Subject-specific information enhances spatial accuracy of high-density diffuse optical tomography.

Functional near-infrared spectroscopy (fNIRS) is a widely used imaging method for mapping brain activation based on cerebral hemodynamics. The accurate quantification of cortical activation using fNIRS data is highly dependent on the ability to correctly localize the positions of light sources and photodetectors on the scalp surface. Variations in head size and shape across participants greatly impact the precise locations of these optodes and consequently, the regions of the cortical surface being reached. Such variations can therefore influence the conclusions drawn in NIRS studies that attempt to explore specific cortical regions. In order to preserve the spatial identity of each NIRS channel, subject-specific differences in NIRS array registration must be considered. Using high-density diffuse optical tomography (HD-DOT), we have demonstrated the inter-subject variability of the same HD-DOT array applied to ten participants recorded in the resting state. We have also compared three-dimensional image reconstruction results obtained using subject-specific positioning information to those obtained using generic optode locations. To mitigate the error introduced by using generic information for all participants, photogrammetry was used to identify specific optode locations per-participant. The present work demonstrates the large variation between subjects in terms of which cortical parcels are sampled by equivalent channels in the HD-DOT array. In particular, motor cortex recordings suffered from the largest optode localization errors, with a median localization error of 27.4 mm between generic and subject-specific optodes, leading to large differences in parcel sensitivity. These results illustrate the importance of collecting subject-specific optode locations for all wearable NIRS experiments, in order to perform accurate group-level analysis using cortical parcellation.

Role of HIV-1 Tat Protein Interactions with Host Receptors in HIV Infection and Pathogenesis.

Each time the virus starts a new round of expression/replication, even under effective antiretroviral therapy (ART), the transactivator of viral transcription Tat is one of the first HIV-1 protein to be produced, as it is strictly required for HIV replication and spreading. At this stage, most of the Tat protein exits infected cells, accumulates in the extracellular matrix and exerts profound effects on both the virus and neighbor cells, mostly of the innate and adaptive immune systems. Through these effects, extracellular Tat contributes to the acquisition of infection, spreading and progression to AIDS in untreated patients, or to non-AIDS co-morbidities in ART-treated individuals, who experience inflammation and immune activation despite virus suppression. Here, we review the role of extracellular Tat in both the virus life cycle and on cells of the innate and adaptive immune system, and we provide epidemiological and experimental evidence of the importance of targeting Tat to block residual HIV expression and replication. Finally, we briefly review vaccine studies showing that a therapeutic Tat vaccine intensifies ART, while its inclusion in a preventative vaccine may blunt escape from neutralizing antibodies and block early events in HIV acquisition.

A cellular screening platform, stably expressing DENV2 NS5, defines a novel anti-DENV mechanism of action of Apigenin based on STAT2 activation.

Type I interferon (IFN-I) evasion by Dengue virus (DENV) is key in DENV pathogenesis. The non-structural protein 5 (NS5) antagonizes IFN-I response through the degradation of the signal transducer and activator of transcription 2 (STAT2). We developed a K562 cell-based platform, for high throughput screening of compounds potentially counteracting the NS5-mediated antagonism of IFN-I signaling. Upon a screening with a library of 1220 approved drugs, 3 compounds previously linked to DENV inhibition (Apigenin, Chrysin, and Luteolin) were identified. Luteolin and Apigenin determined a significant inhibition of DENV2 replication in Huh7 cells and the restoration of STAT2 phosphorylation in both cell systems. Apigenin and Luteolin were able to stimulate STAT2 even in the absence of infection. Despite the "promiscuous" and "pan-assay-interfering" nature of Luteolin, Apigenin promotes STAT2 Tyr 689 phosphorylation and activation, highlighting the importance of screening for compounds able to interact with host factors, to counteract viral proteins capable of dampening innate immune responses.

Confidence of probabilistic predictions modulates the cortical response to pain.

