Repetitive transcranial magnetic stimulation significantly decreases post-stroke depression by increasing brain activity


University of South Australia researchers have made a major breakthrough in the treatment of depression after stroke, using a high frequency brain stimulation device to improve low moods.

A trial led by UniSA stroke researcher Dr Brenton Hordacre has found that large doses of repetitive transcranial magnetic stimulation (rTMS) significantly improve post-stroke depression by increasing brain activity.

Previous studies have experimented with the use of rTMS but this is the first time that a large treatment dose – 30,000 electromagnetic pulses delivered over two weeks – have been trialled, showing positive changes in brain function.

The findings, published in the Journal of Neurology, could signal a non-invasive, alternative treatment for post-stroke depression in place of medication, which can have negative side effects for many people.

South Australians are set to benefit from this research with the brain stimulation device now available at UniSA’s City West campus to treat stroke patients suffering depression.

The $40,000 brain stimulator, partly funded by the Honda Foundation, could also potentially improve motor recovery, helping stroke patients develop new connections in the damaged brain.

“The advantage of using TMS to treat depression is that it has relatively few side effects compared to pharmacological treatments,” Dr Hordacre says.

“It can also be delivered over several sessions but the improvements in depression last well beyond that period.”

An estimated 500,000 people in Australia are living with the effects of a stroke, and this figure jumps by 56,000 each year as a result of people suffering either an ischaemic (clot) stroke or a cerebral haemorrhage (bleed).

One in three people experience depression within five years of their stroke, mostly in the first year, although it can occur at any time.

“A stroke is a life-changing event in itself, bringing about personality, mood and emotional changes, so there is a very strong link between stroke, depression and anxiety,” Dr Hordacre says.

Antidepressants and psychotherapy are commonly used to treat depression post-stroke, but rTMS gives patients another option in the wake of these findings.

Adelaide resident Saran Chamberlain was one of 11 chronic stroke survivors who took part in Dr Hordacre’s trial, receiving 10 sessions of high frequency rTMS for depression.

This is a diagram from the study
Large doses of repetitive trans cranial magnetic stimulation significantly improve post-stroke depression. Credit: UniSA

Saran suffered a stroke in 2013 at the age of 38. She was not a typical candidate (non-smoker, healthy and young) but a stressful job and long work hours are believed to be the main factors in her case.

She was initially left completely paralysed on the left side, and was prescribed medication to deal with the ensuing depression.

When I heard about this trial using repetitive brain stimulation I was keen to try it to see if it made any difference,” Saran said. “It did, and the effects lasted several months.

I am still on antidepressants but I have reduced the dosage quite markedly. This really has made a difference to my life!”

Dr Hordacre says the benefits of UniSA’s brain stimulation device will extend beyond the community, with the university’s allied health students trained to deliver the treatment under supervision.

The treatment will be officially launched in the new year.

Major depressive disorder is a severe illness of high prevalence [[1], [2], [3]]. Thirty percent of patients with depression fail to respond to standard treatments and continue to experience marked disability and high morbidity [4]. These patients are referred to as having treatment resistant depression (TRD).

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has been subject to intensive evaluation as an antidepressant strategy, especially in patients with TRD. It has clear antidepressant efficacy and the response to rTMS has been shown to be clinically meaningful [5]. It is now being increasingly used in clinical practice around the world.

However, a barrier to the utilisation of rTMS is the relatively slow rate of response to treatment, often requiring daily treatments five days per week over four to six weeks. rTMS requires a considerable time commitment from both patients and clinicians and is of limited utility for patients who do not live within convenient traveling distance from treatment centres.

The time needed before treatment response in some patients also makes rTMS unsuitable for some acutely suicidal patients. Instead, electroconvulsive therapy (ECT) is often considered for this subgroup of patients in whom rapid treatment response is sought, although possibly at the expense of cognitive side effects.

The treatment utility of rTMS could be substantially enhanced if the time course of treatment could be meaningfully compressed. Over recent years a number of studies have demonstrated the viability, and provided initial evidence for the efficacy, of “accelerated” rTMS treatment protocols – these usually apply a similar number of treatment sessions as standard rTMS courses but over a shorter period of time [6,7].

