Repeated TMS at Low Frequencies to Reduce Seizure Occurrence
Study Details
Study Description
Brief Summary
Perform non-invasive neuro-navigated repeated Transcranial Magnetic Stimulation (rTMS) at low frequencies (LF) with the intent to reduce the occurrence of seizures over time (long-term protocol). Seizure reduction and improvements in the quality of life in patients with epilepsy will be associated with increased cortical inhibition resulting from the LF-rTMS sessions over time. This procedure using rTMS at low frequencies (LF-rTMS) between 0.5 and 1 Hz is a safe and painless method for noninvasive focal cortical brain stimulation, which will be evaluated in its efficacy at reducing/suppressing seizures. Accordingly, we propose a clinical trial in patients with epilepsy to test whether LF-rTMS can improve seizure suppression. The location of the presumed 3D source in the brain will be stimulated for few minutes (10 to 15 min.). With the same rTMS modality, we will also perform motor threshold mapping in conjunction with its fully integrated and compatible electroencephalography (EEG) module. Up to 100 individuals 18 to 80 years with epilepsy will be enrolled.
In addition, a short-term protocol has been added to test whether LF-rTMS can reduce or suppress status epilepticus in medically refractory participants.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
Long term protocol: Perform non-invasive neuro-navigated repeated Transcranial Magnetic Stimulation (rTMS) at low frequencies (LF) with to reduce the occurrence of seizures over time. Seizure reduction and improvements in the quality of life in patients with epilepsy will be associated with increased cortical inhibition resulting from the LF-rTMS sessions over time. This procedure using rTMS at low frequencies (LF-rTMS) between 0.5 and 1 Hz is a safe and painless method for noninvasive focal cortical brain stimulation, which will be evaluated in its efficacy at reducing/suppressing seizures. Accordingly, we propose a clinical trial in patients with epilepsy to test whether LF-rTMS can improve seizure suppression. The location of the presumed 3D source in the brain will be stimulated for few minutes (10 to 15 min.). Using a double-blinded, sham-controlled design, we will enroll up to 100 participants aged 18-80 with focal and generalized retractable epilepsy. Baseline data will include a detailed seizure diary over 4 weeks, psychometric testing/neuropsychology evaluation, and 20-minute EEG recordings. Each patient will then begin treatment with 14 minute sessions of 1 Hz rTMS or sham rTMS, 120%MT, and 800 stimuli on the position of the calculated 3D source using EEG, MRI, and digitized electrode locations. The protocol will be divided in 3 groups (Groups 1, 2 and 3) as follows:
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Groups 1, 2, and 3: LF-rTMS for 2 weeks (5 days per week for total of 10 days).
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Group 1: protocol total duration: 1 year: LF-rTMS 1 session/week for 1 month (4 days), and LF-rTMS 1 session/month for 11 months
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Group 2: protocol total duration: 1 year: LF-rTMS 1 session/month for 12 months
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Group 3 (placebo protocol, total duration: 1 year): LF-rTMS 1 session/week for 1 month (4 days); and LF-rTMS 1session/month.
During each session EEG may be recorded. Also, we will obtain the number, frequency, and duration of seizure events from an ongoing seizure diary. Psychometric testing will be performed at the beginning of study, 3 months, and at the end of the study. Thus, each patient will have rTMS testing, psychometrics, and EEG recordings. With the same rTMS modality, we will also perform motor threshold mapping in conjunction with its fully integrated and compatible electroencephalography (EEG) module.
