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Purpose Fluorescence-guided surgery applying 5-aminolevulinic acid (5-ALA) in high-grade gliomas is an established method in adults. In children, results have so far been ambiguous. The aim of this study was to investigate 5-ALA-induced fluorescence in pediatric brain tumors by using the surgical microscope and a spectroscopic hand-held probe. Methods Fourteen randomly selected children (age 4–17) with newly MRI-verified brain tumors were included. No selection was based on the suspected diagnosis prior to surgery. All patients received 5-ALA (20 mg /kg) either orally or via a gastric tube prior to surgery. Intratumoral fluorescence was detected with the microscope and the probe. Moreover, fluorescence in the skin of the forearm was measured. Histopathology samples revealed seven low-grade gliomas, four medulloblastomas, one diffuse intrinsic pontine glioma, one glioblastoma and one atypical meningioma. Blood samples were analyzed, and potential clinical side effects were monitored. Results Microscopically, vague fluorescence was visible in two patients. Intratumoral fluorescence could be detected in five patients with the probe, including the two patients with vague microscopic fluorescence. Three of the oldest children had PpIX fluorescence in the skin. Nine children did not show any fluorescence in the tumor or in the skin. No clinical side effects or laboratory adverse events were observed. Conclusion Fluorescence could not be used to guide surgery in this study, neither with the surgical microscope nor with the hand-held probe. In nine children, no fluorescence was discerned and children with noticeable fluorescence were all older than nine years. 5-ALA was considered safe to apply in children.

Objective To evaluate the effects of bilateral caudal zona incerta (cZi) deep brain stimulation (DBS) for Parkinsons disease (PD) one year after surgery and to create anatomical improvement maps based on patient-specific simulation of the electric field. Materials and Methods We report the one-year results of bilateral cZi-DBS in 15 patients with PD. Patients were evaluated on/off medication and stimulation using the Unified Parkinsons Disease Rating Scale (UPDRS). Main outcomes were changes in motor symptoms (UPDRS-III) and quality of life according to Parkinsons Disease Questionnaire-39 (PDQ-39). Secondary outcomes included efficacy profile according to sub-items of UPDRS-III, and simulation of the electric field distribution around the DBS lead using the finite element method. Simulations from all patients were transformed to one common magnetic resonance imaging template space for creation of improvement maps and anatomical evaluation. Results Median UPDRS-III score off medication improved from 40 at baseline to 21 on stimulation at one-year follow-up (48%, p < 0.0005). PDQ-39 summary index did not change but the subdomains activities of daily living (ADL) and stigma improved (25%, p < 0.03 and 75%, p < 0.01), whereas communication worsened (p < 0.03). For UPDRS-III sub-items, stimulation alone reduced median tremor score by 9 points, akinesia by 3, and rigidity by 2 points at one-year follow-up in comparison to baseline (90%, 25%, and 29% respectively, p < 0.01). Visual analysis of the anatomical improvement maps based on simulated electrical fields showed no evident relation with the degree of symptom improvement and neither did statistical analysis show any significant correlation. Conclusions Bilateral cZi-DBS alleviates motor symptoms, especially tremor, and improves ADL and stigma in PD patients one year after surgery. Improvement maps may be a useful tool for visualizing the spread of the electric field. However, there was no clear-cut relation between anatomical location of the electric field and the degree of symptom relief. Funding Agencies|Umea Universitet Funding Source: Medline; Umea University Hospital [Spjutspetsmedel] Funding Source: Medline; Parkinsonfonden Funding Source: Medline; Stiftelsen for Strategisk Forskning [SSF BD150032] Funding Source: Medline; Vetenskapsradet [VR 2016-03564] Funding Source: Medline

Background Deep brain stimulation (DBS) is being investigated as a treatment for therapy-refractory obsessive compulsive disorder (OCD). Many different brain targets are being trialled. Several of these targets such as the ventral striatum (including the nucleus accumbens (NAc)), the ventral capsule, the inferior thalamic peduncle, and the bed nucleus of stria terminalis (BNST)) belong to the same network, are anatomically very close to one another, or even overlap. Data is still missing on how various stimulation parameters in a given target will affect surrounding anatomical areas and impact the clinical outcome of DBS. Methods In a pilot study of eleven participants with DBS of the BNST, we investigate through patient-specific simulation of electric field, which anatomical areas are affected by the electric field, and if this can be related to the clinical results. Our study combined individual patient’s stimulation parameters at 12- and 24-month follow-up with image data from the preoperative MRI and postoperative CT. These data were used to calculate the distribution of electric field and create individual anatomical models of the field of stimulation. Results The individual electric stimulation fields by stimulation in the BNST were similar at both the 12- and 24-month follow-up, involving mainly anterior limb of the internal capsule (ALIC), genu of the internal capsule (IC), BNST, fornix, anteromedial globus pallidus externa (GPe), and the anterior commissure. A statistical significant correlation (p Conclusions Many of the targets under investigation for OCD are in anatomical proximity. As seen in our study, off-target effects are overlapping. Therefore, DBS in the region of ALIC, NAc, and BNST may perhaps be considered to be stimulation of the same target.

Deep brain stimulation (DBS) is a well-established neurosurgical procedure for movement disorders that is also being explored for treatment-resistant psychiatric conditions. This review highlights important consideration for DBS simulation and data analysis. The literature on DBS has expanded considerably in recent years, and this article aims to identify important trends in the field. During DBS planning, surgery, and follow up sessions, several large data sets are created for each patient, and it becomes clear that any group analysis of such data is a big data analysis problem and has to be handled with care. The aim of this review is to provide an update and overview from a neuroengineering perspective of the current DBS techniques, technical aids, and emerging tools with the focus on patient-specific electric field (EF) simulations, group analysis, and visualization in the DBS domain. Examples are given from the state-of-the-art literature including our own research. This work reviews different analysis methods for EF simulations, tractography, deep brain anatomical templates, and group analysis. Our analysis highlights that group analysis in DBS is a complex multi-level problem and selected parameters will highly influence the result. DBS analysis can only provide clinically relevant information if the EF simulations, tractography results, and derived brain atlases are based on as much patient-specific data as possible. A trend in DBS research is creation of more advanced and intuitive visualization of the complex analysis results suitable for the clinical environment.

