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Featured Article
Focused transcranial ultrasound for treatment
of neurodegenerative dementia
Natalie Eleanor Nicodemus
a,
*, Sergio Becerra
a
, Taylor P. Kuhn
b
, Hannah R. Packham
a
,
John Duncan
a
, Kennedy Mahdavi
a
, Jessica Iovine
a
, Santosh Kesari
c,d
, Scott Pereles
e
,
Mike Whitney
e
, Michael Mamoun
f,g
, Daniel Franc
h
, Alexander Bystritsky
i
, Sheldon Jordan
a,j
a
Neurological Associates – The Interventional Group, USA, Los Angeles, CA
b
Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA
c
John Wayne Cancer Institute, Santa Monica, CA
d
Pacific Neuroscience Institute, Santa Monica, CA
e
RAD Alliance, Los Angeles, CA
f
Departments of Research and Psychiatry, VA Greater Los Angeles Healthcare System, Los Angeles, Los Angeles, CA
g
CNS Health, Santa Monica, CA
h
Los Angeles Brain Science Project, Santa Monica, CA
i
Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA
j
Department of Neurology, University of California, Los Angeles, Los Angeles, CA
Abstract Introduction: Preclinical studies support investigation of focused ultrasound for breakdown of ce-
rebral pathologies in neurodegenerative conditions including Alzheimer’s disease (AD) and Parkin-
son’s disease (PD).
Methods: A focused transcranial Doppler device with probes (2 MHz, 520 mW/cm
2
) affixed bilat-
erally was used to target the hippocampus (AD) or substantia nigra (PD) with functional magnetic
resonance imaging navigation for enhanced plaque removal. A total of 22 patients (n 511 AD,
n511 PD) underwent 8 consecutive, weekly, 1-hour treatments wherein sleep was encouraged natu-
rally or pharmacologically. Cognitive and motor functioning assessment was carried out using stan-
dardized evaluations at baseline and conclusion.
Results: Of all, 62.5% of patients had one or more improved cognitive scores without data incongru-
ence, 87% had stable or improved fine motor scores, and 87.5% had stable or improved gross motor
scores. No adverse events were reported.
Discussion: The safety of focused transcranial Doppler and possible enhancement in patient func-
tioning were suggested by outcome data.
Ó2019 The Authors. Published by ElsevierInc. on behalf of the Alzheimer’s Association. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Alzheimer’s; ASL; Cognition; Dementia; Parkinson’s; Sleep; Ultrasound
1. Introduction
Although the primary originating features of Alzheimer’s
disease (AD) and Parkinson’s disease (PD) are yet to be well
defined, these neurodegenerative conditions are characterized
by extracellular deposits of macromolecular material (e.g.,
plaque) which are apparently toxic and may further accelerate
deposit accretion by obstructing the flushing effects of inter-
stitial flow [1–4]. In healthy conditions, a significant
amount of extracellular waste from brain activity appears to
be removed by convection through extracellular spaces,
along perivascular spaces, into the cerebrospinal fluid space,
and then outwards along lymphatic channels [1]. The observa-
tion of plaque accumulation in AD stands as one of
the primary interventional research platforms in the
Primary Research Facility: Neurological Associates – The Interven-
tional Group 2811 Wilshire Blvd., Suite 790, Santa Monica, CA,
USA, 90403.
*Corresponding author. Tel.: 1760-473-5940l; Fax: 1310-453-3685.
E-mail address: natalie@naowla.com
https://doi.org/10.1016/j.trci.2019.06.007
2352-8737/ Ó2019 The Authors. Publishedby Elsevier Inc. on behalf of the Alzheimer’s Association. This isan open accessarticle under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Alzheimer’s & Dementia: Translational Research & Clinical Interventions 5 (2019) 374-381
neurodegenerative domain, and the pathologies of a number
of other neurodegenerative dementias have also been associ-
ated with an accumulation of toxic plaques. Abnormalities in
alpha-synuclein, for example, appear to be implicated in PD
in a manner similar to that of Amyloid-bin AD [2,3].
