Brain Diseases, Cognitive Impairment, Learning Disabilities, Memory Disorders
Conditions
Keywords
Ultrasound, MRI, Learning, Memory, Cognitive Neural Prosthetic
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.
Interventions
DEVICELow Intensity Focused Ultrasound Pulsation to Amygdala
Low intensity focused ultrasound pulsation will be administered to the amygdala in 10 sonications at 650kHz, ispta 720mW/cm, pulse repetition frequency 10Hz, duty cycle 5% duration 30s, with 30s spacing between sonications. Prior to receiving LIFUP sonication, the LIFUP transducer will be aimed at the amygdala and gently strapped in place to their head. Participants will then return to the scanner where a T1 image will verify the position of the LIFUP transducer and allow for estimation of the spatial location of the sonication beam focus. If needed, adjustments to transducer placement will be made to ensure that the beam focus is correctly aimed; an additional T1 will be collected after adjustment. Once correct placement of the transducer has been confirmed, LIFUP will be administered.
DEVICELow Intensity Focused Ultrasound Pulsation to Entorhinal Cortex
Low intensity focused ultrasound pulsation will be administered to the entorhinal cortex in 10 sonications at 650kHz, ispta 720mW/cm, pulse repetition frequency 100Hz, duty cycle 5% duration 30s, with 30s spacing between sonications. Prior to receiving LIFUP sonication, the LIFUP transducer will be aimed at the entorhinal cortex and gently strapped in place to their head. Participants will then return to the scanner where a T1 image will verify the position of the LIFUP transducer and allow for estimation of the spatial location of the sonication beam focus. If needed, adjustments to transducer placement will be made to ensure that the beam focus is correctly aimed; an additional T1 will be collected after adjustment. Once correct placement of the transducer has been confirmed, LIFUP will be administered.
Sponsors
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Participants will be blinded to exactly when the transducer is turned on, and to the region being targeted at each visit. The individual collecting the neuropsychological data will be blinded to which condition (amygdala, entorhinal cortex) the participant completed during the session. The statistical analysts for both the neuropsychological and neuroimaging data will also be blinded to condition.
Intervention model description
Participants will be assigned to both study arms; the order in which they complete the arms will be randomized and counterbalanced. The two visits will be spaced apart by 2 weeks.
Eligibility
Sex/Gender
ALL
Age
35 Years to 90 Years
Healthy volunteers
Yes
Inclusion criteria
* Must be right handed * English must be the dominant language
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Amygdala First, Then 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. | 10 |
| Entorhinal Cortex First, Then 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. | 11 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 2 |
Baseline characteristics
| Characteristic | Amygdala First, Then Entorhinal Cortex | Entorhinal Cortex First, Then Amygdala | Total |
|---|---|---|---|
| Age, Continuous | 60.1 years STANDARD_DEVIATION 8.2 | 61.2 years STANDARD_DEVIATION 9.5 | 60.7 years STANDARD_DEVIATION 8.7 |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 6 Participants | 8 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 3 Participants | 8 Participants |
| Region of Enrollment United States | 10 participants | 11 participants | 21 participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 21 |
| other Total, other adverse events | 1 / 21 | 0 / 21 |
| serious Total, serious adverse events | 0 / 21 | 0 / 21 |
Outcome results
Primary
Average Perfusion in Regions Of Interest
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).
Time frame: Pre-LIFUP and Post-LIFUP at Day 1 and Day 15
Population: All participants who completed both pre and post-LIFUP arterial spin labeling scans at both visits
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LIFUP to Entorhinal Cortex | Average Perfusion in Regions Of Interest | Percent Change Perfusion in the Right Amygdala | 7.07 Percent | Standard Deviation 35 |
| LIFUP to Entorhinal Cortex | Average Perfusion in Regions Of Interest | Percent Change Perfusion in the Left Entorhinal Cortex | 15.75 Percent | Standard Deviation 23 |
| LIFUP to Amygdala | Average Perfusion in Regions Of Interest | Percent Change Perfusion in the Left Entorhinal Cortex | 6.72 Percent | Standard Deviation 34 |
| LIFUP to Amygdala | Average Perfusion in Regions Of Interest | Percent Change Perfusion in the Right Amygdala | 19.52 Percent | Standard Deviation 38 |
Primary
Rey Auditory Verbal Learning Task
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
Time frame: Pre-LIFUP and Post-LIFUP at Day 1 and Day 15
Population: All participants who completed this assessment before and after LIFUP at both the entorhinal cortex and the amygdala visits were included in analyses
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LIFUP to Entorhinal Cortex | Rey Auditory Verbal Learning Task | Pre-LIFUP Learning Trials Total | 50.00 Words Recalled | Standard Deviation 11.09 |
| LIFUP to Entorhinal Cortex | Rey Auditory Verbal Learning Task | Post-LIFUP Learning Trials Total | 47.59 Words Recalled | Standard Deviation 9.21 |
| LIFUP to Entorhinal Cortex | Rey Auditory Verbal Learning Task | Pre-LIFUP Delayed Recall | 10.18 Words Recalled | Standard Deviation 2.98 |
| LIFUP to Entorhinal Cortex | Rey Auditory Verbal Learning Task | Post-LIFUP Delayed Recall | 8.82 Words Recalled | Standard Deviation 3.43 |
| LIFUP to Amygdala | Rey Auditory Verbal Learning Task | Post-LIFUP Delayed Recall | 8.47 Words Recalled | Standard Deviation 3.66 |
| LIFUP to Amygdala | Rey Auditory Verbal Learning Task | Pre-LIFUP Learning Trials Total | 50.29 Words Recalled | Standard Deviation 9.79 |
| LIFUP to Amygdala | Rey Auditory Verbal Learning Task | Pre-LIFUP Delayed Recall | 10.06 Words Recalled | Standard Deviation 2.68 |
| LIFUP to Amygdala | Rey Auditory Verbal Learning Task | Post-LIFUP Learning Trials Total | 47.88 Words Recalled | Standard Deviation 11.1 |
Primary
State Trait Anxiety Inventory - State (STAIS)
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.