For example, we recently showed that a meaningful antidepressant response could be achieved with application of three rTMS sessions per day, over six days [8]. This accelerated regime showed no difference in efficacy from daily rTMS applied over 4 weeks.

Although this is a promising finding, and anecdotally accelerated treatment was popular with patients, the provision of three rTMS sessions per day was practically challenging from a treatment service perspective: in a busy TMS service where patients are scheduled on a daily basis, scheduling 3 treatment sessions is disruptive and often then leaves significant gaps on other days.

An alternative approach to this would be to utilise theta burst stimulation (TBS) in a similar accelerated treatment protocol. TBS is a newer patterned form of rTMS which can be used to produce the same or greater physiological effects compared to standard rTMS but in a markedly reduced period of time (3 min compared to around 40  min for a standard session) [9,10].

Recent research shows that TBS applied on a daily basis may be as effective as standard daily rTMS, using intermittent TBS (iTBS) applied to the left dorsolateral prefrontal cortex (DLPFC) [11] although it is possible that these two interventions work through different mechanisms of action.

Therefore, TBS would appear to be an ideal intervention to use in an intensive/accelerated format where multiple daily sessions could be applied but still in a reduced amount of time. To date only limited research has explored the potential application of accelerated forms of TBS. Duprat et al. randomised 50 patients to receive 20 iTBS sessions (or sham) over 4 days [12] although response duration was difficult to assess due to the trial’s crossover design. We conducted a randomised controlled trial comparing an intensive TBS intervention to standard once daily rTMS to evaluate its relative effectiveness and rapidity of onset of antidepressant effects.

We hypothesised that treatment with an intensive form of TBS would be as effective as standard rTMS with no increase in treatment dropouts or serious adverse events. We chose to use once daily rTMS, rather than once daily iTBS, as the comparator group as daily iTBS was not considered an established treatment option at the time of study design.

There are considerably variable accelerated or intensive protocols described in the literature to date (from 15 sessions in 2 days–20 session across 2 weeks [6,7,13]). In keeping with our previous study of accelerated TMS, we chose to provide an intensive series of treatments (three treatments per day over three days) in the first week followed by two treatment days in week two and then one treatment day in week three and week four in a consolidation phase.

This was chosen to try and balance the number of treatment sessions with the standard group but also to address a problem we found with relapse rates when all treatment was provided in a single week in two initial small unpublished pilot studies. We are referring to our protocol as ‘intensive’ rather than ‘accelerated’ treatment as the primary intent was to produice the same clinical reponse in fewer treatment days with the rapidity of reponse only of secondary interest.

Although there has been an increasing interest in exploring the use of accelerated rTMS treatment protocols in recent years, as well as an increase in studies exploring the therapeutic benefits of TBS, there remains a very limited number of randomised trials demonstrating the efficacy of accelerated TMS in general and accelerated or intensive TBS especially.

This is the first published direct parallel groups comparison showing that an intensive TBS protocol may be used to achieve similar therapeutic benefits as those obtained with a standard daily rTMS treatment schedule. In our study, intensive TBS produced similar clinical benefits to standard rTMS on depression ratings, quality of life and assessments of suicidality without the occurrence of any serious adverse events.

There was not an increased rate of treatment emergent side effects or observable cognitive impairment. The clinical benefits seen were similar to those achieved in our previous study of accelerated rTMS but in that study the lengthy administration of accelerated rTMS was associated with a slightly higher side-effect and dropout rate, neither of which were seen in the current study with intensive TBS [8].

Clearly there are substantial clinical and practical benefits with being able to achieve antidepressant responses more rapidly than what is achievable with standard rTMS treatment regimes. In this context, it is important to separate out two elements of response:

1) can a similar degree of clinical response be achieved (even if it takes the same amount of time) with far fewer treatment days, 2) can a more rapid improvement in symptoms be achieved.

The former would make TMS treatment overall more practical and cheaper (especially where daily treatment provision over 4–6 weeks is too practically or logistically challenging for patients and clinical services) whilst the second element opens the possibility of the treatment of patients with acute risks, such as suicidal ideation.

However, providing multiple lengthy rTMS sessions on a daily basis in an accelerated protocol is also logistically challenging [8]. Providing multiple TBS treatments, as done here, could be achieved in less than 1 h a day which is both convenient for patients and clinic scheduling.

