal

ganglia and cortex Annu Rev Neurosci 19869357-81

29 Graybiel AM The basal ganglia and chunking of action repertoires Neurobiol learn Mem 199870119-36

30 Vaidya CJ Austin G Kirkorian G Ridlehuber HW Desmond JE Glover GH et al Selective effects of

methylphenidate in attention deficit hyperactivity disorder a functional magnetic resonance imaging study Proc

NatlAcad Sci USA 19989514494-9

31 Rapoport Jl Buchsbaum MS Zahn TP Weingartner H ludlow C Mikkelsen EJ Dextroamphetamine cognitive

and behavioral effects in normal prepubertal boys Science 1978199560-3

32 lou HC Henriksen l Bruhn P Focal cerebral dysfunction in developmental learning disabilities lancet

19903358-11

33 Zametkin AJ Nordahl TE Gross M King AC Semple WE Rumsey J et al Cerebral glucose metabolism in

adults with hyperactivity of childhood onset N Engl J Med 19903231361-6

34 Solanto MV Dopamine dysfunction in ADHD integrating clinical and basic neuroscience Behav Brain Res 200213065-71

35 Baving l laucht M Schmidt MH Atypical frontal brain activation in ADHD preschool and elementary school boys

and girls J Am Acad Child Adolesc Psychiatry 1999381363-71

36 Rubia K Overmeyer S Taylor E Brammer M Williams SC Simmons A et al Hypofrontality in attention deficit

hyperactivity disorder during higher-order motor control a study with functional MRI Am J Psychiatry 1999156891-6

37 Rapport MD Moffitt C Attention deficithyperactivity disorder and methylphenidate A review of heightweight

cardiovascular and somatic complaint side effects Clin Psycho I Rev 200222 1107 -31

38 The MTA Cooperative Group Multimodal treatments study of children with ADHD A 14-month randomized

clinical trial of treatment strategies for attention-deficithyperactivity disorder Arch Gen Psychiatry 1999561073-86

39 George MS Sallee FR Nahas Z Oliver NC Wassermann EM Transcranial magnetic stimulation (TMS) as a research tool in Tourette syndrome and related disorders Adv Neurol 2001 85225-35

40 Hallett M Transcranial magnetic stimulation and the human brain Nature 2000406147-150

41 Pascual-Leone A The brain that plays music and is changed by it Ann N Y Acad Sci 2001 930315-29

42 Wassermann EM Lisanby SH Therapeutic application of repetitive transcranial magnetic stimulation a review

Clin Neurophysiol 2001 1121367-77

43 Mally J Stone TW Therapeutic and dose-dependent effect of repetitive microelectroshock induced by

transcranial magnetic stimulation in Parkinsons disease J Neurosci Res 199957935-40

44 Burt T Lisanby SH Sackeim HA Neuropsychiatric applications of transcranial magnetic stimulation a meta

analysis Int J Neuropsychopharmacol 2002573-103

60f8 81182014833 AM

45 Lin KL Pascual-Leone A Transcranial magnetic stimulation and its applications in children Chang Gung Med J

2002 25 424-36

46 Shimamoto H Takasaki K Shigemori M Imaizumi T Ayabe M Shoji H Therapeutic effect and mechanism of

repetitive transcranial magnetic stimulation in Parkinsons disease J Neurol 200248 (Suppl 3)48-52

47 Moll GH Heinrich H Trott G Wirth S Rothenberger A Deficient intracortical inhibition in drug-naive children with

attention-deficit hyperactivity disorder is enhanced by methylphenidate Neurosci Lett 2000284121-5

48 Garcia-Toro M Saiz-Ruiz J Talavera JA Blanco C Chaos theories and therapeutic commonalities among

depression Parkinsons disease and cardiac arrhythmias Comp Psychiatry 199940238-44

49 Arnsten AF Steere JC Hunt RD The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical

cognitive function Potential significance for attention-deficit hyperactivity disorder Arch Gen Psychiatry

199653448-55

50 Seeman P Madras B Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of

dopamine a hypothesis Behav Brain Res 200213079-83

51 Levkovitz Y Grisaru N Segal M Transcranial magnetic stimulation and antidepressive drugs share similar cellular

effects in rat hippocampus Neuropsychopharmacology 2001 24608-16

52 Aspide R Gironi Carnevale UA Sergeant JA Sadile AG Non-selective attention and nitric oxide in putative

animal models of Attention-deficit hyperactivity disorder Behav Brain Res 199895123-33

53 Wassermann EM Risk and safety of repetitive transcranial magnetic stimulation report and suggested guidelines

from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation June 5-7 1996

Electroencephalogr Clin Neurophysiol19981 081-16

54 Leon-Sarmiento FE Hanft RT Bara W Hallett M Wassermann E The influence of visual activation tasks on

motor cortex excitability studied with transcranial magnetic stimulation 2002 wwwabstractshy

on-linecomabstractsAAN

55 Omura Y Losco BM Takeshige C Non-invasive evaluation of the effects of opening and closing of eyes and of

exposure to a minute light beam as well as to electrical or magnetic field on the melatonin serotonin amp other

neuro-transmitters of human pineal gland representation areas amp the heart Acupunct Electrother Res

199318125-51

56 George MS Nahas Z Bohning DE et a TMS and neuroimaging In George M and Belmaker RH eds

Transcraneal Magnetic Stimulation in Neuropsychiatry Washington DC American Psychiatric Press 2000253-68

57 Kim BN Lee JS Cho SC Lee DS Methylphenidate increased regional cerebral blood flow in subjects with

attention deficithyperactivity disorder Yonsei Med J 2001 4219-29

58 Garvey MA Kaczynski KJ Becker DA Bartko JJ Subjective reactions of children to single-pulse transcranial

magnetic stimulation J Child Neurol 2001 16891-4

Acknowledgments

The authors would like to thank Nicole Schleper for English revisions The opinions expressed here are solely the responsibility of the authors

Reprint Address

Address for correspondence Dr Fidias E Leon-Sarmiento 10 Center Drive Building 10 Room 5N234 Brain

70f8 81182014833 AM

among others[39-43] Regarding ADHD specifically TMS seems to be an ideal method for studying the maturational

process of the motor pathways since it clearly excites the corticomotoneuronal system presumed to be involved in this disorder [10]

Ucles et al[10] using single stimulation in children with ADHD found a prolongation of central motor conduction time as

well as some side-to-side stimulation differences compared with those found in age- and sex-matched controls These

findings demonstrated a delay in the maturation of the corticomotoneuronal system in patients with ADHD Moll et a[11]

reported that children with ADHD had significantly reduced intracortical inhibition (ICI) with a normal intracortical

facilitation compared to healthy controls and such ICI showed improvement after giving 10 mg of MPH However most

of the morphophysioneurochemical hallmarks of ADHD involving prefrontal-caudate-cerebellar pathways with noteworthy

dopaminergic abnormalities have not yet been taken into account Therefore we consider that they should be the current

focus if rTMS is to be employed as a therapeutic option

rTMS has been found effective in Parkinson disease depreSSion obsessive-compulsive disorder Tourettes syndrome

and some types of tic[42-44] With regard to children rTMS has been tried with a small number of patients with action

myoclonus progressive myoclonic epilepsy bipolar disorder major depression and schizophrenia45 with some

promising albeit short-lasting positive results Some of these disorders are due to dopamine abnormalities and share

some genetic clinical biochemical neuranatomical and neuro-behavioural similarities with ADHD Even though a complete understanding of the mechanism of action of rTMS has not been developed [42] it is now clear that rTMS at low

frequencies could cause long-term depression of cortico-cortical transmission in normals43 as well as improvement of

symptoms of some neuropsychiatric disorders commented on above including the modulation of several

neurotransmitters such as dopamine and its metabolites (eg homovanilic acid) mainly after prefrontal cortex stimulation [46]

