Supraspinal Mechanisms of Pain and Nociception



Supraspinal Mechanisms of Pain and Nociception


Michael Hauck

Ürgen Lorenz



The preceding chapters addressed the peripheral and spinal mechanisms of nociceptive processing. Neither normal nor pathologic pain can be understood without knowledge about supraspinal mechanisms. The multidimensionality of pain with mainly sensory-discriminative and emotional-affective components has its anatomic counterparts in a variety of supraspinal areas, which are involved in pain processing. Hence, the experience of pain is formed in a distributed network which gates the transformation of peripheral nociceptive input to conscious pain.1 Supraspinal structures include the hindbrain (lower and upper brainstem and cerebellum) and the forebrain. The forebrain has two major divisions, the lower diencephalon involving hypothalamus and thalamus and the cerebrum involving the cortex, basal ganglia, and the limbic system (cingulate cortex, amygdala, hippocampus, Fig. 6.1). In humans, the forebrain anatomically dominates and physiologically controls much more than in other species nociceptive processing. Because of the large proportion of the human forebrain of the entire central nervous system (CNS) volume (85%) when compared to that of the spinal cord (2%), descending modulatory influences assume much greater importance than for example in the rat in which the forebrain comprises 44% and the spinal cord 35% of CNS volume.2,3 Thus, the great variety of psychological phenomena characterizing normal and abnormal pain in humans can only be studied in humans, although anatomic tracing and electrophysiologic techniques and behavioral studies in rodents and primates contributed significantly to our current knowledge about the pathways connecting the dorsal horn with supraspinal structures.


Functional Imaging of Pain in Humans

Since release of the early editions of this handbook, functional brain imaging in human volunteers and patients addressed many questions pertaining to brain structures involved in pain processing. Before going into the details of supraspinal regions engaged in pain processing and perception, we will therefore briefly describe the methodologic basis of these technologies.






FIGURE 6.1 Structure of the brain.


METHODOLOGIES OF NONINVASIVE AND INVASIVE FUNCTIONAL BRAIN IMAGING IN PAIN

Functional imaging techniques applied for the study of pain are positron emission tomography (PET), functional magnetic resonance imaging (fMRI), near-infrared spectroscopy (NIRS), multi-channel electroencephalography (EEG) and magnetoencephalography (MEG), and intracranial recordings. PET measures cerebral blood flow, glucose metabolism, or neurotransmitter kinetics. A very small amount of a labeled compound (called the radiotracer) is intravenously injected into the patient or volunteer. During its uptake and decay in the brain, the radionuclide emits a positron, which, after traveling a short distance, “annihilates” with an electron from the surrounding environment. In case of the most common use of O15-water injection, counting and spatial reconstruction of these occurrences within the brain anatomy allow visualization of the regional cerebral blood flow response (rCBF) as an indicator of neuronal activity. Radio-labeled fluorodeoxyglucose (FDG) is applied to measure regional energy consumption as a function of metabolic rate. An interesting refinement of PET technology represents the use of neurotransmitters as tracers to investigate binding mechanisms and kinetics, for example, in the opioidergic system.

One method of fMRI images blood oxygenation, a technique called blood oxygen level-dependent (BOLD), which exploits the phenomenon that oxygenated and deoxygenated hemoglobin possess different magnetic properties resulting in different relaxation behavior following radiofrequency pulses inside the magnet. An additional fMRI technique called arterial spin labeling (ASL) uses a radio pulse to magnetically “label”
hydrogen atoms ascending through the vasculature and then determines alterations in paramagnetic characteristics as the labeled blood perfuses the brain. The rCBF measures using O15-water PET, the BOLD technique, and the ASL technique rely on neurovascular coupling mechanisms that are not yet fully understood, but which overcompensate local oxygen consumption, thus causing a flow of oxygenated blood into neuronally active brain areas in excess of that used.4

NIRS is an optical approach that also analyses changes in hemoglobin oxygenation levels by using light in the near infrared range (650 to 950 nm). Shortly, NIRS measures the attenuation of light over the cortex and can be applied noninvasively through the skull. Another advantage is the portability of NIRS systems and the possibility to measure in different environments. However, the spatial and temporal resolution in noninvasive measurements is low for NIRS.5

