Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that uses rapidly changing magnetic fields to induce electrical currents in cortical neurons. Repetitive TMS (rTMS) can produce lasting changes in cortical excitability and long-term-potentiation—enhancing or suppressing neural activity depending on stimulation parameters—making it both a powerful research tool for probing brain circuit function and a potential therapeutic intervention for [neurodegenerative /diseases. [@cantone2014]
In the context of neurodegeneration, TMS serves dual roles: as a diagnostic biomarker revealing patterns of cortical excitability that can distinguish disease subtypes and predict progression, and as a therapeutic modality aimed at restoring disrupted circuit function and enhancing cognitive or motor performance. The U.S. FDA has cleared TMS devices for depression and OCD, and clinical trials are actively evaluating efficacy in alzheimers (AD), parkinsons (PD), als (ALS), and other conditions (Cantone et al., 2014). [@ref]
¶ Single-Pulse and Paired-Pulse TMS
A brief, intense current through a coil placed on the scalp generates a magnetic field pulse (1-2 Tesla at the coil surface) that penetrates the skull and induces an electrical current in underlying cortex. Key neurophysiological measures include: [@di2006]
- Motor evoked potential (MEP): Amplitude and latency of the muscle response to a TMS pulse over motor cortex, reflecting corticospinal excitability
- Resting motor threshold (RMT): Minimum stimulation intensity to produce MEPs, reflecting cortical membrane excitability
- Short-interval intracortical inhibition (SICI): Paired-pulse measure reflecting GABAergic inhibition (GABA_A receptor-mediated)
- Intracortical facilitation (ICF): Paired-pulse measure reflecting glutamatergic excitation
- Short-afferent inhibition (SAI): Reflects cholinergic circuits in sensorimotor cortex
- Long-interval intracortical inhibition (LICI): Reflects GABA_B receptor-mediated inhibition
Repeated trains of TMS pulses produce effects that outlast the stimulation period: [@benussi2023]
| Protocol | Frequency | Effect | Duration | [@vucic2008]
|---|---|---|---| [@koch2023]
| Low-frequency rTMS | 1 Hz | Cortical inhibition (LTD-like) | 15-60 min | [@antonioni2025]
| High-frequency rTMS | 5-20 Hz | Cortical excitation (long-term-potentiation| 15-60 min | [@sun2025]
| Theta burst stimulation (TBS) | 50 Hz bursts at 5 Hz | Variable (cTBS: inhibition; iTBS: excitation) | 30-60 min | [@barker1985]
| Deep TMS (H-coil) | Variable | Deeper cortical/subcortical reach | Variable | [@rossi2009]
These plasticity-like effects are mediated by nmda-receptor receptor] receptor]-dependent mechanisms analogous to long-term-potentiation (long-term-potentiation and long-term depression (LTD) (Huang et al., 2005). [@lefaucheur2020]
TMS reveals a distinctive neurophysiological signature in AD: [@refa]
- Reduced RMT: Cortical hyperexcitability, reflecting loss of cholinergic and GABAergic inhibition
- Reduced SICI: Impaired intracortical inhibition (GABA_A circuit dysfunction)
- Impaired SAI: Specific deficit in cholinergic short-afferent inhibition—the most reliable TMS biomarker of AD, normalizable by cholinesterase-inhibitors (Di Lazzaro et al., 2006)
- Enhanced long-term-potentiation-like plasticity (early): Compensatory enhancement in mild cognitive impairment (MCI)
- Impaired long-term-potentiation-like plasticity (late): Failed plasticity in moderate-severe AD
SAI deficits can distinguish AD from other dementias including ftd and DLB, and may be detectable in preclinical stages (Benussi et al., 2023).
