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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5250_Библиотеки_им_академика_М_И_Перельмана.pdf
11 Post-traumatic Stress Disorder
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11.1 Introduction
Post-traumatic stress disorder (PTSD) is a mental health condition triggered by
exposure to a traumatic event, characterized by delayed onset and persistence of
symptoms, with a global lifetime prevalence of 3.9% [1]. Like other mental health
disorders, PTSD arises from the complex interplay of social, psychological, and
biological factors. While anyone can develop PTSD following a potentially traumatic event, individuals with prior traumatic experiences are at heightened risk.
Approximately 70% of people worldwide will encounter a potentially traumatic
event in their lifetime, yet only a minority (5.6%) will develop PTSD [2]. Despite
the availability of effective treatments, only one in four individuals with PTSD in
low- and middle-income countries (LMICs) seek any form of treatment [3].
PTSD is characterized by three core symptom clusters: re-experiencing the
trauma, avoidance and emotional numbing, and hyperarousal. These symptoms
often lead to signicant functional impairment, comorbidities, and a major threat to
social well-being, stability, and economic development. Hence, enhancing research
on PTSD and providing effective treatment and support are critical to mitigating its
societal impact. Trauma-focused therapies, including Cognitive Processing Therapy
(CPT), Prolonged Exposure Therapy (PE), and Eye Movement Desensitization and
Reprocessing (EMDR), are supported by empirical evidence [4], although these
interventions often yield suboptimal outcomes [5]. Despite the effectiveness of
pharmacotherapy and psychotherapy, approximately 20–30% of patients remain
symptomatic [6].
Emerging studies indicate that specic neuroregulatory techniques, such as transcranial magnetic stimulation (TMS), theta burst stimulation (TBS), magnetic seizure therapy (MST), and transcranial direct current stimulation (tDCS), may activate
or inhibit targeted neural circuits to alleviate PTSD symptoms. However, some of
these techniques fail to stimulate deep brain regions, and existing research remains
insufcient. This chapter will provide an in-depth exploration of these neuroregulatory approaches.
11.2 TMS
11.2.1 rTMS
Repetitive Transcranial Magnetic Stimulation (rTMS) is an advanced, noninvasive
neuromodulation technique that alters brain activity through the application of
repeated magnetic pulses, generated by uctuations in the coil’s magnetic eld.
This modulation can inuence both cortical and subcortical brain regions. rTMS is
typically classied into high-frequency (HF-rTMS; 5–20Hz) and low-frequency
(LF-rTMS; ≤1 Hz) categories. It has been proposed that HF-rTMS enhances
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S. Sha et al.
cortical excitability, whereas LF-rTMS dampens cortical activity [7, 8]. While limited research exists, both HF- and LF-rTMS have demonstrated therapeutic potential in PTSD treatment, though there is no consensus regarding the optimal frequency
for therapeutic efcacy.
11.2.1.1 Unilateral rTMS
Efficacy
Unilateral Repetitive Transcranial Magnetic Stimulation (U-rTMS) has emerged as
a promising treatment modality for PTSD.U-rTMS has been shown to signicantly
reduce overall PTSD severity and alleviate core symptoms such as intrusive memories, avoidance behaviors, and hyperarousal [9–11].
Research indicates that U-rTMS targeting specic brain regions yields differential therapeutic effects. For instance, U-rTMS applied to the right dorsolateral prefrontal cortex (DLPFC) has been found to signicantly reduce PTSD-associated
anxiety and depression [12–14], while left DLPFC stimulation has been associated
with improvements in comorbid depression [15, 16].
U-rTMS has also demonstrated potential cognitive benets. Both left- and rightsided U-rTMS have shown trends toward cognitive improvement, with right-sided
U-rTMS particularly enhancing verbal uency [17].
Regarding the durability of effects, studies suggest that U-rTMS can sustain its
therapeutic benets over the long term, with improvements remaining signicant
from 2weeks to 3months posttreatment [12, 18, 19].
