7.1 Background
7.1.2 Repetitive Transcranial Magnetic Stimulation (rTMS)
History of rTMS
Transcranial magnetic stimulation (TMS) was originally developed in the 1980s, by Anthony Barker et al. at the University of Sheffield. It was designed as a tool to study functioning of the brain and nerves. Early studies in depres- sion were small, open label, and done mainly with treatment- resistant patients, but results were suggestive of efficacy [11].
Since the first pilot studies in the 1990s, larger studies have been conducted with careful attention to sham stimulation and blinding. In addition, stimulation protocols have trended toward longer treatment durations, higher treatment inten- sities, and greater cumulative numbers of magnetic pulses [12]. With this evolution, there have been more consistent demonstrations of the effect of rTMS in generating response and remission in depressive disorders in the adult population [13]. rTMS is now considered a first-line treatment in adults who have failed at least one trial of an antidepressant. Newer protocols are being developed with more complex stimula- tion patterns, e.g., theta-burst stimulation, with the hope of generating increased efficacy with shorter treatment times. A 2014 meta-analysis concluded that high-frequency rTMS is associated with clinically meaningful antidepressant effects and few side effects, reported response rate in this meta- analysis was 29.3%, and remission rate was 18.6% [14]. This is much lower than response and remission rates with ECT but still is clinically significant. rTMS treatment is now accepted as an evidence-based treatment for depressive disorders by multiple international authorities [15]. The Clinical TMS Society was founded in 2011 and is a source of consensus- based treatment recommendations [16]. Some (but not all) early studies showed that older age was a negative predictor of response. However, more recent studies (post-2007) with more modern parameter settings show equivalent efficacy to younger adults [13].
Methods of Stimulation
rTMS is administered with a treatment coil, which is an elec- trical wire coil (encased in plastic) which is placed on the scalp surface. A current which varies in time is discharged within this coil. This generates a brief dynamic pulsed mag- netic field. The scalp and the skull are transparent to the mag- netic field and pose no barrier to it. However, neural tissue is conductive, and when the magnetic field reaches the brain, it induces current flow. Because the skull does not impede the magnetic field, TMS can induce relatively large currents in the brain which are relatively focal, and specific areas of the brain can be targeted for stimulation. In repetitive transcra- nial magnetic stimulation (rTMS), a series of repetitive brief magnetic pulses constitute the treatment [17].
In rTMS, the patient remains awake throughout the treat- ment, and no general anesthesia is required. An illustration of an rTMS treatment apparatus appears in .Fig. 7.1. Patients
L.A. McMurray et al.
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are generally seated in a reclining position, and the coil is applied to the scalp at the appropriate location. Treatments are usually administered by a trained technician, under the supervision of a physician. Appropriate emergency medical equipment and assistance should be available at all times [18].
Hearing protection is worn by both patient and technician, as the device generates a loud clicking sound when in operation which can be loud enough to damage hearing with prolonged exposure [19]. Sometimes patients listen to music or audio recordings involving meditation or relaxation [15]. Sessions can be of very short duration in some newer treatment proto- cols (e.g., theta burst) but more commonly last 20 minutes to 1 hour. Treatments are typically administered 5 days per week [20]. The peak magnetic field is comparable to that generated by an MRI device but brief and focal instead of continuous
and large [16]. Several thousand amperes of current in the coil are required to produce a magnetic field sufficiently intense and large to generate neuronal depolarization [21].
Multiple devices and coil shapes are available for use, with regulatory approval depending on the local jurisdic- tion. Details are available from their respective manufac- turers (e.g., Neuronetics, NeuroQore, Brainsway, Magstim, MagVenture) [16]. The figure-8 coil is the most common; it consists of two round coils placed side by side to form the shape of the numeral 8. This arrangement has the effect of producing a focal magnetic field for stimulation. An illus- tration of a figure-8 coil appears in .Fig. 7.2. Another coil, sometimes called a double-cone coil, is shaped to accom- modate the curvature of the skull. An H-shaped coil that fits around the head in a helmet-like configuration produces a
.Fig. 7.1 An example of an rTMS treatment apparatus (©
2017 NeuroQore, Inc. | Mehran Talebinejad | [email protected], used with permission)
.Fig. 7.2 A figure-8 rTMS coil (© 2017 NeuroQore, Inc. | Mehran Talebinejad | [email protected], used with permission)
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focal magnetic field which penetrates somewhat more deeply into the brain than the figure-8 coil. The clinical significance of these different coil shapes remains to be determined [20].
