Conscious Pain Perception Research Articles

Fractal Similarity of Pain Brain Networks.

The conscious perception of pain is the result of dynamic interactions of neural activities from local brain regions to distributed brain networks. Mapping out the networks of functional connections between brain regions that form and disperse when an experimental participant received nociceptive stimulations allow to characterize the pattern of network connections related to the pain experience.Although the pattern of intra- and inter-areal connections across the brain are incredibly complex, they appear also largely scale free, with "fractal" connectivity properties reproducing at short and long-time scales. Our results combining intracranial recordings and functional imaging in humans during pain indicate striking similarities in the activity and topological representation of networks at different orders of temporality, with reproduction of patterns of activation from the millisecond to the multisecond range. The connectivity analyzed using graph theory on fMRI data was organized in four sets of brain regions matching those identified through iEEG (i.e., sensorimotor, default mode, central executive, and amygdalo-hippocampal).Here, we discuss similarities in brain network organization at different scales or "orders," in participants as they feel pain. Description of this fractal-like organization may provide clues about how our brain regions work together to create the perception of pain and how pain becomes chronic when its organization is altered.

The fetal pain paradox.

Controversy exists as to when conscious pain perception in the fetus may begin. According to the hypothesis of cortical necessity, thalamocortical connections, which do not form until after 24-28 weeks gestation, are necessary for conscious pain perception. However, anesthesiologists and neonatologists treat age-matched neonates as both conscious and pain-capable due to observable and measurable behavioral, hormonal, and physiologic indicators of pain. In preterm infants, these multimodal indicators of pain are uncontroversial, and their presence, despite occurring prior to functional thalamocortical connections, has guided the use of analgesics in neonatology and fetal surgery for decades. However, some medical groups state that below 24 weeks gestation, there is no pain capacity. Thus, a paradox exists in the disparate acknowledgment of pain capability in overlapping patient populations. Brain networks vary by age. During the first and second trimesters, the cortical subplate, a unique structure that is present only during fetal and early neonatal development, forms the first cortical network. In the third trimester, the cortical plate assumes this function. According to the subplate modulation hypothesis, a network of connections to the subplate and subcortical structures is sufficient to facilitate conscious pain perception in the fetus and the preterm neonate prior to 24 weeks gestation. Therefore, similar to other fetal and neonatal systems that have a transitional phase (i.e., circulatory system), there is now strong evidence for transitional developmental phases of fetal and neonatal pain circuitry.

Parallel Spinal Pathways for Transmitting Reflexive and Affective Dimensions of Nocifensive Behaviors Evoked by Selective Activation of the Mas-Related G Protein-Coupled Receptor D-Positive and Transient Receptor Potential Vanilloid 1-Positive Subsets of Nociceptors

The high incidence of treatment-resistant pain calls for the urgent preclinical translation of new analgesics. Understanding the behavioral readout of pain in animals is crucial for efficacy evaluation when developing novel analgesics. Mas-related G protein-coupled receptor D-positive (Mrgprd+) and transient receptor potential vanilloid 1-positive (TRPV1+) sensory neurons are two major non-overlapping subpopulations of C-fiber nociceptors. Their activation has been reported to provoke diverse nocifensive behaviors. However, what kind of behavior reliably represents subjectively conscious pain perception needs to be revisited. Here, we generated transgenic mice in which Mrgprd+ or TRPV1+ sensory neurons specifically express channelrhodopsin-2 (ChR2). Under physiological conditions, optogenetic activation of hindpaw Mrgprd+ afferents evoked reflexive behaviors (lifting, etc.), but failed to produce aversion. In contrast, TRPV1+ afferents activation evoked marked reflexive behaviors and affective responses (licking, etc.), as well as robust aversion. Under neuropathic pain conditions induced by spared nerve injury (SNI), affective behaviors and avoidance can be elicited by Mrgprd+ afferents excitation. Mechanistically, spinal cord-lateral parabrachial nucleus (lPBN) projecting neurons in superficial layers (lamina I–IIo) were activated by TRPV1+ nociceptors in naïve conditions or by Mrgprd+ nociceptors after SNI, whereas only deep spinal cord neurons were activated by Mrgprd+ nociceptors in naïve conditions. Moreover, the excitatory inputs from Mrgprd+ afferents to neurons within inner lamina II (IIi) are partially gated under normal conditions. Altogether, we conclude that optogenetic activation of the adult Mrgprd+ nociceptors drives non-pain-like reflexive behaviors via the deep spinal cord pathway under physiological conditions and drives pain-like affective behaviors via superficial spinal cord pathway under pathological conditions. The distinct spinal pathway transmitting different forms of nocifensive behaviors provides different therapeutic targets. Moreover, this study appeals to the rational evaluation of preclinical analgesic efficacy by using comprehensive and suitable behavioral assays, as well as by assessing neural activity in the two distinct pathways.

