Benign Epilepsy With Centrotemporal Spikes, Language Problems, Learning Disorders
Conditions
Keywords
Transcranial Magnetic Stimulation (TMS), Electroencephalogram (EEG), Children, Pediatric, Interictal Epileptiform Discharges, Brain connectivity
Brief summary
Benign epilepsy with centrotemporal spikes (BECTS) is the most common pediatric epilepsy syndrome. Affected children typically have a mild seizure disorder, but yet have moderate difficulties with language, learning and attention that impact quality of life more than the seizures. Separate from the seizures, these children have very frequent abnormal activity in their brain known as interictal epileptiform discharges (IEDs, or spikes), which physicians currently do not treat. These IEDs arise near the motor cortex, a region in the brain that controls movement. In this study, the investigators will use a form of non-invasive brain stimulation called transcranial magnetic stimulation (TMS) to determine the impact of IEDs on brain regions important for language to investigate: (1) if treatment of IEDs could improve language; and (2) if brain stimulation may be a treatment option for children with epilepsy. Participating children will wear electroencephalogram (EEG) caps to measure brain activity. The investigators will use TMS to stimulate the brain region where the IEDs originate to measure how this region is connected to other brain regions. Children will then receive a special form of TMS called repetitive TMS (rTMS) that briefly reduces brain excitability. The study will measure if IEDs decrease and if brain connectivity changes after rTMS is applied. The investigators hypothesize that the IEDs cause language problems by increasing connectivity between the motor cortex and language regions. The investigators further hypothesize that rTMS will reduce the frequency of IEDs and also reduce connectivity between the motor and language region
Interventions
DEVICEActive rTMS
1Hz rTMS delivered for 15-20 minutes
DEVICESham rTMS
sham rTMS delivered for 15-20 minutes
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Children will receive active repetitive TMS (rTMS) on one day and sham stimulation on a second day. The order of stimulation will be randomized on a per-participant basis. Children and parents/guardians will not be told if they are receiving sham or inhibitory rTMS on a given day. The research team will know at the time of stimulation, however, as they will have to choose which coil to use. The TMS-EEG files will be coded and the team member analyzing the files for change in IED (spike) frequency and change in connectivity will be blinded to condition.
Eligibility
Sex/Gender
ALL
Age
5 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* A diagnosis of Benign Epilepsy with Centrotemporal Spikes (BECTS), sometimes called Rolandic Epilepsy. Diagnosis will be based on a history of a focal motor seizure (affecting the face or causing hypersalivation) or a history of a seizure out of sleep AND an EEG with unilateral or bilateral centrotemporal spike waves. * English-speaking
Exclusion criteria
* History of prematurity \< 35 weeks gestational age; * History of serious neurologic problems (i.e. history of other seizure disorder other than simple febrile seizure, head trauma with prolonged loss of consciousness, cerebrovascular accident or neuro-inflammatory disease) * Focal deficits on neurologic exam * History of abnormal MRI (with clear gray or white matter abnormality)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Interictal Epileptiform Discharge (IED) Frequency | Before and after intervention (approximately 4 hours/visit on 2 study days one week apart) | We will count the number of IEDs/minute before and after application of active rTMS as well as before and after sham rTMS. We will compare the change in IEDs induced by the active and sham stimulation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Brain Connectivity | Before and after intervention (approximately 4 hours/visit on 2 study days one week apart) | We will measure brain connectivity before and after application of active rTMS as well as before and after sham rTMS. We will compare the change in connectivity induced by the active and sham stimulation. In particular, we will look at how connectivity changes between the motor cortex and language regions of the brain. We chose 3 regions of interest per hemisphere (-F: Frontal, -M: Motor, -T: Temporal). rTMS was applied to the hemisphere with more spikes on clinical EEG, and hence all regions were further qualified as being ipsilateral (i-) or contralateral (c-) to rTMS application. Connectivity is measured in the weighted Phase Lag Index (wPLI) in the beta-frequency band, a phase-based connectivity measure which runs from a theoretical minimum of 0 (no connectivity) to 1 (complete connectivity). |
Countries
United States
Participant flow
Recruitment details
This study enrolled participants with Self Limited Epilepsy with Centrotemporal Spikes (SeLECTS), formerly known as Benign Epilepsy with Centrotemporal Spikes (BECTS).
Participants by arm
| Arm | Count |
|---|---|
| Children With SeLECTS - Active, Then Sham rTMS Children will receive sham and active (1 Hz) rTMS on 2 separate study visits separated by at least 1 week. | 11 |
| Children With SeLECTS - Sham, Then Active rTMS Children will receive sham and active (1 Hz) rTMS on 2 separate study visits separated by at least 1 week. | 8 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (1 Day) | Withdrawal by Subject | 0 | 1 |
| Second Intervention (1 Day) | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Children With SeLECTS - Active, Then Sham rTMS | Total | Children With SeLECTS - Sham, Then Active rTMS |
|---|---|---|---|
| Age, Continuous | 9.6 years STANDARD_DEVIATION 1.4 | 9.8 years STANDARD_DEVIATION 1.6 | 10.1 years STANDARD_DEVIATION 1.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 16 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 14 Participants | 4 Participants |
| Region of Enrollment United States | 11 Participants | 19 Participants | 8 Participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 10 Participants | 14 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 19 |
| other Total, other adverse events | 2 / 19 | 0 / 19 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 |
Outcome results
Primary
Interictal Epileptiform Discharge (IED) Frequency
We will count the number of IEDs/minute before and after application of active rTMS as well as before and after sham rTMS. We will compare the change in IEDs induced by the active and sham stimulation.
