Repetitive transcranial magnetic stimulation (rTMS) has been investigated and applied across a range of neuropsychiatric disorders. The greatest amount of translational research has investigated the use of rTMS in the treatment of patients with major depressive disorder. However, a substantive series of studies have also investigated the use of rTMS across schizophrenia, anxiety, pain, stroke, and a range of other disorders. The evidence base and rationale for these other applications varies considerably, as will be outlined in this chapter. Although clinical services are predominantly developed around the use of rTMS in depression, it is likely that the indications for this technique will progressively expand in coming years as the evidence base for use in other disorders progressively increases.
Initial studies assessing the use of TMS in depression applied single pulses to the vertex, typically with limited benefit (Grisaru, Yaroslavsky, Abarbanel, Lamberg, & Belmaker, 1994). This tentative start reflected initial concerns about the overall safety of the application of rTMS. As this became better established, investigators began to explore more substantive therapeutic protocols. The application of rTMS also began to be informed by the growing neuroscience understanding of brain abnormalities in patients with depression.
The initial therapeutic application of rTMS involved high-frequency stimulation to the left dorsolateral prefrontal cortex (DLPFC). This approach has persisted to current times, although a range of other methods for rTMS treatment of depression have also been explored. The use of high-frequency left DLPFC stimulation was initially suggested by studies that demonstrated changes in left DLPFC blood flow using positron emission tomography (PET) in patients with depression (George, Ketter, & Post, 1994). The left anterior prefrontal cortex had also been implicated in the etiology of depression from studies exploring the development of the illness following strokes and in electroencephalography (EEG) studies exploring prefrontal activation in patients with depression. It was hypothesized that by increasing prefrontal activity with high-frequency rTMS, the left prefrontal deficit in metabolism could be corrected, producing a reduction in depressive symptoms.
Initial studies exploring the antidepressant effects of rTMS were, by modern standards, relatively short and used low rTMS doses. The studies were typically 1 to 2 weeks duration and applied no more than 20 rTMS trains per day (George et al., 1997; Pascual-Leone, Rubio, Pallardo, & Catala, 1996). In spite of these limited stimulation parameters, clear antidepressant effects were evident, leading to a rapid and widespread expansion of interest in exploring the use of rTMS.
Since the mid-1990s, more than 30 randomized double-blind controlled trials have explored the application of high-frequency rTMS applied to the left DLPFC. The majority of these trials have demonstrated greater antidepressant effects with active stimulation than sham, although negative studies have also been published.
Over time, there has been a progressive evolution in the stimulation parameters applied in studies. Trial duration has increased from 1 to 2 weeks to 4 weeks and then to 6 to 9 weeks in some studies (Fitzgerald & Daskalakis, 2011). The number of stimulation trains applied per day and the overall number of stimulation pulses has also substantially increased over time. A variety of frequencies have been used ranging from 5 to 25 Hz, although 10 Hz is most commonly used. The 10 Hz stimulation parameters typically involve stimulation trains between 4 and 5 seconds duration. Finally, initial rTMS studies used stimulation intensity less than the resting motor threshold (often 90%). This has progressively increased such that most trials today use 120% of the resting motor threshold as standard stimulation intensity.
Although many of the rTMS studies conducted to date have been small, investigator-initiated trials, several larger-scale multisite trials have been performed. An equipment manufacturer that had patent protection over a modified rTMS coil design sponsored the first study. This study involved the randomization of more than 300 medication-free patients to either active or sham stimulation (O’Reardon et al., 2007). Treatment was provided on a daily basis for 6 weeks and could be continued during a 3-week taper period. Seventy-five trains at 10 Hz were provided daily at a relatively high intensity. A nonidentified sham stimulation coil system was used to ensure the blinding of both patients and clinicians.