Different stimulation frequencies produce significantly different effects on the brain. Stimulation at a frequency lower than 1 Hz (low-frequency TMS, sometimes abbreviated LF-rTMS) produces cortical inhibition. Frequencies above 1 Hz (typically 10–20 Hz) produce neuronal excitability and are referred to as high-frequency rTMS (HF-rTMS) [16].
Another important parameter in rTMS is the intensity of the stimulus. It is typically described in proportion to the motor threshold of the individual. The motor threshold is defined as the lowest intensity of stimulation that, when applied to the motor cortex, causes a standard contraction of a muscle in at least 5/10 consecutive trials [20]. Earlier studies of rTMS typically used lower intensities, e.g., 80–100% of thresh- old; more modern studies tend to use higher intensities [13].
There are many variables in rTMS. When describing rTMS treatment, it is important to include the following parameters: site of stimulation, coil shape and orientation relative to the scalp, method of site determination, stimu- lus intensity, stimulus frequency, number of daily sessions, duration of daily sessions, intertrain interval, specific pattern of stimulation (e.g., theta burst), total pulses per session, cumulative pulses per treatment course, and total duration of treatment. These are summarized in .Table 7.1 [22, 23].
Conventionally, there is repetition of individual pulses at a preset interval; theta-burst stimulation is an investigation protocol involving a repetition of short bursts of pulses at a preset interval and can be associated with shorter duration of treatment session [24].
The site of rTMS stimulation was originally determined by finding the motor cortex and moving 5 cm anterior. The motor cortex was found by observing contraction of muscles in the thumb in response to brain stimulation. This method of locating the dorsolateral prefrontal cortex (DLPFC) has proved inaccurate in many cases. Therefore, alternate meth- ods have been developed to determine the appropriate site for stimulation. These include methods that account for difference in skull size (e.g., the F3 method) and the use of neuronavigation. In the F3 method, skull measurements are used to locate the target. In neuronavigation, the patient’s magnetic resonance imaging (MRI) scan is used to deter- mine the site of stimulation. No clear evidence exists to sug- gest that neuronavigation is superior to the F3 method [23].
Published safety parameters describe the current consen- sus on the upper limits of safe application of rTMS in terms of combinations of stimulus intensity, intertrain interval, and frequency [18]. These safety guidelines should not be exceeded in clinical practice.
Mechanism of Action
The precise mechanisms underlying the neural effects of rTMS are largely unknown. rTMS may preferentially acti- vate neural elements oriented horizontally to the brain surface [21]. In addition to the immediate stimulation or inhibition of the cortex (depending on frequency), there
are interhemispheric effects on similar circuits on the non- stimulated side of the brain and persistent effects on the brain due to long- term potentiation [25]. Bashir et al. showed that low- frequency stimulation of the nondominant hemi- sphere in older subjects produced less facilitatory effect in the dominant (unstimulated) hemisphere. Their conclusion was that this may suggest reduced cortical plasticity and interhemispheric communication in those older subjects [21]. Investigations such as this one may help to shed light on possible explanations for the sometimes-reported lower response rates in older patients.
rTMS in the General Adult Population
rTMS is an established treatment for depressive disorders in the adult population [14]. There is also evidence that rTMS is effective as a treatment for treatment-resistant depressive disorder in adults, although greater degrees of treatment resistance are associated with lack of response [22].
