Light Modulation of Brain and Development of Relevant Equipment

Abstract

Light modulation plays an important role in understanding the pathology of brain disorders and improving brain function. Optogenetic techniques can activate or silence targeted neurons with high temporal and spatial accuracy and provide precise control, and have recently become a method for quick manipulation of genetically identified types of neurons. Photobiomodulation (PBM) is light therapy that utilizes non-ionizing light sources, including lasers, light emitting diodes, or broadband light. It provides a safe means of modulating brain activity without any irreversible damage and has established optimal treatment parameters in clinical practice. This manuscript reviews 1) how optogenetic approaches have been used to dissect neural circuits in animal models of Alzheimer’s disease, Parkinson’s disease, and depression, and 2) how low level transcranial lasers and LED stimulation in humans improves brain activity patterns in these diseases. State-of-the-art brain machine interfaces that can record neural activity and stimulate neurons with light have good prospects in the future.

Keywords

Alzheimer’s disease brain-machine interfaces depression optogenetics Parkinson’s disease photobiomodulation transcranial near-infrared stimulation

INTRODUCTION

Optogenetics and photobiomodulation have recently become a focus of neuroscience research. Optogenetics can regulate specific neuronal activity in animals, while stimulation of brain regions with transcranial lasers or light emitting diodes (LEDs) can help improve brain function. Here, we briefly discuss how optogenetic approaches have been used to dissect neural circuits in animal models of depression, Parkinson’s disease (PD), and Alzheimer’s disease (AD), and how stimulation with low level transcranial lasers or LEDs can improve brain activity in people who suffer from these diseases. In order to target these elements or patterns with the most precise and efficient interventions, light stimulation combined with simultaneous recording of neuronal responses is crucial for achieving effective brain photobiomodulation therapy.

OPTOGENETICS

Frances Crick first proposed that light might be used as a means to control the activity of a specific types of neurons, and put forward a preliminary hypothesis for the idea of optogenetics [1]. In 2002, Zemelman et al. developed a method for optically stimulating groups of genetically designated neurons by using Drosophila photoreceptor genes encoding rhodopsin, alpha-arrestin-2, and the alpha subunit of the cognate heterotrimeric G protein. With the help of gene-expression technology, photostimulation was first applied to activate a small group of specific neurons within a population of neurons [2]. By 2005, Boyden et al. had successfully expressed the microbial rhodopsin protein in mammalian neurons and successfully activated the neurons with light [3].

Optogenetics is a technique that introduces the DNA of light-sensitive ion channels into neurons of interest. Under genetic, viral, or activity-dependent control, the expression of light-sensitive ion channels can be targeted to the desired groups of neurons [4]. 1) Genetic: using transgenic animals is the most stable way to express light activated molecules for a long time. 2) Viral: adeno associated virus (AAV) is used most frequently for targeting. AAV containing genetic information of exogenous photosensitive protein can effectively enter neuron, and further use promoter elements to drive the expression of light sensitive ion channels protein from viruses infecting these neurons. Viral vectors carrying the genes encoding light activated proteins can be delivered stereotactically into discrete brain regions [5, 6]. Stereotaxic coordinates for specific brain regions are easily determined from a brain atlas (e.g., The Mouse Brain in Stereotaxic Coordinates by Paxinos and Franklin) [7] that lists rostral–caudal, medial–lateral, and dorsal–ventral distances from bregma, which is assigned position 0. To obtain targeting coordinates for a specific injection region, subtract the atlas coordinates from the position of the animal’s bregma in the stereotaxic apparatus. It is a good method to precisely locate the expression of photogenic protein in single neuron by single cell electroporation. In addition, using viruses specialized to either infect neurons at specific locations or to infect them via their synaptic connections (transsynaptic infection, retrograde or anterograde) can be used for selectively targeting optogene expression. 3) Activity-dependent control: to target expression of optogenetic protein to neurons based on activity patterns. This approach will only allow the reactivation of a subset of neurons that have been activated in recent behavioral episodes, requiring an unambiguous and specific promoter linked to spiking activity in neurons. Then light-sensitive ion channels are expressed through the natural protein translation mechanism of the cell and transported to the neuron’s cell membrane. Once introduced into neurons, these ion channels or pumps can be activated by light and become permeable to positive or negative ions depending on the type of optogenetic protein [8], and this can trigger or suppress action potentials, neurotransmitter release, and thus neuronal signaling. Because these fast-reacting channels are located at the level of the individual neuron, optogenetic light stimulation can manipulate cells with high specificity and temporal precision [3 , 10]. This technique provides a unique mechanism for cell-type targeting and bidirectional control of neuronal activity [11].

