Low Intensity Focused Ultrasound for Learning and Memory and Emotion Regulation

Not Applicable

Completed

• Conditions: Learning Disabilities; Cognitive Impairment; Brain Diseases; Memory Disorders
• Interventions: Device: Low Intensity Focused Ultrasound Pulsation to Amygdala; Device: Low Intensity Focused Ultrasound Pulsation to Entorhinal Cortex

• Registration Number: NCT03717922
• Lead Sponsor: University of California, Los Angeles

Brief Summary

The goal of this clinical trial is to investigate the impact of low intensity focused ultrasound pulsation (LIFUP) to two different brain regions, the amygdala and entorhinal cortex, in older adults. The main questions it aims to answer are:

1. Will LIFUP change brain activity in the targeted regions?

2. Will LIFUP to the amygdala have an impact on anxiety and emotion regulation?

3. Will LIFUP to the entorhinal cortex have an impact on memory performance?

Participants will complete two in-person visits including neuropsychological testing, MRI of the brain, and LIFUP to the brain.

Detailed Description

Medial temporal lobe (MTL)-dependent memory is impacted by a wide range of psychiatric and neurologic conditions. These cognitive limitations often result in limited functional abilities for patients. Currently available pharmacologic and behavioral treatments are somewhat controversial and have minimal evidence-based effectiveness. Recently, deep brain stimulation was used to modulate MTL activity and subsequently improve memory performance. However, such implantable devices require neurosurgery with major associated health risk. At present, there are no publications reporting non-invasive neurostimulation targeting MTL regions to improve memory. The central hypothesis of this project is that non-invasive, low intensity focused ultrasound pulsation (LIFUP) can selectively increase regional MTL activity and thus be used as a cognitive neural prosthetic capable of improving memory performance. The aims of this portion of the study focus on whether LIFUP can increase blood oxygen level dependent (BOLD) activation and perfusion (measured by arterial spin labeling) in the entorhinal cortex and functionally associated regions, and whether LIFUP to the entorhinal cortex will result in improved memory.

The Amygdala is highly involved in emotional response, emotional reactivity and anxiety. Amygdala functions are therefore involved in a wide range of psychiatric disorders including generalized and social anxiety, specific phobia, obsessive compulsive disorder and posttraumatic stress disorder. Therefore, potential clinical implications of amygdala stimulation are great. However, to date, such efforts have been limited by the inability of non-invasive neuromodulation techniques (e.g. transcranial magnetic stimulation - TMS) to reach the amygdala and the highly invasive (i.e. neurosurgical) nature of methods (e.g. deep brain stimulation - DBS) which can, but to our knowledge has rarely been used, target these areas. In order to overcome these current limitations, study investigators propose the use of low intensity focused ultrasound pulsation (LIFUP) to affect amygdala activity to improve emotion regulation. The aim of this portion of the study focuses on whether LIFUP can modulate blood oxygen level dependent (BOLD) activation and perfusion (measured by arterial spin labeling) in the amygdala and functionally associated regions, and whether LIFUP to the amygdala will result in changes to anxiety levels and emotion regulation.

This study will be conducted using a crossover design in which each participant will complete two visits spaced two weeks apart. At one visit, they will receive LIFUP sonication (with parameters hypothesized to be inhibitory) to the right amygdala, and at the other, they will receive sonication (with parameters hypothesized to be excitatory) to the left entorhinal cortex. The order of conditions will be randomized and counterbalanced across participants. Participants will be blinded to condition order, and all other testing will be conducted the same at both visits. This design will allow us to test the effects of two potentially clinically-relevant targets for LIFUP, and will allow us to determine whether observed effects on brain activity, learning and memory, and emotion regulation are target-specific by comparing results between the two LIFUP paradigms.

Study Timeline

• Study First Submitted: 2018-10-22
• Study First Submitted QC: 2018-10-22
• Study First Posted: 2018-10-24
• Study Start: 2019-06-28
• Primary Completion: 2022-12-20
• Study Completion: 2022-12-20
• Results First Submitted: 2023-07-12
• Status Verified: 2024-03
• Results First Submitted QC: 2024-03-18
• Last Update Submitted: 2024-03-18
• Results First Posted: 2024-03-20
• Last Update Posted: 2024-03-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 21

