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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5250_Библиотеки_им_академика_М_И_Перельмана.pdf
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inconsistent results [36]. One study reported no signicant clinical effects of gure-eight coil rTMS on the left DLPFC in patients with bipolar disorder [36, 37].
Similarly, Fitzgerald etal. [37] found no evidence to support the superior efcacy
of gure-eight coil rTMS over sham treatment in patients with bipolar disorder.
Given these inconsistencies and the limited number of dTMS trials for bipolar
disorder, further research is necessary to establish its clinical efcacy. Specically,
studies should focus on whether H1-coil-induced DLPFC stimulation provides
superior outcomes to sham.
4.2.2.2 Safety
In 2013, the United States FDA approved the dTMS protocol, utilizing H1 coils,
for the treatment of MDD [38]. This regulatory milestone highlights the potential
of Deep TMS as a well-tolerated adjunctive therapy for patients with treatmentresistant bipolar depression undergoing adequate pharmacotherapy [34]. Notably,
the study by Tavares etal. reported a higher incidence of scalp pain in the active
treatment groups (20%) compared to the sham groups (0%) (P = 0.05). Other
adverse events, including headache, neck pain, burning sensations, hearing disturbances, and concentration difculties, were observed at comparable rates between
the two groups without signicant differences. Additionally, research conducted by
Rapinesi etal. [39] evaluated the safety of dTMS in a cohort of 82 patients experiencing various depressive episodes, encompassing MDE within MDD, bipolar I
disorder, and MDD with comorbid alcohol use disorder (MDAUD). The absence of
complications or adverse effects (0%) across all participants underscores the safety
and broad applicability of this therapeutic modality in managing diverse depressive
conditions.
4.2.2.3 Treatment Regimen
Rapinesi etal. [39] further demonstrated the efcacy of dTMS targeting the DLPFC
at an intensity of 120% of the MT, delivered unilaterally or bilaterally (preferably
on the left side) using an H1 coil. Stimulation was applied at a frequency of 20Hz
to maximize neural engagement, with each session comprising multiple 2-s pulse
trains interspersed with 20-s intervals to facilitate neural recovery. This protocol
was administered daily over a 4-week period, resulting in a comprehensive treatment regimen totaling 20 sessions.
4.2.2.4 Clinical Recommendations
Systematic reviews [38, 40] have suggested that dTMS may serve as an effective
intervention for bipolar depression and, potentially, for TRD, positioning it as a
promising alternative therapeutic option. However, the current body of clinical trial
data remains insufcient [31] (Table4.1), particularly in the contexts of bipolar
depression and bipolar mania. This evidentiary gap underscores the necessity for
more extensive research to evaluate the long-term durability of dTMS, its therapeutic efcacy, and potential predictors of treatment response.
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4.2.3 Priming TMS
4.2.3.1 Efficacy
Priming TMS introduces an innovative approach within the domain of rTMS by
utilizing subthreshold HF stimulation to enhance the efcacy of subsequent LF
stimulation trains, thereby amplifying neural responsiveness to LF stimulation.
Evidence from a network meta-analysis [40] supports the superior efcacy of
priming TMS (effect size: 6.02) compared to sham therapy in the acute treatment
of MDE in adults. In a clinical trial [41] evaluating sequential bilateral rTMS
versus right-sided unilateral rTMS with a priming protocol, response rates were
57% and 55%, respectively (P= 0.80). Similarly, remission rates were nearly
identical, with 40.2% in the bilateral group and 40.1% in the priming group
(P =0.90), demonstrating no signicant differences between these modalities.
Additional studies suggest that priming TMS achieves higher response rates compared to cTBS, further highlighting its therapeutic potential in managing depression [42].
4.2.3.2 Safety
Priming, a technique that enhances the neural response to rTMS through a preliminary phase of low-intensity HF stimulation, remains an underexplored area.
However, initial studies suggest that priming TMS demonstrates a favorable safety
prole and excellent tolerability, supporting its potential as a viable and safe therapeutic option [40, 42].
