Brain activity changes associated with pain perception variability.

Pain perception can be modulated by several factors. Phenomena like temporal summation leads to increased perceived pain, whereas behavioral conditioning can result in analgesic responses. Furthermore, during repeated, identical noxious stimuli, pain intensity can vary greatly in some individuals. Understanding these variations is important, given the increase in investigations that assume stable baseline pain for accurate response profiles, such as studies of analgesic mechanisms. We utilized functional magnetic resonance imaging to examine the differences in neural circuitry between individuals displaying consistent pain ratings and those who experienced variable pain during a series of identical noxious stimuli. We investigated 63 healthy participants: 31 were assigned to a "consistent" group, and 32 were assigned to a "variable" group dependent on pain rating variability. Variable pain ratings were associated with reduced signal intensity in the dorsolateral prefrontal cortex (dlPFC). Furthermore, the dlPFC connectivity with the primary somatosensory cortex and temperoparietal junction was significantly reduced in variable participants. Our results suggest that investigators should consider variability of baseline pain when investigating pain modulatory paradigms. Additionally, individuals with consistent and variable pain ratings differ in their dlPFC activity and connectivity with pain-sensitive regions during noxious stimulation, possibly reflecting the differences in attentional processing and catastrophizing during pain.

Firing properties of muscle spindles supplying the intrinsic foot muscles of humans in unloaded and freestanding conditions.

We recently developed an approach for recording from muscle spindles in the intrinsic muscles of the foot in freestanding humans by inserting a tungsten microelectrode into the posterior tibial nerve behind the medial malleolus of the ankle. Here we characterize the behavior of muscle spindles in the small muscles of the foot in 1) seated subjects with the leg horizontal and the foot naturally plantarflexed and 2) standing subjects. In the first study, recordings were made from 26 muscle spindle afferents located within flexor digiti minimi brevis ( n = 4), abductor digiti minimi ( n = 3), quadratus plantae ( n = 3), plantar interossei ( n = 4), flexor digitorum brevis ( n = 3), dorsal interossei ( n = 2), and lumbricals ( n = 2), with one each supplying abductor hallucis, adductor hallucis, and flexor hallucis brevis. The identity of another two muscle afferents was unknown. The majority of the units were silent at rest, only seven (27%) being spontaneously active. Because of the anatomic constraints of the foot, some spindles supplying muscles acting on the toes responded to movements of one or more digits. In the second study, 12 muscle spindle afferents were examined during standing. The ongoing discharge of eight spindle afferents covaried with changes in the center of pressure during postural sway. We conclude that the majority of spindle endings in the small muscles of the foot are silent at rest, which may allow them to encode changes in conformation of the foot when it is loaded during standing. Moreover, these muscle spindle afferents can provide useful proprioceptive information during standing and postural sway. NEW & NOTEWORTHY We have characterized the firing properties of muscle spindles in the intrinsic muscles of the human foot for the first time. The majority of the spindle endings are silent in seated subjects, and most fire tonically during standing, their discharge covarying with center of pressure during postural sway. We conclude that spindle endings in the intrinsic muscles of the foot provide useful proprioceptive information during free standing.

Microneurography from the posterior tibial nerve: a novel method of recording activity from the foot in freely standing humans.

The posterior tibial nerve, located behind the medial malleolus of the ankle, supplies the intrinsic muscles of the foot and most of the skin of the sole. We describe a novel approach for recording from this nerve via a percutaneously inserted tungsten microelectrode and provide examples of recordings from presumed muscle spindle endings recorded in freely standing human subjects. The fact that the angular excursions of the ankle joint are small as the foot is loaded during the transition from the seated position to standing means that one can obtain stable recordings of neural traffic in unloaded, loaded, and freely standing conditions. We conclude that this novel approach will allow studies that will increase our understanding of the roles of muscle and cutaneous afferents in the foot in the control of upright posture. NEW & NOTEWORTHY We have performed the first microneurographic studies from the posterior tibial nerve at the ankle. Stability of the recording site allows one to record from muscle spindles in the intrinsic muscles of the foot as well as from cutaneous mechanoreceptors in the sole of the foot during the transition from seated to standing. This novel approach opens up new opportunities for studying the roles of muscle and cutaneous afferents in the foot in the control of upright stance.

The vestibular system does not modulate fusimotor drive to muscle spindles in relaxed leg muscles of subjects in a near-vertical position.