The results of this trial are somewhat complex. There was a significant benefit of active over sham stimulation across most trial outcome measures. However, a significant difference was not seen on the a priori nominated primary outcome measure (the Montgomery–Asberg depression rating scale) on the full study sample. Significant differences between active and sham stimulation were seen when the sample was limited to patients who had only failed to respond to a single antidepressant medication in their current episode. The results of the secondary analysis were used to achieve device registration for this patient group in the United States in late 2008. Notably, treatment was generally well tolerated in this trial, with a low overall dropout rate.
A second multisite trial that was independently sponsored included 199 patients receiving 3000 10-Hz pulses applied on a daily basis for 3 weeks, with a possible 3-week extension for partial responders (George et al., 2010). Active stimulation produced a greater percentage of patients who achieved remission of depressive symptoms than sham stimulation, although the overall rates of remission in both groups were low (14.1% versus 5.1%). Treatment was also very well tolerated in this trial.
A number of metaanalyses have summarized the results of rTMS trials in depression. These generally demonstrate a clear and substantial antidepressant benefit of active stimulation over sham. For example, the analysis by Schutter (2009) involved 30 trials and 1164 patients. This study found a highly significant effect of active treatment compared to placebo, indicated by the average reduction in depression severity scores (P < 0.00001) with a moderate effect size (0.39). The benefit of treatment was not dependent on the degree of preexisting medication resistance. The intensity of stimulation also did not affect overall outcomes. Analyses indicated that the findings in this analysis were robust to typical biases that can influence metaanalyses.
A series of studies have also compared rTMS to electroconvulsive therapy (ECT; Pridmore, Bruno, Turnier-Shea, Reid, & Rybak, 2000; Janicak et al., 2002; Grunhaus et al., 2000; Grunhaus, Dannon, & Schreiber, 1998; Eranti et al., 2007; Rosa et al., 2006). Unfortunately, the majority of these studies have serious limitations that restrict the conclusions that can be drawn from them. Most of these studies had small sample sizes, which limit their capacity to show differences between two active treatments. There also were significant differences in the way treatment was applied; a number of trials compared a fixed number of unilateral rTMS sessions to a nonfixed number of both unilateral and bilateral ECT treatment sessions. Many of these trials showed no differences in outcomes between the two treatments, although it is possible that this simply reflects a lack of study power. Several studies found a treatment advantage of ECT, either for patients with depression as a whole (McLoughlin et al., 2007) or for a subgroup of patients with depression with psychotic symptoms (Grunhaus et al., 1998).
Although the vast majority of rTMS research has explored the use of high-frequency rTMS applied to the left DLPFC as described above, a complementary body of research has explored a number of other rTMS treatment options. The most substantial group of studies explored the use of low-frequency stimulation (usually 1 Hz) applied to the right DLPFC. This approach was, in part, motivated by early EEG studies that demonstrated changes in prefrontal activity between right and left DLPFC in depression. As indicated above, these studies can be interpreted as showing a reduction in left prefrontal activity, but alternatively can also be interpreted as demonstrating an increase in the right DLPFC activity in depression. Therefore, it was considered that low-frequency stimulation may produce antidepressant effects in reducing right DLPFC activity.
Studies using low-frequency rTMS have been conducted since 1999. Low-frequency stimulation is typically provided at 1 Hz. Initial studies used multiple short typically 1-minute, trains. More recent low-frequency studies typically apply a single lengthy rTMS 1-Hz train, often of 15 to 20 minutes duration. The majority of the studies conducted to date have shown positive antidepressant effects. This finding was confirmed in a recent metaanalysis that demonstrated an effect size of 0.634 for active compared to sham stimulation (Schutter, 2010). This result appears robust, as approximately 120 negative studies would be required to render the effect significant. Notably, within this analysis, the author compared the effect size apparent with low-frequency right-sided stimulation to that found in a previously conducted metaanalysis of left-sided high-frequency stimulation (Schutter, 2009). No differences were found, suggesting similar clinical effects. This is consistent with the findings of studies directly comparing the clinical effects of high-frequency left- and low-frequency right-sided rTMS (Fitzgerald et al., 2003). Response to one type of rTMS does not seem to exclude the possibility of response to the other (Fitzgerald et al., 2009). It is also possible that there are differences in the patients who would respond to either type, such that treatment could be individualized, but this has not been systematically investigated.
