TRANSCRANIAL magnetic stimulation (TMS) allows for the safe and non-invasive stimulation of the human brain (Hallett 2000; Pascual-Leone 1999; Wagner et al. 2007). TMS can be used to complement other neuroscience methods to study the pathways between the brain and the spinal cord, and between different cortical and subcortical brain structures. Furthermore, TMS can be used to validate the functional significance of neuroimaging studies in determining the causal relationship between focal brain activity and behavior. Most relevant to the present chapter, is the way in which modulation of brain activity by repetitive TMS (rTMS) can transiently change brain function and be utilized as a therapeutic tool for treatment of a variety of neurological and psychiatric illnesses.
In the past decades, the uses of and accessibility to non-invasive brain stimulation have greatly increased. The potential risks and appropriate precautions in the use of TMS are increasingly well established (Machii et al. 2006; Rossi et al. 2009). New applications of TMS are being explored in normal subjects, and clinical treatment programs for TMS in various neuropsychiatric disorders are being launched. Such expansion has been further catalyzed by the approval of certain clinical applications of TMS in several countries, and most recently the approval by the Food and Drug Administration (FDA) in the United States (US) of the Neurostar treatment for specific forms of medication-resistant depression (Janicak et al. 2008; O’Reardon et al. 2007). In addition to TMS there are other methods of non-invasive brain stimulation, such as transcranial direct current stimulation (tDCS) (Nitsche et al. 2003), which are becoming increasingly established. The number of subjects studied worldwide and the number of research studies published annually has increased yearly (Rossi et al. 2009). Therefore, it seems important to revisit the ethical considerations upon which one should reflect when applying non-invasive brain stimulation to humans. We aim to build on and update the work published by Green et al. (1997) during the early stages of rTMS testing and have aimed at updating our discussion of ethical considerations in the use of TMS in the prior edition of this textbook (see Table 25.1). For example, since 1997, clinical trials have been conducted to evaluate the efficacy of rTMS treatment for major depression and over 100 papers have been published. In a meta-analysis of controlled studies, Burt and colleagues (2002) showed that there was a definite antidepressant effect of rTMS in patients with major depression and a very favorable efficacy-side-effect balance. The positive results of these trials have encouraged researchers to continue these investigations, and there are currently large, multisite studies being conducted in the US and Europe for other conditions including stroke rehabilitation and Parkinson’s disease. Certainly, rTMS appears to be an attractive approach to treat medication-resistant major depression, especially given the significant side effects of the alternative, electroconvulsive therapy (ECT). ECT, while often effective, is associated with adverse effects on cognition and a substantial social burden (O’Connor et al. 2003; UK ECT Review Group 2003). Despite recent FDA approval of a TMS device and application protocol for medication-resistant depression, the efficacy of rTMS in the cited trial was small (Janicak et al. 2008; O’Reardon et al. 2007). Thus even for medication-resistant depression significant ethical questions regarding the use of rTMS remain. For example: (1) Should rTMS only be offered to the relatively few patients who fit the narrow FDA indication? (2) Should other patients with resistant depression be treated with rTMS, and if so, what type of depressed patients—those refractory to medication only or a broad population of depressed patients? (3) Should this new technique be studied as an add-on therapy? (4) Should patients who experience a positive response with this treatment be offered a possibility of “maintenance” treatment, even though that has not been proven safe and effective? (5) Should other patients with depression (young patients or those who have failed multiple medications or have never tried one, for instance) be offered the possibility of receiving this treatment as an off-label therapy? Of course, none of these questions are unique to rTMS—most, if not all, are relevant to any new treatment for depression, including new medications.
Although the use of rTMS to treat other neuropsychiatric disorders has been investigated to a lesser extent, there is a growing body of evidence suggesting that rTMS might be useful, for instance, for Parkinson’s disease (see (Fregni et al. 2005a; Wu et al. 2008) and schizophrenia (Freitas et al. 2009; Hoffman et al. 2003). Questions similar to those posed here regarding treatment of depression also apply to the use of rTMS for patients suffering from these diseases.
Another technique of non-invasive brain stimulation, transcranial direct current stimulation (tDCS), also has a positive effect in depression amelioration (Fregni et al. 2006a). TDCS is inexpensive and relatively simple to administer and might prove to be a suitable alternative for the treatment of depression in areas that lack the financial and technical resources necessary for rTMS. In fact, rTMS opened the field to explore other techniques of non-invasive brain stimulation and novel method such as transcranial alternate and intermittent stimulation are being investigated (Zaghi et al. 2010).
Approval by the US Food and Drug Administration of repetitive TMS with the Northstar system for the treatment of certain patients with medication refractory depression
Expansion of existing and establishment of new clinical programs and clinics offering TMS for therapeutics in a variety of neuropsychiatric disorders (on- and particularly off-label)
Establishment of new TMS protocols that enable greater modulation of cortical excitability and plasticity with shorter exposure
Growing number of applications of TMS and other neuromodulation techniques in neuroscience research
Expansion of TMS protocols to other subject populations, including vulnerable patient populations (e.g. autism spectrum disorders) and children
Development of new, simpler non-invasive brain stimulation method (e.g. transcranial direct current stimulation)
The potential uses of non-invasive brain stimulation that raise important ethical issues are not limited to therapeutic applications in patients with various neuropsychiatric disorders who fail to benefit from traditional interventions. TMS has also been utilized in healthy subjects in experimental settings. The use of TMS for neuroenhancement—the “non-therapeutic” uses of TMS for enhancing cognitive or affective function—raises fundamental ethical questions about the very nature of medicine. Should medical interventions (not just TMS, but also pharmacologic or genetic modifications) be limited to “treatment” of “disease”, or is enhancement of “normal” functioning a legitimate use of medical techniques?
Several authors have shown that rTMS might enhance motor function (Kobayashi et al. 2004), attention (Hilgetag et al. 2001) and working memory (Kahn et al. 2005) in normal subjects—(for review see Pascual-Leone 2006). The modulatory effects of rTMS could also be used, hypothetically, to control or reinforce certain behaviors such as deception, violence, trust, and altruism. In fact, several studies have already moved beyond mere hypothesis, with published results revealing that tDCS can modulate deception (Karim et al. 2009; Priori et al. 2008). Work from Delgado (1976) in primate models illustrates the possibility of guiding complex behavior by brain stimulation. Non-invasive stimulation might permit a safer and easier means of inducing similar behaviorally modifying changes in brain activity in humans. Is neuroenhancement ethically appropriate? If so, with what aims and controls?
The principles that underlie TMS were discovered by Faraday in 1831 (Walsh and Pascual-Leone 2003). A pulse of electric current flowing through a coil of wire generates a magnetic field (Figure 25.1). The rate of change of this magnetic field determines the induction of a secondary current in a nearby conductor. In TMS, the stimulating coil is held over a subject’s head (Figure 25.1) and, as a brief pulse of current is passed through it, a magnetic field is generated that penetrates through the subject’s scalp and skull without attenuation (only decaying by the square of the distance). This time-varying magnetic field induces a current in the subject’s brain that depolarizes neurons and generates effects depending on the brain area targeted. Therefore, in TMS, neural elements are not primarily affected by the exposure to a magnetic field, but rather by the current induced in the brain by electrodeless, non-invasive electric stimulation.
FIG. 25.1 A typical TMS module and MRI guided frameless stereotactic guidance system.
In the early 1980s, Barker and colleagues developed the first compact magnetic coil stimulator at the University of Sheffield. Soon thereafter, TMS devices became commercially available. The design of magnetic stimulators is relatively simple. Stimulators consist of a main unit and a stimulating coil. The main unit is composed of a charging system, one or more energy storage capacitors, a discharge switch, and circuits for pulse shaping, energy recovery, and control functions (Figure 25.2). Different charging systems are possible; the simplest design uses step-up transformers operating at line frequency of 50–60HZ. Energy storage capacitors can also be of different types. The essential factors in the effectiveness of a magnetic stimulator are the speed of the magnetic field rise time and the maximization of the peak coil energy. Therefore, large energy storage capacitors and very efficient energy transfer from the capacitor to the coil are important. Typically, energy storage capacity is around 2000 joules and 500 joules are transferred from the capacitors into the stimulating coil in less than 100μs via a thyristor, an electronic device that is capable of switching large currents in a few microseconds. The peak discharge current needs to be several thousand amperes in order to induce currents in the brain of sufficient magnitude to depolarize neural elements (approximately 10mA/cm2).
