Advances and Challenges in Neuromodulation Therapies for

Post-Traumatic Stress Disorder: A Comparative Analysis of Direct

Stimulation and Neurofeedback Approaches

Xing Yan

Eleanor Roosevelt College, University of California San Diego, San Diego, 92093, U.S.A.

Keywords: Post-Traumatic Stress Disorder (PTSD), Transcranial Magnetic Stimulation (TMS), Decoded Neurofeedback

(DecNef).

Abstract: The number of people with Post-Traumatic Stress Disorder (PTSD) has increased as a result of global wars

and the instability of contemporary society, which affects daily life in minor cases and may even be life-

threatening in serious cases. In this situation, it is urgent to research and improve the methods of treatment of

PTSD. This paper explores the effects and limitations of two neuromodulation approaches: direct stimulation

and non-invasive neurofeedback training. According to a review of several trails, core PTSD symptoms were

successfully reduced by high frequency transcranial magnetic stimulations (TMS) directed at the right

dorsolateral prefrontal cortex (DLPFC), although its effects are short-term and lack long-term data. Non-

invasive neurofeedback training, by modulating brain regions such as the DLPFC and amygdala, enhances

emotional regulation and mitigates PTSD symptoms, with decoded neurofeedback (DecNef) showing

promising potential. However, most research faced challenges, including small sample sizes, heterogeneity in

experimental parameters, and insufficient mechanistic exploration. Future research should focus on expanding

sample sizes, standardizing treatment protocols, and investigating the mechanisms and long-term efficacy of

these treatments.

1 INTRODUCTION

Post-Traumatic Stress Disorder (PTSD) is a normal

psychiatric disorder that severely affects the mood

and functioning of patients. According to the

Diagnostic and Statistical Manual of Mental

Disorders (DSM-5), PTSD is a trauma and stress-

related disorder that is intimately linked to

maladaptive fear of learning and aberrant stress

reactions. The global prevalence of PTSD has

increased in recent years, highlighting the urgent need

for effective treatment strategies. Although

pharmacologic and psychotherapeutic approaches

have been widely adopted, they often fail to give good

outcomes for all patients, problems like high cost,

high recurrence rate, short duration of efficacy of

medicine, and inability to solve the problem in the

long term. In this case, alternative treatment

approaches are needed.

Recent advances in neuromodulation techniques

have shown promise for the treatment of PTSD.

Direct stimulation techniques such as TMS and non-

invasive neurofeedback training have been

investigated for modulating brain activity in specific

regions such as the DLPFC and amygdala. High-

frequency TMS targeting the DLPFC has been shown

to provide significant symptomatic relief, particularly

for intrusive memories and excessive anxiety.

Similarly, neurofeedback approaches provide a non-

invasive means of modulating brain function that may

improve mood regulation and symptom control.

However, existing studies have limitations such as

small sample sizes, inconsistent methods, and lack of

long-term efficacy data.

The purpose of this paper is to compare and

analyze the effectiveness of TMS and neurofeedback

training in the treatment of PTSD by reviewing

relevant studies. Key aspects such as treatment

efficacy, side effects and current limitations are

discussed in order to find a future direction of

neuromodulation therapy for PTSD. Standardized

treatment protocols and further mechanistic

explorations are suggested as key steps in advancing

this area of research.

396

Yan, X.

Advances and Challenges in Neuromodulation Therapies for Post-Traumatic Stress Disorder: A Comparative Analysis of Direct Stimulation and Neurofeedback Approaches.

