Figure 14
Left: image obtained with the standard illuminator (Microscope Pentero 900) at 5 % light intensity. Right: the image is obtained with the circular illuminator set at 9 [V].
Both pictures were previously converted to greyscale.
Figure 15
Data summarized in table 3 are shown; light intensity beyond 50% produced most of glare effects in all conditions and measures with the standard illuminator (C1M1:
condition 1, measure 1; C1M2: condition 1, measure 2; C2M1: condition 1, measure 2; C2M2: condition 2, measure 2).
Lum_5 Lum_10 Lum_15 Lum_20 Lum_25 Lum_30 Lum_35 Lum_40 Lum_45 Lum_50 Lum_55 Lum_60 Lum_65 Lum_70 Lum_75 Lum_80 Lum_85 Lum_90 Lum_95 Lum_100
Standard illumination
48
Cir_1 Cir_2 Cir_3 Lum_5 Lum_10 Lum_15 Lum_20 Lum_25 Lum_30 Lum_35 Lum_40 Lum_45 Lum_50 Lum_55 Lum_60 Lum_65 Lum_70 Lum_75 Lum_80 Lum_85 Lum_90 Lum_95 Lum_100
Condition 1 (0°)
Cir_1 Cir_2 Cir_3 Lum_5 Lum_10 Lum_15 Lum_20 Lum_25 Lum_30 Lum_35 Lum_40 Lum_45 Lum_50 Lum_55 Lum_60 Lum_65 Lum_70 Lum_75 Lum_80 Lum_85 Lum_90 Lum_95 Lum_100
Condition 2 (75°)
Measure 1 Measure 2
49 Figure 16bis
Values obtained compiled from the four measurements (two with the standard illuminator, two with the circular illuminator) and, in both cases, there is a steep increase of glare effect with the increase of light intensity.
0 10000 20000 30000 40000 50000 60000 70000 80000
Lum_50
Light intensity
50 10. Discussion
10.1 Context
Despite the fact that intrinsic optical imaging is very well described in the literature, easy to setup and to perform, as well as inexpensive [32, 40], its use is in clinical settings is still very limited to few accustomed centers. So, one might wonder about the future of this technique. In fact, if intrinsic optical imaging does not find its development in the next few years, it could be doomed to no longer exist. As shown earlier in this manuscript, the concept of intrinsic signals of the brain used to monitor neurovascular coupling, thus functional activity, implies a very close correlation between neuronal activity and the signal to be analyzed. However, several inherent limitations in this technique are identified and thereby could prevent forever its systematic use. Those technical issues are: (1) brain movements, (2) glare effects, (3) time of acquisition, (4) temporal resolution, (5) spatial resolution, depth of penetration and point spread.
In addition to these inherent limitations, the elaboration of a wide multicentric trial involving intrinsic optical imaging technology seems difficult, partly because there is a continuous rise and a constant evolution of very high-performance preoperative functional imaging and neuronavigation techniques (included augmented reality), rendering the concept of intrinsic optical imaging is less attractive. This latter is more invasive, less accurate and requires prolonged exposure of the human brain. At present, the study of somatosensory cortex of the hand by the median nerve stimulation seems the only validated protocol to our knowledge [27]. In our department, only one case in the last 24 months has been a candidate for a serious study of intrinsic optical imaging; in fact, the lesion to be resected was located next to the primary sensory area of the hand. Therefore, there was no need to extend the
51 craniotomy or apply a specific protocol to the specific study of intrinsic optical imaging for this patient. For all other situations encountered, no valid argument has enabled us to justify the study of optical imaging during surgery.
Thus, what makes really sense in the use of intrinsic optical imaging? The answer is probably in its fundamental application in research, as reported by many authors.
Moreover, many functional studies on the animal and on patients have been based on IOI specifically.
10.2 Brain movements
As data acquisition is not instantaneous, the brain is free to move during that time, due to the breathing or the heartbeat or, in the case of awake surgeries, patient’s unavoidable and unpredictable movements. In the past, some authors used to recommend the use of a glass plate (Figure 17) to impede free movements of the cortical surface. This is avoided due to the potential damages that compressive devices could cause to intact brain surface. Therefore, the solution resides in a pre-computational registration step, necessary for decreasing the movement related noise. By averaging multiple recordings, one might obtain a reliable and interpretable signal [43]. Another potential solution is to synchronize the acquisition with cardiac and respiratory cycles.
52 Figure 17: the use of a glass footplate has been reported to prevent brain movements during surgery. This practice has been largely abandoned since, mostly because the risk of ischemia.
10.3 Glare effects
The refraction index of the cortex being different from that of the air, reflections generated by the cortex/air interface create diffusion effects, masking some cortical areas and rendering them not investigable. Furthermore, these can be strong when the reflection angle is close to the light incident angle. It is then important to detect the glare areas in order to omit them from the neuronal activity detection process.
As previously shown, the use of a circular illumination device does not prevent from glare effects and cannot be advocated as an effective add on (Figure 18).
Figure 18: The use of a LED ring mounted on a regular surgical microscope (PENTERO 900) doesn’t decrease glare effects.
10.4 Acquisition time
Mean mapping time reported by accustomed groups is 12 minutes [40]. Research groups are used to intrinsic optical imaging and could have faster acquisition software [32]. However, as actual pre-operative technique are more or less as accurate as intrinsic optical imaging and offer an instantaneous image of the preoperative situation, the necessary resting period due to IOI registration and
53 processing represent a major issue and is, in our opinion, one of the major obstacles to the spread of IOI technology.
