Spatial and temporal variations in forearm skin perfusion captured by laser Doppler perfusion imaging (LDI) have been compared with topographic maps recorded by laser Doppler flowmetry. In order to determine the shortest LDI sampling time required at each measurement site, with an adequate signal-to-noise ratio and with the ability to display the heterogeneity in skin perfusion, the noise-limited resolution of the LDI system as well as various sampling times were tested. The noise-limited resolution for medium and high light intensities were less than 0.5% (temporal) and 0.3% (spatial) of full scale. A sampling time of 1 sec was selected and image presentation was made by performing bilinear interpolation between perfusion values. The same area (10 x 10 mm) was mapped with LDI and topographic mapping at seven different sites. In addition, a larger area covering the surrounding skin was recorded with LDI. The small area recordings with LDI and topographic mapping could be identified in the larger LDI image. High-and low-perfusion spots coincided between the two systems. Temporal variations were studied by repeated LDI recordings of the same areas as above. Small spots were selected in the areas and plotted versus time. Without provocation, the total perfusion changes at each spot showed large variations, but the relative perfusion levels between neighboring spots persisted. Provocation with heat increased the perfusion in all spots.

Deep brain stimulation (DBS) is widely used for reduction of symptoms caused by movement disorders. In this chapter a patient-specific finite element method for modeling and simulation of DBS electric parameters is presented. The individual’s stereotactic preoperative MR-batch of images is used as input to the model in order to classify tissue type and allot electrical conductivity for cerebrospinal fluid, blood and grey as well as white matter. With patient-specific positioning of the DBS electrodes the method allows for investigation of the relative electric field changes in relation to anatomy and DBS-settings. Examples of visualization of the patient-specific electric entities together with the surrounding anatomy are given. The use of the method is exemplified on patients with Parkinson’s disease. Future applications including multiphysics simulations and applicability for new DBS targets and symptoms are discussed.

Deep brain stimulation (DBS) is an effective treatment for movement disorders e.g. Parkinson's disease. Thin electrodes are implanted into the deep brain structures by means of stereotactic technique and electrical stimulations are delivered to the brain tissue. Accuracy and safety during the implantation is important for optimal stimulation effect and minimization of bleedings. In addition to microelectrode recording and impedance measurements, intraoperative optical measurements using laser Doppler perfusion monitoring (LDPM) have previously been suggested as guidance tool during stereotactic DBS implantations. In this study we compare optical trajectories, recorded with LDPM ranging from cortex towards the subthalamic nucleus (STN), to the corresponding magnetic resonance imaging (MRI) trajectories. Inversed gray scales from the T2-weighted MRI were used for comparison with the total light intensity (TLI) representing tissue grayness. Both curves followed a general tendency with a deep dip in the vicinity to the left ventricle. MRI trajectories might help in predicting the optical trajectory but further studies including more data and fine tuning of the comparative methodology are required

A laser Doppler perfusion imaging technique based on dynamic light scattering in tissue is reported. When a laser beam sequentially scans the tissue (maximal area approximately 12 cm*12 cm), moving blood cells generate Doppler components in the backscattered light. A fraction of this light is detected by a remote photodiode and converted into an electrical signal. In the signal processor, a signal proportional to the tissue perfusion at each measurement point is calculated and stored. When the scanning procedure is completed, the system generates a color-coded perfusion image on a monitor. A perfusion image is typically built up of data from 4096 measurement sites, recorded during a time period of 4 min. This image has a spatial resolution of about 2 mm. A theory for the system inherent amplification factor dependence on the distance between individual measurement points and detector is proposed and correction measures are presented. Performance results for the laser Doppler perfusion imager obtained with a flow simulator are presented. The advantages of the method are discussed.

Introduction

The electric field (EF) around the active deep brain stimulation (DBS) contact is of interest for optimizing the therapeutic effect. We have previously developed a method for simulation and visualization of the EF. The aim of the project is to improve the software for quick and user friendly simulations.  

Methods

The ELMA software for brain model creation has been improved by adding quick ROI selection and transformation to an electrical conductivity map based on tissue classification through multiple slices of the preoperative MRI. These data are used as input for Comsol Multiphysics simulations of the EF. Two points along the position of the lead, as seen in the postoperative images, are used for correct placement in the brain model. Multiple DBS lead models are pre-programmed. The active contact and amplitude are user-selected.

Results

After a simulation the result is visualized with a user defined isolevel or isosurface superimposed on the patients preoperative MRI. An example is shown in Fig. 1. The 3389 lead is places in zona inserta (Zi) and contact 1 activated with 2 and 4 V respectively. An isolevel of 0.2 V/mm is used corresponding to a ~ 3-4 µm axon diameter when using a pulse length of 60 µs. More examples will be presented at the meeting.