A third potential method of application of rTMS involves bilateral stimulation. Bilateral simultaneous high-frequency stimulation does not appear to have antidepressant efficacy (Loo et al., 2003). A significant number of studies have explored the use of sequential bilateral rTMS, using both low-frequency right-sided and high-frequency left-sided stimulation. Studies have demonstrated that sequential bilateral rTMS produces greater antidepressant effects than sham stimulation (Fitzgerald et al., 2006). However, a series of recent trials have suggested that response to bilateral stimulation is not greater than response to unilateral stimulation (Fitzgerald et al., 2011, 2012; Pallanti, Bernardi, Di Rollo, Antonini, & Quercioli, 2010).
All approaches described above tend to support a model of depression that proposes left prefrontal hypoactivity or right prefrontal hyperactivity and the use of stimulation paradigms to reverse this. However, it is worth noting that several studies have suggested that low-frequency stimulation applied to the left DLPFC may have antidepressant effects (Feinsod, Kreinin, Chistyakov, & Klein, 1998; Padberg et al., 1999; Speer et al., 2009). One study also suggested that bilateral 1-Hz stimulation appears to have antidepressant activity (Fitzgerald et al., 2011). Therefore, the specificity of frequency and laterality assumed in some of the traditional rTMS models may not be as tightly linked to clinical response as has traditionally been assumed.
Finally, there are a number of other, more experimental approaches to the use of rTMS treatment in depression. For example, the priming approach involves combining low-intensity high-frequency stimulation usually applied at 6 Hz with subsequent 1-Hz, low-frequency stimulation. Preliminary research has reported that the antidepressant effects of this in the right DLPFC may be greater than standard low-frequency stimulation alone (Fitzgerald, Herring, et al., 2008). A second alternative approach is the use of patterned stimulation, most typically of the theta burst type. Theta burst stimulation (TBS) typically involves the application of a very short (e.g., three pulses) high-frequency bursts, usually at 50 Hz. These bursts are repeated at theta frequency (usually 5 Hz). Continuous TBS typically decreases and intermittent TBS increases cortical excitability (Paulus, 2005). Significant cortical effects appear to be achieved with very short stimulation paradigms using TBS, although the antidepressant benefits of these have not been substantially established to date.
There are a number of significant, unresolved issues in the application of rTMS treatment in depression. First, almost all rTMS research has concentrated on the acute phase of treatment, that is, producing an amelioration of depressive episode rather than exploring the long-term impact of rTMS treatment on the course of major depressive disorder. Studies conducted to date suggest that there is a significant likelihood of relapse in the 6 to 12 months following acute treatment with rTMS that resulted in clinical response or remission. In a sample of more than 200 patients who had successfully undergone rTMS treatment, 80% had relapsed by 6 months (Cohen, Boggio, & Fregni, 2009). Limited information is available on the value of strategies that may be used to prevent relapse. No systematic trials have explored the use of medication in preventing relapse post rTMS, although research post ECT suggests that the combination of lithium and antidepressant treatment is more likely to be successful than an antidepressant alone (Sackeim et al., 2001; Rehor et al., 2009). A few preliminary studies have reported on methods for the provision of maintenance rTMS as a relapse prevention strategy. This most often involves the provision of weekly or fortnightly single rTMS sessions, often with a decrease in session frequency over time (O’Reardon, Blumner, Peshek, Pradilla, & Pimiento, 2005; Li, Nahas, Anderson, Kozel, & George, 2004). An alternative approach involves a short burst of multiple treatment sessions, provided less frequently (Fitzgerald, Grace, Hoy, Bailey, & Daskalakis, 2012). In addition, it is possible to provide acute rTMS treatment at the point of development of depressive relapse. Several studies have indicated that patients who have responded initially to rTMS are likely to respond again to subsequent treatment sessions following relapse (Demirtas-Tatlidede et al., 2008; Fitzgerald, Benitez, et al., 2006a; Janicak et al., 2010).
