Repetitive Transcranial Magnetic Stimulation (rTMS): New Tool, New Therapy and New Hope for ADHD

Maria T. Acosta, Fidias E. Leon-Sarmiento

Disclosures

Curr Med Res Opin. 2003;19(2) 

In This Article

The Neuromagnetic Linkage

Transcranial magnetic stimulation (TMS) is a newly developed tool for assessing functionality of the central nervous system (CNS). 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 Tourette's syndrome, obsessive compulsive disorder, depression, schizophrenia, bipolar disorders and ADHD among others.[39,40,41,42,43] 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 al.[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, Tourette's syndrome and some types of tic.[42,43,44] 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 (e.g. 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 play a 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 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 (e.g. 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]

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