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Using artificial intelligence to predict life-threatening bacterial disease in dogs

#artificialintelligence

Leptospirosis, a disease that dogs can get from drinking water contaminated with Leptospira bacteria, can cause kidney failure, liver disease and severe bleeding into the lungs. Early detection of the disease is crucial and may mean the difference between life and death. Veterinarians and researchers at the University of California, Davis, School of Veterinary Medicine have discovered a technique to predict leptospirosis in dogs through the use of artificial intelligence. After many months of testing various models, the team has developed one that outperformed traditional testing methods and provided accurate early detection of the disease. The groundbreaking discovery was published in the Journal of Veterinary Diagnostic Investigation.


Elon Musk-owned Neuralink confirms monkeys died during tests but rejects abuse claim

Daily Mail - Science & tech

Elon Musk's brain-chip firm Neuralink has admitted monkeys died during tests, but denied claims of animal abuse put forward by an animal rights group. The biotech firm is developing a brain-computer interface, that it claims could one day make humans hyper-intelligent, and allow paralyzed people to walk again. Last week the Physicians Committee for Responsible Medicine (PCRM) lodged a complaint with the US Department of Agriculture, alleging several counts of animal abuse between 2017 and 2020, involving test monkeys owned by Neuralink. They claimed the macaque monkeys, housed at a University of California Davis research facility, were subject to experiments that amounted to torture, with evidence of rashes, self-mutilation and brain hemorrhages seen in documentation. Neuralink has hit back at the claims of abuse, calling out the PCRM as a group that oppose any use of animals in research.


Neuralink: Elon Musk's brain implant firm refutes animal abuse claims

ZDNet

Neuralink, Tesla CEO Elon Musk's firm investigating brain-machine interface implants, has issued a statement responding to claims of cruelty in tests. Neuralink said in a blog post that it is "committed to working with animals in the most humane and ethical way possible." It also offered a timeline of its animal testing activities since 2017, covering a 2.5-year partnership with the University of California, Davis, and from 2020, when the company opened its own in-house vivarium. Neuralink is responding to allegations by the Physicians Committee for Responsible Medicine (PCRM), which filed a complaint last week with the US Department of Agriculture for alleged violations of the federal Animal Welfare Act. PCRM claims Neuralink and its lab partner, UC Davis, had conducted deadly and cruel brain experiments on 23 monkeys.


The Elusive Hunt for a Robot That Can Pick a Ripe Strawberry

WIRED

Ten years ago, a company called Agrobot demonstrated a strawberry-harvesting robot in a field in Davis, California. Today, Agrobot's strawberry picker remains a prototype. The long wait underscores the challenge for any berry-picking robot: Identify a berry that is ripe enough to pick, grasp it firmly but without damaging the fruit, and pull hard enough to separate it from the plant without harming the plant. Agrobot CEO Juan Bravo said his company's machine can't compete with people who can pick fruit by hand and pack it into clamshells. Still, growers are looking ahead to a day when it will be hard to find people willing to stoop in the fields all day, and expensive to pay them.


Elon Musk-owned Neuralink's test monkeys were 'tortured', group claims

Daily Mail - Science & tech

Monkeys being tested on by Elon Musk-owned brain chip firm Neuralink were allegedly subject to'torture', an animal rights group claims. The biotech firm is developing a brain-computer interface, that it claims could one day make humans hyper-intelligent, and allow paralysed people to walk again. However, the Physicians Committee for Responsible Medicine (PCRM) alleges that between 2017 and 2020, test monkeys owned by Neuralink were subject to experiments that amounted to torture, with evidence of rashes, self-mutilation and brain hemorrhages in documentation seen by the group. The experiments were a partnership between University of California Davis, and Neuralink, with a reported 23 monkeys involved in the experiment, 15 of which died or were euthanized as a result of complications, or'inadequate animal care'. PCRM lodged a complaint with the US Department of Agriculture on Thursday against UC Davis, claiming the primates faced'extreme suffering as a result of inadequate animal care and the highly invasive experimental head implants during the experiments.'


Can Science Fiction Wake Us Up to Our Climate Reality?

The New Yorker

This content can also be viewed on the site it originates from. Last summer, the science-fiction writer Kim Stanley Robinson went on a backpacking trip with some friends. They headed into the High Sierra, hiking toward Deadman Canyon--a fifty-mile walk through challenging terrain. Now sixty-nine, Robinson has been hiking and camping in the Sierras for half a century. At home, in Davis, California, he tracks his explorations on a wall-mounted map, its topography thick with ink.


The Strange, Unfinished Saga of Cyberpunk 2077

The New Yorker

Mike Pondsmith started playing Dungeons & Dragons in the late seventies, as an undergraduate at the University of California, Davis. The game, published just a few years before, popularized a newish form of entertainment: tabletop role-playing, in which players, typically using dice and a set of rule books, create characters who pursue open-ended quests within an established world. "The most stimulating part of the game is the fact that anything can happen," an early D&D review noted. Soon, other such games hit the market, including Traveller, a sci-fi game published in 1977, the year that "Star Wars" came out. Pondsmith, a tall Black man who grew up in multiple countries because his dad was in the Air Force, loved sci-fi, and fancied himself a bit like Lando Calrissian, the smooth-talking "Star Wars" rogue played by Billy Dee Williams.


Police are investing in facial recognition and AI. Not everyone thinks that it's going well

ZDNet

While the deployment of new technologies in law enforcement agencies is booming, there also seems to be growing pushback from those who will be most affected by the tools. Police officers are using algorithms such as facial-recognition tools to carry out law enforcement, often without supervision or appropriate testing – but it's looking like this is now causing citizens to voice their discontent in what could be a new wave of backlash against such technologies. Invited to speak before UK lawmakers as part of an inquiry into the use of algorithms in policing, a panel of experts from around the world agreed that while the deployment of new technologies in law enforcement agencies is booming, there also seems to be growing pushback from those who will be most affected by the tools. "With respect to certain technologies, we've begun to see some criticism and pushback," said Elizabeth Jo, professor of law at the University of California, Davis. "So for example, while predictive policing tools were embraced by many police departments in the 2010s let's say, in the US you can see small movements towards backlash."