It should also be noted that modulation of dopamine release could be due to GABAergic and glutamatergic

corticostriatal projection the latter being spared in ADHD In fact the recent reduced ICI found in patients with ADHD and demonstrated by TMS is known to be modulated by GABAergic synapsis[47] suggesting that a cortical instability in

the excitatory and inhibitory signals interexchange is present in this disease[48]It is therefore likely that parasitic foci of

autonomous electrical or magnetic neuronal activity modifying the input-output neural shortcuts and decreasing the

appropriate integration and complex dynamics of the CNS as suggested elsewhere[48] seem also to be present in

ADHD patients and perhaps associated conditions Such cortical instability with an imbalance between the so-called

direct and indirect cortical pathways mediating sensory-motor integration might be the most important target for applying the appropriate rTMS treatment in this disorder[12 34]

Because of this the recent findings reported by Strafella et al[12] may may be significant in ADHD cases These authors

showed that rTMS applied to the left mid-dorsolateral prefrontal cortex (MDL-PFC) induced the release of endogenous

dopamine from the left caudate as a consequence of direct corticostriatal axon stimulation increasing the extracellular dopamine concentration measured by the [11C]raclopride binding method[49] These findings are more than interesting

because the clinical benefits of MPH seem to be due to an increase in the resting extracellular levels of dopamine

lowering the levels of pulsatile release of it as well These pharmacological effects also produce a decreased activation of postsynaptic dopamine receptors involved in psychomotor activity modulation[50] making it possible to suggest that a

similar mechanism of action leading to the improvement of clinical symptoms might be considered in ADHD after

applying rTMS The fact that in depressed patients some forms of rTMS also produce similar effects to those described

with the use of conventional pharmacological antidepressants[51] adds strength to the concepts expressed above and

encourage us to apply it to ADHD patients

We concede that rTMS can produce not only a release of amines but also an increase in the production of growth or other trophic factors[43] leading to gene induction modulation and expression[42] and even a release of nitric oxide due

to blood flow changes produced by rTMS[52] The actions of these co-factors could also playa role in leading to the

expected clinical benefits of applying rTMS

Some safety issues must be considered in some of patients since there is a limited experience of possible side-effects

30f8 81182014833 AM

in children and adolescents using TMS particularly rTMS[45] Even though muscle-tension headache that resolved

promptly is the only only side-effect found in children receiving rTMS there is still concern in applying it with pulse

frequencies of 50 Hz or more for periods of several seconds because of the possiblity of seizures[42] At present there

is no reason for applying rTMS at higher frequencies intensities or with longer train durations than those employed in

clinical or research studies Thus frequencies lower than 50 Hz might be used with some confidence in humans until

new safety guidelines on rTMS applications can be published[53] The use of other pharmacological treatment (eg

neuroleptics antidepressants etc) should also be borne in mind when using this tool since such drugs may change cortical excitability and lower seizure thresholds with further increase of the risk of seizures[45]

Some technical considerations should be taken into account as well For example the recent study carried out by Strafella et al[12] demonstrating dopamine release after MDL-PFC stimulation was performed with the subjects eyes

closed This condition modulates the release of dopamine modifies cortical excitability itself[54 55] and could produce a

natural deafferentation that might modify final outcomes Stimulation parameters such as frequency intensity train duration coil size and sham conditions among others must also be considered[42] The individual variations cited with

blood flow and brain metabolism after applying TMS[56] should also be borne in mind when applying rTMS to patients

with ADHD who have been found to have a decreased blood flow and metabolism in the frontal prefrontal and striatum

regions[33 57] Additionally patients with decreased metabolism seem to respond better to higher frequency stimulation

(10 or 20 Hz) with those possessing baseline hypermetabolism responding better to 1 Hz stimulation[42]

If the evidence-based science and experimental effects of rTMS (mostly dopamine modulation) can be replicated in

children with ADHD after systematic clinical research trials to investigate efficacy safety cost-effectiveness and clinical

utility - in comparison to both placebo and standard treatments - we anticipate that this tool and the like might become

an effective and secure treatment to be employed for this neuropsychiatric condition targeting the specific cortical

systems affected Since the available evidence suggests this is a safe and well-tolerated technique for children[58]

rTMS application on ADHD patients is worth trying and we advocate carefully conducted clinical trials the results of which

are awaited with much and obvious interest

References

1 Acosta MT Clinical epidemiological and therapeutical aspects in ADHD Rev Neuro1200031 221

2 Acosta MT Neurobiological aspects in ADHD an update Rev Neuropsicol Neuropsiquiat Neuroc 20001 3-19

3 Castellanos XC Acosta MT ADHD as expression of functional organic disorder Rev Neurologia 2002351-11

4 Mannuzza S Klein RG Bessler A Malloy P Hynes ME Educational and occupational outcome of hyperactive

boys grown up J Am Acad Child Adolesc Psychiatry 1997361222-7

5 Acosta MT Leon-Sarmiento FE ADHD and alcohol abuse in parents Ann NeuroI200252(SuppI1)127

6 Jensen PS Bhatara VS Vitiello B Hoagwood K Feil M Burke LB Psychoactive medication prescribing

practices for US children gaps between research and clinical practice JAm Acad Child Adolesc Psychiatry 199938557-5

7 Acosta MT Montanez P Leon-Sarmiento FE Half brain but not half function Lancet 2002360643

8 Hallett M Functional reorganization after lesions of the human brain studies with transcranial magnetic stimulation Rev Neurol (Paris) 2001 157822-6

9 Leon-Sarmiento FE Electrodiagnostico EEG PE EMG Estimulacion Magnetica In Uribe CS Arana A

Lorenzana P eds Neurologia Medellin CIB 200234-66

10 Ucles P Serrano JL Rosa F Central conduction time of magnetic brain stimulation in attention-deficit

40f8 81182014833 AM

hyperactivity disorder J Child NeuroI200015723-8

11 Moll GH Heinrich H Trott G Wirth S Rothenberger A Deficient intracortical inhibition in drug-naive children with

attention-deficit hyperactivity disorder is enhanced by methylphenidate Neurosci Lett 2000284121-5

12 Strafella AP Paus T Barrett J Dagher A Repetitive transcranial magnetic stimulation of the human prefrontal

cortex induces dopamine release in the caudate nucleus J Neurosci 2001 21 RC157

13 Castellanos FX Giedd IN Marsh WL Hamburger SO Vaituzis AC Dickstein DP et al Quantitative brain

magnetic resonance imaging in attention-deficitlhyperactivity disorder Arch Gen Psychiatry 199653607-16