It has been shown that sinusoidal galvanic vestibular stimulation (sGVS) has no effect on the firing of spontaneously active muscle spindles in either relaxed or voluntarily contracting human leg muscles. However, all previous studies have been conducted on subjects in a seated position. Given that independent vestibular control of muscle spindle firing would be more valuable during postural threat, we tested the hypothesis that this modulation would become apparent for subjects in a near-vertical position. Unitary recordings were made from 18 muscle spindle afferents via tungsten microelectrodes inserted percutaneously into the common peroneal nerve of awake human subjects laying supine on a motorized tilt table. All recorded spindle afferents were spontaneously active at rest, and each increased its firing rate during a weak static contraction. Sinusoidal bipolar binaural galvanic vestibular stimulation (±2 mA, 100 cycles) was applied to the mastoid processes at 0.8 Hz. This continuous stimulation produced a sustained illusion of "rocking in a boat" or "swinging in a hammock." The subject was then moved into a near-vertical position (75°), and the stimulation repeated. Despite robust vestibular illusions, none of the fusimotor-driven spindles exhibited phase-locked modulation of firing during sinusoidal GVS in either position. We conclude that this dynamic vestibular stimulus was insufficient to modulate the firing of fusimotor neurons in the near-vertical position. However, this does not mean that the vestibular system cannot modulate the sensitivity of muscle spindles via fusimotor neurons in free unsupported standing, when reliance on proprioceptive feedback is higher.

Pain inhibits pain; human brainstem mechanisms.

Conditioned pain modulation is a powerful analgesic mechanism, occurring when a painful stimulus is inhibited by a second painful stimulus delivered at a different body location. Reduced conditioned pain modulation capacity is associated with the development of some chronic pain conditions and the effectiveness of some analgesic medications. Human lesion studies show that the circuitry responsible for conditioned pain modulation lies within the caudal brainstem, although the precise nuclei in humans remain unknown. We employed brain imaging to determine brainstem sites responsible for conditioned pain modulation in 54 healthy individuals. In all subjects, 8 noxious heat stimuli (test stimuli) were applied to the right side of the mouth and brain activity measured using functional magnetic resonance imaging. This paradigm was then repeated. However, following the fourth noxious stimulus, a separate noxious stimulus, consisting of an intramuscular injection of hypertonic saline into the leg, was delivered (conditioning stimulus). During this test and conditioning stimulus period, 23 subjects displayed conditioned pain modulation analgesia whereas 31 subjects did not. An individual's analgesic ability was not influenced by gender, pain intensity levels of the test or conditioning stimuli or by psychological variables such as pain catastrophizing or fear of pain. Brain images were processed using SPM8 and the brainstem isolated using the SUIT toolbox. Significant increases in signal intensity were determined during each test stimulus and compared between subjects that did and did not display CPM analgesia (p<0.05, small volume correction). The expression of analgesia was associated with reduction in signal intensity increases during each test stimulus in the presence of the conditioning stimulus in three brainstem regions: the caudalis subdivision of the spinal trigeminal nucleus, i.e., the primary synapse, the region of the subnucleus reticularis dorsalis and in the dorsolateral pons in the region of the parabrachial nucleus. Furthermore, the magnitudes of these signal reductions in all three brainstem regions were significantly correlated to analgesia magnitude. Defining conditioned pain modulation circuitry provides a framework for the future investigations into the neural mechanisms responsible for the maintenance of persistent pain conditions thought to involve altered analgesic circuitry.

Neck proprioceptors contribute to the modulation of muscle sympathetic nerve activity to the lower limbs of humans.

Several different strategies have now been used to demonstrate that the vestibular system can modulate muscle sympathetic nerve activity (MSNA) in humans and thereby contribute to the regulation of blood pressure during changes in posture. However, it remains to be determined how the brain differentiates between head-only movements that do not require changes in vasomotor tone in the lower limbs from body movements that do require vasomotor changes. We tested the hypothesis that neck movements modulate MSNA in the lower limbs of humans. MSNA was recorded in 10 supine young adult subjects, at rest, during sinusoidal stretching of neck muscles (100 cycles, 35° peak to peak at 0.37 ± 0.02 Hz) and during a ramp-and-hold (17.5° for 54 ± 9 s) static neck muscle stretch, while their heads were held fixed in space. Cross-correlation analysis revealed cyclical modulation of MSNA during sinusoidal neck muscle stretch (modulation index 45.4 ± 5.3 %), which was significantly less than the cardiac modulation of MSNA at rest (78.7 ± 4.2 %). Interestingly, cardiac modulation decreased significantly during sinusoidal neck displacement (63.0 ± 9.3 %). By contrast, there was no significant difference in MSNA activity during static ramp-and-hold displacements of the neck to the right or left compared with that with the head and neck aligned. These data suggest that dynamic, but not static, neck movements can modulate MSNA, presumably via projections of muscle spindle afferents to the vestibular nuclei, and may thus contribute to the regulation of blood pressure during orthostatic challenges.