Neurorobotics for neurorehabilitation

Science

Advances in peripheral nervous system (PNS) interfacing present a promising alternative to traditional neuromodulation ([ 1 ][1]), particularly for individuals with upper-limb amputations ([ 2 ][2]–[ 7 ][3]). Implanted electrodes have been shown to diminish phantom limb pain (PLP) in such subjects and enable close-to-natural touch sensations. Individuals with peripheral neural stimulators are even able to control the amount of force exerted by a prosthesis and to discern among objects with different compliances and shapes with prosthesis ([ 2 ][2]–[ 5 ][4]). Successive studies have shown the long-term utility of these technologies ([ 6 ][5], [ 7 ][3]). Having successfully achieved functional stimulation and chronic biocompatibility through neural interfaces, the focus of neuromodulation research is shifting toward achieving optimal design and policy of use ([ 8 ][6]). There is great variety in electrode geometries, stimulating contact numbers, and placement within the nervous system (see the figure) as well as in possible stimulation protocols. Optimization will not be achieved with brute force but requires the development of computational models ([ 9 ][7], [ 10 ][8]) capable of exploiting the knowledge that has been accumulated on this topic. Until recently, most research has focused on hand amputees, neglecting the clinical reality that four out of five amputees have lower-limb loss. Subjects with lower-limb amputation frequently do not engage fully in everyday activities because they are afraid of falls and do not perceive the prosthesis as part of their body (low “embodiment”). Such individuals often report poor satisfaction with their prostheses, citing the prosthesis as an excessive weight, despite prosthetic limbs typically being less than half the weight of a natural limb ([ 11 ][9]). They also tend to have reduced mobility ([ 12 ][10]), which can induce a sedentary lifestyle that promotes disease development and hinders reinsertion into society. PLP is also common and is poorly managed with current medications ([ 13 ][11]). Additionally, those with lower-limb amputations face substantially higher metabolic costs while walking, resulting in an increased risk of heart attack compared with the general population ([ 14 ][12]). We have pioneered a human-machine system that translates prosthetic sensors' readouts into “language” understandable by the nervous system, using a detailed computational model ([ 9 ][7], [ 10 ][8]) that indicates an optimal number of implants for the targeted nerve. Compared with traditional frequency variation, the model favors current amplitude modulation, for increasing efficiency of mapping and closed-loop stimulation ([ 15 ][13]). Placement of the cable connecting implants to the stimulator is a longstanding problem and a frequent cause of failure in implantable technologies during clinical testing ([ 7 ][3], [ 8 ][6]). We addressed this issue during surgical preparation by implementing a release loop and stabilization within the fascia tissue graft with cables embedded in the middle ([ 14 ][12]). We developed a “sensing leg,” for lower-limb amputees, by connecting sensors from the prosthetic knee and under the foot to the residual PNS (see the figure). An effective connection was achieved by equipping a microprocessor-controlled prosthesis with a purposely developed sensorized insole. An external controller that communicates wirelessly with the “sensorized prosthesis” proportionally transduces the readout of the insole and knee sensors into stimulation parameters. The stimulator then injects the current into the intraneural electrodes, eliciting sensations from the missing lower limb. The whole process ran at a delay unperceivable to the user, enabling real-time neuromodulation dependent on leg status. This intervention enabled recovery of rich leg and foot perceptions (such as touch, proprioception, and both simultaneously). Users were able to recognize when the prosthetic leg—physically disconnected from their body and communicating wirelessly with the implants—was touched over different foot positions, flexed, or both. Users were also able to avoid a substantially higher number of stumbles when walking over obstacles, while wearing glasses that blind their lower field of vision, than when not exploiting the restored feedback. Climbing stairs is often a challenge for above-knee amputees, resulting in very slow motion and considerable fatigue. When neuromodulation restored limb perception, their mobility substantially increased ([ 15 ][13]). After these laboratory tests, volunteers stepped outside into a more natural environment. Because of the fully portable neuromodulating system, their confidence was increased, and subjects were able to walk with increased speed over what would normally be challenging sandy terrain. At the same time, volunteers' metabolic consumption was diminished when sensory neurofeedback was switched on. The decreased energy expenditure when using neuromodulation could potentially limit cardiovascular system fatigue—a tremendously important health benefit for lower-limb amputees ([ 14 ][12]). When the implantable system was used in “neuro-pacemaker modality”—stimulating the nerve without connection to the prosthesis—a reduction in PLP was observed. Through precise somatotopic stimulation, we have evoked pleasant, close-to-natural sensations within regions of referred pain. By contrast, commercial stimulation devices mainly deliver prefixed and often ineffective patterns of stimuli, which do not elicit physiologically plausible sensations and fail to deliver effective relief ([ 16 ][14]), and spinal cord stimulators involve the induction of paresthesia (an uncomfortable tingling), which does not always completely relieve the pain ([ 17 ][15]). Meanwhile, neurostimulators that directly target the peripheral nerve deliver either nonselective stimulation or induce an analgesic nerve block, both of which have considerable drawbacks ([ 18 ][16]). Our neuromodulation pain treatment represents a real advance with respect to existing treatments, in that we restore naturalistic percepts, revitalizing the physiological pathway for sensations. Beside the imminent pain relief, this potentially induces beneficial long-term neuroplastic changes at the central nervous system (CNS) level, offering not only an analgesic but also a “curative” effect. As a consequence of the restoration of physiologically plausible sensations, subjects experienced (“embodied”) the prosthesis similar to a real limb. Embodiment is typically measured in “nonfunctional” scenarios [such as rubber-hand experiments ([ 19 ][17])]. We were able to measure an objective functional embodiment ([ 20 ][18]) increase during our experiments with the bionic leg, with and without feedback ([ 15 ][13]). Increased neural embodiment decreased weight perception ([ 11 ][9])—a subjective percept influenced by cognitive processes. Brain cognitive load, measured with