Numerous AD treatment trials of agents designed for either
blocking the production of Amyloid-bplaque with
enzymatic inhibitors or accelerating its destruction with
antibodies have been a focus of research to date. Despite the
robust evidence of problematic plaque accumulation,
current efforts have demonstrated moderate slowing of
cognitive decline at best and have been largely unfruitful in
reversing cognitive impairment [5,6]. This generalized
failure may be partly attributed to the potential inability of
systemic treatments to break up problematic deposits with
sufficient safety and precision. Nevertheless, systemic
approaches remain paramount given the intricate
neuroanatomical landscape of these disorders, which seems
to thoroughly complicate a targeted approach. The
development of a targeted approach, if possible, however,
could radically change the trajectory of dementia research.
The role of slow-wave sleep for disposal of toxic neurolog-
ical byproducts may be particularly relevant to this pursuit,
especially given evidence for impaired slow-wave sleep in
AD [7–10]. Neurophysiology suggests that slow-wave sleep
impairment is potentially related to the locus coeruleus and
lateral hypothalamus. A cascade of events related to these re-
gions, which appear to degenerate in AD and PD pathologies,
have been linked to astrocyte morphing for the convective
removal of byproducts through interstitial spaces [11–17].
Given this conceptual framework, it may be beneficial to
foster slow-wave sleep—or related physiological pro-
cesses—to sufficiently reopen pathways for interstitial fluid
convection to enhance disposal of activity-induced accretion.
The present study sought to incorporate deep sleep facilitation
by minimizing interference and using pharmacologic inter-
vention only when necessary for healthier sleep architecture.
A sedated state characterized by slow waves and inhibition of
norepinephrine may be created with some short acting agents
such as dexmedetomidine [18]. Conceptually, dexmedetomi-
dine may be preferred to other agents because it is a short
acting norepinephrine blocker, which could mimic slow-
wave sleep architecture, opening interstitial spaces and facil-
itating plaque removal. Dexmedetomidine may also be
preferred given its safety profile among the elderly and
acutely ill compared with other anesthetic agents [19–22].
Thus far, techniques including immune therapy aimed at
plaque for solubilizing, mobilizing, and facilitating convec-
tive forces have been minimally effective. The minimal
benefit observed [5,6], however, may still inform a refined
approach for enhancing glymphatic processes. Recently,
focused ultrasound modalities have been developed with
implications for a variety of neurological conditions. This
modality has been used for many applications in health
care, such as fragmentation and mobilization of kidney
stones. The technology has demonstrated capacity to alter
targeted tissues through heating, mechanical distortion, and
chemical changes induced by acoustic energy absorption
processes—all of which have potential implications for the
dissolution of problematic plaque accretion. Noninvasive
cerebral applications include clot lysis in patients with
middle cerebral artery thromboembolism, and higher
intensity heating has been used for targeted ablation in
treating tremor and metastatic disease [23,24]. Safety and
efficacy have been demonstrated in these prior clinical
applications. Future applications are already in development
for low-intensity ultrasound targeted drug delivery, given its
demonstrated ability to penetrate the skull to reach and exert
an effect on deep neural tissue with high spatial (millimeter)
resolution [25,26] resulting in successful changes in
regional neuronal activity in both animals [27] and humans
[28–33]. Indeed, early histology and animal studies of low
intensity focused ultrasound pulsation demonstrated its
ability to produce reversible physiologic effects on neuron
clusters, including increased activity in targeted areas [34].
Notably, a preclinical study of low-intensity focused ultra-
sound has successfully treated amyloid plaque in a mouse
model of AD, showing both that ultrasound can effectively
target subcortical regions of interest (e.g., hippocampus)
and that can successfully aid in the clearance of amyloid
[35–37]. Other studies suggest that hippocampal neogenesis
may also be induced by transcranial ultrasound, indicating
that this modality could have regenerative value for
neurodegenerative conditions [38].
