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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5250_Библиотеки_им_академика_М_И_Перельмана.pdf
5 Schizophrenia
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RCTs randomized controlled trials
RMT resting motor threshold
rTMS repetitive transcranial magnetic stimulation
SANS Scale for the Assessment of Negative Symptoms
SNT Stanford Neuromodulation Therapy
sTMS synchronized transcranial magnetic stimulation
TBS theta burst stimulation
tDCS transcranial direct current stimulation
TMS transcranial magnetic stimulation
TMS-EMG transcranial magnetic stimulation-electromyography
TP3 An area between the Left Temporal 3 electrode and Left Parietal
3 electrode
TPC temporal–parietal cortex
TPJ temporoparietal junction
5.1 Schizophrenia
Schizophrenia is a highly debilitating psychiatric condition with a global lifetime
prevalence of around 1% [1, 2]. The disorder typically appears in early adulthood
and is characterized by ve primary dimensions: positive symptoms, negative
symptoms, cognitive decits, anxiety and depression, and aggressive behavior [3].
Cognitive impairment, which includes difculties with executive function, working
memory and cognitive processing, has a signicant impact on patients’ social functioning and overall disease prognosis in schizophrenia [4]. A substantial body of
evidence has emerged to support the efcacy of transcranial magnetic stimulation
and transcranial direct current stimulation in the treatment of schizophrenia.
However, the optimal stimulation parameters for each disorder are unknown.
Antipsychotic medications are the prevailing treatment for schizophrenia. While
these medications have been shown to be effective in mitigating the positive symptoms of schizophrenia, such as delusions and hallucinations, their efcacy is limited
in addressing the negative symptoms and cognitive impairments associated with the
illness. Notably, a considerable number of patients exhibit treatment-resistant
schizophrenia and do not adequately respond to antipsychotic drugs. In addition, the
adverse effects of antipsychotics may lead to reduced adherence in some patients
with schizophrenia.
In such cases, noninvasive brain stimulation, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), can be promising
treatment options. TMS is a technique that utilizes a magnetic eld to generate an
electric current in a specic region of the brain. This process is initiated by the
application of a pulsed magnetic eld over the scalp. The resulting electric eld
modulates neuronal activity in the targeted area. tDCS entails the application of a
weak electrical current through two or more electrodes positioned on the scalp, with
the purpose of stimulating underlying brain tissue. A substantial body of evidence
has emerged to support the efcacy of TMS or tDCS in the treatment of
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schizophrenia. The biological mechanisms underlying the effects of TMS and tDCS
on neuropsychiatric disorders are intricate and not fully understood. However, the
optimal stimulation parameters for schizophrenia remain to be elucidated. Therefore,
this chapter aims to provide a comprehensive review of the extant literature on the
efcacy and safety of TMS and tDCS paradigms for patients with schizophrenia by
systematically identifying and reviewing relevant studies in the eld.
H. Deng et al.
5.2 TMS
5.2.1 rTMS
5.2.1.1 Unilateral rTMS
Efficacy
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that has been used in psychiatry for its therapeutic potential.
Introduced in the mid-1980s, rTMS has gained recognition as a treatment for major
depression [5] and has also been investigated as a potential intervention for patients
with schizophrenia [6, 7]. The rst randomized controlled trials investigating the
efcacy of unilateral rTMS in schizophrenia patients for both positive and negative
symptoms were conducted in the late 1990s [8]. However, the application of 1Hz
rTMS to right dorsolateral prefrontal cortex (DLPFC) (1200 total pulses) did not
produce any therapeutic benet. Subsequent research has modied the target site
and stimulation frequency for unilateral rTMS in the treatment of schizophrenia. A
recent meta-analysis suggests that targeting the left DLPFC with stimulation frequencies above 1Hz may produce superior therapeutic outcomes [9]. To be noted,
a meta-analysis also found that working memory in schizophrenia could be signicantly improved by high-frequency rTMS (HF-rTMS) over the left DLPFC [10].
Unilateral rTMS shows promise as a viable treatment option for schizophrenia
patients with both positive and negative symptoms, although the optimal parameters
for rTMS therapy remain to be established.