DOI: 10.5220/0014116100004942

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 2nd International Conference on Applied Psychology and Marketing Management (APMM 2025), pages 396-400

ISBN: 978-989-758-791-7

2 POST-TRAUMATIC STRESS

DISORDER (PTSD) AND

NEUROMODULATION

Some parts of the brain are abnormally active in

patients with PTSD, especially at the onset of the

disease. The author learned that specific areas such as

the dorsolateral prefrontal cortex (DLPFC)

experience unusual activity through research

conducted by researchers such as Edinoff, A. N,

Karsen, E. F. This paper has concluded that it is

possible to relieve the symptoms of people with

PTSD by modulating the activity in specific brain

regions. An altered stress response and reinforced

learnt fear behavior are linked to post-traumatic stress

disorder (PTSD), a mental illness that significantly

impairs functioning (Deinoff et al., 2022). According

to the Diagnostic and Statistical Manual (DSM-5), it

is categorized as a "trauma and stressor-related

disorder." A great number of people are suffering

from it. Neuromodulation is the alteration of a

specific brain region’s activity by something that

makes the region more or less active.

Neuromodulation can be achieved by direct

stimulation and non-invasive interventions, and both

methods have their own advantages and

disadvantages in terms of efficiency and efficacy.

3 THERAPY EFFECT OF DIRECT

STIMULATION ON THE

SPECIFIC BRAIN REGION IN

PTSD

Edinoff, Hegefeld and other researchers mentioned

the therapy effects of transcranial magnetic

stimulation (TMS) in PTSD patients (Deinoff et al.,

2022). The participants in this experiment were

mainly PTSD patients, mostly are adult population,

with some patients with other co-morbidities such as

depression. The experiment was designed as a

randomized controlled trial, and the experimenters

used high-frequency TMS and low-frequency TMS to

stimulate the dorsolateral prefrontal cortex (DLPFC)

region. The study applied repetitive transcranial

magnetic stimulation (rTMS) to the DLPFC of

participants. The specific parameters were a

stimulation frequency of 10 Hz, intensity at 120% of

the individual motor threshold, 3,000 pulses per

session, with one session per day for 2 consecutive

weeks, totalling 10 sessions. Testing the effects of

TMS on functional brain networks, especially the

interaction between the DLPFC and the limbic system

by fMRI. In addition, the study used standardized

scales such as the posttraumatic Stress Disorder

Checklist for DSM-5 (PCL-5), clinician-administered

PTSD scale (CPAS) to assess patients' changes in

PTSD symptoms and detect side effects of the

treatment. The data analysis showed that high-

frequency TMS was effective in relieving core PTSD

symptoms like reappearance, flashbacks, and high

arousal, and it was more effective in reducing

symptoms compared to low-frequency TMS. The

results of the experiment showed that TMS exerted a

significant effect on DLPFC, as demonstrated by the

fact that PTSD symptom improvement was

associated with enhanced DLPFC function. The study

reported significant symptom improvement after

treatment, but the duration of effect may be short. In

addition, most studies report the side effects of this

therapy such as headache, nausea, and in rare cases,

possible seizures. Studies have also found that TMS

can improve emotion regulation in PTSD patients by

enhancing the connection between prefrontal cortex

and the limbic system. Researchers have concluded

that TMS is an effective and relatively safe treatment

for PTSD, especially for patients who did not get

good feedback from medication or psychotherapy.

TMS has received attention for its low side effects

and potential neuromodulation abilities compared to

established pharmacological treatments. However,

Edinoff, A. N’s study clearly points out some

limitations. First, the sample sizes are generally

small, which reduces the statistical efficacy and

credibility of the results. Second, there is

heterogeneity in the results of the studies, with some

studies failing to provide a consistent assessment of

efficacy, which may be related to differences in

treatment parameters and study design. In addition,

most of the available studies focused on short-term

efficacy and lacked observations of the persistence of

long-term effects. Finally, although some of the

studies used brain imaging techniques, the current

neural mechanism studies are insufficient to reveal

the mechanism for the role of TMS in the treatment

of PTSD. Mainly because of limitations in research

methods, complexity of inter-brain interactions,

individual response differences, lack of long-term

data, and non-harmonization of TMS parameters.

