Empathy has long been a subject of interest of social sciences, starting with the concept of Einfühlung (“in-feeling” or “feeling into”) as the human capacity to feel the emotions that the artist or writer had worked to represent .em- (“in'”) and pathos, . This heralded the beginning of new, psychological research into the phenomenon, followed by operationalising the concepts of empathy thus firmly rooting it in the fields of sociology and psychology.Later on, Theodor Lipps transformed Einfühlung from a concept of aesthetics into a central category of the philosophy of the social and human sciences and postulated that Einfühlung meant the “experience of another human” underpinned by “inner imitation” or instinctive kinaesthetic sensations in the observer as felt by the observed target . The worThe empathy is considered as a multifaceted construct encompassing (1) affective empathy, i.e., affective sharing, (2) empathic concern: motivation to caring for another's welfare, and (3) perspective taking or cognitive empathy, the ability to consciously put oneself into the mind of another and understand what that person is thinking or feeling . ThroughThe papers in this Research Topic present novel neuroscience research in addition to socially diverse research examining skills, psychology, and interpersonal factors that modulate empathy in specific contexts.Stietz et al.) where the authors argue that the aspects of perspective-taking and affective empathy should not be blended into unifying (“umbrella term”) concept of empathy; but rather consider as distinct neurobiological and phenomenological processes.Despite more than a century of descriptive research into empathy, the definition, and phenomenology of the empathy are still evolving and inquiry is broadening. One of the interesting lines of inquiry centers on whether or not cognitive and affective empathy are part of the same concept. This question is addressed in a paper in this Research Topic  (ent (EQ) , Interpeent (EQ) , Autism ent (EQ) , and Sysent (EQ)  in a larThiriou et al.) considers another aspect of relationship between perspective-taking and empathy. The authors present a bold idea of linking cognitive perspective-taking with emotional/empathic understanding of others' point of view. The authors postulate that this complex association may underlie the insight in people with psychiatric disorders. According to the proposal, affectively experiencing the position of another person about oneself reinforces the insight, i.e., ability to recognise the disorder. This new perspective would certainly warrant an empirical validation.A hypothesis paper . This latter addition could be considered as controversial by empathy researchers who usually conceptualise empathy as an emergence of a matching, rather than contrasting emotion as is the case of, e.g., Schadenfreude (which is not considered as empathetic response). We are looking forward to any comments on this topic by the research community. In the same paper, the author provides their definition of slightly neglected part of empathy, e.g., positive empathy. By positive empathy the author understands our ability to respond to the negative and positive emotion of others with appropriate positive affect. In line with this proposal, another paper  presents a validation of a brief self-report measure of “positive-valence empathy”. Apart from excellent psychometric properties, this measure appears to be a significantly better predictor of overall depressive symptomatology than anhedonia.The Perspective article by Heym et al. examined the relationship between Dark Triad traits and distinct facets of empathy in a large sample (301 participant) from two UK University participant pools and via general online participation schemes. The authors addressed two main issues: (1) whether impaired empathy represents a common “dark core” binding Machiavellianism, narcissism, and psychopathy, and (2) this core explains associations between the dark traits and indirect relational aggression (IRA). The study results did not support the notion that an unempathic core may underpin all Dark Triade traits. The authors postulated that the Dark Triade traits are best viewed as three independent personality traits, rather than a joint (latent) dyad or triad core, at least in the prediction of these specific empathic deficits and indirect relational aggression.The study of Several papers in this Topic were focused on developmental aspects of empathy.Beadle and de la Vega considered age-related aspects of empathy. To summarize, across studies, there is little evidence that emotional empathy is lower in older than younger adults. However, older adults tend to show reduced performance and report lower levels of cognitive empathy. The authors also provide for a useful review of studies on neural bases of empathy in aging that showed (counterintuitively) reduced brain activation in older adults to tasks involving both cognitive and affective empathy.The review paper by Shapira et al.'s study examined genetic and environmental influences on children's emotion recognition, for the first time adding vocal to facial cues of emotion. The authors report shared environmental (rather than genetic) effect on emotion recognition abilities in this cohort.Kanie et al. report results of social cognition and interaction training (SCIT) in a sample of patients with schizophrenia. SCIT was developed by Penn and colleagues, as a program for social cognitive rehabilitation in schizophrenia  borderline personality disorder (BPD), conduct disorder (CD), eating disorders (ED), and posttraumatic stress disorder (PTSD) and comparative neurotypical control populations.Komeda et al. suggest that individuals with ASD empathize with, and are more motivate to help, other people with ASD than neurotypical people. Whereas a study by Neufeld et al. found that, compared to neurotypical controls, the association between reward and mimicry is reduced in people with high autistic traits, and mimicry-related brain responses are less modulated by learned reward value in individuals with autism spectrum disorder. A third ASD study in this issue by Stroth et al. examined females with high functioning ASD and found they are able to share another person's physical or social pain on the neural systems level. However, female participants with ASD also have hypoactivation of the anterior insula when compared to neurotypical female subjects. The measurement of neural correlates provides objective measures and insight into neuro-cognitive empathy among people with ASD.There are three studies that focus specifically on autism spectrum disorder (ASD) examining cognitive empathy, perspective taking, and interpersonal motivations. Findings from Gaffney et al. which focused female participants with anorexia nervosa (AN) drew some analogies with ASD. They found lower cognitive empathy and intact affective empathy profiles among female participants with AN that are similar to that found in other psychiatric and neurodevelopmental conditions, such as autism spectrum disorder (ASD). These findings add to the literature characterizing the socio-emotional phenotype in eating disorders.A study by Flasbeck et al. found that people with BPD showed less activation in the left supramarginal gyrus when viewing angry facial expressions compared to healthy controls. Flasbeck et al. also found differential activation of the left anterior insula among people with BPD in response to the emotional context of facial expressions. Thus, concluding that empathy for pain becomes selectively enhanced among people with BPD. Ducque-Alarcón et al. used fMRI to examine the influence of child abuse on the etiology and neurobiological substrates of BPD. They found hypoconnectivity between the structures responsible for emotion regulation and social cognitive responses in the frontolimbic circuitry  among the BPD group. They concluded that there were differential levels of neural connectivity associated with the types and levels of abuse people had experienced. Another interesting neuroimaging study focused on neural basis of empathy in children and adolescents with early onset conduct disorder (CD). von Polier et al. studied the important role of the amygdala in empathy-related emotional processing among boys with CD. They noted that diminished amygdala responses and their association with low empathy and high callous unemotional traits suggest a pivotal influence of impaired amygdala processing in early-onset CD with notable deficits in empathic behavior. Their study found elevated response in the medial prefrontal cortex in boys with CD which point towards increased demands on self-referential processing to solve empathy tasks, and more cognitive biased processing strategies required for boys with early-onset CD.There are two neuroimaging studies that focused on borderline personality disorder (BPD). A study by Levy et al. is timely in its focus on mothers exposed to wartime trauma who have posttraumatic stress disorder (PTSD). They found that chronic stress takes a toll on the mother's empathic ability and indirectly impacts the neural basis of empathy by disrupting the coherence of both brain and behavior. These findings have important implications for interventions that may not only address PTSD among women but may help address the long term or intergenerational impact of wartime trauma.The study by In conclusion, we believe that this Research Topic provides for an interesting collection of papers covering a wide variety of emotional, cognitive, and neurobiological processes involved in empathy. We hope this will give the readers useful guidance in their research of this fascinating phenomenon.SS conceived the idea of the Research Topic, was involved in editing of submitted manuscripts and writing up the Editorial. DB-C was involved in editing of submitted manuscripts and writing up the Editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Under these unique learning conditions, relaxed avoidance-related beliefs can be exposed to corrective information and become revised accordingly, which may explain long-term increases in acceptance and corresponding reductions in psychopathology. Open research questions and implications for clinical practice are discussed.The efficacy of psychedelic-assisted therapies for mental disorders has been attributed to the lasting change from experiential avoidance to acceptance that these treatments appear to facilitate. This article presents a conceptual model that specifies potential psychological mechanisms underlying such change, and that shows substantial parallels between psychedelic therapy and cognitive behavioral therapy: We propose that in the carefully controlled context of psychedelic therapy as applied in contemporary clinical research, psychedelic-induced belief relaxation can increase motivation for acceptance  Such strategies, which can be actively supported by therapists, may in fact often reduce aversion to some degree. Nevertheless, due to encouragement by therapists and information provided in preparatory sessions, the patient may try and continue within introspection. Initial attempts at engaging with challenging experiences will likely reflect the patient's habitual patterns of responding, and may often rely on what has previously “worked” in everyday life: experiential avoidance. However, due to avoidance sensitivity, the attempt to exert control over the flow of events will likely aggravate aversive features of the experience, which may, in turn, elicit an even stronger avoidant response. Such escalation can be expected to proceed until the patient either resorts to overt avoidance or begins to desist from avoidance altogether. If neither occurs, the patient may soon find themselves in an intensely aversive state of panicAs soon as the patient spontaneously shows a minimum of acceptance toward