EEG and MEG are noninvasive neurophysiologic techniques that measure the respective electrical potentials and magnetic fields generated by neuronal activity of the brain and propagated to the surface of the skull where they are picked up with EEG electrodes or, in the case of its magnetic counterpart, received by supra conducting quantum interference device (SQUID) sensors located outside the skull. Compared with PET and fMRI, EEG and MEG are direct indicators of neuronal activity and yield a higher temporal resolution of investigated brain function. The spatial distributions of EEG potentials and MEG fields at characteristic time points following noxious stimulation are analyzed using an inverse mathematical modeling and spatial filtering to estimate the anatomic origin of the recorded pain-related activity. The spatial acuity of MEG is higher than that of EEG because the latter measures the extracellular volume currents that are distorted by the differentially conducting tissues such as gray and white matter, cerebrospinal fluid, durae, and bone. In contrast, MEG measures the magnetic field perpendicular to the intracellular currents undistorted by the surrounding tissue.

Invasive recordings, which are assessed during neurosurgical interventions in patients ongoing epileptic surgery, or deep brain stimulation (DBS) procedures (most common in Parkinson disease), are extremely helpful to directly measure supraspinal pain signals. Different invasive recording techniques, namely, depth electrodes, subdural grids, subdural strips, and stereoencephalography, are used today.6 Advantage of all these invasive recordings is that the neuronal activity is picked up directly from the neurons and not being distorted by the cerebrospinal fluid, durae, and bone as in EEG or MEG. Disadvantage lies in the invasive nature of the procedure and the only limited area that can be investigated using invasive recordings.


Brainstem

The brainstem represents the connection of the spinal cord with the diencephalon (hypothalamus and thalamus). It comprises the rhombencephalon (pons and medulla) and the mesencephalon (midbrain, see Fig. 6.1). A major rhombencephalic structure is the reticular formation (RF) which encompasses a distributed network of small and large nerve fibers and extends from the medulla up to the level of the thalamus. It has manifold local interneuronal connections within the brainstem and contains both ascending and descending projecting systems. It is divided into three vertical zones. The medial magnocellular zone contains the ascending reticular activating system (ARAS), a major pathway to the thalamus, hypothalamus, and basal forebrain (a group of structures at the base of the frontal lobe, including the nucleus basalis, diagonal band, medial septum, and substantia innominata). The median and paramedian zones contain the raphe nuclei of serotonergic projection neurons. The lateral parvocellular zone receives afferents from amygdala and hypothalamus. RF and basal forebrain have reciprocal connection with virtually all cortical and subcortical structures through cholinergic (from the basal forebrain), noradrenergic (from the locus coeruleus), dopaminergic (from the substantia nigra [SN] and ventral tegmentum [VTA]), and serotoninergic (from the raphe) pathways. Reciprocal connections with the spinal cord mediate motor, respiratory, and cardiovascular functions and pain modulation.

The RF is an important mediator of consciousness and arousal. The stream of information about the outer world that reaches specific nuclei of the thalamus and cortex through the sensory pathways of vision, audition, gustation, and somatosensation is blocked when the activity of the mesencephalic RF, which drives nonspecific thalamic sites, drops below a critical level, such as, for example, during slow wave sleep or certain types of absence epilepsies.7 Wakefulness and arousal are thus closely coupled to the RF, which act as the “energetic supplier” of conscious perception and behavior. Widespread areas of the RF are responsive to noxious stimuli.8 The gigantocellular and magnocellular fields of the medullar RF, that is, the bulboreticular region, mediate escape behavior following acute painful stimuli9,10 and respond neurochemically during persistent pain.11 The close relationship of nociception and pain with arousal and consciousness guarantees optimal alertness and readiness to avoid bodily harm. Sleep is therefore disrupted by the awakening nature of pain through its influence on the RF. Similarly, opioid-induced sedation is antagonized by residual pain. These aspects will be discussed in more detail later.