Inclusion Criteria

• Must be right handed
• English must be the dominant language

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Exclusion Criteria

• contraindications for MRI (e.g. metal implants, pregnancy)
• history of head injury sufficient to warrant medical attention
• history of alcohol abuse or dependence
• history of substance abuse or dependence
• history of major psychiatric illness requiring treatment
• history of cancer or other neoplastic syndromes
• history of major neurologic illness (e.g. epilepsy).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Amygdala first, then Entorhinal Cortex	Low Intensity Focused Ultrasound Pulsation to Entorhinal Cortex	Low Intensity focused ultrasound pulsation (LIFUP) will be administered to the amygdala while participants are in the MRI scanner. Then, 2 weeks later, entorhinal cortex LIFUP will be administered.
Entorhinal Cortex first, then Amygdala	Low Intensity Focused Ultrasound Pulsation to Entorhinal Cortex	Low Intensity focused ultrasound pulsation (LIFUP) will be administered to the entorhinal cortex while participants are in the MRI scanner. Then, 2 weeks later, amygdala LIFUP will be administered.
Amygdala first, then Entorhinal Cortex	Low Intensity Focused Ultrasound Pulsation to Amygdala	Low Intensity focused ultrasound pulsation (LIFUP) will be administered to the amygdala while participants are in the MRI scanner. Then, 2 weeks later, entorhinal cortex LIFUP will be administered.
Entorhinal Cortex first, then Amygdala	Low Intensity Focused Ultrasound Pulsation to Amygdala	Low Intensity focused ultrasound pulsation (LIFUP) will be administered to the entorhinal cortex while participants are in the MRI scanner. Then, 2 weeks later, amygdala LIFUP will be administered.

Primary Outcome Measures

Name	Time	Method
Rey Auditory Verbal Learning Task	Pre-LIFUP and Post-LIFUP at Day 1 and Day 15	The Rey Auditory Verbal Learning Task is an assessment of verbal memory in which a list of 15 words is presented 5 times and participants are asked to repeat all the words they can remember immediately after each list presentation. This is followed by presentation and recall of an interference list. Immediately after the interference trial, the participant is asked to recall the original list. Then, 20 minutes later, they are asked to recall the original list again (delayed recall).; "Learning Trials Total": Total number of words learned / successfully recalled across the five learning trials plus the post-interference immediate recall trial. This score does not include the words recalled from the interference list.; "Delayed Recall": Total number of words recalled during the delayed recall trial of the Rey Auditory Verbal Learning Task
State Trait Anxiety Inventory - State (STAIS)	Pre-LIFUP and Post-LIFUP at Day 1 and Day 15	The "state" section of the State Trait Anxiety Inventory. This is a 20-question self-report assessment in which participants are asked about how they feel "right now, at this very moment" in order to assess current anxiety levels. Each item is scored on a scale of 1 to 4 points. The total assessment has a range of 20 to 80 points. Higher scores represent higher levels of anxiety.
Average Perfusion in Regions Of Interest	Pre-LIFUP and Post-LIFUP at Day 1 and Day 15	Average perfusion in a given region of interest, as measured by arterial spin labeling. Percent change values calculated as ((Post LIFUP Perfusion - Pre LIFUP Perfusion)/Pre LIFUP Perfusion).

Secondary Outcome Measures

Name	Time	Method
Brief Visuospatial Memory Test	Pre-LIFUP and Post-LIFUP at Day 1 and Day 15	Performance on the delayed recall (DR) portion of the Brief Visuospatial Memory Test (BVMT). Score is on a scale of 0-12, with higher scores indicating a better outcome. A score of 12 points represents full recall of all figures in their correct locations.
Emotional Reactivity Task	Pre-LIFUP and Post-LIFUP at Day 1 and Day 15	An emotional reactivity and reappraisal task (ERT) using images from the International Picture Affective System (IAPS). Arousal ratings ranged from 1 (low arousal, "calm") to 9 (high arousal, "excited"). Valence ratings ranged from 1 (negative, "unhappy") to 9 (positive, "happy"). There were 3 instruction conditions: "WATCH", in which a participant was instructed to passively view a negatively-valenced image, "VIEW", in which they were instructed to passively view a neutral image, and "REAPPRAISE", in which participants were asked to change their emotional response to neutral in response to a negatively-valenced image by altering their cognitive construal of the image.; The reported metric "reactivity" was taken from subtracting average responses to "VIEW" from average response to WATCH (i.e. WATCH - VIEW). Reappraisal metric is calculated as REAPPRAISE - WATCH

Trial Locations

Locations (1)

University of California, Los Angeles; 🇺🇸 Los Angeles, California, United States