Time frame: Before and after intervention (approximately 4 hours/visit on 2 study days one week apart)
Population: Participants with Analyzable Data (Remained awake for both active \& sham rTMS sessions)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Children With SeLECTS - Active rTMS | Interictal Epileptiform Discharge (IED) Frequency | Before rTMS | 0 IEDs per 5 minutes |
| Children With SeLECTS - Active rTMS | Interictal Epileptiform Discharge (IED) Frequency | After rTMS | 0 IEDs per 5 minutes |
| Children With SeLECTS - Active rTMS | Interictal Epileptiform Discharge (IED) Frequency | Change from pre-rTMS to post-rTMS | 0 IEDs per 5 minutes |
| Children With SeLECTS - Sham rTMS | Interictal Epileptiform Discharge (IED) Frequency | Before rTMS | 0 IEDs per 5 minutes |
| Children With SeLECTS - Sham rTMS | Interictal Epileptiform Discharge (IED) Frequency | After rTMS | 0 IEDs per 5 minutes |
| Children With SeLECTS - Sham rTMS | Interictal Epileptiform Discharge (IED) Frequency | Change from pre-rTMS to post-rTMS | 0 IEDs per 5 minutes |
Comparison: Within-group analysis of change after active rTMS (post-rTMS compared to pre-rTMS).p-value: 0.04Wilcoxon signed rank test
Comparison: Within-group analysis of change after sham rTMS (post-rTMS compared to pre-rTMS).p-value: 0.46Wilcoxon signed rank test
Comparison: Between-group analysis of change induced by active rTMS versus sham rTMSp-value: 0.12Wilcoxon signed rank test
Secondary
Change in Brain Connectivity
We will measure brain connectivity before and after application of active rTMS as well as before and after sham rTMS. We will compare the change in connectivity induced by the active and sham stimulation. In particular, we will look at how connectivity changes between the motor cortex and language regions of the brain. We chose 3 regions of interest per hemisphere (-F: Frontal, -M: Motor, -T: Temporal). rTMS was applied to the hemisphere with more spikes on clinical EEG, and hence all regions were further qualified as being ipsilateral (i-) or contralateral (c-) to rTMS application. Connectivity is measured in the weighted Phase Lag Index (wPLI) in the beta-frequency band, a phase-based connectivity measure which runs from a theoretical minimum of 0 (no connectivity) to 1 (complete connectivity).
Time frame: Before and after intervention (approximately 4 hours/visit on 2 study days one week apart)
Population: Participants with Analyzable Data (Remained awake for both active \& sham rTMS sessions)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in iF-cM Connectivity | -0.038566551 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in iT-cT Connectivity | -0.041984947 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in iF-iT Connectivity | -0.031871907 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in cF-cT Connectivity | -0.022140561 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in iF-cT Connectivity | -0.017946561 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in cF-cM Connectivity | -0.011221254 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in iF-cF Connectivity | -0.017828074 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in cF-iM Connectivity | -0.031668097 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in iM-cT Connectivity | -0.016437136 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in iM-iT Connectivity | -0.030898043 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in cM-iT Connectivity | -0.026464821 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in cM-cT Connectivity | -0.029060306 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in cF-iT Connectivity | -0.025147033 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in iM-cM Connectivity | -0.032771045 wPLI |
| Children With SeLECTS - Active rTMS | Change in Brain Connectivity | Change in iF-iM Connectivity | -0.028419447 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in iM-cM Connectivity | 0.004707047 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in iF-cF Connectivity | 0.004773205 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in cF-iT Connectivity | 0.001240549 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in cM-iT Connectivity | 0.015413055 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in iF-iT Connectivity | 0.005724761 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in iM-cT Connectivity | 0.010533673 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in iF-cT Connectivity | 0.008023921 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in iF-iM Connectivity | 0.011937066 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in iT-cT Connectivity | -0.000655525 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in cF-cT Connectivity | 0.006909577 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in cF-cM Connectivity | 0.009773165 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in cF-iM Connectivity | 0.01966644 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in iM-iT Connectivity | 0.002850137 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in cM-cT Connectivity | -0.00727134 wPLI |
| Children With SeLECTS - Sham rTMS | Change in Brain Connectivity | Change in iF-cM Connectivity | 0.009032342 wPLI |
Comparison: Within-group analysis of change in cF-iT connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: <0.0001Wilcoxon signed-rank test
Comparison: Within-group analysis of change in cF-iT connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.69Wilcoxon signed rank test
Comparison: Between-group analysis of change in cF-iT connectivity induced by active versus sham rTMS.p-value: <0.0001Wilcoxon signed rank test
Comparison: Within-group analysis of change in cM-iT connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: <0.0001Wilcoxon signed rank test