During transcranial magnetic brain stimulation only the stimulating coil needs to come in close contact with the subject (Figure 25.1). Stimulating coils consist of one or more well-insulated coils of copper wire frequently housed in a molded plastic cover and are available in a variety of shapes and sizes. The geometry of the coil determines the focality of brain stimulation. Figure-of-eight coils (also called butterfly or double coils, Figure 25.2) are constructed with two windings placed side by side and provide the most focal means of brain stimulation with TMS available to date. Current knowledge, largely based on mathematical modeling, suggests that the most focal forms of TMS available today affect an area of 0.5 × 0.5cm at the level of the brain cortex (Wagner et al. 2007). Stimulation is restricted to rather superficial layers in the convexity of the brain (cortex or gray–white matter junction) and direct effect onto deep brain structures is not yet possible. Digitization of the subject’s head and registration of the TMS stimulation sites onto the magnetic resonance image (MRI) of the subject’s brain addresses the issue of anatomical specificity of the TMS effects by identifying the actual brain target in each experimental subject (Figure 25.1). The use of optical digitization and frameless stereotactic systems represents a further improvement by providing on-line information about the brain area targeted by a given coil position on the scalp.
FIG. 25.2 A simple TMS pulse circuit and resultant effects.
The precise mechanisms underlying the brain effects of TMS remain largely unknown (Pascual-Leone et al. 1999; Robertson et al. 2003; Wagner et al. 2007). Currents induced in the brain by TMS flow primarily parallel to the plane of the stimulation coil (approximately parallel to the brain’s cortical surface when the stimulation coil is held tangentially to the scalp). Therefore, in contrast to electrical cortical stimulation, TMS preferentially activates neural elements oriented horizontally to the brain surface. Exactly which neural elements are activated by TMS remains unclear and, in fact, might be variable across different brain areas and different subjects. The combination of TMS with other neuroimaging and neurophysiology techniques provides an enhanced understanding of the mechanisms of action of TMS and a novel approach to study functional connectivity between different areas in the human brain.
Guidelines for research on human subjects in the US are articulated in the 1979 Belmont Report by the US National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. This report defines three governing principles that remain the gold standard for human subject research ethics: (1) respect for persons, (2) beneficence, and (3) justice.
The first principle of respect and the third principle of justice have been addressed in the TMS literature, especially with respect to the basic ethical treatment of subjects (e.g., consent, exclusion, and inclusion criteria, e.g. see Green et al. (1997) and Steven and Pascual-Leone (2006). The first clause of the second principle (i.e. risks reduced to a minimum) is considered at length in the literature on the guidelines for safe use of single pulse TMS as well as rTMS on the normal human brain (Hallett et al. 1999; Rossi et al. 2009; Wassermann 1998). Taking these principles into account, we focus specifically on the issues of beneficence, and on finding the appropriate balance between benefit and risk of TMS.
In the clinical population, TMS has shown promise for treatment of depression (Gross et al. 2007), Parkinson’s disease (Wu et al. 2008), writer’s cramp (Siebner et al. 1999) and chronic pain (Jensen et al.2008), as well as for the rehabilitation for motor neglect (Hilgetag et al. 2001), motor stroke (Mansur et al. 2005), and aphasia (Martin et al. 2004; Naeser et al. 2005a, b) among others (see Table 25.2).
Table 25.2 List of the clinical applications of TMS research that are currently being pursued in research laboratories worldwide
As is common with potential new treatments for which risks are not yet well defined, rTMS was initially studied in patients who have exhausted other, more established forms of treatment. This has meant offering rTMS to patients with relatively severe forms of neurological or psychiatric disorders refractory to conventional therapy. These patients, however, may have diminished autonomy, either as a result of their neuropsychiatric illness, or because they are “desperate” (or both), necessitating special efforts to ensure appropriate informed consent (F. G. Miller and Brody 2003; Minogue et al. 1995). Because studies to date have provided increasing evidence for the relatively benign profile of side-effects of rTMS (Rossi et al. 2009), at least for the duration (usually short term) of the studies, rTMS is now being offered to broader populations, including patients with less severe conditions and those who have not necessarily proven refractory to all available alternatives.
The nature, frequency, and severity of adverse effects of rTMS in a variety of populations are now well documented. A recent review of the experience at the Center for Non-invasive Brain Stimulation at Beth Israel Deaconess Medical Center and Harvard Medical School provides an up-to-date overview of extensive experience in patients with neuropsychiatric diseases as well as subjects recruited as normal healthy controls (Machii et al. 2006). Approximately 10 to 20% of subjects studied with TMS develop a muscle tension headache or a neck ache (23% in Machii and colleagues’ review). These are generally mild discomforts that respond promptly to an aspirin, acetaminophen (Tylenol®) or other common analgesics. Because the sound of the TMS procedure is loud, repetitive TMS can also cause transient hearing loss if the subjects do not wear earplugs during the rTMS studies. Furthermore, TMS can cause very mild and transient memory problems and other cognitive deficits, as well as mood and hormone changes (these rare adverse effects are usually resolved within hours of cessation of TMS). A recent consensus conference on the safety of TMS (Rossi et al. 2009) similarly concluded that the risks of TMS were relatively minor, provided that appropriate guidelines are followed and precautions are taken.
The major risk of TMS is the risk of producing a seizure. The likelihood of inducing a seizure is small. Only 16 seizures induced by rTMS have been reported worldwide among the many thousands of patients studied resulting in a projected risk of less than 1:1000 patients and probably less than 1:10000 TMS sessions (Rossi et al. 2009). The parameters of TMS that have produced seizures during experimentation are well known and documented (Rossi et al. 2009). However even though the risk of seizures is small if safety guidelines are followed, these guidelines are primarily based on experiments in healthy subjects and the risk of seizures may be higher in patients with neuropsychiatric diseases such as stroke and major depression and in patients on certain neuropsychotropic drugs. For example, patients with infarcts or neurological disorders that cause cortical atrophy should be stimulated with great care as the presence of excess cerebrospinal fluid (CSF) can alter the electromagnetic field properties and stimulation near CSF can cause adverse effects (Wagner et al. 2006). Finally, TMS has only been studied for approximately 25 years and the data on potential long-term effects in humans remains insufficient. Although animal studies using TMS have not indicated any risks of brain damage or long-term injury, caution remains imperative.
Since safety guidelines were generated from information on TMS in adults, relatively little is known about the appropriate safety guidelines for application of TMS in children (Frye et al. 2008). A recent study reviewed English-language published studies of TMS (single- and paired-pulse and rTMS) in persons younger than 18 years (the majority with neuropsychiatric disorders) from 1990–2005. The author of this study found 49 studies that in total applied TMS in 1036 children. No seizures were reported for any of the 1036 studied children; although the number of repetitive TMS studies (in contrast with single and paired pulse TMS studies that are safer) were low (Quintana 2005). More generally, the effects of TMS on the developing brain remain unknown. Thus, even though rTMS offers the potential for treating developmental disorders like autism, childhood depression, and obsessive-compulsive disorder among others, particular caution is needed when carrying out research on children until more is known about safety in younger populations from both studies on humans and animal models. Some authors have suggested that clinical trials on children who have medication refractory focal epilepsy represent a reasonable entry point given the current state-of-the-art (Fregni et al. 2005b; Thut et al. 2005).