14 Hynd GW Hern KL Novey ES Eliopulos D Marshall R Gonzalez JJ et al Attention deficit hyperactivity disorder

and asymmetry of the caudate nucleus J Child NeuroI19938339-47

15 Matara M Garcia-Sanchez C Junque C Estevez-Gonzalez A Pujol J Magnetic resonance imaging

measurement of the caudate nucleus in adolescents with attention-deficit hyperactivity disorder and its

relationship with neuropsychological and behavioral measures Arch NeuroI199754963-8

16 Overmeyer S Bullmore ET Suckling J Simmons A Williams SC Santosh PJ et al Distributed grey and white

matter deficits in hyperkinetic disorder MRI evidence for anatomical abnormality in an attentional network

Psychol Med 2001 31 1425-35

17 Mostofsky SH Reiss AL Lockhart P Denckla MB Evaluation of cerebellar size in attention-deficit hyperactivity

disorder J Child NeuroI199813434-9

18 Castellanos FX Giedd IN Berquin PC Walter JM Sharp W Tran T et al Quantitative brain magnetic resonance

imaging in girls with attention-deficitlhyperactivity disorder Arch Gen Psychiatry 2001 58289-95

19 Wender PH Some speculations concerning a possible biochemical basis of minimal brain dysfunction Ann NY

Acad Sci 197320518-28

20 Pliszka SR McCracken JT Maas JW Catecholamines in attention-deficit hyperactivity disorder current

perspectives J Am Acad Child Adolesc Psychiatry 199635264-72

21 Acosta MT Neurobiological and neuropsychological implications from pharmacological treatment of attention

deficit hyperactivity disorder Thesis for obtaining the degree of specialist in child neuropsychology European

Graduate School of Child Neuropsychology and Vrije University Duivendrechtl Amsterdam Netherlands 1997

22 Ernst M Zametkin AJ Matochik JA Jons PH Cohen RM DOPA decarboxylase activity in attention deficit

hyperactivity disorder adults A [fluorine-18]fluorodopa positron emission tomographic study J Neurosci

1998185901-7

23 Krause KH Dresel SH Krause J Kung HF Tatsch K Increased striatal dopamine transporter in adult patients

with attention deficit hyperactivity disorder effects of methylphenidate as measured by Single photon emission

computed tomography Neurosci Lett 2000285107-10

24 Faraone SV Doyle AE Mick E Biederman J Meta-analysis of the association between the 7 -repeat allele of the

dopamine 0(4) receptor gene and attention deficit hyperactivity disorder Am J Psychiatry 2001 1581 052-57

25 Gill M Daly G Heron S Hawi Z Fitzgerald M Confirmation of association between attention deficit hyperactivity

disorder and a dopam ine transporter polymorphism Mol Psychiatry 19972 311-3

26 Swanson JM Flodman P Kennedy J Spence MA Moyzis R Schuck S et al Dopamine genes and ADHD

Neurosci Biobehav Rev 20002421-5

50f8 81182014833 AM

27 Barkley RA Behavioral inhibition sustained attention and executive functions constructing a unifying theory of

ADHD Psychol Bull 1997121 65-94

28 Alexander GE Delong MR Strick Pl Parallel organization of functionally segregated circuits linking basal

ganglia and cortex Annu Rev Neurosci 19869357-81

29 Graybiel AM The basal ganglia and chunking of action repertoires Neurobiol learn Mem 199870119-36

30 Vaidya CJ Austin G Kirkorian G Ridlehuber HW Desmond JE Glover GH et al Selective effects of

methylphenidate in attention deficit hyperactivity disorder a functional magnetic resonance imaging study Proc

NatlAcad Sci USA 19989514494-9

31 Rapoport Jl Buchsbaum MS Zahn TP Weingartner H ludlow C Mikkelsen EJ Dextroamphetamine cognitive

and behavioral effects in normal prepubertal boys Science 1978199560-3

32 lou HC Henriksen l Bruhn P Focal cerebral dysfunction in developmental learning disabilities lancet

19903358-11

33 Zametkin AJ Nordahl TE Gross M King AC Semple WE Rumsey J et al Cerebral glucose metabolism in

adults with hyperactivity of childhood onset N Engl J Med 19903231361-6

34 Solanto MV Dopamine dysfunction in ADHD integrating clinical and basic neuroscience Behav Brain Res 200213065-71

35 Baving l laucht M Schmidt MH Atypical frontal brain activation in ADHD preschool and elementary school boys

and girls J Am Acad Child Adolesc Psychiatry 1999381363-71

36 Rubia K Overmeyer S Taylor E Brammer M Williams SC Simmons A et al Hypofrontality in attention deficit

hyperactivity disorder during higher-order motor control a study with functional MRI Am J Psychiatry 1999156891-6

37 Rapport MD Moffitt C Attention deficithyperactivity disorder and methylphenidate A review of heightweight

cardiovascular and somatic complaint side effects Clin Psycho I Rev 200222 1107 -31

38 The MTA Cooperative Group Multimodal treatments study of children with ADHD A 14-month randomized

clinical trial of treatment strategies for attention-deficithyperactivity disorder Arch Gen Psychiatry 1999561073-86

39 George MS Sallee FR Nahas Z Oliver NC Wassermann EM Transcranial magnetic stimulation (TMS) as a research tool in Tourette syndrome and related disorders Adv Neurol 2001 85225-35

40 Hallett M Transcranial magnetic stimulation and the human brain Nature 2000406147-150

41 Pascual-Leone A The brain that plays music and is changed by it Ann N Y Acad Sci 2001 930315-29

42 Wassermann EM Lisanby SH Therapeutic application of repetitive transcranial magnetic stimulation a review

Clin Neurophysiol 2001 1121367-77

43 Mally J Stone TW Therapeutic and dose-dependent effect of repetitive microelectroshock induced by

transcranial magnetic stimulation in Parkinsons disease J Neurosci Res 199957935-40

44 Burt T Lisanby SH Sackeim HA Neuropsychiatric applications of transcranial magnetic stimulation a meta

analysis Int J Neuropsychopharmacol 2002573-103

60f8 81182014833 AM

45 Lin KL Pascual-Leone A Transcranial magnetic stimulation and its applications in children Chang Gung Med J

2002 25 424-36

46 Shimamoto H Takasaki K Shigemori M Imaizumi T Ayabe M Shoji H Therapeutic effect and mechanism of

repetitive transcranial magnetic stimulation in Parkinsons disease J Neurol 200248 (Suppl 3)48-52

47 Moll GH Heinrich H Trott G Wirth S Rothenberger A Deficient intracortical inhibition in drug-naive children with

attention-deficit hyperactivity disorder is enhanced by methylphenidate Neurosci Lett 2000284121-5

48 Garcia-Toro M Saiz-Ruiz J Talavera JA Blanco C Chaos theories and therapeutic commonalities among

depression Parkinsons disease and cardiac arrhythmias Comp Psychiatry 199940238-44