Figure 1 shows several optogenetic tools that offer flexibility in experimental design and provide powerful and refined ways to manipulation neuronal circuitry. Action potentials can be excited or inhibited by selecting different types of optogenetic proteins and the wavelength of light that will trigger them [8]. For example, blue light sensitive Channelrhodopsin (ChR) selectively allows positively charged ions to enter neurons, which triggers action potentials that are time-locked to the light pulses, while yellow-light sensitive Halorhodopsin (NpHR) selectively pumps negatively charged chloride ions into neurons, which hyperpolarizes their membranes and suppresses action potentials [8, 12].

Fig. 1

Optogenetic tools. Major classes of single-component optogenetic tools include cation-permeable channels for membrane depolarization (such as channelrhodopsins; ChRs), chloride pumps (such as halorhodopsin; NpHR), proton pumps (such as bacteriorhodopsin/proteorhodopsin; BR/PR) for membrane hyperpolarization, and light-activated membrane-bound G protein-coupled (OptoXR) or soluble (bacterial cyclase) receptors that mimic various signaling cascades [12].

Optogenetics has recently become a good method for fast manipulation of genetically identified types of neurons [13], which can activate or silence light-sensitized neurons with high temporal and spatial accuracy, thus providing precise control [14, 15]. Optogenetics has been used in many experiments in which animals could move freely [16, 17]. A benefit of optogenetics is that optical stimulation does not interfere with electrical neuronal recordings, which allows simultaneous optical stimulation and electrophysiological recording and contributing to analysis of real-time closed-loop systems. Another advantage is genetic manipulation allows optogenetics to target specific neuronal circuits and specific neural sub-circuits [18], while electrical stimulation cannot be cell-type specific [19, 20].

Optogenetics for animal models of AD

Optogenetics has been used to study neural circuits that underlie several brain diseases [12], including AD, depression, autism, and parkinsonism. In particular, it has provided a deeper insight of determining the causal relationships between brain activity and behavior in these conditions. For example, optogenetic tools has been used to interfere with specific synaptic molecules or neuronal circuits to reveal the precise mechanisms underlying deficits in animal models of AD. Optogenetic activation of entorhinal cortex II-CA1 parvalbumin synapses with a theta burst stimulation (TBS) paradigm effectively rescued synaptic decay and improved spatial learning and memory in an AD model mouse [21]. It also has been suggested that the decrease of dendritic spine density in dentate gyrus neurons of a mouse model with early AD can be reversed using optogenetic techniques [22]. Furthermore, using optogenetics tools to stimulate neurons can rescue memory loss caused by AD. Roy et al. demonstrated that photo-activating dentate gyrus engram cells could trigger episodic memory recall in an AD model mouse [22]. Moreover, optogenetics tools can also be used to modulate neurotransmitter signals. Activating glutamatergic neurons with optogenetic techniques is useful for theta-wave generation in the hippocampus, which might significantly facilitate learning and memory [23]. These methods have broad prospects for therapeutic application.

Optogenetics for animal models of PD

Transplantation of dopamine-producing neurons into the brain has been tested as a therapy for PD. Before optogenetics, efforts to investigate how transplanted dopamine neurons modulate behavior in animal models of PD usually involved destruction of the grafted cells using toxins [24]. This is problematic because irreversible ablation of the grafted cells makes it difficult to discriminate between different types of cell activity. Steinbeck et al. employed optogenetics as an on-off switch for dopamine release-related neuronal activity, allowing this function to be tested independently of other possible functions within these cells. This work thus demonstrates the utility of optogenetics for investigating how cell therapy promotes recovery in animal models of neurological diseases [25]. Additionally, recent optogenetics studies demonstrate the central role of striatal cholinergic interneuron activity in the production of motor symptoms in PD [26]. Indeed, optogenetic photoinhibition of cholinergic interneurons in dopamine (DA)-depleted mice improved PD-like motor symptomatology by reducing akinesia, bradykinesia, and sensorimotor neglect [27]. Optogenetics will continue to advance our understanding of the neuronal circuitry that modulates PD.

