Ignite Creation Date:
2024-10-26 @ 3:41 PM
Last Modification Date:
2024-10-26 @ 3:41 PM
Study NCT ID:
NCT06610877
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-09-20
Brief Title:
Ultrasound Neuromodulation in Essential Tremor
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Ultrasound Neuromodulation in Essential Tremor
Status:
RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
UNMET
Brief Summary:
This study is being done to test whether low-intensity focused ultrasound LIFU low energy sound waves cause temporary changes in brain activity and behavior when directed at particular parts of the brain By targeting LIFU to the parts of the brain thought to be responsible for essential tremor ET and measuring any associated improvement in tremor the investigators hope to show that LIFU can be a useful tool for studying the brain circuits responsible for tremor and other brain disorders
Detailed Description:
Hypothesis
Precisely targeted low-intensity focused ultrasound LIFU modulation of the dentatorubrothalamic tract DRTT results in transient improvement of essential tremor ET DRTT LIFU neuromodulation produces functional connectivity changes that mirror brain network changes after MR-guided high-intensity focused ultrasound HIFU thalamotomy
Aims
1 To determine the optimal stimulation parameters for DRTT LIFU neuromodulation the investigators will record wrist accelerometer signals while systematically varying pulse repetition frequency duty cycle and acoustic intensity
2 To map network effects of DRTT LIFU neuromodulation the investigators will record resting state fMRI rs-fMRI immediately after DRTT LIFU neuromodulation with the parameters most effective at reducing tremor in each patient
Design
This is a within-subject repeated-measures interventional study designed to determine the set of LIFU stimulation parameters that are maximally effective at producing a temporary tremor reduction when applied to the DRTT - the white matter circuit in the brain in which abnormal activity causes essential tremor
The investigators will recruit patients from the established MR-guided high-intensity focused ultrasound HIFU ET program at UCSF which treats 6-9 patientsmonth Due to the logistical complexity of performing MRI in patients with MR-conditional pacemakers need for device and patient monitoring patients with pacemakers will be excluded from enrollment Study inclusion criteria will otherwise be similar to those for the HIFU procedure itself namely medically refractory tremor that is expected to improve with HIFU thalamotomy without contraindications to MRI or inability to stop anticoagulation As part of their routine pre-procedure evaluation these patients receive a dedicated head CT for calculation of skull density ratio SDR and a 3T brain MRI that includes high resolution diffusion imaging for tractography to identify the DRTT as well as specialized anatomic scans including proton density PD and white matter nulled T1 wm-null T1 sequences to define adjacent thalamic anatomy
Study participants will undergo a single LIFU session lasting 3-4 hours generally in the 1-2 days prior to their HIFU treatment The investigators will perform LIFU stimulation using a commercially available portable neuronavigated focused ultrasound system NeuroFUS PRO BrainBox Cardiff UK and will target LIFU stimulation using the same image-guided protocol used for the patients subsequent HIFU treatment Wrist-based accelerometers MP160 TSD109A BIOPAC Systems Inc will be used to provide a quantitative behavioral readout of the LIFU effect The investigators will use power spectrum density analysis of accelerometer signals to quantify the severity of tremor before and after LIFU and HIFU sonications To evaluate the effect of DRTT LIFU on tremor severity and the contribution of the different acoustic parameters tested the investigators will perform individual- and group-level statistical analyses on the quantified tremor power in the characteristic ET range of 4-12 Hz The hair on the participant39s head will be shave at the start of the session to facilitate the passage of the ultrasound energy an existing requirement of the subsequent HIFU treatment
The transient nature of LIFU tremor reduction on the order of 10-20 minutes will facilitate high-throughput parameter screening through repeated sonications within the same session up to 25 depending on patient response Stimulation protocols consisting of 5 seconds of active stimulation followed by 10 seconds of no stimulation repeated four times total 60 s will be delivered using a range of sample parameters Stimulation parameters will be shuffled in each session to control for carryover effects at the group level After each 60-s stimulation there will be a 3 minute inter-stimulation period during which tremor severity will be monitored every 60 seconds through quantitative accelerometer recordings If a change in tremor severity greater than 50 is found in the post-LIFU period compared to the pre-LIFU baseline the investigators will wait until tremor returns to a level comparable to baseline before proceeding with additional stimulations A similar approach was followed in a recent study by Aubry et al 2024 with the Insightec Exablate system The entire LIFU stimulation session will last approximately 100 minutes sufficient to screen up to 25 stimulation protocols 1 min sonication 3 min wait per protocol depending on tremor response
At the end of the session the investigators will identify the stimulation parameters that produced the largest tremor suppression compared to the respective pre-LIFU baseline They will then deliver a sham off-target or defocused sonication using these maximally effective parameters to control for nonspecific sensory and auditory effects evoked by the ultrasound stimulation Following this the investigators will perform a final active sonication targeting the DRTT with the maximally effective parameters this final stimulation will be immediately followed by a brief 20-30 minute MRI scan to measure the effects of LIFU on brain functional connectivity derived from rs-fMRI