Sympathetic single axonal discharge after spinal cord injury in humans: activity at rest and after bladder stimulation.

STUDY DESIGN: Clinical experimental mechanistic study. OBJECTIVES: (1) To determine in three spinal cord-injured patients whether individual muscle sympathetic nerve fibres below the level of the spinal lesion display spontaneous activity. (2) To determine in these patients if individual sympathetic vasoconstrictor fibres show a prolonged discharge following a bladder stimulus. SETTING: University hospital in Gothenburg, Sweden. METHODS: Microneurographic recordings of action potentials from individual muscle nerve sympathetic fibres in a peroneal nerve. Recordings of skin blood flow and electrodermal responses in a foot. RESULTS: In all patients, there was sparse ongoing spontaneous impulse traffic in individual sympathetic fibres. Brisk mechanical pressure over the urinary bladder evoked a varying number of action potentials in individual fibres, but the activity was brief and did not continue after the end of the evoked multiunit burst. CONCLUSION: Prolonged discharges in individual sympathetic fibres are unlikely to contribute to a long duration of blood pressure increases induced by brief bladder stimuli.

The vestibular system does not modulate fusimotor drive to muscle spindles in contracting leg muscles of seated subjects.

We previously showed that sinusoidal galvanic vestibular stimulation (GVS) does not modulate the firing of spontaneously active muscle spindles in relaxed human leg muscles. However, given that there is little, if any, fusimotor drive to relaxed human muscles, we tested the hypothesis that vestibular modulation of muscle spindles becomes apparent during volitional contractions at levels that engage the fusimotor system. Unitary recordings were made from 28 muscle spindle afferents via tungsten microelectrodes inserted percutaneously into the common peroneal nerve of seated awake human subjects. Twenty-one of the spindle afferents were spontaneously active at rest and each increased its firing rate during a weak static contraction; seven were silent at rest and were recruited during the contraction. Sinusoidal bipolar binaural galvanic vestibular stimulation (±2 mA, 100 cycles) was applied to the mastoid processes at 0.8 Hz. This continuous stimulation produced a sustained illusion of "rocking in a boat" or "swinging in a hammock" but no entrainment of EMG. Despite these robust vestibular illusions, none of the fusimotor-driven muscle spindles exhibited phase-locked modulation of firing during sinusoidal GVS. We conclude that this dynamic vestibular input was not sufficient to modulate the firing of fusimotor neurones recruited during a voluntary steady-state contraction, arguing against a significant role of the vestibular system in adjusting the sensitivity of muscle spindles via fusimotor neurones.

Bilateral activation of the trigeminothalamic tract by acute orofacial cutaneous and muscle pain in humans.

The conscious perception of somatosensory stimuli is thought to be located in the contralateral cerebral cortex. However, recent human brain imaging investigations in the spinal system report bilateral primary somatosensory cortex (SI) activations during unilateral noxious stimuli and that this ipsilateral spinal representation may be independent of transcallosal connections. In the trigeminal system, there is primate evidence for an ipsilateral somatosensory pathway through the thalamus to the face SI. However, the organization of the trigeminal nociceptive pathway in the human is not clear. The aim of this study was to determine whether noxious stimuli applied to the face are transmitted to the cerebral cortex by bilateral pathways. We used functional magnetic resonance imaging (fMRI) to compare ipsilateral and contralateral activation of the thalamus, SI and secondary somatosensory cortex (SII) during muscle and cutaneous orofacial pain and innocuous facial stimulation in healthy human subjects. We found that both muscle and cutaneous noxious stimuli, from injections of hypertonic saline into the right masseter or overlying skin, evoked bilateral increases in signal intensity in the region encompassing the ventral posterior thalamus as well as the face region of SI and SII. In contrast, innocuous unilateral brushing of the lower lip evoked a strict contralateral ventroposterior thalamic activation, but bilateral activation of SI and SII. These data indicate that, in contrast to innocuous inputs from the face, noxious information ascends bilaterally to the face SI through the ventroposterior thalamus in humans.

Effects of deep and superficial experimentally induced acute pain on skin sympathetic nerve activity in human subjects.