The investigation for the treatment of depression using rTMS has been developing quickly and to date represents the most studied clinical application of this technique. The only FDA-approved application of TMS at this writing involves medication-resistant depression. We will discuss some ethical issues associated with this application of TMS, such as clinical trial design and its use outside of the experimental environment and outside the specific (and quite narrow) FDA indication. Furthermore, we will briefly discuss the ethical use of tDCS for the treatment of depression.
Randomized controlled clinical trials are the gold standard for the investigation of new treatments. In neuropsychiatric populations, several variables, such as patient recruitment, trial duration, and type of control group, can be modified in order to provide the results in an ethical manner without compromising the scientific findings. For instance, in investigating treatment of depression using rTMS, which type of patients would be most appropriate—those refractory to medication or a broad spectrum of patients including, for instance, patients with newly diagnosed depression for whom medication has not yet been tried? There are advantages and disadvantages to both approaches. The investigation of patients with depression who are refractory to other medical therapies, such as antidepressants, is widely accepted—these patients do not have any other therapeutic options and, therefore, the best proven treatment will not be withheld from them in a randomized placebo-controlled trial. However this approach has an important caveat: patients with depression resistant to other antidepressant therapies might also be more likely not respond to rTMS—therefore a negative result might be hard to translate to other populations. Indeed, a recent meta-analysis showed that five out of seven studies that used this approach showed no significant depression improvement after active rTMS when compared to sham stimulation (Couturier 2005). In another investigation conducted by our own group, we pooled data from six different studies of rTMS treatment for depression and modeled these data to derive predictors of positive response. The results from the 195 aggregate patients showed that refractory patients have a less effective antidepressant response to rTMS compared with the non-refractory patients (Fregni et al. 2006b). Therefore, studies of refractory patients alone are inadequate to determine the possible effectiveness in broader populations of depressed patients. This conclusion and the large impact of the degree of medication refractoriness on the efficacy of rTMS in depression is further illustrated by the results of the trial that eventually led to the FDA’s approval of one use of rTMS. (Janicak et al. 2008; O’Reardon et al. 2007). The initial overall results of this multisite, carefully designed and controlled trial were essentially negative and only the analysis of subpopulations of patients according to the number of medication trials failed, led to evidence of efficacy of rTMS. Indeed, the FDA approved the treatment for patients who have failed one good trial of an antidepressant, but not more than two, a strikingly narrow but understandable indication, given the poor efficacy data for patients who had failed multiple medication trials.
Another option is to investigate in a general population of depressed patients, including those that could potentially respond to the treatment of standard antidepressant medications. If there is a proven effective therapy (e.g. a certain antidepressant medication), and there is some reason to believe that a new therapy (rTMS) might work, then one could randomize to meds v. rTMS. Or one could have multiple arms: meds v. rTMS v. placebo rTMS. This method quickly becomes complicated; trials become very large and thus also quite expensive.
Another concern is that some patients will be denied an effective treatment if the trial uses a standard placebo control (e.g. placebo medication or sham rTMS). Because depression is common, and because some patients decline to take standard recommended medications, one might also recruit patients from those who have refused pharmacologic treatment. Randomizing them to rTMS or placebo (sham rTMS) would not be depriving them of known effective treatment.
But for patients for whom antidepressant medications are known to be effective, and who are willing to take them, why should non-invasive brain stimulation be investigated? There are several possible advantages to rTMS. First, rTMS has a different profile of risks compared to antidepressant medications and might be better suited to some patients that could eventually respond to either therapy. Second, efficacy of treatment with rTMS might be superior to medication for a subgroup of non-refractory patients. Finally, depending on the antidepressant drug used for comparison, rTMS can be less costly.
In order to perform a randomized, double-blind placebo-controlled clinical trial to investigate the effects of non-invasive brain stimulation in non-refractory depressive patients, the investigators would need to withhold the best proven therapy from the patients in the placebo arm. According to the declaration of Helsinki: “….in any medical study, every patient–including those of a control group, if any–should be assured of the best proven diagnostic and therapeutic methods.” However, some authors defend the use of placebo, against the recommendations of the declaration of Helsinki, if patients with moderate or mild depression without suicide risk are studied on the principle that the lack of treatment for a short period of time would not expose these patients to great risk. Some authors consider this ethically permissible if these patients are adequately informed about this risk (S. M. Miller et al. 2000) and every attempt is made to mitigate it.
The alternative of active-controlled trials comparing new treatments only with standard drugs can lead to the use of new treatments that appear equivalent in efficacy to standard treatment but may be no more effective than placebo. This might be particularly valid if the specific population that is being tested for a new treatment has primarily a placebo response to the standard drug. In this situation, if the new treatment is found to have benefits similar to the standard drug, this new treatment might be equivalent to placebo only. Here the phenomenon of biocreep needs to be considered as well. In other words if active comparisons are made there is the risk that each new comparison treatment, even though it appears roughly similar to standard treatment, will in fact be slightly less effective. Over time it is possible that new treatments may become accepted even though they are not any more effective than placebo. For these reasons, despite the mandate of the declaration of Helsinki, the FDA continues to defend the use of placebo-controlled trials for the development of a new treatment even if effective therapy exists.
Rothman et al. (1994) disagree, basing their argument on the view that no patient should suffer unnecessary pain, even if the condition is not life-threatening (Rothman and Michels 1994). They argue that “active control” testing of brain stimulation—i.e. comparing it against standard antidepressant therapy—is adequate. The advantages of this approach are that: (1) patients in both groups receive active treatments for depression, and (2) results can guide the clinician regarding the choice between antidepressant treatment or brain stimulation. Still as mentioned before, a significant drawback is that the therapeutic effect of the active control might not be different than placebo in the population being investigated. One method to avoid, or at least reduce the likelihood of this problem, is to use of placebo “run-in” phase in which patients are excluded if they present a placebo response in the first weeks of the trials, “placebo-responders” (Lee et al. 2004).
Another drawback of this approach is the large sample size needed to perform this type of study. Because a lack of difference between two treatments is a function of the variance within datasets, a relatively large sample size is needed to decrease the risk of type II error using this study design. In contrast, the sample size needed to perform a placebo-controlled trial is much smaller, thus exposing fewer patients to unnecessary risks and discomforts. Accurate sample size calculations are imperative, therefore, to decide the best study design. Another important issue here is that future research showing patients who are likely to respond to rTMS may increase the effect sizes of a given trial, reducing therefore the number of patients who need to be part in a given research study.
Yet another alternative to placebo-control trials that has been tested is non-invasive brain stimulation as an add-on therapy. In this scenario, all patients receive the standard treatment, and half receive the experimental treatment in addition. Using this approach Rumi et al. (2005) showed that active rTMS and amitryptiline results in a larger antidepressant effect than amitryptiline alone. This approach however is limited in determining whether rTMS has any role in treatment of depression. For example, if there is a ceiling effect, i.e. the improvement induced by antidepressants cannot be further extended, then addition of rTMS would show no added benefit even if rTMS alone were highly effective. Indeed, several rTMS studies were conducted using this approach and some of them showed that rTMS does not add efficacy over the use of standard antidepressant medication (Garcia-Toro et al. 2001; Hausmann et al. 2004).
In summary, in exploring the effectiveness of rTMS for treatment of depression, several alternatives might be pursued: (1) inclusion only of patients that are refractory to available antidepressant medications; (2) investigation of the use of non-invasive brain stimulation as an add-on therapy (to medication); (3) comparison of the effects of non-invasive brain stimulation against an active control; and (4) comparison of rTMS versus placebo among patients who have declined pharmacologic treatment;. Given the evidence that rTMS has some effectiveness in depression, and given the scientific limitations of designs (1) and (2) reviewed earlier, approaches (3) and (4) seem most likely to provide ethically appropriate and scientifically useful information about possible roles for rTMS in depression.