Optogenetics for animal models of depression

The advent of optogenetics has revolutionized research into the mechanisms underlying psychiatric diseases. Optogenetic tools have gradually played a role in mapping relevant neuronal circuitry in animal models of depression, clarifying the differing contributions of limbic areas, including the medial prefrontal cortex, the ventral tegmental area, and nucleus accumbens. Brendan et al. [28] tested two major subtypes of pyramidal neurons in mouse medial prefrontal cortex—those expressing Drd1 or Drd2—and found that optogenetically activating Drd1-expressing pyramidal cells with optogenetics produces rapid and long-lasting antidepressant and anti-anxiolytic responses. In contrast, photostimulation of Drd2 expressing pyramidal cells was ineffective. Optogenetic stimulation of the ventral tegmental area/nucleus accumbens increases levels of brain-derived neurotrophic factor in the nucleus accumbens and induces social avoidance following sub-threshold defeat [29]. The nucleus accumbens primarily contains medium spiny neurons (MSNs) that predominantly express D1- or D2-type DA receptors. Optogenetically stimulating D1-nucleus accumbens neurons in susceptible mice following chronic social defeat-induced stress promoted resilience, while stimulating D2-MSNs in stress naïve mice induced susceptibility to subthreshold defeat [30].

PHOTOBIOMODULATION (PBM)

PBM was accidently discovered in 1967, when Endre Mester attempted to repeat an experiment published by Paul McGuff in which he had used a high-powered laser to treat tumors in rats [31]. Instead of curing the experimental tumors with his low powered laser, Mester succeeded in stimulating hair regrowth and better wound healing in the rats [32]. This discovery led to a series of papers describing what Mester called “laser biostimulation”, and soon became known as “low level laser therapy” (LLLT) [33].

The most well studied mechanism of action of PBM focuses on cytochrome c oxidase (CCO), an enzyme that functions in mitochondrial respiration and is responsible for the final reduction of oxygen to water using the electrons generated from glucose metabolism [34]. CCO enzymatic activity can be inhibited by nitric oxide (NO) (especially in hypoxic or damaged cells). Inhibitory NO can be dissociated by photons of light that are absorbed by CCO (which contains two heme and two copper centers with different absorption spectra) [35]. These absorption peaks are mainly in the red (600–700 nm) and near-infrared (760–940 nm) spectral regions. When NO is dissociated, the mitochondrial membrane potential increases, more oxygen is consumed, more glucose is metabolized, and more ATP is produced by the mitochondria. Figure 2 shows that NO can bind to copper (or heme) centers in CCO and inhibit respiration [36].

Fig. 2

Nitric oxide can bind to copper (or heme) centers in cytochrome c oxidase and inhibit respiration. The nitric oxide may be photo-dissociated by absorption of red or near infrared light, allowing oxygen to return and a sharp increase in respiration and adenosine triphosphate formation [36].

Some researchers believe that the coherent monochromatic lasers that were used in the original discovery of the effect, and whose use continued for many years, are superior to the rather recent introduction of LEDs, that are non-coherent and have a wider band-spread (generally 30 nm full-width half-maximum) [37]. However, most researchers feel that other parameters such as wavelength, irradiance, fluence, and total energy are the most important determinants of efficacy [38]. Wavelengths in the near-infrared light (NIR) region (800–1100 nm) have been the most often used. Power levels have varied markedly from Class IV lasers with total power outputs in the region of 10 W [39] to lasers with more modest power levels (1 W). LEDs can also have widely varying total power levels depending on the size of the array and the number and power of the individual diodes. Irradiance can also vary quite substantially from the Photothera laser [40] and other class IV lasers, which required active cooling (∼700 mW/cm²) to LEDs in the region of 10–30 mW/cm². It is worth noting that LLLT (50 or 200 mW) does not penetrate through 3 cm of skull or brain tissue. Only higher-powered lasers (10–15 W) can penetrate the human skull and underlying brain tissue, and even so, this only penetrates about 1 inch into the brain with only 1% –2% of the power level on the head surface [41]. In order to improve brain function, different fluences have been applied on the scalp or skull of healthy participants, ranging from 10 to 137.5 J/cm² [42 –44]. The overall results from clinical reports indicate that a cortical fluence of approximately 1 to 2 J/cm² per site may be sufficient to achieve positive effects [40, 45]. Several studies have tested the use of transcranial near-infrared stimulation (tNIRS, including laser and LED) in treating various human brain disorders [46]. Principles of light-tissue interactions are shown in Fig. 3 [47].