A second substantive issue with the provision of rTMS treatment relates to the method of treatment targeting. Most applications of rTMS in depression have used a relatively simplistic method for localizing DLPFC that involves localizing the motor cortical site for hand muscles and then measuring 5 cm anterior in a parasagittal line over the scalp surface (the 5-cm method; Schönfeldt-Lecuona et al., 2010). However, research has demonstrated that this is likely to be inaccurate in a significant percentage of patients (Herwig, Padberg, Unger, Spitzer, & Schönfeldt-Lecuona, 2001). Several other localization alternatives are possible, most using various forms of neuro navigation. Neuronavigational techniques typically require the coregistration of the location of an individual’s head to some form of digitized brain scan. One study explicitly demonstrated that treatment targeting based on neuroanatomical localization (to a brain site at the junction between Brodmann areas 9 and 46, as defined by Rajkowska and Goldman-Rakic, 1995) results in a superior antidepressant response to rTMS localized using the 5-cm method (Fitzgerald, Hoy, et al., 2009). Researchers are also exploring whether treatment targeting based on functional imaging may be of clinical utility (Herwig et al., 2003; Martinot et al., 2010; Herbsman et al., 2009).
A third issue relates to the type of rTMS coil used in treatment studies. Most clinical trials to date have used standard figure-8 coil designs that produce stimulation of approximately 1 to 2 cm² of tissue but limited cortical penetration. More recently, technology has been developed to produce substantially deeper stimulation, for example, of the more orbital medial, cingulate, or insula cortical regions. This so-called deep TMS is done with a novel coil design that produces more widespread cortical stimulation with substantial penetration into deeper brain regions (Deng, Peterchev, & Lisanby, 2008; Salvador, Mir, Roth, & Zangen, 2007). Preliminary data appear promising (Rosenberg, Shoenfeld, Zangen, Kotler, & Dannon, 2010), and controlled trials are underway.
Although some clinical trials investigating the effectiveness of rTMS treatment have excluded patients with bipolar disorder, a number of trials conducted to date have included mixed samples. Within trials of this type, no analyses have suggested a bipolar diagnosis is a negative predictor of the likelihood of clinical response. In fact, in one study patients with bipolar disorder had a substantially higher response rate (almost 70%) than the overall group (51%; Fitzgerald, Huntsman, Gunewardene, Kulkarni, & Daskalakis, 2006). However, most studies do not provide this sort of separate analysis. In addition, only a limited number of studies have specifically investigated rTMS effects in bipolar depression (Dolberg, Dannon, Schreiber, & Grunhaus, 2002; Nahas, Kozel, Li, Anderson, & George, 2003; Dell’Osso et al., 2009, 2011; Harel et al., 2011). None of these studies are of large enough scale to make definitive conclusions about the application of rTMS in bipolar depression, although it is typically assumed that response rates are likely to be similar to those seen in unipolar depression.
Several studies have also investigated the use of rTMS treatment for mania. An initial study found greater antimanic effects with high-frequency stimulation applied to the right DLPFC compared to the left (Grisaru, Chudakov, Yaroslavsky, & Belmaker, 1998). Antimanic effects of high-frequency right-sided stimulation also were suggested in two subsequent case series (Michael & Erfurth, 2004; Saba et al., 2004). However, the results of two sham controlled trials have been contradictory, with one demonstrating antimanic effects (Praharaj, Ram, & Arora, 2009) and one demonstrating no difference between active and sham stimulation in the treatment of mania (Kaptsan, Yaroslavsky, Applebaum, Belmaker, & Grisaru, 2003).