Short-term protocol: Use LF-rTMS protocol as described but for up to 5 days in 10 participants with medically refractory status epilepticus. During each session EEG will be recorded.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Group 1: Weekly TMS LF-rTMS intervention for 2 weeks (5 days per week for total of 10 days) , LF-rTMS 1 session/week for 1 month (4 days), and LF-rTMS 1 session/month for 11 months |
Device: Low frequency repeated TMS (LF-rTMS)
Each patient will then begin treatment with 14 minute sessions of 1 Hz rTMS or sham rTMS, 120% minimum threshold (MT), and 800 stimuli on the position of the calculated 3D source using EEG, MRI, and digitized electrode locations. Two different timelines of delivering the rTMS will be compared against a sham/delayed treatment group.
|
| Experimental: Group 2: Monthly TMS LF-rTMS intervention for 2 weeks (5 days per week for total of 10 days), LF-rTMS 1 session/month for 12 months |
Device: Low frequency repeated TMS (LF-rTMS)
Each patient will then begin treatment with 14 minute sessions of 1 Hz rTMS or sham rTMS, 120% minimum threshold (MT), and 800 stimuli on the position of the calculated 3D source using EEG, MRI, and digitized electrode locations. Two different timelines of delivering the rTMS will be compared against a sham/delayed treatment group.
|
| Sham Comparator: Group 3: Sham TMS Sham LF-rTMS for 2 weeks (5 days per week for a total of 10 days), sham LF-rTMS 1 session/week for 1 month (4 days), and sham LF-rTMS 1 session/month for 1 month. After the sham stimulation real LF-rTMS intervention sessions will be delivered as follows: 50% of placebo group will follow group 1 protocol and the other 50% will follow group 2 protocol |
Device: Low frequency repeated TMS (LF-rTMS)
Each patient will then begin treatment with 14 minute sessions of 1 Hz rTMS or sham rTMS, 120% minimum threshold (MT), and 800 stimuli on the position of the calculated 3D source using EEG, MRI, and digitized electrode locations. Two different timelines of delivering the rTMS will be compared against a sham/delayed treatment group.
|
| Experimental: Short-term protocol LF-rTMS intervention daily for up to 5 days in medically refractory status epilepticus participants only |
Device: Low frequency repeated TMS (LF-rTMS)
Each patient will then begin treatment with 14 minute sessions of 1 Hz rTMS or sham rTMS, 120% minimum threshold (MT), and 800 stimuli on the position of the calculated 3D source using EEG, MRI, and digitized electrode locations. Two different timelines of delivering the rTMS will be compared against a sham/delayed treatment group.
|
Outcome Measures
Primary Outcome Measures
- Average weekly seizure frequency (long-term protocol) [From baseline to study completion, approx. 1 year]
The baseline seizure frequency and seizure frequency change after treatment will be computed from average weekly seizure frequencies before and after rTMS treatment for each patient.
- Resolution of epilepsia partialis continua/status epilepticus (short-term protocol) [From start of intervention through 5 days of treatment]
Resolution of the condition, meaning that the definition of either condition is no longer met (i.e., the status epilepticus seizure stops or for epilepsia partialis continua, the seizure frequency slows)
Secondary Outcome Measures
- Scalp EEG: Ratio of right to left Alpha power (long-term protocol) [From baseline to study completion, approx. 1 year]
Alpha asymmetry is known to be common in patients with epilepsy in contrast to healthy controls (where alpha symmetry is seen as more prevalent).
- Scalp EEG: Alpha spectral power (long-term protocol) [From baseline to study completion, approx. 1 year]
Slowing of the alpha rhythm in patients with epilepsy has been observed
- Scalp EEG: Number of interictal epileptiform discharges (long-term protocol) [From baseline to study completion, approx. 1 year]
Interictal discharges are common in those with epilepsy and tends to decrease with treatment.
- Scalp EEG: Frequency-dependent functional connectivity maps (long-term protocol) [From baseline to study completion, approx. 1 year]
Frequency-dependent functional connectivity maps in background EEG corresponding to the delta, theta, alpha, and beta brain oscillations - these functional interactions can help in the characterization of epileptic versus control brain patterns.
