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synchrony, enabling the customization of stimulation parameters to the individual’s
specic neurophysiological requirements. This combination has shown promise in
enhancing cortical plasticity and improving neural circuit function, particularly in
early-course schizophrenia [81, 84]. The primary focus of sTMS is the DLPFC, a
region implicated in executive function and cognitive processing [82]. A substantial
body of research supports the utilization of sTMS for the enhancement of cognitive
performance and the alleviation of symptoms in cases of treatment-resistant schizophrenia. The underlying mechanisms of action of these protocols are thought to
involve the targeting of gamma oscillations and alpha synchrony, which have been
observed to be frequently disrupted in patients, resulting in improvements in cognitive domains and a reduction in hallucinations [78, 79].
5.2.4.4 Clinical Recommendations
sTMS has been shown to align magnetic pulses with the brain’s natural oscillatory
rhythms, thereby enhancing the precision of brain stimulation. This technique has
shown promise in enhancing gamma oscillations in the DLPFC, leading to enhanced
working memory and auditory processing in patients with schizophrenia. Despite
the effectiveness of this technique, further research is necessary to optimize longterm outcomes and stimulation parameters (Table5.1).
5.2.5 TBS
Noninvasive brain stimulation (NIBS) has been demonstrated to modulate cortical
activity in humans [85]. Notably, a modied form of rTMS known as theta burst
stimulation (TBS) has garnered signicant attention due to its effectiveness in eliciting responses with brief stimulation durations at low intensities [86]. Recently, the
TBS protocol has been proposed as a more efcient method for neuroplasticity
across various clinical rehabilitation contexts. The rTMS waveform is transmitted to
the brain via a magnetic eld generated by a coil positioned over the scalp. This
magnetic eld traverses the skull without obstruction and is ultimately converted
into electrical current, stimulating the underlying brain tissue to facilitate neuroplasticity. Thus, the TBS rTMS waveform promotes neuroplasticity through the
conversion of magnetic to electrical current [86].
In summary, TBS comprises bursts of three pulses delivered at a frequency of
50Hz, with an interburst interval of 5Hz [87]. There are two primary paradigms of
TBS: intermittent theta burst stimulation (iTBS) and continuous theta burst stimulation (cTBS). Variations in stimulation parameters, such as pulse delivery frequency
and dosage (number of pulses), can signicantly inuence the strength and duration
of the after-effects of TBS [88–90]. Research examining plasticity changes induced
by TBS indicates that it is one of the most potent NIBS techniques available for
neuromodulation [85].
rTMS has been explored in patients with schizophrenia to address refractory
auditory hallucinations, cognitive decits, and negative symptoms [91–94]. The
iTBS paradigm has been shown to enhance cortical excitability (inducing long-term
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potentiation), whereas the cTBS paradigm has been associated with a reduction in
cortical excitability (inducing long-term depression) [87].
From a therapeutic perspective, TBS sessions are generally shorter than standard
rTMS protocols. The optimal stimulation parameters remain undetermined,
although tolerability appears comparable to standard rTMS, with increased discomfort reported at higher stimulation intensities. Researchers have expressed interest
in utilizing TBS to treat symptoms of schizophrenia [95]. TBS is a well-tolerated
therapeutic intervention and neurophysiological tool, with potential applications for
targeting specic symptom domains of schizophrenia. Notably, iTBS has shown
promise as an intervention for alleviating negative symptoms of the disorder.
To date, several TBS protocols, including iTBS, have been proposed; however,
previous systematic reviews have highlighted inconsistent efcacy ndings across
individual TBS studies in the context of schizophrenia [96].
5.2.5.1 iTBS
Efficacy
Currently, rTMS has gained signicant traction in psychiatry as a NIBS technique,
with iTBS emerging as a more novel form of rTMS [97]. The iTBS is characterized
by the delivery of 600 pulses within a brief duration of 3min [98]. This method
produces a rapid increase in motor cortex excitability, and its excitatory effects may
surpass those of traditional rTMS [99, 100].
