A Cortical Mechanism Linking Saliency Detection and Motor Reactivity in Rhesus Monkeys.

Sudden and surprising sensory events trigger neural processes that swiftly adjust behavior. To study the phylogenesis and the mechanism of this phenomenon, we trained two male rhesus monkeys to keep a cursor inside a visual target by exerting force on an isometric joystick. We examined the effect of surprising auditory stimuli on exerted force, scalp electroencephalographic (EEG) activity, and local field potentials (LFPs) recorded from the dorsolateral prefrontal cortex. Auditory stimuli elicited (1) a biphasic modulation of isometric force, a transient decrease followed by a corrective tonic increase, and (2) EEG and LFP deflections dominated by two large negative-positive waves (N70 and P130). The EEG potential was symmetrical and maximal at the scalp vertex, highly reminiscent of the human "vertex potential." Electrocortical potentials and force were tightly coupled: the P130 amplitude predicted the magnitude of the corrective force increase, particularly in the LFPs recorded from deep rather than superficial cortical layers. These results disclose a phylogenetically preserved corticomotor mechanism supporting adaptive behavior in response to salient sensory events.Significance Statement Survival in the natural world depends on an animal's capacity to adapt ongoing behavior to abrupt unexpected events. To study the neural mechanisms underlying this capacity, we trained monkeys to apply constant force on a joystick while we recorded their brain activity from the scalp and the prefrontal cortex contralateral to the hand holding the joystick. Unexpected auditory stimuli elicited a biphasic force modulation: a transient reduction followed by a corrective adjustment. The same stimuli also elicited EEG and LFP responses, dominated by a biphasic wave that predicted the magnitude of the behavioral adjustment. These results disclose a phylogenetically preserved corticomotor mechanism supporting adaptive behavior in response to unexpected events.

Neural processes responsible for the translation of sustained nociceptive inputs into subjective pain experience.

Tracking and predicting the temporal structure of nociceptive inputs is crucial to promote survival, as proper and immediate reactions are necessary to avoid actual or potential bodily injury. Neural activities elicited by nociceptive stimuli with different temporal structures have been described, but the neural processes responsible for translating nociception into pain perception are not fully elucidated. To tap into this issue, we recorded electroencephalographic signals from 48 healthy participants receiving thermo-nociceptive stimuli with 3 different durations and 2 different intensities. We observed that pain perception and several brain responses are modulated by stimulus duration and intensity. Crucially, we identified 2 sustained brain responses that were related to the emergence of painful percepts: a low-frequency component (LFC, < 1 Hz) originated from the insula and anterior cingulate cortex, and an alpha-band event-related desynchronization (α-ERD, 8-13 Hz) generated from the sensorimotor cortex. These 2 sustained brain responses were highly coupled, with the α-oscillation amplitude that fluctuated with the LFC phase. Furthermore, the translation of stimulus duration into pain perception was serially mediated by α-ERD and LFC. The present study reveals how brain responses elicited by nociceptive stimulation reflect the complex processes occurring during the translation of nociceptive information into pain perception.

Spontaneous dyadic behavior predicts the emergence of interpersonal neural synchrony.

Synchronization of neural activity across brains - Interpersonal Neural Synchrony (INS) - is emerging as a powerful marker of social interaction that predicts success of multi-person coordination, communication, and cooperation. As the origins of INS are poorly understood, we tested whether and how INS might emerge from spontaneous dyadic behavior. We recorded neural activity (EEG) and human behavior (full-body kinematics, eye movements, and facial expressions) while dyads of participants were instructed to look at each other without speaking or making co-verbal gestures. We made four fundamental observations. First, despite the absence of a structured social task, INS emerged spontaneously only when participants were able to see each other. Second, we show that such spontaneous INS, comprising specific spectral and topographic profiles, did not merely reflect intra-personal modulations of neural activity, but it rather reflected real-time and dyad-specific coupling of neural activities. Third, using state-of-art video-image processing and deep learning, we extracted the temporal unfolding of three notable social behavioral cues - body movement, eye contact, and smiling - and demonstrated that these behaviors also spontaneously synchronized within dyads. Fourth, we probed the correlates of INS in such synchronized social behaviors. Using cross-correlation and Granger causality analyses, we show that synchronized social behaviors anticipate and in fact Granger cause INS. These results provide proof-of-concept evidence for studying interpersonal neural and behavioral synchrony under natural and unconstrained conditions. Most importantly, the results suggest that INS could be conceptualized as an emergent property of two coupled neural systems: an entrainment phenomenon, promoted by real-time dyadic behavior.