49 Arnsten AF Steere JC Hunt RD The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical

cognitive function Potential significance for attention-deficit hyperactivity disorder Arch Gen Psychiatry

199653448-55

50 Seeman P Madras B Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of

dopamine a hypothesis Behav Brain Res 200213079-83

51 Levkovitz Y Grisaru N Segal M Transcranial magnetic stimulation and antidepressive drugs share similar cellular

effects in rat hippocampus Neuropsychopharmacology 2001 24608-16

52 Aspide R Gironi Carnevale UA Sergeant JA Sadile AG Non-selective attention and nitric oxide in putative

animal models of Attention-deficit hyperactivity disorder Behav Brain Res 199895123-33

53 Wassermann EM Risk and safety of repetitive transcranial magnetic stimulation report and suggested guidelines

from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation June 5-7 1996

Electroencephalogr Clin Neurophysiol19981 081-16

54 Leon-Sarmiento FE Hanft RT Bara W Hallett M Wassermann E The influence of visual activation tasks on

motor cortex excitability studied with transcranial magnetic stimulation 2002 wwwabstractshy

on-linecomabstractsAAN

55 Omura Y Losco BM Takeshige C Non-invasive evaluation of the effects of opening and closing of eyes and of

exposure to a minute light beam as well as to electrical or magnetic field on the melatonin serotonin amp other

neuro-transmitters of human pineal gland representation areas amp the heart Acupunct Electrother Res

199318125-51

56 George MS Nahas Z Bohning DE et a TMS and neuroimaging In George M and Belmaker RH eds

Transcraneal Magnetic Stimulation in Neuropsychiatry Washington DC American Psychiatric Press 2000253-68

57 Kim BN Lee JS Cho SC Lee DS Methylphenidate increased regional cerebral blood flow in subjects with

attention deficithyperactivity disorder Yonsei Med J 2001 4219-29

58 Garvey MA Kaczynski KJ Becker DA Bartko JJ Subjective reactions of children to single-pulse transcranial

magnetic stimulation J Child Neurol 2001 16891-4

Acknowledgments

The authors would like to thank Nicole Schleper for English revisions The opinions expressed here are solely the responsibility of the authors

Reprint Address

Address for correspondence Dr Fidias E Leon-Sarmiento 10 Center Drive Building 10 Room 5N234 Brain

70f8 81182014833 AM

in children and adolescents using TMS particularly rTMS[45] Even though muscle-tension headache that resolved

promptly is the only only side-effect found in children receiving rTMS there is still concern in applying it with pulse

frequencies of 50 Hz or more for periods of several seconds because of the possiblity of seizures[42] At present there

is no reason for applying rTMS at higher frequencies intensities or with longer train durations than those employed in

clinical or research studies Thus frequencies lower than 50 Hz might be used with some confidence in humans until

new safety guidelines on rTMS applications can be published[53] The use of other pharmacological treatment (eg

neuroleptics antidepressants etc) should also be borne in mind when using this tool since such drugs may change cortical excitability and lower seizure thresholds with further increase of the risk of seizures[45]

Some technical considerations should be taken into account as well For example the recent study carried out by Strafella et al[12] demonstrating dopamine release after MDL-PFC stimulation was performed with the subjects eyes

closed This condition modulates the release of dopamine modifies cortical excitability itself[54 55] and could produce a

natural deafferentation that might modify final outcomes Stimulation parameters such as frequency intensity train duration coil size and sham conditions among others must also be considered[42] The individual variations cited with

blood flow and brain metabolism after applying TMS[56] should also be borne in mind when applying rTMS to patients

with ADHD who have been found to have a decreased blood flow and metabolism in the frontal prefrontal and striatum

regions[33 57] Additionally patients with decreased metabolism seem to respond better to higher frequency stimulation

(10 or 20 Hz) with those possessing baseline hypermetabolism responding better to 1 Hz stimulation[42]

If the evidence-based science and experimental effects of rTMS (mostly dopamine modulation) can be replicated in

children with ADHD after systematic clinical research trials to investigate efficacy safety cost-effectiveness and clinical

utility - in comparison to both placebo and standard treatments - we anticipate that this tool and the like might become

an effective and secure treatment to be employed for this neuropsychiatric condition targeting the specific cortical

systems affected Since the available evidence suggests this is a safe and well-tolerated technique for children[58]

rTMS application on ADHD patients is worth trying and we advocate carefully conducted clinical trials the results of which

are awaited with much and obvious interest

References

1 Acosta MT Clinical epidemiological and therapeutical aspects in ADHD Rev Neuro1200031 221

2 Acosta MT Neurobiological aspects in ADHD an update Rev Neuropsicol Neuropsiquiat Neuroc 20001 3-19

3 Castellanos XC Acosta MT ADHD as expression of functional organic disorder Rev Neurologia 2002351-11

4 Mannuzza S Klein RG Bessler A Malloy P Hynes ME Educational and occupational outcome of hyperactive

boys grown up J Am Acad Child Adolesc Psychiatry 1997361222-7

5 Acosta MT Leon-Sarmiento FE ADHD and alcohol abuse in parents Ann NeuroI200252(SuppI1)127

6 Jensen PS Bhatara VS Vitiello B Hoagwood K Feil M Burke LB Psychoactive medication prescribing

practices for US children gaps between research and clinical practice JAm Acad Child Adolesc Psychiatry 199938557-5

7 Acosta MT Montanez P Leon-Sarmiento FE Half brain but not half function Lancet 2002360643

8 Hallett M Functional reorganization after lesions of the human brain studies with transcranial magnetic stimulation Rev Neurol (Paris) 2001 157822-6

9 Leon-Sarmiento FE Electrodiagnostico EEG PE EMG Estimulacion Magnetica In Uribe CS Arana A

Lorenzana P eds Neurologia Medellin CIB 200234-66

10 Ucles P Serrano JL Rosa F Central conduction time of magnetic brain stimulation in attention-deficit

40f8 81182014833 AM

hyperactivity disorder J Child NeuroI200015723-8

11 Moll GH Heinrich H Trott G Wirth S Rothenberger A Deficient intracortical inhibition in drug-naive children with

attention-deficit hyperactivity disorder is enhanced by methylphenidate Neurosci Lett 2000284121-5

12 Strafella AP Paus T Barrett J Dagher A Repetitive transcranial magnetic stimulation of the human prefrontal

cortex induces dopamine release in the caudate nucleus J Neurosci 2001 21 RC157

13 Castellanos FX Giedd IN Marsh WL Hamburger SO Vaituzis AC Dickstein DP et al Quantitative brain

magnetic resonance imaging in attention-deficitlhyperactivity disorder Arch Gen Psychiatry 199653607-16

14 Hynd GW Hern KL Novey ES Eliopulos D Marshall R Gonzalez JJ et al Attention deficit hyperactivity disorder

and asymmetry of the caudate nucleus J Child NeuroI19938339-47

15 Matara M Garcia-Sanchez C Junque C Estevez-Gonzalez A Pujol J Magnetic resonance imaging

measurement of the caudate nucleus in adolescents with attention-deficit hyperactivity disorder and its

relationship with neuropsychological and behavioral measures Arch NeuroI199754963-8