Considering the foregoing, the present study was devel-
oped to increase plaque removal in neurodegenerative cere-
bral pathology using a modality similar to sonolysis, which
has already demonstrated safety and potential efficacy in hu-
man subjects. The project was outlined as an open-label,
clinical study of patients with mild cognitive impairment
(MCI) or dementia to evaluate feasibility, tolerability, and
efficacy of focused transcranial ultrasound. Aspects of brain
physiology and brain fluid dynamic pathophysiology were
leveraged for optimal application. Particularly, facilitation
of slow-wave sleep by means of sleep deprivation was incor-
porated through minimized stimulant medication, and in
some cases, sublingual administration of dexmedetomidine.
The transcranial ultrasound equipment that has been used for
human clot lysis was adopted to target the hippocampus in
patients with AD. Patients with PD were also included in
this study with the substantia nigra as a target for treatment.
Building upon a robust framework, we sought to investigate
the ability of focused ultrasound and slow-wave sleep mod-
ulation to improve cognitive performance in patients, pre-
sumably through increased removal of extracellular debris.
2. Methods
2.1. Subjects
This study was approved by an institutional review board,
and all patients provided written informed consent. A total of
22 patients (Alzheimer’s, n 511; men: n 58, women:
N.E. Nicodemus et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 5 (2019) 374-381 375
n53) (Parkinson’s, n 511; men: n 58, women 53) aged
40 to 95 were enrolled in this open-label, clinical study. Pa-
tients who demonstrated cognitive decline were identified
within the study clinic and were given the opportunity to pur-
sue inclusion. Further recruitment was not necessary, and pa-
tients were not compensated for participation. A Clinical
Dementia Rating (CDR) between 0.5 (MCI) and 2 (moderate
dementia) was required, which was determined by adminis-
tration of the Quick Dementia Rating System (QDRS). The
QDRS and remaining protocol evaluations were adminis-
tered before entry. Patients were required to have an
advanced magnetic resonance imaging (MRI) of the brain
including volume measurement of the hippocampus, arterial
spin labeling (ASL) perfusion scans, and magnetic reso-
nance spectroscopy of prefrontal cortex, precuneus, and hip-
pocampus. These imaging modalities have been
demonstrated as meaningful clinical indicators for discrim-
inating among neurodegenerative subgroups and show sensi-
tivity to change as patients progress from MCI to dementia.
Participants were required to demonstrate at least one imag-
ing biomarker of AD or PD for inclusion in the study. Other
pathological findings that could be related to the patient’s
condition (e.g., neoplasm, cortical dysplasia, stroke) were
exclusionary. Lumbar puncture for bamyloid-42 and tau
proteins, which has demonstrated sensitivity and specificity
for identifying MCI and AD [39], was also required for
screening. Patients who were unable or unwilling to undergo
any of these screening procedures were excluded. Inability
to give informed consent was also a basis for exclusion,
and progressed cognitive decline to a degree that would
inhibit maintained informed consent could result in removal
from the study unless a legal representative gave written con-
sent. Patients with cognitive decline due to acute illness or
vascular dementia were excluded. Advanced terminal
illness, advanced kidney, pulmonary, cardiac, or liver fail-
ure, and major depressive disorder were all exclusionary
criteria. The Beck Depression Inventory-II, which has
been demonstrated as a statistically valid and reliable mea-
sure of major depressive disorder, was administered as a
depression screening method [40]. Exclusionary criteria
also included the presence of a scalp rash, open wounds on
the scalp, definite or probable pregnancy, breastfeeding,
and an inability to lay down without excessive movement
to achieve deep sleep. Concurrent interventions and thera-
pies were not a basis for exclusion unless the study doctor
deemed them likely to threaten patient safety when used in
conjunction with the study protocol.
2.2. Neurocognitive and behavioral performance
All participants underwent a battery of baseline and
conclusion cognitive assessments. The QDRS, an expedited
evaluation similar to the CDR assessment, was selected as
the primary staging tool for this study [41]. This evaluative
tool consists of 10 (5 cognitive, 5 functional) categories with
5 corresponding descriptions depicting clinical progression
per category. These depictions range in severity according to
the following scale: 0 (normal), 0.5, 1, 2, and 3 (severe).