an aversive aspect of the experience, this may initiate an operant process that can be described as an automatic form of shapingCertain additional context factors that are commonly present in psychedelic therapy  can be aExcursions into grief, loneliness and rage, abandonment. Once I went into the anger it went ‘pouf’ and evaporated.Patient #3 Such reports of exceptional openness to previously “hidden” or “suppressed” feelings during dosing sessions , 48, 49 resurgences): When an avoidant set is (re-)established for a brief moment, perceptual belief updating should be transiently biased towards what is associated with avoidance in the individual's memory. Thereby, periodic resurgences of avoidance may somewhat inevitably direct the flow of private events to what the patient most vigorously avoids in everyday life—which will likely relate to their individual psychopathology. Although speculative at present, it is conceivable that the surfacing of “forgotten” emotional memories [a regular occurrence in psychedelic therapy; . Apart from changes in explicit attitudes, belief relaxation may also facilitate the revision of more implicit expectancies, and reduce threat responses to private events through mechanisms related to extinction learning. In this respect, psychedelic therapy may resemble fear exposure treatment in CBT. Similar mechanisms have been proposed to underlie the therapeutic effects of mindfulness, which aims to broadly reduce reactivity to private events and is widely applied as a means of exposure in third-wave CBTs , i.e., strong suppression of bottom-up information and insensitivity to prediction errors. In line with the notion that psychedelic therapy works by making rigid pathological belief systems malleable , we propave CBTs , 35–37. ave CBTs –79, and ave CBTs . It is wave CBTs . PsychedTo summarize, psychedelic experiences that involve breakthrough experiences and episodes of relatively avoidance-free exposure to otherwise avoided private events may constitute unique learning conditions where relaxed avoidance-related beliefs can be revised with beneficial results. Corresponding changes in explicit attitudes, preconscious assumptions, and more implicit expectancies may profoundly transform the patient's way of relating to private events. The following patient report illustrates how these changes may lead to long-term increases in acceptance:I took away from the experience that I used to get angry about having anxiety, now I think I can have the anxiety, I can just feel it and it will go, I don't have to have the fear or run away.Patient #2 The proposed conceptual model . At its Challenging psychedelic experiences are potential starting points for acceptance-promoting learning processes, but are probably not always therapeutically valuable. In line with this, previous studies have found mixed results regarding long-term effects of challenging experiences: Roseman et al.  found thego-dissolution, i.e., a transiently compromised experience of self that is characterized by a sense of unity with one's surroundings  reducing aversive states. This may constitute a major difference between psychedelic therapy and more conventional methods in psychotherapy (where the patient can more easily reduce aversion by resorting to avoidance), and has important ethical implications for clinical practice. Most importantly, for the patient to be able to provide informed consent, they should be thoroughly informed about potential avoidance-impeding effects of the treatment. This requires that patients are given the opportunity to learn what avoidance is, and may involve not only educational but also experiential elements. Hence, the process of enabling valid informed consent for psychedelic interventions may already necessarily involve substantial elements of psychotherapy.According to our model, operant conditioning of acceptance requires the patient to “start the ball rolling” by spontaneously showing a minimum of acceptance toward an aversive aspect of the experience at some point. Apart from the obvious implications that are already accommodated by current protocols for preparatory sessions , this may inform therapeutic strategies for dealing with challenging experiences: Whereas therapists may initially attempt to facilitate breakthrough by encouraging acceptance, challenging experiences that persist for longer periods of time may indicate that the patient cannot (at present) desist from avoidance sufficiently to induce shaping of acceptance. This situation entails the risk that motivation for acceptance is markedly decreased and further attempts are impeded. It may therefore in some situations be therapeutically beneficial to actually support the patient's decision for avoidant responding before encouraging acceptance again. The ability to gauge the individual patient's distress tolerance on a moment-to-moment basis and strike a sensible balance between encouraging acceptance and supporting avoidance can be considered a key requirement for psychedelic therapists, and should be trained accordingly. It can be argued that such perspective-taking requires first-hand experience with psychedelic states [see  for a diThe proposed model explains increases in acceptance after psychedelic therapy in terms of revised avoidance-related beliefs. After the dosing session, newly established acceptance beliefs and corresponding behavior change may be more or less enduring depending on how generalized and heavily-weighted those beliefs are. In any case, long-term outcomes should be substantially affected by the learning conditions that the patient is exposed to after acute drug effects subside. In most cases, the patient will soon return to an environment that has been to some extent organized around avoidance goals. Continued psychotherapy may then help identify and change persistent habits, routines, and other circumstances that impede the pursuit of more acceptance-oriented approach goals. The same applies to individual deficits that hinder the abandonment of avoidant coping strategies . Therapists should also pay attention to how the patient's social environment responds to changes in behavior and attitudes. For instance, returning to an emotionally invalidating or dismissive environment without appropriate therapeutic support may result in rapid re-establishment of pathological avoidance-related beliefs. It appears unlikely that two or three integration sessions suffice to address such challenges in all cases. Hence, the prevailing brief intervention models employed in contemporary psychedelic therapy studies  may not Assuming that promoting acceptance is one of its core mechanisms, psychedelic therapy can be expected to have most pronounced positive effects in those mental disorders that are typically characterized by excessive experiential avoidance. This encompasses many of the most prevalent mental disorders, including some that are already in the focus of psychedelic research  and others for which modern clinical trials have not yet been conducted, such as panic disorder, posttraumatic stress disorder (PTSD), or psychosomatic disorders. Psychedelic therapy may hold less promise for conditions where avoidance is not considered a central factor, such as attention-deficit/hyperactivity disorder (ADHD) or psychotic disorders . EspeciaWithin suitable diagnostic categories such as depression or addiction, how to determine if an individual patient is likely to benefit from acceptance-informed psychedelic therapy? On the one hand, it can be speculated that those patients who exhibit particularly high levels of experiential avoidance at baseline have the greatest potential for improvement. On the other hand, there may be a tipping point at which patterns of avoidance are too inflexible to make use of challenging psychedelic experiences. According to the proposed model, the shaping-like operant process of conditioning acceptance can be initiated only when the patient is able to show a minimum of acceptance spontaneously. If this is impossible due to personal  factors, this may give rise to prolonged challenging experiences that have no therapeutic value or could even aggravate avoidance-related beliefs. One might assume that such tipping points are localized around the threshold where the inflexibility and pervasiveness of experiential avoidance and related patterns of emotion dysregulation justify the diagnosis of a personality disorder . However, excluding patient populations based on such ideas seems premature without empirical support, especially when considering the substantial need to improve current treatments for personality disorders. Zeifman and Wagner  made a svia avoidance sensitivity (making avoidance more aversive), MDMA seems to facilitate engagement with otherwise avoided private events primarily by attenuating the fear response (making acceptance less aversive). Clinical applications of MDMA-assisted psychotherapy are currently being extended beyond PTSD  is applied in therapeutic interventions following protocols which closely resemble those used for psychedelic therapy . For somond PTSD , and PTSond PTSD . Hence, via operant conditioning, thus engendering episodes of relatively avoidance-free exposure to greatly intensified private events. Under these unique learning conditions, relaxed avoidance-related beliefs can be exposed to corrective experiences and become revised accordingly, potentially leading to long-term increases in acceptance and associated reductions in psychopathology. This model shows substantial parallels between psychedelic therapy and CBT that may be harnessed by using CBT as a therapeutic framework for psychedelic interventions. Empirical research is needed to validate and further develop the proposed model and, more generally, to examine the relative importance of acceptance as a mechanism of action in psychedelic therapy. Therefore, appropriate instruments for measuring processes related to avoidance and acceptance in psychedelic states must be developed. Although still requiring further empirical support, the proposed model demonstrates the usefulness of the relaxed-beliefs account as a basis for building theories of the therapeutic effects of psychedelic drugs.The therapeutic effects of psychedelics appear to depend on psychological processes that are evoked by synergies between these substances' pharmacological action and the context in which they are administered. To better understand and further develop psychedelic therapy, theoretical models that specify these processes are needed. Here, we took a CBT perspective and proposed such a model based on Carhart-Harris and Friston's  relaxed-MW and HJ conceived the central theoretical ideas presented in this article. RE, LM, MK, FB, and GG provided critical feedback. The manuscript was written primarily by MW with contributions from RE, LM, MK, FB, GG, and HJ.Open Access Funding by the Publication Fund of TU Dresden.