.Table 7.1 The rTMS stimulation parameters [22, 23]
Parameter Example
Site of stimulation Left DLPFC Right DLPFC
Bilateral stimulation (simultaneous or sequential)
Coil shape Figure-8
Double-cone H-type Other
Target location Measurement-based (5 cm) method Neuronavigation
BeamF3 Stimulus intensity
(% motor threshold)
80–120%
120% is upper limit of current safety guidelines
Theta burst typically delivered at 80%
Stimulus frequency (Hz)
1 Hz or below—low frequency Above 1 Hz (typically 10–20 Hz)—high frequency
Number of daily sessions
1
Duration of daily sessions
20 minutes—1 hour
Theta burst protocols are shorter; e.g., 6 minutes
Intertrain interval/
specific pattern
Theta burst Paired pulse Quadripulse
Pulses per session 1600 pulses per session
Cumulative pulses 24,000 pulses over a 3-week period Total duration of
treatment
2–6 weeks
Note: DLPFC dorsolateral prefrontal cortex L.A. McMurray et al.
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The Clinical TMS Society has provided a consensus- based review and treatment recommendations [16]. They summarize the existing trials, including three large multi- center randomized controlled studies in an aggregate sample of rTMS in treatment-resistant depression in adults. Their conclusion was that daily rTMS to the left DLPFC had sub- stantial evidence for efficacy and safety when patients were treatment resistant or unable to tolerate conventional treat- ments. There is less evidence for low-frequency stimulation of the right DLPFC and for bilateral protocols involving both high-frequency stimulation of the left DLPFC and low- frequency stimulation of the right DLPFC, but research in this area is ongoing [26].
Real-world open-label data from a rTMS clinic in Australia described outcomes for treatments of 167 patients (adults, no older patients) over a period of 6 years [27]. In that cohort, 28% achieved remission, 12% achieved response, and 23% achieved partial response. Of their responders, the average reduction in scores on the Hamilton Depression Rating Scale (Ham-D) was 15.05 points. Age did not predict response, but degree of treatment resistance was negatively associated with response. Of these, 41 patients returned for a second course of rTMS; 21 patients ultimately went on to maintenance rTMS, at intervals of 1–4 weeks. The courses of rTMS were well tolerated. In this sample, there were no sei- zures and no switches to manic episodes. Most patients (69%) had no side effects. The most common side effects included localized discomfort, mild headaches, and fatigue posttreat- ment. Some concern, however, has been raised about the small magnitude of treatment response [28] and about the durability of the effect of rTMS [29]. Higher treatment inten- sities (e.g., 120% of motor threshold) and longer treatment periods (e.g., 3–6 weeks) may be necessary for efficacy [22].
The search for more robust and consistently effective treat- ment protocols is ongoing in contemporary rTMS research.
Trials Including Older Patients
Several of the earlier studies of rTMS included older sub- jects. Some demonstrated efficacy with no age-related effects. The data on efficacy in older subjects was mixed, however, with other studies showing that younger patients responded better; i.e., older age was negatively associated with treatment response [13]. For example, a 2006 meta- analysis, which pooled data from six clinical trials with a total of 195 patients, found that prior treatment resistance and age were significant negative predictors of response to rTMS [30]. These trials included patients up to age 91 years.
This confirmed earlier work by Figiel et al., which showed a 56% response rate in younger patients, compared to a 23%
response rate in older patients [31]. The reasons for the differential response of older patients may have included a duration of treatment effect; older patients may have required longer courses. There may also have been a con- founding effect of other brain disorders. A controlled trial of 24 older patients (mean age, 62 years) failed to demonstrate an effect of ten sessions of stimulation of the left DLPFC at 100% of motor threshold [32].
In this context, several subsequent studies excluded patients over the age of 65 years. However, the literature suggested that older patients might require higher inten- sity of treatment to account for the effects of age-related frontal cortical atrophy. By adjusting for measured pre- frontal atrophy with increased stimulus intensity (average 114% of motor threshold, range 103–141%), a significant antidepressant effect could be produced [33]. In this study of 18 treatment- resistant older patients with depressive disorders, 27% responded to treatment, and 22% achieved remission.
In addition to increased stimulus intensity, older patients may require longer courses of rTMS [13]. Several large ran- domized controlled trials published after 2007 have not found age to be a negative predictor of response [13]. Developing effective treatment protocols for older patients is a focus of contemporary rTMS research. Modern treatment param- eters for older patients currently under investigation include higher stimulus intensities (e.g., 120% of motor threshold), coils with slightly deeper penetration (e.g., H-type coils), bilateral treatment protocols, and longer treatment courses.