Karsen, Watts & Holtzheimer also reviewed the

effect of TMS on PTSD in their study (Karsen et al.,

2014). The study includes 132 participants in total,

ranging in age from 29 to 55.9, with an average

gender distribution. The participants were mainly

people with different types of PTSD. A variety of

study designs were used, including randomized

Advances and Challenges in Neuromodulation Therapies for Post-Traumatic Stress Disorder: A Comparative Analysis of Direct Stimulation

and Neurofeedback Approaches

397

controlled trials (RCTs), double-blind trials, and

open-label trials. The studies used different TMS

treatment parameters, such as different stimulation

frequencies, stimulation region, and stimulation

intensities. Some studies combined TMS with

exposure therapy. Symptom assessment for PTSD

relies on the standardized quantitative scales PCL and

CAPS. Data analysis indicated that most of the

treatment groups showed significant results on the

PTSD scale, right-side high-frequency TMS was

effective in relieving PTSD symptoms, but the effect

of stimulation frequency on efficacy is unclear. The

article states that TMS has been proved to be an

effective and well-tolerated therapy for PTSD.

Although there are variations in stimulation

frequency and target regions, it significantly reduces

key PTSD symptoms such as intrusive memories,

avoidance behaviour, and heightened alertness.

(Karsen et al., 2014) This also greatly supports the

results of the first experiment. However, the

experiment also has the same problem as Edinoff, A.

N.’s experiment, which is small sample size and

heterogeneity, and it varied widely in the choice of

frequency, number of pulses and stimulation regions.

Most of the studies only assessed short-term efficacy

and lacked long-term research data. In addition, most

studies reported inadequate monitoring of side effects

like seizure risk, headache or scalp discomfort,

hearing effects, and transient changes in cognitive

function or mood. These potential side effects need to

be further evaluated and reported in future studies.

In Che Jiang et al.’s study, they mentioned that

only the high-frequency transcranial magnetic

stimulation of DLPFC showed a significant

advantage in improving PTSD (Jiang et al., 2024).

This supports the results of Karsen's experiment that

high-frequency stimulation of the right side is better

than that of the left side and also reinforces the results

of Edinoff’s experiment. Philip, N. S. and Barredo, J.

also stated in their research that the effective target of

TMS is the right DLPFC, and more than five

treatments are required to get a significant

improvement (Gouveia et al., 2020). However, they

also suggested limitations of this treatment, as PTSD

is a highly heterogeneous condition that may be

associated with different psychiatric disorders, and

therefore identifying a specific treatment for this

patient group may be quite challenging, and it’s better

for future studies to use standardized targeting and

stimulation parameters. Philip, N. S. and other

researchers conducted a trial of intermittent Theta

Burst Stimulation (iTBS) in 2019, a new therapy with

a similar mechanism to TMS. The experiments found

that most of the improvement in clinical symptoms

from iTBS stimulation occurred in early stage,

suggesting that further research is needed on the best

time and duration of iTBS. In addition, the

stimulation method is consistent with the previous

role of TMS in default mode network connectivity 9

(Philip et al., 2019). The efficacy of iTBS proves that

the mechanism of TMS stimulation is unproblematic,

but the disadvantages of both treatments are similar,

which is they both lack long-term effects.

All five experimental papers mentioned above

demonstrate the effectiveness of TMS for the

treatment of PTSD, especially for high-frequency

stimulation of the right DLPFC. Neural activity

modulation through direct stimulation of specific

brain regions can effectively suppress and relieve the

symptoms of PTSD, which also build the basic for

future treatments in this direction. However, this type

of treatment exhibits the disadvantage of a short

effective period, which needs to be further improved

in future experiments. In addition, almost all

experiments contain the limitations of small

experimental sample size, high heterogeneity of

experimental results, and large differences in

experimental parameters. Increasing the sample size

as much as possible, standardizing the experimental

objectives and parameters (e.g. Recruit PTSD

patients with the same comorbidity or no

comorbidity, target a specific part of the brain with a

particular frequency and numbers of stimulation) may

help the experimental results a lot in future

experiments.