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Advances in sensing technology raise the possibility of creating neural interfaces that can more effectively restore or repair neural function and reveal fundamental properties of neural information processing. To realize the potential of these bioelectronic devices, it is necessary to understand the capabilities of emerging technologies and identify the best strategies to translate these technologies into products and therapies that will improve the lives of patients with neurological and other disorders. Here we discuss emerging technologies for sensing brain activity, anticipated challenges for translation, and perspectives for how to best transition these technologies from academic research labs to useful products for neuroscience researchers and human patients. I.New sensing technologies capable of recording from large numbers of neurons for extended periods of time could fundamentally improve our understanding of the brain and the treatment of neurological disorders. Recent advances in sensing technologies from a variety of research domains promise to provide just such improvements in neural interface technology, but each of these approaches have unique technological challenges and opportunities.As part of the IEEE Brain Initiative, we recently gathered a group of researchers and stakeholders in Glasgow, Scotland to discuss the current state of the art for some of these emerging sensing technologies and the opportunities and challenges they present. This review focuses on emerging brain sensing technologies that currently reside in the academic research domain and may come to market in the coming years. For readers interested in brain sensing technologies that are currently commercially available, we encourage them to explore one of the excellent recent reviews of commercial brain sensing technologies –3]..3].In preparing this review we identified three areas where advanced sensors could disrupt brain sensing technology: 1) New electrode technologies , 2) InteII.At a fundamental level, sensors that detect the spiking activity of individual neurons convert sub-millivolt voltages within the brain into electronic signals in the solid-state circuits where all data processing occurs  Fig. 1)Fig. 1). Each of these sensing modalities have unique opportunities and challenges that we address in turn in the sections below.III.Electrodes have the advantage of direct transduction of the voltage produced by neurons, but require close proximity to the cells they intend to study, placing a premium of technologies that minimize damage to the brain. In neuroscience, these electrodes can record voltages in the surrounding electrolyte; stimulate voltages in surrounding electrolyte; patch neurons , measuriDirect electrical transduction brings many advantages, but in contrast to the remote sensing possible with optical techniques, electrodes must be within roughly 100–200 microns of an electrically active cell to isolate action potentials. This requirement for close proximity raises challenges in creating electrodes with appropriate form factors. Biological systems are curved and malleable, while solid-state devices are hard and flat, a difference that can be handled in one of two ways. One can miniaturize the device with respect to the biological tissue , or one can create solid-state devices that can conform to biological tissue (e.g. flexible or pliable electronics) .A.When choosing to employ electronic interfaces, there are enormous advantages to integrating these interfaces with state-of-the-art complementary metal-oxide-semiconductor (CMOS) electronics. First, integration of electronics close to the electrodes improves signal fidelity by delivering gain closer to the transducer, improving noise performance. CMOS-integrated electronics also enable dense electronics, having the potential to mirror the kind of densities achieved in CMOS imagers. Time-multiplexing of amplifiers is another technique used to optimally exploit the density of electronics available .Electrodes themselves fall into two main categories: Faradaic and non-Faradaic . Non-FarActive CMOS multielectrode arrays, employed primarily for in vitro neural studies such as of the retina, set the standard for the density and scaling of the electronics for electrophysiology. Recent work has produced arrays supporting as many as 65k simultaneous recording and stimulating channels . To expaBoth passive  and actiThese are both passive  and actiThese must generally communicate wirelessly to the surface of the brain or skull.There have been several efforts associated with the development of passive silicon shanks. By “passive,” we mean that the shanks themselves have no active electronics. With advanced packaging approaches and custom application-specific integrated circuits (ASICs) for the electronics, passive silicon shanks have been scaled to 1024 electrodes on a single shank. Active CMOS shanks integrate the electronics on the shank itself and can achieve similar scales. Ultra-small passive wired electrodes can be injected  or develElectrical interfaces continue to be an important type of neural interface and maintain several advantages over optical approaches, however they are generally more invasive and require close proximity with the target neurons. The optimal choice of electrode type depends on the problem at hand, and it is often critical to codesign the electrodes and the associated electronics. Scaled CMOS electronics is an important part of the story, and CMOS can be shaped into unusual form factors. Flexibility and small sizes are keys to building these interfaces.Important research topics in electrode development include organic electronics that can increase the capacitance of the electrode-electrolyte interface, nanoscale form factors that can reduce a foreign body response from the tissue, and minimally invasive delivery strategies that can improve chronic electrode performance. These research areas are described in the following sections.B.Organic synthesis allows one to create bioelectronic materials with tunable properties, compatibility with flexible substrates, and mixed electronic/ionic conduction , 35], a, a35], aThe same property of mixed conductivity allows the fabrication of electrochemical transistors. In these devices, ions from the cerebrospinal fluid enter the polymer channel and change the electrical conductivity throughout its volume . This meen route to implantable applications, with the aim of combined measurements of electrophysiology and metabolism in the same location of the brain. In the form of organic light-emitting diodes (OLEDs), organic electronics can be a useful way for local generation of light as will be described in Moreover, electrochemical transistors can be functionalized with redox enzymes, acting as sensitive sensors for metabolites such as glucose and lactate. Recent work shows that these devices offer good stability in cell culture media and that they can measure changes in metabolic activity with a high sensitivity . These dC.As described above, electrodes are one of the most important effective methods for time-resolved electrical detection of individual neuron activities in the living brain–47]. Ho. Ho47]. There has been a growing awareness that reducing the neural probe’s dimension  and rigiD.While very small and/or very flexible electrodes are likely to improve chronic recording performance , 74], d, d74], dIn order to minimize insertion trauma, researchers have developed a novel technique to insert flexible probes into the brain without stiffening . For anyE.In addition to improving system integration and performance of the electrodes at tissue interface, long-term studies in fundamental neuroscience as well as clinical applications in humans also require that these interfaces are robust and reliable with life times from years to decades. While there is plenty of knowledge in the medical devices field with cardiac pacemakers, cochlear implants and deep brain stimulators, the underlying technologies using precision mechanics limit the degree of miniaturization and the number of electrodes and cannot be directly transferred into miniaturized neural implants with dozens to hundreds of channels .As described above, CMOS and other micro (opto-) electromechanical systems (M(O)EMS) offer adequate levels of miniaturization but still have to prove long-term stability in chronic preclinical and clinical settings . PackageOne approach for neural interfaces applying MEMS technologies uses polyimide as flexible substrate and insulation material and thin-film metallization for electrodes, interconnect lines and contact pads to cables and implant packages. Adhesion between the different materials and layers has been identified as one of the key properties for long-term stability . ReliablForeign body reaction leads to scarring reaction around the implants deteriorating the transfer properties of the electrical and optical channels. Carbon as electrode material delivered promising results with respect to reduced tissue reaction . IncorpoThus, in addition to carefully developing sensors at the biotic-abiotic interface, it is critical to design systems for data and power transfer that support these sensors over long periods of time in the harsh and delicate environment inside the body.IV.Using light to sense neural activity has several advantages compared to electrical interfaces. Photons in brain tissue typically travel between 50 and 100 microns before scattering, allowing one to image individual cortical neurons from the surface of the brain. This imaging ability combined with advances in designer proteins for stimulation and measurement, allows one to interface with select cell types –98]. Th. Th98]. Light, however, is not without disadvantages. Information transferred through photons is limited by shot noise, which is most pronounced at high bandwidths and at the low signal levels characteristic of optical reporters of neural activity. The use of light is also an indirect measure of biophysical processes since, in nearly all cases, biological systems must be engineered to emit or be sensitive to light. Photobleaching also limits measurement time. Instrumentation is complex – microscopes are big and bulky generally, despite recent advances in lensless and filterless imaging systems. To overcome some of these challenges, researchers are investigating ways to make miniature, lensless microscopes with dramatically reduced size and weight, and looking toward electrooptic effects that would eliminate the challenges associated with photobleaching.A.Chief among the challenges facing an optical brain computer interface is the creation of a fully implantable imaging system that covers significant areas of the cortex. While miniature microscopes have shown promise for imaging activity in freely moving animals , 100], , 100], tOne approach to overcome the limitations inherent to lens-based microscopes is to replace lenses with compact phase or amplitude masks and computational imaging algorithms to recover an accurate estimate of the scene based on complex sensor data . One approach called “FlatScope” is a device less than a millimeter thick that maintains micron-scale resolution over a field of view several millimeters across . In addiWhile flat, lensless microscopes may solve the size and weight challenge for optical interfaces, there remains a need for brighter and more stable fluorescent indicators of neural activity, as well as more sensitive image sensors that can be incorporated into devices like the FlatScope. Promising new single-photon-sensitive sensors may provide just such advances in imaging technologies. Secondly, to image beyond the first few hundred microns of cortex requires technologies to mitigate the effects of light scattering by brain tissue. While multi-photon microscopy is the most common method to increase the optical imaging depth, it is unclear if the required pulsed lasers can be integrated into chip-scale neural interfaces. One alternative could be to produce light within the brain via bioluminescence to overcome the effects of excitation scattering and enable deeper imaging. Alternatively, integrated photonic probes that produce sheets of excitation light could more than double the imaging depth achieved by epifluorescence microscopy .B.While advances in CMOS technology allow production of fast and sensitive megapixel image sensors, generation of light by miniature integrated electronics remains a challenge, limiting its use for all optical neuronal interfacing, which requires photostimulation of neurons, e.g. through optogenetics, and in many cases excitation of fluorescent voltage or calcium reporters. This is a fundamental limitation of silicon due to its indirect bandgap. One avenue to circumvent this issue is to bond conventional micro LEDs, e.g. based on GaN, onto the silicon chip –106]. H. H106]. 