Quantifying tissue temperature changes induced by infrared neural stimulation: numerical simulation and MR thermometry.

Infrared neural stimulation (INS) delivered via short pulse trains is an innovative tool that has potential for us use for studying brain function and circuitry, brain machine interface, and clinical use. The prevailing mechanism for INS involves the conversion of light energy into thermal transients, leading to neuronal membrane depolarization. Due to the potential risks of thermal damage, it is crucial to ensure that the resulting local temperature increases are within non-damaging limits for brain tissues. Previous studies have estimated damage thresholds using histological methods and have modeled thermal effects based on peripheral nerves. However, additional quantitative measurements and modeling studies are needed for the central nervous system. Here, we performed 7 T MRI thermometry on ex vivo rat brains following the delivery of infrared pulse trains at five different intensities from 0.1-1.0 J/cm2 (each pulse train 1,875 nm, 25 us/pulse, 200 Hz, 0.5 s duration, delivered through 200 µm fiber). Additionally, we utilized the General BioHeat Transfer Model (GBHTM) to simulate local temperature changes in perfused brain tissues while delivering these laser energies to tissue (with optical parameters of human skin) via three different sizes of optical fibers at five energy intensities. The simulation results clearly demonstrate that a 0.5 second INS pulse train induces an increase followed by an immediate drop in temperature at stimulation offset. The delivery of multiple pulse trains with 2.5 s interstimulus interval (ISI) leads to rising temperatures that plateau. Both thermometry and modeling results show that, using parameters that are commonly used in biological applications (200 µm diameter fiber, 0.1-1.0 J/cm2), the final temperature increase at the end of the 60 sec stimuli duration does not exceed 1°C with stimulation values of 0.1-0.5 J/cm2 and does not exceed 2°C with stimulation values of up to 1.0 J/cm2. Thus, the maximum temperature rise is consistent with the thermal damage threshold reported in previous studies. This study provides a quantitative evaluation of the temperature changes induced by INS, suggesting that existing practices pose minimal major safety concerns for biological tissues.

Infrared neural stimulation in human cerebral cortex.

BACKGROUND: Modulation of brain circuits by electrical stimulation has led to exciting and powerful therapies for diseases such as Parkinson's. Because human brain organization is based in mesoscale (millimeter-scale) functional nodes, having a method that can selectively target such nodes could enable more precise, functionally specific stimulation therapies. Infrared Neural Stimulation (INS) is an emerging stimulation technology that stimulates neural tissue via delivery of tiny heat pulses. In nonhuman primates, this optical method provides focal intensity-dependent stimulation of the brain without tissue damage. However, whether INS application to the human central nervous system (CNS) is similarly effective is unknown. OBJECTIVE: To examine the effectiveness of INS on human cerebral cortex in intraoperative setting and to evaluate INS damage threshholds. METHODS: Five epileptic subjects undergoing standard lobectomy for epilepsy consented to this study. Cortical response to INS was assessed by intrinsic signal optical imaging (OI, a method that detects changes in tissue reflectance due to neuronal activity). A custom integrated INS and OI system was developed specifically for short-duration INS and OI acquisition during surgical procedures. Single pulse trains of INS with intensities from 0.2 to 0.8 J/cm2 were delivered to the somatosensory cortex and responses were recorded via optical imaging. Following tissue resection, histological analysis was conducted to evaluate damage threshholds. RESULTS: As assessed by OI, and similar to results in monkeys, INS induced responses in human cortex were highly focal (millimeter sized) and led to relative suppression of nearby cortical sites. Intensity dependence was observed at both stimulated and functionally connected sites. Histological analysis of INS-stimulated human cortical tissue provided damage threshold estimates. CONCLUSION: This is the first study demonstrating application of INS to human CNS and shows feasibility for stimulating single cortical nodes and associated sites and provided INS damage threshold estimates for cortical tissue. Our results suggest that INS is a promising tool for stimulation of functionally selective mesoscale circuits in the human brain, and may lead to advances in the future of precision medicine.

Spatial frequency representation in V2 and V4 of macaque monkey.

Spatial frequency (SF) is an important attribute in the visual scene and is a defining feature of visual processing channels. However, there remain many unsolved questions about how extrastriate areas in primate visual cortex code this fundamental information. Here, using intrinsic signal optical imaging in visual areas of V2 and V4 of macaque monkeys, we quantify the relationship between SF maps and (1) visual topography and (2) color and orientation maps. We find that in orientation regions, low to high SF is mapped orthogonally to orientation; in color regions, which are reported to contain orthogonal axes of color and lightness, low SFs tend to be represented more frequently than high SFs. This supports a population-based SF fluctuation related to the 'color/orientation' organizations. We propose a generalized hypercolumn model across cortical areas, comprised of two orthogonal parameters with additional parameters.