Trained administrators conducted an interview with next of
kin to patients to assign ratings in each of these 10 domains,
which resulted in cognitive and behavioral subtotals. Total
QDRS scores were translated to CDR scores according to
the conversion table outlined in Galvin’s QDRS research[41].
The Repeatable Battery for Assessment of Neuropsycho-
logical Status (RBANS) (versions A, B, C, and D) and the
Montreal Cognitive Assessment (MoCA) (versions 1, 2,
and 3) also served as discrete cognitive performance mea-
sures. The RBANS, a statistically reliable and sensitive stan-
dardized adult (20-89) repeatable measure for detection of
MCI and dementia [42], was used to assess cognitive func-
tioning in terms of immediate memory, visuospatial/
constructional, language, attention, and delayed memory
performance. Domain-specific index scores were evaluated
individually alongside total index scores. The MoCA, a
30-question and approximately 10-minute test shown to be
highly sensitive and reliable for assessment of MCI and de-
mentia, was included to evaluate data convergence [43]. This
test probes multiple domains including visuospatial/execu-
tive, naming, memory, attention, language, abstraction, de-
layed recall, and orientation abilities. Possible scores range
from 0 to 30 with a score of 26 or greater considered to be
normal [43]. Motor functioning, which is particularly rele-
vant in PD, was also evaluated using the Timed 25-Foot
Walk Test (T25-FW) for gross motor functioning and the
Rolyan ÒNine-Hole Pegboard Test (9-HPT) for assessment
of fine motor dexterity. Both movement assessments have
shown statistical validity and reliability [44,45].
2.3. Advanced MRI
Advanced MRI was performed at screening and upon
completion of the study. These scans were performed at
one of three imaging centers in the Los Angeles/Santa Mon-
ica area: Resolution Advanced Imaging Center, Westwood
Open-MRI, and Tower Saint John’s Imaging. Patients were
required to undergo follow-up imaging at the same center
as baseline. All acquisition parameters were approved by
the Food and Drug Administration. Routine neuroradiolog-
ical interpretations were rendered by collaborating neurolo-
gists and neuroradiologists as part of a dementia consensus
conference. The findings of these neuroimaging studies
were used to help determine patient disease classification.
Two patients consented to have additional ASL MRI se-
quences for observation of regional cerebrovascular perfusion
for investigation of direct physiological effects. These se-
quences were performed immediately before and after their
final sessions of treatment. Postprocessing was performed us-
ing FMRIB Software Library [46] with identical parameters.
ASL data were superimposed over the acquired T1-weighted
brain image demonstrating a map of cerebral perfusion.
Voxel-based comparisons showing perfusion values relative
to the acquired data range were used for quantification.
N.E. Nicodemus et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 5 (2019) 374-381376
2.4. Procedure
Screened participants underwent eight consecutive,
weekly, 1-hour focused ultrasound sessions using the
DWL Doppler Box X [47]. Ultrasound was delivered using
a 2 MHz transducer at a power of 520 mW/cm, which is un-
der the Food and Drug Administration-allowed threshold of
750 mW/cm. Parameters were adapted for this novel context
because of the safety demonstrated in prior studies of sono-
thrombolysis for treatment of stroke [48]. While patient-
specific accumulated plaque cannot be directly targeted,
regions implicated in the pathology of various neurodegen-
erative syndromes were targeted. The mesial temporal lobe
was targeted in AD and the substantia nigra was targeted
in PD cases.
Targeting was done with a combined approach of MRI
and Doppler guidance. First, the posterior cerebral artery
was identified on the patient’s T1 MRI sequence in 3 dimen-
sions. Potential deformation of acoustic waves by the skull
was minimized by using the “temporal window,” a thin re-
gion of the skull that usually allows for successful insonation.
Using the OsiriX imaging viewing software, measurements
to surface fiducials were made for location identification
when projected tangentially to the skull’s surface at the thin-
nest region of the temporal window [49]. These measure-
ments were used to mark the patient’s scalp at the target
site bilaterally. Monitoring probes attached to a DWL Elastic
Headband were then placed on the drawn targets. To further
refine transducer placement, Doppler waveforms were used
to identify the posterior cerebral artery, which runs from
medial to the mesial temporal lobe. The monitoring probe
was manipulated until the posterior cerebral artery was de-
tected with blood flow moving away from the probe to target
the hippocampal region and with flow moving toward the
probe to target the substantia nigra region. After the trans-
ducers were affixed bilaterally, power was increased to the
investigational therapeutic level, 520 mW/cm.