Pain typically evolves over time, and the brain needs to learn this temporal evolution to predict how pain is likely to change in the future and orient behavior. This process is termed temporal statistical learning (TSL). Recently, it has been shown that TSL for pain sequences can be achieved using optimal Bayesian inference, which is encoded in somatosensory processing regions. Here, we investigate whether the confidence of these probabilistic predictions modulates the EEG response to noxious stimuli, using a TSL task. Confidence measures the uncertainty about the probabilistic prediction, irrespective of its actual outcome. Bayesian models dictate that the confidence about probabilistic predictions should be integrated with incoming inputs and weight learning, such that it modulates the early components of the EEG responses to noxious stimuli, and this should be captured by a negative correlation: when confidence is higher, the early neural responses are smaller as the brain relies more on expectations/predictions and less on sensory inputs (and vice versa). We show that participants were able to predict the sequence transition probabilities using Bayesian inference, with some forgetting. Then, we find that the confidence of these probabilistic predictions was negatively associated with the amplitude of the N2 and P2 components of the vertex potential: the more confident were participants about their predictions, the smaller the vertex potential. These results confirm key predictions of a Bayesian learning model and clarify the functional significance of the early EEG responses to nociceptive stimuli, as being implicated in confidence-weighted statistical learning.

Computational and neural mechanisms of statistical pain learning.

Pain invariably changes over time. These fluctuations contain statistical regularities which, in theory, could be learned by the brain to generate expectations and control responses. We demonstrate that humans learn to extract these regularities and explicitly predict the likelihood of forthcoming pain intensities in a manner consistent with optimal Bayesian inference with dynamic update of beliefs. Healthy participants received probabilistic, volatile sequences of low and high-intensity electrical stimuli to the hand during brain fMRI. The inferred frequency of pain correlated with activity in sensorimotor cortical regions and dorsal striatum, whereas the uncertainty of these inferences was encoded in the right superior parietal cortex. Unexpected changes in stimulus frequencies drove the update of internal models by engaging premotor, prefrontal and posterior parietal regions. This study extends our understanding of sensory processing of pain to include the generation of Bayesian internal models of the temporal statistics of pain.

Prefrontal Responses during Proactive and Reactive Inhibition Are Differentially Impacted by Stress in Anorexia and Bulimia Nervosa.

Binge eating is a distressing, transdiagnostic eating disorder symptom associated with impulsivity, particularly in negative mood states. Neuroimaging studies of bulimia nervosa (BN) report reduced activity in frontostriatal regions implicated in self-regulatory control, and an influential theory posits that binge eating results from self-regulation failures under stress. However, there is no direct evidence that psychological stress impairs self-regulation in binge-eating disorders, or that any such self-regulatory deficits generalize to binge eating in underweight individuals (i.e., anorexia nervosa bingeing/purging subtype; AN-BP). We therefore determined the effect of acute stress on inhibitory control in 85 women (BN, 33 women; AN-BP, 22 women; 30 control participants). Participants underwent repeated functional MRI scanning during performance of the Stop-signal anticipation task, a validated measure of proactive (i.e., anticipation of stopping) and reactive (outright stopping) inhibition. Neural and behavioral responses to induced stress and a control task were evaluated on 2 consecutive days. Women with BN had reduced proactive inhibition, while prefrontal responses were increased in both AN-BP and BN. Reactive inhibition was neurally and behaviorally intact in both diagnostic groups. Both AN-BP and BN groups showed distinct stress-induced changes in inferior and superior frontal activity during both proactive and reactive inhibition. However, task performance was unaffected by stress. These results offer novel evidence of reduced proactive inhibition in BN, yet inhibitory control deficits did not generalize to AN-BP. Our findings identify intriguing alterations of stress responses and inhibitory function associated with binge eating, but they counsel against stress-induced failures of inhibitory control as a comprehensive explanation for loss-of-control eating.SIGNIFICANCE STATEMENT Binge eating is a common psychiatric syndrome that feels uncontrollable to the sufferer. Theoretically, it has been related to reduced self-regulation under stress, but there remains no direct evidence for this link in binge-eating disorders. Here, we examined how experimentally induced stress affected response inhibition in control participants and women with anorexia nervosa and bulimia nervosa. Participants underwent repeated brain scanning under stressful and neutral conditions. Although patient groups had intact action cancellation, the slowing of motor responses was impaired in bulimia nervosa, even when the likelihood of having to stop increased. Stress altered brain responses for both forms of inhibition in both groups, yet performance remained unimpaired. These findings counsel against a simple model of stress-induced disinhibition as an adequate explanation for binge eating.