Our data suggests that we may be able to address one of these two clinical problems. Intensive TBS appeared to have similar clinical efficacy to standard rTMS and as such could potentially be utilized in a relatively standard clinical protocol to achieve similar treatment response. However, we did not necessarily see any evidence that the clinical benefits seen with the intensive TBS regime occurred earlier or more rapidly.

As seen in Fig. 2, the greatest degree of therapeutic change occurred relatively early in the course of treatment on the QIDS but this was the case in both treatment arms, and the pattern of symptom reduction was almost identical on the MADRS. There was no suggestion that the TBS group achieved clinical response substantially more rapidly than the group receiving standard rTMS.

This was true for both the MADRS and the QIDS, as well as for the measures of suicidality. Even though almost all of the TBS treatment protocol was administered in the first two weeks, this did not appear to result in a more rapid reduction in the severity of depressive symptoms.

In addition, although the patients in the TBS group received almost the equivalent of two weeks of sessions in the first week, they had not achieved a similar clinical response to that seen in the standard group after two weeks of therapy. This suggests that it may take neural circuits some time to adjust to the administration of magnetic stimulation protocols regardless of how these are applied or that an even greater dose application, which is likely to be impractical, might be required to try to achieve an earlier clinical response.

As seen in Table 2, there was no trend towards greater rates of response or remission in either group. In contrast, findings from our previous study [8] suggested greater rates of response and remission with standard over accelerated rTMS. It is notable, however, that the overall response and remission rates in this study were relatively modest.

It is quite possible that this was related to the overall dose of treatment provided. Our standard rTMS treatment group only received 20 sessions over four weeks which is a modest dose compared to the 30 sessions/6 weeks of treatment that is commonly used in clinical practice [29]. We do not yet have a comprehensive understanding of what is the optimally effective dose of TBS in standard, or intensive format, but it would be reasonable to assume that is likely to be greater than the relatively modest doses provided here. Given the ease of provision of TBS sessions, it would not be difficult to increase TBS duration and hence, dose, beyond what our protocol provided while still enabling overall briefer treatment sessions for patients, over what a standard rTMS course allows.

The safety and tolerability of the intensive TBS condition in this study is worthy of note. rTMS is generally safe and its associated adverse effects well-tolerated. Serious adverse effects, such as seizure induction, are rare [30,31]. Seizure induction is associated with high-frequency sitmulation [32] and in this context it would be reasonable to assume that TBS protocols may be associated with greater rates of seizure (or other unidentified issues).

Fortunately, this does not appear to have been the case when TBS has been used in standard once daily treatment schedules. So far the intensive use of TBS also appears to be well tolerated and without common serious adverse events [33,34].

It is worth noting that across both our accelerated rTMS study [8] and this study, anecdotally accelerated/intensive protocols were favored by patients. Any additional burden of treatment on the day of therapy was considered minor relative to the savings in time and clinic attendance requirements that accelerated/intensive treatment protocols allowed.

The most uncertain element in the intensive TBS parameters we developed was the choice of the duration patients would wait between stimulation trains in each treatment session, in this case 15 min. Although it would be convenient to assume that the dose of a TBS session could be increased by simply lengthening the duration of the application of stimulation (for example, doubling the number of pulses in a treatment session by increasing iTBS duration from 190s to 380s), preclinical studies exploring the effects of TBS on motor cortical excitability have demonstrated that longer durations of stimulation may have less or even opposite effects on cortical excitability [35,36].

A limited number of studies, again focusing on the effects of TBS on motor cortical excitability, have demonstrated that greater effects are produced when two TBS sessions are applied some time apart, rather than continuously, although there are fairly inconsistent results in this literature (see Table 1 in Ref. [37]).

For example, Tse et al. found a significant increase in motor cortical excitability when two iTBS blocks were applied at a 15 min interval (and a reduction in excitability when they were applied at a 5 min interval) [37]. The only study to date applying three iTBS trains using a 15 min inter train interval found a significant increase in motor cortical excitability with three trains compared to 2 trains or a single train of iTBS [38].

However, it is difficult to know how applicable these motor cortical studies are to the application of TBS applied to the prefrontal cortex in a condition such as depression. In a recent study, we explored the application of prefrontal TBS, using TMS evoked potentials measured with EEG as an outcome measure [39].