The procedure took place in a quiet room monitored by
medical staff. Patients were instructed to try to sleep for
the duration of the hour-long procedure. Standard clinical
techniques were used to promote sleep in the office,
including mild sleep deprivation and discontinuation of
stimulating medications. If patients otherwise indicated an
inability to fall asleep, dexmedetomidine was given at a
dose congruent with patient height, weight, and medical his-
tory. This medication was administered sublingually using a
Teleflex Intranasal Mucosal Atomization Device, which al-
lowed the medication to be administered in the form of a
spray [50]. Patients were instructed to keep the medication
in their mouth for about 2 minutes, or until fully absorbed.
Pulse oximetry and blood pressure were monitored
throughout the duration of treatment when dexmedetomi-
dine was given, which was only given when necessary for
sleep. The ultrasound procedure and any methods utilized
to achieve deep sleep were replicated each week. Patients
were discharged at the end of treatment when fully awake
and, if given medication or if otherwise necessary, in the
care of a responsible adult.
3. Results
3.1. Tolerability and feasibility
All patients were able to tolerate treatment without notable
side effects. Posterior cerebral arteries were successfully inso-
nated in all patients, demonstrating the feasibility of targeting
methods. Sleep was achieved by all patients during treatment.
Dexmedetomidine, which was administered regularly in 14
patients, had no accompanying adverse events. This medica-
tion, then, appeared to be a safe sleep agent for use in an older
adult population.
3.2. Cognitive faculties
Twenty-one of 22 patients (95.5%) had stable CDR
scores after treatment. Six of 22 patients (27.3%) demon-
strated clinically meaningful improvement in RBANS total
index scores while 15 of 22 (68.2%) had clinically stable
scores. Three patients (13.6%) demonstrated a clinically
meaningful decline on the RBANS. Clinically significant
improvement on the MoCA was seen in 7 patients (31.8%)
while 8 patient scores (36.4%) showed no clinically signifi-
cant change. Seven patients (31.8%) demonstrated a clini-
cally significant decline in MoCA performance.
Assessment of data convergence revealed 1 patient
(4.5%) with clinically significant improvement on all 3
cognitive measures secondary to ultrasound treatment.
Data incongruence, which was defined as clinically signifi-
cant improvement in one or more measure with an opposing
decline in another, was seen in 3 patients (13.6%). Two of 22
patients (9.1%) improved on at least 2 cognitive measures
without any incongruence; Two patients (9.1%) had clini-
cally significant decline on at least 2 of the 3 cognitive mea-
sures without incongruence. Fouteen patients (63.6%) had a
combination of at least one improved score without incon-
gruence at conclusion. Seven patients (31.8%) had a combi-
nation of at least one declined score without incongruence at
conclusion.
3.3. Motor functioning
Assessment of fine motor dexterity using the 9-HPT re-
vealed 1 (4.5%) clinically significant improvement of the
dominant hand after ultrasound, 3 (14.3%) clinically signif-
icant declines after ultrasound, and 19 (90.5%) stable mea-
sures (1 patient did not complete the follow-up 9-HPT, and
results were therefore thrown out). Gross motor functioning
on the T25-FW revealed 2 (9.1%) clinically significant im-
provements, 3 (13.6%) clinically significant declines, and
17 (77.3%) stable outcomes. Convergence of data showed
no incongruence among individual patient motor func-
tioning scores. No patients had clinically significant
improvement or decline on both measures after ultrasound.
N.E. Nicodemus et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 5 (2019) 374-381 377
3.4. Imaging assessment
ASL imaging sequences perfromed immediately before
and after one 1-hour session of ultrasound for a subsample
of two patients showed markedly increased perfusion at
the targeted hippocampal region after ultrasound (Fig. 1).