Background: Optics can be used for guidance in deep brain stimulation (DBS) surgery. The aim was to use laser Doppler flowmetry (LDF) to investigate the intraoperative optical trajectory along the ventral intermediate nucleus (VIM) and zona incerta (Zi) regions in patients with essential tremor during asleep DBS surgery, and whether the Zi region could be identified. Methods: A forward-looking LDF guide was used for creation of the trajectory for the DBS lead, and the microcirculation and tissue greyness, i.e., total light intensity (TLI) was measured along 13 trajectories. TLI trajectories and the number of high-perfusion spots were investigated at 0.5-mm resolution in the last 25 mm from the targets. Results: All implantations were done without complications and with significant improvement of tremor (p < 0.01). Out of 798 measurements, 12 tissue spots showed high blood flow. The blood flow was significantly higher in VIM than in Zi (p < 0.001). The normalized mean TLI curve showed a significant (p < 0.001) lower TLI in the VIM region than in the Zi region. Conclusion: Zi DBS performed asleep appears to be safe and effective. LDF monitoring provides direct in vivomeasurement of the microvascular blood flow in front of the probe, which can help reduce the risk of hemorrhage. LDF can differentiate between the grey substance in the thalamus and the transmission border entering the posterior subthalamic area where the tissue consists of more white matter tracts.

BACKGROUND Accurate stereotactic biopsies of brain tumors are imperative for diagnosis and tailoring of the therapy. Repetitive needle insertions enhance risks of brain lesioning, hemorrhage, and complications due to prolonged procedure. OBJECTIVE To investigate clinical benefits of a combined 5-aminolaevulinic acid (5-ALA) fluorescence and laser Doppler flowmetry system for the detection of malignant brain tumor and blood vessels in stereotactic biopsies. METHODS Planning of targets and trajectories was followed by optical measurements in 20 patients, using the Leksell Stereotactic System and a manual insertion device. Fluorescence spectra, microvascular blood flow, and tissue grayness were recorded each millimeter along the paths. Biopsies were taken at preplanned positions. The diagnoses were compared with the fluorescence signals. The recordings were plotted against measurement positions and compared. Sites indicating a risk of hemorrhage were counted as well as the time for the procedures. RESULTS Signals were recorded along 28 trajectories, and 78 biopsies were collected. The final diagnosis showed 17 glioblastomas, 2 lymphomas, and 1 astrocytoma grade III. Fluorescence was seen along 23 of the paths with 4 having the peak of 5-ALA fluorescence 3 mm or more from the precalculated target. There was increased microcirculation in 40 of 905 measured positions. The measurement time for each trajectory was 5 to 10 min. CONCLUSION The probe provided direct feedback of increased blood flow along the trajectory and of malignant tissue in the vicinity of the target. The method can increase the precision and the safety of the biopsy procedure and reduce time. Funding: LiU Cancer Strategic Research Grant; Swedish Childhood Cancer FoundationEuropean Commission [MT 20130043]; ALF Grants Region Ostergotland; Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research [RMX18-0056]

Deep brain stimulation (DBS) is an intervention used for several neurological conditions such as Parkinson’s disease. To evaluate the clinical response in relation to anatomical location, electric field simulation using the finite element method is commonly used. The models presented in different studies are varying in complexity and this study aims to evaluate the effect of including anisotropy in the tissue model using homogenous tissue with varying level of anisotropy both parallel and perpendicular to the DBS lead. As a benchmark, data from one patient was included and simulations was performed in zona incerta (Zi) and the internal capsule (IC). The parameters investigated were impedance, volume within the 0.2 V/mm isosurface, radial and longitudinal expansion as well as visual representation of the isosurface. The investigations show that both the impedance and volume are increasing with increasing anisotropy together with the electric field isosurface in the principal direction of the anisotropy. When comparing different stimulation modes, current control (CC) stimulation had a steeper increase with increasing anisotropy for all parameters compared to voltage control (VC) stimulation. This could be due to a joint effect of the anisotropy and the increasing impedance. The result from the patient simulations are in the anisotropy range where simulations from the homogenous models starts to have a higher slope for all parameters. This indicates that including anisotropy in computer models will be of importance in areas of high anisotropy.

Introduction: Lead movement after deep brain stimulation may occur and influence the affected volume of stimulation. The aim of the study was to investigate differences in lead position between the day after surgery and approximately 1 month postoperatively and also simulate the electric field (EF) around the active contacts in order to investigate the impact of displacement on affected volume. Methods: Twenty-three patients with movement disorders underwent deep brain stimulation surgery (37 leads). Computed tomography at the 2 time points were co-fused respectively with the stereotactic images in Surgiplan. The coordinates (x, y, and z) of the lead tips were compared between the 2 dates. Eleven of these patients were selected for the EF simulation in Comsol Multiphysics. Postoperative changes of EF spread in the tissue due to conductivity changes in perielectrode space and due to displacement were evaluated by calculating the coverage coefficient and the Sørensen-Dice coefficient. Results: There was a significant displacement (mean ± SD) on the left lead: x (0.44 ± 0.72, p < 0.01), y (0.64 ± 0.54, p < 0.001), and z (0.62 ± 0.71, p < 0.001). On the right lead, corresponding values were: x (−0.11 ± 0.61, ns), y (0.71 ± 0.54, p < 0.001), and z (0.49 ± 0.81, p < 0.05). The anchoring technique was a statistically significant variable associated with displacement. No correlation was found between bilateral (n = 14) versus unilateral deep brain stimulation, gender (n = 17 male), age n = 8), and calculated air volume. The simulated stimulation volume was reduced after 1 month because of the perielectrode space. When considering perielectrode space and displacement, the volumes calculated the day after surgery and approximately 1 month later were partly overlapped. Conclusion: The left lead tip displayed a tendency to move lateral, anterior, and inferior and the right a tendency to move anterior and inferior. The anchoring technique was associated to displacement. New brain territory was affected due to the displacement despite considering the reduced stimulated volume after 1 month. Postoperative changes in perielectrode space and small lead movements are reasons for delaying programming to 4 weeks following surgery.