electroencephalography, also decreased while walking with the neuroprosthesis and performing a dual task ([ 15 ][13]). ![Figure][19] Different neurotechnologies for the peripheral nervous system (PNS) interfacing Various types of neural electrodes are utilized in individuals with upper- and lower-limb amputation to take input from prosthesis sensors and transduce it into electrical stimulation—restoring sensation from missing appendages. GRAPHIC: C. BICKEL/ SCIENCE BASED ON S. RASPOPOVIC Neuromodulation triggered by a robotic device influences sensorimotor strategies employed by users, by means of its integration into their “traditional” nervous system. To better understand underlying mechanisms, we measured gait features of leg amputees during motor tasks of different difficulty while using the neuroprosthesis. They performed an easy task (walking over ground) and a challenging task (ascending and descending stairs) while gait and neurostimulating parameters were collected. The neuroprosthesis reshaped subjects' legs' kinematics toward a more physiological gait owing to sensorimotor strategies that allowed users to intuitively exploit various features of the neural code during different tasks ([ 21 ][20]). These strategies included different temporal order, or spatial usage of stimulation channels, resulting in simple but robust intuitively integrated neural codes for different motor behaviors. In a hypothetical scenario, which required a leg amputee to simulate driving a conventional car, we demonstrated a finer pressure estimation from the prosthesis, suggesting that even a simple neural code could effectively improve wearable neuromodulating devices. These studies not only provided clear evidence of the benefit of neuromodulation for lower-limb amputees but also provided insights into fundamental mechanisms of supraspinal integration of the restored sensory modalities. Even with only a limited restoration of sensations from foot and knee, the CNS was able to successfully integrate and exploit this information. Analogous findings were observed in animals that compensated for lack of a single sensory modality through supraspinal structures ([ 22 ][21]). The health benefits achievable from neuromodulation are of paramount importance to millions of impaired individuals. Because the economic cost of such technologies remains considerable, it is important to emphasize the accompanying benefits, which could eliminate the need for treatments related to pain or cardiovascular problems ([ 1 ][1]). Together with pioneering results in neuromodulating treatment for neuropathy, the described research presents a conceptually new framework for neuroprosthetic device design, implementation, and testing. This iterative framework consists of (i) developing a deep understanding of the problem through models and experiments, (ii) influencing the device design, and (iii) a meticulously planned clinical testing phase. Multifaceted validation of experiments—including functional, emotional, and cognitive outcomes—feeds back to increase our knowledge and further optimize design. Model-based, deep understanding of the effects of neuromodulation could benefit future projects in the emerging field of bioelectronic medicine ([ 23 ][22], [ 24 ][23]). GRAND PRIZE WINNER Stanisa Raspopovic Stanisa Raspopovic received undergraduate degrees from the University of Pisa and a PhD from Scuola Superiore Sant'Anna, Italy. After completing his postdoctoral fellowship at EPFL, he started his laboratory in the Department of Health Science and Technology at ETH Zürich in 2018. His research focuses on deep understanding of nervous system interaction with electric field through computational modeling, design of sensory neuroprostheses, and bioelectronics solutions and the investigation of human interaction with these. FINALIST Weijian Yang Weijian Yang received his undergraduate degree from Peking University and a PhD from the University of California, Berkeley. After completing his postdoctoral fellowship at Columbia University, he started his laboratory in the Department of Electrical and Computer Engineering at the University of California, Davis in 2017. His research aims to develop advanced optical methods and neurotechnologies to interrogate and modulate brain activity, with a goal to understand how neural circuits organize and function and how behaviors emerge from neuronal activity. [ www.sciencemag.org/content/373/6555/635 ][24] 1. [↵][25]1. S. Raspopovic , Science 370, 290 (2020). [OpenUrl][26][Abstract/FREE Full Text][27] 2. [↵][28]1. S. Raspopovic et al ., Sci. Transl. Med. 6, 222ra19 (2014). [OpenUrl][29][Abstract/FREE Full Text][30] 3. 1. J. A. George et al ., Sci. Robot. 4, eaax2352 (2019). [OpenUrl][31] 4. 1. D. W. Tan et al ., Sci. Transl. Med. 6, 257ra138 (2014). [OpenUrl][32][Abstract/FREE Full Text][33] 5. [↵][34]1. C. M. Oddo et al ., eLife 5, e09148 (2016). [OpenUrl][35][CrossRef][36][PubMed][37] 6. [↵][38]1. M. Ortiz-Catalan et al ., N. Engl. J. Med. 382, 1732 (2020). [OpenUrl][39] 7. [↵][40]1. F. M. Petrini et al ., Ann. Neurol. 85, 137 (2019). [OpenUrl][41][CrossRef][42] 8. [↵][43]1. S. Raspopovic et al ., Nat. Mater. 20, 925 (2021). [OpenUrl][44] 9. [↵][45]1. S. Raspopovic et al ., Proc. IEEE 105, 34 (2017). [OpenUrl][46] 10. [↵][47]1. M. Zelechowski et al ., J. Neuroeng. Rehabil. 17, 24 (2020). [OpenUrl][48] 11. [↵][49]1. G. Preatoni et al ., Curr. Biol. 31, 1065 (2021). [OpenUrl][50] 12. [↵][51]1. L. Nolan et al ., Gait Posture 17, 142 (2003). [OpenUrl][52][CrossRef][53][PubMed][54][Web of Science][55] 13. [↵][56]1. H. Flor , Lancet Neurol. 1, 182 (2002). [OpenUrl][57][CrossRef][58][PubMed][59][Web of Science][60] 14. [↵][61]1. F. M. Petrini et al ., Nat. Med. 25, 1356 (2019). [OpenUrl][62][CrossRef][63][PubMed][64] 15. [↵][65]1. F. M. Petrini et al ., Sci. Transl. Med. 11, eaav8939 (2019). [OpenUrl][66][Abstract/FREE Full Text][67] 16. [↵][68]1. C. Richardson, 2. J. Kulkarni , J. Pain Res. 10, 1861 (2017). [OpenUrl][69] 17. [↵][70]1. K. Kumar et al ., Surg. Neurol. 