A central mechanism of analgesia in mice and humans lacking the sodium channel NaV1.7.

Deletion of SCN9A encoding the voltage-gated sodium channel NaV1.7 in humans leads to profound pain insensitivity and anosmia. Conditional deletion of NaV1.7 in sensory neurons of mice also abolishes pain, suggesting that the locus of analgesia is the nociceptor. Here we demonstrate, using in vivo calcium imaging and extracellular recording, that NaV1.7 knockout mice have essentially normal nociceptor activity. However, synaptic transmission from nociceptor central terminals in the spinal cord is greatly reduced by an opioid-dependent mechanism. Analgesia is also reversed substantially by central but not peripheral application of opioid antagonists. In contrast, the lack of neurotransmitter release from olfactory sensory neurons is opioid independent. Male and female humans with NaV1.7-null mutations show naloxone-reversible analgesia. Thus, inhibition of neurotransmitter release is the principal mechanism of anosmia and analgesia in mouse and human Nav1.7-null mutants.

Dissociable hormonal profiles for psychopathology and stress in anorexia and bulimia nervosa.

BACKGROUND: Anorexia nervosa (AN) and bulimia nervosa (BN) are complex psychiatric conditions, in which both psychological and metabolic factors have been implicated. Critically, the experience of stress can precipitate loss-of-control eating in both conditions, suggesting an interplay between mental state and metabolic signaling. However, associations between psychological states, symptoms and metabolic processes in AN and BN have not been examined. METHODS: Eighty-five women (n = 22 AN binge/purge subtype, n = 33 BN, n = 30 controls) underwent remote salivary cortisol sampling and a 2-day, inpatient study session to examine the effect of stress on cortisol, gut hormones [acyl-ghrelin, peptide tyrosine tyrosine (PYY) and glucagon-like peptide-1] and food consumption. Participants were randomized to either an acute stress induction or control task on each day, and plasma hormones were serially measured before a naturalistic, ad libitum meal. RESULTS: Cortisol-awakening response was augmented in AN but not in BN relative to controls, with body mass index explaining the most variance in post-awakening cortisol (36%). Acute stress increased acyl-ghrelin and PYY in AN compared to controls; however, stress did not alter gut hormone profiles in BN. Instead, a group-by-stress interaction showed nominally reduced cortisol reactivity in BN, but not in AN, compared to controls. Ad libitum consumption was lower in both patient groups and unaffected by stress. CONCLUSIONS: Findings extend previous reports of metabolic dysfunction in binge-eating disorders, identifying unique associations across disorders and under stress. Moreover, we observed disrupted homeostatic signaling in AN following psychological stress, which may explain, in part, the maintenance of dysregulated eating in this serious illness.

Pain Control by Co-adaptive Learning in a Brain-Machine Interface.

Innovation in the field of brain-machine interfacing offers a new approach to managing human pain. In principle, it should be possible to use brain activity to directly control a therapeutic intervention in an interactive, closed-loop manner. But this raises the question as to whether the brain activity changes as a function of this interaction. Here, we used real-time decoded functional MRI responses from the insula cortex as input into a closed-loop control system aimed at reducing pain and looked for co-adaptive neural and behavioral changes. As subjects engaged in active cognitive strategies orientated toward the control system, such as trying to enhance their brain activity, pain encoding in the insula was paradoxically degraded. From a mechanistic perspective, we found that cognitive engagement was accompanied by activation of the endogenous pain modulation system, manifested by the attentional modulation of pain ratings and enhanced pain responses in pregenual anterior cingulate cortex and periaqueductal gray. Further behavioral evidence of endogenous modulation was confirmed in a second experiment using an EEG-based closed-loop system. Overall, the results show that implementing brain-machine control systems for pain induces a parallel set of co-adaptive changes in the brain, and this can interfere with the brain signals and behavior under control. More generally, this illustrates a fundamental challenge of brain decoding applications-that the brain inherently adapts to being decoded, especially as a result of cognitive processes related to learning and cooperation. Understanding the nature of these co-adaptive processes informs strategies to mitigate or exploit them.