There is evidence in experimental animals that deep and superficial pain exert differential effects on cutaneous sympathetic activity. Skin sympathetic nerve activity (SSNA) was recorded from the common peroneal nerve of awake human subjects and injections of 0.5 ml hypertonic saline was made into the tibialis anterior muscle (causing a deep, dull ache) or 0.2 ml into the overlying skin (causing a sharp burning pain) at unexpected times. Both deep and superficial pain caused increases in SSNA immediately on injection and preceding the onset of pain for both muscle and skin pain (10.1 +/- 2.4 vs. 15.3 +/- 5.3 s; muscle versus skin, respectively). SSNA increases were short lasting (104.2 +/- 13.4 vs. 81.8 +/- 11.7 s; muscle versus skin pain) and did not follow muscle and skin pain profiles. Sweat release occurred following both intramuscular and subcutaneous injections of hypertonic saline. While muscle or skin pain invariably caused changes in skin blood flow as well as increases in sweat release, skin blood flow increased in females and decreased in males. We conclude that both acute muscle and skin pain cause an increase in SSNA, sweat release and gender-dependent changes in skin blood flow.

Neuropathic pain and primary somatosensory cortex reorganization following spinal cord injury.

The most obvious impairments associated with spinal cord injury (SCI) are loss of sensation and motor control. However, many subjects with SCI also develop persistent neuropathic pain below the injury which is often severe, debilitating and refractory to treatment. The underlying mechanisms of persistent neuropathic SCI pain remain poorly understood. Reports in amputees describing phantom limb pain demonstrate a positive correlation between pain intensity and the amount of primary somatosensory cortex (S1) reorganization. Of note, this S1 reorganization has also been shown to reverse with pain reduction. It is unknown whether a similar association between S1 reorganization and pain intensity exists in subjects with SCI. The aim of this investigation was to determine whether the degree of S1 reorganization following SCI correlated with on-going neuropathic pain intensity. In 20 complete SCI subjects (10 with neuropathic pain, 10 without neuropathic pain) and 21 control subjects without SCI, the somatosensory cortex was mapped using functional magnetic resonance imaging during light brushing of the right little finger, thumb and lip. S1 reorganization was demonstrated in SCI subjects with the little finger activation point moving medially towards the S1 region that would normally innervate the legs. The amount of S1 reorganization in subjects with SCI significantly correlated with on-going pain intensity levels. This study provides evidence of a link between the degree of cortical reorganization and the intensity of persistent neuropathic pain following SCI. Strategies aimed at reversing somatosensory cortical reorganization may have therapeutic potential in central neuropathic pain.

Effects of deep and superficial experimentally induced acute pain on muscle sympathetic nerve activity in human subjects.

Human studies conducted more than half a century ago have suggested that superficial pain induces excitatory effects on the sympathetic nervous system, resulting in increases in blood pressure (BP) and heart rate (HR), whereas deep pain is believed to cause vasodepression. To date, no studies have addressed whether deep or superficial pain produces such differential effects on muscle sympathetic nerve activity (MSNA). Using microneurography we recorded spontaneous MSNA from the common peroneal nerve in 13 awake subjects. Continuous blood pressure was recorded by radial arterial tonometry. Deep pain was induced by intramuscular injection of 0.5 ml hypertonic saline (5%) into the tibialis anterior muscle, superficial pain by subcutaneous injection of 0.2 ml hypertonic saline into the overlying skin. Muscle pain, with a mean rating of 4.9 +/- 0.8 (S.E.M.) on a 0-10 visual analog scale (VAS) and lasting on average 358 +/- 32 s, caused significant increases in MSNA (43.9 +/- 10.0%), BP (5.4 +/- 1.1%) and HR (7.0 +/- 2.0%) - not the expected decreases. Skin pain, rated at 4.9 +/- 0.6 and lasting 464 +/- 54 s, also caused significant increases in MSNA (38.2 +/- 12.8%), BP (5.1 +/- 2.1%) and HR (5.6 +/- 2.0%). The high-frequency (HF) to low-frequency (LF) ratio of heart rate variability (HRV) increased from 1.54 +/- 0.25 to 2.90 +/- 0.45 for muscle pain and 2.80 +/- 0.52 for skin pain. Despite the different qualities of deep (dull and diffuse) and superficial (burning and well-localized) pain, we conclude that pain originating in muscle and skin does not exert a differential effect on muscle sympathetic nerve activity, both causing an increase in MSNA and an increase in the LF:HF ratio of HRV. Whether this holds true for longer lasting experimental pain remains to be seen.