50, 110, discussion 120 (1998). [OpenUrl][71][CrossRef][72][PubMed][73][Web of Science][74] 18. [↵][75]1. Y. A. Patel, 2. R. J. Butera , J. Neural Eng. 15, 031002 (2018). [OpenUrl][76] 19. [↵][77]1. M. Botvinick, 2. J. Cohen , Nature 391, 756 (1998). [OpenUrl][78][CrossRef][79][PubMed][80][Web of Science][81] 20. [↵][82]1. G. Rognini et al ., J. Neurol. Neurosurg. Psychiatry 90, 833 (2019). [OpenUrl][83][FREE Full Text][84] 21. [↵][85]1. G. Valle et al ., Sci. Adv. 7, eabd8354 (2021). [OpenUrl][86][FREE Full Text][87] 22. [↵][88]1. S. Rossignol et al ., Physiol. Rev. 86, 89 (2006). [OpenUrl][89][CrossRef][90][PubMed][91][Web of Science][92] 23. [↵][93]1. M. A. Hamza et al ., Diabetes Care 23, 365 (2000). [OpenUrl][94][Abstract][95] 24. [↵][96]1. L. V. Borovikova et al ., Nature 405, 458 (2000). [OpenUrl][97][CrossRef][98][PubMed][99][Web of Science][100] [1]: #ref-1 [2]: #ref-2 [3]: #ref-7 [4]: #ref-5 [5]: #ref-6 [6]: #ref-8 [7]: #ref-9 [8]: #ref-10 [9]: #ref-11 [10]: #ref-12 [11]: #ref-13 [12]: #ref-14 [13]: #ref-15 [14]: #ref-16 [15]: #ref-17 [16]: #ref-18 [17]: #ref-19 [18]: #ref-20 [19]: pending:yes [20]: #ref-21 [21]: #ref-22 [22]: #ref-23 [23]: #ref-24 [24]: http://www.sciencemag.org/content/373/6555/635 [25]: #xref-ref-1-1 "View reference 1 in text" [26]: 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/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6InNjaXRyYW5zbWVkIjtzOjU6InJlc2lkIjtzOjE0OiI2LzI1Ny8yNTdyYTEzOCI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM3My82NTU1LzYzNC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [34]: #xref-ref-5-1 "View reference 5 in text" [35]: {openurl}?query=rft.jtitle%253DeLife%26rft.volume%253D5%26rft.spage%253De09148%26rft_id%253Dinfo%253Adoi%252F10.7554%252FeLife.09148%26rft_id%253Dinfo%253Apmid%252F26952132%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [36]: /lookup/external-ref?access_num=10.7554/eLife.09148&link_type=DOI [37]: /lookup/external-ref?access_num=26952132&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [38]: #xref-ref-6-1 "View reference 6 in text" [39]: {openurl}?query=rft.jtitle%253DN.%2BEngl.%2BJ.%2BMed.%26rft.volume%253D382%26rft.spage%253D1732%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [40]: #xref-ref-7-1 "View reference 7 in text" [41]: {openurl}?query=rft.jtitle%253DAnn.%2BNeurol.%26rft.volume%253D85%26rft.spage%253D137%26rft_id%253Dinfo%253Adoi%252F10.1002%252Fana.25384%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [42]: /lookup/external-ref?access_num=10.1002/ana.25384&link_type=DOI [43]: #xref-ref-8-1 "View reference 8 in text" [44]: {openurl}?query=rft.jtitle%253DNat.%2BMater.%26rft.volume%253D20%26rft.spage%253D925%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [45]: #xref-ref-9-1 "View reference 9 in text" [46]: {openurl}?query=rft.jtitle%253DProc.%2BIEEE%26rft.volume%253D105%26rft.spage%253D34%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [47]: #xref-ref-10-1 "View reference 10 in text" [48]: {openurl}?query=rft.jtitle%253DJ.%2BNeuroeng.%2BRehabil.%26rft.volume%253D17%26rft.spage%253D24%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [49]: #xref-ref-11-1 "View reference 11 in text" [50]: {openurl}?query=rft.jtitle%253DCurr.%2BBiol.%26rft.volume%253D31%26rft.spage%253D1065%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [51]: #xref-ref-12-1 "View reference 12 in text" [52]: {openurl}?query=rft.jtitle%253DGait%2B%2526%2Bposture%26rft.stitle%253DGait%2BPosture%26rft.aulast%253DNolan%26rft.auinit1%253DL.%26rft.volume%253D17%26rft.issue%253D2%26rft.spage%253D142%26rft.epage%253D151%26rft.atitle%253DAdjustments%2Bin%2Bgait%2Bsymmetry%2Bwith%2Bwalking%2Bspeed%2Bin%2Btrans-femoral%2Band%2Btrans-tibial%2Bamputees.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0966-6362%252802%252900066-8%26rft_id%253Dinfo%253Apmid%252F12633775%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [53]: /lookup/external-ref?access_num=10.1016/S0966-6362(02)00066-8&link_type=DOI [54]: /lookup/external-ref?access_num=12633775&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [55]: /lookup/external-ref?access_num=000181734500008&link_type=ISI [56]: #xref-ref-13-1 "View reference 13 in text" [57]: 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{openurl}?query=rft.jtitle%253DNat.%2BMed.%26rft.volume%253D25%26rft.spage%253D1356%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41591-019-0567-3%26rft_id%253Dinfo%253Apmid%252F31501600%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [63]: /lookup/external-ref?access_num=10.1038/s41591-019-0567-3&link_type=DOI [64]: /lookup/external-ref?access_num=31501600&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [65]: #xref-ref-15-1 "View reference 15 in text" [66]: 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#xref-ref-16-1 "View reference 16 in text" [69]: {openurl}?query=rft.jtitle%253DJ.%2BPain%2BRes.%26rft.volume%253D10%26rft.spage%253D1861%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [70]: #xref-ref-17-1 "View reference 17 in text" [71]: {openurl}?query=rft.jtitle%253DSurgical%2Bneurology%26rft.stitle%253DSurg%2BNeurol%26rft.aulast%253DKumar%26rft.auinit1%253DK.%26rft.volume%253D50%26rft.issue%253D2%26rft.spage%253D110%26rft.epage%253D120%26rft.atitle%253DEpidural%2Bspinal%2Bcord%2Bstimulation%2Bfor%2Btreatment%2Bof%2Bchronic%2Bpain--some%2Bpredictors%2Bof%2Bsuccess.%2BA%2B15-year%2Bexperience.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0090-3019%252898%252900012-3%26rft_id%253Dinfo%253Apmid%252F9701116%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [72]: /lookup/external-ref?access_num=10.1016/S0090-3019(98)00012-3&link_type=DOI [73]: /lookup/external-ref?access_num=9701116&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [74]: /lookup/external-ref?access_num=000075183100017&link_type=ISI [75]: #xref-ref-18-1 "View reference 18 in text" [76]: {openurl}?query=rft.jtitle%253DJ.%2BNeural%2BEng.%26rft.volume%253D15%26rft.spage%253D031002%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [77]: #xref-ref-19-1 "View reference 19 in text" [78]: {openurl}?query=rft.jtitle%253DNature%26rft.stitle%253DNature%26rft.aulast%253DBotvinick%26rft.auinit1%253DM.%26rft.volume%253D391%26rft.issue%253D6669%26rft.spage%253D756%26rft.epage%253D756%26rft.atitle%253DRubber%2Bhands%2B%2527feel%2527%2Btouch%2Bthat%2Beyes%2Bsee.%26rft_id%253Dinfo%253Adoi%252F10.1038%252F35784%26rft_id%253Dinfo%253Apmid%252F9486643%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [79]: /lookup/external-ref?access_num=10.1038/35784&link_type=DOI [80]: /lookup/external-ref?access_num=9486643&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [81]: /lookup/external-ref?access_num=000072089500037&link_type=ISI [82]: #xref-ref-20-1 "View reference 20 in text" [83]: {openurl}?query=rft.jtitle%253DJ.%2BNeurol.%2BNeurosurg.%2BPsychiatry%26rft_id%253Dinfo%253Adoi%252F10.1136%252Fjnnp-2018-318570%26rft_id%253Dinfo%253Apmid%252F30100550%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [84]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiam5ucCI7czo1OiJyZXNpZCI7czo4OiI5MC83LzgzMyI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM3My82NTU1LzYzNC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [85]: #xref-ref-21-1 "View reference 21 in text" [86]: 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[97]: {openurl}?query=rft.jtitle%253DNature%26rft.stitle%253DNature%26rft.aulast%253DBorovikova%26rft.auinit1%253DL.%2BV.%26rft.volume%253D405%26rft.issue%253D6785%26rft.spage%253D458%26rft.epage%253D462%26rft.atitle%253DVagus%2Bnerve%2Bstimulation%2Battenuates%2Bthe%2Bsystemic%2Binflammatory%2Bresponse%2Bto%2Bendotoxin.%26rft_id%253Dinfo%253Adoi%252F10.1038%252F35013070%26rft_id%253Dinfo%253Apmid%252F10839541%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [98]: /lookup/external-ref?access_num=10.1038/35013070&link_type=DOI [99]: /lookup/external-ref?access_num=10839541&link_type=MED&atom=%2Fsci%2F373%2F6555%2F634.atom [100]: /lookup/external-ref?access_num=000087212000049&link_type=ISI