2 down to the μm2 range. By modifying OLED microdisplays that were originally developed for near-to-eye display applications, we demonstrated photostimulation of channelrhodopsin 2 (ChR2) expressing cells from >105 individually addressable blue-emitting OLED pixels . . 2 down D pixels . Using tD pixels , 111]..2 down tC.Light may also provide an answer for ultraminiature multichannel brain sensors. While the multi-site electrical neural probes describe above have enabled multiplexed neural activity measurements , their lOne potential solution to these problems is to multiplex neural signals optically, into an optical fiber. Because visible or infrared light contains terahertz (THz) frequencies, the available signal bandwidth in an optical context is very high, concordant with the use of optical communications for long-range data transfer in the telecommunications industry and increasingly in parallel computing hardware. Optical communication channels, in addition, can potentially shrink towards the size of the optical wavelength, e.g., in the range of one micron, or below using plasmonic or other optical confinement techniques. Because the light is confined to an optical fiber in such a scenario, the massive optical scattering of the brain tissue does not pose a problem.To implement such optical multiplexing, there are two possibilities. One is to amplify and/or digitize locally and then transmit via optical fiber. This has some of the same issues, however, in terms of size and power consumption as a pure electrical approach. An alternative possibility is to leverage electro-optic modulation to allow an un-amplified neural signal to be directly transduced into a detectable modulation of an optical wave traveling in a small optical fiber. Electro-optic modulator devices which can create such effects are, interestingly, now scaled down to the micrometer size scale , and morRecently, preliminary designs have been proposed to allow fiber-based electro-optic neural activity sensing . The desV.Compared of electrical and optical techniques, magnetic sensing of neural activity has the advantage of being completely non-invasive and has high temporal resolution. However, the fields produced are so small compared to the earth’s magnetic field. As a result, the measurement of such fields has been traditionally carried out by magnetometers based on superconducting quantum interference devices , which aRecent improvements in the sensitivity of atomic magnetometers , which aAlong with the improvements in sensitivity obtained over the last decade, there have been parallel improvements in miniaturization and manufacturability. Chip-scale atomic magnetometers , 123] c c123] coIt is anticipated that further development of this sensor technology may lead both to portable systems capable of, for example, measuring brain activity during epileptic seizures, and to operation without the stringent shielding requirements required for superconducting quantum interference device (SQUID)-based systems . These, VI.As part of the workshop, a panel of neural sensors researchers discussed some of the challenges facing neural interface technology, and proposed suggestions for how they could be addressed. Some of the main themes that emerged from that discussion included: 1) A proposal that flagship research in neural interfaces should be focused on one or more clinical or commercial needs that involves a significant population of beneficiaries 2) Developing application spaces should draw on clearly articulated basic science questions 3) New sensing techniques are needed that change the risk profile associated with neural sensing and 4) The need for translation-based teams to involve people from many different disciplines, including some not traditionally associated with conventional neural interface research.A.A common theme of the panel’s deliberations was the idea that to best advance brain sensor technology, the community should nucleate around high-priority applications rather than focus on arbitrary technical or scientific metrics. Instead, the technical metrics would be driven by the needs of the target application. With this approach it may be easier to clearly articulate a focused set of engineering design constraints and next step research goals that could be used to advance sensor technology, provide a more direct path to clinical translation, and help motivate research support. The panel felt that selecting flagship application(s) should involve identifying a space in which neural interfaces provided a potential means to benefit a larger number of people relative to smaller niche clinical domains. The panel did not feel that identifying one or more specific application spaces would significantly impede neural interface research, as the overlapping needs of many goal applications meant that advancing neural sensor technology for a given goal application would still benefit neural technology at large.The panel also expressed that many neural sensing technology questions that involved identifying necessary performance metrics and pressing technical challenges were difficult to answer except in the context of specific applications . For example, the panel noted that designing systems capable of monitoring single neurons may be necessary to enable brain-computer interface (BCI) control of dexterous prosthetics hands or for basic neuroscience studies, but local field potential (LFP) activity may be sufficient for other BCI applications (e.g. computer cursor control), and thus it was difficult to prioritize a goal sensor resolution for neural interface research as a whole. However, the panel noted that in the case of BCI, the clinical population of severely paralyzed individuals who would potentially benefit from either approach would be relatively small compared to the clinical need in spaces such as pain management, with opiate addiction becoming a national crisis , 128], , 128], aB.While the panel advocated identifying one or more high-priority application spaces, it also emphasized the need to improve our basic scientific understanding of the relevant neural mechanisms associated with: 1) the proposed application, 2) the factors affecting device performance, and 3) the information content of the recorded data. The panel expressed the opinion that when considering potential high priority application domains, the degree to which the fundamental problems associated with the application having been historically well studied and well understood should be a significant selection criterion. Similarly, research efforts going forward would benefit by being able to frame their basic science questions in regards to the identified application(s) in order to more clearly articulate their goals. For example, when asked to assess the importance of novel sensing methods ability to monitor individual neurons, the panel pointed out that basic research would be necessary to determine whether single neuron recording fidelity was important for a given application. More specifically, research would be necessary to better quantify the information content of LFP data relative to single neuron recordings, the temporal stability of LFP information, the stability by which single neurons can be tracked over time for a given method, how well information content scaled with additional sensors for single neuron vs LFP sources, etc., Only with such basic work would it be possible to assess the need for single neuron monitoring for a proposed application. Similarly, when discussing the major impediments to current clinical translation efforts, the panel articulated a number of areas for which basic research would be necessary to overcome translation hurdles, including: safety studies regarding optogenetic techniques, establishing the consistency with which specific neurons could be linked to sensor recordings, studies regarding which neural regions should be targeted for a given application, and investigations into the long and short term impacts of parameters such as electrode stiffness on tissue damage and neural monitoring.C.As part of the its deliberations, the panel returned several times to the idea that a major goal for both neural sensing and stimulation technologies should be to reduce risk profiles associated with deploying and using the technologies. New application spaces, whether commercial or clinical, must consider the risk as well as the benefit to the user, which implies that reducing risk significantly expands the space of possible applications that could be used as high-priority focus areas to support neural interface research. For example, basic research evaluating the impact of electrode motion, both over short and long timescales, may show that flexible electrodes significantly reduce the risk profile for implanted electrodes. Similarly, when challenged to identify the major impediments to translating neural interface technology to clinical practice, the panel highlighted that surgical implantation of a device significantly complicated clinical translation opportunities, and even more so impacted potential commercial applications. With regard to the latter, the panel believed that pursuing noninvasive technologies for neural recording and stimulation would facilitate identification of a high-priority, large population application spaces. The panel pointed out there was significant public interest in neural interfaces, extending even to growing DIY (“do it yourself”) communities that are emerging around neural recording technologies  will be important to help open up new application spaces. The panel also noted that good communication and leadership skills were necessary (but unfortunately often lacking) for coordinating efforts within a given team. Some of the panelists pointed to personal experiences in which they believed that the necessary types of expertise to support individual components of a project, such as clinical testing and different types of engineering sills, had been present in a team, but the main difficulties had been in bringing the components together effectively. Thus, they advocated for teams to draw on members with expertise (to some degree) that crosses different discipline boundaries to help facilitate team communication and integration of a project’s different scientific and engineering components.E.The workshop concluded with a discussion among breakout groups to identify the grand challenges for Brain sensing. From these discussions a consensus emerged that there are no clear grand challenges for a technology because there is not a singular goal for neural sensing research. Rather, the group reported that the biggest challenges related to the coordinating the many different engineering pieces that must work together for a functional neural technology and creating robust technologies that can be easily distributed. The groups reported that there is currently a huge barrier to entry for neurotechnology developers if they need to create the end-to-end solution. A move toward modular components in neurotech would allow engineers to focus on developing one element of a system that would could integrate into existing systems. The groups suggested that neurotechnology development platforms similar to what has been done in the software industry could also a empower crowd sourced solutions and communities of DIY’ers to contribute to the neurotech movement. Finally, the groups argued that the largest engineering challenge is not unified, but rather a collection of specific technology challenges ranging from device performance, packaging, biocompatibility, robust operation, connectors, wireless power and data, etc. that together must be solved for “surgeon-proof” technologies. Despite these challenges the panels remained optimistic that these are solvable problems over the next decade.