Highlights: • Non-linear iterative structural normalization method focused on the deep brain. • Multi-modality image data from deep brain stimulation patients. • Comparison of ANTS, FNIRT and DRAMMS for the non-linear registrations using different settings for each. • Evaluation of the registration tools based on the analysis of 58 structures of the deep brain segmented manually by a single expert. • ANTS was identified as the best performing non-linear registration tool., Deep brain stimulation (DBS) therapy requires extensive patient-specific planning prior to implantation to achieve optimal clinical outcomes. Collective analysis of patient’s brain images is promising in order to provide more systematic planning assistance. In this paper the design of a normalization pipeline using a group specific multi-modality iterative template creation process is presented. The focus was to compare the performance of a selection of freely available registration tools and select the best combination. The workflow was applied on 19 DBS patients with T1 and WAIR modality images available. Non-linear registrations were computed with ANTS, FNIRT and DRAMMS, using several settings from the literature. Registration accuracy was measured using single-expert labels of thalamic and subthalamic structures and their agreement across the group. The best performance was provided by ANTS using the High Variance settings published elsewhere. Neither FNIRT nor DRAMMS reached the level of performance of ANTS. The resulting normalized definition of anatomical structures were used to propose an atlas of the diencephalon region defining 58 structures using data from 19 patients.

Deep brain stimulation (DBS) is an established technique for reduction of symptoms in movement disorders. Finite element method (FEM) simulations of the electric field magnitude (EF) are useful for estimating the affected tissue around the DBS lead and this can help optimize the therapy. This paper describes how patient-specific FEM models can be set up with the aid of the Matlab-based in-house software tool ELMA. Electrode placement is determined from two coordinates in postoperative medical imaging and electric conductivity is assigned from preoperative magnetic resonance imaging (MRI) and patient-specific DBS data. Simulations are performed using the equation for steady currents in Comsol Multiphysics (CM). The simulated EF is superimposed on the preoperative MRI for evaluation of affected structures. The method is demonstrated with patient-specific simulations in the zona incerta and a globus pallidus example containing cysts with higher conductive which causes considerable distortion of the EF. The improved software modules and precise lead positioning simplifies and reduces the time for DBS EF modelling and simulation. Funding agencies: Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research [BD15-0032]; Swedish Research Council (Vetenskapsriddet)Swedish Research Council [2016-03564]; Knut and Alice Wallenberg Foundation (Project Seeing Organ Function)

Deep brain stimulation (DBS) is an established therapy for movement disorders such as essential tremor (ET). Positioning of the DBS lead in the patients brain is crucial for effective treatment. Extensive evaluations of improvement and adverse effects of stimulation at different positions for various current amplitudes are performed intraoperatively. However, to choose the optimal position of the lead, the information has to be "mentally" visualized and analyzed. This paper introduces a new technique called "stimulation maps," which summarizes and visualizes the high amount of relevant data with the aim to assist in identifying the optimal DBS lead position. It combines three methods: outlines of the relevant anatomical structures, quantitative symptom evaluation, and patient-specific electric field simulations. Through this combination, each voxel in the stimulation region is assigned one value of symptom improvement, resulting in the division of stimulation region into areas with different improvement levels. This technique was applied retrospectively to five ET patients in the University Hospital in Clermont-Ferrand, France. Apart from identifying the optimal implant position, the resultant nine maps show that the highest improvement region is frequently in the posterior subthalamic area. The results demonstrate the utility of the stimulation maps in identifying the optimal implant position. Graphical abstract Funding Agencies|Swiss National Science FoundationSwiss National Science Foundation (SNSF) [CR3212_153370]; Germaine de Stael program of the Swiss Academy of Engineering Sciences; French Ministry of Health [2011-A00774-37]; Swedish Research CouncilSwedish Research Council [2016-03564]; Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research [BD15-0032]

Patient MRI from DBS implantations in the subthalamic nucleus (STN) were reviewed and it was found that around 10% had Virchow-Robin spaces (VRS). Patient-specific models were developed to evaluate changes in the electric field (EF) around DBS leads. The patients (n = 7) were implanted bilaterally either with the standard voltage-controlled lead 3389 or with the directional current-controlled lead 6180. The EF distribution was evaluated by comparing simulations using patient-specific models with homogeneous models without VRS. The EF, depicted with an isocontour of 0.2 V/mm, showed a deformation in the presence of the VRS around the DBS lead. For patient-specific models, the radial extension of the EF isocontours was enlarged regardless of the operating mode or the DBS lead used. The location of the VRS in relation to the active contact and the stimulation amplitude, determined the changes in the shape and extension of the EF. It is concluded that it is important to take the patients? brain anatomy into account as the high conductivity in VRS will alter the electric field if close to the DBS lead. This can be a cause of unexpected side effects. Funding Agencies|Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research [SSF BD15-0032]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [VR 201603654]

There are many techniques using sensors and wearable devices for detecting and monitoring patients with Parkinson&#x02BC s disease &#x0028 PD &#x0029. A recent development is the utilization of human interaction with computer keyboards for analyzing and identifying motor signs in the early stages of the disease. Current designs for classification of time series of computer-key hold durations recorded from healthy control and PD subjects require the time series of length to be considerably long. With an attempt to avoid discomfort to participants in performing long physical tasks for data recording, this paper introduces the use of fuzzy recurrence plots of very short time series as input data for the machine training and classification with long short-term memory &#x0028 LSTM &#x0029 neural networks. Being an original approach that is able to both significantly increase the feature dimensions and provides the property of deterministic dynamical systems of very short time series for information processing carried out by an LSTM layer architecture, fuzzy recurrence plots provide promising results and outperform the direct input of the time series for the classification of healthy control and early PD subjects.