4.2.3.3 Treatment Regimen
Priming TMS remains an area of ongoing exploration within the therapeutic framework for bipolar disorder. A study by Fitzgerald etal. [41] involving 179 participants, including individuals with bipolar I disorder in a depressive episode (n=27)
and bipolar II disorder in a depressive episode (n= 13), has provided valuable
insights into the potential efcacy of this approach. The treatment protocol began
with a priming HF stimulation phase at 6Hz, delivered at 90% of RMT intensity,
and administered over 20cycles, each lasting 5 s. This was followed by an LF
phase, consisting of 1Hz stimulation at 110% RMT intensity, continuously delivered for a total of 900 pulses. The treatment course extended up to 4weeks, with
ve sessions per week, resulting in a total of 20 sessions. The stimulation site was
precisely located 6cm anteriorly to the optimal scalp location for eliciting maximum thumb abductor muscle response.
4.2.3.4 Clinical Recommendations
Although the clinical evidence supporting priming TMS is still evolving, it represents a promising strategy for enhancing the efcacy of rTMS.This approach holds
signicant potential to augment the clinical utility of rTMS, particularly in patients
exhibiting insufcient responses to conventional therapies. However, the current
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data on its application for bipolar disorder, encompassing both manic and depressive episodes, are insufcient to offer denitive recommendations for priming TMS
use [31] (Table 4.1). Consequently, future research should focus on optimizing
rTMS parameters, including frequency, intensity, and session duration, to rene
treatment efcacy. Additionally, exploring the synergistic effects of combining
rTMS with other therapeutic modalities, such as pharmacological treatments, is
essential to determine the most effective integrated approach.
X. Yang et al.
4.2.4 Synchronized TMS
4.2.4.1 Efficacy
Synchronized TMS is a brain stimulation technique that utilizes rotating spherical neodymium magnets, synchronized with an individual’s alpha wave frequency, to create a global magnetic eld distribution along the midline of the
scalp [40]. The underlying mechanism involves the modulation of oscillatory
activity through the programmed frequency of synchronized stimulation, which
resets thalamocortical oscillators and restores endogenous oscillatory rhythms
[43]. A recent review found no compelling evidence to support the efcacy of
synchronized TMS in the treatment of MDE, with a notable scarcity of studies
specically investigating its application in bipolar disorder [44]. Further investigation in this area is warranted.
4.2.4.2 Safety
Evidence suggests that synchronized TMS is associated with a reduced incidence of
adverse effects compared to conventional rTMS, likely due to the absence of neural
depolarization [40, 45]. Additionally, synchronized TMS consumes less energy than
traditional rTMS, potentially leading to reduced treatment costs and enhanced
safety proles [46].
4.2.4.3 Treatment Regimen
Current research is predominantly focused on unipolar depression, with the eld
still in its early stages. The limited number of studies and small sample sizes underscore the need for further exploration. Notably, no studies have yet examined the
application of synchronized TMS in bipolar disorder [45].
4.2.4.4 Clinical Recommendations
As of now, no clinical recommendations exist regarding the use of synchronized
TMS for the treatment of bipolar disorder, including both depressive and manic
episodes [44] (Table4.1).
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4.2.5 TBS
4.2.5.1 iTBS
Efficacy
A meta-analysis has demonstrated that both iTBS and HF-rTMS exhibit comparable efcacy, acceptability, and safety proles for the treatment of treatment-resistant
MDD.However, a randomized controlled trial by McGirr etal. [47] found that iTBS
targeting the left DLPFC was ineffective for patients with acute bipolar depression.
Preliminary evidence suggests that the mechanism of iTBS, when aimed at the frontal lobe, may be associated with physiological changes in the mPFC of patients with
acute bipolar depression [48]. Despite these ndings, no dedicated reviews or metaanalyses have specically addressed the relationship between iTBS and bipolar disorder, leaving the effectiveness of iTBS in this context poorly dened due to limited
research.
Safety
The safety prole of iTBS has become a central focus in neuromodulation research.
Current clinical evidence supports that iTBS exhibits a safety prole comparable to
conventional rTMS, with no reports of seizures or signicant adverse events [47].