Conclusion

The software for patient-specific simulations of EF around DBS electrodes has been improved for quicker simulations and more DBS leads. As a next step user friendly Apps will be implemented.

Laser Doppler flowmetry (LDF) has been adapted for optical guidance during stereotactic deep brain stimulation (DBS) surgery. It has been used in more than 130 DBS implantations. The necessary steps to go from experimental studies to clinical use in the neurosurgical setting are reviewed.

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.

Objective: To analyze the relationship between the electric field and the volume of tissue activated (VTA) during model-based investigations of deep brain stimulation (DBS).

Background: An important factor for the therapeutic outcome of DBS is the spatial distribution of the stimulation field in the target area. Finite element models and simulations of DBS are increasingly being used to study the distribution of the stimulation field in relation to patient specific anatomy. The stimulation field is often defined as a VTA derived from computational axon models that are coupled to the finite element simulations. This approach however, is not feasible in many research centers due to the complexity of developing a computational axon model, as well as the extensive execution time when solving such models.

Methods: A detailed computer axon cable model was developed to study axonal activation in response to various DBS stimulation configurations. A range of axon models were set up and coupled to finite element models of DBS. DBS simulations were performed for Medtronic lead model 3389 during monopolar configurations for a range of amplitudes and pulse widths. Activation thresholds for the electric fields were derived by measuring the field strength at the maximum radius of activation for each configuration.

Results: Simulations showed that the electric field thresholds were related to stimulation amplitude, pulse width, and axon diameter. For large axons, the electric field threshold was not dependent on the amplitude, thus implying a low sensitivity of the electric field curvature.

Conclusions: Electric field thresholds can be used to predict the VTA during model-based investigations of DBS without the necessity of computer axon models. The use of electric field thresholds may substantially simplify the process of performing model-based investigations of DBS in the future.

It would be of great value to have a precise and non-damaging neuromodulation technique in the field of basic neuroscience research and for clinical treatment of neurological diseases. Infrared neural modulation (INM) is a new modulation modality developed in the last decade, which uses pulsed or continues infrared (IR) light with a wavelength of 1200 to 2200 nm to directly alter neural signals. INM includes both infrared neural stimulation (INS) and infrared neural inhibition (INI). INM is widely investigated for use on peripheral nerves, cochlear nerve fibers, cardiac cells, and the central nervous system. This technique holds the advantages of contact-free and high spatiotemporal precision compared to the traditional electrical stimulation. It does not depend on genetic modification and exogenous absorbers as other optical techniques, such as the optogenetic technique and the enhanced near-infrared neural stimulation (e-NIR). These advantages make INM a viable technique for research and clinical applications. The primary mechanism of the INM is believed to be a photothermal effect, where the IR laser energy absorbed by water leads to a rapid local temperature change. However, so far the details of the mechanism of action potential (AP) generation and inhibition remain elusive. Another issueis that the cells may be endangeredbythe heat exposure, consequently triggering a physiologicalmalfunction or even permanent damage.These concernshave hindered the transfer of the INM technique to the clinical therapy.Therefore, the general aim of this study was to improve the understanding of the details of how INM affects the cells. Laser parameters for safe and efficient stimulation were investigated on the basis of being useful for clinical applications. A tailored heating model and in vitro INM experiments on cortex neurons were used to reach this goal.The first paper was a feasibility study. A 1550nm laser with a beam spot diameter of around 6 mm was used to irradiate the rat cortex neurons, which were seeded on multi-electrode arrays (MEA) and formed well-connected networks. A heating model based on an estimated laser beam (standard Gaussian distribution) was used to simulate temperaturechanges. The damage signal ratio (DSR),based on the temperature,was calculated to predict the heat damage. The average spike rate of all the working electrodes from two MEAs was used to evaluate the degree of theinhibition of the neural networks. Results IVshowed that it is possible to use the 1550 nm laser to safely inhibit the neural network activity and that the degree of the INI is dependent on the power of the laser.The second paper wasan application and mechanism study. The aim of this study was to investigate the safety, efficiency, and cellular mechanism of INI. The same laser as in paper Iwas used in this study. A 20 X objective was used to decrease the beam spot diameteraround 240 μm. The measured laser profile (high order Gaussian beam) was used in the heating model to predict the temperature. The model was verified by local temperature measurements viamicropipette. The action potential rates, measured by the MEA electrodes, were quantified for different temperatures. Bicuculline was added to the cortex neuron cultures to induce hyperexcitation of the neural network. The results showed that the INI is temperature dependent and that the temperature needs to be less than 46 °C at 30 s laser irradiation for safe inhibition. The IR laser couldalso be used to inhibit the hyperexcitedactivity. The degree of inhibition, for the assessed subpopulation of neurons, was better correlated with the action potential amplitude than the width of it and INIcan be accomplished without inhibitory synapses