Fig. 3

Principles of light-tissue interactions. A) Light at short wavelengths has low tissue penetration. Light at high wavelengths displays high tissue penetration and delivers therapeutic levels of energy to deeper structures. Whereas surface structures exposed to high wavelengths may be exposed to inhibitory energy densities (e.g., 100 J/cm²), light with a certain power density targeting a surface redistributes in a proportionally higher tissue volume due to diffraction (bending of waves). Multiple scattering of light allows for spreading out of waves and increases the treatment volume. Thus, a lower applied energy can be used to achieve an effective energy density at higher depths. B) Because radiant exposure (J/cm²) is the product of irradiance (W/cm²) and time, the energy delivered to tissues as a result of a constant irradiance can be increased by increasing exposure time. Thus, tissue penetration can also be affected by exposure time. When sources of low-level light therapy are used with high exposure times, deep structures can be treated with biomodulatory amounts of energy, while avoiding ablative effects. C) Tissues vary in their photoacceptor content, transmittance, and relaxation time. This accounts for interspecies and interregional variations in light penetration (e.g., gray matter versus white matter in the brain). In addition, metabolically active tissues such as nervous tissue may exhibit variations in relaxation times due to changes in the redox states of photoacceptors. Depending on their activation state, this not only affects tissue penetration, but also the susceptibility of nervous tissues to low-level light therapy [47].

PBM in treating patients with AD

Several animal studies have shown positive outcomes using transcranial PBM in mouse models of neurodegenerative diseases such as AD [48, 49] and PD [50, 51], which has led to interest in using it to treat human patients with AD or PD. A small pilot study investigated the effect of the Vielight Neuro system (see Fig. 4) (a combination of tPBM and intranasal PBM) on 5 patients with mild to moderately-severe AD [52]. Patients were given 12 weeks of treatment, and levels of memory and cognition were compared before and after treatment. All patients received 14 in-clinic treatment sessions twice weekly during the first two weeks, once weekly for the final 10 weeks, and a no treatments during a 4-week follow-up period. Memory and cognition were assessed using the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale–Cognitive subscale scales. At baseline, MMSE scores ranged from 10 to 24, with two patients having severe dementia and three having mild dementia. Statistically significant improvements were present in cognition after 12 weeks of active treatment. They also reported better sleep, fewer angry outbursts, decreased anxiety and wandering, and no related adverse events. A recent Monte Carlo simulation study suggested that a transcranial multidirectional irradiation approach using multiple-LED arrays (181 point-sources over the entire scalp) enhances cerebral photon flux and uniformity of photon distribution, without causing a rise in temperature [53]. Another small placebo-controlled pilot study involving 11 patients with AD (MMSE between 15–25) treated 6 of the patients with a NIR helmet for 6 min daily over 28 consecutive days with NIR 1072 nm light (1100 LEDs set in 15 arrays of 70 LEDs/array. All matched to 1060–1080 nm and pulsed at 10 Hz with a 50% duty cycle) and 3 placebo control and 2 dropouts. Results showed changes in executive functioning: clock drawing, immediate recall, praxis memory, visual attention, and task switching (Trails A & B), as well as a trend of improved EEG amplitude and connectivity measures [54].

Fig. 4

tPBM for Alzheimer’s disease. Light-emitting diode devices (810 nm, 10-Hz pulses) using transcranial and intranasal PBM (fluence 24.6 J/cm² per LED for transcranial stimulation, 13.8 J/cm² for single intranasal diode stimulation) have been used to treat the cortical nodes of the default mode network (bilateral mesial prefrontal cortex, precuneus/posterior cingulate cortex, angular gyrus, and hippocampus) [52].