The α2/α3GABAA receptor modulator TPA023B alleviates not only the sensory but also the tonic affective component of chronic pain in mice.

Diminished synaptic inhibition in the spinal dorsal horn is a major contributor to pathological pain syndromes of neuropathic or inflammatory origin. Drugs that enhance the activity of dorsal horn α2/α3GABAARs normalize exaggerated nociceptive responses in rodents with neuropathic nerve lesions or peripheral inflammation but lack most of the typical side effects of less specific GABAergic drugs. It is however still unknown whether such drugs also reduce the clinically more relevant conscious perception of pain. Here, we investigated the effects of the α2/α3GABAAR subtype-selective modulator TPA023B on the tonic aversive component of pain in mice with peripheral inflammation or neuropathy. In neuropathic mice with a chronic constriction injury of the sciatic nerve, TPA023B not only reversed hyperalgesia to tactile and heat stimuli but also was highly effective in the conditioned place preference test. In the formalin test, TPA023B not only reduced licking of the injected paw but also reversed facial pain expression scores in the mouse grimace scale assay. Taken together, our results demonstrate that α2/α3GABAA receptor subtype-selective modulators not only reduce nociceptive withdrawal responses but also alleviate the tonic aversive components of chronic pain.

The Modular Organization of Pain Brain Networks: An fMRI Graph Analysis Informed by Intracranial EEG.

Intracranial EEG (iEEG) studies have suggested that the conscious perception of pain builds up from successive contributions of brain networks in less than 1 s. However, the functional organization of cortico-subcortical connections at the multisecond time scale, and its accordance with iEEG models, remains unknown. Here, we used graph theory with modular analysis of fMRI data from 60 healthy participants experiencing noxious heat stimuli, of whom 36 also received audio stimulation. Brain connectivity during pain was organized in four modules matching those identified through iEEG, namely: 1) sensorimotor (SM), 2) medial fronto-cingulo-parietal (default mode-like), 3) posterior parietal-latero-frontal (central executive-like), and 4) amygdalo-hippocampal (limbic). Intrinsic overlaps existed between the pain and audio conditions in high-order areas, but also pain-specific higher small-worldness and connectivity within the sensorimotor module. Neocortical modules were interrelated via “connector hubs” in dorsolateral frontal, posterior parietal, and anterior insular cortices, the antero-insular connector being most predominant during pain. These findings provide a mechanistic picture of the brain networks architecture and support fractal-like similarities between the micro-and macrotemporal dynamics associated with pain. The anterior insula appears to play an essential role in information integration, possibly by determining priorities for the processing of information and subsequent entrance into other points of the brain connectome.