Extensive clinical trials and systematic reviews of other mental health conditions,
such as schizophrenia, have afrmed the safety of iTBS as a noninvasive neuromodulation method, with minimal side effects and a very low risk of severe complications [49]. Nonetheless, ongoing research is monitoring the long-term safety of
iTBS to ensure its safe and effective application in clinical settings.
Treatment Regimen
iTBS is a form of patterned rTMS characterized by bursts of three pulses at 50Hz,
occurring at a 5Hz inter-burst frequency [50]. This technique is notable for its brief
application time, sustained effects, and more accurate reection of physiological
neural activity patterns. The various TBS protocols affect neuronal excitability differently, with iTBS specically increasing excitability through a 2-s stimulation
train followed by an 8-s pause [51]. Optimal stimulation is applied over the left
DLPFC at an intensity ranging from 80% to 120% of MT [51].
Clinical Recommendations
The current evidence base for iTBS in the treatment of bipolar depression or mania
is insufcient to provide denitive clinical recommendations [31] (Table4.1).
4.2.5.2 Accelerated iTBS
Efficacy
In a meta-analysis encompassing ve RCTs involving 239 patients with bipolar
disorder or MDD experiencing MDE, Cai etal. [52] demonstrated that the iTBS
protocol achieved a superior therapeutic response rate compared to sham
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stimulation. Specically, active accelerated iTBS showed a signicantly higher
response rate than sham stimulation (39.8% versus 19.0%), although the remission
rates were comparable between the two groups (36.5% versus 16.2%) [52]. A systematic review of ve double-blinded RCTs, involving a total of 239 individuals
with MDD or bipolar disorder in depressive episodes, also revealed that active iTBS
was more effective than sham stimulation in terms of therapeutic outcomes. In a
recent RCT, Sheline et al. [53] examined the efcacy of accelerated iTBS for
treatment- refractory bipolar disorder with moderate to severe depressive episodes.
The primary outcome measure was the change in MADRS scores before and after
the intervention. The ndings indicated that accelerated iTBS signicantly alleviated depressive symptoms compared to sham stimulation, with an estimated difference of −14.75, suggesting its potential as a promising treatment for individuals
with treatment-resistant bipolar disorder [53].
Safety
A pilot RCT involving 26 individuals diagnosed with bipolar depression found that
twice-daily iTBS was well-tolerated, with no adverse events reported, further supporting its safety and tolerability [54]. Moreover, a meta-analysis by Mutz etal. [40]
showed that the discontinuation rates were similar between the active and sham
iTBS groups, reinforcing the treatment’s acceptability and tolerability in both
conditions.
Treatment Regimen
In the context of TRD, Sheline etal. [53] conducted a study where participants
received 10 daily sessions of image-guided active or sham accelerated iTBS over
5days, with one session per hour. The stimulation was set at 90% of the RMT, accumulating to a total of 90,000 pulses.
In a study on bipolar depression, Bulteau etal. [54] applied iTBS to the left
DLPFC at 80% of the RMT.The protocol utilized a 50Hz frequency, with triplet
pulses delivered at 200ms intervals within bursts occurring every 10s. Patients
attended two daily sessions, spaced 3h apart, amounting to either 30 sessions over
3weeks or 10sessions in cases of early remission. Each session involved 990 pulses
organized into two burst sequences, each consisting of three pulses at 50 Hz,
repeated every 200ms, with 10-s intervals between bursts.
The Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, developed by Cole etal. at Stanford University [55, 56], is specically designed
for the treatment of TRD.It utilizes an accelerated iTBS protocol, grounded in
neuroscience principles. Participants in the SAINT protocol underwent magnetic
resonance imaging (MRI) and resting-state functional MRI (fMRI) scans, with neuronavigation used to identify the left DLPFC region most anticorrelated with the
subgenual anterior cingulate cortex (sgACC). This region was then targeted for
iTBS.Sessions were delivered at 90% of the MT, each consisting of 1800 pulses
with a 50-min intersession interval. The pulses, delivered at 50Hz in 2-s bursts,
were spaced with an 8-s interval between bursts. A total of 10 daily sessions were
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conducted, delivering 18,000 pulses over 5 consecutive days, accumulating to a
total of 90,000 pulses.