16 Overmeyer S Bullmore ET Suckling J Simmons A Williams SC Santosh PJ et al Distributed grey and white

matter deficits in hyperkinetic disorder MRI evidence for anatomical abnormality in an attentional network

Psychol Med 2001 31 1425-35

17 Mostofsky SH Reiss AL Lockhart P Denckla MB Evaluation of cerebellar size in attention-deficit hyperactivity

disorder J Child NeuroI199813434-9

18 Castellanos FX Giedd IN Berquin PC Walter JM Sharp W Tran T et al Quantitative brain magnetic resonance

imaging in girls with attention-deficitlhyperactivity disorder Arch Gen Psychiatry 2001 58289-95

19 Wender PH Some speculations concerning a possible biochemical basis of minimal brain dysfunction Ann NY

Acad Sci 197320518-28

20 Pliszka SR McCracken JT Maas JW Catecholamines in attention-deficit hyperactivity disorder current

perspectives J Am Acad Child Adolesc Psychiatry 199635264-72

21 Acosta MT Neurobiological and neuropsychological implications from pharmacological treatment of attention

deficit hyperactivity disorder Thesis for obtaining the degree of specialist in child neuropsychology European

Graduate School of Child Neuropsychology and Vrije University Duivendrechtl Amsterdam Netherlands 1997

22 Ernst M Zametkin AJ Matochik JA Jons PH Cohen RM DOPA decarboxylase activity in attention deficit

hyperactivity disorder adults A [fluorine-18]fluorodopa positron emission tomographic study J Neurosci

1998185901-7

23 Krause KH Dresel SH Krause J Kung HF Tatsch K Increased striatal dopamine transporter in adult patients

with attention deficit hyperactivity disorder effects of methylphenidate as measured by Single photon emission

computed tomography Neurosci Lett 2000285107-10

24 Faraone SV Doyle AE Mick E Biederman J Meta-analysis of the association between the 7 -repeat allele of the

dopamine 0(4) receptor gene and attention deficit hyperactivity disorder Am J Psychiatry 2001 1581 052-57

25 Gill M Daly G Heron S Hawi Z Fitzgerald M Confirmation of association between attention deficit hyperactivity

disorder and a dopam ine transporter polymorphism Mol Psychiatry 19972 311-3

26 Swanson JM Flodman P Kennedy J Spence MA Moyzis R Schuck S et al Dopamine genes and ADHD

Neurosci Biobehav Rev 20002421-5

50f8 81182014833 AM

27 Barkley RA Behavioral inhibition sustained attention and executive functions constructing a unifying theory of

ADHD Psychol Bull 1997121 65-94

28 Alexander GE Delong MR Strick Pl Parallel organization of functionally segregated circuits linking basal

ganglia and cortex Annu Rev Neurosci 19869357-81

29 Graybiel AM The basal ganglia and chunking of action repertoires Neurobiol learn Mem 199870119-36

30 Vaidya CJ Austin G Kirkorian G Ridlehuber HW Desmond JE Glover GH et al Selective effects of

methylphenidate in attention deficit hyperactivity disorder a functional magnetic resonance imaging study Proc

NatlAcad Sci USA 19989514494-9

31 Rapoport Jl Buchsbaum MS Zahn TP Weingartner H ludlow C Mikkelsen EJ Dextroamphetamine cognitive

and behavioral effects in normal prepubertal boys Science 1978199560-3

32 lou HC Henriksen l Bruhn P Focal cerebral dysfunction in developmental learning disabilities lancet

19903358-11

33 Zametkin AJ Nordahl TE Gross M King AC Semple WE Rumsey J et al Cerebral glucose metabolism in

adults with hyperactivity of childhood onset N Engl J Med 19903231361-6

34 Solanto MV Dopamine dysfunction in ADHD integrating clinical and basic neuroscience Behav Brain Res 200213065-71

35 Baving l laucht M Schmidt MH Atypical frontal brain activation in ADHD preschool and elementary school boys

and girls J Am Acad Child Adolesc Psychiatry 1999381363-71

36 Rubia K Overmeyer S Taylor E Brammer M Williams SC Simmons A et al Hypofrontality in attention deficit

hyperactivity disorder during higher-order motor control a study with functional MRI Am J Psychiatry 1999156891-6

37 Rapport MD Moffitt C Attention deficithyperactivity disorder and methylphenidate A review of heightweight

cardiovascular and somatic complaint side effects Clin Psycho I Rev 200222 1107 -31

38 The MTA Cooperative Group Multimodal treatments study of children with ADHD A 14-month randomized

clinical trial of treatment strategies for attention-deficithyperactivity disorder Arch Gen Psychiatry 1999561073-86

39 George MS Sallee FR Nahas Z Oliver NC Wassermann EM Transcranial magnetic stimulation (TMS) as a research tool in Tourette syndrome and related disorders Adv Neurol 2001 85225-35

40 Hallett M Transcranial magnetic stimulation and the human brain Nature 2000406147-150

41 Pascual-Leone A The brain that plays music and is changed by it Ann N Y Acad Sci 2001 930315-29

42 Wassermann EM Lisanby SH Therapeutic application of repetitive transcranial magnetic stimulation a review

Clin Neurophysiol 2001 1121367-77

43 Mally J Stone TW Therapeutic and dose-dependent effect of repetitive microelectroshock induced by

transcranial magnetic stimulation in Parkinsons disease J Neurosci Res 199957935-40

44 Burt T Lisanby SH Sackeim HA Neuropsychiatric applications of transcranial magnetic stimulation a meta

analysis Int J Neuropsychopharmacol 2002573-103

60f8 81182014833 AM

45 Lin KL Pascual-Leone A Transcranial magnetic stimulation and its applications in children Chang Gung Med J

2002 25 424-36

46 Shimamoto H Takasaki K Shigemori M Imaizumi T Ayabe M Shoji H Therapeutic effect and mechanism of

repetitive transcranial magnetic stimulation in Parkinsons disease J Neurol 200248 (Suppl 3)48-52

47 Moll GH Heinrich H Trott G Wirth S Rothenberger A Deficient intracortical inhibition in drug-naive children with

attention-deficit hyperactivity disorder is enhanced by methylphenidate Neurosci Lett 2000284121-5

48 Garcia-Toro M Saiz-Ruiz J Talavera JA Blanco C Chaos theories and therapeutic commonalities among

depression Parkinsons disease and cardiac arrhythmias Comp Psychiatry 199940238-44

49 Arnsten AF Steere JC Hunt RD The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical

cognitive function Potential significance for attention-deficit hyperactivity disorder Arch Gen Psychiatry

199653448-55

50 Seeman P Madras B Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of

dopamine a hypothesis Behav Brain Res 200213079-83

51 Levkovitz Y Grisaru N Segal M Transcranial magnetic stimulation and antidepressive drugs share similar cellular

effects in rat hippocampus Neuropsychopharmacology 2001 24608-16

52 Aspide R Gironi Carnevale UA Sergeant JA Sadile AG Non-selective attention and nitric oxide in putative

animal models of Attention-deficit hyperactivity disorder Behav Brain Res 199895123-33

