Neuromodulation
Non-Invasive Brain Stimulation: Current Treatment Approaches
Last updated: March 2026 • Prof. Dr. Burhanettin Uludağ
Neuromodulation is the targeted alteration of nervous system activity using electrical, magnetic, ultrasonic, or optical energy. In recent years, non-invasive brain stimulation methods have increasingly established their place in clinical practice for treating neuropsychiatric and neurological diseases.
On this page, you can find the four main neuromodulation methods, their evidence levels, and clinical applications alongside current literature.
rTMS — Magnetic Stimulation
Modulates cortical excitability with repetitive magnetic pulses. FDA-approved for depression and pain.
tES — Electrical Stimulation
Alters cortical activity with low-intensity electrical current. Portable and home-applicable.
TPS — Pulse Stimulation
Deep brain stimulation with ultrasonic shock waves. CE-approved for Alzheimer treatment.
PBM — Photobiomodulation
Enhances mitochondrial function with red and near-infrared light. Promising for neurodegeneration.
Repetitive Transcranial Magnetic Stimulation (rTMS)
What is it?
rTMS is based on the principle of inducing electrical current in the brain cortex through a variable magnetic field applied via a coil placed on the skull. Repeated pulses permanently modulate cortical excitability beyond the stimulation period, explained by long-term potentiation (LTP) and long-term depression (LTD)-like synaptic plasticity mechanisms.
Key Parameters
Clinical Applications
Major Depressive Disorder
Düzey A — Kesin EtkinlikrTMS has the strongest evidence level among neuromodulation applications for treatment-resistant depression. High-frequency (10-20 Hz) rTMS or iTBS over left DLPFC has been FDA-approved since 2008.
Stanford SAINT protocol: 10 sessions of iTBS per day for 5 days reported 79% remission rate in treatment-resistant depression.
Neuropathic Pain
Düzey A — Kesin EtkinlikHigh-frequency (10-20 Hz) rTMS over primary motor cortex (M1) has reached definite efficacy level for chronic neuropathic pain. Repeated M1-rTMS sessions provide analgesic effects lasting up to 6 months. Stimulation is typically applied at 80-90% motor threshold with 1500-3000 pulses.
Migraine
Düzey B — Olası EtkinlikrTMS over DLPFC has shown medium-to-large effect sizes for acute treatment and prophylaxis of migraine. Single-pulse TMS for acute treatment of migraine aura is FDA-approved (SpringTMS device).
Motor Stroke Rehabilitation
Düzey A — Kesin EtkinlikExcitatory rTMS over the affected hemisphere or inhibitory rTMS over the intact hemisphere has definite efficacy for post-stroke motor recovery.
Addiction (Smoking & Alcohol)
FDA OnaylıDeep TMS (H-coil) with bilateral DLPFC and insula stimulation has been FDA-approved for smoking cessation since 2020 (BrainsWay system).
OCD (Obsessive Compulsive Disorder)
FDA OnaylıDeep TMS with medial prefrontal cortex and anterior cingulate cortex stimulation received FDA approval for OCD in 2018.
Epilepsy
Düzey C — Muhtemel EtkinlikLow-frequency (inhibitory) rTMS over the epileptic focus provides possible efficacy-level evidence for reducing seizure frequency in focal epilepsies.
Alzheimer's and Mild Cognitive Impairment
Düzey C — Muhtemel EtkinlikHigh-frequency rTMS over left DLPFC or bilateral parietal cortex has shown improvement in cognitive performance in Alzheimer patients.
ADHD
Düzey C — Muhtemel EtkinlikHigh-frequency rTMS over right DLPFC has reported improvement in attention and impulsivity symptoms. Large-scale RCTs are awaited.
Transcranial Electrical Stimulation (tES)
What is it?
Transcranial electrical stimulation modulates cortical excitability by applying steady or alternating low-intensity electrical current through the skull.
tDCS
Steady direct current (1-2 mA). Anodal: excitability ↑, Cathodal: ↓
tACS
Sinusoidal alternating current. Targets specific brain oscillations.
tRNS
Random noise current. Increases cortical excitability via stochastic resonance.
Advantages: Low cost, portability, home application potential, and minimal side effects (most common: mild tingling and redness).