Safety
U-rTMS is generally regarded as a low-risk, well-tolerated treatment, with most
adverse effects being mild and transient. No major adverse events, such as seizures,
have been reported in current studies. Common side effects include temporary headache, syncope, scalp discomfort, and transient changes in hearing [20]. Some studies have also noted additional adverse events, such as dizziness, neck pain,
sleepiness, and brief mood disturbances [6].
Treatment Regimen
The optimal parameters for U-rTMS treatment in PTSD have garnered considerable
attention, particularly regarding the targeted brain regions. The DLPFC has emerged
as a central area of focus, given its pivotal role in emotion regulation [21]. Typically,
either the right or left DLPFC is targeted to modulate activity in the ventromedial
prefrontal cortex (vmPFC), a key region involved in emotional processing.
Signicant improvements in PTSD core symptoms have been observed with
U-rTMS targeting both the left and right DLPFC [13, 14, 22]. However, there remains
ongoing debate about whether left or right DLPFC yields better treatment outcomes
in patients with PTSD.Studies over the past decades have produced inconsistent
results. For instance, one randomized controlled trial (RCT) suggested that right
DLPFC-targeted U-rTMS produces a larger effect compared to left DLPFC stimulation, whereas another review found no signicant difference between the two
approaches [9, 17]. This highlights the need for further research with larger sample
sizes to resolve the issue of the optimal brain target in PTSD treatment.
11 Post-traumatic Stress Disorder
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An additional area of clinical debate is the choice between high- and lowfrequency U-rTMS.Both approaches have shown mixed results in terms of efcacy.
Some studies [13, 14, 18, 22] have demonstrated the effectiveness of low-frequency
U-rTMS, while others [12, 15] have failed to show signicant benets. Similarly,
while some research [12, 23] supports the effectiveness of high-frequency U-rTMS,
other studies [18] have found no distinction between high-frequency stimulation
and sham treatments.
Several meta-analyses [9, 10] suggest that high-frequency TMS is more effective
than low-frequency TMS in the treatment of PTSD, producing a signicantly larger
therapeutic effect. These meta-analyses predominantly focus on studies utilizing
U-rTMS, though a limited number also include bilateral rTMS and deep TMS, which
may slightly confound the conclusions. Therefore, while high- frequency U-rTMS
may appear more efcacious, the question of whether high- or low-frequency
U-rTMS is superior remains unresolved and warrants further investigation.
Treatment parameters, such as session duration and frequency, though less frequently discussed, are also important potential moderators of treatment efcacy.
Typical rTMS sessions range from 20 to 45min, with treatment frequencies varying
from two to ve sessions per week [10, 24].
A previous study indicated no signicant differences in effect size based on the
number of treatment sessions or the total number of TMS pulses delivered over the
course of treatment. Moreover, high-dose TMS protocols did not show superior efcacy compared to mid-dose protocols, suggesting that improving the efciency of
TMS treatments could make them more accessible to a broader patient population [9].
This meta-analysis focused mainly on U-rTMS studies, with a few exceptions involving other TMS modalities. Consequently, the impact of treatment parameters such as
session duration and frequency on the effectiveness of U-rTMS remains uncertain.
Clinical Recommendations
The right DLPFC, as a potentially promising brain target, warrants increased clinical attention and further investigation, particularly in light of its superior effectiveness demonstrated in an RCT study. Additionally, high-frequency stimulation has
been associated with potentially larger treatment effects, with some reviews advocating for its use. However, these recommendations remain inadequately substantiated by sufcient empirical evidence (see Table11.1).
Consensus on the optimal parameters remains elusive, primarily due to the limited clinical evidence and the mixed results reported in current studies. To clarify the
ideal treatment parameters and establish evidence-based clinical recommendations,
further investigations are essential.
11.2.1.2 Bilateral rTMS
Efficacy
In the limited literature, bilateral rTMS (B-rTMS) targeting the DLPFC has been
demonstrated to effectively reduce overall PTSD severity signicantly [23].