Recently, as TBS paradigms have expanded in the treatment of major depressive
disorder (MDD), researchers have also shown interest in utilizing iTBS to address
symptoms of schizophrenia. The most commonly used theta burst paradigm, iTBS,
delivers triplet burst pulses at a frequency of 50Hz, with bursts occurring every
5Hz. This paradigm has been found to enhance cortical excitability, inducing longterm potentiation [95]. Evidence suggests that the TBS protocol mimics the coupling of theta and gamma rhythms, resulting in alterations in cortical excitability
[87]. One randomized controlled trials (RCTs) study demonstrated a signicant
advantage of active iTBS over sham iTBS in improving neurocognitive performance in older adults with schizophrenia [101].
Additionally, research has indicated that iTBS applied to the left DLPFC is associated with reductions in negative symptom scores, overall symptom scores, Positive
and Negative Syndrome Scale (PANSS) general subscale scores, depressive symptom scores, and anxiety symptom scores, as well as improvements in overall cognitive impairment scores compared to sham treatment [96]. Lisman and Idiart reported
that theta-frequency oscillations modulate high-frequency gamma oscillations,
which are linked to cognitive processing in human recognition memory [102].
Furthermore, by inuencing the intrinsic circuitry of the motor cortex, iTBS
enhances the amplitude of later I-waves and induces long-term potentiation like
changes at synaptic connections within the motor cortex [103, 104].
iTBS paradigms can effectively modulate corticospinal excitability in healthy individuals, resulting in increased excitability with iTBS.A previous study on TBS [105]
found that the potentiating effect of iTBS was greater than the inhibitory effect of
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cTBS.The most pronounced effect sizes for iTBS are typically observed at mid-time
points, specically 20–30min poststimulation. Notably, delivering 1200 pulses of iTBS
at this mid-time point yielded a more substantial effect compared to 600 pulses, whereas
the differences associated with cTBS were relatively marginal [85].
However, research has revealed an unexpected outcome with 1200 pulses of
iTBS at later time points, showing a nonsignicant trend toward motor-evoked
potential (MEP) suppression. This nding suggests that the optimal interval for
iTBS to elicit longer-lasting effects has yet to be determined, and the underlying
mechanisms of action for iTBS remain incompletely understood.
Preliminary evidence indicates that adjunctive iTBS may confer benets in the
treatment of neurocognitive function in older patients with schizophrenia. Future
RCTs with larger sample sizes focusing on the neurocognitive effects of adjunctive
iTBS in this population are warranted to verify these ndings [101].
In summary, the results suggest that iTBS is associated with therapeutic benets
for schizophrenia, particularly in alleviating negative symptoms, depressive symptoms, anxiety symptoms, and cognitive impairment. Larger-scale, long-term studies
on TBS protocols are necessary to evaluate the durability of their effects (e.g.,
through continuation studies).
Safety
To ensure safety, the stimulator was powered by a 5V direct current source, incorporating a 5-s ramp up and ramp down period at the beginning and end of each
session to minimize discomfort for participants [106]. Common adverse events
associated with transcranial magnetic stimulation (TMS) included headache (6.6%),
arm/hand/other pain (2.6%), numbness or tingling (2.6%), other sensations (2.6%),
weakness (1.3%), and miscellaneous events (1.3%) [107].
A previous study found that changes in positive symptom scores, all-cause discontinuation rates, discontinuation rates due to adverse events, incidence of headaches, and incidence of dizziness did not signicantly differ between any TBS
protocols and sham treatments [96].
It is important to note that while the adverse effects reported in the majority of
case reports and clinical trials were limited to mild headaches, fatigue, and minor
neck pain, two case reports documented serious adverse events. The rst involved a
15-year-old who experienced a seizure during an iTBS session [108]. Although seizures are considered a very rare adverse effect of rTMS, their occurrence should not
be underestimated [109]. Adhering to specic safety protocols can minimize, but
not entirely eliminate, this risk. Specically, accurate intensity settings based on
motor threshold (MT) and careful screening of participants for risk factors, such as
a history of epilepsy, should be taken into account [110, 111].