Clinical Recommendations
Due to the limited body of research, no clinical guidelines currently exist for the use
of accelerated iTBS in the treatment of bipolar depression or mania [31] (Table4.1).
4.2.5.3 Continuous TBS
Efficacy
The efcacy of cTBS remains uncertain. A systematic review [40] found no substantial evidence supporting the application of cTBS for MDE.Similarly, a metaanalysis evaluating the therapeutic effects of TBS in patients with MDD or bipolar
disorder reported no signicant clinical advantages [52]. Studies focusing on individuals with acute-phase bipolar depression have also yielded inconsistent results
regarding the efcacy of intensive iTBS in this population [57]. While some analyses observed improvements in depressive symptoms within the total sample, active
cTBS failed to outperform sham treatment in alleviating these symptoms.
Safety
From a safety perspective, cTBS is widely considered a safe and well-tolerated
intervention, particularly in managing MDE among patients with bipolar disorder.
Dellink etal. [59] identied headaches (38%), local pain (27%), and tingling (14%)
as the most common adverse events. However, isolated case reports have indicated
the potential for cTBS to induce generalized seizures, underscoring the need for
vigilance [58]. Large-scale, methodologically robust studies are required to clarify
the therapeutic potential and safety prole of cTBS in bipolar disorder.
Treatment Regimen
The standard target for continuous cTBS is the right DLPFC.Protocols vary signicantly across studies. For instance, one approach involves delivering cTBS at 50Hz
in bursts of three pulses, repeated every 200ms at a frequency of 5Hz, with a total
of 600 pulses per session administered three times daily (1800 pulses per day) over
5days at 80% of the RMT [57]. In contrast, an alternative protocol employs cTBS
at 110% of the RMT, using the same pulse pattern but with ve sessions per day.
Each session delivers 900 stimuli with 15-min intervals between sessions, resulting
in 4500 stimuli daily and a cumulative total of 18,000 stimuli over 4 treatment
days [59].
Clinical Recommendations
Due to limited sample sizes and short follow-up periods, current studies have failed
to demonstrate signicant differences in treatment outcomes, precluding specic
recommendations for bipolar depression or mania at this time [31] (Table 4.1).
Future investigations should prioritize larger sample sizes and extended follow-up
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durations to provide more denitive insights into the efcacy and long-term outcomes of cTBS in this patient population.
4.2.5.4 Bilateral TBS
Efficacy
The efcacy of bilateral TBS remains uncertain based on recent preliminary ndings. A double-blind, 6-week, sham-controlled RCT [60] evaluated the impact of
bilateral TBS targeting the right and left DLPFC in adults experiencing acute mixed
episodes of bipolar disorder and MDD. Changes in MADRS scores at week 3
revealed no statistically signicant differences between groups. Similarly, the
response and remission rates at week 6, assessed using MADRS, demonstrated no
signicant distinction between active and sham groups (response rate: 35.7% vs.
43.7%; remission rate: 28.5% vs. 37.5%).
A systematic review [61] encompassing six RCTs with 285 participants—82%
diagnosed with MDD and 18% with a depressive episode of bipolar disorder—compared active bilateral TBS with sham stimulation. The analysis indicated no signicant superiority of active bilateral TBS over sham in response rates (48.3% vs.
29.5%, P =0.07) or remission rates (32.9% vs. 26.7%, P= 0.37). However, the
inclusion of mixed diagnoses underscores a critical gap in research exploring the
exclusive application of bilateral TBS in bipolar disorder. This limitation highlights
the need for dedicated studies to optimize protocols and evaluate potential benets
in this specic population.
Safety
The limited number of RCTs investigating rTMS for bipolar disorder remains a
signicant barrier to drawing denitive conclusions. Notably, the RCT conducted
by Tavares etal. [60] represents a key investigation into the antidepressant efcacy
and safety prole of bilateral TBS applied over the DLPFC in individuals with bipolar and unipolar mixed depression. The study reported no signicant differences in
the incidence of treatment-emergent manic switches between active and sham
groups, suggesting a comparable safety prole for both interventions. These ndings are essential for assessing rTMS as a viable therapeutic modality in bipolar
disorder.