Quantification of relative cerebral perfusion in various re-
gions demonstrated a greater than 150% increase in relative
blood perfusion at the bilateral hippocampi in patient 1. A
greater than 50% increase in relative perfusion was seen at
the right hippocampus of patient 2, but the left hippocampus
had only a 7% increase in relative perfusion.
4. Discussion
Feasibility was demonstrated through successful target
insonation and the ability of all study patients to treatment
without adverse events. Outcome data was generally stable
across cognitive and motor domains among patients, which
further supports safety in the given population. Co-occurring
interventions make it difficult to identify direct relationships
between outcome and the various aspects of the study proto-
col or incidental variables. Less than 30% of patients, how-
ever, demonstrated clinically significant decline in cognitive
or motor domains, which supports overall safety. Of all,
62.5% of patients demonstrated clinically significant
improvement on at least one cognitive measure, suggesting
some positive interventional effect. Incongruent changes to
cognitive status observed (decline on one measure, improve-
ment on another) in 3 patients could indicate differences in
regionally specific sensitivities among the outcome mea-
sures. Co-occurring interventions, specifically tyrosine ki-
nase inhibitor (TKI) intake, modified the investigational
premise over the course of this study. To detect data trends
that might differentiate ultrasound and TKI effects, addi-
tional data were observed for comparison of change before
and after inclusion of this focused ultrasound study in indi-
vidual patient care (see Supplementary Results). The addi-
tional data from 14 patients demonstrated a trend toward
overall positive outcome after the inclusion of ultrasound
with ongoing TKI treatment. Because of the nature of these
degenerative conditions, any positive change may be consid-
ered noteworthy becaue decline is more common in these
conditions than improvement without an intervention of
therapeutic value. Counterintuitively, comparison of results
before and after ultrasound demonstrated equally prevalent
improvement and decline in patient cognitive status.
Given the limited timeframe and lack of later follow-up,
detection of longer-term benefit is currently unavailable. It
is unlikely that the breakdown and removal of plaque alone
(through either the ultrasound, TKI, or a combined approach)
would be sufficient to overcome deficits given the neuronal
loss engendered by their presence. Toward this end, future
studies may benefit from inclusion of blood and/or
cerebrospinal fluid-based monitoring of histological markers
(e.g., amyloid peptides, alpha-synuclein, activated macro-
phages) to help further elucidate the cellular mechanism of
action underlying the results reported herein. More regenera-
tive methods, possibly in the form of stem cells or exosomes,
may provide further benefit to cognitive status. The observa-
tion of cognitive performance improvement occurring more
frequently than motor performance improvement could fall
in line with this concept. The substantia nigra may receive
less therapeutic benefitfrom the treatments investigated here-
in for one or a combination of several reasons. These include
that the substantia nigra is typically at least 70% degenerated
before the onset of motor symptoms [51] and therefore the
removal of plaque occurs too late in the degenerative process
or that chemical alterations secondary to the degeneration,
which would not likely have been modified by breakdown
of plaque with the TKI or ultrasound directly, are responsible
for ongoing progression of motor decline.
Ultrasound for targeted delivery of regenerative therapies
or neurochemical interventions may be the next step for
improved patient outcome. Efficacy of the combined MRI
Fig. 1. Pre– and post– ultrasound arterial spin labeling (ASL) sequences demonstrating a color map of relative blood flow perfusion with red (lower) to yellow
(higher) perfusion values, which was registered and superimposed over a T1-weighted MRI of the brain. Four three-panel images demonstrate the results of 2
patients (A and B) (1) immediately before and (2) immediately after one-hour of ultrasound treatment.
N.E. Nicodemus et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 5 (2019) 374-381378
and Doppler navigational methods was demonstrated in 2
case studies using ASL imaging before and after 1 hour of
ultrasound. These imaging sequences revealed relatively se-
lective hyperperfusion of the targeted ultrasound region such
that the efficacy of ultrasound for targeted drug delivery
seems particularly plausible. It is also possible that the
mechanism of action in this study was that of targeted
drug delivery given the concurrent use of the TKI medica-
tion. Because of the nonlimiting inclusion criteria, this study
design does not allow for delineation of therapeutic mecha-
nism. Observation of ASL response to focused ultrasound
could be beneficial for better understanding of blood flow
modulation and enhanced perfusion in a larger dataset.