Other researchers found that the side effect prole was generally mild, with the
exception of one incident of hypertension resulting from iTBS [112].
Future studies should systematically collect data on adverse events using standardized rating scales and incorporate long-term follow-up assessments
(6–12 months) to evaluate adverse events, hearing, and neurocognitive outcomes [113].
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Treatment Regimen
The treatment protocol consisted of 20 sessions of iTBS at 80% resting motor
threshold (RMT), delivered over 10 workdays (990 pulses per session, repeated
twice daily) targeting the left DLPFC.Thirty-three trains of iTBS were administered as 10 bursts of stimulation for 2s, followed by an 8-s pause. Each burst comprised three pulses at 50Hz. Previous study reported a signicant reduction in the
Scale for the SANS score in the active group compared with the sham group at the
6-month follow-up [114].
Another treatment protocol involved 10 sessions of iTBS at 80% RMT, also
delivered over 10 workdays (a total of 600 pulses per session). Twenty trains of
iTBS were delivered as 10 bursts of stimulation for 2s, followed by an 8-s pause.
Each burst consisted of three pulses at 50Hz. Researchers observed signicant
improvement in the negative symptoms of patients in the study group compared
with the sham group [115].
In a different protocol, 42 sessions of iTBS were administered at 80% RMT over
14 consecutive days (totaling 600 pulses per session, with 3 sessions per day, and
15min between each session, resulting in 1800 total pulses per day). Twenty trains
of iTBS were delivered as 10 bursts of stimulation for 2s, followed by an 8-s pause.
Each burst comprised three pulses at 50Hz. Both overall and negative symptom
scores improved in the active arm, but not in the sham group [116].
In another study, all patients were scheduled to attend once daily for 4weeks,
totaling 20sessions. For 10 and 20Hz stimulation, the initial stimulation intensity
was set at 80% RMT and gradually increased to 110%. A total of 1500 pulses were
delivered in each session, consisting of 5s of stimulation trains (at either 10 or
20Hz) followed by 30s of rest. The TBS protocol included prolonged iTBS sessions (2400 pulses) delivered at 80% MT.The trains of iTBS were administered as
10 bursts of stimulation for 2s, with each burst comprising three pulses at 50Hz. In
all three active arms of the study, there were signicant decreases in the PANSS and
SANS scores, but not in the sham arm [29].
In a different protocol, the treatment protocol consisted of 10sessions of
iTBS at 100% active motor threshold (AMT), delivered over 5 workdays (a total
of 600 pulses per session, with one session in the morning and another in the
afternoon). Twenty trains of iTBS were administered as 10 bursts of stimulation
for 2s, followed by an 8-s pause. Each burst comprised three pulses at 50Hz.
There was a signicant improvement in negative symptom scores when baseline
measurements were compared with posttreatment and follow-up assessments
(PANSS sub-scores). Furthermore, improvements in mood and cognition were
signicant when comparing baseline with posttreatment and follow-up evaluations [112].
In another study, participants received 3 daily sessions of iTBS treatment, separated by 15min, over a duration of 4weeks. The stimulation parameters included
600 pulses delivered over 189s. The pulses were administered at 50Hz and repeated
at 5Hz. The target area was determined using an MRI-neuro-navigation system.
The study reported a signicant difference in measures of social cognition between
participants in the active and sham groups at both the 2-week and 4-week
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follow-ups. Additionally, there were signicant differences in negative symptom
scores between the active and sham groups, while no signicant differences were
observed in positive symptom scores between the two groups.
In another study, the treatment protocol involved 3 daily sessions of iTBS, separated by 15min, with a total of 1800 pulses delivered per day. The trains of iTBS
were administered as 10 bursts of stimulation for 2s, followed by an 8-s pause, with
each burst consisting of three pulses at 50Hz. This study reported a signicant
effect of active iTBS compared with sham on n-back task performance, particularly
on the 3-back task [117].