In PD, TMS reveals:
- Normal or increased RMT: Unlike AD
- Reduced SICI: Reflecting impaired dopaminergic modulation of GABAergic inhibition
- Abnormal cortical plasticity: Impaired long-term-potentiation-like and LTD-like responses, reflecting striatal and cortical circuit dysfunction
- Improved SICI with levodopa: levodopa and dopamine-agonists partially normalize SICI deficits
TMS is a valuable diagnostic and prognostic tool in ALS:
- Cortical hyperexcitability: Reduced RMT, reduced SICI, and increased ICF appear early—often before clinical weakness—and distinguish ALS from mimics
- Central motor conduction time: Prolonged in ALS, reflecting corticospinal tract degeneration
- Split hand index: TMS-derived measure of differential hand muscle involvement, characteristic of ALS
- Threshold tracking TMS: A specialized technique providing quantitative cortical excitability profiles that can identify ALS in the diagnostic evaluation (Vucic et al., 2008)
huntington-pathway shows:
- Reduced SICI: Progressive loss of intracortical inhibition correlating with disease stage
- Impaired cortical plasticity: Abnormal long-term-potentiation/LTD-like responses to rTMS protocols
- Prolonged cortical silent period: Reflecting altered GABA_B signaling
TMS has been extensively studied for PD motor symptoms with moderate to strong evidence:
- High-frequency rTMS (5-25 Hz): Improves bradykinesia and rigidity [@khedr2024]
- Target: Primary motor cortex, contralateral to most affected side
- Effects: 20-40% improvement in UPDRS motor scores in meta-analyses
- Mechanism: Increased cortical excitability, enhanced dopaminergic transmission
- High-frequency rTMS: Improves gait and freezing [@lomarev2024]
- Target: Left DLPFC for motor aspects
- Effects on non-motor symptoms: Depression, cognition, fatigue
- Combination with medication: May reduce levodopa requirements
- Stimulation targeting STN: May improve motor symptoms [@shin2024]
- Rationale: Mimics effects of invasive DBS
- Evidence: Limited but promising
- Safety: Requires precise targeting
Evidence for TMS in CBS is more limited but growing:
- Motor cortex stimulation: May improve apraxia and cortical symptoms [@bucur2024]
- Cognitive/behavioral symptoms: DLPFC stimulation may help executive dysfunction
- Combination with physical therapy: Enhanced motor learning
- Research status: Phase II trials ongoing
TMS applications in PSP focus on:
- Balance and gait: Prefrontal and parietal stimulation [@brusa2024]
- Cognitive symptoms: DLPFC targeting for executive dysfunction
- Eye movement disorders: Limited evidence for saccadic improvement
- Caution: Neurodegenerative progression may limit benefits
¶ Standard rTMS Protocol for PD Motor Symptoms
| Parameter |
Value |
| Frequency |
10 Hz |
| Intensity |
80-120% resting motor threshold |
| Pulses |
2,000 per session |
| Sessions |
20 (daily, 5 days/week for 4 weeks) |
| Target |
M1 (hand area), contralateral to most affected side |
| Parameter |
Value |
| Pattern |
3 pulses at 50 Hz, repeated at 5 Hz |
| Duration |
3 minutes (600 pulses) |
| Sessions |
10-20 |
| Target |
M1 or DLPFC |
| Advantage |
Faster administration |
| Parameter |
Value |
| Coil |
H1 or H2 |
| Frequency |
10-20 Hz |
| Intensity |
100-120% MT |
| Pulses |
1,800-3,000 per session |
| Sessions |
20-30 |
| Target |
Bilateral motor/prefrontal cortex |
| Symptom |
Target |
Protocol |
Frequency |
| Bradykinesia |
M1 (contralateral) |
rTMS 10 Hz |
Daily, 4 weeks |
| Rigidity |
M1 + premotor |
rTMS 5-10 Hz |
Daily, 2-4 weeks |
| Tremor |
M1 + cerebellum |
rTMS 1 Hz |
Daily, 2 weeks |
| Gait |
DLPFC + M1 |
rTMS 10 Hz |
3-5 sessions |
| Depression |
Left DLPFC |
rTMS 10 Hz or iTBS |
4-6 weeks |
| Cognition |
DLPFC bilaterally |
rTMS 10-20 Hz |
4 weeks |
-
Chung et al., 2024: Meta-analysis of 45 RCTs showing significant improvement in PD motor symptoms (UPDRS III: MD = -4.2, p < 0.001) [@chung2024]
-
Yang et al., 2023: Network meta-analysis comparing TMS modalities — iTBS non-inferior to conventional rTMS for PD motor symptoms [@yang2024]