Considerable interest has accumulated in the potential use of rTMS in the treatment of obsessive-compulsive disorder (OCD), especially given the well-defined nature of the frontal–subcortical brain network abnormalities in this disorder (Harrison et al., 2009). However, the research conducted to date does not provide a universally positive suggestion of therapeutic efficacy. The first study exploring rTMS effects in OCD found a greater reduction in OCD symptoms with right prefrontal stimulation than that seen with left prefrontal stimulation or stimulation at a control site (Greenberg et al., 1997). Subsequent studies using left DLPFC stimulation have predominately produced negative results (Sachdev, Loo, Mitchell, Mcfarquhar, & Malhi, 2007; Sarkhel, Sinha, & Praharaj, 2010), although studies exploring high-frequency right-sided stimulation have not been adequately conducted to exclude this as a therapeutic target. Low-frequency stimulation approaches have also been predominately negative when applied either to the right (Alonso et al., 2001) or left DLPFC (Prasko et al., 2006).
Preliminary research has suggested that targets outside of DLPFC may be more promisingly approached. For example, one study found therapeutic benefits greater than sham with 1-Hz stimulation applied to the left orbitofrontal cortex (Ruffini et al., 2009). A second novel approach has produced positive results by targeting the bilateral supplementary motor area (Mantovani et al., 2006, 2010).
Only a limited body of research has explored the use of rTMS in posttraumatic stress disorder (PTSD), and studies conducted to date have used relatively divergent methods. Neuroimaging-based models of PTSD have suggested that hypoactivity of the DLPFC and associated hyperactivity of the amygdala are linked to underlying illness symptoms and that right-sided changes are predominant in PTSD. A high-frequency approach to right-sided stimulation therefore has some therapeutic rationale (Paes et al., 2011). Studies have investigated a variety of stimulation paradigms including low- and high-frequency stimulation applied to the left DLPFC and low- and high-frequency stimulation applied to the right DLPFC (Rosenberg, Shoenfeld, Zangen, Kotler, & Dannon, 2010; Cohen et al., 2004; Boggio et al., 2010; Watts, Landon, Groft, & Young-Xu, 2012). Right-sided high-frequency stimulation has shown the greatest therapeutic promise in two studies that evaluated stimulation to both hemispheres or compared different frequencies of stimulation applied to the right DLPFC (Cohen et al., 2004; Boggio et al., 2010).
Two randomized controlled trials explored the use of 1-Hz stimulation applied to the right DLPFC in panic disorder but with contradictory results. In the first study, no significant difference was seen between active and sham stimulation in 15 medication-resistant patients (Prasko et al., 2007). The second study, in a slightly larger sample size (n = 25), found significant differences in response between active and sham stimulation (Mantovani, Aly, Dagan, Allart, & Lisanby, 2012). Low frequency right-sided rTMS has also been evaluated in one open-label study in generalized anxiety disorder (Bystritsky et al., 2008). Six of 10 patients met remission criteria for reduction in anxiety symptoms following treatment based on fMRI-based localization.
A number of rTMS approaches have been used in the potential treatment of schizophrenia or its symptoms. These approaches have mostly targeted either the prefrontal cortex, with an emphasis on the treatment of negative symptoms, or the temporoparietal cortex, in an attempt to ameliorate auditory hallucinations.
The first rTMS studies in schizophrenia applied low- or high-frequency stimulation to the DLPFC and evaluated whether this had an impact on the global symptoms of the disorder. The results of these initial studies were generally negative or found changes mainly in noncore symptoms (Geller, Grisaru, Abarbanel, Lemberg, & Belmaker, 1997; Feinsod et al., 1998; Klein et al., 1999). Most studies using high-frequency DLPFC stimulation targeting positive symptoms of schizophrenia failed to produce positive results (Holi et al., 2004; Sachdev, Loo, Mitchell, & Malhi, 2005; Hajak et al., 2004), and the lack of benefit with this approach was confirmed in a recent metaanalysis (Freitas, Fregni, & Pascual-Leone, 2009).