PBM in treating patients with PD

In PD, there is much abnormal activity in the cortex [55, 56], a structure that is within range of near infrared light signal when applied from an extracranial source. Near infrared light may help normalize this neural activity, leading to improvements in movement [57]. A recent non-controlled and non-randomized clinical report indicated that improvements in speech, cognition, freezing episodes, and gait were evident after transcranial light therapy in patients with parkinsonism [58]. Further, a rather accidental finding has been reported in one patient with PD who was treated with light (660 nm, laser) for a dental problem; the patient exhibited reduced parkinsonian symptoms following the light treatment [59]. Light irradiation via the nasal cavity (intranasal method) or the oral cavity have also resulted in improved PD symptoms [59, 60] (see Fig. 5). PD pathogenesis is linked to abnormalities in the substantia nigra pars compacta (SNc), a midbrain structure located 80–100 mm from the coronal suture, below the dura. In fact, the limited ability of light to penetrate deep into the brain restricts the delivery of a sufficient dose to midbrain neurons. In recent years, there have been attempts to develop an effective technique for delivering light to deeper brain regions such as the SNc, using the same intracranial approach as is used in the deep brain stimulation technique [61] (see Fig. 5). Intracranial delivery of light via an implanted optical fibers has been described as a novel technology used both for PBM [51] and optogenetic studies [12]. Further, Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light capable of converting low-energy incident NIR photons into high-energy visible emission. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy [62]. Importantly, there is a need for major, systematic, long-term clinical trials that investigate the neuroprotective and symptomatic effects of light therapy on large numbers of patients [63].

Fig. 5

Different approaches for light delivery or the purpose of brain photobiomodulation therapy. (a) Transcranial. (b) Intracranial. (c) Intranasal. (d) Oral cavity [46].

PBM for depression and anxiety

Schiffer et al. [64] used a fairly small area (1 W 810 nm) LED array and applied light to the foreheads of patients with major depression or anxiety. They found improvements on the Hamilton depression rating scale (HAM-D) and the Hamilton anxiety rating scale (HAM-A) after a single treatment. They also found increased regional cerebral blood flow in the frontal pole during light delivery using a commercial NIR spectroscopy device. Cassano et al. [65] treated patients who had major depression with tPBM using an 810 nm laser (700 mW/cm² with a fluence of 84 J/cm² delivered per session for 6 sessions). The authors reported significant decreases in HAM-D17 scores, indicating significant reduction in depressive symptoms. Additionally, safety and efficacy of tNIRS (823 nm; continuous wave; 28.7×2 cm²; 36.2 mW/cm²; up to 65.2 J/cm²; 20–30 min/session) were investigated in a double-blind, sham-controlled study in patients with major depression [66]. tNIRS was delivered to dorsolateral prefrontal cortex, bilaterally and simultaneously, twice a week, for 8 weeks. The study found an antidepressant effect based on changes in HAM-D17 total score at endpoint, and the effect sizes were 0.90, 0.75, and 1.5 (Cohen’s d). Further, tNIRS was fairly well tolerated, with no serious adverse events. In another study [67], attention bias modification (ABM) using adjunctive transcranial laser stimulation was tested in 51 adult participants who had elevated symptoms of depression. The participants were randomized to one of three conditions: right forehead, left forehead, or sham. Participants received another transcranial laser stimulation two days later and were assessed for depressive symptoms after one and two weeks. Right transcranial laser stimulation led to greater symptom improvement among participants whose attention was responsive to ABM (i.e., attention was directed away from negative stimuli). Minimal changes in depression were observed in the left and sham transcranial laser stimulation. The beneficial effects of ABM on depression symptoms may be enhanced when paired with adjunctive interventions such as right prefrontal transcranial laser stimulation.