Clinical Recommendations
The iTBS-like protocol emits 10 bursts and repeats every 10s. In DC mode, direct
current is delivered with an adjustable intensity ranging from 0 to 3mA, generated
by an adjustable current source and controlled by eight switches along with specic
resistors. The duration of electrical stimulation can be set from 0 to 60min, with
increments of 1min [86].
The most commonly used theta burst paradigm, iTBS, delivers triplet burst
pulses at a frequency of 50Hz, with bursts occurring every 5Hz. This paradigm has
been found to enhance cortical excitability, inducing long-term potentiation [95].
Further research is needed to investigate optimal TBS stimulation parameters, particularly for iTBS, to ensure these paradigms can be effectively translated into clinical settings [85]. The clinical recommendation levels for iTBS still requires further
exploration and consensus (Table5.1).
5.2.5.2 Accelerated iTBS
To improve response rates, accelerated stimulation protocols are currently being
investigated. Unlike traditional daily sessions, which typically extend over
2–4weeks, these accelerated protocols deliver the same number of stimulation sessions within a shorter timeframe. Recently, accelerated iTBS, a form of rTMS that
utilizes bursts of high-frequency stimulation at repeated intervals, has been successfully implemented [118]. This method has been found to elicit rapid clinical
responses after just 4days of stimulation and signicantly shorten the overall duration of the treatment protocol, providing advantages for both patients and caregivers
[98, 119, 120].
However, randomized controlled studies on the effectiveness of a iTBS for
improving social cognition and negative symptoms in individuals with schizophrenia are very limited [100].
In a case series report, accelerated iTBS was delivered to the TPJ over 5days,
with 5 sessions conducted each day, aimed at controlling AVH in three patients
[121]. Two of the patients demonstrated signicant improvement in AVH [95].
Another study found that accelerated iTBS can effectively ameliorate social cognition and negative symptoms in individuals with schizophrenia.
These ndings suggest that accelerated iTBS may be a safe and effective neuromodulation technique for enhancing the overall functional recovery of individuals
with schizophrenia, indicating a promising clinical application [100].
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H. Deng et al.
Efficacy
Research has demonstrated that accelerated iTBS administration can benet individuals with schizophrenia. These accelerated protocols not only have the potential
to treat a larger number of patients within the same timeframe but also to reduce the
frequency of patient visits to rTMS clinics. As a result, this enhances overall accessibility and promotes better treatment adherence [122, 123].
However, no signicant changes were observed in positive symptoms or general
psychopathology [100]. In another study, accelerated iTBS was applied over the left
TPJ for 5days, with 5 sessions per day, aimed at controlling AVH in three patients
[121]. Notably, two of these patients exhibited signicant improvements in
their AVH.
Future studies should explore the long-term effects of accelerated iTBS, considering both the duration of intervention and the intensity of stimulation, on social
cognition and negative symptoms in individuals with chronic schizophrenia.
Safety
The accelerated iTBS protocol demonstrated good tolerability and a favorable
safety prole. Adverse side effects were minimal; notably, no instances of seizures,
fainting, speech difculties, comprehension issues, or cognitive impairments were
observed. The most commonly reported side effect was the occasional mild headache, which typically resolved either spontaneously or after the administration of
acetaminophen [124].
These ndings suggest that accelerated iTBS may improve the overall functional
recovery of individuals with schizophrenia, and that it is a safe and effective neuromodulation technique with good clinical application prospects [100].
Treatment Regimen
Accelerated iTBS was conducted using a Brain Ultimate M-100 transcranial magnetic stimulator (Brain Ultimate, Atlanta, USA) equipped with a 70-mm air-cooled
buttery coil. The parameters for accelerated iTBS included: three pulses per burst,
50Hz bursts, with a 2-s on and 8-s off cycle; totaling 600 pulses per session, resulting in a total duration of 3min and 9s, at an RMT intensity of 120% [99]. Given
that high-dose TBS may induce discomfort in patients [125], the protocol involved
three iTBS rounds per treatment day, separated by 15min (totaling 1800 pulses
per day).