Evaluation of euthanasia of sheep with intravenous saturated salt solutions to enable the collection of whole, intact brains

Abstract Captive bolts or firearms are unsuitable for euthanasia of livestock when an intact brain is required for diagnostics. Injectable barbiturates can be used, but this method carries risk of poisoning animals eating the carcase. Intravenous saturated salt solutions have been used to euthanase heavily sedated ruminants and are cheap, readily available and not a risk to scavenging animals. However, there is concern that they may be painful or cause distress to animals that are not unconscious. This study aimed to determine the suitability of saturated salt solutions, in combination with xylazine, as a method of euthanasia of ruminants using a sheep model. Thirty-two sheep were sedated with xylazine (0.4 mg kg-1 IM) and euthanased with an intravenous overdose of pentobarbitone (PENT; n = 10), saturated potassium chloride (KCL; n = 11) or saturated magnesium sulphate (MGS; n = 10). Time until end of rhythmic breathing and cardiac arrest, and movement events were recorded. Conscious perception of pain was evaluated by measuring cortical brain activity by electroencephalography (EEG). There was no evidence of perceived pain or unpleasant sensory experience for any treatment as indicated by P50, P95 and Ptot and so all methods were deemed humane. Time until transient EEG was comparable for all treatments. Time until onset of isoelectric EEG was prolonged for KCL. Animals euthanased with KCL consistently exhibited severe reflex movements during infusion (eg kicking, convulsion). No severe movement events were observed in animals euthanased with MGS, hence, physiological and movement data support the preferential use of MGS over KCL.

Voltage gated sodium channels as therapeutic targets for chronic pain.

Being maladaptive and frequently unresponsive to pharmacotherapy, chronic pain presents a major unmet clinical need. While an intact central nervous system is required for conscious pain perception, nociceptor hyperexcitability induced by nerve injury in the peripheral nervous system (PNS) is sufficient and necessary to initiate and maintain neuropathic pain. The genesis and propagation of action potentials is dependent on voltage-gated sodium channels, in particular, Nav1.7, Nav1.8 and Nav1.9. However, nerve injury triggers changes in their distribution, expression and/or biophysical properties, leading to aberrant excitability. Most existing treatment for pain relief acts through non-selective, state-dependent sodium channel blockage and have narrow therapeutic windows. Natural toxins and developing subtype-specific and molecular-specific sodium channel blockers show promise for treatment of neuropathic pain with minimal side effects. New approaches to analgesia include combination therapy and gene therapy. Here, we review how individual sodium channel subtypes contribute to pain, and the attempts made to develop more effective analgesics for the treatment of chronic pain.

A Brainstem-Spinal Circuit Controlling Nocifensive Behavior

Response to danger needs to be rapid and appropriate. In humans, nocifensive behaviors often precede conscious pain perception. Much is known about local spinal cord circuits for simple reflexive responses, but the mechanisms underlying more complex behaviors remain poorly understood. We now describe a brainstem circuit that controls escape responses to select noxious stimuli. Tracing experiments characterized a highly interconnected excitatory circuit involving the dorsal spinal cord, parabrachial nucleus (PBNl), and reticular formation (MdD). Acombination of chemogenetic, optogenetic, and genetic ablation approaches revealed that PBNlTac1 neurons are activated by noxious stimuli and trigger robust escape responses to heat through connections to the MdD. Remarkably, MdDTac1 neurons receive excitatory input from the PBN and target both the spinal cord and PBN; activation of these neurons phenocopies the behavioral effects of PBNlTac1 neuron stimulation. These findings identify a substrate for controlling appropriate behavioral responses to painful stimuli.

Effects of Subanesthetic Ketamine Administration on Visual and Auditory Event-Related Potentials (ERP) in Humans: A Systematic Review.