A view of the RF as a “diffuse arousal network”12 has been replaced by the acknowledgement of localized reticular cell groups with highly specific functions and connections in the coordination of head and eye movements, postural orientation, and autonomic visceral control.13 Also, the understanding of RF in pain has become more differentiated. The subnucleus reticularis dorsalis (SRD) represents a homogenous population of neurons in the caudal-dorsal medulla whose axons form both ascending and descending collaterals to the thalamus and spinal cord, respectively. SRD neurons are strongly activated by noxious cutaneous and visceral stimuli from any part of the body.14 It is regarded a medullary substrate of the link between nociceptive and motor activities. SRD has also been suggested as major supraspinal site mediating the “pain-inhibits-pain,” or counterirritation, phenomenon as formulated in the concept of diffuse noxious inhibitory controls (DNIC).15 As part of a spinal-bulbospinal feedback loop, SRD is proposed to facilitate the extraction of nociceptive information by increasing the signal-to-noise ratio between a pool of deep dorsal horn neurons activated by a tonic painful focus and the remaining population of such neurons, which are inhibited for simultaneous phasic noxious input. Youssef et al.16 used fMRI in healthy test participants and observed that the magnitude of signal reduction in SRD following repetitive phasic heat stimuli applied to the right lip correlated with magnitude of analgesia produced by a conditioning pain exerted by injection of hypertonic saline into the tibialis anterior muscle.


PERIAQUEDUCTAL GRAY MATTER—A KEY STRUCTURE OF ENDOGENOUS ANALGESIA

The periaqueductal gray (PAG) is a midbrain territory located medially adjacent to the RF surrounding the cerebral aqueduct in a horse shoe-shaped manner by sparing ventral regions subserving distinct ocular-motor functions unrelated to pain.17 The PAG plays a critical role in the expression of a variety of emotion-related behaviors including pain.18 It represents a key structure in relaying descending pathways from the limbic system (prefrontal cortex, amygdala, and hypothalamus) to midbrain (e.g., inferior and superior colliculi), pons (e.g., locus coeruleus, lateral parabrachial nucleus, dorsolateral
pontine tegmentum), the raphe nuclei of the rostroventral medulla (RVM) and the deeper layers of the spinal cord (Rexed layers V, VII, VIII). Midbrain, pontine, medullar, and spinal connections are all reciprocal, such that the PAG is connecting afferents from these origins to medial thalamic nuclei and hypothalamus.19 Early systematic studies identified PAG and RVM as brainstem sites that elicit powerful surgical levels of analgesia through focal brain stimulation,20 subsequently more elaborated and referred to as stimulus-induced analgesia.21,22,23 A milestone contribution to the understanding of the interaction between PAG and RVM and its role in opioid analgesia was delivered by Fields and colleagues’24 working group who identified two classes of pain modulatory cells in the RVM exerting inhibitory and facilitatory actions through respective off- and on-cells. Off-cells are activated by local infusion of µ-opioid agonists, and their activity inhibits nociceptive transmission. In contrast, on-cells facilitate nociceptive transmission, are inhibited by local µ-opioids, and are activated by naloxone and morphine abstinence. Approximately 15% of RVM neurons are serotonergic and are neither on- nor off-cells and do not respond to opioids.25 Some respond to baroreceptor input integrating cardiovascular and nociceptive function.26 Descending serotonergic fibers from the RVM project to dorsal horn neurons via the dorsolateral funiculus and mediate the analgesic effect of opioid receptor activation. Also noradrenergic structures in the brainstem, namely, the locus coeruleus, are regarded to be pain inhibitory through activation of α2-adrenoceptors on central terminals of primary afferent nociceptors (presynaptic inhibition), by direct α2-adrenergic action on spinal pain-relay neurons (postsynaptic inhibition), and by α2-adrenergic activation of inhibitory interneurons.27 However, the central as well as the peripheral efficacy of pain inhibition can vary depending on neuroplastic changes following inflammation and injury.27 Taylor and Westlund28 recently reviewed evidences that argue for a pain facilitatory action of locus coeruleus neurons under conditions of neuropathic pain, especially at later stages after the traumatic lesion.