Hierarchical models of pain: Inference, information-seeking, and adaptive control.

Computational models of pain consider how the brain processes nociceptive information and allow mapping neural circuits and networks to cognition and behaviour. To date, they have generally have assumed two largely independent processes: perceptual inference, typically modelled as an approximate Bayesian process, and action control, typically modelled as a reinforcement learning process. However, inference and control are intertwined in complex ways, challenging the clarity of this distinction. Here, we consider how they may comprise a parallel hierarchical architecture that combines inference, information-seeking, and adaptive value-based control. This sheds light on the complex neural architecture of the pain system, and takes us closer to understanding from where pain 'arises' in the brain.

Fine-Grained Mapping of Cortical Somatotopies in Chronic Complex Regional Pain Syndrome.

It has long been thought that severe chronic pain conditions, such as complex regional pain syndrome (CRPS), are not only associated with, but even maintained by a reorganization of the somatotopic representation of the affected limb in primary somatosensory cortex (S1). This notion has driven treatments that aim to restore S1 representations in CRPS patients, such as sensory discrimination training and mirror therapy. However, this notion is based on both indirect and incomplete evidence obtained with imaging methods with low spatial resolution. Here, we used fMRI to characterize the S1 representation of the affected and unaffected hand in humans (of either sex) with unilateral CRPS. The cortical area, location, and geometry of the S1 representation of the CRPS hand were largely comparable with those of both the unaffected hand and healthy controls. We found no differential relation between affected versus unaffected hand map measures and clinical measures (pain severity, upper limb disability, disease duration). Thus, if any map reorganization occurs, it does not appear to be directly related to pain and disease severity. These findings compel us to reconsider the cortical mechanisms underlying CRPS and the rationale for interventions that aim to "restore" somatotopic representations to treat pain.SIGNIFICANCE STATEMENT This study shows that the spatial map of the fingers in somatosensory cortex is largely preserved in chronic complex regional pain syndrome (CRPS). These findings challenge the treatment rationale for restoring somatotopic representations in complex regional pain syndrome patients.

Characterizing the Short-Term Habituation of Event-Related Evoked Potentials.

Fast-rising sensory events evoke a series of functionally heterogeneous event-related potentials (ERPs). Stimulus repetition at 1 Hz induces a strong habituation of the largest ERP responses, the vertex waves (VWs). VWs are elicited by stimuli regardless of their modality, provided that they are salient and behaviorally relevant. In contrast, the effect of stimulus repetition on the earlier sensory components of ERPs has been less explored, and the few existing results are inconsistent. To characterize how the different ERP waves habituate over time, we recorded the responses elicited by 60 identical somatosensory stimuli (activating either non-nociceptive Aß or nociceptive Aδ afferents), delivered at 1 Hz to healthy human participants. We show that the well-described spatiotemporal sequence of lateralized and vertex ERP components elicited by the first stimulus of the series is largely preserved in the smaller-amplitude, habituated response elicited by the last stimuli of the series. We also found that the earlier lateralized sensory wave habituates across the 60 trials following the same decay function of the VWs: this decay function is characterized by a large drop at the first stimulus repetition followed by smaller decreases at subsequent repetitions. Interestingly, the same decay functions described the habituation of ERPs elicited by repeated non-nociceptive and nociceptive stimuli. This study provides a neurophysiological characterization of the effect of prolonged and repeated stimulation on the main components of somatosensory ERPs. It also demonstrates that both lateralized waves and VWs are obligatory components of ERPs elicited by non-nociceptive and nociceptive stimuli.

Perceptual learning to discriminate the intensity and spatial location of nociceptive stimuli.