Revisiting a classical theory of sensory specificity: assessing consistency and stability of thermosensitive spots.

Thermal sensitivity is not uniform across the skin, and is particularly high in small (∼1 mm2) regions termed "thermosensitive spots." These spots are thought to reflect the anatomical location of specialized thermosensitive nerve endings from single primary afferents. Thermosensitive spots provide foundational support for "labeled line" or specificity theory of sensory perception, which states that different sensory qualities are transmitted by separate and specific neural pathways. This theory predicts a highly stable relation between repetitions of a thermal stimulus and the resulting sensory quality, yet these predictions have rarely been tested systematically. Here, we present the qualitative, spatial, and repeatability properties of 334 thermosensitive spots on the dorsal forearm sampled across four separate sessions. In line with previous literature, we found that spots associated with cold sensations (112 cold spots, 34%) were more frequent than spots associated with warm sensations (41 warm spots, 12%). Still more frequent (165 spots, 49%) were spots that elicited inconsistent sensations when repeatedly stimulated by the same temperature. Remarkably, only 13 spots (4%) conserved their position between sessions. Overall, we show unexpected inconsistency of both the perceptual responses elicited by spot stimulation and of spot locations across time. These observations suggest reappraisals of the traditional view that thermosensitive spots reflect the location of individual thermosensitive, unimodal primary afferents serving as specific labeled lines for corresponding sensory qualities.NEW & NOTEWORTHY Thermosensitive spots are clustered rather than randomly distributed and have the highest density near the wrist. Surprisingly, we found that thermosensitive spots elicit inconsistent sensory qualities and are unstable over time. Our results question the widely believed notion that thermosensitive spots reflect the location of individual thermoreceptive, unimodal primary afferents that serve as labelled lines for corresponding sensory qualities.

Ultralow-frequency neural entrainment to pain.

Nervous systems exploit regularities in the sensory environment to predict sensory input, adjust behavior, and thereby maximize fitness. Entrainment of neural oscillations allows retaining temporal regularities of sensory information, a prerequisite for prediction. Entrainment has been extensively described at the frequencies of periodic inputs most commonly present in visual and auditory landscapes (e.g., >0.5 Hz). An open question is whether neural entrainment also occurs for regularities at much longer timescales. Here, we exploited the fact that the temporal dynamics of thermal stimuli in natural environment can unfold very slowly. We show that ultralow-frequency neural oscillations preserved a long-lasting trace of sensory information through neural entrainment to periodic thermo-nociceptive input as low as 0.1 Hz. Importantly, revealing the functional significance of this phenomenon, both power and phase of the entrainment predicted individual pain sensitivity. In contrast, periodic auditory input at the same ultralow frequency did not entrain ultralow-frequency oscillations. These results demonstrate that a functionally significant neural entrainment can occur at temporal scales far longer than those commonly explored. The non-supramodal nature of our results suggests that ultralow-frequency entrainment might be tuned to the temporal scale of the statistical regularities characteristic of different sensory modalities.

Feedforward and feedback pathways of nociceptive and tactile processing in human somatosensory system: A study of dynamic causal modeling of fMRI data.

Nociceptive and tactile information is processed in the somatosensory system via reciprocal (i.e., feedforward and feedback) projections between the thalamus, the primary (S1) and secondary (S2) somatosensory cortices. The exact hierarchy of nociceptive and tactile information processing within this 'thalamus-S1-S2' network and whether the processing hierarchy differs between the two somatosensory submodalities remains unclear. In particular, two questions related to the ascending and descending pathways have not been addressed. For the ascending pathways, whether tactile or nociceptive information is processed in parallel (i.e., 'thalamus-S1' and 'thalamus-S2') or in serial (i.e., 'thalamus-S1-S2') remains controversial. For the descending pathways, how corticothalamic feedback regulates nociceptive and tactile processing also remains elusive. Here, we aimed to investigate the hierarchical organization for the processing of nociceptive and tactile information in the 'thalamus-S1-S2' network using dynamic causal modeling (DCM) combined with high-temporal-resolution fMRI. We found that, for both nociceptive and tactile information processing, both S1 and S2 received inputs from thalamus, indicating a parallel structure of ascending pathways for nociceptive and tactile information processing. Furthermore, we observed distinct corticothalamic feedback regulations from S1 and S2, showing that S1 generally exerts inhibitory feedback regulation independent of external stimulation whereas S2 provides additional inhibition to the thalamic activity during nociceptive and tactile information processing in humans. These findings revealed that nociceptive and tactile information processing have similar hierarchical organization within the somatosensory system in the human brain.