The biologic significance of endogenous pain control is generally seen in the context of behavioral conflicts in which the subject needs to disengage from pain in order to fight or escape at the presence of body injury. Analogous human life situations are sporting competition or combat, during which a subject may fail to be aware of even severe tissue damage, which becomes painful when the victim releases engagement in these activities. Thus, forebrain input to the PAG mediates contextual information, from the prefrontal cortex, the amygdala, the anterior cingulate cortex (ACC), and the hypothalamus about momentary behavioral goals, past experience, and bodily needs. Evidence furthermore indicates that injury and inflammation causing increased sensitivity toward painful stimuli (primary hyperalgesia) triggers the RVM as key structure of a feedback pain inhibiting circuitry.29 There is solid evidence by fMRI that PAG and RVM are also mediating the placebo response in humans.30,31

Using the expression of the immediate early gene, c-fos, as a marker of neuronal activation, an interesting regional distinction for deep versus cutaneous pain had been demonstrated within the midbrain PAG. Noxious stimulation of a range of deep somatic and visceral structures evoked a selective increase in Fos expression in the ventrolateral PAG column (vlPAG), whereas, noxious cutaneous stimulation evoked Fos expression predominantly in the lateral PAG column (lPAG).32 vlPAG and lPAG areas are suggested to represent different modes of behavioral adaptation characterizing inescapable and escapable types of pain, respectively. Earlier studies showed that both deep pain as well as microinjection of excitatory amino acids (EAA) into the vlPAG of freely moving animals evoked a response of quiescence, decreased vigilance, decreased reactivity, hypotension, and bradycardia. In contrast, cutaneous pain as well as activation of the lPAG-evoked fight-and-flight behavior, increased vigilance, hyperreactivity, hypertension, and tachycardia. Lumb et al.33,34 presented evidence that differential representation of escapable and inescapable pain in the PAG extends to distinct representations of “first” and “second” pain, as indicated by the columnar distribution of neurones activated by inputs from respective Aδ and C nociceptors. Furthermore, the functional organization of projections from circumscribed regions of the hypothalamus to the different columns of the PAG indicates that the behavioral significance of the pain signal is also represented in brain regions other than the PAG. Such specificity may coordinate antinociception with adequate behavioral and autonomic responses to prevent damage, in case of an imminent threat, or promote healing when an injury is already manifest.

Finally, the PAG is a promising target in invasive DBS to treat chronic pain, first applied by Hosobuchi et al.35 and Richardson and Akil36 in humans. However, its use is limited due to loss of efficacy over time and intolerable side effects. It remains to be cleared whether more precise electrode positioning and simultaneous stimulation of distinct locations37 or a better understanding of pain mechanisms that are sensitive or insensitive to DBS will help to achieve better outcome. In chronic neuropathic and central pain syndromes, DBS of the PAG appears less effective than nociceptive pain.38


MESOLIMBIC DOPAMINE SYSTEM

The mesolimbic system comprises dopaminergic brainstem sites, that is, the VTA and the SN projecting to the striatum. Neurons originating in the SN pars compacta innervate D1-and D2-receptors of the dorsal striatum (putamen and caudate nucleus) that are functionally integrated into the motor loop of the basal ganglia (see the following text). The nucleus accumbens of the ventral striatum is regarded the key structure of a mesolimbic circuitry receiving input from SN and VTA mediating motivational salience and valence of painful stimuli to drive pain avoidance and pain endurance depending on the situational context.39 The mesolimbic circuitry is furthermore regarded important for the encoding of the rewarding effect of pain relief.40 Chronic fibromyalgia and low back pain have been observed to be associated with reduced responses of the mesolimbic circuitry to salient stimuli41,42 that could account for the depressive comorbidity in these patients.39