With further study, the changes to relative cerebral perfusion
observed in this study could further support a mechanism for
therapeutic benefit with a broad range of applications. He-
modynamic changes on ASL imaging could, however, also
support the original goal of breaking down pathologically
relevant protein accumulations for facilitated removal. For
future development, refined targeting and greater selectivity
could be available with systems that combine multiple ultra-
sound sources in a spherical array or hybrid system at the
temporal window, acoustic wave correction for skull distor-
tion, and thermal imaging with MRI, so called high-intensity
focused ultrasound [48].
Similarly, inclusion of blood and/or cerebrospinal fluid-
based histopathological markers of amyloid, synuclein, and
macrophage activity could provide additional insight into
the mechanism of therapeutic action. Although outside
the scope of this study, animal modeling could also provide
meaningful insight into the mechanism of action of ultra-
sound on amyloid disposal as well as provide additional in-
formation about the specific ultrasound parameters (e.g.,
pulse repetition frequency) which yield the greatest thera-
peutic benefit. Because mechanical and heating effects
may be helpful for direct dissolution and mobilization of
amyloid plaque, the established ability of transcranial ultra-
sound to stimulate neuronal discharge may facilitate
convective forces by the release of glutamate and the sub-
sequent activation of astrocyte filopodia similar to the acti-
vation seen in slow-wave sleep [30,52]. Enhancement,
then, may be made through one Hertz pulse rates to
cohere with natural burst rates of neurons in slow-wave
sleep. Alternatively or perhaps additionally, it is possible
that ultrasound is inducing, recruiting, or enhancing
gamma oscillations within the hippocampus that have
recently been shown to increase amyloid removal via
enhanced microglial colocalization with amyloid [52].
While gamma oscillations are certainly a possible mecha-
nism, this process is unlikely to be the only driving factor
behind our findings, as gamma oscillations have not been
reliably demonstrated to occur in other targeted regions,
such as the substantia nigra. Finally, it will be important
for such studies to use a technique to quantitatively assess
plaque density before and after treatment to further eluci-
date the mechanism of therapeutic action.
Overall, the present study provides data to support ongoing
investigation in targeted ultrasound therapeutics, suggesting a
slowing of neurodegeneration and indicating potential for
regenerative developments through directed delivery of thera-
peutic substances. Advanced imaging gives more insight into
mechanism of action, specifically regarding targeted modifi-
cation of blood perfusion using hour-long ultrasound delivery.
Further research should include larger sample sizes and
extended follow-up to better understand the efficacy of this
intervention, but this study demonstrates an early framework
of advanced technological clinical research in a dominantly
pharmacologic interventional setting.
Acknowledgments
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
All contributing authors have reviewed this submission and
indicate no conflicts of interest.
Supplementary Data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.trci.2019.06.007.
RESEARCH IN CONTEXT
1. Systematic review: The authors reviewed literature
using traditional (e.g., PubMed) sources and meeting
abstracts and presentations. Sleep and insufficient
disposal of problematic accumulations appear to be
relevant for neurodegenerative pathology in Parkin-
son’s and Alzheimer’s diseases. Focused ultrasound
may have the ability to facilitate disposal of toxic ag-
gregations, and sleep management may also be
important in this process.
2. Interpretation: Our findings led to the hypothesis that
focused ultrasound delivered in a targeted manner
with imaging and Doppler guidance may be able to
inhibit decline and promote improved cognition.
3. Future directions: This study demonstrates an early
framework of advanced technological clinical
research in a dominantly pharmacologic interven-
tional setting. Further research should include larger
sample sizes and extended follow-up to better un-
derstand the efficacy of this intervention and the new
possibilities enabled by its mechanism, namely in-
clusion of potentially regenerative substances, such
as stem cells or exosomes.
N.E. Nicodemus et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 5 (2019) 374-381 379
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