While the initial FDA approval for rTMS in depression is quite narrow, as explained earlier, it is possible that other patients might benefit. For example, what if a patient in an rTMS study appears to benefit and wants to continue rTMS beyond the study period for an indication that is not FDA-approved? Is it ethical to deny treatment after the study is terminated? One alternative is to offer it as an off-label intervention for those patients—a treatment not approved by the FDA—for which those patients might be asked to sign a consent form acknowledging that the treatment remains experimental. There is an intense debate about the use of an off-label treatment (Bickerstaffe et al. 2006). The practice of prescribing medicines for indications or in dosage regimens that are different than the terms of the products specification is common in medicine (Bickerstaffe et al. 2006). For example, a national report from a healthcare organization in Canada concludes that pediatric prescriptions in Canada are often prescribed off-label, as pharmaceutical companies do not have an incentive to obtain approval for a drug for more than one purpose (http://www.law.utoronto.ca/healthlaw/docs/student_Rabinovitch-NationalFormulary.pdf). In the case of off-label rTMS, the benign profile of side effects provides support for belief in a favorable benefit–risk ratio, since even among patients for whom efficacy is unproven the risks (at least for short-term use) are almost certainly low. (As mentioned earlier, thousands of rTMS trials on patients and healthy subjects have been conducted and data from these studies demonstrate short-term safety if technical guidelines are carefully followed (Rossi et al. 2009; Wassermann 1998).) Nonetheless, few data regarding long-term effects of rTMS are available, and both clinical caution and scrupulously careful informed consent are both clearly warranted.
As new data are gathered, both FDA-approved and off-label use of rTMS for patients may become more and more widespread. Depending on whether rTMS is covered by medical insurance, and on the extent of continued problems of uninsured patients, issues of distributive justice may surface. If rTMS is believed effective but is not covered by medical insurance, then equitable access to this approach to treating suffering may not be possible.
In a broader context, approval of a certain form of TMS for a given indication (major depression) has led to a further expansion of already existing clinics offering rTMS for treatment of various neuropsychiatric conditions. Such clinics often bank on the patients’ hope and faith in help from a novel therapy. The efficacy data for many of the offered indications is at best limited. Such practices should thus be viewed with caution and a responsible, conservative approach by the involved physicians is critical.
Like rTMS, tDCS is a technique of brain stimulation that can modulate brain activity, and therefore be used for depression treatment. In fact several trials have shown positive results (see review (Murphy et al. 2009). In tDCS, the cerebral cortex is stimulated through a weak constant electric current in a non-invasive and painless manner (Wagner et al. 2007). This weak current is presumed to induce focal changes in cortical excitability—increases or decreases depending on the electrode polarity—that last beyond the period of stimulation. Several studies reveal that this technique might modulate cortical excitability in the human motor cortex (Baudewig et al. 2001; Nitsche and Paulus 2000; Rosenkranz et al. 2000), and visual cortex (Antal et al. 2001, 2002). Although this technique has already been shown to be a promising treatment for major depression (Fregni et al. 2006a), continuous methodological improvements on electrode size and position and paradigms of stimulation, might yield an enhanced outcome in the future.
TDCS and rTMS have similar modulatory effects, but in the treatment of depression, tDCS might have two important advantages over both rTMS and drugs: (1) tDCS treatment is inexpensive and (2) it is easy to administer (Fregni et al. 2005c; Nitsche et al. 2003). The device used to deliver the tDCS is simple, can cost less than 100 USD, and can be manufactured locally (Fregni et al. 2005d). The equipment is fully reusable and utilizes one standard battery that can last several weeks. This treatment is easily administered and used after specific but relatively minimal training. Finally, tDCS has other mechanisms of action such as it is a purely neuromodulatory tool that can change the resting neuronal membrane threshold thus can modulate the neuronal spontaneous firing, being therefore an interesting technique to enhance the effect of other behavioral interventions such as cognitive behavioral therapy. Establishing efficacy in various populations requires, however, rigorous assessments, with the same issues as discussed earlier for rTMS.
The ease of application and access make tDCS potentially appealing though also raise concerns for the ease of abuse. As an approach to improve mental health in areas of the world with limited resources, tDCS might prove to be a promising solution. However, developing world issues are extremely complex and cannot be taken lightly. Naturally, the implementation of tDCS for depression treatment should be considered for any nation only if it is proven to be at least as efficacious as the gold standard. The standard of proof in this regard has to be as stringent for its implementation in developing countries as elsewhere. However, as antidepressants—the gold standard for depression—are often not available in poor countries, it has been argued that a treatment that is more effective than placebo but less effective than drugs (or TMS) could have value (Lenfant 2001). Again, this is a complex issue where multiple solution approaches are needed, including making antidepressants more widely available worldwide, but for the time being, the shortage of medications is a critical problem in low-income countries. Even in developed countries, people without health insurance are regularly faced with the decision of stopping antidepressant treatment because of the high cost. Poor patients often interrupt treatment for the same reason, endangering themselves through risks of worsening or relapse of their depression. Moreover, is well established that a higher prevalence of depression is found among poor, illiterate, and urban migrants (Almeida-Filho et al. 2004; Wohlfarth 1997). Therefore, the sickest population is the one with the greatest inability to attain or afford a regular antidepressant treatment. Given such a scenario, it can be argued that investigating low-cost approaches such as tDCS has the potential to be very beneficial.
As reasonable as these arguments may be, the history of debates regarding HIV treatments in resource-poor settings provides instructive guidance. The HIV treatment regimens in wealthy nations were not only extraordinarily expensive, but also far more complex than antidepressant medications. It was widely believed that providing access to highly-effective antiretroviral medications in developing countries was unrealistic, and many experts have discussed either settling for less effective treatment approaches or even for no treatment at all. But great progress has been made in less than a decade in reducing the price of medications, in expanding distribution systems, and in proving that compliance rates equaling or exceeding those in developed countries can be achieved even in the poorest regions of the world. The moral acceptability of any approach to HIV treatment that does not aspire to the same quality of care that is offered in developed countries is now quite properly widely questioned. Similar considerations need to be applied to the temptation of widespread implementation of certain device-based interventions in developing countries on the basis of expense.
Despite the scientific, technical, and economic potential of tDCS, further phase II trials showing efficacy of this technique are necessary. Another issue is the safety of this technique. Among the data available, Nitsche and Paulus (2001) showed that tDCS does not change serum neuron specific enolase concentration (a sensitive marker of neuronal damage), blood-brain barrier function, or cerebral vasculature (Nitsche and Paulus 2001; Nitsche et al. 2003, 2004). In another study, the safety of tDCS was tested with respect to neurocognitive and motor function (simple reaction test and Pegboard Grooved test). No significant deterioration with tDCS was found. On the contrary, the authors reported a significant improvement of verbal fluency after stimulation of the prefrontal cortex. These findings are in agreement with safety studies performed in our lab (Fregni et al. 2006c). Finally, a recent study reviewed the safety of tDCS, concluding the tDCS is associated with only a few and mild adverse effects (Nitsche et al. 2008). Although these early data and a recent review by Wasserman and Grafman (2005) suggest that the technique may prove to be intrinsically safe, more studies are clearly needed to determine full safety guidelines (Wassermann and Grafman 2005).
Placebo and nocebo represent important concepts in medicine as they can impact neurophysiological processes and, thus, interfere in the disease pathophysiology (de la Fuente-Fernandez et al. 2001; Strafella 2006). The placebo/nocebo effect is also an important confounder in clinical trials. For instance, placebos induce an antidepressant response, on average, in 30% of patients with major depression (Laporte and Figueras 1994).
The consequence of changes in the activity of neural networks in response to plastic changes induced by organic afferents and emotional expectations from placebo or nocebo effects provides a target for neuromodulation. It is conceivable that by increasing activity in specific nodes of these networks, so as to maximize placebo, the healing powers of the patient’s own body may be enhanced. At the same time, by suppressing activity in other nodes, the deleterious effects of nocebo may be reduced. To this end, rTMS could be used in clinical practice to enhance placebo and decrease nocebo effects and in randomized trials to disrupt and perhaps block the placebo effect and (thus, disentangling the effect of a new treatment from the placebo effect).