However, there remains considerable debate regarding whether bilateral DLPFC
stimulation is superior to unilateral DLPFC stimulation [20]. While some studies
suggest that bilateral stimulation may lead to a greater reduction in PTSD severity
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Table 11.1 TMS in PTSD
Clinical recommendations
Length
TMS
rTMS Right
DLPFC
Deep TMS Unclear Unclear Unclear Unclear NA
Priming TMS Unclear Unclear Unclear Unclear NA
Synchronized
TMS
b
TBS
MST Unclear Unclear Unclear Unclear NA
a
The WFSBP Guidelines mentions rTMS as B-grade recommendation for PTSD treatment
b
TBS includes iTBS, accelerated iTBS, continuation TBS, and bilateral TBS
Unclear Unclear Unclear Unclear NA
Unclear Unclear Unclear Unclear NA
High(10Hz) 20 10 B-grade
(min)
a
Duration
(sessions)
Levels+referencesTarget Frequency
Recommendationa [25]
S. Sha et al.
compared to unilateral stimulation (on either the right or left DLPFC), other studies
report comparable effects between bilateral and unilateral right DLPFC stimulation
[23, 26].
Further research is needed to clarify the optimal targeting strategy for DLPFC
stimulation in the treatment of PTSD.
Safety
The side effect prole associated with B-rTMS is generally low, with most adverse
events being mild and transient [6]. No major adverse events have been reported in
existing trials. A few studies found that only a small number of patients with PTSD
experienced transient headaches and discomfort, either during the initial sessions of
B-rTMS or following treatment completion [23, 27].
Treatment Regimen
One study exploring bilateral DLPFC stimulation (20Hz, 100% MT, 1200/2400 pulses
per session, 10 sessions in total) not only signicantly reduced PTSD symptoms but
also achieved faster initial effects compared to unilateral right DLPFC stimulation [23].
Although most therapeutic B-rTMS studies have focused on the DLPFC, another
study targeting the dorsomedial prefrontal cortex (dmPFC) reported improvements
in overall severity in patients with comorbid PTSD and eating disorders (10/20/50Hz,
120% MT, 3000/600 pulses per session, 20–30 sessions in total) [27].
Clinical Recommendations
Based on the limited studies available, high-frequency stimulation (10–20Hz) targeting the DLPFC can be recommended for B-rTMS in the treatment of PTSD,
given its efcacy in alleviating overall PTSD severity, as well as associated depression and anxiety [23, 26].
Additionally, the dmPFC is emerging as a novel stimulation target, with preliminary evidence suggesting its potential efcacy [27]. However, further large-scale
studies are needed to validate its effectiveness.
11 Post-traumatic Stress Disorder
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11.2.1.3 Accelerated rTMS
Efficacy
Accelerated rTMS (A-rTMS) remains an experimental intervention with limited
clinical evidence to support its widespread use. Although its potential has been
explored in patients with Major Depressive Disorder (MDD) and Generalized
Anxiety Disorder (GAD) [28–31], its application in the treatment of PTSD remains
insufciently investigated.
Among the few existing studies, trends suggesting anxiolytic and antidepressant
effects have been observed in individuals with GAD, MDD, and Postpartum
Depression following A-rTMS treatment [28, 29, 32–34]. Preliminary evidence also
indicates that A-rTMS may reduce the intensity of suicidal ideation in suicidal inpatients [35]. However, whether similar therapeutic outcomes can be achieved in
patients with PTSD remains uncertain and warrants further investigation in future
studies.
Safety
In the limited available literature, A-rTMS has been reported to be safe and welltolerated, with minimal adverse effects, such as scalp discomfort [33]. Nevertheless,
additional studies are required to assess its safety prole specically within the
context of PTSD treatment.
Treatment Regimen
Given the scarcity of research on A-rTMS for PTSD, optimal treatment parameters
remain undened.
Brain targets, particularly the right DLPFC, have shown promising results with
conventional rTMS for PTSD [17], underscoring the need for further clinical investigations to determine whether comparable outcomes can be achieved using A-rTMS
protocols.
Clinical Recommendations
Further research is essential to establish the efcacy and safety of A-rTMS in the
treatment of PTSD before any clinical recommendations can be made.