Ketamine is a non-competitive N-Methyl-D-Aspartate (NMDA) receptor antagonist whose effect in subanesthetic doses has been studied for chronic pain and mood disorders treatment. It has been proposed that ketamine could change the perception of nociceptive stimuli by modulating the cortical connectivity and altering the top-down mechanisms that control conscious pain perception. As this is a strictly central effect, it would be relevant to provide fresh insight into ketamine's effect on cortical response to external stimuli. Event-related potentials (ERPs) reflect the combined synchronic activity of postsynaptic potentials of many cortical pyramidal neurons similarly oriented, being a well-established technique to study cortical responses to sensory input. Therefore, the aim of this study was to examine the current evidence of subanesthetic ketamine doses on patterns of cortical activity based on ERPs in healthy subjects. To answer the question whether ERPs could be potential markers of the cortical effects of ketamine, we conducted a systematic review of ketamine's effect on ERPs after single and repeated doses. We have searched PubMed, EMBASE and Cochrane Databases and pre-selected 141 articles, 18 of which met the inclusion criteria. Our findings suggest that after ketamine administration some ERP parameters are reduced (reduced N2, P2, and P3 amplitudes, PN and MMN) while others remain stable or are even increased (P50 reduction, PPI, P1, and N1 amplitudes). The current understanding of these effects is that ketamine alters the perceived contrast between distinct visual and auditory stimuli. The analgesic effect of ketamine might also be influenced by a decreased affective discrimination of sensorial information, a finding from studies using ketamine as a model for schizophrenia, but that can give an important hint not only for the treatment of mood disorders, but also to treat pain and ketamine abuse.

Prognostic Factors Associated with Recovery of Ambulation and Urinary Continence in Dogs with Acute Lumbosacral Spinal Cord Injury.

BackgroundLimited information is available about prognostic factors for recovery after spinal cord injury (SCI) to the L4‐S3 segments. Previous research suggests that L4‐S3 SCI does not have a worse prognosis than T3‐L3 SCI.Hypothesis/ObjectivesTo elucidate prognostic factors for regaining urinary continence and ambulation in dogs with L4‐S3 SCI and compare prognosis to T3‐L3 SCI.Animals/MethodsA retrospective study on 61 nonambulatory dogs with L4‐S3 SCI, matched to dogs with T3‐L3 SCI, compared 3 weeks after onset. Prognostic factors explored using logistic regression and used for matching: nonchondrodystrophic dogs >15 kg versus dogs that were chondrodystrophic or <15 kg; compressive versus noncompressive lesions; presence versus absence of conscious pain perception (CPP); and lower vs upper motor neuron (LMN/UMN) incontinence.ResultsFewer L4‐S3 dogs regained continence compared to T3‐L3 dogs (64 vs 85%, P = .0033), but no difference existed for regaining ambulation (66 vs 75%, P = .1306). In L4‐S3 SCI dogs, fewer dogs regained continence with loss of CPP (P < .001), LMN incontinence (P = .004), and noncompressive lesions (P = .006). Negative prognostic factors for regaining ambulation included absent CPP (P < .001) and large nonchondrodystrophic breed (P = .022).Conclusions and Clinical ImportanceDogs with L4‐S3 SCI have a poorer short‐term prognosis than do dogs with T3‐L3 SCI. Dogs with L4‐S3 SCI had a poor prognosis with loss of CPP, or noncompressive lesions combined with LMN incontinence. Small‐breed or chondrodystrophic dogs with retained CPP, compressive lesions, and UMN incontinence had an excellent prognosis. These findings may help guide decision‐making in L4‐S3 SCI.

Affective touch and attachment style modulate pain: a laser-evoked potentials study.

Affective touch and cutaneous pain are two sub-modalities of interoception with contrasting affective qualities (pleasantness/unpleasantness) and social meanings (care/harm), yet their direct relationship has not been investigated. In 50 women, taking into account individual attachment styles, we assessed the role of affective touch and particularly the contribution of the C tactile (CT) system in subjective and electrophysiological responses to noxious skin stimulation, namely N1 and N2-P2 laser-evoked potentials. When pleasant, slow (versus fast) velocity touch was administered to the (non-CT-containing) palm of the hand, higher attachment anxiety predicted increased subjective pain ratings, in the same direction as changes in N2 amplitude. By contrast, when pleasant touch was administered to CT-containing skin of the arm, higher attachment anxiety predicted attenuated N1 and N2 amplitudes. Higher attachment avoidance predicted opposite results. Thus, CT-based affective touch can modulate pain in early and late processing stages (N1 and N2 components), with the direction of effects depending on attachment style. Affective touch not involving the CT system seems to affect predominately the conscious perception of pain, possibly reflecting socio-cognitive factors further up the neurocognitive hierarchy. Affective touch may thus convey information about available social resources and gate pain responses depending on individual expectations of social support.This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’.