International audience; Deep brain stimulation (DBS) represents today a well-established treatment for movement disorders. Nevertheless the exact mechanism of action of DBS remains incompletely known. During surgery, numerous stimulation tests are frequently performed in order to evaluate therapeutic and adverse effects before choosing the optimal implantation site for the DBS lead. Anatomical structures responsible for the induced adverse effects have been investigated previously, but only based on stimulation data obtained with the implanted DBS lead. The present study introduces a methodology to identify these anatomical structures during intraoperative stimulation tests based on patient-specific electric field simulations and visualization on the patient specific anatomy. The application to 4 patients undergoing DBS surgery and presenting dysarthria, paresthesia or pyramidal effects shows the different anatomical structures, which might be responsible for the adverse effects. Several of the identified structures have been previously described in the literature. To draw any statistically significant conclusions, the methodology has to be applied to further patients. Together with the visualization of the therapeutic effects, this new approach could assist the neurosurgeons in the future in choosing the optimal implant position.

Deep brain stimulation is a well-established technique for symptomatic treatment of e.g. Parkinsons disease and essential tremor. Computer simulations using the finite element method (FEM) are widely used to estimate the affected area around the DBS electrodes. For the reliability of the simulations, it is important to match used simulation parameters with experimental data. One such parameter is the electric field magnitude threshold EFt required for axon stimulation. Another is the conductivity of the perielectrode space (PES) around the electrode. At the acute stage after surgery the PES will be characterized by an increased conductivity due to inflammation and edema while the later chronic stage will be characterized by a lower conductivity due to gliosis and minor scar formation. In this study, the EFt and the electric conductivity of the PES have been estimated by comparing FEM simulations with clinical studies of activation distance, pulse length and electrode impedance. The resulting estimates are an EFt of 0.2 V/mm at the common pulse width of 60 mu s and a chronaxie of 62 mu s. Estimated electric conductivities for the PES are 0.14 S/m in the acute stage and 0.05 S/m in the chronic stage, assuming a PES width of 250 mu m. These values are thus experimentally justified to use in FEM simulations of DBS. Funding Agencies|Swedish Research Council (Vetenskapsradet) [2016-03564]; Swedish Foundation for Strategic Research [BD15-0032]; Knut and Alice Wallenberg Foundation

Background: Laser Doppler flowmetry (LDF) can be used to measure cerebral microcirculation in relation to stereotactic deep brain stimulation (DBS) implantations. Objective: To investigate the microcirculation and total light intensity (TLI) corresponding to tissue grayness in DBS target regions with high-resolution LDF recordings, and to define a resolution which enables detection of small vessels. Methods: Stereotactic LDF measurements were made prior to DBS implantation with 0.5-mm steps in the vicinity to 4 deep brain targets (STN, GPi, Vim, Zi) along 20 trajectories. The Mann-Whitney U test was used to compare the microcirculation and TLI between targets, and the measurement resolution (0.5 vs. 1 mm). The numbers of high blood flow spots along the trajectories were calculated. Results: There was a significant difference (p < 0.05) in microcirculation between the targets. High blood flow spots were present at 15 out of 510 positions, 7 along Vim and GPi trajectories, respectively. There was no statistical difference between resolutions even though both local blood flow and TLI peaks could appear at 0.5-mm steps. Conclusions: LDF can be used for online tracking of critical regions presenting blood flow and TLI peaks, possibly relating to vessel structures and thin laminas along stereotactic trajectories.

Summary Background Using 5-aminolevulinic acid (ALA) as an intraoperative fluorescence contrast has been proven to improve the resection of glioblastoma and contribute to prolonged patient survival. ALA accumulates as protoporphyrin IX (PpIX) in the tumor cells and is administered in an advised dose of 20 mg/kg body weight (b.w.) for brain tumor resection using fluorescence surgical microscopes. PpIX fluorescence availability and intensities of a four folds lower ALA dose (5 mg/kg b.w.) has been investigated in glioblastomas and skin using a spectroscopy system adapted for surgical guidance. Methods A total of 30 adult patients diagnosed with high grade gliomas were included in the analysis. ALA was orally administered in doses of 5 mg/kg b.w. ( n = 15) dissolved in orange juice or 20 mg/kg b.w. ( n = 15) dissolved in water. A fluorescence spectroscopy system with a handheld fiber-optical probe was used for performing the quantitative fluorescence measurements. Results The binominal comparison of the diagnostic performance parameters showed no significant statistical difference ( p > 0.05). The median fluorescence values in tumor were 2–3 times higher for the high ALA dose group. No PpIX was detected in the skin of the patients in the low dose group (0/4) while PpIX was detected in the skin of the majority of the patients in the high ALA dose group (13/14). Conclusions Application of 5 mg/kg ALA was evaluated as equally reliable as the higher dose regarding the diagnostic performance when guidance was performed using a spectroscopic system. Moreover, no PpIX was detected in the skin of the patients.

Continuous optical monitoring of local cerebral microcirculation could benefit neurointensive care patients treated for subarachnoid hemorrhage (SAH). The aim of the study was to evaluate laser Doppler flowmetry (LDF) and diffuse reflectance spectroscopy (DRS) for long-term monitoring of brain microcirculation and oxygen saturation (SO2) in the neurointensive care unit (NICU). A fiber optic probe was designed for intraparenchymal use and connected to LDF and DRS for assessment of the local blood flow (perfusion and tissue reflectance (TLI)) and SO2in the brain. The optically monitored parameters were compared with conventional NICU monitors and Xe-CT. The LDF signals were low with median and 25 to 75% interquartiles of perfusion = 70 (59 to 83) a.u. and TLI = 2.0 (1.0 to 2.4) a.u. and showed correlation with the NICU monitors in terms of heart rate. Median and interquartiles of SO2 were 17.4 (15.7 to 19.8) %. The lack of correlation between local perfusion and cerebral perfusion pressure indicated intact cerebral autoregulation. The systems were capable of monitoring both local perfusion and SO2 with stable signals in the NICU over 4 days. Further clinical studies are required to evaluate the optical systems’ potential for assessing the onset of secondary brain injury. Funding agencies: Swedish Research Council [621-2010-4216, 621-2013-6078]; ALF Grants Region Ostergotland [LIO-599651]