Trials Specific to Older Patients
There have been relatively few randomized controlled tri- als of rTMS solely in older adults [34]. These are summa- rized in .Table 7.2 [12, 32, 35, 36]. A preliminary trial of rTMS for late-life depressive disorders was published in 2001 [12]. In this study, 20 patients over the age of 50 (mean age, 60.7 years) were treated with stimulation over the left DLPFC at 80% of motor threshold for a total of five ses- sions. Scores on Ham-D improved by 39.7%, response rate was 30%, and remission rate was 20%. However, this was a negative trial, as the treatment results were not significantly different from results in the sham group. This study did have significant limitations, including a small sample size, under- dosing, and an imperfect method of sham control. This study did find that responders had greater volumes in the prefrontal cortex than nonresponders, suggesting a possible explanation for the failure of some older adults to respond to rTMS. Another early trial by of rTMS in older patients with treatment-resistant depressive disorder found no sig- nificant effect of high-frequency left prefrontal rTMS in 24 treatment-resistant subjects [32].
In contrast to these studies, another earlier trial of high- frequency left prefrontal rTMS for poststroke depressive disorder showed efficacy after 2 weeks of treatment, with no demonstrable age-related effects on treatment response [35].
The same group reported in 2008 on the results of a larger trial with two separate experiments in patients with vascular depressive disorder. These trials involved a larger number of subjects and were able to demonstrate efficacy with a higher stimulus intensity (110%) and a longer duration of treatment (15 sessions). Among the older subjects, active rTMS was only significantly effective in the prolonged treatment condi- tion. Age was a negative predictor of response. In this trial, greater antidepressant response to rTMS was associated with larger volume of gray matter in the frontal area. The
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treatment was well tolerated, with no significant side effects or impact on cognition [36]. In fact, patients who were receiving active rTMS showed improvement in speed of per- formance on the Trails B test, independent of response to rTMS. This finding suggests the possibility that rTMS could enhance cognition independent of its effect on depression.
In addition to the studies previously described, there have been several open trials of rTMS in late life. These are sum- marized in .Table 7.3 [33, 37–39]. Collectively, these stud- ies showed reduction in Hamilton Depression Rating Scale (Ham-D) scores of 31.6–48.6%, response rates of 28–58.5%, and remission rates of 10–29.2%. Note that all but one of these studies defined response as a 50% reduction in pretreatment Ham-D and remission as a Ham-D below 8; the exceptional study [38] used a more permissive criterion for response of
at least a 25% improvement in Ham-D and treated for only 2 weeks. Nahas et al. attempted to compensate for age-related atrophy in the prefrontal cortex by adjusting the stimulus intensity, based on MRI data for each participant. In that study, patients with depressive disorder with late-life onset responded less well than patients with early-onset depres- sive disorder. White matter hyperintensities did not have a demonstrable impact on treatment response [33].
Indications for rTMS Major Depressive Disorder
The primary indication for rTMS is major depressive disor- der. It is considered a first-line treatment for patients who have failed at least one trial of an antidepressant medication
.Table 7.2 Randomized controlled studies of rTMS specific to older patients [12, 32, 35, 36]
Authors,
year Type of depres- sion
Total sub- jects
Mean age (SD)
Age range (years)
TMS param- eters
% improve- ment on Ham-D scores
Response
rate (%) Remis- sion rate (%)
Treat- ment more effective than sham
Age-related findings
Jorge et al.
(2008) part 1
Vascular 30 62.9 (7.2) (active group)
50 and older
L, 10 sessions, 10 Hz, 110%, 1200 pulses
33.1 33.3 13.3 Yes More
treatments improved response
Jorge et al.
(2008) part 2
Vascular 62 64.3 (9.4)
50 and older
L, 15 sessions, 10 Hz, 110%, 1200 pulses
42.4 39.4 27.3 Yes Older
patients benefited more from prolonging treatment;
age was negative predictor of response Jorge
et al.
(2004)
Post- stroke
20 63.1
(8.1)
Not reported
L, 10 sessions, 10 Hz, 110%, 1000 pulses
38 30 10 Yes No
Mosi- mann et al.