Movement vigor: Frameworks, exceptions, and nomenclature.

Shadmehr and Ahmed cogently argue that vigor of appetitive movements is positively correlated with their value, and that value can therefore be inferred by measuring vigor. Here, we highlight three points to consider when interpreting this account: (1) The correlation between vigor and value is not obligatory, (2) the vigor effect also arises in frameworks other than optimal foraging, and (3) the term vigor can be misinterpreted, thereby affecting rigor.

Saliency Detection as a Reactive Process: Unexpected Sensory Events Evoke Corticomuscular Coupling.

Survival in a fast-changing environment requires animals not only to detect unexpected sensory events, but also to react. In humans, these salient sensory events generate large electrocortical responses, which have been traditionally interpreted within the sensory domain. Here we describe a basic physiological mechanism coupling saliency-related cortical responses with motor output. In four experiments conducted on 70 healthy participants, we show that salient substartle sensory stimuli modulate isometric force exertion by human participants, and that this modulation is tightly coupled with electrocortical activity elicited by the same stimuli. We obtained four main results. First, the force modulation follows a complex triphasic pattern consisting of alternating decreases and increases of force, time-locked to stimulus onset. Second, this modulation occurs regardless of the sensory modality of the eliciting stimulus. Third, the magnitude of the force modulation is predicted by the amplitude of the electrocortical activity elicited by the same stimuli. Fourth, both neural and motor effects are not reflexive but depend on contextual factors. Together, these results indicate that sudden environmental stimuli have an immediate effect on motor processing, through a tight corticomuscular coupling. These observations suggest that saliency detection is not merely perceptive but reactive, preparing the animal for subsequent appropriate actions.SIGNIFICANCE STATEMENT Salient events occurring in the environment, regardless of their modalities, elicit large electrical brain responses, dominated by a widespread "vertex" negative-positive potential. This response is the largest synchronization of neural activity that can be recorded from a healthy human being. Current interpretations assume that this vertex potential reflects sensory processes. Contrary to this general assumption, we show that the vertex potential is strongly coupled with a modulation of muscular activity that follows the same pattern. Both the vertex potential and its motor effects are not reflexive but strongly depend on contextual factors. These results reconceptualize the significance of these evoked electrocortical responses, suggesting that saliency detection is not merely perceptive but reactive, preparing the animal for subsequent appropriate actions.

The effect of salient stimuli on neural oscillations, isometric force, and their coupling.

Survival in a suddenly-changing environment requires animals not only to detect salient stimuli, but also to promptly respond to them by initiating or revising ongoing motor processes. We recently discovered that the large vertex brain potentials elicited by sudden supramodal stimuli are strongly coupled with a multiphasic modulation of isometric force, a phenomenon that we named cortico-muscular resonance (CMR). Here, we extend our investigation of the CMR to the time-frequency domain. We show that (i) both somatosensory and auditory stimuli evoke a number of phase-locked and non-phase-locked modulations of EEG spectral power. Remarkably, (ii) some of these phase-locked and non-phase-locked modulations are also present in the Force spectral power. Finally, (iii) EEG and Force time-frequency responses are correlated in two distinct regions of the power spectrum. An early, low-frequency region (∼4 Hz) reflects the previously-described coupling between the phase-locked EEG vertex potential and force modulations. A late, higher-frequency region (beta-band, ∼20 Hz) reflects a second coupling between the non-phase-locked increase of power observed in both EEG and Force. In both time-frequency regions, coupling was maximal over the sensorimotor cortex contralateral to the hand exerting the force, suggesting an effect of the stimuli on the tonic corticospinal drive. Thus, stimulus-induced CMR occurs across at least two different types of cortical activities, whose functional significance in relation to the motor system should be investigated further. We propose that these different types of corticomuscular coupling are important to alter motor behaviour in response to salient environmental events.

No temporal contrast enhancement of simple decreases in noxious heat.