Community-acquired pneumonia (CAP) is the leading cause of death from infectious disease worldwide and disproportionately affects older adults and children. In high-income countries, pneumonia is one of the most common reasons for hospitalisation and (when recurrent) is associated with a risk of developing chronic pulmonary conditions in adulthood. Pneumococcal pneumonia is particularly prevalent in older adults, and here, pneumonia is still associated with significant mortality despite the widespread use of pneumococcal vaccination in middleand high-income countries and a low prevalence of resistant organisms. In older adults, 11% of pneumonia survivors are readmitted within months of discharge, often with a further pneumonia episode and with worse outcomes. In children, recurrent pneumonia occurs in approximately 10% of survivors and therefore is a significant cause of healthcare use. Current antibiotic trials focus on short-term outcomes and increasingly shorter courses of antibiotic therapy. However, the high requirement for further treatment for recurrent pneumonia questions the effectiveness of current strategies, and there is increasing global concern about our reliance on antibiotics to treat infections. Novel therapeutic targets and approaches are needed to improve outcomes. Neutrophils are the most abundant immune cell and among the first responders to infection. Appropriate neutrophil responses are crucial to host defence, as evidenced by the poor outcomes seen in neutropenia. Neutrophils from older adults appear to be dysfunctional, displaying a reduced ability to target infected or inflamed tissue, poor phagocytic responses and a reduced capacity to release neutrophil extracellular traps (NETs); this occurs in health, but responses are further diminished during infection and particularly during sepsis, where a reduced response to granulocyte colony-stimulating factor (G-CSF) inhibits the release of immature neutrophils from the bone marrow. Of note, neutrophil responses are similar in preterm infants. Here, the storage pool is decreased, neutrophils are less able to degranulate, have a reduced migratory capacity and are less able to release NETs. Less is known about neutrophil function from older children, but theoretically, impaired functions might increase susceptibility to infections. Targeting these blunted responses may offer a new paradigm for treating CAP, but modifying neutrophil behaviour is challenging; reducing their numbers or inhibiting their function is associated with poor clinical outcomes from infection. Uncontrolled activation and degranulation can cause significant host tissue damage. Any neutrophil-based intervention must walk the tightrope described by Heinrich Rohrer, facilitating necessary phagocytic functions while preventing bystander host damage, and this is a significant challenge which this review will explore. Community-acquired pneumonia (CAP) is the leading cause of infectious death globallyIn child survivors of sepsis, a quarter of children are discharged with some form of disability, and 1 in 10 ha severe disability at discharge.The direct and indirect costs of pneumonia exceed €10 billion per annum in Europe,This review will explore why children and older adults are more susceptible to pneumonia and consider what therapeutic strategies might be deployed to improve outcomes.Common causes of CAP are listed in Streptococcus pneumoniae (SP), non-typeable Haemophilus influenzae (ntHI) and Mycoplasma pneumoniae are the most common causative bacteria identified in CAP,Staphylococcus aureus are more commonly found in patients with existing lung disease and those from nursing homesAcross high-income countries, Determining aetiology is more challenging in children than in adults. Young children are not typically able to expectorate sputum and have low rates of blood culture positivity. Children also have high carriage or colonisation rates of common respiratory pathogens. For example, in healthy children, certain pathogens can be present at rates of 20%–25% in nasopharyngeal swabsThere are some well-established risk factors that partially explain the high incidence of CAP in the older adult. Advanced age alone is a significant risk factor for CAP,Vaccination against pneumococcal disease is common in high-income countries.Young children have not had the lifespan to develop accumulated insults, which increase the susceptibility to infection. However, there are accepted risk factors, including younger age, existing respiratory disease, previous respiratory infection, vaccination status and presence of environmental pollution, including parental smoking see .The host immune response to infection changes across the life course, both in the very young and with age and frailty. Changes associated with increasing age are termed immunosenescence. The deficits in innate and adaptive immunity seen with ageing are well described, and all predispose towards a less organised and effective response to infection, as described in The immune system in neonates must strike a balance between exposure to multiple pathogens while tolerating acquisition of colonising organisms, without creating a hostile inflammatory environment. Neonates rely heavily on transfer of immunoglobulins from the mother both via the placenta and in breastmilk; thus, maternal immunity is key to early protective responses.Alveolar macrophages (AMs) are the first cells activated by pulmonary infection and are avid phagocytesNeutrophils are key effector cells during infections in CAP, as shown by the high incidence and severity of CAP in patients with specific neutrophil deficitset alTo understand how neutrophil functions might contribute to poor outcomes in CAP requires an understanding of how these cells function optimally. Classical neutrophil functions have been extensively reviewed elsewhere , causing ] neutrophil activation and recruitment, and concentrations of CXCL8 correlate with increasing disease severity.Senescence or biological ageing is the gradual deterioration of functional characteristics associated with age and can refer to a whole organism (such as the ageing human), a tissue or cell. Immunosenescence is an age-associated immune dysfunction and is associated with ‘inflamm-ageing’,S. aureus infection model.Neutrophil functions also demonstrate immunosenescence. Neutrophil numbers are maintained, both in the periphery and as progenitors in the bone marrowDuring severe infections in older adults and aged mice, profound neutrophil dysfunction has been described across all effector functions. Toll-like receptor signalling  is decreased in older age.Reduced NETosis has been described in older adults with CAP,Examining the impact of infection on neutrophils in children is challenging for three reasons. First, children are a very heterogeneous population with vast differences seen from preterm infants through to young adults.The fetus develops in a sterile intrauterine environment, meaning that at birth, it relies on its innate immune system; however, neutrophils from preterm infants have significant functional differences compared with those from older infants see . NeutropCandida species.Preterm infants have reduced migrational capacity compared with term infants,Deficits in neonatal phagocytosis have been attributed to lack of maternal immunoglobulin to facilitate opsonisation.et al has investigated the dysfunction seen in monocytes from preterm infants and concluded that there are major differences in the metabolic pathways between preterm infants and adults, and this may explain the broad defects seen.Understanding the mechanisms underlying these observations is challenging. Certainly, the immune system of an infant needs to have significant tolerance to prevent uncontrolled activation on exposure to the maternal microbiome and environmental factors.et al identified that migration was significantly poorer in healthy children than in healthy adults,It is unclear when neutrophils from children develop ‘young adult’ characteristics. Yegin Cytosolic calcium is crucial to many neutrophil effector functions. Impaired calcium flux has been associated with defective migration, ROS generation and degranulation,Studies of aged human CAP have not assessed neutrophil function before the infective insult, so it is unclear whether the impaired effector functions seen in CAP reflect a lower baseline preceding the event or a response to CAP. However, exposing neutrophils from young adults to pooled plasma from older patients with CAP and sepsis replicates the functional deficits seen in sepsis,Neutrophils have very few mitochondria, which do not play a role in energy metabolism, and the energy required for neutrophil activity is derived from glycolysis.Hyperlactataemia is an independent predictor of mortality in both pneumonia and sepsis.Recent studies involving the effects of tumour-derived lactate suggest that lactate may have an immunosuppressive effect in its local environment and is an active signalling molecule in a wide range of immune cells via specific receptors.There is evidence to show that excessive or blunted neutrophil activity can worsen outcomes for patients, be they young or old. Neutrophils can cause significant tissue damage with proteases; this proteolytic activity is required for normal function but is also associated with tissue damage. High levels of proteases are identified in the bronchoalveolar fluid from patients with severe pneumoniaEx vivo treatment of neutrophils from patients with sepsis with G-CSF improves phagocytosis.NETosis has also been associated with significant tissue damage. Patients with the highest levels of NETosis had increased risk of progression to ARDS and increased mortality,Clearly, this suggests that there is an optimal level of neutrophil functions, and any therapy targeting neutrophils needs to normalise rather than exaggerate function to prevent excessive tissue damage, which is associated with increased mortality. Early studies have suggested this can be achieved, potentially through modification of neutrophil signalling pathways.CAP can be considered as a sentinel event that signals high risk of short-term and long-term mortality and future readmission in both young children and older adults. Despite widespread use of vaccination, low prevalence of antimicrobial resistance and improvements in sepsis care, mortality and reinfection rates remain high, with survivors often left with significant impairments. Age-related changes in neutrophil function may be one of the reasons that the very young and the very old are more likely to develop CAP, and heightened dysfunctional responses during infection may be causally associated with poorer outcomes and the increased likelihood of secondary infection. Our evolving understanding of immunology has allowed us to harness the immune system to better target cancer cells, and more recently, there is building evidence that immunosenescent neutrophil dysfunction can be improved. Individual cellular functions can be modified by focusing on selective pathways, but in the face of global cellular dysfunction at the extremes of age, there may be more benefit if fundamental biological pathways are targeted, such as cellular energetics. Modifying neutrophil therapeutically remains a challenge, but perhaps now is the time to walk the tightrope Heinrich Rohrer referred to and see if we can use this highly effective phagocyte to improve patient outcomes.