Patients will then proceed with their scheduled HIFU treatment which will include similar intra-procedure wrist-base accelerometer measurements to document behavioral effects of HIFU on ET as well as post treatment MRI to evaluate for post-treatment complications and to measure the effects of HIFU on brain functional connectivity as assessed with rs-fMRI
Precisely targeted low-intensity focused ultrasound LIFU modulation of the dentatorubrothalamic tract DRTT results in transient improvement of essential tremor ET DRTT LIFU neuromodulation produces functional connectivity changes that mirror brain network changes after MR-guided high-intensity focused ultrasound HIFU thalamotomy
Aims
1 To determine the optimal stimulation parameters for DRTT LIFU neuromodulation the investigators will record wrist accelerometer signals while systematically varying pulse repetition frequency duty cycle and acoustic intensity
2 To map network effects of DRTT LIFU neuromodulation the investigators will record resting state fMRI rs-fMRI immediately after DRTT LIFU neuromodulation with the parameters most effective at reducing tremor in each patient
Design
This is a within-subject repeated-measures interventional study designed to determine the set of LIFU stimulation parameters that are maximally effective at producing a temporary tremor reduction when applied to the DRTT - the white matter circuit in the brain in which abnormal activity causes essential tremor
The investigators will recruit patients from the established MR-guided high-intensity focused ultrasound HIFU ET program at UCSF which treats 6-9 patientsmonth Due to the logistical complexity of performing MRI in patients with MR-conditional pacemakers need for device and patient monitoring patients with pacemakers will be excluded from enrollment Study inclusion criteria will otherwise be similar to those for the HIFU procedure itself namely medically refractory tremor that is expected to improve with HIFU thalamotomy without contraindications to MRI or inability to stop anticoagulation As part of their routine pre-procedure evaluation these patients receive a dedicated head CT for calculation of skull density ratio SDR and a 3T brain MRI that includes high resolution diffusion imaging for tractography to identify the DRTT as well as specialized anatomic scans including proton density PD and white matter nulled T1 wm-null T1 sequences to define adjacent thalamic anatomy
Study participants will undergo a single LIFU session lasting 3-4 hours generally in the 1-2 days prior to their HIFU treatment The investigators will perform LIFU stimulation using a commercially available portable neuronavigated focused ultrasound system NeuroFUS PRO BrainBox Cardiff UK and will target LIFU stimulation using the same image-guided protocol used for the patients subsequent HIFU treatment Wrist-based accelerometers MP160 TSD109A BIOPAC Systems Inc will be used to provide a quantitative behavioral readout of the LIFU effect The investigators will use power spectrum density analysis of accelerometer signals to quantify the severity of tremor before and after LIFU and HIFU sonications To evaluate the effect of DRTT LIFU on tremor severity and the contribution of the different acoustic parameters tested the investigators will perform individual- and group-level statistical analyses on the quantified tremor power in the characteristic ET range of 4-12 Hz The hair on the participant39s head will be shave at the start of the session to facilitate the passage of the ultrasound energy an existing requirement of the subsequent HIFU treatment
The transient nature of LIFU tremor reduction on the order of 10-20 minutes will facilitate high-throughput parameter screening through repeated sonications within the same session up to 25 depending on patient response Stimulation protocols consisting of 5 seconds of active stimulation followed by 10 seconds of no stimulation repeated four times total 60 s will be delivered using a range of sample parameters Stimulation parameters will be shuffled in each session to control for carryover effects at the group level After each 60-s stimulation there will be a 3 minute inter-stimulation period during which tremor severity will be monitored every 60 seconds through quantitative accelerometer recordings If a change in tremor severity greater than 50 is found in the post-LIFU period compared to the pre-LIFU baseline the investigators will wait until tremor returns to a level comparable to baseline before proceeding with additional stimulations A similar approach was followed in a recent study by Aubry et al 2024 with the Insightec Exablate system The entire LIFU stimulation session will last approximately 100 minutes sufficient to screen up to 25 stimulation protocols 1 min sonication 3 min wait per protocol depending on tremor response
At the end of the session the investigators will identify the stimulation parameters that produced the largest tremor suppression compared to the respective pre-LIFU baseline They will then deliver a sham off-target or defocused sonication using these maximally effective parameters to control for nonspecific sensory and auditory effects evoked by the ultrasound stimulation Following this the investigators will perform a final active sonication targeting the DRTT with the maximally effective parameters this final stimulation will be immediately followed by a brief 20-30 minute MRI scan to measure the effects of LIFU on brain functional connectivity derived from rs-fMRI
Patients will then proceed with their scheduled HIFU treatment which will include similar intra-procedure wrist-base accelerometer measurements to document behavioral effects of HIFU on ET as well as post treatment MRI to evaluate for post-treatment complications and to measure the effects of HIFU on brain functional connectivity as assessed with rs-fMRI
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None