Accurate discrimination of the intensity and spatial location of nociceptive stimuli is essential to guide appropriate behaviour. The ability to discriminate the attributes of sensory stimuli is continuously refined by practice, even throughout adulthood - a phenomenon called perceptual learning. In the visual domain, perceptual learning to discriminate one of the features that define a visual stimulus (e.g., its orientation) can transfer to a different feature of the same stimulus (e.g., its contrast). Here, we performed two experiments on 48 volunteers to characterize perceptual learning in nociception, which has been rarely studied. We investigated whether learning to discriminate either the intensity or the location of nociceptive stimuli (1) occurs during practice and is subsequently maintained, (2) requires feedback on performance, and (3) transfers to the other, unpractised stimulus feature. First, we found clear evidence that perceptual learning in discriminating both the intensity and the location of nociceptive stimuli occurs, and is maintained for at least 3 hours after practice. Second, learning occurs only when feedback is provided during practice. Finally, learning is largely confined to the feature for which feedback was provided. We discuss these effects in a predictive coding framework, and consider implications for future studies.

Multisensory integration in hemianopia and unilateral spatial neglect: Evidence from the sound induced flash illusion.

Recent neuropsychological evidence suggests that acquired brain lesions can, in some instances, abolish the ability to integrate inputs from different sensory modalities, disrupting multisensory perception. We explored the ability to perceive multisensory events, in particular the integrity of audio-visual processing in the temporal domain, in brain-damaged patients with visual field defects (VFD), or with unilateral spatial neglect (USN), by assessing their sensitivity to the 'Sound-Induced Flash Illusion' (SIFI). The study yielded two key findings. Firstly, the 'fission' illusion (namely, seeing multiple flashes when a single flash is paired with multiple sounds) is reduced in both left- and right-brain-damaged patients with VFD, but not in right-brain-damaged patients with left USN. The disruption of the fission illusion is proportional to the extent of the occipital damage. Secondly, a reliable 'fusion' illusion (namely, seeing less flashes when a single sound is paired with multiple flashes) is evoked in USN patients, but neither in VFD patients nor in healthy participants. A control experiment showed that the fusion, but not the fission, illusion is lost in older participants (>50 year-old), as compared with younger healthy participants (<30 year-old). This evidence indicates that the fission and fusion illusions are dissociable multisensory phenomena, altered differently by impairments of visual perception (i.e. VFD) and spatial attention (i.e. USN). The occipital cortex represents a key cortical site for binding auditory and visual stimuli in the SIFI, while damage to right-hemisphere areas mediating spatial attention and awareness does not prevent the integration of audio-visual inputs in the temporal domain.

Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7.

Loss-of-function mutations in the SCN9A gene encoding voltage-gated sodium channel Nav1.7 cause congenital insensitivity to pain in humans and mice. Surprisingly, many potent selective antagonists of Nav1.7 are weak analgesics. We investigated whether Nav1.7, as well as contributing to electrical signalling, may have additional functions. Here we report that Nav1.7 deletion has profound effects on gene expression, leading to an upregulation of enkephalin precursor Penk mRNA and met-enkephalin protein in sensory neurons. In contrast, Nav1.8-null mutant sensory neurons show no upregulated Penk mRNA expression. Application of the opioid antagonist naloxone potentiates noxious peripheral input into the spinal cord and dramatically reduces analgesia in both female and male Nav1.7-null mutant mice, as well as in a human Nav1.7-null mutant. These data suggest that Nav1.7 channel blockers alone may not replicate the analgesic phenotype of null mutant humans and mice, but may be potentiated with exogenous opioids.

Implicit body representations and tactile spatial remapping.

To perceive the location of a tactile stimulus in external space (external tactile localisation), information about the location of the stimulus on the skin surface (tactile localisation on the skin) must be combined with proprioceptive information about the spatial location of body parts (position sense)--a process often referred to as 'tactile spatial remapping'. Recent research has revealed that both of these component processes rely on highly distorted implicit body representations. For example, on the dorsal hand surface position sense relies on a squat, wide hand representation. In contrast, tactile localisation on the same skin surface shows large biases towards the knuckles. These distortions can be seen as behavioural 'signatures' of these respective perceptual processes. Here, we investigated the role of implicit body representation in tactile spatial remapping by investigating whether the distortions of each of the two component processes (tactile localisation and position sense) also appear when participants localise the external spatial location of touch. Our study reveals strong distortions characteristic of position sense (i.e., overestimation of distances across vs along the hand) in tactile spatial remapping. In contrast, distortions characteristic of tactile localisation on the skin (i.e., biases towards the knuckles) were not apparent in tactile spatial remapping. These results demonstrate that a common implicit hand representation underlies position sense and external tactile localisation. Furthermore, the present findings imply that tactile spatial remapping does not require mapping the same signals in a frame of reference centred on a specific body part.