Safety
In addition to efcacy, the safety of rTMS in schizophrenia has been evaluated
in numerous clinical trials and meta-analyses [11–13]. In terms of safety, unilateral rTMS has been shown to be a noninvasive and safe method of brain stimulation for schizophrenia, with minimal serious adverse effects. Commonly
reported side effects include mild headache and localized scalp discomfort,
which have been documented in the majority of studies [14, 15]. Mild headache
can usually be relieved with oral analgesics such as paracetamol. Currently,
HF-rTMS, rather than low-frequency rTMS (LF-rTMS), may be a viable treatment option for schizophrenia. The safety and tolerability of HF-TMS is receiving increasing attention from researchers. HF-rTMS over the DLPFC has been
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shown to be safe and tolerable in some recent clinical trials and systematic
reviews on the safety of rTMS [16, 17].
Apart from mild headache and discomfort, seizures are a major reason for discontinuation of rTMS treatment in patients with schizophrenia. According to a
meta-analysis of safety evaluations of rTMS treatments in neuropsychiatric disorders, the odds of having a seizure were 4.7 times higher with TMS compared to
sham stimulation [18]. This suggests that TMS should be considered with caution,
with close monitoring for possible adverse effects and further research into the
safety of TMS.
Treatment Regimen
Most studies fall into two stimulation camps regarding the efcacy of unilateral
rTMS in schizophrenia. The rst camp is stimulation of the temporal–parietal cortex (TPC) for the improvement of auditory hallucinations, which are a cardinal
symptom of schizophrenia. Hoffman etal. found that persistent auditory hallucinations were signicantly improved with a 1Hz rTMS protocol [12], and this phenomenon was reproducible [19, 20]. However, unilateral rTMS targeting the TPC
did not show a signicant effect in the active rTMS group compared to the sham
group in certain clinical trials [21, 22]. The variability of ndings regarding the
efcacy of unilateral rTMS has necessitated further investigation of alternative
parameters for this treatment modality.
The second camp targets negative symptoms or cognitive dysfunction by stimulating the DLPFC.Cohen etal. found that negative symptom scores and cognitive
performance could be signicantly reduced by 20 Hz rTMS targeting the left
DLPFC [23]. A similar benecial effect of unilateral rTMS, and a specicity of
stimulation frequency, has been observed in subsequent studies [24–26]. However,
similar to the inconsistencies in TPC, some studies have shown inconsistent replication in DLPFC [27, 28]. Therefore, the challenge of interpreting the inconsistent
ndings persists, suggesting that advancements in technology may offer a potential
solution.
Clinical Recommendations
Table 5.1 shows the clinical recommendation levels for this regimen. In favor of a
possible benet of low-frequency unilateral rTMS of the TPC on negative symptoms and auditory hallucinations, it seems reasonable to give a level C
recommendation.
5.2.1.2 Bilateral rTMS
Efficacy
Bilateral rTMS has been investigated as a potential treatment for schizophrenia
in addressing both positive and negative symptoms. Unlike unilateral rTMS,
which targets a single hemisphere, bilateral rTMS stimulates both hemispheres,
often focusing on the DLPFC.Studies suggest that bilateral rTMS may offer
enhanced therapeutic outcomes compared to unilateral rTMS, particularly for
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Levels+referencesTarget Frequency Length (min)
Duration
(sessions)
