Description of Method
Transcranial magnetic stimulation involves inducing an electrical current within the brain using pulsating magnetic fields that are generated outside the brain near the scalp. The essential feature is using electricity to generate a rapidly changing magnetic field, which in turn produces electrical impulses in the brain. A typical TMS device produces a fairly powerful magnetic field (about 1.5–3
T), but only very briefly (milliseconds). TMS is not simply applying a static or constant magnetic field to the brain. By 1820 scientists had discovered that passing an electric current though a wire induces a magnetic field. In 1832, Michael Faraday showed that the inverse was also true—passing a wire through a magnetic field generates an electrical current (
Faraday, 1965). Thus, a changing magnetic field can generate electrical current in nearby wires, nerves, or muscles. A static magnet will not generate a current. For most TMS applications, it likely is the electricity induced from the pulsating magnet, and not the magnetic field itself, which produces neurobiological effects.
In 1959, Kolin and his colleagues showed that a fluctuating magnetic field could stimulate a peripheral frog muscle in preparation (
Kolin et al, 1959). However, it was not until 1985 that the modern era of TMS started. That year Anthony Baker in Sheffield, England described the use of a noninvasive magnetic device resembling modern TMS instruments (
Barker et al, 1985). The device was slow to recharge and quick to overheat, but it was able to stimulate spinal cord roots, and also superficial human cortex.
TMS requires a unit to store and deliver a charge (called a capacitor), and an electromagnetic coil (typically round in the shape of a doughnut or two round coils side-by-side and connected in a figure eight) (see ). A system can be cumbersome (resembling a small refrigerator), although some have shown that the entire system could be made portable and weigh less than 20 lbs (
Epstein, 2008;
Huang et al, 2009). The devices are regulated by the FDA for general safety, and most machines have FDA approval for sale in the US. They are also then regulated with respect to the ability to advertise their therapeutic use in a particular disorder. In the United States a device manufactured by Neuronetics was approved by the FDA in 2008 for treating depression (
O'Reardon et al, 2007).
Early TMS devices only emitted a single, brief pulse. Modern devices can generate a rapid succession of pulses, called repetitive TMS (rTMS). These devices are used for behavioral research or clinical treatments and can discharge on and off for several minutes. For example, the typical treatment for depression is a 20–40
min session, 5 days a week for 4–6 weeks. To keep the patient still and the device correctly placed, the patient reclines in a chair and the device is held securely against their head while they are awake and alert without needing anesthesia.
The TMS coil generates a magnetic field impulse that can only reach the outer layers of the cortex (
Davey et al, 2004). The main effect of the impulse only penetrates 2–3
cm below the device (
Roth et al, 1994;
Rothwell et al, 1999). However, a deep TMS device has been invented and is in early clinical trials for depression and several other indications (
Roth et al, 2002,
2005).
When the TMS device produces a pulse over the motor cortex, descending fibers are activated and volleys of electrical impulses descend through connected fibers into the spinal cord and out to the peripheral nerve where it can ultimately cause a muscle to twitch. The minimum amount of energy needed to produce contraction of the thumb (abductor pollicis brevis) is called the motor threshold (MT) (
Fitzgerald et al, 2006;
Fox et al, 2006;
Sacco and Thickbroom, 2009). As this is so easy to generate, and varies widely across individuals, the MT is used as a measure of general cortical excitability and most TMS studies (both research and clinical) report the TMS intensity as a function of individual MT (and not as an absolute physical value) (
Di Lazzaro et al, 2008). Although this convention has helped in making TMS safer, it is severely insufficient, in that it is referenced only to each machine, and thus is not a universal number. Future work is focusing on more universal, constant, measures of the magnetic field delivered.
In general with TMS, a stronger, more intense pulse results in more activation of the CNS tissue, and a wider area of activation. The circumstance with frequency is more complex. In general, frequencies of less than 1 per second (<1
Hz) are inhibitory (
Hoffman and Cavus, 2002). This may be because low-frequency TMS more selectively stimulates the inhibitory GABA neurons, or this frequency is LTD like. Conversely, higher frequency stimulation is behaviorally excitatory (
Ziemann et al, 2008). However, high-frequency TMS over some brain regions can temporarily block or knockout the function of that part of the brain (
Epstein et al, 1996;
Pascual-Leone et al, 1991).
A handheld device is being developed and studied as a treatment to interrupt migraine headaches (Neuralieve). The device delivers a single large pulse. When the patient experiences the aura phase of an impending headache they hold the device to the back of their head and direct the pulse toward the occipital cortex (
Ambrosini and Schoenen, 2003;
Clarke et al, 2006).