Selective corticofugal modulation on sound processing in auditory thalamus of awake marmosets.

Cortical feedback has long been considered crucial for the modulation of sensory perception and recognition. However, previous studies have shown varying modulatory effects of the primary auditory cortex (A1) on the auditory response of subcortical neurons, which complicate interpretations regarding the function of A1 in sound perception and recognition. This has been further complicated by studies conducted under different brain states. In the current study, we used cryo-inactivation in A1 to examine the role of corticothalamic feedback on medial geniculate body (MGB) neurons in awake marmosets. The primary effects of A1 inactivation were a frequency-specific decrease in the auditory response of most MGB neurons coupled with an increased spontaneous firing rate, which together resulted in a decrease in the signal-to-noise ratio. In addition, we report for the first time that A1 robustly modulated the long-lasting sustained response of MGB neurons, which changed the frequency tuning after A1 inactivation, e.g. some neurons are sharper with corticofugal feedback and some get broader. Taken together, our results demonstrate that corticothalamic modulation in awake marmosets serves to enhance sensory processing in a manner similar to center-surround models proposed in visual and somatosensory systems, a finding which supports common principles of corticothalamic processing across sensory systems.

Targeted Optical Neural Stimulation: A New Era for Personalized Medicine.

Targeted optical neural stimulation comprises infrared neural stimulation and optogenetics, which affect the nervous system through induced thermal transients and activation of light-sensitive proteins, respectively. The main advantage of this pair of optical tools is high functional selectivity, which conventional electrical stimulation lacks. Over the past 15 years, the mechanism, safety, and feasibility of optical stimulation techniques have undergone continuous investigation and development. When combined with other methods like optical imaging and high-field functional magnetic resonance imaging, the translation of optical stimulation to clinical practice adds high value. We review the theoretical foundations and current state of optical stimulation, with a particular focus on infrared neural stimulation as a potential bridge linking optical stimulation to personalized medicine.

DeepBhvTracking: A Novel Behavior Tracking Method for Laboratory Animals Based on Deep Learning.

Behavioral measurement and evaluation are broadly used to understand brain functions in neuroscience, especially for investigations of movement disorders, social deficits, and mental diseases. Numerous commercial software and open-source programs have been developed for tracking the movement of laboratory animals, allowing animal behavior to be analyzed digitally. In vivo optical imaging and electrophysiological recording in freely behaving animals are now widely used to understand neural functions in circuits. However, it is always a challenge to accurately track the movement of an animal under certain complex conditions due to uneven environment illumination, variations in animal models, and interference from recording devices and experimenters. To overcome these challenges, we have developed a strategy to track the movement of an animal by combining a deep learning technique, the You Only Look Once (YOLO) algorithm, with a background subtraction algorithm, a method we label DeepBhvTracking. In our method, we first train the detector using manually labeled images and a pretrained deep-learning neural network combined with YOLO, then generate bounding boxes of the targets using the trained detector, and finally track the center of the targets by calculating their centroid in the bounding box using background subtraction. Using DeepBhvTracking, the movement of animals can be tracked accurately in complex environments and can be used in different behavior paradigms and for different animal models. Therefore, DeepBhvTracking can be broadly used in studies of neuroscience, medicine, and machine learning algorithms.

Instrument design and characterization for high resolution MALDI-MS imaging of tissue sections.

In previous work, we have reported using a MALDI imaging time-of-flight mass spectrometer for the detection of protein ions from tissue sections with spatial resolution of 25 microm. We present here imaging mass spectrometry results obtained with a high-resolution scanning MALDI time-of-flight mass spectrometer, equipped with a coaxial laser illumination ion source, capable of achieving irradiation areas as small as 40 microm(2) (ca 7 microm diameter). MALDI-generated analyte ion signals from these very small irradiation volumes can be observed in a molecular weight range up to 27,000. High-resolution imaging mass spectrometry images were successfully generated from matrix thin film samples and tissue sections with scanning resolutions at and below 10 microm. This work also provides fundamental characterization of the ion signal dependence as a function of various focus and fluence parameters that will be required for extension to tissue imaging at the subcellular level.

Infrared laser desorption and ionization of polypeptides from a polyacrylamide gel.

We observed direct desorption and ionization of angiotensin II and bovine insulin from a frozen polyacrylamide gel without the addition of an exogenous matrix, using picosecond pulses from a tunable, mid-infrared free-electron laser tuned to strong absorption bands of the gel. At 5.7, 5.9, 6.1 and 6.3 microm we were able to desorb and ionize both analyte molecules, with the strongest analyte signal generated at 5.9 microm. However, no analyte signal was observed at 5.5 microm. Consistent with a previous report, we did not observe ions of either polypeptide at 2.9 microm, in spite of strong overall absorption. We discuss the implications of this wavelength-dependent ionization, including possible ablation mechanisms and energy partitioning between competing vibrational modes.