H. Deng et al.
[23–26, 29–34]
[12, 19, 20, 35]
Clinical recommendations
Left TPC 1Hz 20 10–12 Third-line
Auditory-verbal
hallucinations
10 or 20 10 (twice daily) Third-line [40–45]
LF (1Hz) 16 15 Third-line [39]
LF (1Hz) or HF
Wernicke’s and right
homologous regions
Left or bilateral TPJ;
Auditory-verbal
hallucinations
20 10, 20 Third-line [49, 50]
(20Hz)
HF (20Hz) 15 20 Third-line [46–48]
6Hz (priming)
and 1Hz
the temporoparietal
area
PFC
Left temporoparietal
region
hallucinations
hallucinations
(treatment)
TMS
Table 5.1 Clinical recommendations of TMS in schizophrenia
Unilateral rTMS Negative symptoms Left DLPFC 10–20Hz 20 10–20 Third-line
Bilateral rTMS Negative symptoms Bilateral DLPFC HF (10 or 20Hz) 20 20, 30 Third-line [24, 36–38]
Accelerated rTMS Auditory-verbal
Deep TMS Negative symptoms Left DLPFC; bilateral
Priming TMS Auditory-verbal
Synchronized TMS Unclear Unclear Unclear Unclear Unclear N/A
TBS Unclear Unclear Unclear Unclear Unclear N/A
iTBS Unclear Unclear Unclear Unclear Unclear N/A
Accelerated iTBS Unclear Unclear Unclear Unclear Unclear N/A
Continuation TBS Unclear Unclear Unclear Unclear Unclear N/A
Bilateral TBS Unclear Unclear Unclear Unclear Unclear N/A
MST Unclear Unclear Unclear Unclear Unclear N/A
Abbreviations: N/A not applicable, rTMS repetitive transcranial magnetic stimulation, TMS transcranial magnetic stimulation
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reducing negative symptoms, which are often resistant to other treatments.
Some studies found that bilateral stimulation of the prefrontal cortex signicantly improved working memory performance and reduced negative symptoms
as measured by the Scale for the Assessment of Negative Symptoms (SANS)
[24, 36, 51]. Additionally, another study also demonstrated that bilateral pre-
frontal rTMS may improve negative symptoms in that it can normalize an
increased brain response to ambiguous emotional stimuli [37]. However, not all
studies report consistent results, with some showing no signicant differences
between bilateral and unilateral or sham treatments [38, 52], especially for positive symptoms such as auditory hallucinations [40, 41, 53].
Safety
Most adverse effects associated with bilateral rTMS are transient and mild. For
example, a study on HF-rTMS reported no severe adverse reactions, with only a
small percentage of patients discontinuing due to discomfort such as persistent
headaches [38, 52]. However, like any therapeutic intervention, it is essential to
understand the potential risks and side effects associated with its use. The most
frequently reported side effects of bilateral rTMS are twitching of the facial muscles
during rTMS stimulation and transient, mild headache after rTMS stimulation [24].
These sensations are typically benign and diminish shortly after the session concludes [40]. Additionally, although the overall risk of seizures with rTMS is low, it
remains one of the most serious potential side effects. Bilateral rTMS has been
associated with a slightly increased risk of seizures compared to sham stimulation,
but this risk is generally very low, especially when patients are carefully screened
for seizure risk factors prior to treatment [13].
Treatment Regimen
Most studies on bilateral rTMS for schizophrenia focus on two primary areas of
stimulation: the DLPFC and, less commonly, the TPC.These studies aim to address
both positive symptoms, such as auditory hallucinations, and negative symptoms,
such as cognitive decits and emotional withdrawal. The DLPFC is commonly targeted for alleviating negative symptoms such as emotional withdrawal, lack of
motivation, and cognitive impairments. Studies have employed high-frequency
stimulation (usually 10–20 Hz) applied bilaterally to the DLPFC. For example,
some studies have shown a signicant reduction in negative symptom severity after
patients received 3weeks of 10 Hz bilateral rTMS treatment, compared to sham
treatment [24, 36]. However, the results of another study suggest that HF-rTMS
(20 Hz) targeting the bilateral DLPFC does not alleviate negative symptoms in
patients with schizophrenia [38]. Bilateral rTMS targeting the TPC has also been
explored for treating persistent auditory hallucinations, a prominent positive symptom of schizophrenia. However, a study showed that rTMS of the left temporoparietal region appeared more efcient in reducing auditory hallucinations when
compared to bilateral or sham stimulation [54].
Taken together, despite some promising ndings, the efcacy of bilateral rTMS
for schizophrenia remains variable across studies. Some trials have reported
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H. Deng et al.
signicant improvements, while others have shown limited or no effect compared to
sham treatments. This variability highlights the need for further research to optimize stimulation parameters, such as frequency, intensity, and session duration, to
achieve more consistent outcomes [38].