However, if placebo can help some patients that undergo placebo-controlled clinical trials, one can argue that it would be unethical to block this potential therapeutic effect of placebo in order to improve the scientific quality of a clinical trial. This assumes, however, that the “placebo effect” interferes with scientific “rigor.” If the point of a clinical trial is to determine the likely effectiveness of an intervention in actual clinical practice, then since we know that for many interventions overall effectiveness includes some degree of placebo effect, research interventions that included blocking any placebo effects might not be generalizable to clinical practice in the real world. If the point of a clinical trial is to determine effects that are specifically attributable to the active pharmacologic agent under study, however, then if rTMS were able to block the placebo effect, it is possible that fewer patients would be needed in a phase III clinical trial. This would in turn mean that fewer non-placebo responders would be exposed to receive no adequate treatment. Certainly, all research subjects would have to be adequately informed about the use of a placebo-blocker method.
Until recently, scientists relied on naturally occurring lesions in the human brain to draw conclusions about the functioning of specific neural regions. The effects of naturally-occurring lesions are, however, imprecise, often irreversible, variable from patient to patient, and do not always occur in isolation of other neurological disorders. Since TMS (at least single pulse TMS) has only a transient effect, it can be utilized to investigate the importance of a given brain area in the normal, functioning human brain by creating a temporary “virtual lesion” (Pascual-Leone 2006; Pascual-Leone et al. 1998; Walsh and Pascual-Leone 2003; Walsh et al. 2005, 2006). For this reason, TMS is used today to investigate a myriad of neuroscientific questions about the functioning of the normal human brain. Some studies have aimed at understanding early sensory processing system using single-pulse TMS at different time-points after visual stimulation (e.g. Amassian et al. 1991; Corthout et al. 1999), while others have investigated higher visual processing (e.g. Ashbridge et al. 1997) with the same relatively safe parameters. Motor processing is also studied extensively with single pulse TMS on normal subjects (e.g. De Gennaro et al. 2003; Robertson et al. 2003; Theoret et al. 2004).
RTMS studies at rates of repetition well below safety limits are also conducted on normal subjects to investigate phenomena varying from self-recognition (Keenan et al. 2000) to sequence learning (Robertson et al. 2001). Other studies utilize rTMS at parameters nearing the limit of safety guidelines, and some appear to exceed reasonable ethical criteria. For example, researchers have recently begun to investigate the induction of long-term depression (LTD) and long-term potentiation (LTP) (the mechanisms of neuroplasticity) using rTMS protocols in the normal human brain (Iyer et al. 2003 and Huang et al. 2005 respectively). These studies, while potentially producing valuable scientific knowledge, raise significant questions about the risk–benefit ratio for research subjects. The scientific value of such research is that learning how to induce LTD and LTP could provide major new understanding of brain function that might have significant implications for diagnosis and treatment of diseases like depression, epilepsy, Parkinson’s and other neurological disorders. However, as described earlier, increasing the length and rate of stimulation both contribute to the higher risk of seizure. LTP induction requires only 20–190s, but stimulation must be applied at 50Hz (in the theta range) for its induction. The parameters necessary to induce LTD are not as concerning since they involve stimulation at a relatively low repetitive rate (for example 6Hz followed by 1Hz), though it might need to be applied for a long period of time (20min). Other forms of repetitive TMS, for example asynchronous trains in the theta burst pattern have also been introduced recently. All these forms of stimulation attempt to produce a potentially deleterious effect without precise knowledge of how long this effect will last, or how treatable the effect would be. That appears to violate basic standards of research on human subjects, especially when seeking maximal knowledge first through animal models has not always been done. In fact, a recent study showed that a 5-day course of rTMS is associated with structural changes in the gray matter (May et al. 2006) and raises a red flag for the use of repetitive sessions of rTMS in healthy subjects. Although these effects could have also been a result of changes in brain perfusion, investigators must be aware of a possible detrimental effect of consecutive sessions of rTMS in healthy subjects when planning TMS studies on healthy subjects.
Given that rTMS can modulate brain function, an important question arises: Is it ethical to use rTMS to inhibit some behaviors such as or aggressive behavior or reinforce others such as altruistic behavior, trust, and moral behavior? Should rTMS be used to improve some aspects of cognition such as working memory? Is it ethical to use it in normal subjects to improve their performance? We will briefly discuss the aspects of using rTMS in otherwise healthy subjects.
RTMS can be used to inhibit some undesirable behaviors such as aggression and deception. Deception occurs, for example, when one person attempts to deliberately make someone believe things that are not true. Because society values the ability to detect, and perhaps prevent, deception, the polygraph was developed in 1921 as a device to monitor physiological function associated with deception. More sophisticated approaches to deception detection include brain fingerprinting based on scalp-recorded EEG (Dickson and McMahon 2005) and fMRI. A study using the latter technique has shown more activation in right anterior frontal cortices anterior cingulate and posterior visual cortex associated with well-rehearsed lies, i.e. the ones that fit into a coherent story, versus spontaneous lies (Ganis et al. 2003). Rather than recording neural correlates of such behaviors, the possibility of inhibiting them exists with rTMS: imagine a scenario of inhibiting rehearsal of lies before a criminal trial. Indeed, intellectual property protection for such notions have been filed and granted in the US. On the one hand TMS could be used to help establish one’s innocence or to inhibit aggressive behaviors. On the other, even in the face of national security, the use of brain stimulation is likely to be widely (though not universally) considered unethical if coerced or against subjects’ will.
The advance of the neuroimaging techniques has furthered the understanding of some behaviors such as altruism and trust. For instance, de Quervain (2004) has shown that people can feel rewarded from punishing norm violations and this behavior is associated with an activation of reward-related brain areas such as the dorsal striatum. Trust has been shown to be associated with an activation of the amygdala and the specific neurotransmitter oxytocin (Damasio 2005). Currently rTMS cannot stimulate such deep brain areas selectively, but this capability might become available in the future and special coil designs capable to reach deep into the brain are already available (e.g. Brainsway’s H-coil). With the rapid development of neurotechnology, implantable brain stimulators are entirely within the range of possibilities and the “psycho-civilized” society envisioned by Delgado (1969) might not always be science fiction. Akin to the genetic manipulation to obtain better, more fit people, brain stimulation might create a superior, privileged society (or at least a group of individuals that, rightly or not, judge themselves “superior” and might have power to take advantage of that), a divide that would be ethically unjust.
Are non-therapeutic uses of TMS for enhancing cognitive or affective function, ethical? Does the benefit of increasing mental facility above and beyond natural levels justify an increased risk in the patient population?
The idea that targeted brain stimulation (excitatory or inhibitory) can enhance or beneficially alter cognitive function has not been lost by the Hollywood industry (see Total Recall 1990 or Eternal Sunshine of the Spotless Mind 2004) let alone the scientific community. But this is not a futuristic issue, as recent studies using TMS and other forms of non-invasive stimulation like direct current stimulation, are exploring neuroenhancing applications in the normal population (e.g. Kobayashi et al. 2004; Antal et al. 2004; Fregni et al. 2005d, respectively). For instance, Kobayashi et al. (2004) discovered that by inhibiting cortical activity in the right motor cortex (which controls the left hand), the reaction time to a sequential finger movement task can be increased in the right hand without affecting the performance in the left hand. Similarly, Hilgetag et al. (2001) found enhanced attention to the ipsilateral field of a person’s spatial environment in normal subjects following suppression of the parietal cortex by rTMS. Others have reported facilitatory behavioral effects of rTMS on working memory, naming, abstract thinking, color perception, motor learning, and perceptual learning (Theoret et al. 2003).