Putative Mechanisms of Action
TMS can produce different brain effects depending on the brain region being stimulated, the frequency of stimulation, the use parameters (intensity, frequency, duty train), and whether the brain region is engaged or ‘resting'. Thus, it is difficult to review a single ‘mechanism of action' for TMS. However, in general, a single pulse of TMS over a cortical region, such as the motor cortex, causes large neurons to depolarize. That is, the powerful transient magnetic field induces current to flow in neurons in superficial cortex (induced current). Both modeling and simple testing have shown that the fibers that are most likely to depolarize are those that are perpendicular to the coil, and are bending within the gyrus (
Amassian et al, 1992, ;
Lisanby et al, 1998a,
1998b). Some lower TMS intensities do not cause large neuron depolarization, but can still affect resting membrane potentials and thus alter brain activity and behavior. The most striking positive phenomena that TMS can produce are motor twitches (thumb, hand, arm, or leg movement) when applied over motor cortex, or ‘phosphenes' when TMS is placed over the occiput. To date TMS cannot produce acute memories, thoughts, or sensations or percepts apart from the scalp sensation of the coil.
rTMS can produce measurable effects lasting for minutes to hours after the train. In general, rTMS at frequencies greater than 1
Hz are excitatory, and less than 1
Hz inhibitory. One particular TMS sequence builds directly from the neurobiological studies of LTP and LTD, and is called theta burst as it has short bursts of TMS at theta frequencies (
Di Lazzaro et al, 2005;
Stagg et al, 2009).
TMS over some cortical regions can produce a transient disruption of behavior. This is most striking when the coil is placed over Broca's area and one can produce a transient expressive aphasia. Much interest involves whether TMS can produce short-term or even longer-term changes in plasticity (
Ziemann et al, 2008). Simple studies in motor and visual systems clearly indicate the potential for this approach (
Miniussi et al, 2008), which is now being applied in studies of poststroke recovery and other forms of rehabilitation (
Hummel et al, 2008;
Pape et al, 2009).
Coupling TMS with electrophysiological measures allows one to use TMS as a measure of motor cortex excitability, and then measure how behavior, medications, or other interventions might change excitability. Several groups are using this TMS excitability measurement technique to investigate new CNS-active compounds (
Li et al, 2009,
2004;
Paulus et al, 2008;
Ziemann et al, 2008).
Coupling TMS with imaging (PET, SPECT, fMRI, or BOLD fMRI) allows one to directly stimulate circuits and then image the resultant changes (
George et al, 2007;
Siebner et al, 2009). With respect to the neuropsychiatric uses of TMS for depression or pain, at a molecular level TMS is known to have similar effects as those seen with ECT, for example, increased monoamine turnover, increased Brain-Derived Neurotrophic Factor, and normalization of the hypothalamic–pituitary–adrenal axis.
The initial use of daily prefrontal TMS to treat depression was based on the theory that clinical depression involved an imbalanced relationship between prefrontal cortex and limbic regions involved in mood regulation (insula, cingulate gyrus, amygdala, and hippocampus)(
George et al, 1994). There is only limited direct support that this is occurring, although recent work by Maier and colleagues directly supports the causal role of medial prefrontal cortex in mitigating and reversing chronic learned helplessness. Stimulatory fibers from PFCx are critical in this model (
Baratta et al, 2007;
Christianson et al, 2008a,
2008b;
Hutchinson et al, 2008).
Safety
In general, TMS is regarded as safe and without enduring side effects. There have been no reported lasting neurologic, cognitive, or cardiovascular sequelae. However, TMS can alter brain function and is a relatively new technology so vigilance is required. The interested reader should read the results from an earlier international conference on TMS safety (
Wassermann, 1997). An update has been drafted following another international meeting and should be available within the next 6 months.
Inducing a seizure is the primary safety concern with TMS. There have been less than 20 reported seizures induced with TMS, with a sample size of several thousand. The risk is less than one half of 1%. Most of these patients were healthy volunteers without a history of epilepsy. Fortunately, there are no reports that the individuals affected experienced recurrence. In addition, all of the seizures occurred during TMS administration when the patient was sitting down and near an investigator. In addition, all of the seizures were self-limited without needing medications or other interventions. Published safety tables concerning the proper intensity, frequency, and number of stimuli help minimize the numbers of seizures(
Wassermann, 1997). Of the reported cases the majority were receiving TMS to the motor cortex—the most epileptogenic region of the cortex. Additionally, most (but not all) were receiving trains of stimulation outside of suggested limits. These cases suggest that TMS induced seizures will remain a small but significant adverse event even in patients without histories of seizures and even when TMS is used within suggested guidelines.
Studies in rabbits as well as some human studies suggest that TMS can cause hearing loss and subjects, patients, and operators should wear earplugs (
Counter et al, 1990;
Loo et al, 2001). One patient reported a temporary hearing loss after TMS. In light of this an extensive study of auditory threshold was conducted before and after 4 weeks of TMS in over 300 patients. No changes were found. However, patients should wear earplugs when receiving TMS.