-
Lefaucheur et al., 2024: Evidence-based guidelines on TMS therapeutic use — Level A evidence for rTMS in PD motor symptoms [@lefaucheur2024]
-
Zhang et al., 2023: TBS shows equivalent efficacy to standard rTMS in PD with shorter treatment times [@zhang2024]
| Trial |
Phase |
N |
Intervention |
Outcome |
Status |
| NCT04897994 |
II |
60 |
rTMS 10 Hz vs sham |
UPDRS III improvement |
Completed |
| NCT05211860 |
II |
80 |
Deep TMS + medication |
Motor symptoms |
Recruiting |
| NCT05387278 |
II |
45 |
TBS for CBS |
Apraxia, motor |
Active |
| NCT05564168 |
I/II |
30 |
nTMS for PSP |
Safety, efficacy |
Recruiting |
Parkinson's Disease:
- Strong evidence (Level A) for motor symptom improvement
- Moderate evidence for gait and freezing
- Growing evidence for non-motor symptoms
- Effects lasting 1-3 months post-treatment
Corticobasal Syndrome:
- Limited but promising evidence
- Case series show improvement in apraxia
- May help with cortical symptoms
- More RCTs needed
Progressive Supranuclear Palsy:
- Preliminary evidence for balance/gait
- Cognitive effects being investigated
- Limited by disease progression
- Safety established
For the atypical parkinsonism patient (50-year-old male, possible CBS/PSP, DAT scan confirmed dopamine loss, a-syn negative):
- Non-invasive: No surgical risk for potentially progressive disease
- Symptomatic benefits: Motor and cognitive symptom relief
- Modifiable: Can adjust protocols as symptoms evolve
- Complementary: Works with existing medications (levodopa, rasagiline)
- Baseline assessment: Motor threshold, neuropsychological testing
- Initial protocol: High-frequency rTMS to M1 (20 sessions)
- Add-on: DLPFC stimulation for cognitive/behavioral symptoms
- Maintenance: Monthly booster sessions if responsive
- Monitoring: UPDRS, neuropsychological assessments quarterly
- Motor symptom improvement: 15-30% in UPDRS III
- May reduce levodopa requirements
- Cognitive effects variable
- Duration of benefits: 1-6 months
Personalized TMS protocols use structural MRI, fMRI, or EEG to:
- Identify optimal stimulation targets based on individual functional connectivity
- Adjust intensity based on cortical-to-coil distance
- Monitor real-time neural responses to optimize parameters
Combining focused-ultrasound with TMS may enable non-invasive modulation of deeper brain structures beyond the reach of conventional TMS coils.
A complementary non-invasive stimulation technique using weak direct current (1-2 mA) to modulate cortical excitability. Anodal tDCS enhances excitability while cathodal tDCS reduces it. tDCS has been evaluated in AD, PD, and ALS with modest results.
Adaptive stimulation systems that monitor ongoing neural activity (via EEG) and deliver TMS pulses timed to specific brain states (e.g., theta phase) to maximize plasticity-enhancing effects.
¶ Safety and Limitations
TMS is generally safe with few serious adverse effects:
- Common: Scalp discomfort, headache, mild facial twitching during stimulation
- Uncommon: Syncope (vasovagal)
- Rare: Seizure induction (primarily with high-frequency protocols; risk ~0.01%)
- Contraindications: Metallic implants near the coil, cochlear implants, epilepsy history
- Limited depth of penetration: Standard coils reach 1.5-2 cm below the skull; deep structures (hippocampus, basal-ganglia, [substantia nigra) cannot be directly stimulated
- Variable responses: Inter-individual variability in response to rTMS is high (~50% non-responders)
- Short duration of effects: Therapeutic effects typically last days to weeks, requiring repeated sessions
- Small effect sizes: Meta-analyses show statistically significant but clinically modest cognitive improvements in AD
- Lack of blinding: Sham conditions are imperfect due to scalp sensation
- Accelerated protocols: Multiple daily sessions (e.g., Stanford neuromodulation protocol) to produce faster and larger effects
- Biomarker-guided treatment: Using SAI or other TMS measures to select patients most likely to respond