Treatment Regimen
In this study [60], the bilateral TBS sessions were administered in the following
sequence: cTBS targeting the right DLPFC was followed by iTBS targeting the left
DLPFC.The parameters for cTBS consisted of bursts of three pulses at a frequency
of 50Hz, with a 20-ms interval between stimuli, applied continuously for a duration
of 120s, resulting in a total of 1800 pulses delivered to the right DLPFC.For iTBS,
bursts of three pulses at 50Hz, with a 20-ms interval between stimuli, were administered for 2s and repeated every 10s over a total duration of 570s, also culminating in 1800 pulses delivered to the left DLPFC.The stimulation intensity was set at
80% of the MT.The study spanned a total duration of 6weeks. A total of 1800
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pulses were administered per session, resulting in a cumulative dose of 75,600
pulses throughout the study.
Clinical Recommendations
At present, no clinical guidelines exist for the use of bilateral TBS in treating bipolar disorder, including both depressive and manic episodes [37] (Table4.1).
4.2.6 MST
4.2.6.1 Efficacy
MST represents an innovative and promising neuromodulation therapy. The technique induces therapeutic seizures by applying alternating magnetic elds, which
generate eddy currents within the cerebral cortex [62]. MST requires anesthetic
administration and medical monitoring setups akin to those utilized for
ECT. However, unlike ECT, which directly stimulates the brain via external electrodes, MST employs a modied TMS device to deliver high- frequency magnetic
pulses, inducing seizures to achieve therapeutic effects [63].
MST has demonstrated potential efcacy in managing treatment-resistant bipolar disorder. A systematic review [64] evaluating MST for unipolar and bipolar
depression consistently reported signicant antidepressant effects, with remission
rates ranging from 30% to 40%. In comparison, ECT has shown higher remission
rates of 50–70% under similar conditions. Notably, MST was associated with minimal cognitive side effects, offering a superior cognitive safety prole compared to ECT.
An open-label clinical study [65] further validated MST’s therapeutic potential
for bipolar depression. Among 26 patients undergoing at least eight treatments,
MST achieved a response rate of 38.5% and a remission rate of 23.1%, with minimal cognitive impairments reported. In a subsequent study [66], the same group
observed a signicant reduction in suicidal ideation among patients with bipolar
depression treated with MST, underscoring its effectiveness in addressing this critical symptom.
A comparative study assessing the efcacy and cognitive side effects of MST
versus ECT in bipolar mania treatment [67] provided additional insights. ECT demonstrated therapeutic effectiveness in 95.0% of patients (19 out of 20), while MST
was effective in 86.4% (19 out of 22). Both interventions produced comparable
reductions in Young Mania Rating Scale (YMRS) scores. However, cognitive outcomes favored MST; patients undergoing ECT experienced declines in verbal performance, whereas those treated with MST exhibited no signicant changes in
language function. Furthermore, attention-related outcomes did not differ signicantly between the groups. These ndings highlight MST’s high efcacy and
reduced cognitive side effects, positioning it as a promising alternative to ECT for
managing bipolar mania.
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X. Yang et al.
4.2.6.2 Safety
Compared to ECT, MST offers comparable overall efcacy while resulting in signicantly fewer cognitive side effects. The key advantage of MST lies in its capacity
to induce seizures with greater specicity to targeted brain regions, minimizing cognitive impairments such as retrograde and anterograde amnesia and reducing other
adverse effects. As highlighted by Singh etal. [68], this reduction in cognitive side
effects represents a substantial advantage in clinical practice. These attributes
enhance patient compliance and suggest that MST may shape the future trajectory
of neuromodulation therapies. Nevertheless, further investigation is essential to
validate MST’s efcacy and safety for critical clinical presentations, such as acute
phases of bipolar disorder. Future research should prioritize the exploration of novel
stimulation targets and conduct large-scale RCTs to provide robust evidence.