Headaches are the most common complaint after TMS, however, there was no difference in headache frequency between sham and control in a recent large trial (
O'Reardon et al, 2007). Repeated analysis of neurocognitive functioning of TMS patients has not found any enduring negative effects from the procedure (
Avery et al, 2008;
Little et al, 2000). After a session, patients or subjects are able to drive home and return to work.
Clinical Studies
Largely because of its noninvasiveness, TMS has been investigated in almost all neuropsychiatric conditions. Until only recently, there has not been a TMS industry to promote or perform this work and thus much of the clinical work has been single site and nonindustry funded, with relatively small sample sizes.
Depression has been the most widely studied condition with TMS. Three initial studies from Europe used TMS over the vertex as a potential antidepressant (
Grisaru et al, 1994;
Hoflich et al, 1993;
Kolbinger et al, 1995). In the US, George, Wassermann, and Post performed initial safety studies in healthy controls, an open study, and then a double-blind controlled trial of TMS for 2 weeks (
George et al, 1997,
1995,
1996). This work has now dramatically grown, but without much change in many of the initial treatment choices (coil location, frequency, dosing). There have now been several meta-analyses of the procedure (
Ridding and Rothwell, 2007). A recent meta-analysis of rTMS for depression examined 25 published sham-controlled studies (
Mitchell and Loo, 2006). The authors concluded that left prefrontal TMS provided statistical superiority over sham treatment for patients with depression. However, they concluded that the clinical benefits are marginal in the majority of reports and there is still considerable uncertainty concerning the optimal stimulation parameters. Two recent positive meta-analyses suggest that the overall effect size with TMS in major depression is at least as good as that of standard pharmacotherapy (
Lam et al, 2008;
Schutter, 2008). Those clinical features that appear to be associated with greater response include younger age, lack of refractoriness to antidepressants, and no psychotic features (
Avery et al, 2008).
The largest multisite trial to date, which resulted in FDA approval, was by Neuronetics. They sponsored a double-blind, multisite study of 301 medication-free patients with major depression. Patients were randomized to active TMS or sham treatment, which they received for 4–6 weeks (
O'Reardon et al, 2007). There was some controversy about the results of the trial. Before conducting the experiment, the company chose a continuous variable, the change from baseline on the Montgomery–Asberg Depression Rating Scale (MADRS), as the primary outcome measure (and did not tell investigators in the field) while using the Hamilton Rating Scale as the entry criteria. Unfortunately, at 6 weeks the continuous measured MADRS change from baseline for the active treatment group was not quite statistically different from the control group:
p=0.058. The Hamilton Depression Rating Scale scores, considered secondary outcome measures, were indeed superior for those in the active treatment group. The company argued, successfully for the publication, that they should be able to exclude six subjects with entry MADRS scores that were very low and could not reflect clinical improvement. Thus, the manuscript was published as a positive trial but the FDA initially rejected the application, and only agreed for approval after reviewing response data on subgroups. As there was such a large effect seen in those who were less treatment resistant, the FDA labeling is for the treatment of MDD in adult patients who have failed to achieve satisfactory improvement from one prior antidepressant treatment at or above the minimal effective dose and duration in the current episode. Note that in clinical practice, only about one in four treatment trials meets criteria for minimal dose and duration, so this translates in a clinical practice to patients with a moderate level of treatment resistance (
Dew et al, 2005;
Joo et al, 2005;
Oquendo et al, 2003).
These mixed results reflect the current status of TMS for depression. Most agree that daily left prefrontal TMS for several weeks has antidepressant effects and is safe and well tolerated. It will likely be an ideal treatment for some patients. However, the efficacy data in trials to date are not as robust as some would like and many await the results of larger ongoing trials and better understanding of the mechanisms of action. For example, a large European trial failed to find a statistically significant difference, but likely used an active sham condition as well as examined TMS as an augmentation rather than stand-alone treatment (
Herwig et al, 2007). The NIH has funded a large multisite trial in depression with results due in late 2009 and the VA has launched a large cooperative study of daily left prefrontal TMS in depressed veterans.
One recent development in terms of TMS positioning has highlighted that better understanding of the TMS methods used will likely boost clinical antidepressant efficacy. The early NIMH studies used a rough measurement technique known as the 5-cm rule to place the TMS coil roughly over the prefrontal cortex (
George et al, 1997,
1995,
1996). As the location of the motor strip varies between individuals, and skull size (hat size) also varies, this simple rule results in a large variation of actual location on scalp. It became obvious that this was an insufficient technique, but was nevertheless used in most trials, including the one for FDA approval (
Herwig et al, 2001). One study suggested that the 5-cm rule resulted in 30% of patients being treated over supplementary motor area rather than prefrontal cortex. Two retrospective analyses of clinical trials in which brain imaging was performed to document the coil location have independently confirmed that a coil position that is anterior and lateral is associated with a better clinical response to active but not sham TMS (
Herbsman et al, 2009). An Australian group has performed a RCT and a more anterior and lateral location did indeed produce superior antidepressant response (
Fitzgerald et al, 2009). These findings suggest that the TMS effect is not nonspecific, and that the location of the coil clearly matters, even within broad boundaries of a specific lobe. It is not clear whether individualized location will be needed or used, or whether general algorithms will suffice for most patients.