Some brain diseases are caused by neurons being abnormally excited, such as Parkinson’s disease (PD) and epilepsy. The aim of this study was to investigate the feasibility and the efficacy of infrared laser irradiation for inhibiting neuronal network activity. We cultured rat cortex neurons, forming neural networks with spontaneous neural activity, on multi-electrode arrays (MEAs). To inhibit the activity of the networks we irradiated the neurons using different intensity of 1550 nm infrared laser light. A temperature model was created using COMSOL Multiphysics software to predict the temperature change at different laser intensity irradiation. Our initial result shows that the wavelength of 1550 nm infrared laser can be used to inhibit the network activity of cultivated rat cortex neurons directly and reversibly. The degrees of network inhibition can be manipulated by changing the laser intensity. The optical thermal effect is considered the primary mechanism during infrared neural inhibition (INI). These results demonstrate that INI could potentially be useful in the treatment of neurological disorders and that temperature may play an important role in INI.

Despite the many advantages of biomimetic calcium phosphates (CaPs) coatings, there is a troublesome problem of low cohesion in the coatings. The low cohesion originates from the absence of bonding between CaP crystals, leading to cracks during drying of the coatings. In this study, based on a simplified Singh-Tirumkudulu model, the critical cracking thickness (CCT) of biomimetic CaPs coatings has been calculated. CaPs crystal size is the key factor influencing the CCT, except for the particle's shear modulus. Biomimetic CaPs coatings with different thickness have been prepared by soaking Ti substrates with a transition layer of TiO2 (rutile) in Dulbecco's phosphate buffer saline solution (DPBS) for 1, 2, 4 and 6 weeks. The morphology, thickness, and whether cracks formed or not were evaluated by SEM. The simplified Singh and Tirumkudulu model has been verified in terms of our experimental results and data obtained from previous literatures. Via dedicated experiments and calculations it is concluded that a thickness of about approximately 2 gm is the critical value for a crack-free CaPs coating given that the CaPs crystal size is smaller than 100 nm. The model could be used in the future design of crack-free biomimetic coatings.

Sealing exposed dental tubules is the most effective and long-term way to relieve the pain induced by dental sensitivity. A bioactive hollow sphere (strontium substituted calcium phosphate) was synthesized and added in toothpaste to study its effect on dental hypersensitivity via tooth tubules occlusion and mineralization. The size of spheres is perfect for penetrating into dental tubules, reaching to 20 pm into the tubules. The exposed dental tubules were occluded by spheres and new apatite layer after 3 days brushing. The spheres attached to the surface of dentin and the mineralized surface contained two layers, a porous layer followed by a dense apatite layer. The porous layer can be dissolved in an acidic solution, but the following dense layer could be kept even after soaking in an acid solution. In conclusion, Sr-substituted calcium phosphate spheres could be a good candidate for at-home treatment of dental hypersensitivity.

Glioblastoma multiforme (GBM), a highly malignant primary brain tumor, is difficult to distinguish from from its surrounding functioning tissue under direct vision in the operating field, since it grows in an infiltrative growth pattern. The main challenge in the surgical treatment of GBM is to fully resect the tumor and avoid neurological impairment. In this paper we extend previous proof-of-principle studies by extending the clinical potential of OTP with the introduction of more sophisticated multivariate analysis schemes. The aim is to distinguish tumor and healthy tissue as well as possible using singular value decomposition (SVD) and cluster analysis methods.

Personalized and pervasive healthcare devices help seamlessly integrate healthcareand wellness into the daily life, independent of time and space. Silicon IntegratedCircuit (IC) has been used in many advanced healthcare applications due to thecompact size and ultra-low power consumption. Meanwhile, printed electronics(PE) is considered as a promising approach enabling cost-effective manufacturingof thin, flexible, and light-weight devices. A hybrid integration of IC and PE providesa new solution for the future wearable healthcare devices. In this chapter, firstlya customized bio-sensing IC is demonstrated, which can detect and process variousbio-signals; secondly, the feasibility and performance of using inkjet printingtechnology as enabling technology has been examined for the fabrication of flexiblebio-sensing devices. Finally, a wearable and flexible Bio-Patch is presented byleveraging hybrid integration of PE and bio-sensing IC. In-vivo test results showthat the flexible Bio-Patch provides high quality ECG signal comparable with theone gained by bedside ECG machine.