11.2.2 Deep TMS
11.2.2.1 Efficacy
Deep TMS (D-TMS) is a neuromodulation and neurostimulation technique that
operates on the principle of electromagnetic induction within the brain [36]. The
intensity and density of the induced electromagnetic eld are sufcient to depolarize neurons, with repetitive transcranial magnetic stimulation pulses modulating
cortical excitability. Depending on the stimulation parameters, this modulation can
either reduce or enhance neuronal activity, with effects that may persist beyond the
duration of the stimulation sequence [37]. While standard TMS typically employs
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No. 8 coils, D-TMS can utilize various coil types, including H-type coils [38],
C-type core coils [39], and round crown coils [40]. Among these, only the H-coil
has been tested for safety and efcacy and is the sole coil type used in clinical trials
[41]. The H-coil’s ability to reach depths of up to 6cm enables it to modulate both
cortical activity and deep neural circuits [36].
Clinically, the efcacy of D-TMS for mental disorders characterized by hyperactivity or heightened arousal, such as PTSD, remains inconsistent [42]. Two clinical
trials have investigated the use of H1 [43] and H7 coils [44] for D-TMS treatment
in patients with PTSD.The rst study [43] demonstrated signicant therapeutic
effects when D-TMS was combined with exposure therapy. Specically, the group
receiving combined D-TMS and exposure therapy showed greater improvements in
Clinician-Administered PTSD Scale (CAPS) scores compared to those in the exposure therapy combined with the sham operation group or the D-TMS-only treatment
group. However, the limited number of studies on sham-controlled D-TMS in PTSD
populations means that these results are not denitive. In contrast, the second trial
[44] reached an opposing conclusion, where both active and pseudo-D-TMS groups
were treated simultaneously with exposure therapy. Surprisingly, the sham group
showed greater improvement. The reasons for this discrepancy remain unclear. The
authors [42] suggest that the differences may arise from the distinct brain regions
targeted by the coils in each study: the former focused on the medial prefrontal
cortex (mPFC), while the latter targeted the bilateral mPFC and anterior cingulate
cortex (ACC). The therapeutic efcacy of various coil types in treating PTSD warrants further investigation.
11.2.2.2 Safety
The common side effects associated with D-TMS in patients with PTSD primarily
include discomfort at the application site [43] and mild headache [43, 45]. Some
patients may withdraw from trials due to increased discomfort or anxiety [43, 45].
Headaches are typically self-limiting and rarely necessitate pain medication [43].
Seizures are an infrequent occurrence, with one case of transient tonic-clonic generalized seizures reported after the eighth treatment. These seizures were selflimiting and did not require special intervention [43]. Although rare, instances of
suicidal ideation and attempts have been noted, though they cannot be directly
attributed to D-TMS therapy itself [45].
11.2.2.3 Treatment Regimen
Studies [12, 17, 18] have shown that rTMS applied to the right DLPFC yields more
substantial improvements in PTSD compared to stimulation of the left DLPFC.A
prior clinical trial using f8 coils on the left frontal cortex indicated only modest
improvements in core PTSD symptoms [15]. These ndings suggest that hemisphere targeting should be an important consideration when customizing D-TMS
protocols for patients with PTSD.
Previous studies [43] commonly employed a treatment regimen of three sessions
per week over 4weeks. The most recent trial [44], utilizing H7 coils, targeted the
bilateral mPFC and ACC, with treatment parameters including 18Hz frequency, 2-s
11 Post-traumatic Stress Disorder
pulse trains, 20-s intertrain intervals, 80 pulses per group, and a resting motor
threshold of 100%. However, these treatment protocols were administered in conjunction with exposure therapy, and the efcacy of D-TMS alone remains an area
requiring further investigation.
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11.2.2.4 Clinical Recommendations
In the context of MDD, D-TMS was approved by the U.S.FDA in 2013 for MDD
treatment [46]. Due to its unique coil structure, D-TMS can stimulate deeper brain
regions and larger volumes than traditional rTMS.However, even in MDD clinical
studies, response and remission rates with D-TMS compared to sham treatments
have not been consistently signicant [47]. Currently, clinical research on PTSD
remains limited. Notably, a study by Hung etal. [48] found that only the combination of D-TMS and antidepressants demonstrated superior efcacy over placebo
drugs, while D-TMS alone had no signicant effect. This insight may guide future
clinical research, highlighting the need for additional randomized controlled trials
to conrm the efcacy of D-TMS in PTSD treatment (see Table11.1).