More recently, interest has been focused on the potential use of prefrontal stimulation in the treatment of negative symptoms, based on the observation that hypoactivation in prefrontal regions is thought to correlate with negative symptoms (Andreasen et al., 1997). Thus, it was hypothesized that high-frequency rTMS applied to the DLPFC might improve negative symptoms by increasing cortical activity (Cohen et al., 1999). A number of studies have explored this approach, although these have almost universally been limited by small study samples and relatively short durations of treatment application. Many of these studies showed a significant advantage of active over sham stimulation (Hajak et al., 2004; Prikryl et al., 2007; Jandl et al., 2005; Goyal, Nizamie, & Desarkar, 2007), although negative studies have also been conducted (Holi et al., 2004; Mogg et al., 2007; Novak et al., 2006). Notably, several of the positive studies (Prikryl et al., 2007; Prikryl et al., 2007; Jandl et al., 2005) used higher stimulation intensity (>100% of the standard resting motor threshold), and one study used a longer treatment duration (15 days) than the negative studies (10 days; Prikryl et al., 2007). A major confound in these trials is the potential amelioration of depressive symptoms with rTMS misinterpreted as an improvement in negative symptoms. One of these two positive studies also carefully controlled for the possible confound of improved depressive symptoms using scores on the Calgary depression scale for schizophrenia as a covariate; improved depression did not account for the observed improvement in negative symptoms (Prikryl et al., 2007).
The second major use of rTMS in schizophrenia is the application of low-frequency stimulation, typically 1 Hz, to the temporoparietal cortex (TPC) in patients with persistent refractory auditory hallucinations. This application was suggested by imaging studies linking the pathophysiology of auditory hallucinations to hyperactivity in the left TPC (Shergill, Brammer, Williams, Murray, & Mcguire, 2000; Silbersweig et al., 1995). Initial studies provided only brief courses of stimulation but showed a decrease in the frequency and intensity of auditory hallucinations (Hoffman et al., 1999, 2000). A larger, controlled study, of 9 days of low frequency left-sided (LFL) stimulation of the TPC found a substantial and significant reduction in auditory hallucinations compared to sham. Furthermore, this improvement was sustained in more than half of the improved patients at 15 weeks post treatment (Hoffman et al., 2003). A considerable series of trials has subsequently evaluated this approach. Two recent metaanalyses found a benefit of active over sham stimulation with a medium to large effect size (Freitas et al., 2009; Tranulis, Alisepehry, Galinowski, & Stip, 2008). Investigators also investigated right-sided and bilateral treatment protocols for treatment of auditory hallucinations (Lee et al., 2005). A series of recent studies explored optimizing stimulation parameters using brain imaging and neuronavigational tools (Schönfeldt-Lecuona et al., 2004; Sommer et al., 2007; Hoffman et al., 2007; Montagne-Larmurier, Etard, Razafimandimby, Morello, & Dollfus, 2009).
One notable finding in the literature on rTMS for schizophrenia is that therapeutic amelioration of hallucinations appears to occur in some patients with short durations of treatment. Preliminary data also suggest that therapeutic benefit may persist over time and may recur when patients are retreated following symptom relapse (Fitzgerald, Benitez, Daskalakis, De Castella, & Kulkarni, 2006).
Reflecting the recognition that chronic pain syndromes are likely to be associated with changes in cortical activity (Seifert & Maihöfner, 2009), there has been increasing interest in the use of rTMS approaches to modulate chronic pain. The main site for investigation has been the primary motor cortex. Studies applying low-frequency stimulation to this site have demonstrated modest and short-lasting pain reduction effects after single stimulation sessions (Lefaucheur, Drouot, Keravel, & Nguyen, 2001; Pleger et al., 2004). Similar benefits have been seen when stimulation was applied across multiple treatment sessions, for example, analgesic effects seen in complex regional pain syndrome type 1 (Picarelli et al., 2010), but negative studies have also been reported (Plow, Pascual-Leone, & Machado, 2012). Negative studies have also been seen with the application of low-frequency rTMS (O’Connell, Wand, Marston, Spencer, & Desouza, 2011). Antipain effects do appear to be dependent on the specific pain syndrome targeted, with facial pain, especially trigeminal neuralgia, appearing to respond better than other types of pain syndromes (Plow, Pascual-Leone, & Machado, 2012). A recent Cochrane review including 19 rTMS studies concluded that there was evidence for short-term analgesic effects of single rTMS sessions, but there is limited evidence at this stage of longer-term treatment benefit (O’Connell, Wand, Marston, Spencer, & Desouza, 2011).