Snyder and his colleagues (2003) reported that latent savant-like qualities could be revealed in normal control subjects following low-frequency rTMS to the left frontotemporal cortex. Subjects (11 right-handed males) performed a battery of tests before, immediately after, and 45 minutes following rTMS treatment. These tests included drawing animals from memory, drawing novel faces from images provided by the researcher and proofreading. Of 11 subjects, four showed dramatic stylistic changes in drawing immediately after rTMS as compared to the drawings produced before and 45mm after stimulation (Snyder et al. 2003). This TMS-induced unmasking of increased artistic and language abilities was surprising to the subjects. One subject, who wrote an article about his experiences comments that he “could hardly recognize” the drawings as his own even though he had watched himself render each image. He added: “Somehow over the course of a very few minutes, and with no additional instruction, I had gone from an incompetent draftsman to a very impressive artist of the feline form” (Osborne 2003).
Whether or not savant-like capabilities can be revealed in all persons is a matter of debate. Morrell et al. (2000) conducted a study similar to the Snyder et al. (2003) study with only minimal success, suggesting that factors like sex, age, genes, and environment might play a role in determining whether or not TMS can induce savant-like responses in the normal population (just as these factors likely play a role in whether or not neurological damage leads to savant symptoms in the patient population) (Snyder et al. 2003). However, it remains a distinct possibility that TMS could, soon, induce reliable neurocognitive enhancement of motor, attentional, artistic or language abilities in the normal human brain.
Some believe neurostimulation is no different than enhancement by other mechanisms, as both are presumably a result of altering neuronal firing and modulating brain plasticity (see Pascual-Leone et al. 1998). There exist ethicists who argue both for (e.g. Caplan 2003) and against (e.g. Kass 2003; Sandel 2002—see http://www.bioethics.gov/background/sandelpaper.html) enhancement. Michael Sandel, a member of the President’s Council on Bioethics, raises the concern that non-therapeutic enhancement poses a threat to human dignity. Sandel believes that “…what is troubling about enhancement is that it represents the triumph in our time of willfulness over giftedness, of dominion over reverence, of molding over beholding.” However, the capacity of being molded (plasticity) is an intrinsic property of the human brain and represents evolution’s invention to enable the nervous system to escape the restrictions of its own genome and to thus adapt to environmental pressures, physiologic changes, and experiences. Dynamic shifts in the strength of pre-existing connections across distributed neural networks, changes in task-related cortico-cortical and cortico-subcortical coherence, and modifications of the mapping between behavior and neural activity take place continuously in response to any and all changes in afferent input or efferent demand. Such rapid, ongoing, changes might be followed by the establishment of new connections through dendritic growth and arborization. Plasticity is not an occasional state of the nervous system; instead, it is the normal ongoing state of the nervous system throughout the lifespan. We should therefore not conceive of the brain as a stationary object capable of activating a cascade of changes that we shall call plasticity, nor as an orderly stream of events, driven by plasticity. We might be served better by thinking of the nervous system as a continuously changing structure of which plasticity is an integral property and the obligatory consequence of each sensory input, each motor act, association, reward signal, action plan, or awareness. In this framework, notions of psychological processes as distinct from organic-based functions or dysfunctions cease to be informative. Behavior will lead to changes in brain circuitry, just as changes in brain circuitry will lead to behavioral changes. Therefore, all environmental interactions, and certainly educational approaches, represent interventions that mold the brain of the actor. Given this perspective, it is conceivable that neuromodulation with properly controlled and carefully applied neurophysiologic methods could be potentially a safer, more effective and more efficient means of guiding plasticity and thus shaping behavior. Plasticity is a double-edged sword, to be sure, and harbors dangers of evolving patterns of neural activation that might in and of themselves lead to abnormal behavior. Plasticity is the mechanism for development and learning, as much as it can be the cause of pathology.
The challenge we face as scientists, therefore, is to learn enough about the mechanisms of plasticity to be able to determine the parameters of TMS that will optimally modulate neuronal firing for patients, and perhaps for the non-patient population. Defining “optimal” is the accompanying immediate ethical challenge. Challenges of preventing or overcoming inequities of access to the underserved, and ethical issues of coercion will also be important (see Farah et al. 2004). TMS scientists and neuroethicists would do well, therefore, to jointly take the lead in pursuing these issues further and in ensuring that the utilization of rTMS as a clinical and a possibly enhancement tool become clearly defined. Otherwise, we risk in the not too distant future, being face with depressed patients using their at-home TMS machines instead of following a regimen of drug therapy or college students “zapping” their frontal or parietal lobes before taking the SATs. Ultimately such applications might prove appropriate; however, they require carefully designed, well controlled trials, based on suitable ethical considerations. Without such a cautious approach, ease of application of TMS, tDCS, and future non-invasive neuromodulatory techniques threaten to cause more harm than good.
Work on this chapter was supported in part by Grant Number UL1 RR025758–Harvard Clinical and Translational Science Center, from the National Center for Research Resources and National Institutes of Health grant K 24 RR018875 to APL and a grant within the Harvard Medical School Scholars in Clinical Science Program (NIH K30 HL04095–03) to FF. The content of this chapter is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
The authors would like to thank Dan W. Brock, Professor of Medical Ethics in the Department of Social Medicine, Harvard Medical School, for his comments in an earlier version of this paper, and Jennifer Perez for editorial assistance.
Almeida-Filho, N., Lessa, I., Magalhaes, L., et al. (2004). Social inequality and depressive disorders in Bahia, Brazil: interactions of gender, ethnicity, and social class. Social Science & Medicine, 59, 1339–53.
Amassian, V.E., Somasundaram, M., Rothwell, J.C., et al. (1991). Paraesthesias are elicited by single pulse, magnetic coil stimulation of motor cortex in susceptible humans. Brain, 114, 2505–20.
Antal, A., Nitsche, M.A., and Paulus, W. (2001). External modulation of visual perception in humans. Neuroreport, 12, 3553–5.
Antal, A., Kincses, T.Z., Nitsche, M.A., et al. (2002). Pulse configuration-dependent effects of repetitive transcranial magnetic stimulation on visual perception. Neuroreport, 13, 2229–33.
Antal, A., Kincses, T.Z., Nitsche, M.A., Bartfai, O., and Paulus, W. (2004). Excitability changes induced in the human primary visual cortex by transcranial direct current stimulation: direct electrophysiological evidence. Investigational Ophthalmology & Visual Science, 45, 702–7.
Ashbridge, E., Walsh, V., and Cowey, A. (1997). Temporal aspects of visual search studied by transcranial magnetic stimulation. Neuropsychologia, 35, 1121–31.
Baudewig, J., Nitsche, M.A., Paulus, W., and Frahm, J. (2001). Regional modulation of BOLD MRI responses to human sensorimotor activation by transcranial direct current stimulation. Magnetic Resonance in Medicine, 45, 196–201.
Bickerstaffe, R., Brock, P., Husson, J.M., et al. (2006). Ethics and pharmaceutical medicine – the full report of the Ethical Issues Committee of the Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the UK. International Journal of Clinical Practice, 60, 242–52.
Burt, T., Lisanby, S.H., and Sackeim, H.A. (2002). Neuropsychiatric applications of transcranial magnetic stimulation: a meta analysis. International Journal of Neuro-psychopharmacology, 5, 73–103.
Caplan, A.L. (2003). Is better best? A noted ethicist argues in favor of brain enhancement. Scientific American, 289, 104–5.
Corthout, E., Uttl, B., Walsh, V., Hallett, M., and Cowey, A. (1999). Timing of activity in early visual cortex as revealed by transcranial magnetic stimulation. Neuroreport, 10, 2631–4.
Couturier, J.L. (2005). Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression: a systematic review and meta-analysis. Journal of Psychiatry & Neuroscience, 30, 83–90.
Damasio, A. (2005). Human behaviour: brain trust. Nature, 435, 571–2.
De Gennaro, L., Ferrara, M., Bertini, M., et al. (2003). Reproducibility of callosal effects of transcranial magnetic stimulation (TMS) with interhemispheric paired pulses. Neuroscience Research, 46, 219–27.
de la Fuente-Fernandez, R., Ruth, T.J., Sossi, V., Schulzer, M., Calne, D.B., and Stoessl, A.J. (2001). Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease. Science, 293, 1164–6.
