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.

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.

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.

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.

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.

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.

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.

Statistical learning shapes pain perception and prediction independently of external cues.

The placebo and nocebo effects highlight the importance of expectations in modulating pain perception, but in everyday life we don't need an external source of information to form expectations about pain. The brain can learn to predict pain in a more fundamental way, simply by experiencing fluctuating, non-random streams of noxious inputs, and extracting their temporal regularities. This process is called statistical learning. Here, we address a key open question: does statistical learning modulate pain perception? We asked 27 participants to both rate and predict pain intensity levels in sequences of fluctuating heat pain. Using a computational approach, we show that probabilistic expectations and confidence were used to weigh pain perception and prediction. As such, this study goes beyond well-established conditioning paradigms associating non-pain cues with pain outcomes, and shows that statistical learning itself shapes pain experience. This finding opens a new path of research into the brain mechanisms of pain regulation, with relevance to chronic pain where it may be dysfunctional.

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.

Linking pain and the body: neural correlates of visually induced analgesia.

The visual context of seeing the body can reduce the experience of acute pain, producing a multisensory analgesia. Here we investigated the neural correlates of this "visually induced analgesia" using fMRI. We induced acute pain with an infrared laser while human participants looked either at their stimulated right hand or at another object. Behavioral results confirmed the expected analgesic effect of seeing the body, while fMRI results revealed an associated reduction of laser-induced activity in ipsilateral primary somatosensory cortex (SI) and contralateral operculoinsular cortex during the visual context of seeing the body. We further identified two known cortical networks activated by sensory stimulation: (1) a set of brain areas consistently activated by painful stimuli (the so-called "pain matrix"), and (2) an extensive set of posterior brain areas activated by the visual perception of the body ("visual body network"). Connectivity analyses via psychophysiological interactions revealed that the visual context of seeing the body increased effective connectivity (i.e., functional coupling) between posterior parietal nodes of the visual body network and the purported pain matrix. Increased connectivity with these posterior parietal nodes was seen for several pain-related regions, including somatosensory area SII, anterior and posterior insula, and anterior cingulate cortex. These findings suggest that visually induced analgesia does not involve an overall reduction of the cortical response elicited by laser stimulation, but is consequent to the interplay between the brain's pain network and a posterior network for body perception, resulting in modulation of the experience of pain.

Fine-grained nociceptive maps in primary somatosensory cortex.

Topographic maps of the receptive surface are a fundamental feature of neural organization in many sensory systems. While touch is finely mapped in the cerebral cortex, it remains controversial how precise any cortical nociceptive map may be. Given that nociceptive innervation density is relatively low on distal skin regions such as the digits, one might conclude that the nociceptive system lacks fine representation of these regions. Indeed, only gross spatial organization of nociceptive maps has been reported so far. However, here we reveal the existence of fine-grained somatotopy for nociceptive inputs to the digits in human primary somatosensory cortex (SI). Using painful nociceptive-selective laser stimuli to the hand, and phase-encoded functional magnetic resonance imaging analysis methods, we observed somatotopic maps of the digits in contralateral SI. These nociceptive maps were highly aligned with maps of non-painful tactile stimuli, suggesting comparable cortical representations for, and possible interactions between, mechanoreceptive and nociceptive signals. Our findings may also be valuable for future studies tracking the time course and the spatial pattern of plastic changes in cortical organization involved in chronic pain.

Changes in cortical oscillations linked to multisensory modulation of nociception.

Pain can be modulated by several contextual factors. For example, simply viewing one's own body can reduce pain, suggesting that the visual context may influence the processing of nociceptive stimuli. We studied changes in electroencephalographic (EEG) oscillatory activity related to visual modulation of nociception, comparing cortical oscillations during innocuous or noxious contact heat, while participants viewed either their own hand or a neutral object at the same location. Viewing the body compared with viewing the object reduced the intensity ratings of noxious stimuli, but not of innocuous heat. Time-frequency analysis of EEG data revealed that noxious, as opposed to warm, stimulation was associated with reduced beta (15-25 Hz) power. Classically, such decreases in oscillatory power indicate increases in sensory cortical activation. These event-related oscillatory changes were moreover modulated by the visual context; viewing one's own body increased noxious stimulation-induced beta oscillatory activity bilaterally, relative to viewing a neutral object, possibly indicating inhibition of cortical nociceptive processing. These results demonstrate that visual-nociceptive interactions involve changes in sensorimotor EEG rhythms.

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.

tDCS modulation of visually induced analgesia.

Multisensory interactions can produce analgesic effects. In particular, viewing one's own body reduces pain levels, perhaps because of changes in connectivity between visual areas specialized for body representation, and sensory areas underlying pain perception. We tested the causal role of the extrastriate visual cortex in triggering visually induced analgesia by modulating the excitability of this region with transcranial direct current stimulation (tDCS). Anodal, cathodal, or sham tDCS (2 mA, 10 min) was administered to 24 healthy participants over the right occipital or over the centro-parietal areas thought to be involved in the sensory processing of pain. Participants were required to rate the intensity of painful electrical stimuli while viewing either their left hand or an object occluding the left hand, both before and immediately after tDCS. We found that the analgesic effect of viewing the body was enhanced selectively by anodal stimulation of the occipital cortex. The effect was specific for the polarity and the site of stimulation. The present results indicate that visually induced analgesia may depend on neural signals from the extrastriate visual cortex.

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.

Cross-modal processing in the occipito-temporal cortex: a TMS study of the Müller-Lyer illusion.

The Müller-Lyer illusion occurs both in vision and in touch, and transfers cross-modally from vision to haptics [Mancini, F., Bricolo, E., & Vallar, G. Multisensory integration in the Müller-Lyer illusion: From vision to haptics. Quarterly Journal of Experimental Psychology, 63, 818-830, 2010]. Recent evidence suggests that the neural underpinnings of the Müller-Lyer illusion in the visual modality involve the bilateral lateral occipital complex (LOC) and right superior parietal cortex (SPC). Conversely, the neural correlates of the haptic and cross-modal illusions have never been investigated previously. Here we used repetitive TMS (rTMS) to address the causal role of the regions activated by the visual illusion in the generation of the visual, haptic, and cross-modal visuo-haptic illusory effects, investigating putative modality-specific versus cross-modal underlying processes. rTMS was administered to the right and the left hemisphere, over occipito-temporal cortex or SPC. rTMS over left and right occipito-temporal cortex impaired both unisensory (visual, haptic) and cross-modal processing of the illusion in a similar fashion. Conversely, rTMS interference over left and right SPC did not affect the illusion in any modality. These results demonstrate the causal involvement of bilateral occipito-temporal cortex in the representation of the visual, haptic, and cross-modal Müller-Lyer illusion, in favor of the hypothesis of shared underlying processes. This indicates that occipito-temporal cortex plays a cross-modal role in perception both of illusory and nonillusory shapes.

Visual distortion of body size modulates pain perception.

Pain is a complex subjective experience that is shaped by numerous contextual factors. For example, simply viewing the body reduces the reported intensity of acute physical pain. In this study, we investigated whether this visually induced analgesia is modulated by the visual size of the stimulated body part. We measured contact heat-pain thresholds while participants viewed either their own hand or a neutral object in three size conditions: reduced, actual size, or enlarged. Vision of the body was analgesic, increasing heat-pain thresholds by an average of 3.2 °C. We further found that visual enlargement of the viewed hand enhanced analgesia, whereas visual reduction of the hand decreased analgesia. These results demonstrate that pain perception depends on multisensory representations of the body and that visual distortions of body size modulate sensory components of pain.

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.

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.