Manipulating neuronal circuits, in concert

Science

Perception and behavior emerge from the coordinated and orchestrated activity of neurons in brain circuits. Individual, functionally coherent neurons form ensembles, which become the building blocks of large-scale circuitry to drive the brain machinery ([ 1 ][1]). The ability to modulate brain activity in a spatiotemporal pattern with high specificity (millisecond time scale and cellular resolution) has great implications for interfacing with this sophisticated machinery. In fundamental science, it provides a powerful tool to dissect neuronal circuits in very fine detail and study causality among neural activity, circuit dynamics, and behavior ([ 2 ][2]–[ 6 ][3]). In translational medicine, it plays an important role in treating brain disorders ([ 7 ][4], [ 8 ][5]) and holds great promise to become a new tool for precision medicine. Electrical stimulation is the most mature approach to modulating brain activity. However, penetrating electrodes are highly invasive, and there is a lack of spatial specificity in the targeted brain regions. Therefore, neurons in a large brain volume are indiscriminately stimulated simultaneously regardless of their individual function in the brain circuit and resultant link to behavior. Such low spatial specificity and the associated unspecific off-target effects not only limit the application of these approaches in studying brain circuits, but also pose concerns with regard to overall efficacy and side effects in clinical therapy ([ 9 ][6], [ 10 ][7]). Optical methods, particularly when coupled with optogenetics ([ 11 ][8], [ 12 ][9]), offer a new approach to modulating brain activity with cell-type specificity. Although high spatial specificity can be achieved in two-dimensional (2D) samples, such as thin brain slices, early use of optogenetics in living brains faced the same challenges as electrical stimulation: The dispersed light failed to distinguish individual cells in a 3D volume and instead stimulated all neurons together. Two-photon light resolves the problem of spatial specificity and achieves cellular resolution. Borrowing this technique from laser scanning microscopy, two-photon optogenetics sequentially stimulates neurons one by one ([ 13 ][10], [ 14 ][11]). Although specificity is high, sequential single-cell stimulation fails to mimic intrinsic activity patterns in the brain, where multiple neurons can fire action potentials simultaneously. Metaphorically speaking, manipulating neurons in a circuit is akin to pressing the keys of a piano keyboard. Photostimulating neurons one at a time is like playing the piano with a single finger, which would fail to produce a rhythmic and melodious concert piece. To modulate neural activity in a coordinated manner, it is necessary to simultaneously stimulate an ensemble of neurons, distributed in a 3D brain volume, with cellular resolution—as if playing the piano with all 10 fingers. We are among the first to tackle this challenge in vivo ([ 15 ][12]) and demonstrate the power of optogenetics in studying the link between neural activity and behavior ([ 2 ][2]) (see the figure). Leveraging the computer-generated hologram, we encoded the 3D spatial information of the targeted neurons into the phase hologram using a spatial light modulator, to develop two-photon 3D holographic techniques for precision optogenetics ([ 15 ][12]). By projecting a holographic light pattern, which contains beamlets focused on the target neurons in a mouse brain, we can precisely modulate the activity of neuronal ensembles. Two-photon excitation ensures that the light can penetrate deep into the scattering tissue and stimulate the target neurons distributed in a 3D volume with excellent specificity. To maximize the number of neurons that can be stimulated at once without imposing high doses of light (and thus heat) on the brain, we increased the two-photon excitation efficiency by adapting a low–repetition rate femtosecond laser. This allowed us to simultaneously stimulate a large group of neurons (>50) with a minimum amount of light power (a few milliwatts per neuron). By rapidly switching the holograms (millisecond time scale), we can stimulate different groups of neurons with high temporal specificity. Our two-photon holographic optogenetics approach thus enables modulating the neuronal activity in a desired spatiotemporal pattern. To expertly manipulate brain circuitry, we needed a 3D neuronal map. We built a dual-path microscope with two different lasers, integrating two-photon high-speed volumetric calcium imaging with two-photon holographic optogenetics ([ 15 ][12]). The imaging path was equipped with an electrically tunable lens for fast 3D imaging ([ 15 ][12], [ 16 ][13]), and the optogenetics path was equipped with a spatial light modulator to generate the 3D photostimulation pattern. To avoid cross-talk between imaging and optogenetics, we selected indicators and opsins with distinct light excitation spectra: calcium indicator GCaMP6 ([ 17 ][14]) for imaging and opsin C1V1 ([ 18 ][15]) for optogenetics. Using this dual-path microscope, we were among the first to demonstrate simultaneous 3D imaging and holographic photostimulation of cortical activity in awake mice (see the figure). Such an all-optical setup allowed us to precisely stimulate an arbitrary group of neurons while monitoring the response of the circuit, and thus enabled closed-loop control of brain activity, all with high temporal specificity and cellular resolution across a large 3D brain volume. ![Figure][16] Two-photon holographic optogenetics ( A ) Schematics of simultaneous two-photon volumetric calcium imaging and two-photon 3D holographic patterned photostimulation in a mouse brain. A user-defined group of neurons can be stimulated simultaneously with high spatiotemporal specificity. ( B ) Closed-loop control of neuronal activity and behavior. The neuronal circuit imaged during animal behavior provides a map to modulate the brain through two-photon holographic optogenetics. We demonstrated mouse performance in a Go/No-Go visual discrimination task can be enhanced by photoactivating only two core ensemble neurons in visual cortex ([ 2 ][2]). GRAPHIC: H. BISHOP/ SCIENCE BASED ON W. YANG Understanding