Hypothalamus

The hypothalamus occupies the ventral half of the diencephalon below the thalamus on either side of the third ventricle. It lies just above the pituitary gland with which it is intimately coupled for various neuroendocrine secretions subserving autonomic functions. Neurosecretory neurons are mainly located in periventricular and supraoptic nuclei. Fiber tracts to the pituitary gland are subdivided into two parts: (1) magnocellular secretory cells expressing vasopressin and oxytocin innervate the posterior pituitary gland and (2) parvocellular secretory cells expressing gonadotropins, releasing and inhibiting hormones that innervate the anterior pituitary gland. The hypothalamus receives nociceptive inputs from the midbrain parabrachial nucleus, the ventrolateral medulla, and the spinal and trigeminal dorsal horn.43,44 The nucleus of the solitary tract (NTS), a major relay of cardiorespiratory, visceral, and gustatory information, is also connected with the hypothalamus. Its role in nociception is not quite clear, but the convergence of autonomic, visceral, and nociceptive information in the hypothalamus underpins the importance of it for the control of homeostasis as part of the brain’s defense system. More recent research points to a pain inhibitory role of hypothalamic orexin neurons (orexin-A and orexin-B), similar to opioidergic neurons, acting on the
PAG as the most important supraspinal site.45,46 Interestingly, hypothalamic orexin neurons mediate analgesia induced by odorants in mice.47


Thalamus

The thalamus is the major structure of the diencephalon, which additionally contains, in relation to thalamus, basally the hypothalamus, laterally the globus pallidus and nucleus subthalamicus, and medially the third ventricle. With the exception of the olfactory system, all sensory systems send afferent input to the thalamus from where it is projected into the specific cortical representation areas. This is why the thalamus is often referred to as the gate to consciousness. The intralaminar and ventral motor nuclei are the main targets of thalamic inputs from the striatum (putamen and caudate nucleus). Corticostriatal and striatothalamocortical connections form the sensory-motor loop of the basal ganglia which is under control of dopaminergic input from the midbrain SN pars compacta (see earlier discussion). The thalamic extension of the ARAS contributes to arousal and wakefulness driven by the midbrain RF (see earlier discussion). The multidimensional nature of pain as composed of sensorydiscriminative and affective-motivational determinants first introduced by Melzack and Casey48 four decades ago formed a conceptual framework that guided many research groups studying supraspinal pain mechanisms. One of their postulates was that sensory and affective pain dimensions are anatomically represented by spinal pathways that differentially target respective lateral and medial nuclei of the dorsal thalamus.


THE LATERAL PAIN SYSTEM—THE SENSORYDISCRIMINATIVE PATHWAY

The cell bodies of spinothalamic tract (STT) fibers are located in the most superficial layers, lamina I, the outer region of lamina II, and deeper laminae V to VI49 according to the Rexed scheme. STT axons cross via the anterior commissure to the anterolateral portion of the contralateral hemisphere and have their main thalamic targets in lateral nuclei, namely, ventral posterolateral (VPL; from the body) and posteromedial (VPM; from the face) nuclei and the ventral posterior inferior (VPI) nucleus. These fibers contribute to thermal and pain sensation. The lateral thalamic nuclei have small receptive fields and mostly gradual stimulus response functions over nonnoxious and noxious intensities, representing the “wide-dynamic-range,” or to a lesser extent, over noxious range only, representing the “nociceptive-specific” type of cells. These features render lateral thalamic targets of spinal nociceptive afferents ideally suited for the encoding of spatial localization and intensity of painful stimuli, similar to the properties of touch. The sensory-discriminative determinant of pain is thus governed by a spinal afferent pathway that mainly reaches lateral thalamic nuclei, from where neuronal activity is projected into the contralateral primary (SI) and bilateral secondary (SII) somatosensory cortices and mid and posterior sections of the insula (see the following text). Invasive DBS of the VPL demonstrated improvement of chronic neuropathic and central pain.50


SPINAL CONNECTIONS TO BRAINSTEM AND MEDIAL THALAMUS—THE AFFECTIVE PATHWAY

Although direct connections of lamina I STT cells exist with medial thalamic nuclei, namely, the central lateral nucleus and intralaminar complex,51,52,53 the major source of nociceptive input to the medial thalamus is likely indirect through the brainstem that relays spinoreticular, spinomesencephalic, and spinoparabrachial input from both superficial and deeper dorsal horn. Medial thalamic nuclei project densely into key structures of the limbic system, such as the ACC, the amygdala, the hippocampus, the anterior insula, and prefrontal cortex, which represent the perceived intrusion and threat by pain, referred to as affective-motivational and cognitive-evaluative determinants of pain.48