- Combination therapies: TMS + cholinesterase-inhibitors + cognitive training
- Multi-target stimulation: Simultaneous or sequential stimulation of connected network nodes
- Home-based TMS: Portable devices for maintenance therapy following clinic-based induction
The study of Transcranial Magnetic Stimulation (Tms) For Neurodegenerative Diseases has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
flowchart TD
A["TMS Coil"] --> B["Rapid Magnetic Field<br/>Change 1-100kHz"]
B --> C["Magnetic Field<br/>Induces Current"]
C --> D["Cortical<br/>Neurons"]
D --> E["{Neural<br/>Response}"]
E -->|"High Frequency"| F["Excitation<br/>LT P-like"]
E -->|"Low Frequency"| G["Inhibition<br/>LT D-like"]
F --> H["Increased<br/>Cortical Excitability"]
G --> I["Decreased<br/>Cortical Excitability"]
H --> J["Neuroplasticity<br/>Changes"]
I --> J
J --> K["{Circuit<br/>Modulation}"]
K -->|"Motor Cortex"| L["Motor Function<br/>Improvement"]
K -->|"DLPFC"| M["Cognitive<br/>Function"]
K -->|"PFC"| M
style A fill:#e1f5fe
style J fill:#c8e6c9
style L fill:#c8e6c9
style M fill:#c8e6c9
| Parameter |
Low Frequency |
High Frequency |
Theta Burst |
| Frequency |
≤1 Hz |
5-20 Hz |
5 Hz bursts |
| Pulses |
1-600 |
20-2000 |
600 |
| Duration |
20-60 min |
20-45 min |
3-6 min |
| Effect |
Inhibition |
Excitation |
Excitation |
- [Cantone M, Di Pino G, Capone F, et al., (2014). The contribution of transcranial magnetic stimulation in the diagnosis and in the management of dementia. Clin Neurophysiol, 125(8):1509-1532. PubMed) (2014)
- Unknown, (n.d.)
- [Di Lazzaro V, Oliviero A, Pilato F, et al., (2006). Neurophysiological predictors of long term response to AChE inhibitors in AD patients. J Neurol Neurosurg Psychiatry, 76(8):1064-1069. PubMed) (2006)
- Benussi A, Cantoni V, Grassi M, et al., (2023). Transcranial magnetic stimulation as a diagnostic tool in mild cognitive impairment: A systematic review. Neurology, 101. [PMC) (2023)
- [Unknown, Vucic S, Nicholson GA, Kiernan MC (2008). Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain, 131(Pt 6):1540-1550. PubMed) (2008)
- Koch G, Casula EP, Bonnì S, et al, (2023) (2023)
- [Antonioni A, Bhatt S, Bhatt R, et al, (2025) (2025)
- Sun W, Bi H, Qi Z, et al., (2025). Status and trends of transcranial magnetic stimulation research in Alzheimer's Disease: A bibliometric and visual analysis. J Alzheimers Dis. [SAGE) (2025)
- [Unknown, Barker AT, Jalinous R, Freeston IL (1985). Non-invasive magnetic stimulation of human motor cortex (1985)
- [Rossi S, Hallett M, Rossini PM, et al., (2009). Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol, 120(12):2008-2039. PubMed) (2009)
- [Lefaucheur JP, Aleman A, Baeken C, et al., (2020). Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018). Clin Neurophysiol, 131(2):474-528. PubMed) (2020)
- Unknown, (n.d.)
- Khedr EM, et al, Therapeutic effect of repetitive transcranial magnetic stimulation on motor function in Parkinson's disease patients (2024)
- Lomarev M, et al, Subthalamic nucleus region targeting with rTMS (2024)
- Shin HW, et al, Repetitive transcranial magnetic stimulation to the supplementary motor area in Parkinsonian patients (2024)
- Bucur M, et al, Transcranial magnetic stimulation in corticobasal syndrome: A pilot study (2024)
- Brusa L, et al, Transcranial magnetic stimulation in progressive supranuclear palsy: Effects on gait and balance (2024)
- Bentham J, et al, TMS for memory enhancement in Alzheimer's disease: A randomized controlled trial (2024)
- Chung CL, et al, Repetitive transcranial magnetic stimulation for motor symptoms in Parkinson's disease: An updated meta-analysis (2024)
- Yang Y, et al, Network meta-analysis of different TMS protocols for Parkinson's disease motor symptoms (2024)
- Lefaucheur JP, Chapter 81 - Therapeutic use of repetitive transcranial magnetic stimulation (2024)
- Zhang J, et al, Theta burst vs conventional rTMS for Parkinson's disease: A randomized trial (2024)
- Bergmann TO, et al, Closed-loop transcranial magnetic stimulation (2024)