Clinical Recommendations
As the DLPFC is implicated in the negative symptoms of schizophrenia, the use of
bilateral rTMS with high-frequency stimulation (10–20Hz) to this region may be
effective in reducing symptoms such as cognitive impairments and emotional withdrawal. Table5.1 shows the clinical recommendation levels for this regimen.
5.2.1.3 Accelerated rTMS
Efficacy
Accelerated rTMS is an emerging technique aimed at enhancing the therapeutic
effects of standard rTMS by increasing the frequency and intensity of treatment sessions. They can provide the same number of sessions and pulses as a traditional
6-week treatment course in just 1week because of the increased number of daily
stimulation sessions, which may accelerate treatment response and enhance treatment outcomes [55]. The efcacy of accelerated rTMS in treating schizophrenia,
particularly for alleviating negative symptoms and cognitive impairments, has been
explored in several studies. Some studies showed that LF-rTMS (2 sessions/day) to
the left temporoparietal cortex signicantly improved hallucinatory symptoms in
patients with schizophrenia [42, 56]. Studies with HF-rTMS treatment targeting the
temporoparietal junction (TPJ) also showed signicant improvement in hallucinatory symptoms [43], while some studies showed no signicant improvement [44,
45]. Another study exploring accelerated rTMS for the treatment of negative symp-
toms showed signicant improvement in the majority of patients who received 3–5
sessions of treatment per day [57]. This suggests that accelerated rTMS holds promise as a faster-acting intervention compared to conventional rTMS schedules, especially for patients with treatment-resistant symptoms.
However, there are also ndings that auditory verbal hallucinations (AVH) in
patients with schizophrenia did not signicantly improve with LF-rTMS treatment
targeting the TPJ [40]. A study using intensive cerebellar intermittent theta burst
stimulation (iCiTBS) in a treatment-resistant schizophrenia patient has found similar results, with no signicant difference in schizophrenia psychopathology, cognitive functions, and global improvement between active and sham treatment [58].
Therefore, there remain gaps in understanding the long-term efcacy and optimal
protocols for accelerated rTMS in schizophrenia.
Safety
Studies demonstrate that accelerated rTMS, which involves multiple daily sessions,
is generally well-tolerated. Common side effects include mild headaches and scalp
discomfort, with no signicant reports of serious adverse effects like seizures [56,
59]. In a comprehensive review, Cauleld etal. highlighted that increasing session
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frequency does not signicantly elevate the risk of adverse outcomes, making accelerated rTMS comparable in safety to standard protocols [55]. Additionally, an openlabel study by Sverak etal. found that accelerated rTMS was well-received, with
most patients showing no serious side effects [57]. The consensus across studies is
that accelerated rTMS can be safely implemented in schizophrenia treatment, offering faster symptom alleviation without compromising patients’ safety [60]. These
ndings demonstrate the potential of accelerated rTMS as an efcient therapeutic
tool in psychiatric treatment, particularly for patients needing more rapid
interventions.
Treatment Regimen
In an accelerated protocol, sessions are often scheduled twice or thrice daily for up
to 5days per week, resulting in a total of 20–30 sessions over 2–3weeks [24, 36,
40, 42, 43, 45, 55, 56]. Similar to other rTMS treatment regimens, the main targets
of accelerated rTMS are the DLPFC for negative symptoms of schizophrenia [24,
36, 57] and the TPJ for hallucinatory symptoms [40, 42, 43, 45, 56].
Clinical Recommendations
Accelerated rTMS shows promise as a faster alternative to traditional rTMS protocols, offering a condensed treatment course with 2–5 sessions per day over a span
of 1–2weeks. This approach is particularly benecial for patients with treatmentresistant symptoms, such as negative symptoms and cognitive impairments, as studies have demonstrated signicant improvements in these domains. More importantly,
given its potential to accelerate symptom alleviation without increasing adverse
outcomes, it is recommended for patients requiring more rapid intervention.
Table5.1 shows the clinical recommendation levels for this regimen.