4 THERAPY EFFECT OF

NON-INVASION

NEUROFEEDBACK TRAINING

ON THE SPECIFIC BRAIN

REGION IN PTSD

In addition to the direct stimulation therapies

associated with TMS described above, non-invasive

neuromodulation therapies also seem to have good

results. Ros’s study showed a kind of non-invasion

treatment called neurofeedback training.

Neurofeedback training is non-invasive,

personalized, and helps individuals regulate their

brain activity through real-time feedback, which has

a lasting effect and is widely used to improve

problems such as attention, anxiety, and depression.

The experiment included 21 patients in the PTSD

group and 40 healthy adults in the healthy control

group. The PTSD patients were evaluated according

to DSM criteria, and neurofeedback used EEG to

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measure alpha wave amplitude. The study used fMRI

techniques to measure participants' brain activity

while viewing visual stimuli. The data was analyzed

using functional connectivity analysis to assess

synchronized activity between different areas of the

visual cortex, and graph theory analysis is used to

understand the topology of brain networks. The

effects of real neurofeedback (NFB) were compared

with sham neurofeedback (SHAM) in the healthy

group, and only NFB treatment was used in the PTSD

group. The results showed that single-session

neurofeedback training has improved neurodynamic

symptoms in PTSD patients by modulating alpha-

wave long range time correlation (Ros et al., 2017).

This study supports the theory that neurofeedback

improves EEG dynamics and is consistent with other

studies on NFB for ADHD and depression. The

limitations of this trial are that there were only 21

PTSD patients, and no SHAM comparisons were

made in the PTSD group, which may be biased. This

study greatly proved that non-invasion

neurofeedback treatment is effective in treating PTSD

symptoms. However, the study had the limitation of

not comparing the efficacy and persistence of effects

with other therapies.

Kohl and Mehle’s experiment also support the

result from the last study. They experimented in a

systematic review of fNIRS-based neurofeedback

research. The experiment involved 441 individuals,

337 were healthy individuals and 104 were patients.

This study focused on neurofeedback training using

functional Near-Infrared Spectroscopy (fNIRS), a

functional neuroimaging technique based on cerebral

hemodynamics, which is non-invasive.

Measurements were made using the fNIRS technique

to measure prefrontal cortex, especially areas such as

the DLPFC. The results show that multiple studies

have demonstrated that individuals can modulate

hemodynamic signaling in the cerebral cortex via

fNIRS neurofeedback. In addition, in healthy

participants, fNIRS neurofeedback helped to

modulate motor control and prefrontal function, and

in clinical participants, it helped to improve

symptoms. Patients were observed to experience a

reduction in impulsivity and anxiety-based

symptoms, suggesting the potential of this approach

for mood regulation and cognitive improvement

(Kohl et al., 2020). The reduced symptoms are also

components that need to be improved in patients with

PTSD. However, the quality of the current study is

considered moderate due to the lack of large

randomized controlled trials, resulting in insufficient

statistical efficacy. Compared to other neurofeedback

studies, fNIRS neurofeedback research is still in its

early stages and further studies are needed to validate

its specificity and potential clinical utility.

Nicholson and Rabellin studied the neural activity

of the amygdala during emotion regulation in patients

with PTSD. The results showed that PTSD patients

were able to effectively reduce the level of amygdala

activation by rt-fMRI-nf training (Nicholson et al.,

2017). In addition, the patients' symptoms improved

and their emotion regulation ability was enhanced

after the training. This study suggests that the rt-

fMRI-nf technique can be used as an effective tool for

emotion regulation training in patients with PTSD.