Offset analgesia (OA) studies have found that small decreases in the intensity of a tonic noxious heat stimulus yield a disproportionately large amount of pain relief. In the classic OA paradigm, the decrease in stimulus intensity is preceded by an increase of equal size from an initial noxious level. Although the majority of researchers believe this temporal sequence of two changes is important for eliciting OA, it has also been suggested that the temporal contrast mechanism underlying OA may enhance detection of simple, isolated decreases in noxious heat. To test whether decreases in noxious heat intensity, by themselves, are perceived better than increases of comparable sizes, we used an adaptive two-interval alternative forced choice task to find perceptual thresholds for increases and decreases in radiant and contact heat. Decreases in noxious heat were more difficult to perceive than increases of comparable sizes from the same initial temperature of 45°C. In contrast, decreases and increases were perceived equally well within a common range of noxious temperatures (i.e., when increases started from 45°C and decreases started from 47°C). In another task, participants rated the pain intensity of heat stimuli that randomly and unpredictably increased, decreased, or remained constant. Ratings of unpredictable stimulus decreases also showed no evidence of perceptual enhancement. Our results demonstrate that there is no temporal contrast enhancement of simple, isolated decreases in noxious heat intensity. Combined with previous OA findings, they suggest that long-lasting noxious stimuli that follow an increase-decrease pattern may be important for eliciting the OA effect. NEW & NOTEWORTHY Previous research suggested that a small decrease in noxious heat intensity feels surprisingly large because of sensory enhancement of noxious stimulus offsets (a simplified form of "offset analgesia"). Using a two-alternative forced choice task where participants detected simple increases or decreases in noxious heat, we showed that decreases in noxious heat, by themselves, are no better perceived than increases of comparable sizes. This suggests that a decrease alone is not sufficient to elicit offset analgesia.

The search for pain biomarkers in the human brain.

Non-invasive functional brain imaging is used more than ever to investigate pain in health and disease, with the prospect of finding new means to alleviate pain and improve patient wellbeing. The observation that several brain areas are activated by transient painful stimuli, and that the magnitude of this activity is often graded with pain intensity, has prompted researchers to extract features of brain activity that could serve as biomarkers to measure pain objectively. However, most of the brain responses observed when pain is present can also be observed when pain is absent. For example, similar brain responses can be elicited by salient but non-painful auditory, tactile and visual stimuli, and such responses can even be recorded in patients with congenital analgesia. Thus, as argued in this review, there is still disagreement on the degree to which current measures of brain activity exactly relate to pain. Furthermore, whether more recent analysis techniques can be used to identify distributed patterns of brain activity specific for pain can be only warranted using carefully designed control conditions. On a more general level, the clinical utility of current pain biomarkers derived from human functional neuroimaging appears to be overstated, and evidence for their efficacy in real-life clinical conditions is scarce. Rather than searching for biomarkers of pain perception, several researchers are developing biomarkers to achieve mechanism-based stratification of pain conditions, predict response to medication and offer personalized treatments. Initial results with promising clinical perspectives need to be further tested for replicability and generalizability.

Cognitive gadgets and cognitive priors.

Some of the foundations of Heyes' radical reasoning seem to be based on a fractional selection of available evidence. Using an ethological perspective, we argue against Heyes' rapid dismissal of innate cognitive instincts. Heyes' use of fMRI studies of literacy to claim that culture assembles pieces of mental technology seems an example of incorrect reverse inferences and overlap theories pervasive in cognitive neuroscience.

Alpha and gamma oscillation amplitudes synergistically predict the perception of forthcoming nociceptive stimuli.

Ongoing fluctuations of intrinsic cortical networks determine the dynamic state of the brain, and influence the perception of forthcoming sensory inputs. The functional state of these networks is defined by the amplitude and phase of ongoing oscillations of neuronal populations at different frequencies. The contribution of functionally different cortical networks has yet to be elucidated, and only a clear dependence of sensory perception on prestimulus alpha oscillations has been clearly identified. Here, we combined electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) in a large sample of healthy participants to investigate how ongoing fluctuations in the activity of different cortical networks affect the perception of subsequent nociceptive stimuli. We observed that prestimulus EEG oscillations in the alpha (at bilateral central regions) and gamma (at parietal regions) bands negatively modulated the perception of subsequent stimuli. Combining information about alpha and gamma oscillations predicted subsequent perception significantly more accurately than either measure alone. In a parallel experiment, we found that prestimulus fMRI activity also modulated the perception of subsequent stimuli: perceptual ratings were higher when the BOLD signal was higher in nodes of the sensorimotor network and lower in nodes of the default mode network. Similar to what observed in the EEG data, prediction accuracy was improved when the amplitude of prestimulus BOLD signals in both networks was combined. These findings provide a comprehensive physiological basis to the idea that dynamic changes in brain state determine forthcoming behavioral outcomes. Hum Brain Mapp 37:501-514, 2016. © 2015 Wiley Periodicals, Inc.

Assessment of nonlinear interactions in event-related potentials elicited by stimuli presented at short interstimulus intervals using single-trial data.