5.2.2 Deep TMS
5.2.2.1 Efficacy
Compared with traditional TMS, deep transcranial magnetic stimulation (dTMS)
can target deeper and larger brain regions, making it a very promising treatment
option [61–63]. The rst study to apply dTMS to the treatment of schizophrenia
showed signicant improvement in negative symptoms and cognitive function after
patients received 4weeks of dTMS treatment [46]. Some subsequent studies have
also demonstrated improvements of negative symptoms and cognitive decits in
schizophrenia with dTMS treatment [47, 48]. However, in the study by Rabany
et al., there was no signicant between-group difference in the improvement of
negative symptoms [48]. In other studies, no signicant reduction in negative symptoms was observed in either active or sham treatment groups [64, 65].
Another key area of research is the use of dTMS for positive symptoms, such as
hallucinations. Rosenberg etal. conducted an open-label study using dTMS over the
left temporoparietal cortex, which exhibited no signicant reductions in auditory
hallucinations after treatment [65]. Conversely, the study by Rabany et al.
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H. Deng et al.
demonstrated a positive shift in positive symptoms following dTMS treatment [48].
However, no signicant between-group differences were observed in either study.
5.2.2.2 Safety
The safety of dTMS in treating schizophrenia has been the subject of extensive
research. The consensus across numerous studies is that dTMS is generally
well-tolerated, with few severe adverse events. The most commonly reported
adverse effects are typically mild, including headaches, scalp discomfort and
transient fatigue and are consistent with those reported in other noninvasive
brain stimulation techniques such as traditional rTMS [46, 66]. Importantly,
dTMS has not been associated with an increased risk of seizures or cognitive
impairments, even in patients receiving daily treatments for extended periods
[61, 65]. Studies focusing on schizophrenia have conrmed the safety of dTMS,
particularly when used as an add-on therapy for improving negative symptoms
and auditory hallucinations. Patients receiving dTMS reported minor and reversible side effects, while serious complications remained rare across trials [48,
67]. Overall, the safety prole of dTMS is favorable, with most studies support-
ing its continued use as a noninvasive and effective option for treating schizophrenia symptoms, especially when traditional pharmacological treatments
have proven insufcient.
5.2.2.3 Treatment Regimen
The treatment regimen of dTMS in schizophrenia is typically characterized by
a standardized protocol that is designed to target negative symptoms and cognitive impairments. Most studies utilize high-frequency (typically 10–20 Hz)
dTMS applied to the DLPFC, an area implicated in the negative and cognitive
symptoms of schizophrenia [46–48]. The treatment is typically administered in
the form of daily sessions, with each session lasting approximately 20min, over
a period of 2–5weeks. This results in a total of 15–30 sessions. Additionally,
several studies have explored the use of low-frequency dTMS over regions like
the TPJ to reduce auditory hallucinations, another key symptom of schizophrenia [68, 69]. Patients undergoing this protocol receive 1Hz stimulation for
about 20min per session [65]. This approach has shown efcacy, particularly in
treatment-resistant patients who did not respond to antipsychotic medications.
The efcacy of dTMS is contingent on various factors, including the frequency
of stimulation, the location of the stimulation site, and the duration of the treatment regimen. However, a substantial body of research has reached a consensus
that the most substantial effects in terms of the reduction of schizophrenia
symptoms are observed in cases where the treatment is administered over an
extended period of time [61, 66, 67].
5.2.2.4 Clinical Recommendations
The capacity of dTMS to access deeper brain regions in comparison to conventional
TMS makes it a suitable option for patients exhibiting treatment-resistant
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symptoms. The clinical recommendation levels for this regimen are shown in
Table5.1. However, further exploration and validation in studies with larger samples are required to fully explore its specic treatment protocols and effects.
5.2.3 Priming TMS
5.2.3.1 Efficacy
Priming TMS is dened as the application of high-frequency stimulation (typically
6–10Hz) prior to LF-rTMS.The purpose of priming is to enhance cortical excitability and thereby augment the therapeutic effects of rTMS [70]. This approach is
designed to modulate cortical excitability and increase the therapeutic effects of
subsequent LF-rTMS, which is known to reduce the cortical hyperactivity associated with schizophrenia symptoms like auditory hallucinations [48, 52].