Time frame: Pre-LIFUP and Post-LIFUP at Day 1 and Day 15
Population: All participants who completed this assessment before and after LIFUP at both the entorhinal cortex and the amygdala visits were included in analyses. One additional participant was removed due to presumed accidental reversal of the scale during the pre-LIFUP assessment, in which all of their responses were exactly flipped relative to their post-LIFUP responses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LIFUP to Entorhinal Cortex | State Trait Anxiety Inventory - State (STAIS) | STAIS Pre-LIFUP | 25.81 score on a scale | Standard Deviation 6.67 |
| LIFUP to Entorhinal Cortex | State Trait Anxiety Inventory - State (STAIS) | STAIS Post-LIFUP | 29.25 score on a scale | Standard Deviation 10.64 |
| LIFUP to Amygdala | State Trait Anxiety Inventory - State (STAIS) | STAIS Pre-LIFUP | 30.69 score on a scale | Standard Deviation 12 |
| LIFUP to Amygdala | State Trait Anxiety Inventory - State (STAIS) | STAIS Post-LIFUP | 30.63 score on a scale | Standard Deviation 15.09 |
Secondary
Brief Visuospatial Memory Test
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.
Time frame: Pre-LIFUP and Post-LIFUP at Day 1 and Day 15
Population: All participants who completed the assessment at all time points
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LIFUP to Entorhinal Cortex | Brief Visuospatial Memory Test | BVMT DR Pre-LIFUP | 9.63 score on a scale | Standard Deviation 2.16 |
| LIFUP to Entorhinal Cortex | Brief Visuospatial Memory Test | BVMT DR Post-LIFUP | 8.56 score on a scale | Standard Deviation 3.03 |
| LIFUP to Amygdala | Brief Visuospatial Memory Test | BVMT DR Pre-LIFUP | 10.50 score on a scale | Standard Deviation 1.41 |
| LIFUP to Amygdala | Brief Visuospatial Memory Test | BVMT DR Post-LIFUP | 8.63 score on a scale | Standard Deviation 2.83 |
Secondary
Emotional Reactivity Task
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
Time frame: Pre-LIFUP and Post-LIFUP at Day 1 and Day 15
Population: All participants who completed the IAPS ERT at all timepoints
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LIFUP to Entorhinal Cortex | Emotional Reactivity Task | Pre-LIFUP Reactivity - Arousal | 2.24 score on a scale | Standard Deviation 2.78 |
| LIFUP to Entorhinal Cortex | Emotional Reactivity Task | Post-LIFUP Reactivity - Arousal | 2.14 score on a scale | Standard Deviation 2.98 |
| LIFUP to Entorhinal Cortex | Emotional Reactivity Task | Pre-LIFUP Reappraisal - Arousal | -0.10 score on a scale | Standard Deviation 0.55 |
| LIFUP to Entorhinal Cortex | Emotional Reactivity Task | Post-LIFUP Reappraisal - Arousal | 0.22 score on a scale | Standard Deviation 0.97 |
| LIFUP to Entorhinal Cortex | Emotional Reactivity Task | Pre-LIFUP Reactivity - Valence | -3.06 score on a scale | Standard Deviation 1.84 |
| LIFUP to Entorhinal Cortex | Emotional Reactivity Task | Post-LIFUP Reactivity - Valence | -2.65 score on a scale | Standard Deviation 3.14 |
| LIFUP to Entorhinal Cortex | Emotional Reactivity Task | Pre-LIFUP Reappraisal - Valence | 0.54 score on a scale | Standard Deviation 1.11 |
| LIFUP to Entorhinal Cortex | Emotional Reactivity Task | Post-LIFUP Reappraisal - Valence | 0.07 score on a scale | Standard Deviation 0.19 |
| LIFUP to Amygdala | Emotional Reactivity Task | Post-LIFUP Reappraisal - Valence | 0.32 score on a scale | Standard Deviation 0.83 |
| LIFUP to Amygdala | Emotional Reactivity Task | Pre-LIFUP Reactivity - Arousal | 2.20 score on a scale | Standard Deviation 2.62 |
| LIFUP to Amygdala | Emotional Reactivity Task | Pre-LIFUP Reactivity - Valence | -3.44 score on a scale | Standard Deviation 1.31 |
| LIFUP to Amygdala | Emotional Reactivity Task | Post-LIFUP Reactivity - Arousal | 3.02 score on a scale | Standard Deviation 2.25 |
| LIFUP to Amygdala | Emotional Reactivity Task | Pre-LIFUP Reappraisal - Valence | 0.37 score on a scale | Standard Deviation 0.87 |
| LIFUP to Amygdala | Emotional Reactivity Task | Pre-LIFUP Reappraisal - Arousal | -0.18 score on a scale | Standard Deviation 0.45 |
| LIFUP to Amygdala | Emotional Reactivity Task | Post-LIFUP Reactivity - Valence | -3.21 score on a scale | Standard Deviation 1.71 |
| LIFUP to Amygdala | Emotional Reactivity Task | Post-LIFUP Reappraisal - Arousal | -0.36 score on a scale | Standard Deviation 0.94 |