The contention that slowly and rapidly conducting nociceptors project differentially to respective medial and lateral thalamic nuclei had been recently challenged. Using intracerebral recordings of laser-evoked potentials in patients receiving neurosurgery due to refractory partial epilepsy, Bastuji et al.54 identified three major thalamic regions, namely, the centrolateral (CL), VPL, and anterior pulvinar responding equally and simultaneously to phasic nociceptive laser input. The authors conclude that at least part of the nociceptive input driven by rapidly conducting Aδ fibers reaches both lateral and medial thalamic regions arguing for rapid medial thalamic projection to cingulate structures to subserve rapid orienting reactions to, and withdrawal from, the noxious stimulus. This suggests that both medial and lateral thalamic sites contribute to the exteroceptive function of escapable pain.

In contrast, Craig55 hypothesized that pain is a purely interoceptive perception such as hunger, thirst, or itch. It originates in specific lamina I neurons which impinge on specific thalamic nuclei, such as the posterior part of the ventral medial nucleus (VMpo) and the ventral caudal part of the mediodorsal nucleus (MDvc). These distinct thalamic nuclei relay afferent input to the dorsal posterior insula and caudal ACC, respectively, and form separate pathways regarded as important elements of a hierarchical system subserving homeostasis, linking thermal sensation and pain contributing to the sense of the physiologic condition of the body (interoception) with subjective feelings and emotion.


Cortex

The human cortex is divided according to functional and anatomic criteria. The German neuroanatomist and psychiatrist Brodmann56 introduced a systematic classification of the human cortex based on cytoarchitectonic properties, which, in refined modification, is still often referred to in the neuroimaging literature. Functional classifications consider the specific relevance of different cortical structures for motor, sensory, cognitive, emotional, or autonomic information processing. These functional areas can be divided into hierarchically organized subregions, for example, primary and secondary projection areas or network systems consisting of distributed areas. The current view is that higher order projection areas and distributed networks rather than a unique “pain center” represent the cortical substrate of pain perception. This view is consistent with the multidimensional definition of pain48,57 which postulates differential projection of lateral and medial thalamic pathways to respective sensory and limbic cortical structures in addition to cortico-cortical as well as cortico-subcortical interactions for the composition of sensory-discriminative, affective-motivational, and cognitive-evaluative determinants (see earlier discussion). According to this concept, the primary (SI) and secondary somatosensory (SII) cortices receiving input from lateral thalamic nuclei are responsible for sensorydiscriminative processing. Emotional content and aversive quality to noxious stimuli motivating escape and avoidance behavior are linked to limbic areas. The limbic system involves cortical and subcortical areas from the frontal, parietal, and temporal lobe that from a ring (limbus) around the upper brainstem and diencephalon, first regarded by Papez58 as important for emotion. It includes the cingulate cortex, the insula, the prefrontal cortex, and, as subcortical structures, amygdala, hippocampus, medial thalamus, and hypothalamus. Taken together, it is important to highlight that the multidimensionality of pain is neuroanatomically reflected in multiple cortical sites being involved in pain processing.







FIGURE 6.2 Schematic anatomic localization of cortical areas, which are regarded as important for pain processing. Somatosensory areas, which are responsible for sensory-discriminative pain processing such as intensity and stimulus decoding, are the primary (SI) and secondary somatosensory cortex (SII). Adjacent to SII is the insula (Ins), which belongs to the limbic system and is involved in emotional-affective pain processing. Other limbic structures include the cingulate gyrus (CI) with its subdivisions anterior cingulate cortex (ACC), midcingulate cortex (MCC), and posterior cingulate gyrus (PCC). Finally, the prefrontal cortex (PFC) plays an important role in cognitive-evaluative pain processing especially for the organization of context-dependent pain behavior.