Poor judgment of distance between nociceptive stimuli.

Although pain is traditionally assumed to be poorly localized, recent work indicates that spatial acuity for nociception is surprisingly high. Here we investigated whether the nervous system can also accurately estimate the distance between two nociceptive stimuli. Estimating distance implies a metric representation of spatial relations, a property that underlies abilities such as perceiving the size of external objects. We presented pairs of simultaneous nociceptive or non-nociceptive somatosensory stimuli, and asked participants to judge the distance between them. Judgments of distance between nociceptive stimuli were much worse than judgments of distance between non-nociceptive tactile stimuli, even on skin regions where spatial acuity for nociception exceeded spatial acuity for touch. Control experiments ruled out explanations based on inaccurate localization of double nociceptive stimuli. Thus, the nervous system poorly represents the distance between two nociceptive stimuli. The dissociation between high spatial acuity and poor distance judgment in the nociceptive system may reflect a specialization for computing accurate spatial representations useful to protect the body, rather than to perceive the size of external objects.

Touch inhibits subcortical and cortical nociceptive responses.

The neural mechanisms of the powerful analgesia induced by touching a painful body part are controversial. A long tradition of neurophysiologic studies in anaesthetized spinal animals indicate that touch can gate nociceptive input at spinal level. In contrast, recent studies in awake humans have suggested that supraspinal mechanisms can be sufficient to drive touch-induced analgesia. To investigate this issue, we evaluated the modulation exerted by touch on established electrophysiologic markers of nociceptive function at both subcortical and cortical levels in humans. Aδ and C skin nociceptors were selectively activated by high-power laser pulses. As markers of subcortical and cortical function, we recorded the laser blink reflex, which is generated by brainstem circuits before the arrival of nociceptive signals at the cortex, and laser-evoked potentials, which reflect neural activity of a wide array of cortical areas. If subcortical nociceptive responses are inhibited by concomitant touch, supraspinal mechanisms alone are unlikely to be sufficient to drive touch-induced analgesia. Touch induced a clear analgesic effect, suppressed the laser blink reflex, and inhibited both Aδ-fibre and C-fibre laser-evoked potentials. Thus, we conclude that touch-induced analgesia is likely to be mediated by a subcortical gating of the ascending nociceptive input, which in turn results in a modulation of cortical responses. Hence, supraspinal mechanisms alone are not sufficient to mediate touch-induced analgesia.

Whole-body mapping of spatial acuity for pain and touch.

OBJECTIVE: Tactile spatial acuity is routinely tested in neurology to assess the state of the dorsal column system. In contrast, spatial acuity for pain is not assessed, having never been systematically characterized. More than a century after the initial description of tactile acuity across the body, we provide the first systematic whole-body mapping of spatial acuity for pain. METHODS: We evaluated the 2-point discrimination thresholds for both nociceptive-selective and tactile stimuli across several skin regions. Thresholds were estimated using pairs of simultaneous stimuli, and also using successive stimuli. RESULTS AND INTERPRETATION: These two approaches produced convergent results. The fingertip was the area of highest spatial acuity, for both pain and touch. On the glabrous skin of the hand, the gradient of spatial acuity for pain followed that observed for touch. On the hairy skin of the upper limb, spatial acuity for pain and touch followed opposite proximal-distal gradients, consistent with the known innervation density of this body territory. Finally, by testing spatial acuity for pain in a rare participant completely lacking Aß fibers, we demonstrate that spatial acuity for pain does not rely on a functioning system of tactile primary afferents. This study represents the first systematic characterization of spatial acuity for pain across multiple regions of the body surface.