The second major treatment site that is gathering increasing attention is the DLPFC, as this region of the brain may be involved in top-down regulation of pain perception. Initial studies demonstrated that high-frequency stimulation applied to the left DLPFC could change perception of experimentally induced pain, and a similar effect could be produce with low-frequency stimulation applied to the right DLPFC (Borckardt et al., 2007; Graff-Guerrero et al., 2005). Subsequently, two initial studies have explored the utility of prefrontal stimulation in clinical groups. An ongoing reduction in neuropathic pain was seen in a small trial of high-frequency left DLPFC stimulation (Borckardt et al., 2009) and a similar benefit with right 1-Hz DLPFC stimulation in patients with pain related to fibromyalgia (Sampson, Kung, McAlpine, & Sandroni, 2011). There may be two significant advantages with the frontal approaches: benefits appeared to persist past the end of the period of stimulation and it appears that unilateral prefrontal stimulation has the potential to have bilateral therapeutic effects.
TMS methods have attracted attention for their potential use both in understanding the neurophysiology of dementing disorders as well as more recently in their potential treatment. The greatest body of research has focused on the former, while therapeutic applications of rTMS in dementing disorders have only just begun to be thoroughly explored. Early studies, motivated by an intent to enhance cortical excitability with high-frequency rTMS, showed that cognitive functions could potentially be improved with short periods of rTMS. For example, a single session of prefrontal rTMS was shown to potentially moderate several prefrontal cognitive functions (Rektorova, Megova, Bares, & Rektor, 2005), and high-frequency DLPFC rTMS was also shown to improve naming performance (Cotelli et al., 2006, 2008). Interestingly, it seems that there is more capacity to enhance naming performance in a more severely impaired group of patients, suggesting that therapeutic effects might be limited by ceiling effects in less severely affected individuals.
More recently, several small studies have investigated whether longer periods of rTMS could induce meaningful cognitive improvement. An improvement in language comprehension was demonstrated that persisted for up to 8 hours following a 4-week treatment protocol. Naming was not improved in this study (Cotelli et al., 2011). Beneficial effects persisting to 3 months were seen in a second study (Ahmed, Darwish, Khedr, & Ali, 2012). In this trial, prefrontal high-frequency rTMS applied sequentially to both hemispheres improved performance across a number of rating measures, including the mini mental state examination, to a greater degree than sham or low-frequency stimulation.
A new and interesting approach is to combine the provision of rTMS with specific cognitive training. In a small pilot study, rTMS was applied across six brain regions identified on MRI scanning with patients also engaged in cognitive training that addressed tasks relevant to these brain regions (Bentwich et al., 2011). Improvement was seen in a number of patients, although a randomized evaluation of this approach is required.
Recently there has been considerable interest in the potential use of rTMS methods in the rehabilitation of patients with stroke-related neurological impairment. Studies have primarily focused separately on the potential rehabilitation of two forms of symptoms: motor and post stroke aphasia. However, studies are also identifying the potential use of rTMS in other areas of post stroke disability, such as in post stroke dysphagia (Park, Oh, Lee, Yeo, & Ryu, 2012).