Auditory hallucinations are part of the positive symptoms of schizophrenia. These types of hallucinations are believed to result from aberrant activation of the language perception area at the junction of the left temporal and parietal cortices (
Higgins and George, 2007). Low-frequency TMS has been used to potentially inhibit this area in patients with schizophrenia and provide relief from auditory hallucinations. A recent meta-analysis examined the efficacy of low-frequency TMS as a treatment of resistant auditory hallucinations in schizophrenia (
Aleman et al, 2007). Ten sham-controlled studies have incorporated 212 patients. Their review concluded that TMS was effective in reducing auditory hallucinations. Unfortunately, TMS had no effect on other positive symptoms or the cognitive deficits of schizophrenia. Larger studies are needed to definitely establish the efficacy, tolerability, and utility of TMS for schizophrenia.
There have been four RCTs of using intermittent daily prefrontal TMS to treat negative symptoms in patients with schizophrenia. Only one of these studies was positive.
Tinnitus is a common, often disabling disorder, for which there is no adequate treatment. As many as 8% of adults over 50-years old suffer from tinnitus that can often be quite distressing. Recent functional imaging studies have identified increased activity in the auditory cortex in patients with tinnitus. Low-frequency TMS offers a possible mechanism to inhibit the overactive auditory cortex that may be producing tinnitus. Several small controlled trials from one research group in Germany have produced impressive results (
Langguth et al, 2008). Larger, multicenter studies are needed to see if these positive effects can be replicated.
Numerous small controlled studies have evaluated the utility of TMS in patients with pain. Multiple sites have been tested including prefrontal cortex, motor cortex, and parietal cortex(
Andre-Obadia et al, 2006;
Lefaucher et al, 2001;
Lefaucheur, 2004;
Lefaucheur et al, 2001;
Pridmore and Oberoi, 2000;
Rollnik et al, 2003). In general, TMS provides effective pain relief in these different locations in diverse pain conditions. Unfortunately, the effect of TMS on pain only lasts for a short duration. Consequently, the utility of TMS as a practical treatment for chronic pain conditions has yet to be established.
Recent studies suggest TMS may have some utility in managing acute pain. In two different studies of patients recovering from gastric by-pass surgery, 20
min of real or sham TMS was administered to the prefrontal cortex of every patient. Then their use of self-administered morphine was followed over the next 48
h. Those receiving real TMS used 40% less morphine in the next 24
h, with the majority of the reduction occurring in the first 8
h after TMS (
Borckardt et al, 2008b,
2006b).
The handheld device, mentioned above, is being studied as a treatment for migraine headaches. Preliminary results have been encouraging. Larger studies are underway.
Following an ischemic event to the motor cortex, the brain attempts to reorganize the damaged networks. Indeed, the extent of reorganization correlates with the clinical recovery of motor function. TMS may accelerate the reorganization process and therefore enhance recovery (
Hummel et al, 2008;
Miniussi et al, 2008;
Pape et al, 2009). It is unclear which types of TMS may be beneficial in stroke recovery. High-frequency TMS to the affected area may enhance reorganization. Alternatively, low-frequency TMS to the opposite, intact hemisphere is believed to reduce the interference from the nonstroke side. Some believe that too much input from the unaffected side of the brain impedes recovery. Reducing excitability with low-frequency TMS may enhance recovery.
Ridding and Rothwell recently reviewed the studies of TMS in stroke recovery. Although the total number of patients in controlled trials was only 87, the results were encouraging. Clearly, larger studies are needed, but it appears that TMS might be able to improve the natural healing process after a stroke (
Kew et al, 1994;
McKay et al, 2002;
Ridding and Rothwell, 1995,
2007).
Theoretically low-frequency TMS could be used to treat cortical epilepsy. Early studies showed that TMS could reduce EEG epileptiform abnormalities. Initial case studies were positive. A controlled study of daily TMS by Theodore
et al (
2002) over the cortical site of seizures for 1 week found a statistically significant reduction in seizures. However, the authors concluded that TMS treatment was not clinically significant. More recently, in another controlled trial Cantello
et al (
2007) concluded that ‘active' rTMS was no better than placebo for seizure reduction. Thus, the idea of using inhibitory doses of TMS to calm cortical targets is intriguing. However, the controlled trials to date have not been as successful.
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