53 Wassermann EM Risk and safety of repetitive transcranial magnetic stimulation report and suggested guidelines

from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation June 5-7 1996

Electroencephalogr Clin Neurophysiol19981 081-16

54 Leon-Sarmiento FE Hanft RT Bara W Hallett M Wassermann E The influence of visual activation tasks on

motor cortex excitability studied with transcranial magnetic stimulation 2002 wwwabstractshy

on-linecomabstractsAAN

55 Omura Y Losco BM Takeshige C Non-invasive evaluation of the effects of opening and closing of eyes and of

exposure to a minute light beam as well as to electrical or magnetic field on the melatonin serotonin amp other

neuro-transmitters of human pineal gland representation areas amp the heart Acupunct Electrother Res

199318125-51

56 George MS Nahas Z Bohning DE et a TMS and neuroimaging In George M and Belmaker RH eds

Transcraneal Magnetic Stimulation in Neuropsychiatry Washington DC American Psychiatric Press 2000253-68

57 Kim BN Lee JS Cho SC Lee DS Methylphenidate increased regional cerebral blood flow in subjects with

attention deficithyperactivity disorder Yonsei Med J 2001 4219-29

58 Garvey MA Kaczynski KJ Becker DA Bartko JJ Subjective reactions of children to single-pulse transcranial

magnetic stimulation J Child Neurol 2001 16891-4

Acknowledgments

The authors would like to thank Nicole Schleper for English revisions The opinions expressed here are solely the responsibility of the authors

Reprint Address

Address for correspondence Dr Fidias E Leon-Sarmiento 10 Center Drive Building 10 Room 5N234 Brain

70f8 81182014833 AM

hyperactivity disorder J Child NeuroI200015723-8

11 Moll GH Heinrich H Trott G Wirth S Rothenberger A Deficient intracortical inhibition in drug-naive children with

attention-deficit hyperactivity disorder is enhanced by methylphenidate Neurosci Lett 2000284121-5

12 Strafella AP Paus T Barrett J Dagher A Repetitive transcranial magnetic stimulation of the human prefrontal

cortex induces dopamine release in the caudate nucleus J Neurosci 2001 21 RC157

13 Castellanos FX Giedd IN Marsh WL Hamburger SO Vaituzis AC Dickstein DP et al Quantitative brain

magnetic resonance imaging in attention-deficitlhyperactivity disorder Arch Gen Psychiatry 199653607-16

14 Hynd GW Hern KL Novey ES Eliopulos D Marshall R Gonzalez JJ et al Attention deficit hyperactivity disorder

and asymmetry of the caudate nucleus J Child NeuroI19938339-47

15 Matara M Garcia-Sanchez C Junque C Estevez-Gonzalez A Pujol J Magnetic resonance imaging

measurement of the caudate nucleus in adolescents with attention-deficit hyperactivity disorder and its

relationship with neuropsychological and behavioral measures Arch NeuroI199754963-8

16 Overmeyer S Bullmore ET Suckling J Simmons A Williams SC Santosh PJ et al Distributed grey and white

matter deficits in hyperkinetic disorder MRI evidence for anatomical abnormality in an attentional network

Psychol Med 2001 31 1425-35

17 Mostofsky SH Reiss AL Lockhart P Denckla MB Evaluation of cerebellar size in attention-deficit hyperactivity

disorder J Child NeuroI199813434-9

18 Castellanos FX Giedd IN Berquin PC Walter JM Sharp W Tran T et al Quantitative brain magnetic resonance

imaging in girls with attention-deficitlhyperactivity disorder Arch Gen Psychiatry 2001 58289-95

19 Wender PH Some speculations concerning a possible biochemical basis of minimal brain dysfunction Ann NY

Acad Sci 197320518-28

20 Pliszka SR McCracken JT Maas JW Catecholamines in attention-deficit hyperactivity disorder current

perspectives J Am Acad Child Adolesc Psychiatry 199635264-72

21 Acosta MT Neurobiological and neuropsychological implications from pharmacological treatment of attention

deficit hyperactivity disorder Thesis for obtaining the degree of specialist in child neuropsychology European

Graduate School of Child Neuropsychology and Vrije University Duivendrechtl Amsterdam Netherlands 1997

22 Ernst M Zametkin AJ Matochik JA Jons PH Cohen RM DOPA decarboxylase activity in attention deficit

hyperactivity disorder adults A [fluorine-18]fluorodopa positron emission tomographic study J Neurosci

1998185901-7

23 Krause KH Dresel SH Krause J Kung HF Tatsch K Increased striatal dopamine transporter in adult patients

with attention deficit hyperactivity disorder effects of methylphenidate as measured by Single photon emission

computed tomography Neurosci Lett 2000285107-10

24 Faraone SV Doyle AE Mick E Biederman J Meta-analysis of the association between the 7 -repeat allele of the

dopamine 0(4) receptor gene and attention deficit hyperactivity disorder Am J Psychiatry 2001 1581 052-57

25 Gill M Daly G Heron S Hawi Z Fitzgerald M Confirmation of association between attention deficit hyperactivity

disorder and a dopam ine transporter polymorphism Mol Psychiatry 19972 311-3

26 Swanson JM Flodman P Kennedy J Spence MA Moyzis R Schuck S et al Dopamine genes and ADHD

Neurosci Biobehav Rev 20002421-5

50f8 81182014833 AM

27 Barkley RA Behavioral inhibition sustained attention and executive functions constructing a unifying theory of

ADHD Psychol Bull 1997121 65-94

28 Alexander GE Delong MR Strick Pl Parallel organization of functionally segregated circuits linking basal

ganglia and cortex Annu Rev Neurosci 19869357-81

29 Graybiel AM The basal ganglia and chunking of action repertoires Neurobiol learn Mem 199870119-36

30 Vaidya CJ Austin G Kirkorian G Ridlehuber HW Desmond JE Glover GH et al Selective effects of

methylphenidate in attention deficit hyperactivity disorder a functional magnetic resonance imaging study Proc

NatlAcad Sci USA 19989514494-9

31 Rapoport Jl Buchsbaum MS Zahn TP Weingartner H ludlow C Mikkelsen EJ Dextroamphetamine cognitive

and behavioral effects in normal prepubertal boys Science 1978199560-3

32 lou HC Henriksen l Bruhn P Focal cerebral dysfunction in developmental learning disabilities lancet

19903358-11

33 Zametkin AJ Nordahl TE Gross M King AC Semple WE Rumsey J et al Cerebral glucose metabolism in

adults with hyperactivity of childhood onset N Engl J Med 19903231361-6

34 Solanto MV Dopamine dysfunction in ADHD integrating clinical and basic neuroscience Behav Brain Res 200213065-71

35 Baving l laucht M Schmidt MH Atypical frontal brain activation in ADHD preschool and elementary school boys

and girls J Am Acad Child Adolesc Psychiatry 1999381363-71

36 Rubia K Overmeyer S Taylor E Brammer M Williams SC Simmons A et al Hypofrontality in attention deficit

hyperactivity disorder during higher-order motor control a study with functional MRI Am J Psychiatry 1999156891-6