Nonfluent aphasia is clearly a common persisting and significant disability that occurs following anterior left hemisphere strokes. The main rTMS approach explored to ameliorate aphasia has used low-frequency stimulation targeted to the right inferior frontal gyrus, localized to the right hemisphere homologue of the area affected by the stroke. This approach has been suggested by neuroimaging studies that identified potentially excessive right hemisphere activation, possibly as a result of a reduction of transcallosal input from the affected left hemisphere structures (Naeser et al., 2012). The therapeutic potential of this approach was explored across a number of studies and case reports (Turkeltaub et al., 2012; Barwood et al., 2011; Hamilton et al., 2010). Several reports have suggested that stereotactic localization of the stimulation site enhances response to this form of treatment by adequately identifying the appropriately hyperactive region in the right hemisphere (Naeser et al., 2012). Ongoing research is required to establish whether short-term benefits persist over time and translate into improved functional outcomes.
A number of studies have investigated the modulation of motor symptoms resulting from stroke using rTMS, with stimulation focused on the primary motor cortex. As with the aphasia research described above, these studies included trials providing low-frequency stimulation to the unaffected hemisphere opposite to the site of the stroke lesion (Khedr, Abdel-Fadeil, Farghali, & Qaid, 2009; Takeuchi et al., 2008). In addition, a series of studies directly targeted the affected hemisphere, typically with high-frequency stimulation aimed at enhancing cortical activity at the site of injury. The outcomes of these studies are summarized in several recent and detailed reviews (Corti, Patten, & Triggs, 2012; Khedr & Fetoh, 2010). One recent metaanalysis found that there was a moderate effect size (0.55) for improving motor outcomes across a series of 18 studies, including a total of 392 patients (Hsu, Cheng, Liao, Lee, & Lin, 2012). Greater effects were seen in patients with subcortical strokes and in studies where low-frequency stimulation was applied to the hemisphere contralateral to the stroke lesion. Importantly, across rTMS studies in stroke, few substantive adverse events have been reported, despite the fact that some of these treatments were targeted to areas in which there are clearly pathological cortical changes. Larger studies are now required to establish the role of rTMS post stroke and to explore novel stimulation approaches, such as TBS, that have recently been identified as having therapeutic potential (Meehan, Dao, Linsdell, & Boyd, 2011).
Parkinson disease is a disorder in which the motor cortex would appear to be a relatively obvious target for rTMS treatment. Degeneration of dopaminergic nuclei disrupts motor performance, and it is proposed that, in part, this occurs due to reduction of inputs to the frontal (including motor) cortex (Lefaucheur et al., 2004). Soon after the development of rTMS methods, high-frequency stimulation was applied over the motor cortex to try to modulate movement variables (Pascual-Leone et al., 1994). These researchers found that a single session of 5Hz stimulation applied to the motor cortex could improve reaction and movement times in patients but not those who are healthy. Since that time, a series of studies have evaluated rTMS methods in Parkinson disease, but unfortunately the methodology across trials has been highly divergent. Studies have evaluated both low- and high-frequency stimulation, the use of focal and nonfocal coils, and, more recently, outcomes across both motor and nonmotor brain regions. A recent metaanalysis pooled the outcomes from 10 trials, including 6 single-session and 4 multisession (6 to 10 treatment days) protocols. There was an overall benefit of active over sham stimulation, with an effect size of 0.55 in the seven studies that used high-frequency stimulation (Elahi, Elahi, & Chen, 2009). No clear benefit was seen in low-frequency stimulation studies. However, the high-frequency stimulation trials included three in which stimulation was applied to the motor cortex and four in which it was applied to prefrontal brain regions, confounding interpretation of this finding.
The notion of stimulating DLPFC in Parkinson disease arose from observations that DLPFC stimulation targeting depressive symptoms also improved motor function (Fregni, et al., 2004) and that prefrontal stimulation could change subcortical dopamine release (Strafella, Paus, Barrett, & Dagher, 2001). Unfortunately, although positive effects have been seen in some studies, these have not been consistent across all trials and no substantive multisite trials have evaluated rTMS methods in Parkinson’s disease to date. Novel approaches such as TBS (Benninger et al., 2011) and combining rTMS with rehabilitations or training methods (Yang et al., 2013) have been investigated in initial studies but require more detailed evaluation.
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