Simultaneously, the TMS Navigation System (Brain Ultimate, Atlanta, USA)
was employed to precisely locate the coil, which was positioned using the Visor 2.0,
tangential to the skull with the handle oriented in a posterolateral direction. The
stimulation target was identied in the left DLPFC, which may serve as an effective
target for individuals with schizophrenia [126]. Treatment sessions were conducted
in a sitting or semirecumbent position, occurring once daily, ve times per week, for
4weeks, culminating in a total of 20sessions. All equipment and parameters were
standardized and calibrated by the manufacturer. During treatment, subjects were
required to wear noise-canceling earplugs and remove all objects sensitive to magnetic elds, including watches, cell phones, jewelry, and metal dentures.
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In a case series report, accelerated intermittent iTBS was administered over the
left TPJ for 5days, with 5 sessions each day, to control AVH in three patients [121].
Each session comprised 1800 pulses delivered over 2min, with bursts of stimulation at 50Hz repeated every 200 ms. The target location was determined using
neuronavigation. Notably, two patients, who had experienced only one antipsychotic treatment failure, demonstrated signicant improvement in their AVH [121].
Previous study also found that accelerated iTBS can effectively improve social
cognition and alleviate negative symptoms in individuals with schizophrenia [100].
Clinical Recommendations
To date, the most rapid iTBS (left DLPFC) treatment protocol is the Stanford
Neuromodulation Therapy (SNT) [127]. This protocol involves 10sessions of iTBS
(left DLPFC) delivered daily, culminating in a total of 18,000 pulses per day (i.e.,
equivalent to the total number of pulses in the conventional 6-week iTBS protocol)
over 5 consecutive days [123, 127]. The levels of clinical recommendation for
accelerated iTBS require further investigation and consensus (Table5.1).
5.2.5.3 Continuation TBS
Efficacy
TBS protocols, developed patterns of rTMS, exhibit an excitatory effect when the
stimulation is intermittent (iTBS) and a suppressive effect when the stimulation is
continuous (cTBS). cTBS, a rened paradigm of rTMS, has been shown to offer
greater clinical benets compared to traditional rTMS methods, demonstrating
more profound and lasting effects on cortical excitability. This enhanced efcacy is
attributed to its lower intensity, fewer pulses, and shorter stimulation duration [128,
129]. The suppressive effect of cTBS on cortical excitability is achieved by deliver-
ing three pulses at 50Hz, repeated every 200ms for a total duration of 40s, at an
intensity of 80% of the AMT [130].
In a previous study investigating the safety and tolerability of TBS, the safety,
tolerability, and antidepressant efcacy of cTBS targeting the right DLPFC were
validated. This was accomplished using various stimulation protocols ranging from
600 to 900 stimuli per train, resulting in a total of 1200–3600 stimuli per session
[131]. Additionally, it has been observed that repeating the cTBS sequence after
15min can signicantly extend the duration of its effects [132, 133].
One study demonstrates that both cTBS and rTMS can reduce symptoms of
schizophrenia-related AVH; however, cTBS generally provides greater therapeutic
benets. cTBS was associated with more signicant improvements in clinical
symptoms, as assessed by the PANSS and the Auditory Hallucination Rating Scale
(AHRS), as well as in cognitive functions evaluated by the MATRICS Consensus
Cognitive Battery (MCCB). Additionally, cTBS treatments resulted in increased
serum levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived
neurotrophic factor (GDNF), with a more notable increase observed following
cTBS [132]. The cTBS paradigm has also been found to decrease cortical excitability, inducing long-term depression [87].
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H. Deng et al.
Safety
cTBS was demonstrated to be well tolerated, and notably, no adverse events or serious adverse events were reported [113].
Moreover, cTBS treatment did not result in an elevation in the occurrence of
adverse events, nor did it cause an increase in treatment discontinuations due to any
reason. This clearly suggests that cTBS is not only safe but also well tolerated when
it comes to the treatment of auditory hallucinations [134].