37 Rapport MD Moffitt C Attention deficithyperactivity disorder and methylphenidate A review of heightweight

cardiovascular and somatic complaint side effects Clin Psycho I Rev 200222 1107 -31

38 The MTA Cooperative Group Multimodal treatments study of children with ADHD A 14-month randomized

clinical trial of treatment strategies for attention-deficithyperactivity disorder Arch Gen Psychiatry 1999561073-86

39 George MS Sallee FR Nahas Z Oliver NC Wassermann EM Transcranial magnetic stimulation (TMS) as a research tool in Tourette syndrome and related disorders Adv Neurol 2001 85225-35

40 Hallett M Transcranial magnetic stimulation and the human brain Nature 2000406147-150

41 Pascual-Leone A The brain that plays music and is changed by it Ann N Y Acad Sci 2001 930315-29

42 Wassermann EM Lisanby SH Therapeutic application of repetitive transcranial magnetic stimulation a review

Clin Neurophysiol 2001 1121367-77

43 Mally J Stone TW Therapeutic and dose-dependent effect of repetitive microelectroshock induced by

transcranial magnetic stimulation in Parkinsons disease J Neurosci Res 199957935-40

44 Burt T Lisanby SH Sackeim HA Neuropsychiatric applications of transcranial magnetic stimulation a meta

analysis Int J Neuropsychopharmacol 2002573-103

60f8 81182014833 AM

45 Lin KL Pascual-Leone A Transcranial magnetic stimulation and its applications in children Chang Gung Med J

2002 25 424-36

46 Shimamoto H Takasaki K Shigemori M Imaizumi T Ayabe M Shoji H Therapeutic effect and mechanism of

repetitive transcranial magnetic stimulation in Parkinsons disease J Neurol 200248 (Suppl 3)48-52

47 Moll GH Heinrich H Trott G Wirth S Rothenberger A Deficient intracortical inhibition in drug-naive children with

attention-deficit hyperactivity disorder is enhanced by methylphenidate Neurosci Lett 2000284121-5

48 Garcia-Toro M Saiz-Ruiz J Talavera JA Blanco C Chaos theories and therapeutic commonalities among

depression Parkinsons disease and cardiac arrhythmias Comp Psychiatry 199940238-44

49 Arnsten AF Steere JC Hunt RD The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical

cognitive function Potential significance for attention-deficit hyperactivity disorder Arch Gen Psychiatry

199653448-55

50 Seeman P Madras B Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of

dopamine a hypothesis Behav Brain Res 200213079-83

51 Levkovitz Y Grisaru N Segal M Transcranial magnetic stimulation and antidepressive drugs share similar cellular

effects in rat hippocampus Neuropsychopharmacology 2001 24608-16

52 Aspide R Gironi Carnevale UA Sergeant JA Sadile AG Non-selective attention and nitric oxide in putative

animal models of Attention-deficit hyperactivity disorder Behav Brain Res 199895123-33

53 Wassermann EM Risk and safety of repetitive transcranial magnetic stimulation report and suggested guidelines

from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation June 5-7 1996

Electroencephalogr Clin Neurophysiol19981 081-16

54 Leon-Sarmiento FE Hanft RT Bara W Hallett M Wassermann E The influence of visual activation tasks on

motor cortex excitability studied with transcranial magnetic stimulation 2002 wwwabstractshy

on-linecomabstractsAAN

55 Omura Y Losco BM Takeshige C Non-invasive evaluation of the effects of opening and closing of eyes and of

exposure to a minute light beam as well as to electrical or magnetic field on the melatonin serotonin amp other

neuro-transmitters of human pineal gland representation areas amp the heart Acupunct Electrother Res

199318125-51

56 George MS Nahas Z Bohning DE et a TMS and neuroimaging In George M and Belmaker RH eds

Transcraneal Magnetic Stimulation in Neuropsychiatry Washington DC American Psychiatric Press 2000253-68

57 Kim BN Lee JS Cho SC Lee DS Methylphenidate increased regional cerebral blood flow in subjects with

attention deficithyperactivity disorder Yonsei Med J 2001 4219-29

58 Garvey MA Kaczynski KJ Becker DA Bartko JJ Subjective reactions of children to single-pulse transcranial

magnetic stimulation J Child Neurol 2001 16891-4

Acknowledgments

The authors would like to thank Nicole Schleper for English revisions The opinions expressed here are solely the responsibility of the authors

Reprint Address

Address for correspondence Dr Fidias E Leon-Sarmiento 10 Center Drive Building 10 Room 5N234 Brain

70f8 81182014833 AM

27 Barkley RA Behavioral inhibition sustained attention and executive functions constructing a unifying theory of

ADHD Psychol Bull 1997121 65-94

28 Alexander GE Delong MR Strick Pl Parallel organization of functionally segregated circuits linking basal

ganglia and cortex Annu Rev Neurosci 19869357-81

29 Graybiel AM The basal ganglia and chunking of action repertoires Neurobiol learn Mem 199870119-36

30 Vaidya CJ Austin G Kirkorian G Ridlehuber HW Desmond JE Glover GH et al Selective effects of

methylphenidate in attention deficit hyperactivity disorder a functional magnetic resonance imaging study Proc

NatlAcad Sci USA 19989514494-9

31 Rapoport Jl Buchsbaum MS Zahn TP Weingartner H ludlow C Mikkelsen EJ Dextroamphetamine cognitive

and behavioral effects in normal prepubertal boys Science 1978199560-3

32 lou HC Henriksen l Bruhn P Focal cerebral dysfunction in developmental learning disabilities lancet

19903358-11

33 Zametkin AJ Nordahl TE Gross M King AC Semple WE Rumsey J et al Cerebral glucose metabolism in

adults with hyperactivity of childhood onset N Engl J Med 19903231361-6

34 Solanto MV Dopamine dysfunction in ADHD integrating clinical and basic neuroscience Behav Brain Res 200213065-71

35 Baving l laucht M Schmidt MH Atypical frontal brain activation in ADHD preschool and elementary school boys

and girls J Am Acad Child Adolesc Psychiatry 1999381363-71

36 Rubia K Overmeyer S Taylor E Brammer M Williams SC Simmons A et al Hypofrontality in attention deficit

hyperactivity disorder during higher-order motor control a study with functional MRI Am J Psychiatry 1999156891-6

37 Rapport MD Moffitt C Attention deficithyperactivity disorder and methylphenidate A review of heightweight

cardiovascular and somatic complaint side effects Clin Psycho I Rev 200222 1107 -31

38 The MTA Cooperative Group Multimodal treatments study of children with ADHD A 14-month randomized

clinical trial of treatment strategies for attention-deficithyperactivity disorder Arch Gen Psychiatry 1999561073-86

39 George MS Sallee FR Nahas Z Oliver NC Wassermann EM Transcranial magnetic stimulation (TMS) as a research tool in Tourette syndrome and related disorders Adv Neurol 2001 85225-35