10.5 Spatio-temporal acquisition and point-spread
As the hemodynamic response due to neurovascular coupling has a strong spatial correlation, spatial resolution of intrinsic optical imaging is accurate. However, the spatial extent of these correlations is not homogeneously distributed throughout the cortical surface; a post-registration analysis of acquired data is necessary (detection tool independent on the size of the neuronal activity)1.
The minimal spatial resolution that allows the detection of the neuronal activity is around 200 [µm]; besides that, the same order of temporal resolution is required to detect very fast action potentials [41]. As previously exposed, IOI signals do not monitor directly neuronal activity; hence, there is an incompressible time-lapse due to the neurovascular coupling, which prevents instantaneous monitoring of neuronal activity (see Figure 19). As a net result, there is a loss of spatial and time resolutions and a decreased signal-to-noise ratio. This is due to the technique itself and this time bias can be overcome only with the direct detection of action potentials, which is not the purpose of intrinsic optical imaging.
54 Figure 19: temporal evolution of the optical signals in a rat model after stimulus of a whisker (grey area) at an isobestic point λ=550 [nm] (thick black line) and λ= 610 nm (thick grey line). Thin lines correspond to the error margins [24], [43]. The grey zone represent the time to peak latency, due to the indirect monitoring (monitoring through the neurovascular coupling).
55 10.6 Intrinsic optical imaging and electrophysiology
When comparing intrinsic optical imaging with electrophysiology monitoring (somatosensory or motor evoked potentials, direct cortical stimulation mapping), signals obtained are correlated [25, 34]. Areas identified by direct intrinsic optical imaging are also detected by cortical stimulation mapping. However, intrinsic signals tend to diffuse to adjacent, non-activated areas (point spread), creating false positive signals and leading to biased results. Furthermore, signals rising from neurovascular coupling may be imprecise or biased, although the relation between neuronal activity and metabolic phenomenon is supposed to be very tight.
Despite clear limitations, latest data published [32, 40] appear positive; in the publication of Sobottka et al., the frontier between functional cortex and the adjacent lesion was identified with a high reliability (p<0.005). Moreover, the identification of the intact somatosensory cortex was obtained with a sensitivity of 94.4 % and specificity about 100%. Those results were obtained in a cohort of 41 patients candidates to the resection of a lesion adjacent to the post-central gyrus.
Hence, with the stimulation of the contralateral median nerve, S1 was highlighted and a satisfactory safe resection of the lesion obtained. Mean mapping time was 12 minutes, which is, to our knowledge, the fastest IOI procedure reported. Noordmans et al. identified an epileptogenic focus on S1 in one patient superposing EcoG and intrinsic optical imaging with a good outcome because it resulted in the resection of the epileptic focus with improvement of the quality of life of the patient after the surgery.
56 10.7. What’s next: the emergence of functional ultrasonography
This technique has been y reported by Macé et al. [42]. Despite the fact that it is only applied to the animal for the moment, it seems quite an interesting and promising technology in mapping blood volume changes in the whole brain. The difference with conventional ultrasonography is the increased speed of acquisition and the absence of vascular noise, allowing the imaging of blood dynamics. Spatial and temporal resolutions reported are higher than any other functional brain imaging modalities. The authors report a spatial resolution of 100x100 [µm], slice thickness of 200 [µm] and penetration depth over 2 [cm] coupled with a very short acquisition time (≈ 200 [ms]).
57 11. Conclusion
Intrinsic optical imaging is an interesting technology, designed to directly visualize functional architecture and physiological processes during surgery, aiding neurosurgeons with resections of tumors, arteriovenous malformations or epileptic foci. Several authors have established the usefulness of intrinsic optical imaging in fundamental neurosciences, including the identification of visual cortex columns, olfactory pathways and cortical plasticity. The experience with intrinsic optical imaging in clinical daily practice and successful results demonstrate that an accurate, repetitive use of the technique by an adequately trained surgical team is successful. This it is the case, for example, in Dresden.
However, we identified three major limitations to the use of intrinsic optical imaging during routine intracranial procedure factors: firstly, the mounting of the CCD camera on the microscope induces a dysbalance of the device. Secondly, glare effects and therefore false-positive signals are withdrawals for the use of IOI in the patient, even if a circular illuminating device is used. Thirdly, brain pulsations, brain shift and patient movements are factors representing potential bias to the interpretation of the signals. The use of a glass footplate has been described; this solution is unsafe, as it can cause cerebral contusion in healthy cortical regions.
Pre- and intra-operative monitoring techniques have been developed to be ready to use and safe. The best modality is represented by intra-operative magnetic resonance imaging, which will be available around 2018 in Geneva University Hospital. Intra-operative magnetic resonance imaging, coupled to augmented reality, intra-operative fluorescence and even ultrasonography will certainly improve rate of total resection of tumors, exclusion of cerebral AVMs and extent of resection of epileptic foci. All those techniques differ from intrinsic optical imaging in their
58 signal record: they provide direct analysis of the signal and visualization of architectural structures and metabolic processes, contrary to intrinsic optical imaging.
Still, these limitations could be overcome by engineers and software programmers, and intrinsic optical imaging would be then improved. However, the intrinsic delay of the signal and mostly the low signal to noise ratio may render intrinsic optical imaging obsolete; intrinsic optical imaging was originally designed to see live intra-operative pathophysiological processes, delay and low signal-to-noise ratio represent the ultimate obstacle to the wide use of the technique.
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