PURPOSE: Protoporphyrin (PpIX) fluorescence allows discrimination of tumor and normal brain tissue during neurosurgery. A handheld fluorescence (HHF) probe can be used for spectroscopic measurement of 5-ALA-induced PpIX to enable objective detection compared to visual evaluation of fluorescence. However, current technology requires that the surgeon either views the measured values on a screen or employs an assistant to verbally relay the values. An auditory feedback system was developed and evaluated for communicating measured fluorescence intensity values directly to the surgeon. METHODS: The auditory display was programmed to map the values measured by the HHF probe to the playback of tones that represented three fluorescence intensity ranges and one error signal. Ten persons with no previous knowledge of the application took part in a laboratory evaluation. After a brief training period, participants performed measurements on a tray of 96 wells of liquid fluorescence phantom and verbally stated the perceived measurement values for each well. The latency and accuracy of the participants' verbal responses were recorded. The long-term memorization of sound function was evaluated in a second set of 10 participants 2-3 and 7-12 days after training. RESULTS: The participants identified the played tone accurately for 98% of measurements after training. The median response time to verbally identify the played tones was 2 pulses. No correlation was found between the latency and accuracy of the responses, and no significant correlation with the musical proficiency of the participants was observed on the function responses. Responses for the memory test were 100% accurate. CONCLUSION: The employed auditory display was shown to be intuitive, easy to learn and remember, fast to recognize, and accurate in providing users with measurements of fluorescence intensity or error signal. The results of this work establish a basis for implementing and further evaluating auditory displays in clinical scenarios involving fluorescence guidance and other areas for which categorized auditory display could be useful. Funding agencies: Swedish Childhood Cancer foundation [MT 2013-0043]; Cancer network at Linkoping University (LiU-cancer); National Institutes of Health [P41 EB015902, P41 EB015898, R01EB014955, U24CA180918] OTP

BACKGROUND: Deep brain stimulation (DBS) in patients with severe, refractory Tourette syndrome (TS) has demonstrated promising but variable results thus far. The thalamus and anteromedial globus pallidus internus (amGPi) have been the most commonly stimulated sites within the cortico-striato thalamic circuit, but an optimal target is yet to be elucidated. OBJECTIVES: This study of 15 patients with long-term amGPi DBS for severe TS investigated whether a specific anatomical site within the amGPi correlated with optimal clinical outcome for the measures of tics, obsessive compulsive behaviour (OCB), and mood. METHODS: Validated clinical assessments were used to measure tics, OCB, quality of life, anxiety, and depression before DBS and at the latest follow-up (17-82 months). Electric field simulations were created for each patient using information on electrode location and individual stimulation parameters. A subsequent regression analysis correlated these patient-specific simulations to percentage changes in outcome measures in order to identify any significant voxels related to clinical improvement. RESULTS: A region within the ventral limbic GPi, specifically on the medial medullary lamina in the pallidum at the level of the AC-PC, was significantly associated with improved tics but not mood or OCB outcome. CONCLUSIONS: This study adds further support to the application of DBS in a tic-related network, though factors such as patient sample size and clinical heterogeneity remain as limitations and replication is required. Funding agencies: National Institute of Health Research (NIHR) Biomedical Research Centre at the UCL Institute of Neurology and UCLH-National Hospital for Neurology and Neurosurgery, London, UK; Swedish Research Council (Vetenskapsradet) [2016-03564]; Swedish Foundation fo

Background The mechanism by which deep brain stimulation of the nucleus subthalamicus improves Parkinson’s disease symptoms remains unclear. In a previous perioperative study, we showed that there ...

Background: Intracerebral hemorrhage (ICH) is the most feared complication in deep brain stimulation (DBS) surgery. The aim of the study was to evaluate patient safety and outcome using laser Doppler flowmetry (LDF) as guidance tool during DBS implantations. Methods: An LDF probe adapted for the stereotactic system was used as guide for creation of the trajectory. The microcirculation along 83 preplanned trajectories was measured with the guide during DBS surgery for movement disorders. The microvascular blood flow levels were investigated for all measurement positions. Medical record and postoperative radiology were retrospectively reviewed. Results: Of 2,963 measurement positions, 234 (7.9%) showed at least a doubled blood flow compared to the surrounding tissue. Of these 2.2% had a more than 5 times higher blood flow in front of the probe tip. Along 1 trajectory, a small ICH was detected during surgery. Increased blood flow was more common close to sulci and verticals. Conclusion: Real-time LDF measurement of the microcirculation using a forward-looking probe during DBS surgery can detect blood flow peaks and further minimize the risk of developing ICH. No separate guide tube is necessary as the probe also creates the trajectory for the DBS lead.

Background Visualization of the tumor is crucial for differentiating malignant tissue from healthy brain during surgery, especially in the tumor marginal zone. The aim of the study was to introduce a fluorescence spectroscopy-based hand-held probe (HHF-probe) for tumor identification in combination with the fluorescence guided resection surgical microscope (FGR-microscope), and evaluate them in terms of diagnostic performance and practical aspects of fluorescence detection. Material and Methods Eighteen operations were performed on 16 patients with suspected high-grade glioma. The HHF-probe and the FGR-microscope were used for detection of protoporphyrin (PpIX) fluorescence induced by 5-aminolevulinic acid (5-ALA) and evaluated against histopathological analysis and visual grading done through the FGR-microscope by the surgeon. A ratio of PpIX fluorescence intensity to the autofluorescence intensity (fluorescence ratio) was used to quantify the spectra detected by the probe. Results Fluorescence ratio medians (range 0 – 40) measured by the probe were related to the intensity of the fluorescence in the FGR-microscope, categorized as “none” (0.3, n = 131), “weak” (1.6, n = 34) and “strong” (5.4, n = 28). Of 131 “none” points in the FGR-microscope, 88 (67%) exhibited fluorescence with the HHF-probe. For the tumor marginal zone, the area under the receiver operator characteristics (ROC) curve was 0.49 for the FGR-microscope and 0.65 for the HHF-probe. Conclusions The probe was integrated in the established routine of tumor resection using the FGR-microscope. The HHF-probe was superior to the FGR-microscope in sensitivity; it detected tumor remnants after debulking under the FGR-microscope. The combination of the HHF-probe and the FGR-microscope was beneficial especially in the tumor marginal zone. Funding agencies: Swedish Governmental Agency for Innovation Systems (Vinnova); Swedish Foundation for Strategic Research (SSF); Swedish Research Council (VR) [311-2006-7661, 523-2013-2735]; NovaMedTech; Swedish Childhood Cancer Foundation [MT 2013-0043]; ALF Grants Region