However, this study does have certain drawbacks,

though. First, the results' generalizability may be

impacted by the limited sample size, there were only

20 participants. Second, personalized trauma-related

words were utilized during neurofeedback training

sessions, it may trigger strong emotional reactions

and affect the training effect. This study modulated

the activity of the amygdala through neurofeedback

training, and although the modulation region was

different from the previous two experiments, it also

achieved the same effect of relieving the symptoms

of PTSD, which also proved the feasibility of

neurofeedback training treatment. Maculed-Franchi’s

article focuses on describing that EEG neurofeedback

training can modulate DLPFC activity, which

confirms the validity of the neurofeedback training

from previous experiments (Micoulaud-Franchi et al.,

2014). It also supports the importance of DLPFC

region in PTSD treatment. The experiment's main

limitations include the short number of

investigations, the comparatively small number of

participants in each study, and the varied

methodology regarding to the EEG-NF protocols'

features.

Chiba, T. and Kanazawa described a new type of

neurofeedback therapy called decoded

Neurofeedback (DecNef) in their research.

Conventional neurofeedback is based on average

neural signals in specific brain regions, which makes

it difficult to induce neural representations associated

with specific traumas, and DecNef may help to

improve this. DecNef allows patients to implicitly

modulate the multivariate somatostatin pattern of

BOLD signalling associated with fearful stimuli, the

effects of which may originate from exposure or

counterconditioning, or a combination of both (Chiba

et al., 2019). According to preliminary research,

DecNef's three days of feedback training helped to

reduce PTSD symptoms. This result was similar to

both the neurofeedback technique and traditional

exposure therapy, despite its uncertain nature.

Although this is a new approach to neurofeedback, it

Advances and Challenges in Neuromodulation Therapies for Post-Traumatic Stress Disorder: A Comparative Analysis of Direct Stimulation

and Neurofeedback Approaches

399

also gets similar results as conventional methods and

has the potential to be able to induce neural

representations associated with specific traumas

based on this new approach, which has a good

prospect for future research.

The above studies demonstrate that the

neurofeedback approach to non-invasion is effective

and promising. In addition, it has shown comparable

results to direct stimulation of brain regions, and

Chiba and Kanazawa's novel neurofeedback

modality, DecNef, may help to improve the

effectiveness of this kind of treatment and clarify the

mechanism in the future. All the experiments had

similar limitations to the experiments with direct

stimulation and lacked a large experimental sample

and insufficient statistical efficacy, resulting in

experimental data that are not generalized. Secondly,

many of the experiments demonstrated results that

were effective in relieving patients' symptoms, but the

underlying mechanisms need to be explored, and

more in-depth researches are needed. For example,

detecting the effect of neurological interventions by

brain imaging techniques, or recording changes in the

way neurons are connected in the brain by using

human connectome projects (HCP). It is

recommended that the sample size of the experiments

should be increased and the new DecNef

neurofeedback should be combined with

conventional neurofeedback for testing and

comparison.

5 CONCLUSION

This study reviewed two major neuromodulation

therapies for the treatment of PTSD: direct brain

stimulation therapies such as TMS and non-invasive

neurofeedback training. The results indicate that

while high-frequency transcranial magnetic

stimulation that targets the DLPFC can effectively

alleviate PTSD symptoms including intrusive

memories and hyper anxiety, its effects are typically

transient. Similarly, neurofeedback training,

including new techniques such as decoded DecNef,

has shown promising results in enhancing emotion

regulation and relieving symptoms by modulating

brain activity in areas such as the DLPFC and

amygdala.

The main limitations identified include small

sample sizes, high heterogeneity of study parameters,

and insufficient exploration of underlying

mechanisms, especially in terms of long-term

efficacy. To solve these issues, future studies should

focus on standardizing experiment approaches,

increasing sample sizes, and combining new

technologies such as DecNef with traditional

approaches. In addition, exploring the neural

mechanisms underlying these therapies is critical to

refining and improving their clinical efficacy.

The significance of this study is to provide a

comprehensive understanding of the current progress

and challenges of neuromodulation therapies for

PTSD. By identifying research gaps and making

actionable recommendations, this paper will

contribute to the advancement of targeted and

effective therapies for patients with PTSD.

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