With their limited size and coding capacity, all viruses must exploit their host cells for the machinery and raw material they require for replication. At the same time, infected cells deploy an armada of antiviral effector proteins the virus must evade or counteract. This back-and-forth assault, commonly referred to as an “arms race,” impacts viral replication, tropism, and disease severity . How virHost factors are proteins encoded by cellular genes that affect an intruding virus. Those that ablate viral replication or spread are antiviral factors, while those that enable or enhance the infection perform pro-viral roles and are host dependency factors (HDFs). All of these participate in the battle between pathogen and host and are often under strong evolutionary selection. The identities and functions of these proteins can be as unique and diverse as viruses themselves. It is unsurprising that despite development of powerful systems-level methodologies, we still possess an incomplete knowledge of the virus–host interface for even the best-studied pathogens.Antiviral factors involved in intrinsic or innate immune signaling as well as host restriction have been studied in great molecular depth for many viruses that cause human disease. These are perhaps best exemplified by the interferon-stimulated genes (ISGs), which number in the dozens, if one considers only core or ancestral ISGs, or up to hundreds or even thousands with more generous definitions, depending on the cell and tissue type . While wIndividual HDFs have been discovered and characterized for many viral systems –6. DespiThe term “undiscovered country” in the title makes passing reference to Hamlet’s most famous soliloquy. The bard used it to illustrate our ignorance of and hesitation to explore the afterlife. We find these themes on exploration analogous to our knowledge gap of HDFs regulating later stages of viral infections. The “undiscovered country” of HDFs during later stages of replication exists not due to fear but the technical and biological limits of our methods.Earlier discovery-based methods, like random gene perturbation or ectopic overexpression with complementary DNA (cDNA) libraries, have given way to more targeted and high-throughput techniques. While many techniques exist for studying both genetic and physical interactions between a virus and its host , here, wProgrammable nucleases, like CRISPR/Cas9 systems, have helped overcome many limitations for both gain- and loss-of-function screens ,13. CRISAlmost all of these highlighted approaches rely on genetic perturbation prior to infection and screening. Hits from these approaches frequently display a strong bias towards factors affecting the very earliest stages of infection, including attachment and entry. This is in part due to the key role of these events during infection but also a technical artifact that many screens use reporter or single-cycle version of the virus of interest that do not fully capture the full replicative cycle. Despite this limitation, these approaches have provided tremendous insights into entry factors or receptors for many viruses, such as Epstein–Barr virus , human iNumerous advances continue to emerge to help navigate around technical and biological limitations. One strategy to limit early stage biases and rediscovery of known receptors and entry factors is to bypass canonical attachment and entry pathways. For enveloped viruses such as HIV or IAV, this can be achieved by replacing native envelope proteins with those from a different virus, like murine leukemia virus or vesicular stomatitis virus, to generate pseudotyped particles ,27. WhilGenetic investigations of HDFs in virally-infected cells have mostly comprised survival-based selections. However, other experimental strategies and phenotypic endpoints can be chosen. For instance, detection of viral protein expression at a specific time postinfection using fluorescence-activated cell sorting (FACS) or microscopy can be used as a readout for viral replication . Cells bAn emergent benefit of open science is the ability to aggregate large-scale results from different experiments and techniques that addressed similar questions . Meta-anWhen an HDF is expressed and how much is made can drastically change its biological effect. This information is lost where the genetic manipulation is static, like a gene knockout or constitutive CRISPRa cell line. Experimentally manipulating HDF timing and abundance enables probing of additional aspects of viral replication, while, at the same time, minimizing the bias towards early stages of infection. A suite of tools has been developed for inducible and tunable alterations to target gene expression on a genome-wide scale at times chosen by the researcher . For CasAn alternative approach is to fool the virus into revealing its own Achilles’ heel(s). Through clever molecular virology, the virus under study is engineered to perturb targeted host genes itself . In contA more recent study utilized HIV capable of packaging single-guide RNAs (sgRNAs) into progeny virions . RecombiLike their antiviral counterparts, HDFs can dictate the success or failure of infections. This can be based on their expression levels, allelic profiles, and splicing patterns. Importantly, the evolution of eukaryotic genes is significantly slower than that of a virus . Therefo


The social/behavioral HIV Decision-Making Study (DMS) assesses informed consent and trial experiences of individuals in HIV remission trials in Thailand. We convened a 1-d multi-stakeholder participatory workshop in Bangkok. We provide a meeting summary and reactions from DMS investigators.Workshop members viewed de-identified interview excerpts from DMS participants. They deliberated on the findings and made recommendations regarding informed choice for remission trials. Notes and recordings were used to create a summary report, which was reviewed by members and refined.Workshop members’ recommendations included HIV education and psychosocial support to establish the basis for informed choice, key trial information to be provided in everyday language, supportive decision-making processes and psychosocial care during and after the trial. Concerns included participant willingness to restart antiretrovirals after trial-mandated treatment interruption, unintended influence of the research team on decision-making and seemingly altruistic motivations for trial participation that may signal attempts to atone for stigmatized behavior.The workshop highlighted community perspectives and resulted in recommendations for supporting informed choice and psychosocial and physical health. These are the first such recommendations arising from a deliberative process. Although some elements are rooted in the Thai context, most are applicable across remission trials. It builds on the South East Asia Research Collaboration in HIV (SEARCH010/RV254) clinical research study. SEARCH 010/RV254  is a long-term observational cohort of individuals enrolled during acute HIV infection in Thailand .A DMS overview is shown in Figure We conducted a 1-d participatory workshop in Bangkok, Thailand, in April 2019. The goal was to engage a diverse stakeholder group to critically examine DMS findings and develop recommendations for improving the conduct of future HIV remission trials, particularly trials that include treatment interruption. Workshop members were provided with, and asked to discuss, excerpts of interviews associated with the SEARCH RV405 remission trial.The participatory workshop comprised 12 Thai members invited for their diverse perspectives and cultural knowledge, including CAB members, people living with HIV (PLHIV), medical professionals, social scientists and Thai non-governmental organization representatives . The moderator is a well-known and experienced HIV advocate in Thailand. Members were recommended by the moderator and the SEARCH research team. All workshop members were knowledgeable about HIV but their familiarity with remission research varied. None of the workshop members were directly associated (as a clinician or participant) with a SEARCH remission trial.The meeting facilitators are members of the DMS team: a UNC researcher who is a native Thai speaker (NQO), a BSSR scientist who conducts the DMS interviews (TJ) and the senior BSSR scientist (HLP), who participated via real-time translation.The meeting objectives and processes were developed by DMS investigators with consultation by the Thai-based meeting moderator and SEARCH clinical research team.Members were provided with de-identified transcript excerpts selected on relevance to the workshop goals. Specifically, these comprised longitudinal interview data from RV405 participants and decliners from the time of consent and trial's end. Interview topics included HIV diagnosis narrative, experience starting and maintaining use of ART, remission trial decision-making, reflections on trial results and decision satisfaction. Interviews with participants included trial experiences such as stopping and restarting ART during the trial.To create the interview excerpt documents, DMS investigators first selected a subset of participants and decliners to represent a range of decision-making attitudes and experiences. Ultimately, DMS investigators selected excerpts from 4 participants out of 19 and 4 decliners out of 6. Transcripts included both the original Thai and the English translation. Transcript documents were organized into subsections, arranged by timing of the interview and content of the excerpts. Given the geographic proximity of Thai workshop members and interviewees, we removed identifying information including names and other details that we anticipated could lead to re-identification. On the day of the workshop, each member read two documents, one for a trial participant and one for a trial decliner.The workshop members were informed that the meeting had three key objectives:Identify key information that PLHIV need to make an informed trial choice;Use DMS interview data to find support for or against informed choices being made regarding trial participation;Make recommendations about how to ensure that PLHIV can make an informed choice about joining or declining HIV remission trials.All workshop activities occurred during the 1-d workshop. After introductions and a review of the objectives and processes of the workshop, the meeting followed the organizational structure described below. The meeting was audio-recorded after agreement by the members. The agenda is available as Additional file 1.The Chief of SEARCH provided an overview of the SEARCH research cohort, which comprised individuals diagnosed and treated during the acute phase of HIV infection and the SEARCH remission trials. The Chief of SEARCH provided her perspective on the relevance of the DMS study to provide guidance on the ethical issues that impact participants during remission trial processes. To promote open, candid dialogue, the Chief of SEARCH then left the meeting and no SEARCH investigators or staff were present during the discussion. Next, the DMS aims and processes were described, along with additional detail about the RV405 remission trial. Finally, members were reminded of the sensitive nature of the data presented in the de-identified transcript excerpts and how to maintain the confidentiality of RV405 participants and decliners.The moderator then led a full-group discussion about what would be needed to make a good choice about participating in an HIV remission trial. Prompts included:What does a ‘good choice’ mean for you?What type of information is needed?How should participants be supported over time? What if they change their mind?Workshop members were asked to read their assigned, de-identified participant and decliner interview excerpts. Workshop members were given the following prompt by the moderator: ‘Discuss instances where decision-making and decision satisfaction were good and places with more worries.’ Regarding participant data, they considered: ‘Were there concerning or positive things about participants’ experiences during the trial?’ Workshop members were given time to discuss the data, ask questions and provide immediate reactions.The final session was a facilitated discussion to generate specific recommendations for researchers involved in planning and conducting remission trials. The discussion focused on the following question: ‘What do interview data and your own experiences tell you about recommendations to support good decision-making?’Prompts included:What specific types of knowledge/information are needed?Who should be involved in decision-making?What are signs of good and poor decision-making?Are some motivations more concerning than others?The facilitators took extensive notes, which were reviewed and compared against the workshop audiotape. The facilitators then summarized the themes and recommendations via a consensus process. These results were checked by the moderator. A draft report was prepared, translated into Thai, sent to all workshop members for review and comment then refined. All workshop members were invited to coauthor the manuscript but only three agreed to authorship due to time requirements.The report is summarized in the Results section. The Discussion section was written as a response by the USA-based DMS investigators, with input from all authors. The final version has been translated to Thai to ensure access for Thai stakeholders.The workshop members identified several cross-cutting needs applicable to SEARCH and the broader Thai HIV population. These concerns were neither reduced nor exacerbated by the DMS interview data. First, workshop members were concerned about the well-being of the SEARCH participants, regardless of enrollment in a clinical trial. They advocated for additional psychological support and stigma reduction efforts, including interventions tailored to the primarily men-who-have-sex-with-men SEARCH cohort. Providing such support was perceived to be the responsibility of the SEARCH and the DMS research teams.A second cross-cutting need was continuity of treatment, including for participants who may want to withdraw from SEARCH or transition care at study end. Workshop members advocate for participants to be informed of treatment options outside the SEARCH cohort and potential implications of research participation. Regarding the latter, there is a risk that remission trial participation leads to ART resistance and there may be no guarantee of post-trial access to another, equally effective antiretroviral regime. Workshop members felt researchers had a responsibility to assist those in such a situation.Workshop members referenced individual risks of remission trial participation that included ART resistance, HIV symptom progression and increase of HIV reservoir size. They worried that stopping ART temporarily could affect participants’ discipline for taking ART as prescribed. In addition, workshop members considered the risk of transmission to sexual partners during ATI and the complexities of disclosing HIV status and remission trial participation  to potential sexual partners. The need for education and support about these risks is described further in the remission trial information and support recommendations section.Workshop members also expressed concerns about potential psychosocial harms, some of which might be exacerbated in the Thai cultural context. For example, they described the potential influence of Kreng Jai, which can be translated as an attitude of respect and consideration for others and an obligation to do the ‘right thing’ in the short term. It involves avoiding conflict or inconvenience of another person, particularly one who is of higher social status.Potential harms applicable across all cultural contexts included unrealistic trial expectations that could lead to psychological harm if not met during the trial. The members emphasized the importance of understanding participant motivations and discouraging those based on misperceptions, for example, of HIV as a frightening and fatal disease, which may lead participants to see research participation as the only way to escape a terrifying situation. Similarly, workshop members reported the importance of BSSR investigators to longitudinally assess expectations and decision satisfaction during trials and, as necessary, intervene to realign participant expectations with scientific expectations, provide education and/or provide additional psychosocial support.Recommendations fell into three thematic areas. Those related to supportive decision-making center around improving participants’ baseline understanding of HIV, understanding their motivations and goals and enhancing the process of decision-making. Recommendations related to information provision and comprehension refer to trial-related information that should be provided to potential trial participants during the informed consent process. The final set, on providing ongoing support, outlines approaches with which to support participants both during and after remission trial participation.The recommendations in Table After workshop members had reviewed and discussed interview excerpts from RV405 participants and decliners, their initial input was only slightly altered. In most cases, the workshop members felt that participants had sufficient information and made reasonable choices. Members identified examples of information and support needs being met, or not fully met, during education and consent processes and during the trial. Most considered the transcripts to reinforce the need to have additional psychological counseling available based on data from several interviews indicating internalized stigma, lack of disclosure, limited HIV-associated support and/or worries about long-term health outcomes.Finally, workshop members reacted skeptically to reports in the DMS data about altruism as a primary motivation for participating in potentially risky remission research. Their concern was that what appears as altruism may in fact signal a desire to atone for stigmatized behavior linked to sexual orientation and acquisition of HIV in accordance with the Thai/Buddhist culture's focus on ‘merit-making’. Merit-making is an act of atonement that may lead to uncertain long-term rewards or rewards in the next life. They described this as particularly relevant in Thailand where HIV is still misunderstood as a life-threatening disease. Workshop members felt that research participation should not be used to compensate for perceived moral wrongs and thus this kind of merit-making motivation should be actively discouraged. Instead, any potential for direct medical or incidental benefit was a more acceptable motivation. Rounding out this complex picture, members did understand that the chance of direct medical benefit from the study intervention was very low.After some deliberation, workshop members came to a consensus that motivations of ‘mutual benefit’ may be the most acceptable and realistic. Mutual benefit would include the potential for short or longer term personal benefit, whether medical or ancillary benefits such as psychological benefits of participating, together with motivations related to improving scientific knowledge. Workshop members ultimately recommended that study teams emphasize the potential for longer term scientific advancements that may benefit the participant and the community, rather than short-term personal medical benefits or merit-making through participation.The workshop achieved its objectives of engaging in a deliberative process and creating a set of recommendations. Though the workshop objectives focused on supporting informed choice for HIV remission studies, members advocated for a broader range of recommendations. These included: education about HIV and treatment options, stigma reduction efforts and global psychosocial support for all PLHIV to provide a strong backbone upon which trial decisions can be implemented; participant-friendly trial information; anticipatory guidance about the ATI experience and transmission risk; careful recruitment and consenting approaches that include exploration of participant motivations and assessment of comprehension; and ongoing efforts to assess and enhance the well-being of participants in HIV remission trials Figure .The workshop recommendations were framed in response to members’ perception of risks of remission trial participation that included medical and psychosocial risks to participants and to sexual partners. Since these risks are universal to HIV remission trials, the associated recommendations should be broadly applicable. A few of their concerns (e.g. the importance of merit-making in the Buddhist culture) are culturally rooted and may be less applicable to other settings.,Further, our workshop recommendations overlap with two recent recommendation-focused publications.This section reflects the further deliberation on the participatory workshop results by the authoring group, which includes the decision-making study investigators and three Thai workshop members. The authoring group endorses the workshop recommendations with the understanding that national, regional and local regulations and sociomedical context will make some of the specific recommendations more or less applicable or feasible.It was reassuring that DMS interview excerpts did not cause major concerns about how cohort members made decisions whether to join or decline trial participation. This matched the DMS study team's interpretation. The workshop recommendations primarily arose out of the diverse stakeholders’ own experiences and expertise, although members found support for their recommendations within the DMS study data. The notable exception was the concern about altruistic motivations, which arose primarily from the DMS study data.The workshop left the DMS research team with four issues to consider. First, the need for additional counseling and support for PLHIV was consistently reported. Members felt that DMS data reflected this need to a higher degree than the DMS investigators did. What might account for this difference in perception? Workshop members, as local stakeholders, are more familiar with the social contexts of Thai PLHIV and may thus start from a different set of preconceived notions about the challenges faced by participants, independent of their involvement (or not) in remission trials. It is also possible that participants downplayed their psychosocial challenges due to social desirability bias, Kreng Jai-influenced concerns about reporting negative perceptions of SEARCH or as a matter of Thai reservedness, thus making it less obvious to outside researchers. It may be that the process of excerpting interviews retained more problematic components of the interviews while removing more positive or benign interview content, resulting in a different overall interpretation for workshop members. In any case, it is reasonable to recommend implementation of pilots for enhanced mental health services to be offered through the SEARCH cohort. Currently available services include counseling, a social/support club and psychiatric services for those who are referred by the SEARCH clinicians.,Second, workshop members raised concerns about the unintended influence of the SEARCH team on trial decision-making, especially given the Thai culture and influence of Kreng Jai. DMS data indicate that belonging to SEARCH influenced decisions of some individuals recruited to remission trials.Third, workshop members’ views about altruism gave rise to a complicated set of issues. The first is the potential impact of internalized stigma on decision-making for trial participation. Research participation driven by internalized stigma challenges the ideal of voluntary choice. Goffman defines stigma as reducing the individual in question ‘from a whole and usual person to a tainted, discounted one.’Further, the voluntary nature of research participation could be compromised if participants joined trials to ‘make merit’ to atone for their sexuality or HIV status. The proportion of research participants who are motivated in this questionable way is unknown. If merit-making is a widespread motivation for action in the Thai context, might there also be merit-making motivations untainted by stigma? Regardless, it may be unreasonable to discourage all such motivations. In future analyses we will attempt to further differentiate motivations associated with stigma, atonement and Kreng Jai. Without the workshop, these complexities and nuances would not have been raised.,Fourth, workshop members were highly supportive of BSSR conducted alongside remission trials to assess psychosocial needs, trial motivations and outcomes such as willingness to restart ART after treatment interruption. Workshop members, however, raised questions about the obligations of BSSR investigators. For scientists who conduct in-depth interviews, is it acceptable to simply collect data as observers? Or do we have an obligation to provide supportive and educational services, in the same manner that workshop members perceived the SEARCH research team to have such obligations? These challenges are not unique to our setting; historicalOur approach of providing workshop members with de-identified interview excerpts was required for practicability and confidentiality. It is unclear how workshop members’ reactions may have differed if full interview transcripts were shared, that is, whether they would be reassured further or if they might identify other areas of concern. Workshop members read transcripts in the original Thai while the analysis was conducted using English translations. This may have contributed to different interpretations. Though the workshop facilitators, the moderator and investigators have diverse identities, it is inevitable that positionality influenced the authors’ perspectives and interpretations of the workshop.,This participatory workshop advanced understanding of stakeholder perspectives on HIV remission research through deliberative engagement of members with knowledge stemming from experience and formal and informal instruction. It resulted in recommendations for supporting informed choice and mental and physical health. Although there are elements to the recommendations rooted in the specific Thai context, many conceptually overlap with prior recommendationsAdditional research should further assess participation motivations as well as anticipated and experienced risks, spanning physical, psychosocial and transmission risks. Such data are vital to foster nuanced recommendations over time. In addition, this evidence base informs the implementation and evaluation of interventions to support decision-making and the well-being of PLHIV, those considering remission trial participation, their partners who share trial-related risks and/or the broader community impacted by HIV remission research.Supplementary data are available at International Health online.ihaa067_Supplemental_FileClick here for additional data file.


Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with atypicalities in social interaction. Although psychological and neuroimaging studies have revealed divergent impairments in psychological processes  and neural activity  related to the processing of social stimuli, it remains difficult to integrate these findings. In an effort to resolve this issue, we review our psychological and functional magnetic resonance imaging (fMRI) findings and present a hypothetical neurocognitive model. Our psychological study showed that emotional modulation of reflexive joint attention is impaired in individuals with ASD. Our fMRI study showed that modulation from the amygdala to the neocortex during observation of dynamic facial expressions is reduced in the ASD group. Based on these findings and other evidence, we hypothesize that weak modulation from the amygdala to the neocortex—through which emotion rapidly modulates various types of perceptual, cognitive, and motor processing functions—underlies the social atypicalities in individuals with ASD. Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with atypicalities in reciprocal social interaction . CharactThe neurocognitive mechanisms underlying the social atypicalities of ASD remain elusive. Psychological studies have shown that various types of social cognitive processes are atypical in individuals with ASD compared with those of typically developing (TD) individuals; these atypicalities include emotional, perceptual, cognitive, and motor processing . In ASD via which emotion rapidly modulates various types of perceptual, cognitive, and motor processing functions, underlies the social atypicalities of individuals with ASD.In this article, we briefly review our psychological and neuroscientific findings and present a neurocognitive model seeking to further the understanding of this issue. Our psychological experiment revealed that individuals with ASD exhibit impaired rapid emotional modulation of attentional shift triggered by gaze. Our functional magnetic resonance imaging (fMRI) study demonstrated that individuals with ASD exhibit weak modulatory effects from the amygdala to the neocortical network during the observation of facial expressions. Based on these findings and other evidence, we speculate that weak modulation from the amygdala to the neocortex, In the first psychological experiment, we investigated the modulatory effect of emotion on reflexive joint attention .Clinical observations have suggested that one of the most obvious social atypicalities in individuals with ASD is a deficit of joint attention with others . HoweverWe tested this hypothesis in adolescent/adult individuals with ASD and TD controls using a dynamic fearful gaze as the cue of the cueing paradigm.We tested 11 high-functioning individuals with ASD  and 11 age- and sex-matched TD individuals . All participants in the ASD group had intelligence quotients (IQs) in the normal range and were diagnosed with Asperger’s disorder or pervasive developmental disorder not otherwise specified (PDD-NOS) with milder symptoms of Asperger’s disorder.As cue stimuli, dynamic fearful and neutral facial expressions with changing gaze directions were presented Figure 1In each trial Figure 1t-tests for RT differences . Similar findings have been reported in other studies that used different experimental paradigms. For instance, one previous study using the visual search paradigm showed that the facilitated perception of happy facial expressions in TD individuals was lacking in individuals with ASD . When dyIn the second fMRI experiment, we explored the functional neural networking patterns underlying atypical processing of dynamic facial expressions .Multiple previous fMRI studies have evaluated the brain activities associated with atypical facial expression processing in individuals with ASD . Althouvia subcortical visual pathways that bypass the neocortical visual pathways . Following analysis of group differences in regional brain activity, we performed DCM and compared models featuring modulation of dynamic expressions from the amygdala to the neocortical network, from the neocortical network to the amygdala, and a joint effect. We predicted that the first model would optimally explain the between-group differences.We tested 31 high-functioning individuals with ASD  and 31 age- and sex-matched TD individuals . All participants in the ASD group had IQs in the normal range and were diagnosed with Asperger’s disorder or PDD-NOS with milder symptoms of Asperger’s disorder.The dynamic expression stimuli used were video clips of Japanese models that progressed from neutral to angry or from neutral to happy in terms of facial expression Figure 2During each stimulus trial, after point fixation, the dynamic face or dynamic mosaic stimulus was presented. During each dummy-target trial, a red cross was presented instead of the stimulus and participants were instructed to press a button when the cross appeared.t-tests. Then, DCM was performed in a standard manner  were significantly lower in the ASD than the TD group.We used DCM to compare three models of the modulatory influences of dynamic facial expressions between the amygdala and neocortical network Figure 2The overall activities of the subcortical and neocortical regions involved in specific aspects of facial expression processing  were reduced in the ASD group during observation of dynamic facial expressions. These results are largely consistent with previous findings , 72.Furthermore, DCM demonstrated that the model featuring modulation of dynamic facial expression from the amygdala to the neocortical network optimally explained the differences between the ASD and TD groups. The ASD group exhibited reduced modulation. The atypical functional networking patterns in individuals with ASD are in line with the previous description of weak modulation of dynamic expression within neocortical regions  and weakIn summary, our psychological data demonstrate that individuals with ASD exhibit impaired rapid emotional modulation of attentional shift triggered by gaze. Our fMRI study demonstrated that individuals with ASD exhibit weak modulation from the amygdala to the neocortex during facial expression processing.Although there is minimal direct evidence in individuals with ASD related to these topics, findings and theories in TD individuals have provided suggestions to further understand these psychological and neural phenomena. From a psychological perspective, considerable evidence and influential theories suggest that emotional processing can be rapidly implemented, even before subjective stimulus perception . Abundanvia subcortical visual pathways , neuroimaging investigation using such tasks could provide direct tests of the neurocognitive model we proposed. Testing different stimuli  would be valuable, as previous fMRI studies have reported different activation patterns with different stimuli; for example, static social stimuli evoked different patterns of neural activity compared to dynamic stimuli in individuals with ASD , 72.Second, because findings regarding ASD could be subject to multiple confounding factors, such as trait anxiety  and alexThird, the neurocognitive model we propose in this article may not be specific to ASD but common across several neurodevelopmental and neuropsychiatric disorders. Some studies have reported behavioral problems having to do with emotional modulation and neurological abnormalities in amygdala activity and connectivity in other clinical groups. For example, previous studies have reported that individuals with attention-deficit hyperactivity disorder were impaired in emotion recognition from facial expressions  and showBased on our psychological and neuroimaging data and other related evidence, we presented our hypothetical neurocognitive model that weak modulation from the amygdala to neocortical regions—through which emotion rapidly modulates various types of perceptual, cognitive, and motor processing functions—underlies social atypicalities in individuals with ASD. Our model may enable integration of divergent psychological and neuroscientific findings showing atypical psychological and neural processes in individuals with ASD. However, the model lacks sufficient evidence. We hope that our hypothesis will stimulate empirical research regarding social atypicalities in individuals with ASD.The original contributions presented in the study are included in the article/supplementary material; further inquiries can be directed to the corresponding author.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.All authors designed the research and wrote the manuscript. All authors contributed to the article and approved the submitted version.This study was supported by funds from Japan Science and Technology Agency CREST (JPMJCR17A5).TK was employed by company ATR-Promotions.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The ability to suppress irrelevant but attention grabbing stimuli in our environment is critical for maintaining goal-directed control during many daily activities, such as avoiding junk foods while dieting or ignoring distractions while driving. Although we know much about the properties of environmental cues that make them susceptible to attentional capture , we know far less about how to disengage from such distractions, particularly the neural mechanisms involved in these processes.absent trials, participants were fast to find the target, and as expected, on distractor-present trials, participants were slow; their attention was effectively captured by the pop-out color, slowing their search and identification of the target in the array.In a recent paper by Lega et al. , the autInterestingly, the authors showed that delivering triple-pulse 10 Hz TMS at 100% of resting motor threshold to the right FEF 100 ms after the presentation of the search array reduced the slowing of reaction times (RTs) on distractor-present trials compared to stimulation over a control (sham) location. Notably, this reduction to the RT interference effect on distractor-present trials following FEF stimulation was specific to the right hemisphere and did not have the same effect over the left hemisphere. Moreover, right IPS stimulation generated a similar reduction in RT slowing on distractor-present trials compared to the sham stimulation, but this difference was not statistically significant and numerically smaller than the difference produced by right FEF stimulation. Although no discussion was provided about the TMS parameters selected and how this may affect the selectivity of the effect, the results indicate that targeting the right FEF produced the largest modulatory effects on distractor processing. This is a fascinating and highly relevant finding because it suggests that non-invasive brain stimulation may have the potential to train or improve attentional control over task-irrelevant, salient distractors.Importantly, the benefit to RT through reduced distractor interference following right FEF stimulation can be interpreted in two ways. One explanation is that stimulation of the right FEF improved distractor filtering processes by activating neural circuits involved in attention regulation, allowing for more successful disengagement and control of task-irrelevant information. A second explanation is that the stimulation impaired attention biasing, or pop-out detection, processes by disrupting neural circuits responsible for attentional capture from salient visual features. Lega et al.  favor thLega et al.  argued tA second reason Lega et al.  favor thLega et al.  posit thMore experimental work is needed to test the competing hypotheses of distractor filtering and attentional capture. Once these mechanisms have been teased apart, interesting avenues can be explored as the current findings on TMS modulation of distractor processing are of wide interest and relevance. For example, the findings have implications for recent work showing that rewarding stimuli can involuntarily capture attention in a visual search paradigm even when they directly conflict with current goals [e.g., (Anderson et al., Whereas feature-based attentional capture works through the physical salience of the distractors, value-modulated attentional capture works through their reward salience (Della Libera and Chelazzi, DT wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.