Clinical Applications
Depression
Düzey B — Olası EtkinlikAnodal tDCS over left DLPFC provides probable efficacy-level evidence in major depressive disorder. Home-based remote tDCS has been shown effective.
Neuropathic Pain & Fibromyalgia
Düzey B — Olası EtkinlikAnodal tDCS over M1 has shown analgesic effects in chronic pain and fibromyalgia.
Epilepsy
Düzey C — Muhtemel EtkinlikCathodal tDCS over the epileptic focus may reduce seizure frequency by decreasing cortical excitability.
Addiction
Düzey C — Muhtemel EtkinlikAnodal tDCS over DLPFC has reduced craving in alcohol, nicotine, and substance addiction.
Transcranial Pulse Stimulation (TPS)
What is it?
TPS is the non-invasive application of focused short ultrasonic pulses (shock waves) to brain tissue through the skull. It received CE approval for Alzheimer disease treatment in 2018 (Neurolith device, Storz Medical). Unlike other methods, it has the capacity to reach deep brain structures.
TPS in Alzheimer's Disease
Matt ve ark. (2025)
JAMA Network Open
60 Alzheimer patients in a randomized, double-blind, sham-controlled crossover study. Verum TPS showed significant cognitive improvement in younger patient subgroup. fMRI demonstrated increased memory-related brain activation.
Brain Stimulation (2024)
Brain Stimulation
10 patients in open-label study: TPS significantly reduced neuropsychiatric symptoms (NPI score decrease of 23.9 points in 30 days, Cohen's d = 1.43).
Cont ve ark. (2022)
Frontiers in Neurology
101 neurodegenerative disease patients real-world data. No side effects reported in over 80% of patients.
Wojtecki ve ark. (2025)
GeroScience
Post-TPS changes in EEG-based oscillation network activity — increased functional connectivity and plastic reorganization findings.
Brain Sciences (2025)
Brain Sciences
10 Alzheimer patients with 1-year follow-up. Long-term positive effects on memory, speech, orientation, and depressive symptoms.
TPS in Parkinson's Disease
The safety of TPS in Parkinson's disease has been evaluated with no side effects observed (Alon et al., 2012). Acute effects on gait and balance have been reported. Clinical studies in this area are ongoing.
Other Potential Applications
Safety
TPS is generally well tolerated. Reported side effects include painless pressure sensation, mild headache, and transient numbness, all reversible. Over 60% of patients reported no side effects.
Photobiomodulation (PBM)
What is it?
Transcranial photobiomodulation (tPBM) is the non-invasive application of low-intensity red (600-670 nm) or near-infrared (800-1100 nm) light to brain tissue through the skull.
Mechanism of Action
Primary target: Mitochondrial cytochrome c oxidase (Complex IV)
Clinical Evidence
Alzheimer's and Mild Cognitive Impairment
Umut VericiIn a systematic review of 35 clinical studies, 82.9% reported positive improvement in cognitive function after tPBM. Preclinical studies have shown reduction in amyloid plaque burden, suppression of neuroinflammation, and support for hippocampal neurogenesis.
Parkinson's Disease
Umut VericiIn animal models, tPBM has reduced dopaminergic neuron loss and improved motor performance. Human studies are limited but show positive trends.
Traumatic Brain Injury
Umut VericitPBM reported positive results in 87.5% of 7 studies for cognitive recovery after traumatic brain injury.
Limitations
Transcranial penetration is the fundamental limitation of PBM. Light must pass through hair, scalp, blood, skull bone, and bone marrow. Energy reaching deep brain structures is limited. Standard protocols have not yet been established.