the role of neuronal ensembles could lead to new insight into how behaviors emerge as well as innovative therapies for brain diseases ([ 8 ][5]). Using our alloptical method, we studied the causal link between ensemble activity and behavior and demonstrated an efficient approach to modulate behavior ([ 2 ][2]) (see the figure). We designed a Go/No-Go visual discrimination task, in which two orientations of drifting gratings were randomly displayed and the mouse discriminated between them by licking a waterspout. We hypothesized that modulation of ensemble activity could affect behavior. We holographically photoactivated a random group of unspecific neurons in the mouse visual cortex during the task. Unsurprisingly, the resultant “noise” in the visual cortex decreased task performance. We then asked if directed neuronal modulation could improve the task outcome. Using a machine learning algorithm, we extracted the neuronal ensembles and the core ensemble neurons related to the “Go-cue” of the visual stimuli in the visual cortex. Surprisingly, holographic photoactivation of only two core ensemble neurons during the Go-cue could enhance task performance ([ 2 ][2]). Through imaging, we observed that the activation of core ensemble neurons drove widespread recruitment of other neurons within the ensemble. Such a pattern completion mechanism, potentially involving recurrent neural networks, eventually amplified the activation effect of core ensemble neurons and ultimately modulated the behavioral outcome. This effect was so pronounced that the holographic activation could elicit mouse licking associated with the Go-cue even when the Go-cue was not physically presented ([ 2 ][2]). Compared to previous approaches whereby large brain regions are stimulated at once, either electrically or through single-photon optogenetics, our holographic approach provides much greater specificity and efficiency. Not only does our study prove the functional and behavioral relevance of neuronal ensembles and provide a direct illustration of pattern completion, but the ability to precisely write information into the brain to trigger behavior opens a new avenue in precision medicine to correct the pathophysiology of mental disorders ([ 8 ][5]). The invention of optogenetics has given neuroscientists a new tool to modulate cell-type–specific neuronal activity. Our in vivo two-photon holography technique has brought optogenetics into a new, precision era. Today and in the near future, 4D spatiotemporal modulation patterns, which parallel the intrinsic physiology of the neural system, could be applied to elicit recurrent activity and recruit downstream activity and behavior. We have demonstrated the triggering of visually guided behavior through two-photon holographic optogenetics in the mouse visual cortex ([ 2 ][2]), and others have applied this technique to the mouse hippocampus ([ 4 ][17]), to drive spatial behavior. In other animal models such as the larval zebrafish ([ 6 ][3]), the method has been used to elicit motor behavior. In each case, activation of only a small number of neurons was able to modulate animal behavior. In addition to studying circuit causality, two-photon holographic optogenetics is an ideal tool to induce network plasticity through Hebbian plasticity ([ 19 ][18]). By repeatedly photostimulating a group of neurons, we demonstrated that functional connectivity increased in a subset of these neurons ([ 20 ][19]). When pairing the holographic photoactivation of a behaviorally unspecific ensemble with a behavioral reward, it was shown that the animal could learn to associate the ensemble activation with the award ([ 3 ][20], [ 21 ][21], [ 22 ][22]). Such findings suggest that two-photon holographic optogenetics could be used to reprogram the brain and create an artificial link between neuronal activity and cognitive states. This result has tremendous translational importance and could potentially be used to reestablish brain functions of a damaged region in a new region. The past 3 years have witnessed a new wave of findings enabled by two-photon holographic optogenetics in awake mice. Much could be done to further exploit its potential, particularly in translational medicine. In our noninvasive demonstrations, target neurons were confined to the cortical layers. The ability to target deep brain regions with a noninvasive or minimally invasive approach will greatly broaden its application. The closed-loop, real-time control of imaging, optogenetics, and monitoring of behavior could potentially create a new type of brain machine interface. As the first type of precise brain modulation modality, we envision that two-photon holographic optogenetics ([ 15 ][12], [ 23 ][23]–[ 27 ][24]) will continue to play a pivotal role in both fundamental neuroscience and translational medicine. FINALIST Weijian Yang Weijian Yang received his undergraduate degree from Peking University and a PhD from the University of California, Berkeley. After completing his postdoctoral fellowship at Columbia University, he started his laboratory in the Department of Electrical and Computer Engineering at the University of California, Davis in 2017. His research aims to develop advanced optical methods and neurotechnologies to interrogate and modulate brain activity, with a goal to understand how neural circuits organize and function and how behaviors emerge from neuronal activity. [ www.sciencemag.org/content/373/6555/635 ][25] 1. [↵][26]1. R. Yuste , Nat. Rev. Neurosci. 16, 487 (2015). [OpenUrl][27][CrossRef][28][PubMed][29] 2. [↵][30]1. L. Carrillo-Reid et al ., Cell 178, 447 (2019). [OpenUrl][31] 3. [↵][32]1. J. H. Marshel et al ., Science 365, eaaw5202 (2019). [OpenUrl][33][Abstract/FREE Full Text][34] 4. [↵][35]1. N. T. M. Robinson et al ., Cell 183, 1586 (2020). [OpenUrl][36][CrossRef][37] 5. 1. K. Daie, 2. K. Svoboda, 3. S. Druckmann , Nat. Neurosci. 24, 259 (2021). [OpenUrl][38] 6. [↵][39]1. M. dal Maschio et al ., Neuron 94, 774 (2017). [OpenUrl][40] 7. [↵][41]1. A. M. Lozano et al ., Nat. Rev. Neurol. 15, 148 (2019). [OpenUrl][42][CrossRef][43][PubMed][44] 8. [↵][45]1. L. Carrillo-Reid, 2. W. Yang, 3. J. E. Kang Miller, 4. D. S. Peterka, 5. R. Yuste , Annu. Rev. Biophys. 