4.2.6.3 Treatment Regimen
For depressive episodes, MST is typically administered at 100Hz, using 100% of
the device’s maximum output, for a 10-s duration [69]. In contrast, for manic episodes, MST protocols involve treatment sessions two to three times per week over a
2-week period, with each session lasting 8–10min [67]. The device operates at a
frequency of 75Hz at maximum output, with magnetic stimulation durations starting at 4 s and incrementally increasing by 4–8 s, not exceeding 20 s in total.
Adjustments are made to achieve an optimal seizure duration, dened as 15s or
more, conrmed through electroencephalogram (EEG) monitoring.
4.2.6.4 Clinical Recommendations
Due to the limited body of research, no graded clinical recommendations currently
exist for MST in the treatment of bipolar depression or mania [8] (Table4.1).
4.3 tDCS
4.3.1 Conventional tDCS
4.3.1.1 Efficacy
Conventional tDCS has demonstrated efcacy in managing bipolar disorder, particularly bipolar depression. A systematic review and meta-analysis evaluating the
effectiveness and tolerability of tDCS in bipolar depression reported signicant
reductions in depression scores, with a medium effect size observed post-acute
treatment (SMD=0.71) and a large effect size at the study endpoint (SMD=1.27)
[9]. This therapeutic effect is attributed to the modulation of neural synchronization
within the emotional brain network at both cortical and subcortical levels [70].
Furthermore, emerging evidence indicates that tDCS can enhance cognitive function in patients with bipolar disorder [71, 72]. However, the limited data regarding
its efcacy in hypomanic, manic, or mixed episodes underscores the need for further targeted investigations.
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4.3.1.2 Safety
The safety prole of tDCS in bipolar disorder is generally favorable, with no serious
adverse events reported [8]. In a meta-analysis of bipolar depression [9], six cases
of affective switching were documented among 46 patients undergoing tDCS.These
occurrences were typically mild and transient, arising during or shortly after stimulation. Moreover, functional magnetic resonance imaging studies have conrmed
that tDCS does not cause brain tissue edema, disrupt the blood–brain barrier, or
induce other structural alterations [73].
4.3.1.3 Treatment Regimen
The efcacy of tDCS is inuenced by specic protocol parameters. Electrode congurations such as F3-F8 and F3-F4 are commonly used, as they generate robust
electric elds in the DLPFC and have been associated with signicant antidepressant effects in bipolar disorder [74]. Stimulation intensity typically ranges from
0.029 and 0.08mA/cm2, employing a constant direct current mode without pulsed
or variable frequency [75]. Recommended treatment regimens include two 20-min
sessions per day for 14days [76]. However, higher intensities, such as 2.5mA over
30-min sessions spanning 20 treatments, may exceed the optimal dose for many
patients [77, 78]. A recent systematic review [74] further highlights the lack of consensus on ideal stimulation parameters, including intensity, duration, session frequency, and total current dose, for achieving optimal outcomes in bipolar disorder.
4.3.1.4 Clinical Recommendations
Given the current paucity of robust research, graded clinical recommendations for
the use of conventional tDCS in treating bipolar disorder, including depressive and
manic episodes, are not yet available [8, 79] (Table4.3). Further studies are essential to delineate the role of tDCS in this context and establish evidence-based protocols for its application.
4.3.2 HD-tDCS
4.3.2.1 Efficacy
HD-tDCS represents a signicant advancement in neuromodulation therapy,
employing rened current ow models to improve the precision of stimulation
delivery. This approach allows for personalized customization of electrode placement and current intensity, aligning with the unique brain anatomy and therapeutic
needs of individual patients. Such precision not only enhances the efcacy of treatment but also reduces the likelihood of adverse effects. A recent network metaanalysis of randomized controlled trials [80] demonstrated that HD-tDCS targeting
the F3 region signicantly alleviates depressive symptoms compared to sham controls, with no notable increase in dropout rates or side effects. Additionally, emerging evidence suggests that glial cell-derived neurotrophic factor (GDNF) may serve
as a predictive biomarker for manic episodes treated with HD-tDCS, offering a
pathway for personalized therapeutic strategies [81].