Pain networks from the inside: Spatiotemporal analysis of brain responses leading from nociception to conscious perception.

Conscious perception of painful stimuli needs the contribution of an extensive cortico-subcortical network, and is completed in less than one second. While initial activities in operculo-insular and mid-cingulate cortices have been extensively assessed, the activation timing of most areas supporting conscious pain has barely been studied. Here we used intracranial EEG to investigate the dynamics of 16 brain regions (insular, parietal, prefrontal, cingulate, hippocampal and limbic) during the first second following nociceptive-specific laser pulses. Three waves of activation could be defined according to their temporal relation with conscious perception, ascertained by voluntary motor responses. Pre-conscious activities were recorded in the posterior insula, operculum, mid-cingulate and amygdala. Antero-insular, prefrontal and posterior parietal activities started later and developed during time-frames consistent with conscious voluntary reactions. Responses from hippocampus, perigenual and perisplenial cingulate developed latest and persisted well after conscious perception occurred. Nociceptive inputs reach simultaneously sensory and limbic networks, probably through parallel spino-thalamic and spino-parabrachial pathways, and the initial limbic activation precedes conscious perception of pain. Access of sensory information to consciousness develops concomitant to fronto-parietal activity, while late-occurring responses in the hippocampal region, perigenual and posterior cingulate cortices likely underlie processes linked to memory encoding, self-awareness and pain modulation. Hum Brain Mapp 37:4301-4315, 2016. © 2016 Wiley Periodicals, Inc.

Pain Perception Within Consciousness

As a psychological state, pain is perceived by the affected individual and it corresponds to a form of conscious awareness as a subjective conscious experience mediated in part by beliefs or emotions. Regardless of its 'physical' origins, pain, like all other perceptions, is a mental experience at different degrees of consciousness. The experience of pain requiring a stimulus, a feeling or emotion, and an effect or result, consists of an intermingling of chemical, biological, psychological, physiologic, socioeconomic, cultural, ethnic backgrounds, emotional, and cognitive factors. Not only the activation but also the connections are involved in conscious pain perception. Moreover, interconnectivity between the periaqueductal matter and orbitofrontal cortex is the key to cognitive-emotional responses associated with pain. Thus, the central pain control processes arising from interactions among the cognitive-evaluative, motivational-affective, and sensory-discriminative systems characterize the pain response, being also influenced by both noxious input and cognitive self-regulation. Neuroimaging studies (Davis et al., 2015) in healthy volunteers showed that pain cannot be localized in an isolated “pain center” in the brain, but it rather encompasses a neural circuitry.

Commentary: Cortical responses to salient nociceptive and not nociceptive stimuli in vegetative and minimal conscious state.

We read with great interest the work by de Tommaso et al. (2015) assessing cortical responsiveness to nociceptive and multimodal sensory stimuli in patients affected by chronic disorders of consciousness (DOC). In their valuable work, the authors attempted to assign each patient to the most appropriate DOC category by using auditory, visual, somatosensory, and nociceptive laser stimuli. Interestingly, the motor responsiveness to nociceptive stimuli assessed through the Coma Recovery Scale-Revised and the Nociception Coma Scale-Revised correlated with each evoked response, but Laser Evoked Potentials (LEPs). The latter were recognizable in all of the patients, independently from the preservation of other sensory modalities and the motor responsiveness to nociceptive stimuli. Hence, LEP absence should not be considered as a demonstration of the inability to experience pain, since the preservation does not per se indicate a conscious pain perception in DOC (de Tommaso et al., 2015). However, it is to note that we should be aware in interpreting authors' findings since these are based on a very limited number of patients (i.e., only 4 MCS and 5 VS). Moreover, since the presence vs. absence of LEPs was based on a subjective visual identification of the event-related potential waveforms, the possibility of misinterpretations (mainly due to very low signal-to-noise ratio) should be taken into account.