SENSORY AREAS


Primary Somatosensory Cortex

The primary somatosensory cortex (SI) is located in the parietal lobe within the postcentral gyrus (Fig. 6.2). It includes the Brodmann areas 1, 2, 3a, and 3b, the latter two occupying the depth and the posterior wall of the central sulcus and generally considered to be the major recipient of cutaneous somatosensory input. Early studies of patients with cortical lesions reported controversial results. Whereas Head and Holmes59 did not find deficits in pain sensitivity following cortical lesions, studies on World War I and II injury victims with lesion of SI (area 3a) reported loss of cutaneous pain sensibility.60,61,62 Experimental data using single-cell recordings in awake monkeys revealed a strong correlation between SI firing rate and stimulus intensity and duration of painful stimuli.63 Patients with subdural electrodes implanted for surgical treatment of intractable epilepsy showed encoding of intensity of painful stimuli within SI.64 Direct intracerebral electrical stimulation of SI in awake patients, however, failed to elicit painful sensations.65,66 Thus, it appears that SI processes nociceptive input, but it is not sufficient to cause a pain sensation. Due to its spatial and intensity-encoding properties, SI is regarded to contribute to discriminative analysis of painful stimuli but does obviously not cause the aversive nature of pain perception.

Consistent evidence for SI involvement in pain processing is derived from other functional neuroimaging studies in humans. SI is organized somatotopically; that is, neighboring peripheral skin areas are also represented by neighboring cortical sites. Human imaging studies established a somatotopic organization of SI for painful laser stimuli (Fig. 6.3).67 Accordingly, laser stimuli at the foot and hand activated SI regions medially, near the interhemispheric gap, or more laterally, respectively. Ploner et al.68 and Tran et al.69 showed that laser-evoked MEG responses to Aδ- and C-fiber activation, respectively, appeared simultaneously in SI and SII, a finding which contrasts with the sequential activation of SI and SII following tactile stimuli. Kanda et al.70 confirmed these results by using implanted subdural electrodes. Yet, not all functional imaging studies revealed SI activation related to pain. PET and fMRI studies exhibited robust SI activity following painful stimuli when using contact heat,71,72,73 laser radiant heat,67,74 or electrical pain75,76 but less consistently during spontaneous or provoked clinical pain states.77,78 Casey et al.79 noted a clear temporal dynamic of SI activity following painful contact heat using PET. Notably, hypnotic suggestion of sensory pain quality enhanced SI activity following thermal stimulation,80 whereas that of the affective pain quality did not.81 This latter result with experimental pain stimuli fits with clinical observation that SI lesions alter sensory qualities but leave affective or cognitive aspects of pain, especially chronic pain largely unchanged.82 Furthermore, paininduced BOLD activations in SI are more likely correlated with stimulus intensity than perceived pain,83 although other authors
showed that gamma oscillations in SI reflect pain perception and not the stimulus intensity.84 Collective evidence thus indicates that noninvasive imaging methods strongly support the participation of SI in sensory-discriminative aspects of pain perception, although temporal aspects of the applied stimulus method and imaging technique and attentional and cognitive factors can significantly modify SI activity.79,85,86






FIGURE 6.3 Somatotopic organization of somatosensory areas. Experimental pain was induced using an infrared laser, which elicits a short burning and pinprick-like pain sensation. Laser stimuli were given at both hands and feet, before pain-induced activation of the primary (SI) and secondary somatosensory (SII) areas were localized using functional magnetic resonance imaging (fMRI) technique. Pain-induced activation after hand stimulation (red) was found in SI near the interhemispheric gap, whereas foot stimulation (green) elicits more lateral activation of SI. Pain-induced localization in SII is less spatially separated between hand and foot stimulation. The center of the colored circles is the mean coordinate of the subjects, whereas the radius of the circle is the standard deviation. L, left; R, right. (Reprinted from Bingel U, Lorenz J, Glauche V, et al. Somatotopic organization of human somatosensory cortices for pain: a single trial fMRI study. Neuroimage 2004;23[1]:224-232. Copyright © 2004 Elsevier. With permission.)

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