Treatment Regimen
The previous study employed a cTBS intervention consisting of 25 sessions delivered over 5 consecutive days to the left primary motor cortex (M1 area), dened as
the point of maximal stimulation of the abductor pollicis brevis. Each cTBS session
involved a total of 600 pulses delivered over 200 bursts, utilizing a protocol of
50Hz bursts of three pulses every 200ms for a duration of 40s, with an intensity
set at 80% of the individual RMT.The RMT intensity was measured as the minimum stimulus required to induce contraction of the right thumb at least ve out of
ten times. The study demonstrated the feasibility and potential of cTBS intervention
as an effective preventive measure against olanzapine-induced weight gain by
enhancing cognitive restraint in eating behavior among drug-naive rst-episode
individuals with schizophrenia [135].
Researchers also found that when the number of stimulation sessions exceeded
10 and the total number of pulses surpassed 6000, cTBS treatment could signicantly improve auditory hallucination symptoms in patients. This nding underscores the importance of appropriate parameters in determining the clinical efcacy
of cTBS for the treatment of auditory hallucinations.
In a case involving a patient with very late-onset schizophrenia-like psychosis,
cTBS was applied over the TPJ, specically at TP3 (an area between the T3 and P3
electrodes). A MagPro X100 stimulator was used to deliver the stimulation with a
gure-eight coil (MCF-B65) for 10 working days. During the rst 3days, the cTBS
group received two double trains of stimulation (with a 15-min interval), while from
days 4 to 10, they received one double train. Each train consisted of 801 pulses
delivered in 267 bursts, with each burst comprising three pulses at 30Hz, repeated
every 100ms, and delivered at 90% of the RMT.The researchers reported that the
stimulation facilitated the effects of medication and reduced AVH.They speculated
that cTBS may serve as a benecial adjunct to pharmacological treatment to enhance
its efcacy [136].
In another case report, the effects of 1 Hz rTMS and cTBS on AVH were
described [137]. A 40-year-old female patient suffering from AVH initially received
1Hz rTMS twice daily for 10days, but no improvement was observed in her symptoms. After 1month, cTBS was applied over electrode TP3 (approximately located
at the temporoparietal cortex), following a similar regimen as rTMS, for 10days at
2sessions per day. A MagPro R30 stimulator delivered the stimulations via a gureeight coil (MCF-B65) over 10 working days. She received double trains of stimulation with a 30-min interval between them. Each train consisted of 600 pulses
delivered in 200 bursts, each comprising three pulses at 30Hz, repeated every
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200ms. The cTBS sessions were applied at 80% of the RMT.After the 16th treatment, the patient reported complete suppression of AVH for several hours, and by
the ninth day of treatment, she noted a signicant reduction in her AVH symptoms.
Following the treatment, she received maintenance sessions and reported very low
AVH scores (below 5) [137].
In another study, the stimulations were delivered at a 48-h interval, and the
stimulation site was determined based on the 10–20 EEG system. The iTBS
treatment and sham protocols consisted of a single session at 80% RMT, totaling 600 pulses. The 20 trains of iTBS were delivered as 10 bursts of stimulation
over 2s, followed by 8s off. Each burst comprised three pulses at 50Hz and was
repeated every 200ms. The cTBS group received one train of stimulation at
100% RMT, consisting of 801 pulses delivered in 267 bursts, with each burst
comprising three pulses at 30Hz, repeated every 100ms. The authors reported
that cTBS resulted in a meaningful and signicant difference compared to sham
stimulation, along with improvements in manual dexterity [95]. To explore
motor responses in adolescent patients with schizophrenia, transcranial magnetic stimulation-electromyography (TMS-EMG) was used to measure the MEP
responses in 20 patients and 20 healthy control individuals before and after
receiving cTBS and iTBS [138]. While both iTBS and cTBS produced excitatory and inhibitory plastic effects, the inhibitory effect of cTBS in patients was
reported to be signicantly larger compared to the healthy control group,
whereas the excitatory effect of iTBS was signicantly lower in the patient
group compared to healthy control.
Auditory hallucinations are the most commonly occurring psychotic symptoms
in schizophrenia. cTBS has been employed as an adjunctive treatment for these
hallucinations.