The aim was to quantify the influence of heterogeneous isotropic and heterogeneous anisotropic tissue on the spatial distribution of the electric field during deep brain stimulation (DBS). Three finite element tissue models were created of one patient treated with DBS. Tissue conductivity was modelled as I) homogeneous isotropic, II) heterogeneous isotropic based on MRI, and III) heterogeneous anisotropic based on diffusion tensor MRI. Modelled DBS electrodes were positioned in the subthalamic area, the pallidum, and the internal capsule in each tissue model. Electric fields generated during DBS were simulated for each model and target-combination and visualized in 3D with isolevels at 0.20 (inner), and 0.05 V m-1 (outer). F-test and vector analysis was used for statistical evaluation of the distribution of the electric field. Heterogeneous isotropic tissue altered the spatial distribution of the electric field by up to 4% at inner, and up to 10% at outer isolevel. Heterogeneous anisotropic tissue had a larger impact on the distribution of the electric field with an influence of up to 18% and 15% at each isolevel, respectively. The influence of heterogeneous and anisotropic tissue on the electric field may be clinically relevant in anatomic regions that are functionally subdivided and surrounded by multiple fibres of passage. funding agencies|Swedish Foundation for Strategic Research (SSF)||Swedish Research Council (VR)| 621-2008-3013 |Swedish Governmental Agency for Innovation Systems (VINNOVA)| 311-2006-7661

Microdialysis can be used in parallel to deep brain stimulation (DBS) to relate biochemical changes to the clinical outcome. The aim of the study was to use the finite element method to predict the tissue volume of influence (TVI(max)) and its cross-sectional radius (r (TVImax)) when using brain microdialysis, and visualize the TVI(max) in relation to patient anatomy. An equation based on Fick's law was used to simulate the TVI(max). Factorial design and regression analysis were used to investigate the impact of the diffusion coefficient, tortuosity and loss rate on the r (TVImax). A calf brain tissue experiment was performed to further evaluate these parameters. The model was implemented with pre-(MRI) and post-(CT) operative patient images for simulation of the TVI(max) for four patients undergoing microdialysis in parallel to DBS. Using physiologically relevant parameter values, the r (TVImax) for analytes with a diffusion coefficient D = 7.5 × 10(-6) cm(2)/s was estimated to 0.85 ± 0.25 mm. The simulations showed agreement with experimental data. Due to an implanted gold thread, the catheter positions were visible in the post-operative images. The TVI(max) was visualized for each catheter. The biochemical changes could thereby be related to their anatomical origin, facilitating interpretation of results.

In this paper, we investigate the possibility of using accurate prediction models for the prediction of protoporphyrin bleaching dynamics to achieve photobleaching-insensitive methods to improve the evaluation of data in an existing clinical fluorescence-guided resection technique. To simulate the scenario, measurements were carried out in vivo on skin of healthy volunteers using a compact fiber-based fluorescence spectroscopy system. We have developed an effective method for the parameterization of sequences of bleaching spectra. We analyze convergence and decay rates with respect to initial conditions and excitation irradiance. We also discuss the consequences and the potential for bleaching-insensitive measurements and their applicability in a few examples from in vivo open brain surgery.

Background and Objective: Total tumor resection in patients with glioblastoma multiforme (GBM) is difficult to achieve due to the tumor’s infiltrative way of growing and morphological similarity to the surrounding functioning brain tissue. The diagnosis is usually subjectively performed using a surgical microscope. The objective of this study was to develop and evaluate a hand-held optical touch pointer using a fluorescence spectroscopy system to quantitatively distinguish healthy from malignant brain tissue intraoperatively. Study Design/Materials and Methods: A fluorescence spectroscopy system with pulsed modulation was designed considering optimum energy delivery to the tissue, minimal photobleaching of PpIX and omission of the ambient light background in the operating room (OR). 5-Aminolevulinic acid (5-ALA) of 5 mg/kg body weight was given to the patients with a presumed GBM prior to surgery. During the surgery a laser pulse at 405 nm was delivered to the tissue. PpIX in glioblastoma tumor cells assigned with peaks at 635 and 704 nm was detected using a fiber optical probe. Results/Conclusion: By using the pulsed fluorescence spectroscopy, PpIX fluorescence is quantitatively detected in the GBM. An effective suppression of low power lamp background from the recorded spectra in addition to a significant reduction of high power surgical lights is achieved. Lasers Surg. Med. 42:9–14, 2010. 2010 Wiley-Liss, Inc.

Aim: The aim of this study is to investigate reflected light intensity combined with impedance for navigation aid during stereotactic neurosurgery. Methods: During creation of 21 trajectories for stereotactic implantation of deep brain stimulation electrodes in the globus pallidus internus or subthalamus (zona incerta or subthalamic nucleus), impedance at 512 kHz and reflected light intensity at 780 nm were measured continuously and simultaneously with a radio frequency electrode containing optical fibres. The signals were compared with anatomy determined from pre- and postoperative MRI and CT. The measurements were performed within minutes and signal analysis was done post-operatively. Results: Reflected light intensity was low from cortex, lateral ventricle, caudate nucleus and putamen. It was intermediate from globus pallidus and thalamus while it was high from subcortical white matter, internal capsule and the subthalamus. The electric impedance was less consistent but generally low in the cortex, intermediate in subcortical white matter, the putamen, the globus pallidus and the thalamus and high in the internal capsule and the subthalamus. Conclusion: Reflected light intensity and electric impedance give complementary information about passed tissue and the combination seems promising for navigation aid during stereotactic neurosurgery. Original Publication: Johannes D. Johansson, Patric Blomstedt, Neda Haj-Hosseini, Tommy Bergenheim, Ola Eriksson and Karin Wårdell, Combined diffuse light reflectance and electric impedance measurements for navigation aid in deep brain surgery, 2009, Stereotactic and Functional Neurosurgery, (87), 2, 105-113. http://dx.doi.org/10.1159/000202977 Copyright: S. Karger AG http://www.karger.com/