Optogenetics is designed to open or close ion channels in specific groups of neurons in order to trigger action potentials, while the effect of PBM is much more generalized in nature. The most accepted mechanism of action is to promote energy metabolism. A new cellular mechanism for NIR light at 980 nm based on activation of heat or light sensitive calcium ion channels [68]. And repeated exposure to 1072 nm infrared stimulation of the cortex surface improves cognitive and behavioral functioning as indicated by normalization of EEG activity [54]. The exact mechanism still needs further study. While many researchers believe that PBM for brain disorders will become one of the most important medical applications of light therapy in the coming years and decades [69, 70]. PBM therapy has the potential to develop into a safe and effective neuroprotective treatment for patients with brain disorders [63]. At present, the trend is to use closed-loop regulation, which records the neuronal responses and changes the parameters of regulation in a timely fashion. Because light stimulation and electrical responses do not interfere with each other, scientists hope to help to effectively regulate brain activity by developing a similar device that combines optical stimulation and neural recording.

DEVICE DEVELOPMENT

Combining optogenetics with electrophysiological recordings is an advanced approach for studying brain microcircuits. Figure 6 shows a flow chart of closed-loop recording and stimulation, with corresponding data transmission and analysis.

Fig. 6

Flow chart of the process for large-scale silicon probe recording and closed-loop targeted feedback perturbation of neurons in their native networks [13].

Because electrically recording neuronal activity is usually invasive, a trade-off exists between large-scale monitoring of neurons at multiple recording sites within a small area and minimizing the tissue damage inflicted by the electrodes [71]. The spike-amplitude waveforms of neurons change with the distance and direction of the electrode from the neuron, thus two or more adjacent recording sites are required to triangulate the distance between the spike-emitting cell and the electrodes. Action potentials can be measured by placing a conductor close to the neuron in the early days, but more than one electrode is needed to record another neuron [13]. Stereotrodes and tetrodes, containing two and four tightly twisted wires, respectively, were usually used to record electrical events [72, 73]. However, these methods suffer from low firing-rates of many neurons and low amplitudes of many detected spikes. Moreover, probes movements may cause mechanical damage.

Micro-Electro-Mechanical System recording devices were introduced to increase the number of recording sites and reduce the technical limitations inherent in wire electrodes [74]. Most of these electrode arrays are fabricated by photolithographic patterning of thin films of conductors and insulators on a silicon substrate, which allows for adjusting the size, shape, and arrangement of the electrodes according to the neural density and local circuit architecture of a specific brain region [13]. Silicon-based microelectrodes, which are easily integrated with current CMOS technology, have been designed with denser electrode arrays [75 –79].

Cables that restrict animal movements disrupt behavioral studies. To deal with this issue, small wireless brain-implantable platforms have been developed to allow the study of small freely behaving laboratory animals without cable tethering [80, 81]. Many wireless multi-channel systems have been successfully used in small animals [82 –84], some of which have made impressive reductions in the size of the implant [81, 85].

Miniature LED and/or laser diodes can be coupled to short, small diameter multimode fibers and attached directly to the shanks of a silicon probe [8], which, due to their small size and weight, allow fast, multisite, and multi-wavelength optogenetic manipulations in freely behaving animals while also monitoring the activity of the manipulated neurons [86]. Multiple light-guiding methods have been proposed, such as using light-guiding fibers with deposited electrode material [87], assembling optic fibers with Utah recording electrodes [88], and producing penetrating optic fibers arrays [89]. Integrating assembled LEDs into the vicinity of the target site deep in the neural tissue is an alternative approach [90]. An optical probe can be fabricated directly from an LED Gallium Nitride substrate. Silicon probes integrated on mini (100–500μm width/length dimensions) or micro scale (<100μm dimensions) LEDs have also been proposed by some studies [91, 92].

Brain machine interfaces are designed to create artificial communication paths between the brain and external hardware [93]. The collection of evoked neuronal activity can be used to assess the effects of optical stimulation in specific brain regions [94], thus closed-loop brain-machine interfaces that are integrated with neuronal recording, stimulation, signal processing, transmission, and other modules are important for neuronal experiments. Qazi et al. proposed smartphone-controlled, minimally invasive, soft optofluidic probes with replaceable plug-like drug cartridges for chronic in vivo pharmacology and optogenetics with selective manipulation of brain circuits to monitor activity of mice for over four weeks via programmable wireless drug delivery and photostimulation [95]. Currently numerous studies are focusing on the design and improvement of systems for electrical stimulation combined with neuronal recording [96 –99]. However, systems that combine recording with optical stimulation, especially integrated on one chip, remain lacking.