Subgroup analyses revealed that patients receiving adjuvant cTBS for more than
10stimulation sessions, with a total number of pulses exceeding 6000, experienced
statistically signicant improvements in their hallucination symptoms. Each cTBS
session was conducted at an intensity of 80% of the RMT, at a frequency of 5Hz,
lasting for 40s. Each stimulation consisted of three bursts at 50Hz, amounting to a
total of 600 pulses, which resulted in a session duration of 15min. Participants
underwent a 15-min rTMS session ve times per week for 4weeks.
Overall, cTBS provides greater therapeutic benets compared to rTMS.It was
associated with more signicant improvements in clinical symptoms, as assessed by
the PANSS and the AHRS, as well as in cognitive functions evaluated by the
MCCB.The cTBS group generally exhibited a higher therapeutic effect than the
rTMS group.
Clinical Recommendations
cTBS is a form of continuous transcranial stimulation that emits 10 bursts and
repeats every 2s. cTBS involves uninterrupted TBS trains lasting 20s (300 pulses)
or 40s (600 pulses) and has been shown to decrease cortical excitability for up to
60min [87]. Researchers also found that when the number of stimulation sessions
exceeded 10 and the total number of pulses surpassed 6000, cTBS treatment could
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signicantly improve auditory hallucination symptoms in patients. The cTBS utilizes a protocol of 50Hz bursts or 30Hz bursts. The levels of clinical recommendation for cTBS require further investigation and consensus (Table5.1).
5.2.5.4 Bilateral TBS
Efficacy
To enhance the efcacy and efciency of rTMS for auditory hallucinations, researchers provided initial evidence for the effectiveness of continuous bilateral theta-burst
stimulation, a patterned form of rTMS that exerts its inhibitory effects after a signicantly shorter stimulation period (40s) compared to the commonly applied 1Hz
rTMS (10–30min) [139]. Additional case studies [137, 140, 141], case series [142],
comparisons with 1-Hz rTMS [143], and a sham-controlled pilot study [144] indicate an even larger effect size.
In this rst controlled pilot study, some of the time saved by the shorter cTBS stimulation trains was utilized for a sequential bilateral treatment approach. Stimulation of the
right temporoparietal area through sequential bilateral stimulation was included to
address the hypothesis that right temporoparietal hyperactivity may also contribute to
the genesis of auditory hallucinations (AH) [39]. After 3weeks (15 sessions) of blinded
treatment involving 16 patients, an analysis of covariance with baseline scores on the
Psychotic Symptom Rating Scale—Auditory hallucinations (PSYRATS-AH) as a
covariate revealed a statistical trend toward a reduction in AH with bilateral cTBS compared to sham stimulation. This nding suggests the efcacy of bilateral cTBS in treating AH.However, a recent trial did not nd signicant differences between left unilateral
cTBS and sham treatment after a 5-day regimen (two treatments with a 30-min break)
in a group of 71 patients with AH [145]. Therefore, the 15 sessions of once-daily bilateral cTBS are likely to be more effective [144]. Nevertheless, the equal or additional
benets of right temporoparietal [146, 147] or bilateral [39] TMS have not yet been
convincingly demonstrated [148].
The brief stimulation trains of cTBS [145] allow for bilateral application, which may
enhance the treatment effects, particularly in light of ndings from imaging studies [39].
The 3-week treatment period is based on the results of a pilot study [144], which demonstrated that extending the treatment duration did not signicantly improve the efcacy
of cTBS.Another study found that reducing stimulation time to less than 2 min for
bilateral stimulation could signicantly enhance its practicality.
This evidence supports the notion that the bilateral application of cTBS represents an innovative, briefer, and potentially more effective stimulation paradigm
compared to placebo stimulation.
Safety
Studies have demonstrated that the short-term application of bilateral TBS-DBS is
not only safe but also effective [149]. In a recent controlled clinical trial using bilateral cTBS, researchers have demonstrated that theta burst stimulations of the temporal and temporoparietal cortex are safe with respect to hearing and speech
perception [148].