Clinical Indications and Evidence Levels
Evidence Level Classification (Lefaucheur et al., 2020)
| Indication | rTMS | tDCS | TPS | PBM |
|---|---|---|---|---|
| Depression | Düzey A — Kesin Etkinlik | Düzey B — Olası Etkinlik | Araştırma Aşaması | Sınırlı Kanıt |
| Neuropathic Pain | Düzey A — Kesin Etkinlik | Düzey B — Olası Etkinlik | Araştırma Aşaması | Araştırma Aşaması |
| Migraine | Düzey B — Olası Etkinlik | Düzey C — Muhtemel Etkinlik | — | — |
| Motor Stroke | Düzey A — Kesin Etkinlik | Düzey B — Olası Etkinlik | — | — |
| Alzheimer's | Düzey C — Muhtemel Etkinlik | Düzey C — Muhtemel Etkinlik | RKÇ Pozitif | Umut Verici |
| Parkinson | Düzey C — Muhtemel Etkinlik | Düzey C — Muhtemel Etkinlik | Araştırma Aşaması | Umut Verici |
| Epilepsy | Düzey C — Muhtemel Etkinlik | Düzey C — Muhtemel Etkinlik | — | — |
| Smoking Cessation | FDA Onaylı | Düzey C — Muhtemel Etkinlik | — | — |
| Alcohol Addiction | Düzey C — Muhtemel Etkinlik | Düzey C — Muhtemel Etkinlik | — | — |
| OKB / OCD | FDA Onaylı | Sınırlı Kanıt | — | — |
| ADHD | Düzey C — Muhtemel Etkinlik | Düzey C — Muhtemel Etkinlik | — | — |
| Autism | Sınırlı Kanıt | Sınırlı Kanıt | — | — |
| TBI Cognitive | Sınırlı Kanıt | Düzey C — Muhtemel Etkinlik | — | Umut Verici |
rTMS FDA-Approved Indications (as of 2026)
References
Guidelines and Key Review Articles
- Lefaucheur JP, et al. Evidence-based guidelines on rTMS: An update (2014–2018). Clin Neurophysiol. 2020;131:474-528.
- Fregni F, et al. Evidence-based guidelines for tDCS in neurological and psychiatric disorders. Int J Neuropsychopharmacol. 2021;24:256-313.
- Cole E, et al. Accelerated theta burst stimulation: safety, efficacy, and future advancements. Biol Psychiatry. 2024;95:523-535.
rTMS — Neuropathic Pain
- Attal N, Genin T. rTMS for chronic pain: State of the art and perspectives. Neuromodulation. 2025.
- Thomas L, et al. Effects of multiple rTMS sessions on pain relief in chronic neuropathic pain. Eur J Pain. 2025;29:e4763.
- Zhou J, et al. Revisiting the effects of rTMS over DLPFC on pain: An updated systematic review. Brain Stimul. 2024;17:928-937.
rTMS — Depression and Addiction
- Cole EJ, et al. Stanford SAINT: A randomized, double-blind, sham-controlled trial. Am J Psychiatry. 2022;179:132-141.
- Zangen A, et al. Transcranial magnetic stimulation for smoking cessation. JAMA. 2020.
TPS — Transcranial Pulse Stimulation
- Matt E, et al. Ultrasound neuromodulation with TPS in Alzheimer disease: A randomized clinical trial. JAMA Netw Open. 2025;8(2):e2459170.
- Cont C, et al. Retrospective real-world pilot data on TPS in Alzheimer's. Front Neurol. 2022;13:948204.
- TPS improves neuropsychiatric symptoms in Alzheimer's disease. Brain Stimul. 2024.
- Wojtecki L, et al. Electrical brain networks before and after TPS in Alzheimer's. GeroScience. 2025;47:953-964.
- Brain Sciences 2025: TPS long-term feasibility in Alzheimer's disease — 1 year follow-up.
Photobiomodulation
- Brain photobiomodulation: A potential treatment in Alzheimer's and Parkinson's diseases. JPAD. 2025.
- Chan AS, et al. Can transcranial photobiomodulation improve cognitive function? Ageing Res Rev. 2022;83:101786.
- Dole M, et al. Effects of transcranial photobiomodulation on brain activity in humans. Rev Neurosci. 2023;34:671-693.
- Transcranial photobiomodulation for brain diseases: review. Neurophoton. 2024;11(1):010601.
General Neuromodulation Reviews
- Koch G, et al. The emerging field of non-invasive brain stimulation in Alzheimer's. Brain. 2024;awae292.
- TMS in the treatment of neurological diseases. Front Neurol. 2022;13:793253.
- Beisteiner R, Lozano AM. Transcranial ultrasound innovations ready for broad clinical application. Adv Sci. 2020;7(23):2002026.
This page is for educational purposes and does not substitute medical advice. Neuromodulation treatments should be administered after specialist physician evaluation and individual indication assessment.
Last updated: March 2026 • © Norosera Neurology Clinic — Prof. Dr. Burhanettin Uludağ