Some systems have been proposed based on commercial off-the-shelf (COTS) products. Gagnon-Turcotte et al. designed a wireless headstage for combining optogenetics with multichannel electrophysiological recording. It is built with COTS material and includes 32 recording channels and 32 optical stimulation channels. The implemented prototype features a lifespan of up to 105 minutes, and uses a lightweight (2.8 g) and compact (17×18×10 mm) printed circuit board [15].

The integration of both neuronal recording and optogenetic stimulation in a single integrated circuit are key issues for brain machine interface design, in particular, scaling down the bulky size of COTS components. Recent work provides some solutions for this problem. Chen et al. introduced a 0.18-μm CMOS integrated circuit with a neuronal recording amplifier and a laser/LED driver for simultaneous extracellular electrophysiology recording and optogenetic neural manipulation. The dimension of the chip is 2.9×1.6 mm [8]. Ramezani et al. proposed a neuronal interface that consists of a 4-channel neural recording module and a 6-channel optical driver. The chip was implemented in a 0.35-μm CMOS technology occupying 1.95×1.10 mm, and tested in vivo and in vivo [18]. Gagnon-Turcotte et al. have demonstrated a 0.13-μm CMOS neural interface SoC which has been tested in vivo using a wireless experimental platform in both the ventral posteromedial nucleus and the motor cortex of a virally mediated Channelrhodopsin-2 rat. The proposed SoC enables simultaneous 10-channel electronic recording for action potentials and/or the local field potentials, and 4-channal optical stimulation [80, 100].

A simplified block diagram is shown in Fig. 7. The neural recording module is used for the acquisition of neuronal signals and the identification of neuronal signatures through subsequent signal analysis. It usually consists of a low-noise pre-amplifier and an analog-to-digital converter (ADC). The neuronal recording system first filters and amplifies multichannel electrode signals from a noisy environment [101], usually targeting the signal modality (action potentials or local field potentials). Several studies have focused on designing neuronal amplifiers [102 –106], especially on reducing power consumption [103 , 106], increasing the number of recording channels, or improving noise reduction [105]. The analog signals are then digitized by the ADC and processed using real-time software. Many studies have described their ADCs used in neuronal recording [107 –111], including the successive approximation register ADC and the sigma-delta ADC. Optical stimulation usually applies LED drivers which are designed based on current mirror or capacitor discharging techniques [112, 113].

Fig. 7

Block diagram of neuronal signal processing. This block diagram contains the neuronal recording path, optical stimulation path, digital control module, wireless transceiver, electrode array, and LED array.

For practical application, the system needs to meet several key requirements including low power consumption, small physical size, great durability, high reliability, and as few peripherals as possible [114, 115]. Safety issue is another important consideration. Large power consumption may generate strong heat radiation, which may cause permanent tissue damage. In order to reduce the damage at the interface between electrode and tissue, there is a maximum power density of exposed neural tissue area [97]. Low power consumption can also extend the battery life and increase the service time of the equipment. A small highly integratable neuronal interface chip can reduce the cost and is easier to implement.

CONCLUSION

Optogenetics can precisely regulate specific neurons to explore disease-related neuronal circuits in animal models. Low level tNIRs using both lasers and LEDs may improve brain function through promoting energy metabolism and are starting to be applied as treatment to modulate brain activity in cases of brain disorders. Light stimulation has a promising future. The development of devices that combine light stimulation with neuronal recording will lead to more effective neuromodulation, especially with respect to cognitive, affective, and motor disorders.

Footnotes

ACKNOWLEDGMENTS

This work was supported in part by the National Natural Science Foundation of China (No. 81701297, No. 61801027), National Key R&D Program of China (No. 2016YFC1306302, No. 2018YFA0108503, No. 2018YFC1314500), and China Postdoctoral Science Foundation (No. 2018M631356). We thank Adam Phillips, PhD, from Liwen Bianji, Edanz Editing China (), for editing the English text of a draft of this manuscript.

Authors’ disclosures available online ().

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