The pain matrix reloaded: a salience detection system for the body

Neuroimaging and neurophysiological studies have shown that nociceptive stimuli elia salience detection system for the bodycit responses in an extensive cortical network including somatosensory, insular and cingulate areas, as well as frontal and parietal areas. This network, often referred to as the "pain matrix", is viewed as representing the activity by which the intensity and unpleasantness of the perception elicited by a nociceptive stimulus are represented. However, recent experiments have reported (i) that pain intensity can be dissociated from the magnitude of responses in the "pain matrix", (ii) that the responses in the "pain matrix" are strongly influenced by the context within which the nociceptive stimuli appear, and (iii) that non-nociceptive stimuli can elicit cortical responses with a spatial configuration similar to that of the "pain matrix". For these reasons, we propose an alternative view of the functional significance of this cortical network, in which it reflects a system involved in detecting, orienting attention towards, and reacting to the occurrence of salient sensory events. This cortical network might represent a basic mechanism through which significant events for the body's integrity are detected, regardless of the sensory channel through which these events are conveyed. This function would involve the construction of a multimodal cortical representation of the body and nearby space. Under the assumption that this network acts as a defensive system signaling potentially damaging threats for the body, emphasis is no longer on the quality of the sensation elicited by noxious stimuli but on the action prompted by the occurrence of potential threats

Transcranial magnetic stimulation over human secondary somatosensory cortex disrupts perception of pain intensity

AbstractPain is a complex sensory experience resulting from the activity of a network of brain regions. However, the functional contribution of individual regions in this network remains poorly understood. We delivered single-pulse transcranial magnetic stimulation (TMS) to the contralateral primary somatosensory cortex (S1), secondary somatosensory cortex (S2) and vertex (control site) 120 msec after selective stimulation of nociceptive afferents using neodymium:yttrium–aluminium–perovskite (Nd:YAP) laser pulses causing painful sensations. Participants were required to judge either the intensity (medium/high) or the spatial location (proximal/distal) of the stimulus in a two-alternative forced choice paradigm. When TMS pulses were delivered over S2, participants' ability to judge pain intensity was disrupted, as compared to S1 and vertex (control) stimulation. Signal-detection analysis demonstrated a loss of sensitivity to stimulation intensity, rather than a shift in perceived pain level or response bias. We did not find any effect of TMS on the ability to localise nociceptive stimuli on the skin. The novel finding that TMS over S2 can disrupt perception of pain intensity suggests a causal role for S2 in encoding of pain intensity

The “pain matrix” in pain-free individuals

Human functional imaging provides a correlative picture of brain activity during pain. A particular set of central nervous system structures (eg, the anterior cingulate cortex, thalamus, and insula) consistently respond to transient nociceptive stimuli causing pain. Activation of this so-called pain matrix or pain signature has been related to perceived pain intensity, both within and between individuals,1,2 and is now considered a candidate biomarker for pain in medicolegal settings and a tool for drug discovery. The pain-specific interpretation of such functional magnetic resonance imaging (fMRI) responses, although logically flawed,3,4 remains pervasive. For example, a 2015 review states that “the most likely interpretation of activity in the pain matrix seems to be pain.”4 Demonstrating the nonspecificity of the pain matrix requires ruling out the presence of pain when highly salient sensory stimuli are presented. In this study, we administered noxious mechanical stimuli to individuals with congenital insensitivity to pain and sampled their brain activity with fMRI. Loss-of-function SCN9A mutations in these individuals abolishes sensory neuron sodium channel Nav1.7 activity, resulting in pain insensitivity through an impaired peripheral drive that leaves tactile percepts fully intact.5 This allows complete experimental disambiguation of sensory responses and painful sensation