The objective was to develop a physical action potential generator (Paxon) with the ability to generate a stable, repeatable, programmable, and physiological-like action potential. The Paxon has an equivalent of 40 nodes of Ranvier that were mimicked using resin embedded gold wires (Ø = 20 μm). These nodes were software controlled and the action potentials were initiated by a start trigger. Clinically used Ag-AgCl electrodes were coupled to the Paxon for functional testing. The Paxon's action potential parameters were tunable using a second order mathematical equation to generate physiologically relevant output, which was accomplished by varying the number of nodes involved (1-40 in incremental steps of 1) and the node drive potential (0-2.8 V in 0.7 mV steps), while keeping a fixed inter-nodal timing and test electrode configuration. A system noise floor of 0.07 ± 0.01 μV was calculated over 50 runs. A differential test electrode recorded a peak positive amplitude of 1.5 ± 0.05 mV (gain of 40x) at time 196.4 ± 0.06 ms, including a post trigger delay. The Paxon's programmable action potential like signal has the possibility to be used as a validation test platform for medical surface electrodes and their attached systems.

Background: Deep brain stimulation (DBS) systems in current mode and new lead designs are recently available. To switch between DBS-systems remains complicated as clinicians may lose their reference for programming. Simulations can help increase the understanding. Objective: To quantitatively investigate the electric field (EF) around two lead designs simulated to operate in voltage and current mode under two time points following implantation. Methods: The finite element method was used to model Lead 3389 (Medtronic) and 6148 (St Jude) with homogenous surrounding grey matter and a peri-electrode space (PES) of 250 μm. The PES-impedance mimicked the acute (extracellular fluid) and chronic (fibrous tissue) time-point. Simulations at different amplitudes of voltage and current (n=236) were performed using two different contacts. Equivalent current amplitudes were extracted by matching the shape and maximum EF of the 0.2 V/mm isolevel. Results: The maximum EF extension at 0.2 V/mm varied between 2-5 mm with a small difference between the leads. In voltage mode EF increased about 1 mm at acute compared to the chronic PES. Current mode presented the opposite relationship. Equivalent EFs for lead 3389 at 3 V were found for 7 mA (acute) and 2.2 mA (chronic). Conclusions: Simulations showed a major impact on the electric field extension between postoperative time points. This may explain the clinical decisions to reprogram the amplitude weeks after implantation. Neither the EF extension nor intensity is considerably influenced by the lead design. However, the EF distribution is affected by the larger contact of Lead 6148 generating an electric field below the tip.

Models and simulations are commonly used to study deep brain stimulation (DBS). Simulated stimulation fields are often defined and visualized by electric field isolevels or volumes of tissue activated (VTA). The aim of the present study was to evaluate the relationship between stimulation field strength as defined by the electric potential V, the electric field E, and the divergence of the electric field ∇(2) V, and neural activation. Axon cable models were developed and coupled to finite-element DBS models in three-dimensional (3-D). Field thresholds ( VT , ET, and ∇(2) VT ) were derived at the location of activation for various stimulation amplitudes (1 to 5 V), pulse widths (30 to 120 μs), and axon diameters (2.0 to 7.5 μm). Results showed that thresholds for VT and ∇(2) VT were highly dependent on the stimulation amplitude while ET were approximately independent of the amplitude for large axons. The activation field strength thresholds presented in this study may be used in future studies to approximate the VTA during model-based investigations of DBS without the need of computational axon models. This work was supported by the European Union's Seventh Framework Programme IMPACT (Grant 305814) and by the Swedish Research Council (Grant 621-2013-6078). Asterisk indicates corresponding author.

Despite an increasing use of deep brain stimulation (DBS) the fundamental mechanisms underlying therapeutic and adverse effects remain largely unknown. The simulations of electric entities are increasingly used to evaluate stimulation effects. To our knowledge, so far no group has considered such simulations combined with a side effect analysis of data obtained during intraoperative test stimulations. The aim of the present paper is to introduce a method allowing patient-specific electric field simulations for stimulation amplitudes inducing side effects during deep brain stimulation surgery. Two female patients presenting essential tremor, both bilaterally implanted in the ventral intermediate nucleus (VIM) region in the Clermont-Ferrand University Hospital were included in the study. Intraoperative test stimulations were performed on central and posterior trajectories in each hemisphere at 8-9 positions per trajectory. At each position in addition to the evaluation of the therapeutic effects, side effects such as pyramidal symptoms and paresthesia without localization indicator or paresthesia with localization indicated by the patient (in the hand or in the fingers) were noted. The anatomical structures such as VIM and its neighbors were preoperatively manually outlined using the iPlan software (Brainlab, Feldkirchen, Germany) according to spontaneous MRI contrasts [1]. The so identified structures were exported via a specifically designed interface (VVLink, Brainlab, Feldkirchen, Germany). Whenever side effects occurred the inducing stimulation amplitude was chosen for electric field simulations. A finite element method [2] was applied to calculate the electric field distribution. Conductivity values were deduced from the patient's T1 weighted MRI. An isofieldlevel of 0.2V/mm was chosen and the points of the isosurface were exported. They were visualized together with the extracted anatomical structures and the trajectories. The different structures present inside the volume defined by the isofield level and their appearance were determined. Combinations of structures always appearing together for a specific side effect were identified. For both patients, 8 electric field simulations were successfully performed. A first analysis showed that pyramidal effects appear when parts of the ventrooral nucleus (VO) and the VIM were present inside the isosurface. The ventrocaudal lateral nucleus (VCL), the ventrocaudal medial nucleus (VCM) and the VIM were among the identified structures in hand paresthesia (