40 Hallett M Transcranial magnetic stimulation and the human brain Nature 2000406147-150

41 Pascual-Leone A The brain that plays music and is changed by it Ann N Y Acad Sci 2001 930315-29

42 Wassermann EM Lisanby SH Therapeutic application of repetitive transcranial magnetic stimulation a review

Clin Neurophysiol 2001 1121367-77

43 Mally J Stone TW Therapeutic and dose-dependent effect of repetitive microelectroshock induced by

transcranial magnetic stimulation in Parkinsons disease J Neurosci Res 199957935-40

44 Burt T Lisanby SH Sackeim HA Neuropsychiatric applications of transcranial magnetic stimulation a meta

analysis Int J Neuropsychopharmacol 2002573-103

60f8 81182014833 AM

45 Lin KL Pascual-Leone A Transcranial magnetic stimulation and its applications in children Chang Gung Med J

2002 25 424-36

46 Shimamoto H Takasaki K Shigemori M Imaizumi T Ayabe M Shoji H Therapeutic effect and mechanism of

repetitive transcranial magnetic stimulation in Parkinsons disease J Neurol 200248 (Suppl 3)48-52

47 Moll GH Heinrich H Trott G Wirth S Rothenberger A Deficient intracortical inhibition in drug-naive children with

attention-deficit hyperactivity disorder is enhanced by methylphenidate Neurosci Lett 2000284121-5

48 Garcia-Toro M Saiz-Ruiz J Talavera JA Blanco C Chaos theories and therapeutic commonalities among

depression Parkinsons disease and cardiac arrhythmias Comp Psychiatry 199940238-44

49 Arnsten AF Steere JC Hunt RD The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical

cognitive function Potential significance for attention-deficit hyperactivity disorder Arch Gen Psychiatry

199653448-55

50 Seeman P Madras B Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of

dopamine a hypothesis Behav Brain Res 200213079-83

51 Levkovitz Y Grisaru N Segal M Transcranial magnetic stimulation and antidepressive drugs share similar cellular

effects in rat hippocampus Neuropsychopharmacology 2001 24608-16

52 Aspide R Gironi Carnevale UA Sergeant JA Sadile AG Non-selective attention and nitric oxide in putative

animal models of Attention-deficit hyperactivity disorder Behav Brain Res 199895123-33

53 Wassermann EM Risk and safety of repetitive transcranial magnetic stimulation report and suggested guidelines

from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation June 5-7 1996

Electroencephalogr Clin Neurophysiol19981 081-16

54 Leon-Sarmiento FE Hanft RT Bara W Hallett M Wassermann E The influence of visual activation tasks on

motor cortex excitability studied with transcranial magnetic stimulation 2002 wwwabstractshy

on-linecomabstractsAAN

55 Omura Y Losco BM Takeshige C Non-invasive evaluation of the effects of opening and closing of eyes and of

exposure to a minute light beam as well as to electrical or magnetic field on the melatonin serotonin amp other

neuro-transmitters of human pineal gland representation areas amp the heart Acupunct Electrother Res

199318125-51

56 George MS Nahas Z Bohning DE et a TMS and neuroimaging In George M and Belmaker RH eds

Transcraneal Magnetic Stimulation in Neuropsychiatry Washington DC American Psychiatric Press 2000253-68

57 Kim BN Lee JS Cho SC Lee DS Methylphenidate increased regional cerebral blood flow in subjects with

attention deficithyperactivity disorder Yonsei Med J 2001 4219-29

58 Garvey MA Kaczynski KJ Becker DA Bartko JJ Subjective reactions of children to single-pulse transcranial

magnetic stimulation J Child Neurol 2001 16891-4

Acknowledgments

The authors would like to thank Nicole Schleper for English revisions The opinions expressed here are solely the responsibility of the authors

Reprint Address

Address for correspondence Dr Fidias E Leon-Sarmiento 10 Center Drive Building 10 Room 5N234 Brain

70f8 81182014833 AM

45 Lin KL Pascual-Leone A Transcranial magnetic stimulation and its applications in children Chang Gung Med J

2002 25 424-36

46 Shimamoto H Takasaki K Shigemori M Imaizumi T Ayabe M Shoji H Therapeutic effect and mechanism of

repetitive transcranial magnetic stimulation in Parkinsons disease J Neurol 200248 (Suppl 3)48-52

47 Moll GH Heinrich H Trott G Wirth S Rothenberger A Deficient intracortical inhibition in drug-naive children with

attention-deficit hyperactivity disorder is enhanced by methylphenidate Neurosci Lett 2000284121-5

48 Garcia-Toro M Saiz-Ruiz J Talavera JA Blanco C Chaos theories and therapeutic commonalities among

depression Parkinsons disease and cardiac arrhythmias Comp Psychiatry 199940238-44

49 Arnsten AF Steere JC Hunt RD The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical

cognitive function Potential significance for attention-deficit hyperactivity disorder Arch Gen Psychiatry

199653448-55

50 Seeman P Madras B Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of

dopamine a hypothesis Behav Brain Res 200213079-83

51 Levkovitz Y Grisaru N Segal M Transcranial magnetic stimulation and antidepressive drugs share similar cellular

effects in rat hippocampus Neuropsychopharmacology 2001 24608-16

52 Aspide R Gironi Carnevale UA Sergeant JA Sadile AG Non-selective attention and nitric oxide in putative

animal models of Attention-deficit hyperactivity disorder Behav Brain Res 199895123-33

53 Wassermann EM Risk and safety of repetitive transcranial magnetic stimulation report and suggested guidelines

from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation June 5-7 1996

Electroencephalogr Clin Neurophysiol19981 081-16

54 Leon-Sarmiento FE Hanft RT Bara W Hallett M Wassermann E The influence of visual activation tasks on

motor cortex excitability studied with transcranial magnetic stimulation 2002 wwwabstractshy

on-linecomabstractsAAN

55 Omura Y Losco BM Takeshige C Non-invasive evaluation of the effects of opening and closing of eyes and of

exposure to a minute light beam as well as to electrical or magnetic field on the melatonin serotonin amp other

neuro-transmitters of human pineal gland representation areas amp the heart Acupunct Electrother Res

199318125-51

56 George MS Nahas Z Bohning DE et a TMS and neuroimaging In George M and Belmaker RH eds

Transcraneal Magnetic Stimulation in Neuropsychiatry Washington DC American Psychiatric Press 2000253-68

57 Kim BN Lee JS Cho SC Lee DS Methylphenidate increased regional cerebral blood flow in subjects with

attention deficithyperactivity disorder Yonsei Med J 2001 4219-29

58 Garvey MA Kaczynski KJ Becker DA Bartko JJ Subjective reactions of children to single-pulse transcranial

magnetic stimulation J Child Neurol 2001 16891-4

Acknowledgments

The authors would like to thank Nicole Schleper for English revisions The opinions expressed here are solely the responsibility of the authors

Reprint Address

Address for correspondence Dr Fidias E Leon-Sarmiento 10 Center Drive Building 10 Room 5N234 Brain

70f8 81182014833 AM

Stimulation Unit NINDS National Institutes of Health Bethesda MD 20892 USA Tel 301-402-3736 Fax 301-402-1007 emailleonfnindsnihgov

Curr Med Res Opin 200319(2) copy 2003 Librapharm Limited

80f8 81182014833 AM