In this study we compared the application of one or two blocks of iTBS applied 15 min apart (to a sham stimulation condition). Both the single and repeated blocks of TBS increased markers of cortical excitability (increasing the amplitude of the TMS evoked N100 and P200 components).

However, a greater effect of stimulation was not seen when the TBS condition was repeated compared to when it was applied in a single block. Even though this study investigated TBS applied to a brain region more relevant to depression than the motor cortex, the results were derived from healthy controls over one session of testing. As such, the clinical translatability of these findings remain uncertain.

The fact that two blocks of iTBS applied 15 min apart did not show greater cortical conditioning effects, however, suggested 15 min was probably not the optimal time interval needed to produce maximal changes in cortical excitability. The design of future intensive TBS trials could well be informed by further preclinical studies of this sort.

It is interesting that we found improvements in cognitive performance in both groups but that these improvements were found on a wider variety of tasks in the iTBS compared to the standard rTMS group. It was also notable that improvements in cognition in both groups did not correlate with improvements in mood as would most typically be expected.

Multiple lines of evidence have supported the notion that rTMS has the capacity to improve cognition across different neuropsychiatric disorders (for example [40,41]) and our data here in a very preliminary way suggest that potentially iTBS may have more of a pro-cognitive effect than standard TMS approaches.

There are several significant limitations affecting our ability to interpret the results of this study. First, it was not possible to keep patients blinded to treatment group. Second, we could not match both the number of treatment sessions and pulse number at the same time. We chose to approximate the session numbers although for practical reasons these were not exactly equivalent (20 and 21), a difference unlikely to make a meaningful difference to the outcomes.

Third, it is possible that a larger study may reveal trends towards treatment effects that we did not find with our sample size. However, we saw no meaningful trend to a difference in mean reductions in MADRS scores or on any of the other outcome variables, and no trend towards differences in response and remission rates. Although our results do not hold the weight of a large multisite randomised trial, they certainly do provide a strong indication that intensive TBS treatment may have the capacity to produce the same clinical effects as standard courses of rTMS therapy.

Related to this concern, given the pilot study stage of this research, we did not power and design the study as a true test of non-inferiority. It is also important to note that our design, which entailed an unequal number of treatment session per week across the groups, makes direct comparison of the rate of symptom change problematic. However, our overall intent, to assess the overall clinical value of this form of protocol, versus standard TMS, required a direct comparison and we accepted a compromise in this regard.

In addition, we did not include the collection of biomarkers that may have been utilized to examine whether there were determinants of response to either of the forms of treatment. It is also possible that we would have seen a greater antidepressant effect with iTBS provided at subthreshold intensity given that preliminary research suggests that the intensity of iTBS stimulation is likely to be relevant to its clinical effects [42].

However, we chose suprathreshold intensity as this had been used in a several depression iTBS studies and we did not have the benefit of knowledge of the Chung et al. outcomes at the time of designing this trial – systematic research in clinical populations is required to understand whether low intensities of stimulation will produce greater clinical effects.

Our recent data, and data from other groups, also suggest that longer durations between iTBS stimulation sessions may produce greater results [39,43]. However, it is problematic to assume that we can directly infer optimal treatment variables from single session studies conducted in healthy control subjects.

The overall dose (e.g. 4 weeks of standard treatment) is also likely to have contributed to the relatively limited response and remission rates although we chose this design deliberately to provide relative group treatment equality and maximize the success of rater blinding. We also included both uni and bipolar patients and a quite heterogenous and unwell population of patients, which may have affected outcomes although both groups have showed response in previous mixed samples.

Finally, we did not systematically collect data on the preference of patients for one or other of forms of treatment. As with our previous trial of accelerated standard TMS, anecdotally patients certainly expressed preference for the shorted accelerated/intensive group but we did not establish this with systematic data collection.

In conclusion, the use of iTBS appears to be a very promising TMS protocol to apply in intensive treatment protocols. Intensive TBS appears to be well tolerated and produced clinical effects similar to those seen with a standard course of rTMS treatment. Notably, iTBS seemed safe even at 120% of the RMT and in the intensive schedule. However, the intensive TBS protocol we applied did not produce a more rapid onset of antidepressant effects. Further research, especially a large multisite trial with longer follow up, is required to validate the use of intensive TBS.

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Source:University of South Australia


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