- DICOM stimulation maps (long-term protocol) [From baseline to study completion, approx. 1 year]
To determine motor threshold maps
- Scalp EEG: Ratio of right to left Alpha power (short-term protocol) [From start of intervention through 5 days of treatment]
Alpha asymmetry is known to be common in patients with epilepsy in contrast to healthy controls (where alpha symmetry is seen as more prevalent).
- Scalp EEG: Alpha spectral power (short-term protocol) [From start of intervention through 5 days of treatment]
Slowing of the alpha rhythm in patients with epilepsy has been observed
- Scalp EEG: Number of interictal epileptiform discharges (short-term protocol) [From start of intervention through 5 days of treatment]
Interictal discharges are common in those with epilepsy and tends to decrease with treatment.
- Scalp EEG: Frequency-dependent functional connectivity maps (short-term protocol) [From start of intervention through 5 days of treatment]
Frequency-dependent functional connectivity maps in background EEG corresponding to the delta, theta, alpha, and beta brain oscillations - these functional interactions can help in the characterization of epileptic versus control brain patterns.
Eligibility Criteria
Criteria
Long-term protocol:
Inclusion Criteria:
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Experience ≥ 3 seizures/month in the month prior to starting study (any type of seizure will count)
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No status epilepticus in the last 12 months
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No change in medication in last 30 days
Exclusion Criteria:
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Presence of implanted electronic devices (e.g., pacemaker, medication pump, brain or vagus nerve stimulator, cochlear implant)
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Presence of intracranial metal (e.g., aneurysm clip)
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Unable to cooperate with non-sedated, navigated TMS testing
Short-term protocol:
Inclusion Criteria:
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Epilepsia partialis continua or status epilepticus
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At least 2 medications failed
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At least 24 hours of acute phase
Exclusion Criteria:
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Presence of implanted electronic devices (e.g., pacemaker, medication pump, brain or vagus nerve stimulator, cochlear implant)
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Presence of intracranial metal (e.g., aneurysm clip)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Baptist Hospital of Miami | Miami | Florida | United States | 33176 |
Sponsors and Collaborators
- Baptist Health South Florida
- U.S. National Science Foundation
- Florida International University
Investigators
- Principal Investigator: Alberto Pinzon, M.D., Ph.D., Baptist Health South Florida
Study Documents (Full-Text)
None provided.More Information
Publications
- Fox MD, Liu H, Pascual-Leone A. Identification of reproducible individualized targets for treatment of depression with TMS based on intrinsic connectivity. Neuroimage. 2013 Feb 1;66:151-60. doi: 10.1016/j.neuroimage.2012.10.082. Epub 2012 Nov 7.
- Hallett M. Transcranial magnetic stimulation and the human brain. Nature. 2000 Jul 13;406(6792):147-50. Review.
- Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol. 2003 Mar;2(3):145-56. Review.
- Plewnia C, Pasqualetti P, Große S, Schlipf S, Wasserka B, Zwissler B, Fallgatter A. Treatment of major depression with bilateral theta burst stimulation: a randomized controlled pilot trial. J Affect Disord. 2014 Mar;156:219-23. doi: 10.1016/j.jad.2013.12.025. Epub 2013 Dec 28.
- Rossini PM, Rossi S. Transcranial magnetic stimulation: diagnostic, therapeutic, and research potential. Neurology. 2007 Feb 13;68(7):484-8. Review.
- Siebner HR, Hartwigsen G, Kassuba T, Rothwell JC. How does transcranial magnetic stimulation modify neuronal activity in the brain? Implications for studies of cognition. Cortex. 2009 Oct;45(9):1035-42. doi: 10.1016/j.cortex.2009.02.007. Epub 2009 Mar 3.
- Udupa K, Sathyaprabha TN, Thirthalli J, Kishore KR, Raju TR, Gangadhar BN. Modulation of cardiac autonomic functions in patients with major depression treated with repetitive transcranial magnetic stimulation. J Affect Disord. 2007 Dec;104(1-3):231-6. Epub 2007 May 8.
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