A novel method to selectively elicit cold sensations without touch

BACKGROUND: Thermal and tactile stimuli are transduced by different receptor classes. However, mechano- and thermo-sensitive afferents interact at spinal and supraspinal levels. Yet, most studies on responses to cooling stimuli are confounded by mechanical contact, making these interactions difficult to isolate. Methods for precise control of non-mechanical thermal stimulations remain challenging, particularly in the cold range. NEW METHOD: We developed a non-tactile, focal, temperature-controlled, multi-purpose cooling stimulator. This method controls the exposure of a target skin region to a dry-ice source. Using a thermal camera to monitor skin temperature, and adjusting the source-skin distance accordingly, we could deliver non-tactile cooling stimuli with customisable profiles, for studying different aspects of cold sensation. RESULTS: To validate our method, we measured absolute and relative thresholds for cold sensation without mechanical contact in 13 human volunteer participants, using the method of limits. We found that the absolute cold detection threshold was 32.71oC ± 0.88oC. This corresponded to a threshold relative to each participant's baseline skin temperature of -1.08oC ± 0.37oC. COMPARISONS WITH EXISTING METHOD: Our method allows cooling stimulation without the confound of mechanical contact, in a controllable and focal manner. CONCLUSIONS: We report a non-contact cooling stimulator and accompanying control system. We used this to measure cold thresholds in the absence of confounding touch. Our method enables more targeted studies of both cold sensory pathways, and of cold-touch interactions

Evidence against pain specificity in the dorsal posterior insula

The search for a pain centre in the brain has long eluded neuroscientists. Although many regions of the brain have been shown to respond to painful stimuli, all of these regions also respond to other types of salient stimuli. In a recent paper, Segerdahl et al. (Nature Neuroscience, 2015) claims that the dorsal posterior insula (dpIns) is a pain-specific region based on the observation that the magnitude of regional cerebral blood flow (rCBF) fluctuations in the dpIns correlated with the magnitude of evoked pain. However, such a conclusion is, simply, not justified by the experimental evidence provided. Here we discuss three major factors that seriously question this claim

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

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. While 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

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 (LFP) recorded from the dorso-lateral 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 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 cortico-motor 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 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, invasively, from 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 cortico-motor mechanism supporting adaptive behavior in response to unexpected events

A supramodal representation of the body surface

The ability to accurately localize both tactile and painful sensations on the body is one of the most important functions of the somatosensory system. Most accounts of localization refer to the systematic spatial relation between skin receptors and cortical neurons. The topographic organization of somatosensory neurons in the brain provides a map of the sensory surface. However, systematic distortions in perceptual localization tasks suggest that localizing a somatosensory stimulus involves more than simply identifying specific active neural populations within a somatotopic map. Thus, perceptual localization may depend on both afferent inputs and other unknown factors. In four experiments, we investigated whether localization biases vary according to the specific skin regions and subset of afferent fibers stimulated. We represented localization errors as a ‘perceptual map’ of skin locations. We compared the perceptual maps of stimuli that activate Aβ (innocuous touch), Aδ (pinprick pain), and C fibers (non-painful heat) on both the hairy and glabrous skin of the left hand. Perceptual maps exhibited systematic distortions that strongly depended on the skin region stimulated. We found systematic distal and radial (i.e., towards the thumb) biases in localization of touch, pain, and heat on the hand dorsum. A less consistent proximal bias was found on the palm. These distortions were independent of the population of afferent fibers stimulated, and also independent of the response modality used to report localization. We argue that these biases are likely to have a central origin, and result from a supramodal representation of the body surface

The balance of feelings: vestibular modulation of bodily sensations.

The vestibular system processes information about head movement and orientation. No unimodal vestibular cortex has been identified in the mammalian brain. Rather, vestibular inputs are combined with many other sensory signals in the cortex. This arrangement suggests that vestibular input could influence processing in other sensory modalities. Here we show that vestibular stimulation differentially modulates two submodalities of the somatosensory system, increasing sensitivity to tactile input, and independently reducing sensitivity to nociceptive input. These modulations of touch and pain can clearly be distinguished from supramodal attentional effects of vestibular stimulation, because they are bilateral and operate in different directions. Outside the artificial conditions of laboratory stimulation, the vestibular system codes movements of the head, indicating a new relation between the body and the external world. We suggest the vestibular system participates in a form of sensory signal management, changing the balance between the various sensory systems as the relation between the body and the external environment changes. This sensory rebalancing may be a crucial element in the brain's capacity to reorient towards novel or salient features in the environment