Parameters
The biological substrate deals with the underlying physiological process which is used as a measure of functionality by each of the techniques. The biological substrate that is measured dictates whether a technique gives direct access to functionality (i.e. measures electrical activity of neurons) or by proxy (i.e. metabolisms or blood dynamics) through the so-called process of neurovascular coupling (NVC).
Electrical
As neurons activate, they produce electrical activity known as action potentials through passive and/or active exchanges of ions across the neuron’s cell membrane. These electrical signals are measurable on a single-neuron level, as well as of groups of neurons (local field potentials) or full brain regions, as is the case for electro-encephalography (EEG). Detecting this electrical activity is a direct measure of neuronal activity and functional activation.
Conversely, administering electrical current to regions of interest to produce or interrupt functions can be used in an intra-operative setting to form an in-vivo cartography of the brain. One of the most wide-spread applications of the latter involves electrocortical stimulation mapping (ESM) during awake surgery (1).
Neurovascular Coupling
The term Neurovascular Coupling (NVC) describes the mechanisms responsible for linking (electrical) neuronal activity to corresponding changes in blood dynamics (2,3). These mechanisms consist of intricate interplays between many different components including neurons, astrocytes, pericytes, and smooth muscle cells (SMC) of neighboring arterioles (4). With an increase in activation of neurons, energy consumption increases, which needs to be metabolized locally from glucose and oxygen supplied by blood through local vessels. In response to transient neural activity nearby vessels dilate, substantially increasing Cerebral Blood Flow (CBF) and Cerebral Blood Volume (CBV), known as ‘functional hyperemia’. Although the exact physiological processes underlying this coupling remain to be elucidated, many functional techniques use the changes in metabolism or blood dynamics as a proxy for the actual electrical neuronal activity, assuming that the increase in blood flow matches the metabolic need of the tissue (5). This means that temporally, the CBV impulse response function is thought to start at 0.3 s and peak at 1 s in response to ultrashort stimuli (300 μs), which is much slower than the underlying electrical activity (6). Spatially, the resolution of e.g. sensory-evoked CBV response can go down to one cortical column (∼100 μm) (6,7).
Blood Dynamics
With the term ‘blood dynamics’ we encompass the range of vascular-related changes which correspond to the increase in energy consumption produced by activated neurons. These changes include an increase in CBF, changes in vessel diameter (dilatation/constriction) as well as changes in Cerebral Blood Volume (CBV) (5). In contrast to the electrical activity, which is a direct measure of neuronal activation, blood dynamics serve as a proxy, with significant latencies between neuronal activity and hemodynamic response. Many of the efforts within blood-dynamics-based functional techniques, such as fMRI, focus on understanding these response characteristics using so-called hemodynamic response function (HRF), applying this knowledge to improve statistical models used for identification of active regions (8). The physiological processes underlying this response remain unelucidated, especially in light of the potential neurovascular variances or even neurovascular decoupling which might be present in neurological disease (9,10).
Metabolism
In addition to the blood dynamics, objectifying the metabolic processes coupled to the neuronal activation can also provide functional information. Positron Emission Tomography (PET), for example, makes use of radioactively labeled chemicals which have a metabolic role (11). An example of such a radiotracers is 18F-FDG, which labels glucose as it is metabolized in the brain. Detection of this radioactively-labeled glucose, can indicate a regional increase in energy consumption – and by definition – a regional functional response to for example a functional task. Metabolic techniques such as PET are also used to visualize generalized brain metabolism, which can be an indication of pathologies such as Parkinson’s or Alzheimer’s disease (12).
This category includes those parameters inherent to the imaging technique and its underlying technical characteristics. Possible parameters of importance here include spatial and temporal resolution, imaging depth and field of view, each of which will be discussed below within the context of intra-operative use by a neurosurgeon.
Spatial resolution
The spatial resolution of a technique concerns the physical dimensions that the technique’s smallest unit of measure represents. In case of images, this would concern the physical dimensions represented by a single pixel within the image. The spatial resolution of a functional technique in an intra-operative setting dictates the precision with which (the boundaries of) functional structures can be identified and distinguished, and as a consequence, the precision with which decisions can be made based on these techniques. Ideally, spatial resolution is small enough to readily and safely distinguish what is for example tumor and what is eloquent brain tissue. However, there is also a limit to how useful an increase in spatial resolution can be. With very high spatial resolution, but no ability to act with the same resolution (e.g. no ability to cut or resect on a micrometer-scale), a super high-resolution technique might effectively not lead to an improvement of safety and surgical success in an intra-operative setting.
Depth of Penetration
Not only the spatial resolution but also the depth of the brain which can be covered, is an important factor dictating a technique’s intra-operative potential.
Depth penetration is often a characteristic inherent to the technique’s contrast mechanism: optical techniques generally present with low penetration due to high scattering by the tissue, whereas ultrasonic scattering is orders of magnitudes weaker, allowing for deeper penetration (13). Often there is also a trade-off between a technique’s spatial resolution and its penetration-depth. Wanting to look at deeper brain regions, such as nuclei or functional tracts, might come at the cost of seeing these structures with less resolution. On the other hand, having access to superficial cortical regions only can expose relevant functional regions, but might not draw the full picture needed in an intra-operative setting. In a neuro-oncological procedure, for example, awake mapping of the eloquent cortical areas can be a powerful tool to ensure safe tumor removal. However, without the ability to identify the involvement of deeper structures such as the pyramidal tract or the arcuate fasciculus, post-operative neurological deficits might nevertheless occur.