Dickson, K. and McMahon, M. (2005). Will the law come running? The potential role of “brain fingerprinting” in crime investigation and adjudication in Australia. Journal of Law and Medicine, 13, 204–22.
Farah, M.J., Illes, J., Cook-Deegan, R., et al. (2004). Neurocognitive enhancement: what can we do and what should we do? Nature Reviews Neuroscience, 5, 421–5.
Fregni, F., Simon, D.K., Wu, A., and Pascual-Leone, A. (2005a). Non-invasive brain stimulation for Parkinson’s disease: a systematic review and meta-analysis of the literature. Journal of Neurology, Neurosurgery & Psychiatry, 76, 1614–23.
Fregni, F., Thome-Souza, S., Bermpohl, F., et al. (2005b). Antiepileptic effects of repetitive transcranial magnetic stimulation in patients with cortical malformations: An EEG and clinical studY. Stereotactic and Functional Neurosurgery, 83, 57–62.
Fregni, F., Boggio, P.S., Nitsche, M., and Pascual-Leone, A. (2005c). Transcranial direct current stimulation. British Journal of Psychiatry, 186, 446–7.
Fregni, F., Boggio, P.S., Mansur, C.G., et al. (2005d). Transcranial direct current stimulation of the unaffected hemisphere in stroke patients. Neuroreport, 16, 1551–5.
Fregni, F., Boggio, P.S., Nitsche, M.A., Marcolin, M.A., Rigonatti, S.P., and Pascual-Leone, A. (2006a). Treatment of major depression with transcranial direct current stimulation. Bipolar Disorders, 8, 203–4.
Fregni, F., Marcolin, M.A., Myczkowski, M.L., et al. (2006b). Predictors of antidepressant response in clinical trials of transcranial magnetic stimulation. International Journal of Neuropsychopharmacology, 9, 641–54.
Fregni, F., Thome-Souza, S., Nitsche, M.A., Freedman, S.D., Valente, K.D., and PascualLeone, A. (2006c). A controlled clinical trial of cathodal DC polarization in patients with refractory epilepsy. Epilepsia, 47, 335–42.
Freitas, C., Fregni, F., and Pascual-Leone, A. (2009). Meta-analysis of the effects of repetitive transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia. Schizophrenia Research, 108, 11–24.
Frye, R.E., Rotenberg, A., Ousley, M., and Pascual-Leone, A. (2008). Transcranial magnetic stimulation in child neurology: current and future directions. Journal of Child Neurology, 23, 79–96.
Ganis, G., Kosslyn, S.M., Stose, S., Thompson, W.L., and Yurgelun-Todd, D.A. (2003). Neural correlates of different types of deception: an fMRI investigation. Cerebral Cortex, 13, 830–6.
Garcia-Toro, M., Mayol, A., Arnillas, H., et al. (2001). Modest adjunctive benefit with transcranial magnetic stimulation in medication-resistant depression. Journal of Affective Disorders, 64, 271–5.
Green, R.M., Pascual-Leone, A., and Wasserman, E.M. (1997). Ethical guidelines for rTMS research. IRB, 19, 1–7.
Gross, M., Nakamura, L., Pascual-Leone, A., and Fregni, F. (2007). Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? A systematic review and meta-analysis comparing the recent vs. the earlier rTMS studies. Acta Psychiatrica Scandinavica, 116, 165–73.
Hallett, M. (2000). Transcranial magnetic stimulation and the human brain. Nature, 406, 147–50.
Hallett, M., Wassermann, E.M., Pascual-Leone, A., and Valls-Sole, J. (1999). Repetitive transcranial magnetic stimulation. The International Federation of Clinical Neurophysiology. Electroencephalography and Clinical Neurophysiology Supplement, 52, 105–13.
Hausmann, A., Kemmler, G., Walpoth, M., et al. (2004). No benefit derived from repetitive transcranial magnetic stimulation in depression: a prospective, single centre, randomised, double blind, sham controlled “add on” trial. Journal of Neurology, Neurosurgery and Psychiatry, 75, 320–2.
Hilgetag, C.C., Theoret, H., and Pascual-Leone, A. (2001). Enhanced visual spatial attention ipsilateral to rTMS-induced ‘virtual lesions’ of human parietal cortex. Nature Neuroscience, 4, 953–7.
Hoffman, R.E., Hawkins, K.A., Gueorguieva, R., et al. (2003). Transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory hallucinations. Archives of General Psychiatry, 60, 49–56.
Huang, Y.Z., Edwards, M.J., Rounis, E., Bhatia, K.P., and Rothwell, J.C. (2005). Theta burst stimulation of the human motor cortex. Neuron, 45, 201–6.
Iyer, M.B., Schleper, N., and Wassermann, E.M. (2003). Priming stimulation enhances the depressant effect of low-frequency repetitive transcranial magnetic stimulation. Journal of Neuroscience, 23, 10867–72.
Janicak, P.G., O’Reardon, J.P., Sampson, S.M., et al. (2008). Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure and during reintroduction treatment. Journal of Clinical Psychiatry, 69, 222–32.
Jensen, M.P., Hakimian, S., Sherlin, L.H., and Fregni, F. (2008). New insights into neuromodulator approaches for the treatment of pain. Journal of Pain, 9, 193–9.
Kahn, I., Pascual-Leone, A., Theoret, H., Fregni, F., Clark, D., and Wagner, A.D. (2005). Transient disruption of ventrolateral prefrontal cortex during verbal encoding affects subsequent memory performance. Journal of Neurophysiology, 94, 688–98.
Karim, A.A., Schneider, M., Lotze, M., et al. (2010). The truth about lying: inhibition of the anterior prefrontal cortex improves deceptive behavior. Cerebral Cortex, 20, 205–13.
Kass, L.R. (2003). Ageless bodies, happy souls: biotechnology and the pursuit of perfection. New Atlantis, 1, 9–29.
Keenan, J.P., Wheeler, M.A., Gallup, G.G., Jr., and Pascual-Leone, A. (2000). Self-recognition and the right prefrontal cortex. Trends in Cognitive Science, 4, 338–44.
Kobayashi, M., Hutchinson, S., Theoret, H., Schlaug, G., and Pascual-Leone, A. (2004). Repetitive TMS of the motor cortex improves ipsilateral sequential simple finger movements. Neurology, 62, 91–8.
Laporte, J.R., and Figueras, A. (1994). Placebo effects in psychiatry. Lancet, 344, 1206–9.
Lee, S., Walker, J.R., Jakul, L., and Sexton, K. (2004). Does elimination of placebo responders in a placebo run-in increase the treatment effect in randomized clinical trials? A metaanalytic evaluation. Depression and Anxiety, 19, 10–19.
Lenfant, C. (2001). Can we prevent cardiovascular diseases in low- and middle-income countries? Bulletin of the World Health Organization, 79, 980–7.
Machii, K., Cohen, D., Ramos-Estebanez, C., and Pascual-Leone, A. (2006). Safety of rTMS to non-motor cortical areas in healthy participants and patients. Clinical Neurophysiology, 117, 455–71.
Mansur, C.G., Fregni, F., Boggio, P.S., et al. (2005). A sham stimulation-controlled trial of rTMS of the unaffected hemisphere in stroke patients. Neurology, 64, 1802–4.
Martin, P.I., Naeser, M.A., Theoret, H., et al. (2004). Transcranial magnetic stimulation as a complementary treatment for aphasia. Seminars in Speech and Language, 25, 181–91.
May, A., Hajak, G., Ganssbauer, S., et al. (2006). Structural brain alterations following 5 days of intervention: dynamic aspects of neuroplasticity. Cerebral Cortex, 17, 205–10.
Miller, F.G. and Brody, H. (2003). A critique of clinical equipoise. Therapeutic misconception in the ethics of clinical trials. Hastings Center Report, 33, 19–28.