Assessment of nociceptive system in vegetative and minimally conscious state by using laser evoked potentials

Primary objective: The aim of this study is to assess if laser evoked potentials (LEPs) examination should be considered as an objective evidence of potential or residual pain perception capacity in vegetative (VS) and minimally conscious state (MCS) patients and if it could be a feasible methodology in order to differentiate these two clinical entities.Research design: This is a cross-sectional observational study focusing on the role of LEP examination, which is an easy and objective neurophysiological approach of the nociceptive system.Methods and procedures: Thirteen VS and 10 MCS patients were enrolled. All subjects were evaluated clinically by using validated behavioural scales and underwent to upper and lower limbs LEP recording.Main outcomes and results: Intra-group LEPs analysis in VS patients highlighted significant differences for N2P2 latency (p = 0.036) and amplitude (p = 0.018). Inter-group LEPs analysis showed significant differences in post-anoxic condition for N2P2 latency (p = 0.034), amplitude (p = 0.034) and a trend in N2P2 latency in brain trauma (p = 0.07). Interestingly, correlation analysis showed a significant relationship between N2P2 amplitude and Coma Recovery Scale-Revised scoring in the post-traumatic VS (r = 0.823, p = 0.044).Conclusions: The findings lead to detection of potential markers of conscious pain perception in patients with DOC, with important impact on therapeutic and rehabilitative management, and provide new information that may allow a better differential diagnosis.

Moving Toward Conscious Pain Processing Detection in Chronic Disorders of Consciousness: Anterior Cingulate Cortex Neuromodulation

It has been assumed that patients with chronic disorders of consciousness (DOC) do not feel pain, but it is possible that some of them just cannot report it. Modulation of γ-band oscillatory activity (γBO) in centroparietal areas (considered as a marker of either subjective pain perception processes or pain-related motor behavior preparation) by part of the anterior cingulate cortex (ACC) has been proposed to be suggestive of conscious pain perception and could therefore be used to assess the maintenance of some level of conscious pain perception in patients with DOC. Hence, we used a repetitive transcranial magnetic stimulation (rTMS) approach in an attempt to trigger frontoparietal output. We enrolled 10 healthy participants (HC), 10 patients in a minimally conscious state (MCS), and 10 with unresponsive wakefulness syndrome (UWS), who underwent a 1-Hz rTMS protocol over ACC. Before and after the neurostimulation paradigm, we measured the pain-rating assessment (pVAS), γBO, latency, and the amplitude of cortical nociceptive potentials evoked by transcutaneous electric sinusoidal stimuli (EEP). In all the HC and MCS and in 2 of the UWS subjects, rTMS increased γBO and reduced the EEP amplitude, whereas pVAS scoring improved in the HC. Our findings provide some evidence about conscious pain processing even in patients with severe DOC and show that rTMS over ACC may be a useful approach to better investigate the level of conscious impairment. PerspectivePatients with DOC may not be able to respond to pain stimuli, although they may feel it. The possibility of detecting residual pain perceptions by means of a noninvasive neuromodulation paradigm, studying the correlation between the ACC and centroparietal γBO, may help clinicians to better assess pain in such individuals.

Guidelines for recognition, assessment and treatment of pain: WSAVA Global Pain Council members and co-authors of this document:.