Depth Resolution
Not only the penetrative depth of a technique is relevant, but also whether the technique can offer actual resolution in the depth axis. Some techniques, such as LDF, can sample the biological substrate up to several centimeters in the brain, but without the ability to spatially discerned the signal along this depth axes. In contrast, techniques such as fUS, are depth-resolved and are able to provide this spatial resolution along the depth-axis.
Field of view
The field of view is a third aspect which together with the spatial resolution and depth of penetration dictates how much of the brain can be seen at once or after one acquisition session. In this paper we discuss the field of view on a scale ranging from neuronal level to the whole brain.
Temporal resolution
The temporal resolution tells us how fast a technique is able to sample the biological substrate which is underlying a technique. Whether a technique’s temporal resolution is ‘sufficient’ to reconstruct the time course of the dynamic process depends on the actual temporal resolution of the underlying biological substrate.
Intra-operative Availability
Whether a technique allows for real-time, intra-operative detection, measurement, imaging or mapping of brain tissue functionality can be of great consequence. Techniques such as functional Magnetic Resonance Imaging (fMRI) allow for pre-operative planning of the surgical procedure based on identification of functional regions, for example in close proximity to the tumor’s borders (14). However, intra-operatively, these images need to be merged with the in-vivo brain anatomy in sight of the surgeon. Due to the inevitable brain shift after cranio- and durotomy, pre-operative images only provide a rough estimation of the 3D-locus of the tumor during surgery (15). In fact, in most clinical settings, these fMRIs are not available intra-operatively. Techniques which do allow for intra-operative acquisition, have the potential to be more in line with the in-vivo anatomy. However, for intra-operative acquisition, new challenges arise such as acquisition time and ease of use.
Apart from technical characteristics, the usefulness of these functional techniques in the context of neurosurgery is heavily dependent on other parameters such as mobility and compatibility with surgical workflow. Several of the functional techniques discussed here will already have a history of clinical use, while others are only used in a pre-clinical stage, but hold promise of applicability in an intra-operative setting.
Mobility
Whether a technique is hand-held or not, can be moved from one operating room to another, or requires its own dedicated space (as is the case of intra-operative MRIs for example (16)), has a huge impact on the technique’s applicability in a clinical and especially intra-operative context. Interruption of the surgical workflow, for example to prepare and move a patient to a scanner, is to be avoided as much as possible. What is more, techniques which allow a patient to wear or even implant the device, move the frontiers of a functional technique beyond that of the operating room alone, opening up possibilities of pre- and post-operative planning or monitoring.
Transcranial ability
Written from the intra-operative perspective, the ability for a technique to penetrate through the skull (transcranial) might in first instance sound of secondary importance. In the OR-setting, we assume that the tissue of interest (be it the brain or the spinal cord) is already exposed and accessible. Often, intra-operative techniques require even more, in terms of for example an awake patient so that measurements are not disrupted by the use of anesthetics. However, a technique with a transcranial ability has the potential for pre-operative surgical planning, as well as post-operative monitoring, which might add to the intra-operative goals.
Need for Contact
Whether or not a technique needs to make physical contact with the brain to sample the biological substrate, can be of great consequence for the surgical workflow. When using cortical grids, for example, the surgeon is not able to manipulate the brain during acquisition of the functional map, which dictates the surgical workflow. In contrast, optical techniques such as LDF do not require physical contact with the brain, and can be even incorporated into conventional surgical microscopes (17).
Multimodal potential
In the intra-operative or clinical setting in general, techniques are often used in concomitance. Being able to confirm tumor-location with ultrasound in addition to the intra-operatively available MRI, for example, can serve as a confirmation of tumor borders (18). However, some techniques are inherently more difficult to combine with others, due to for example electrical or susceptibility artifacts.
Visual Presentation
In the intra-operative setting especially, surgeons need to be able to act quickly and with relative certainty based on the feedback they receive from the functional technique. How this information or brain functionality is presented, can greatly influence its effectiveness in an intra-operative setting. One can imagine how volumetric, or 3D-information representing a surgeon’s field of view, might be more intuitive than presenting a single 2D-slice or signal trace representing functionality in part of the regions of interest. However, some techniques do not readily allow for 3D or even 4D, or require significantly longer acquisition times to facilitate this multidimensionality, which is also potentially problematic in an intra-operative setting. On the other hand, the cognitive load of interpreting the results of a technique cannot be too high in an intra-operative setting, which is a challenge for multidimensional techniques.
Acquisition time
Many of the technical parameters described above, together influence how long a single acquisition and a full acquisition session might take for a technique. In case of fMRI, for example, whole brain imaging can be achieved. However, 30-minute functional acquisition sessions are conventional in the clinical setting in-house (Erasmus MC, Rotterdam, The Netherlands). In the intra-operative setting, interruption of surgical workflow and as a consequence, prolonging the surgical duration, can have severe consequences, including an increased risk of surgical site infection (19).
Costs
The costs of acquiring and maintaining the materials and skills for a certain intra-operative technique is a very relevant consideration in view of healthcare economics, and the responsibility to guarantee access to all in need for medical care.
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