11.2.3 Priming TMS
11.2.3.1 Efficacy
As a variant of low-frequency TMS, priming transcranial magnetic stimulation
involves a specic regimen wherein a short-term high-intensity, high-frequency
TMS (“prime stimulation”) is applied before administering low-frequency right
DLPFC rTMS [49]. Previous studies have demonstrated that the antidepressant
effects of priming with 1Hz right rTMS were superior to those of 1Hz right rTMS
alone [50]. A recent study [51] found that applying iTBS 10min after priming with
continuation TBS (cTBS) resulted in a greater motor-evoked potential (MEP)
change compared to iTBS following sham treatment. Although differing from the
concepts under consideration, this nding offers valuable insights for incorporating
priming TMS in clinical research design. To date, no studies have investigated the
application of priming TMS in patients with PTSD.
11.2.3.2 Safety
A recent network meta-analysis [30] found that priming TMS produced a stronger
antidepressant response than cTBS, with transcranial stimulation associated with a
lower dropout rate compared to sham stimulation. However, due to the lack of clinical research on priming TMS for PTSD, its potential adverse effects remain unexplored. The safety of this technique requires further validation, supported by larger
clinical trials.
11.2.3.3 Treatment Regimen
The treatment approach employed in the current study serves as a signicant reference point. Unlike other TMS therapies, D-TMS itself serves as a form of priming
therapy, using high-frequency stimulation for priming followed by low-frequency
302
right DLPFC rTMS [49]. In the TBS treatment group, conventional iTBS was
administered following a 10-min priming stimulation [51].
S. Sha et al.
11.2.3.4 Clinical Recommendations
To date, randomized controlled trials evaluating priming TMS remain limited [50,
52], signaling the need for further investigation. Moreover, research into its specic
applications for PTSD treatment is even more scarce, representing a notable gap in
current research (see Table11.1).
11.2.4 Synchronized TMS
11.2.4.1 Efficacy
Synchronous transcranial magnetic stimulation (synchronized TMS) utilizes loweld sinusoidal stimulation through a rotating spherical neodymium magnet positioned along the scalp’s midline, synchronized with the individual’s alpha EEG
frequency [30, 53]. By harnessing the brain’s natural resonance at the individual
alpha frequency, synchronized TMS is thought to achieve antidepressant effects
using lower intensity energy than traditional high-frequency rTMS [54].
Furthermore, research by the same team indicated that synchronized TMS may
offer greater benets to patients with more severe baseline depression and anxiety
compared to pseudo-synchronized TMS [55], although this conclusion has not been
universally corroborated across studies [30]. Most current studies focus on depression, providing some reference and guidance for PTSD treatment. A prospective,
sham-controlled, multi-site pilot study by Noah etal. [56] involving 23 veterans
with PTSD and MDD under pharmacological treatment showed that all participants
experienced signicant reductions in PTSD and MDD symptoms. Notably, active
stimulation signicantly alleviated moderate to severe PTSD symptoms, including
“threshold PTSD” symptom count, PCL score, and QIDS score.
11.2.4.2 Safety
Similar to priming TMS, the safety prole of synchronized TMS requires further
investigation, particularly through randomized controlled trials and comparative
studies with other TMS modalities. Previous studies suggest that synchronized
TMS may cause side effects such as headache and nausea. However, relevant
research remains limited [56].
11.2.4.3 Treatment Regimen
Currently, there is no authoritative recommendation for the use of synchronized
TMS in PTSD treatment. However, the design of prior studies, such as Noah etal.’s
[56], offers valuable insights. In their experiment, participants received either active
or sham synchronized TMS for 4weeks (ve sessions per week), followed by an
optional non-blind synchronized TMS for an additional 4weeks.
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11.2.4.4 Clinical Recommendations
The existing clinical evidence primarily involves populations with comorbid PTSD
and MDD [56]. Given the high comorbidity of these conditions, this body of
research offers signicant implications for PTSD treatment. Further development in
synchronized TMS research, particularly involving larger sample sizes and more
specic patient populations, is urgently needed (see Table11.1).