Karol Mathews DVM DVSc DACVECC (Canada) Peter W Kronen Dr Vet Med, DVM DECVAA (Switzerland) Duncan Lascelles BSc BVSc PhD DSAS DECVS DACVS MRCVS (USA) Andrea Nolan MVB DVA PhD DECVAA DECVPT MRCVS (UK) Sheilah Robertson BVMS (Hons) PhD DACVAA DECVAA DECAWBM (WSEL) DACAW MRCVS (USA) Paulo VM Steagall MV MS PhD DACVAA (Brazil/Canada) Bonnie Wright DVM DACVAA (USA) Kazuto Yamashita DVM MS PhD DJCVS (Japan)

Imagerie cérébrale et douleur : perception unique, réseaux multiples

Here, the “pain matrix” is designed as a fluid system, made up of lots of networks interacting with each other. A nociceptive matrix receiving spinothalamic input (mainly the operculo-insular region) ensures the specific nature of somatic pain, and is the only thing that, if destroyed, results in selective impairment of heat and pain perception. The transition between a cortical nociception and conscious pain is dependent on a secondary network that includes at least the anterior, posterior parietal and prefrontal insular regions. These secondary regions are not specifically nociceptive: their stimulation does not lead to pain and when destroyed pain relief is not generated; their joint activation is necessary for the conscious perception of pain, its attentional modulation and the control of associated vegetative reactions. The immediate pain experience that ensues may even be transformed based on beliefs, emotions and expectations of the individual, through the activity of tertiary regions, including the perigeniculate cingulate, orbitofrontal and limbic networks. The pain that we remember is the result of continuous interactions between these sub-systems, and the substantial changes in the pain experience can be obtained by acting on each of them.

Corneal pain activates a trigemino-parabrachial pathway in rats

Corneal pain is mediated by primary afferent fibers projecting to the dorsal horn of the medulla, specifically the trigeminal nucleus caudalis. In contrast to reflex responses, the conscious perception of pain requires transmission of neural activity to higher brain centers. Ascending pain transmission is mediated primarily by pathways to either the thalamus or parabrachial nuclei. We previously showed that some corneal afferent fibers preferentially contact parabrachial-projecting neurons in the rostral pole of the trigeminal nucleus caudalis, but the role of these projection neurons in transmitting noxious information from the cornea has not been established. In the present study, we show that noxious stimulation of the corneal surface activates neurons in the rostral pole of the nucleus caudalis, including parabrachially projecting neurons that receive direct input from corneal afferent fibers. We used immunocytochemical detection of c-Fos protein as an index of neuronal activation after noxious ocular stimulation. Animals had previously received injections of a retrograde tracer into either thalamic or parabrachial nuclei to identify projection neurons in the trigeminal dorsal horn. Noxious stimulation of the cornea induced c-Fos in neurons sending projections to parabrachial nuclei, but not thalamic nuclei. We also confirmed that corneal afferent fibers identified with cholera toxin B preferentially target trigeminal dorsal horn neurons projecting to the parabrachial nucleus. The parabrachial region sends ascending projections to brain regions involved in emotional and homeostatic responses. Activation of the ascending parabrachial system may explain the extraordinary salience of stimulation of corneal nociceptors.

Effects of Transcranial Direct Current Stimulation on Hemodynamic Responses to Pain

Painful (noxious) stimuli cause increases in heart rate blood pressure, and peripheral vascular resistance. This response is due to a both direct nociceptive reflex responses and conscious pain perception. Transcranial direct current stimulation (tDCS) is effective in modulating pain perception threshold in healthy volunteers and thus might be used to dissociate afferent (skin pain receptors) and efferent (cortical pain perception) components in the response to pain. We examined systemic (heart rate and blood pressure) and regional (calf blood flow/resistance) responses to cold pressor tests at 14, 7, and 0 °C before and after tDCS (active and sham) in 15 volunteers. All hemodynamic responses were graded with temperature (14&lt;7&lt;0 °C, P&lt;0.05). tDCS reduced the perceived pain score, but only at 14 °C (P&lt;0.05). This coincided with a slight reduction in peak heart rate response of ~1–2 beats. However, aside from this, tDCS had no effect on hemodynamic responses. Hence, tDCS may alter the pain perception threshold but this has minimal impact on nociceptive activation of cardiovascular centers.