Image processing algorithms in pathology commonly include automated decision points such as classifications. While this enables efficient automation, there is also a risk that errors are induced. A different paradigm is to use image processing for enhancements without introducing explicit classifications. Such enhancements can help pathologists to increase efficiency without sacrificing accuracy. In our work, this paradigm has been applied to Ki-67 hot spot detection. Ki-67 scoring is a routine analysis to quantify the proliferation rate of tumor cells. Cell counting in the hot spot, the region of highest concentration of positive tumor cells, is a method increasingly used in clinical routine. An obstacle for this method is that while hot spot selection is a task suitable for low magnification, high magnification is needed to discern positive nuclei, thus the pathologist must perform many zooming operations. We propose to address this issue by an image processing method that increases the visibility of the positive nuclei at low magnification levels. This tool displays the modified version at low magnification, while gradually blending into the original image at high magnification. The tool was evaluated in a feasibility study with four pathologists targeting routine clinical use. In a task to compare hot spot concentrations, the average accuracy was 75±4.1% using the tool and 69±4.6% without it (n=4). Feedback on the system, gathered from an observer study, indicate that the pathologists found the tool useful and fitting in their existing diagnostic process. The pathologists judged the tool to be feasible for implementation in clinical routine.

The principles of cancer treatment has for years been radical resection of the primary tumor. In the oncologic surgeries where the affected cancer site is close to the lymphatic system, it is as important to detect the draining lymph nodes for metastasis (lymph node mapping). As a replacement for conventional radioactive labeling, indocyanine green (ICG) has shown successful results in lymph node mapping; however, most of the ICG fluorescence detection techniques developed are based on camera imaging. In this work, fluorescence spectroscopy using a fiber-optical probe was evaluated on a tissue-like ICG phantom with ICG concentrations of 6-64 μM and on breast tissue from five patients. Fiber-optical based spectroscopy was able to detect ICG fluorescence at low intensities; therefore, it is expected to increase the detection threshold of the conventional imaging systems when used intraoperatively. The probe allows spectral characterization of the fluorescence and navigation in the tissue as opposed to camera imaging which is limited to the view on the surface of the tissue

Fluorescence guidance using 5-aminolevulinic acid (5-ALA) for brain tumor resection is a recent technique applied to the highly malignant brain tumors. Five-ALA accumulates as protoporphyrin IX fluorophore in the tumor cells in different concentrations depending on the tumor environment and cell properties. Our group has developed a fluorescence spectroscopy system used with a hand-held probe intra-operatively. The system has shown improvement of fluorescence detection and allows quantification that preliminarily correlates with tumor malignancy grade during surgery. However, quantification of fluorescence is affected by several factors including the initial fluorophore concentration, photobleaching due to operating lamps and attenuation from the blood. Accordingly, an optical phantom was developed to enable controlled fluorescence measurements and evaluation of the system outside of the surgical procedure. The phantom mimicked the optical properties of glioma at the specific fluorescence excitation wavelength when different concentrations of the fluorophore were included in the phantom. To allow evaluation of photobleaching, kinetics of fluorophore molecules in the phantom was restricted by solidifying the phantoms. Moreover, a model for tissue autofluorescence was added. The fluorescence intensity’s correlation with fluorophore concentration in addition to the photobleaching properties were investigated in the phantoms and were compared to the clinical data measured on the brain tumor.

BACKGROUND: Deep brain stimulation (DBS) requires precise and safe navigation to the chosen target. Optical measurements allow monitoring of gray-white tissue boundaries (total light intensity [TLI]) and microvascular blood flow during stereotactic procedures. OBJECTIVE: To establish the link between TLI/blood flow and anatomy along trajectories toward the ventral intermediate nucleus (Vim) and subthalamic nucleus (STN). METHODS: Stereotactic laser Doppler measurements were obtained with millimeter precision from the cortex toward the Vim (n = 13) and STN (n = 9). Optical trajectories of TLI and blood flow were created and compared with anatomy by superimposing the Schaltenbrandt-Wahren atlas on the patients' pre- and postoperative images. Measurements were divided into anatomic subgroups and compared statistically. RESULTS: Typical TLI trajectories with well-defined anatomic regions could be identified for the Vim and STN. TLI was significantly lower (P < .001) and microvascular blood flow significantly higher (P = .01) in the Vim targets. Of 1285 sites, 38 showed blood flow peaks, 27 of them along the Vim trajectories. High blood flow was more common close to the sulci and in the vicinity of the caudate/putamen. Along 1 Vim trajectory, a slight bleeding was suspected during insertion of the probe and confirmed with postoperative computed tomography. CONCLUSION: Laser Doppler is useful for intraoperative guidance during DBS implantation because simultaneous measurement of tissue grayness and microvascular blood flow can be done along the trajectory with millimeter precision. Typical but different TLI trajectories were found for the Vim and STN.

The laser Doppler technique is used to assess tissue perfusion. Traditionally an integrated, ω-weighted (first-order filter) power spectrum is used to estimate perfusion. In order to be able to obt ...

Quantification of blood fraction (fblood), blood oxygenation (S), melanin, lipofuscin and oxidised and reduced Cytochrome aa 3 and c was done from diffuse reflectance spectra captured in cortex, white matter, globus pallidus internus (GPi) and subthalamus during stereotactic implantations of 29 deep brain stimulation (DBS) electrodes with the aim of investigating whether the chromophores can give physiological information about the targets for DBS. Double-sided Mann-Whitney U -tests showed more lipofuscin in GPi compared to white matter and subthalamus (p < 0.05). Compared to the other structures, fbloodwas significantly higher in cortex (p < 0.05) and S lower in GPi (p < 0.05). Median values and range for fblood were 1.0 [0.2–6.0]% in the cortex, 0.3 [0.1–8.2]% in white matter, 0.2 [0.1–0.8]% in the GPi and 0.2 [0.1–11.7]% in the subthalamus. Corresponding values for S was 20 [0–81]% in the cortex, 29 [0–78]% in white matter, 0 [0–0]% in the GPi and 0 [0–92]% in the subthalamus. In conclusion, the measurements indicate very low oxygenation and blood volume for DBS patients, especially in the GPi. It would be of great interest to investigate whether this is due to the disease, the normal situation or an artefact of doing invasive measurements.