46, 271 (2017). [OpenUrl][46][CrossRef][47][PubMed][48] 9. [↵][49]1. D. Cyron , Front. Integr. Neurosci. 10, 17 (2016). [OpenUrl][50] 10. [↵][51]1. M. Z. Zarzycki, 2. I. Domitrz , Acta Neuropsychiatr. 32, 57 (2020). [OpenUrl][52][PubMed][53] 11. [↵][54]1. G. Nagel et al ., Proc. Natl. Acad. Sci. U.S.A. 100, 13940 (2003). [OpenUrl][55][Abstract/FREE Full Text][56] 12. [↵][57]1. E. S. Boyden, 2. F. Zhang, 3. E. Bamberg, 4. G. Nagel, 5. K. Deisseroth , Nat. Neurosci. 8, 1263 (2005). [OpenUrl][58][CrossRef][59][PubMed][60][Web of Science][61] 13. [↵][62]1. R. Prakash et al ., Nat. Methods 9, 1171 (2012). [OpenUrl][63][CrossRef][64][PubMed][65][Web of Science][66] 14. [↵][67]1. J. P. Rickgauer et al ., Nat. Neurosci. 17, 1816 (2014). [OpenUrl][68][CrossRef][69][PubMed][70] 15. [↵][71]1. W. Yang et al ., eLife 7, e32671 (2018). [OpenUrl][72][CrossRef][73][PubMed][74] 16. [↵][75]1. S. Han, 2. W. Yang, 3. R. Yuste , Cell Rep. 27, 2229 (2019). [OpenUrl][76][CrossRef][77][PubMed][78] 17. [↵][79]1. T. W. Chen et al ., Nature 499, 295 (2013). [OpenUrl][80][CrossRef][81][PubMed][82][Web of Science][83] 18. [↵][84]1. O. Yizhar et al ., Nature 477, 171 (2011). [OpenUrl][85][CrossRef][86][PubMed][87][Web of Science][88] 19. [↵][89]1. D. O. Hebb , The Organization of Behavior: A Neuropsychological Theory (Wiley, 1949). 20. [↵][90]1. L. Carrillo-Reid et al ., Science 353, 691 (2016). [OpenUrl][91][Abstract/FREE Full Text][92] 21. [↵][93]1. H. W. Dalgleish et al ., eLife 9, e58889 (2020). [OpenUrl][94][CrossRef][95] 22. [↵][96]1. J. V. Gill et al ., Neuron 108, 382 (2020). [OpenUrl][97][CrossRef][98] 23. [↵][99]1. W. Yang, 2. R. Yuste , Curr. Opin. Neurobiol. 50, 211 (2018). [OpenUrl][100][CrossRef][101] 24. 1. A. M. Packer et al ., Nat. Methods 12, 140 (2015). [OpenUrl][102][CrossRef][103][PubMed][104] 25. 1. A. R. Mardinly et al ., Nat. Neurosci. 21, 881 (2018). [OpenUrl][105][CrossRef][106][PubMed][107] 26. 1. A. Forli et al ., Cell Rep. 22, 3087 (2018). [OpenUrl][108] 27. [↵][109]1. I.-W. Chen et al ., J. Neurosci. 39, 3484 (2019). [OpenUrl][110][Abstract/FREE Full Text][111] [1]: #ref-1 [2]: #ref-2 [3]: #ref-6 [4]: #ref-7 [5]: #ref-8 [6]: #ref-9 [7]: #ref-10 [8]: #ref-11 [9]: #ref-12 [10]: #ref-13 [11]: #ref-14 [12]: #ref-15 [13]: #ref-16 [14]: #ref-17 [15]: #ref-18 [16]: pending:yes [17]: #ref-4 [18]: #ref-19 [19]: #ref-20 [20]: #ref-3 [21]: #ref-21 [22]: #ref-22 [23]: #ref-23 [24]: #ref-27 [25]: http://www.sciencemag.org/content/373/6555/635 [26]: #xref-ref-1-1 "View reference 1 in text" [27]: {openurl}?query=rft.jtitle%253DNat.%2BRev.%2BNeurosci.%26rft.volume%253D16%26rft.spage%253D487%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnrn3962%26rft_id%253Dinfo%253Apmid%252F26152865%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [28]: /lookup/external-ref?access_num=10.1038/nrn3962&link_type=DOI [29]: /lookup/external-ref?access_num=26152865&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [30]: #xref-ref-2-1 "View reference 2 in text" [31]: {openurl}?query=rft.jtitle%253DCell%26rft.volume%253D178%26rft.spage%253D447%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [32]: #xref-ref-3-1 "View reference 3 in text" [33]: {openurl}?query=rft.jtitle%253DScience%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aaw5202%26rft_id%253Dinfo%253Apmid%252F31320556%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [34]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjE3OiIzNjUvNjQ1My9lYWF3NTIwMiI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM3My82NTU1LzYzNS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [35]: #xref-ref-4-1 "View reference 4 in text" [36]: {openurl}?query=rft.jtitle%253DCell%26rft.volume%253D183%26rft.spage%253D1586%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.cell.2020.09.061%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [37]: /lookup/external-ref?access_num=10.1016/j.cell.2020.09.061&link_type=DOI [38]: 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{openurl}?query=rft.jtitle%253DNat.%2BRev.%2BNeurol.%26rft.volume%253D15%26rft.spage%253D148%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41582-018-0128-2%26rft_id%253Dinfo%253Apmid%252F30683913%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [43]: /lookup/external-ref?access_num=10.1038/s41582-018-0128-2&link_type=DOI [44]: /lookup/external-ref?access_num=30683913&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [45]: #xref-ref-8-1 "View reference 8 in text" [46]: {openurl}?query=rft.jtitle%253DAnnu.%2BRev.%2BBiophys.%26rft.volume%253D46%26rft.spage%253D271%26rft_id%253Dinfo%253Adoi%252F10.1146%252Fannurev-biophys-070816-033647%26rft_id%253Dinfo%253Apmid%252F28301770%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [47]: /lookup/external-ref?access_num=10.1146/annurev-biophys-070816-033647&link_type=DOI [48]: /lookup/external-ref?access_num=28301770&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [49]: #xref-ref-9-1 "View reference 9 in text" [50]: {openurl}?query=rft.jtitle%253DFront.%2BIntegr.%2BNeurosci.%26rft.volume%253D10%26rft.spage%253D17%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [51]: #xref-ref-10-1 "View reference 10 in text" [52]: {openurl}?query=rft.jtitle%253DActa%2BNeuropsychiatr.%26rft.volume%253D32%26rft.spage%253D57%26rft_id%253Dinfo%253Apmid%252Fhttp%253A%252F%252Fwww.n%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [53]: /lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [54]: #xref-ref-11-1 "View reference 11 in text" [55]: {openurl}?query=rft.jtitle%253DProc.%2BNatl.%2BAcad.%2BSci.%2BU.S.A.%26rft_id%253Dinfo%253Adoi%252F10.1073%252Fpnas.1936192100%26rft_id%253Dinfo%253Apmid%252F14615590%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [56]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoicG5hcyI7czo1OiJyZXNpZCI7czoxMjoiMTAwLzI0LzEzOTQwIjtzOjQ6ImF0b20iO3M6MjI6Ii9zY2kvMzczLzY1NTUvNjM1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [57]: #xref-ref-12-1 "View reference 12 in text" [58]: {openurl}?query=rft.jtitle%253DNature%2Bneuroscience%26rft.stitle%253DNat%2BNeurosci%26rft.aulast%253DBoyden%26rft.auinit1%253DE.%2BS.%26rft.volume%253D8%26rft.issue%253D9%26rft.spage%253D1263%26rft.epage%253D1268%26rft.atitle%253DMillisecond-timescale%252C%2Bgenetically%2Btargeted%2Boptical%2Bcontrol%2Bof%2Bneural%2Bactivity.