Comparison: Within-group analysis of change in cM-iT connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.43Wilcoxon signed rank test
Comparison: Between-group analysis of change in cM-iT connectivity induced by active versus sham rTMS.p-value: <0.0001Wilcoxon signed rank test
Comparison: Within-group analysis of change in iF-cM connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.002Wilcoxon signed rank test
Comparison: Within-group analysis of change in iF-cM connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.54Wilcoxon signed rank test
Comparison: Between-group analysis of change in iF-cM connectivity induced by active versus sham rTMS.p-value: 0.007Wilcoxon signed rank test
Comparison: Within-group analysis of change in iF-iT connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.002Wilcoxon signed rank test
Comparison: Within-group analysis of change in iF-iT connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.32Wilcoxon signed rank test
Comparison: Between-group analysis of change in iF-iT connectivity induced by active versus sham rTMS.p-value: 0.01Wilcoxon signed rank test
Comparison: Within-group analysis of change in iF-cF connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.003Wilcoxon signed rank test
Comparison: Within-group analysis of change in iF-cF connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.29Wilcoxon signed rank test
Comparison: Between-group analysis of change in iF-cF connectivity induced by active versus sham rTMS.p-value: 0.02Wilcoxon signed rank test
Comparison: Within-group analysis of change in iM-cT connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.003Wilcoxon signed rank test
Comparison: Within-group analysis of change in iM-cT connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.66Wilcoxon signed rank test
Comparison: Between-group analysis of change in iM-cT connectivity induced by active versus sham rTMS.p-value: 0.008Wilcoxon signed rank test
Comparison: Within-group analysis of change in iF-cT connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.005Wilcoxon signed rank test
Comparison: Within-group analysis of change in iF-cT connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.87Wilcoxon signed rank test
Comparison: Between-group analysis of change in iF-cT connectivity induced by active versus sham rTMS.p-value: 0.11Wilcoxon signed rank test
Comparison: Within-group analysis of change in iF-iM connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.012Wilcoxon signed rank test
Comparison: Within-group analysis of change in iF-iM connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.46Wilcoxon signed rank test
Comparison: Between-group analysis of change in iF-iM connectivity induced by active versus sham rTMS.p-value: 0.02Wilcoxon signed rank test
Comparison: Within-group analysis of change in iT-cT connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.01Wilcoxon signed rank test
Comparison: Within-group analysis of change in iT-cT connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.99Wilcoxon signed rank test
Comparison: Between-group analysis of change in iT-cT connectivity induced by active versus sham rTMS.p-value: 0.04Wilcoxon signed rank test
Comparison: Within-group analysis of change in cF-cT connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.01Wilcoxon signed rank test
Comparison: Within-group analysis of change in cF-cT connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.31Wilcoxon signed rank test
Comparison: Between-group analysis of change in cF-cT connectivity induced by active versus sham rTMS.p-value: 0.05Wilcoxon signed rank test
Comparison: Within-group analysis of change in cF-cM connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.03Wilcoxon signed rank test
Comparison: Within-group analysis of change in cF-cM connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.2Wilcoxon signed rank test
Comparison: Between-group analysis of change in cF-cM connectivity induced by active versus sham rTMS.p-value: 0.04Wilcoxon signed rank test
Comparison: Within-group analysis of change in cF-iM connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.05Wilcoxon signed rank test
Comparison: Within-group analysis of change in cF-iM connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.59Wilcoxon signed rank test
Comparison: Between-group analysis of change in cF-iM connectivity induced by active versus sham rTMS.p-value: 0.12Wilcoxon signed rank test
Comparison: Within-group analysis of change in iM-iT connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.1Wilcoxon signed rank test
Comparison: Within-group analysis of change in iM-iT connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.57Wilcoxon signed rank test
Comparison: Between-group analysis of change in iM-iT connectivity induced by active versus sham rTMS.p-value: 0.06Wilcoxon signed rank test
Comparison: Within-group analysis of change in cM-cT connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.12Wilcoxon signed rank test
Comparison: Within-group analysis of change in cM-cT connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.69Wilcoxon signed rank test
Comparison: Between-group analysis of change in iM-cM connectivity induced by active versus sham rTMS.p-value: 0.04Wilcoxon signed rank test
Comparison: Between-group analysis of change in cM-cT connectivity induced by active versus sham rTMS.p-value: 0.14Wilcoxon signed rank test
Comparison: Within-group analysis of change in iM-cM connectivity during active rTMS (post-rTMS versus pre-rTMS).p-value: 0.12Wilcoxon signed rank test
Comparison: Within-group analysis of change in iM-cM connectivity during sham rTMS (post-rTMS versus pre-rTMS).p-value: 0.6Wilcoxon signed rank test