Studies indicate that priming before LF-rTMS enhances the depressant effect on
cortical excitability, making it more effective in reducing both positive and negative
symptoms in schizophrenia patients [67, 70]. The enhanced cortical plasticity
induced by the priming protocol is believed to potentiate the effects of LF-rTMS,
leading to more sustained symptom relief [49]. However, other studies have found
that priming TMS did not improve treatment response in patients with treatmentresistant schizophrenia, particularly in reducing auditory hallucinations and cognitive dysfunction [50].
5.2.3.2 Safety
The safety prole of priming TMS in treating schizophrenia has been widely studied, with the majority of ndings indicating that it is a safe, well-tolerated intervention. Studies consistently report that this approach does not increase the risk of
serious adverse effects such as seizures, which are a major concern with some
neurostimulation techniques [70, 71]. Common side effects associated with priming
TMS include mild headaches, scalp discomfort, and temporary fatigue, all of which
typically resolve shortly after treatment and are consistent with traditional rTMS
protocols [50, 72]. Importantly, long-term studies indicate that repeated sessions of
priming TMS do not lead to cognitive impairments or neurological complications,
even when administered over multiple weeks or at higher intensities [73]. Given the
relatively mild and transient nature of the side effects, priming TMS continues to be
considered a safe alternative or adjunct treatment for patients with schizophrenia.
5.2.3.3 Treatment Regimen
The treatment regimen for priming TMS in schizophrenia typically involves a twophase protocol aimed at enhancing the efcacy of LF-rTMS [70]. The priming TMS
protocol consists of an initial “priming” stimulation phase of HF-rTMS (6–10Hz),
followed by low-frequency (1Hz) stimulation applied to specic cortical regions,
such as the DLPFC or TPJ.The treatment regimen generally comprises daily sessions over a period of 2–4 weeks, with each session lasting approximately
110
20–30 min. The high-frequency priming phase is scheduled to last for approximately 10min, followed by 20min of low-frequency stimulation [73].
H. Deng et al.
5.2.3.4 Clinical Recommendations
The administration of priming TMS has been demonstrated to enhance cortical
excitability and promote symptom alleviation in individuals diagnosed with schizophrenia. The clinical recommendation levels for this regimen are shown in Table5.1.
This approach is generally safe, with mild side effects such as headaches and scalp
discomfort. While effective for many, responses may vary, particularly in treatmentresistant cases.
5.2.4 Synchronized TMS
5.2.4.1 Efficacy
Synchronized transcranial magnetic stimulation (sTMS) is an innovative neuromodulation technique that involves delivering magnetic pulses synchronized to the
brain’s intrinsic oscillatory rhythms. This method aims to improve the precision of
brain stimulation by aligning with the individual’s natural cortical activity, making
it a promising intervention for schizophrenia [74]. Patients diagnosed with schizophrenia have been shown to exhibit impaired cortical inhibition of gamma oscillations in the DLPFC when compared to both healthy subjects and patients diagnosed
with bipolar disorder [75–77]. Studies have shown that sTMS signicantly enhances
gamma oscillations in the frontal cortex, leading to improvements in working memory and auditory processing, both of which are compromised in schizophrenia
patients [78, 79]. However, further research is required to optimize long-term outcomes and to determine the most effective stimulation parameters.
5.2.4.2 Safety
sTMS, being synchronized to the patient’s brain oscillations, is designed to optimize efcacy while minimizing overstimulation, thereby reducing the risk of
adverse effects [80, 81]. The most common side effects, such as mild headaches or
scalp discomfort, tend to be transient and resolve shortly after the treatment session
[75]. The risk of more serious side effects, such as seizures, remains low with sTMS,
which aligns with the safety prole seen in traditional TMS protocols. A substantial
body of research, encompassing trials on treatment-resistant schizophrenia, reports
an absence of major neurological complications, even with extended or frequent
sessions [82, 83]. Overall, sTMS provides a favorable safety prole with minimal
side effects, supporting its ongoing use in the treatment of schizophrenia symptoms.
5.2.4.3 Treatment Regimen
The treatment regimen for sTMS typically involves the delivery of pulses synchronized to the brain’s natural oscillatory frequencies, which has been demonstrated to
enhance the effect of TMS.By synchronizing the magnetic pulses with the patient’s
cortical activity, sTMS provides real-time feedback on cortical excitability and