Miller, S.M., Liu, G.B., Ngo, T.T., et al. (2000). Interhemispheric switching mediates perceptual rivalry. Current Biology, 10, 383–92.
Murphy, D.N., Boggio, P., and Fregni, F. (2009). Transcranial direct current stimulation as a therapeutic tool for the treatment of major depression: insights from past and recent clinical studies. Current Opinion in Psychiatry, 22, 306–11.
Naeser, M.A., Martin, P.I., Nicholas, M., et al. (2005a). Improved naming after TMS treatments in a chronic, global aphasia patient – case report. Neurocase, 11, 182–93.
Naeser, M.A., Martin, P.I., Nicholas, M., et al. (2005b). Improved picture naming in chronic aphasia after TMS to part of right Broca’s area: an open-protocol study. Brain and Language, 93, 95–105.
Nitsche, M.A. and Paulus, W. (2000). Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. Journal of Physiology, 527, 633–9.
Nitsche, M.A. and Paulus, W. (2001). Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology, 57, 1899–901.
Nitsche, M.A., Liebetanz, D., Antal, A., Lang, N., Tergau, F., and Paulus, W. (2003). Modulation of cortical excitability by weak direct current stimulation–technical, safety and functional aspects. Supplements to Clinical Neurophysiology, 56, 255–76.
Nitsche, M.A., Niehaus, L., Hoffmann, K.T., et al. (2004). MRI study of human brain exposed to weak direct current stimulation of the frontal cortex. Clinical Neurophysiology, 115, 2419–23.
O’Connor, M., Brenninkmeyer, C., Morgan, A., et al. (2003). Relative effects of repetitive transcranial magnetic stimulation and electroconvulsive therapy on mood and memory: a neurocognitive risk-benefit analysis. Cognitive and Behavioral Neurology, 16, 118–27.
O’Reardon, J.P., Solvason, H.B., Janicak, P.G., et al. (2007). Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biological Psychiatry, 62, 1208–16.
Osborne, L. (2003). Savant for a day. New York Times, 22 June, pp. 38 (col 31).
Pascual-Leone, A. (2006). Disrupting the brain to guide plasticity and improve behavior. Progress in Brain Research, 157, 315–29.
Pascual-Leone, A., Tormos, J.M., Keenan, J., Tarazona, F., Canete, C., and Catala, M.D. (1998). Study and modulation of human cortical excitability with transcranial magnetic stimulation. Journal of Clinical Neurophysiology, 15, 333–43.
Pascual-Leone, A., Bartres-Faz, D., and Keenan, J.P. (1999). Transcranial magnetic stimulation: studying the brain-behaviour relationship by induction of ‘virtual lesions’. Philosophical Transactions of the Royal Society of London B: Biological Sciences, 354, 1229–38.
Priori, A., Mameli, F., Cogiamanian, F., et al. (2008). Lie-specific involvement of dorsolateral prefrontal cortex in deception. Cerebral Cortex, 18, 451–5.
Quintana, H. (2005). Transcranial magnetic stimulation in persons younger than the age of 18. Journal of ECT, 21, 88–95.
Robertson, E.M., Tormos, J.M., Maeda, F., and Pascual-Leone, A. (2001). The role of the dorsolateral prefrontal cortex during sequence learning is specific for spatial information. Cerebral Cortex, 11, 628–35.
Robertson, E.M., Theoret, H., and Pascual-Leone, A. (2003). Studies in cognition: the problems solved and created by transcranial magnetic stimulation. Journal of Cognitive Neuroscience, 15, 948–60.
Rosenkranz, K., Nitsche, M.A., Tergau, F., and Paulus, W. (2000). Diminution of training-induced transient motor cortex plasticity by weak transcranial direct current stimulation in the human. Neuroscience Letters, 296, 61–3.
Rossi, S., Hallett, M., Rossini, P.M., and Pascual-Leone, A. (2009). Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clinical Neurophysiology, 120, 2008–39.
Rothman, K.J. and Michels, K.B. (1994). The continuing unethical use of placebo controls. New England Journal of Medicine, 331, 394–8.
Rumi, D.O., Gattaz, W.F., Rigonatti, S.P., et al. (2005). Transcranial magnetic stimulation accelerates the antidepressant effect of amitriptyline in severe depression: a double-blind placebo-controlled study. Biological Psychiatry, 57, 162–6.
Siebner, H.R., Tormos, J.M., Ceballos-Baumann, A.O., et al. (1999). Low-frequency repetitive transcranial magnetic stimulation of the motor cortex in writer’s cramp. Neurology, 52, 529–37.
Snyder, A.W., Mulcahy, E., Taylor, J.L., Mitchell, D.J., Sachdev, P., and Gandevia, S.C. (2003). Savant-like skills exposed in normal people by suppressing the left frontotemporal lobe. Journal of Integrated Neuroscience, 2, 149–58.
Steven, M.S. and Pascual-Leone, A. (2006). Transcranial Magnetic Stimulation and the Human Brain: An Ethical Evaluation. In J. Illes (ed.), 21st Century Neuroethics: Defining the Issues in Research, Practice and Policy. Oxford: Oxford University Press.
Strafella, A.P., Ko, J.H., and Monchi, O. (2006). Therapeutic application of transcranial magnetic stimulation in Parkinson’s disease: The contribution of expectation. Neuroimage, 31, 1666–72.
Theoret, H., Kobayashi, M., Valero-Cabre, A., and Pascual-Leone, A. (2003). Exploring paradoxical functional facilitation with TMS. Supplements to Clinical Neurophysiology, 56, 211–19.
Theoret, H., Halligan, E., Kobayashi, M., Merabet, L., and Pascual-Leone, A. (2004). Unconscious modulation of motor cortex excitability revealed with transcranial magnetic stimulation. Experimental Brain Research, 155, 261–4.
Thut, G., Ives, J.R., Kampmann, F., Pastor, M.A., and Pascual-Leone, A. (2005). A new device and protocol for combining TMS and online recordings of EEG and evoked potentials. Journal of Neuroscience Methods, 141, 207–17.
UK ECT Review Group. (2003). Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet, 361, 799–808.
Wagner, T., Fregni, F., Eden, U., et al. (2006). Transcranial magnetic stimulation and stroke: A computer-based human model study. Neuroimage, 30, 857–70.
Wagner, T., Valero-Cabre, A., and Pascual-Leone, A. (2007). Noninvasive human brain stimulation. Annual Review of Biomedical Engineering, 9, 527–65.
Walsh, V. and Pascual-Leone, A. (2003). TMS in Cognitive Science: Neurochronometrics of Mind. Cambridge, MA: MIT Press.
Walsh, V., Pascual-Leone, A., and Kosslyn, S.M. (2005). Transcranial Magnetic Stimulation: A Neurochronometrics of Mind. Cambridge, MA: MIT Press.
Walsh, V., Desmond, J.E., and Pascual-Leone, A. (2006). Manipulating brains. Behavioral Neurology, 17, 131–4.
Wassermann, E.M. (1998). 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. Electroencephalography and Clinical Neurophysiology, 108, 1–16.
Wassermann, E.M. and Grafman, J. (2005). Recharging cognition with DC brain polarization. Trends in Cognitive Science, 9, 503–5.
Wohlfarth, T. (1997). Socioeconomic inequality and psychopathology: are socioeconomic status and social class interchangeable? Social Science & Medicine, 45, 399–410.
Wu, A.D., Fregni, F., Simon, D.K., Deblieck, C., and Pascual-Leone, A. (2008). Noninvasive brain stimulation for Parkinson’s disease and dystonia. Neurotherapeutics, 5, 345–61.
Zaghi, S., Acar, M., Hultgren, B., Boggio, P., and Fregni, F. (2010). Noninvasive brain stimulation with low-intensity electrical currents:putative mechanisms of action for direct and alternating current stimulation. Neuroscientist, 16, 285–307.