(2004)
Mid/
late-life
24 62 (12) 41–80 L, 10
sessions, 20 Hz, 100%, 1600 pulses
20% 26.6 Not
reported
No No
Manes et al.
(2001)
Late-life 20 60.7 (9.8)
50 or older
L, 5 sessions, 20 Hz, 80%, 800 pulses
39.7 30 20 No No
Note: Ham-D Hamilton Depression Rating Scale, L left L.A. McMurray et al.
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[40]. Greater degrees of treatment resistance are associated with lack of response to rTMS, so it may be preferable to use rTMS earlier in the treatment course of major depressive disorder. As discussed above, older age has been associated with poor response to rTMS, but emerging data suggests that older adults may require higher stimulus intensities and lon- ger courses of treatment for a positive response. Taking this into account, it would be reasonable to consider rTMS for an older adult with major depressive disorder, either early onset or late onset.
Bipolar Depression
Ten out of 23 randomized controlled trials described in a 2016 systematic review included patients with bipolar depression (an episode of depression within bipolar disor- der), usually a very small proportion of the overall sample (under 20%) [29]. There have been relatively few controlled trials specific to bipolar depression. Sequential bilateral rTMS was tried in this population in 49 patients (mean age 47.9 years, standard deviation 11.9) and failed to separate from sham treatment in a 4-week trial [41]. The very limited efficacy data (two randomized controlled trails) prior to this study was mixed. The efficacy of rTMS in bipolar depression thus remains unclear.
Depressive Episode with Psychotic Features Depressive episode with psychotic features is a common pre- sentation in older patients. Evidence to date suggests that a depressive episode with psychotic features responds less well to rTMS [13]. A meta-analysis comparing ECT and rTMS,
conducted in 2014, found that ECT was superior to rTMS for this presentation of depressive disorder [42]. As available data is limited, however, it remains possible that longer or more intense treatment protocols of rTMS might be more effective for this subtype of depressive disorder.
Vascular Depressive Disorder
rTMS has been studied in vascular depressive disorder and found to be safe and effective in this context [36]. It remains unclear if the presence of subcortical vascular changes affect response to the treatment, either positively or negatively.
White matter hyperintensities did not have a demonstrable impact on treatment response in one of the early trials of rTMS in late-life depressive disorder [33]. However, if there is ischemic damage in the frontal cortex, rTMS should be avoided due to the risk of provoking a seizure in this context [36].
Depressive Disorder in the Context of Major or Mild Neurocognitive Disorder (Formerly Dementia) with Behavioral Disturbances
There is no data regarding the safety and efficacy of rTMS in the context of depressive disorders comorbid with major or mild neurocognitive disorder [36]. The use of rTMS in mild and major neurocognitive disorder is currently being explored, and there is some preliminary data regarding the tolerability of the procedure in this context [9]. There may also be practical concerns in more severe major neurocogni- tive disorder, as the patient must cooperate with the proce- dure and sit quietly in one position for a significant period.
.Table 7.3 Open-label studies of rTMS specific to older patients [33, 37–39]
Authors,
year Type of depres- sion
Total sub- jects
Mean age (SD)
Age range (years)
TMS parameters % improve- ment on Ham-D scores
Response
rate (%) Remis- sion rate (%)
Age-related findings
Hizli Sayar et al.
(2013)
Late life 54 66.57 (5.77)
60–83 100%, LDLPFC, 18 sessions, 25 Hz, 1000 pulses
48.6 58.5 29.2 None reported
Abraham et al.
(2007)
Late life 20 66.8 (6.4)
60–80 100%, LDLPFC, 10 sessions, 10 Hz, 1600 pulses
31.6 30 10 None reported
Nahas et al.
(2004)
Late life 18 61.2 (7.3)
55–75 114% (103–
141%), LDLPFC, 15 sessions, 5 Hz, 1600 pulses
35.2 28 22 Stimulus intensity
adjusted for DLPFC atrophy;
less response with late-onset depression Fabre
et al.
(2004)
Vascular 11 67.9 (6.7)
56–77 100%, 16 sessions, 5 Hz,
35% 45 Not
reported
Worsened verbal fluency
Note: Ham-D Hamilton Depression Rating Scale, LDLPFC left dorsolateral prefrontal cortex
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