11.2.5 TBS
Theta burst stimulation (TBS) is a noninvasive brain stimulation technique employed
to modulate neural circuits involved in psychiatric and neurological disorders, offering a novel approach to the treatment of PTSD [57]. TBS modalities primarily
include intermittent theta-burst stimulation (iTBS), accelerated intermittent thetaburst stimulation (AITBS), and bilateral TBS.
iTBS, a relatively recent form of rTMS, is characterized by shorter treatment
durations compared to traditional rTMS protocols. It involves the delivery of bursts
consisting of three high-frequency (50Hz) TMS pulses every 200ms for a duration
of 2s, repeated every 10s in an intermittent manner [58].
AITBS is an advanced variant of noninvasive brain stimulation (NIBS) utilizing
transcranial magnetic stimulation (TMS) to target specic brain regions. This
method delivers multiple TBS sessions per day, each comprising a series of brief
magnetic pulses at a theta frequency (approximately 5Hz) [59].
11.2.5.1 iTBS
Efficacy
iTBS has demonstrated efcacy in treating depression and shows potential for
PTSD intervention. Several studies have reported signicant improvements in
PTSD symptoms, as well as in social, occupational, and depressive functioning,
within 2weeks, with continued progress observed at one-month follow-ups [60].
When compared to conventional rTMS, iTBS may offer a similarly effective yet
more time-efcient treatment option [61]. However, research on iTBS in PTSD
remains limited, and the robustness of these ndings requires further investigation.
Safety
Safety assessments of iTBS in PTSD have been conducted in multiple clinical trials,
with side effects consistent with those observed in rTMS studies, such as mild headaches and discomfort at the treatment site. Although the risk of seizures is low, it
remains a consideration, necessitating vigilant monitoring for patient safety [60].
Overall, current data support iTBS as a safe and well-tolerated treatment modality
for PTSD [61].
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S. Sha et al.
Treatment Regimen
The typical iTBS treatment regimen for PTSD involves delivering magnetic pulses
to the right DLPFC.Protocols vary across studies, but a common approach includes
daily sessions for 10–15days, with each session lasting approximately 3–10min
[60, 61]. To achieve optimal therapeutic effects, a cumulative dose of iTBS over an
extended period may be required.
The DLPFC has been identied as a key target for iTBS in PTSD therapy
[60–62].
In studies investigating iTBS, the stimulation intensity is generally set at 80% of
the resting motor threshold (RMT), with 50Hz bursts delivered at a frequency of
5Hz [58]. Each iTBS session typically involves the administration of 1800 pulses
over 9.5min [60].
Clinical Recommendations
Targeting the right DLPFC for iTBS treatment in PTSD is recommended, as this
region has demonstrated the most consistent efcacy in alleviating PTSD symptoms. The stimulation intensity should be set at 80% of the RMT, with bursts of
50Hz delivered at a frequency of 5Hz. This protocol offers a balanced approach,
optimizing both efcacy and safety. A minimum of 10–15 treatment sessions over
several weeks is typically required to achieve signicant symptom improvements,
with extended treatment durations potentially necessary to sustain therapeutic
benets.
iTBS shows considerable promise as an effective and time-efcient treatment for
PTSD.However, further investigation is essential to rene treatment parameters,
assess long-term efcacy, and identify potential biomarkers predictive of treatment
response.
11.2.5.2 Accelerated iTBS
Efficacy
Research focused on patients with PTSD suggests that AITBS may also be an effective treatment modality [60, 63]. Notably, case reports indicate that AITBS targeting
the DLPFC appears to yield better outcomes for individuals with MDD comorbid
with PTSD [59]. Nonetheless, research in this area remains scarce, and higher-level
evidence is lacking.
Safety
AITBS is generally considered a safe and well-tolerated treatment. Commonly
reported side effects include mild to moderate discomfort at the stimulation site,
headaches, and transient increases in anxiety or depressive symptoms. These side
effects are typically short-lived and manageable, with most patients tolerating the
treatment without signicant adverse events.
Notably, the safety of AITBS for PTSD has not been fully established across all
patient populations. For example, patients with conditions such as epilepsy or metal
implants in the head may face an increased risk of adverse events and should