Intraoperative functional Ultrasound (fUS)-imaging during awake and anesthetized neurosurgical procedures

A plethora of methods, tools and techniques have essentially contributed to our
understanding of brain functioning. Today, one of the most promising techniques
is ultrasound imaging. Recent advances in computing power and the ability to
record raw ultrasound signals have enabled a technique called highframe-rate
(HFR) ultrasound, which offers images at thousands of frames-persecond. Because
of the high temporal resolution, this technique is sensitive for very small
Doppler shifts (also called µDoppler), such as those caused by the moving blood
inside brain vasculature. The HFR ultrasound technology to measure local
increases of CBV as a result of neural activity is referred to as functional
ultrasound (fUS). The clinical application of this innovative technique of fUS
could have great benefits in fields such as that of neurosurgery.

On a daily basis, neurosurgeons face the difficult task to identify and
distinguish pathological tissue such as brain tumors, AVMs and/or ischemic
stroke tissue from functional healthy tissue, with the ultimate aim of
maximizing excision of pathological tissue and minimizing postoperative
neurological damage. However, visualization of healthy functional neurological
tissue, in relation to pathological tissue, both pre- and intra-operatively,
remains a significant challenge and bottleneck in the treatment. With the
introduction, adaptation and application of fUS to the clinical field of
neurosurgery, we will be equipped with a tool that enables us to better
delineate pathological from healthy tissue during surgery. Indeed, by relying
on the characteristic neurovascular changes that can be specifically associated
with functional or pathological neuronal tissue, fUS will allow us to make
image-guided decisions during the neurosurgical dissection. With the additional
use of the ultrasound contrast agent, the image quality of the vascular
structure and dynamics can increase substantially. The higher signal-to-noise
ratio that comes with the use of the contrast agent can increase imaging depths
to reach deeper tumors, achieve higher resolution to visualize smaller
vasculature, and lead to better delineation of tumor boundaries.

With the potential benefits that fUS presents, the research group aims to
conduct a first, proof-of-principle study in the clinic, using fUS
intra-operatively during the neurosurgical procedure of awake craniotomy for
the indication of brain tumor removal.

Firstly, to assess the ability of fUS to discriminate between functional and
non-functional brain areas using task-specific brain-activity during an awake
neurosurgical procedure. Secondly, to assess the ability of fUS to discriminate
between healthy vs. pathological tissue such as (vascular) tumor tissue and
ArterioVenous Malformations (AVMs), based on differences in microvasculature
both in the awake patient group (tumor) and patients under anaesthesia (tumor
and AVM). In addition we will assess cerebral blood volume (CBV) of healthy vs
tumor tissue using contrast enhanced ultrasound (CEUS).

Group A: Patients undergoing awake neurosurgery for tumor removal. Based on the
(extended) clinical pre-operative fMRI and functional map created by using
intraoperative electrocortical stimulation mapping (ESM) (the golden standard
during routine awake craniotomy surgery), we will identify and image functional
and adjacent non-functional brain areas related to specific tasks using fUS.
The tasks used will range from muscle movements to speaking, and will be
alternated with control tasks. Additionally, we will subject patients to a
post-operative fMRI to further validate the fUS-defined functional areas deeper
in the brain. This will be performed in the awake patient group only. In
addition we will perform fUS CBV imaging of healthy vs. tumor tissue before and
after tumor resection. The fUS imaging will last a maximum of 22 minutes in
total, the total scanning time in the fMRI will be max. 1,5 hour. Group B:
Patients undergoing anesthetized neurosurgery for tumor or AVM removal. We
will perform healthy vs. tumor- or AVM-tissue fUS imaging before and after
tumor resection. The fUS imaging will last a maximum of 22 minutes in total.
Group C: Patients undergoing anesthetized neurosurgery for tumor or AVM
removal. We will perform healthy vs. tumor- or AVM-tissue fUS and CEUS imaging.
The measurements will be repeated after tumor removal is completed, but before
the skull is closed. The total imaging time during the surgical procedure will
be a maximum of 22 minutes.

As functional mapping using ESM and Ultrasound is already an integral element
of awake craniotomy surgery, the nature and extent of the burden for the
patient remains limited. The patient will have no burden of the imaging process
using fUS and the specific tasks we will ask the patient to perform will be
very similar to the tasks already performed during ESM. The tasks together will
not take longer than 22 minutes, minimizing the extra time necessary for
surgery. In addition, as fUS-imaging is very similar to any type of ultrasound
imaging already used in a clinical setting and during awake craniotomy surgery,
there will be no additional risks associated with participation. Also, the
exposure levels for the fUS imaging sequences (insonification with unfocussed
beams) are well below FDA limits. For the non-awake patient group (both tumors
and AVMs), a similar situation as described above applies, with the difference
that patients will be subjected to tumor- or AVM-imaging only and will not be
awake to consciously experience the 22 min. extension of the surgical
procedure.
The ultrasound contrast agent used in CEUS, Sonovue, is safe (Sonovue -
European Public Assessment Report, 2020) and registered for Doppler
measurements. It is already used routinely in EMC's Cardiology department for
cardiac function assessments. The most common adverse reactions in clinical
trials are headache (2.3%), injection site pain (1.4%) and local injection site
reactions including hematoma, warmth and paresthesia (1.7%). There is a very
small chance of an allergic reaction after administration of ultrasound
contrast agents (0.01%).'
If an allergic reaction occurs during the study, the anesthesiologist will
treat the patient with the most suitable medication and appropriate dosage.
Additional blood tests will not be required. The risks associated with
participation can be considered negligible and the burden can be considered
minimal.
Finally, the awake patient group is specifically asked to undergo an additional
1,5 hours of fMRI-scanning, divided over a pre- and post-operative session. As
the pre-operative session is already part of the standard clinical procedure,
we expect limited additional burden for the patients. For the post-operative
session, the duration will be limited to max. 1 hour and the session will be
planned after the surgical procedure at a moment best convenient to the
patient. There are no risks associated with undergoing the fMRI-scan. The
longer duration in the scanner can, however, lead to additional psychological
burden/discomfort, especially if the patients is already anxious for the scan.
Taking everything into account, we expect that the extent the burden for the
awake patient group (although slightly higher than the anesthetized patients),
is acceptable.
Patient participation in the study will, however, lead to the benefit of
further determining and increasing the potential use of fUS as a new and highly
powerful intra-operative imaging tool, which has the ability to present areas
of functional tissue deep inside the brain and show differences in tissue
vascularity even when tumor or AVM-tissue appears similar to healthy tissue in
an intraoperative setting.