The recording of brain event-related potentials (ERPs) is a widely used technique to investigate the neural basis of sensory perception and cognitive processing in humans. Due to the low magnitude of ERPs, averaging of several consecutive stimuli is typically employed to enhance the signal to noise ratio (SNR) before subsequent analysis. However, when the temporal interval between two consecutive stimuli is smaller than the latency of the main ERP peaks, i.e., when the stimuli are presented at a fast rate, overlaps between the corresponding ERPs may occur. These overlaps are usually dealt with by assuming that there is a simple additive superposition between the elicited ERPs and consequently performing algebraic waveform subtractions. Here, we test this assumption rigorously by providing a statistical framework that examines the presence of nonlinear additive effects between overlapping ERPs elicited by successive stimuli with short interstimulus intervals (ISIs). The results suggest that there are no nonlinear additive effects due to the time overlap per se but that, for the range of ISIs examined, the second ERP is modulated by the presence of the first stimulus irrespective of whether there is time overlap or not. In other words, two ERPs that overlap in time can still be written as an addition of two ERPs but with the second ERP being different from the first. This difference is also present in the case of nonoverlapping ERPs with short ISIs. The modulation effect elicited on the second ERP by the first stimulus is dependent on the ISI value.

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.

Caloric vestibular stimulation modulates nociceptive evoked potentials.

Vestibular stimulation has been reported to alleviate central pain. Clinical and physiological studies confirm pervasive interactions between vestibular signals and somatosensory circuits, including nociception. However, the neural mechanisms underlying vestibular-induced analgesia remain unclear, and previous clinical studies cannot rule out explanations based on alternative, non-specific effects such as distraction or placebo. To investigate how vestibular inputs influence nociception, we combined caloric vestibular stimulation (CVS) with psychophysical and electrocortical responses elicited by nociceptive-specific laser stimulation in humans (laser-evoked potentials, LEPs). Cold water CVS applied to the left ear resulted in significantly lower subjective pain intensity for experimental laser pain to the left hand immediately after CVS, relative both to before CVS and to 1 h after CVS. This transient reduction in pain perception was associated with reduced amplitude of all LEP components, including the early N1 wave reflecting the first arrival of nociceptive input to primary somatosensory cortex. We conclude that cold left ear CVS elicits a modulation of both nociceptive processing and pain perception. The analgesic effect induced by CVS could be mediated either by subcortical gating of the ascending nociceptive input, or by direct modulation of the primary somatosensory cortex.

Better safe than sorry? The safety margin surrounding the body is increased by anxiety.

The defensive peripersonal space represents a "safety margin" advantageous for survival. Its spatial extension and the possible relationship with personality traits have never been investigated. Here, in a population of 15 healthy human participants, we show that the defensive peripersonal space has a sharp boundary, located between 20 and 40 cm from the face, and that within such space there is a thin, "highest-risk area" closest to the face (i.e., an "ultra-near" defensive space). Single-subject analysis revealed clear interindividual differences in the extension of such peripersonal space. These differences are positively related to individual variability in trait anxiety. These findings point to the potential for measuring a range of defensive behaviors in relation to individual levels of anxiety. Such measures will allow developing procedures to test risk assessment abilities, particularly in professions that require reacting quickly to aversive stimuli near the body, such as firemen, policemen, and military officers. This may also lead to possible interventions to improve their performance under pressure.

The blink reflex and its modulation - Part 1: Physiological mechanisms.

The blink reflex (BR) is a protective eye-closure reflex mediated by brainstem circuits. The BR is usually evoked by electrical supraorbital nerve stimulation but can be elicited by a variety of sensory modalities. It has a long history in clinical neurophysiology practice. Less is known, however, about the many ways to modulate the BR. Various neurophysiological techniques can be applied to examine different aspects of afferent and efferent BR modulation. In this line, classical conditioning, prepulse and paired-pulse stimulation, and BR elicitation by self-stimulation may serve to investigate various aspects of brainstem connectivity. The BR may be used as a tool to quantify top-down modulation based on implicit assessment of the value of blinking in a given situation, e.g., depending on changes in stimulus location and probability of occurrence. Understanding the role of non-nociceptive and nociceptive fibers in eliciting a BR is important to get insight into the underlying neural circuitry. Finally, the use of BRs and other brainstem reflexes under general anesthesia may help to advance our knowledge of the brainstem in areas not amenable in awake intact humans. This review summarizes talks held by the Brainstem Special Interest Group of the International Federation of Clinical Neurophysiology at the International Congress of Clinical Neurophysiology 2022 in Geneva, Switzerland, and provides a state-of-the-art overview of the physiology of BR modulation. Understanding the principles of BR modulation is fundamental for a valid and thoughtful clinical application (reviewed in part 2) (Gunduz et al., submitted).