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnn1525%26rft_id%253Dinfo%253Apmid%252F16116447%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [59]: /lookup/external-ref?access_num=10.1038/nn1525&link_type=DOI [60]: /lookup/external-ref?access_num=16116447&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [61]: /lookup/external-ref?access_num=000231483800028&link_type=ISI [62]: #xref-ref-13-1 "View reference 13 in text" [63]: {openurl}?query=rft.stitle%253DNat%2BMethods%26rft.aulast%253DPrakash%26rft.volume%253D9%26rft.spage%253D1171%26rft.atitle%253DTwo-photon%2Boptogenetic%2Btoolbox%2Bfor%2Bfast%2Binhibition%252C%2Bexcitation%2Band%2Bbistable%2Bmodulation.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnmeth.2215%26rft_id%253Dinfo%253Apmid%252F23169303%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [64]: /lookup/external-ref?access_num=10.1038/nmeth.2215&link_type=DOI [65]: /lookup/external-ref?access_num=23169303&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [66]: /lookup/external-ref?access_num=000312093500018&link_type=ISI [67]: #xref-ref-14-1 "View reference 14 in text" [68]: {openurl}?query=rft.jtitle%253DNat.%2BNeurosci.%26rft.volume%253D17%26rft.spage%253D1816%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnn.3866%26rft_id%253Dinfo%253Apmid%252F25402854%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [69]: /lookup/external-ref?access_num=10.1038/nn.3866&link_type=DOI [70]: /lookup/external-ref?access_num=25402854&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [71]: #xref-ref-15-1 "View reference 15 in text" [72]: {openurl}?query=rft.jtitle%253DeLife%26rft.volume%253D7%26rft.spage%253De32671%26rft_id%253Dinfo%253Adoi%252F10.7554%252FeLife.32671%26rft_id%253Dinfo%253Apmid%252F29412138%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [73]: /lookup/external-ref?access_num=10.7554/eLife.32671&link_type=DOI [74]: /lookup/external-ref?access_num=29412138&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [75]: #xref-ref-16-1 "View reference 16 in text" [76]: {openurl}?query=rft.jtitle%253DCell%2BRep.%26rft.volume%253D27%26rft.spage%253D2229%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.celrep.2019.04.075%26rft_id%253Dinfo%253Apmid%252F31091458%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [77]: /lookup/external-ref?access_num=10.1016/j.celrep.2019.04.075&link_type=DOI [78]: /lookup/external-ref?access_num=31091458&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [79]: #xref-ref-17-1 "View reference 17 in text" [80]: {openurl}?query=rft.jtitle%253DNature%26rft.volume%253D499%26rft.spage%253D295%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnature12354%26rft_id%253Dinfo%253Apmid%252F23868258%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [81]: /lookup/external-ref?access_num=10.1038/nature12354&link_type=DOI [82]: /lookup/external-ref?access_num=23868258&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [83]: /lookup/external-ref?access_num=000321910700027&link_type=ISI [84]: #xref-ref-18-1 "View reference 18 in text" [85]: {openurl}?query=rft.jtitle%253DNature%26rft.stitle%253DNature%26rft.aulast%253DYizhar%26rft.auinit1%253DO.%26rft.volume%253D477%26rft.issue%253D7363%26rft.spage%253D171%26rft.epage%253D178%26rft.atitle%253DNeocortical%2Bexcitation%252Finhibition%2Bbalance%2Bin%2Binformation%2Bprocessing%2Band%2Bsocial%2Bdysfunction.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnature10360%26rft_id%253Dinfo%253Apmid%252F21796121%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [86]: /lookup/external-ref?access_num=10.1038/nature10360&link_type=DOI [87]: /lookup/external-ref?access_num=21796121&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [88]: /lookup/external-ref?access_num=000294603900027&link_type=ISI [89]: #xref-ref-19-1 "View reference 19 in text" [90]: #xref-ref-20-1 "View reference 20 in text" [91]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DCarrillo-Reid%26rft.auinit1%253DL.%26rft.volume%253D353%26rft.issue%253D6300%26rft.spage%253D691%26rft.epage%253D694%26rft.atitle%253DImprinting%2Band%2Brecalling%2Bcortical%2Bensembles%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aaf7560%26rft_id%253Dinfo%253Apmid%252F27516599%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [92]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzNTMvNjMwMC82OTEiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNzMvNjU1NS82MzUuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [93]: #xref-ref-21-1 "View reference 21 in text" [94]: 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{openurl}?query=rft.jtitle%253DCurr.%2BOpin.%2BNeurobiol.%26rft.volume%253D50%26rft.spage%253D211%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.conb.2018.03.006%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [101]: /lookup/external-ref?access_num=10.1016/j.conb.2018.03.006&link_type=DOI [102]: {openurl}?query=rft.jtitle%253DNat.%2BMethods%26rft.volume%253D12%26rft.spage%253D140%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnmeth.3217%26rft_id%253Dinfo%253Apmid%252F25532138%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [103]: /lookup/external-ref?access_num=10.1038/nmeth.3217&link_type=DOI [104]: /lookup/external-ref?access_num=25532138&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [105]: {openurl}?query=rft.jtitle%253DNat.%2BNeurosci.%26rft.volume%253D21%26rft.spage%253D881%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41593-018-0139-8%26rft_id%253Dinfo%253Apmid%252F29713079%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [106]: /lookup/external-ref?access_num=10.1038/s41593-018-0139-8&link_type=DOI [107]: /lookup/external-ref?access_num=29713079&link_type=MED&atom=%2Fsci%2F373%2F6555%2F635.atom [108]: {openurl}?query=rft.jtitle%253DCell%2BRep.%26rft.volume%253D22%26rft.spage%253D3087%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [109]: #xref-ref-27-1 "View reference 27 in text" [110]: {openurl}?query=rft.jtitle%253DJ.%2BNeurosci.%26rft_id%253Dinfo%253Adoi%252F10.1523%252FJNEUROSCI.1785-18.2018%26rft_id%253Dinfo%253Apmid%252F30833505%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [111]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam5ldXJvIjtzOjU6InJlc2lkIjtzOjEwOiIzOS8xOC8zNDg0IjtzOjQ6ImF0b20iO3M6MjI6Ii9zY2kvMzczLzY1NTUvNjM1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==