Cutaneous vasoconstriction as a measure of incipient autonomic dysreflexia during penile vibratory stimulation in spinal cord injury.

STUDY DESIGN: Measurement of haemodynamic responses, cutaneous blood flow and sweat release during penile vibratory stimulation (PVS) in spinal cord-injured men. OBJECTIVE: To assess the validity of using markers of sympathetic activity (cutaneous blood flow and sweat release) as a measure of incipient autonomic dysreflexia during PVS in spinal cord-injured men. SETTING: Prince of Wales Medical Research Institute, Australia. SUBJECTS: Ten spinal cord-injured men with injuries ranging from C3 to T6. METHODS: Continuous arterial pressure, intermittent auscultation, heart rate (HR), respiration, cutaneous blood flow and sweat release from both finger and toe were recorded during PVS. RESULTS: Vibration of the penis caused immediate cutaneous vasoconstriction, but negligible sweat release, in the hands and feet of the quadriplegics and the feet of the paraplegics. Systolic blood pressure (BP) increased by up to 90 mm Hg, and a compensatory vagal bradycardia was observed in five of the six quadriplegics and two of the four paraplegic subjects. CONCLUSION: Given that there was-in general-an inverse relationship between BP and skin blood flow, we conclude that continuous measurements of skin blood flow above and below the lesion can provide important information on the state of the sympathetic nervous system and early identification of reflexly evoked increases in sympathetic vasoconstrictor drive, below a spinal lesion. Coupled with a decrease in HR, this cutaneous vasoconstriction infers an increased BP.

Anatomical changes in human motor cortex and motor pathways following complete thoracic spinal cord injury.

A debilitating consequence of complete spinal cord injury (SCI) is the loss of motor control. Although the goal of most SCI treatments is to re-establish neural connections, a potential complication in restoring motor function is that SCI may result in anatomical and functional changes in brain areas controlling motor output. Some animal investigations show cell death in the primary motor cortex following SCI, but similar anatomical changes in humans are not yet established. The aim of this investigation was to use voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) to determine if SCI in humans results in anatomical changes within motor cortices and descending motor pathways. Using VBM, we found significantly lower gray matter volume in complete SCI subjects compared with controls in the primary motor cortex, the medial prefrontal, and adjacent anterior cingulate cortices. DTI analysis revealed structural abnormalities in the same areas with reduced gray matter volume and in the superior cerebellar cortex. In addition, tractography revealed structural abnormalities in the corticospinal and corticopontine tracts of the SCI subjects. In conclusion, human subjects with complete SCI show structural changes in cortical motor regions and descending motor tracts, and these brain anatomical changes may limit motor recovery following SCI.

Assessing the capacity of the sympathetic nervous system to respond to a cardiovascular challenge in human spinal cord injury.

STUDY DESIGN: Measurement of haemodynamic responses and cutaneous blood flow during an inspiratory-capacity apnoea following spinal cord injury (SCI). OBJECTIVE: To assess the capacity of the sympathetic nervous system to respond to a cardiovascular challenge following SCI. SETTING: Prince of Wales Medical Research Institute, Australia. SUBJECTS: Thirteen spinal cord injured subjects with injuries ranging from C5-T8 and eight able-bodied control subjects. METHODS: Continuous blood pressure, an electrocardiogram, respiration and cutaneous blood flow were recorded during a static maximum inspiratory breath-hold for 40 s. RESULTS: On average, systolic blood pressure decreased 26% from baseline in the spinal group during the breath-hold and remained below baseline throughout the entire apnoeic period. Heart rate in this group had an initial decrease from baseline but quickly increased throughout the breath-hold, being 17% above baseline in the recovery period. Systolic pressure in the control group decreased 12% from baseline at the beginning of the breath-hold but quickly stabilized for the remainder of the apnoea, with heart rate initially decreasing 22% and remaining below baseline throughout the breath-hold. CONCLUSION: A maximal inspiratory breath-hold, which is known to cause a sustained increase in muscle sympathetic nerve activity, is a simple test to perform in supine spinal cord-injured subjects, and provides information on the capacity of muscle and splanchnic vasoconstrictor activity to increase blood pressure in SCI. A sustained decrease in blood pressure, coupled with an increase in heart rate, infers interruption of sympathetic vasoconstrictor pathways to muscle and splanchnic vascular beds.

Selective activation of muscle and skin nociceptors does not trigger exaggerated sympathetic responses in spinal-injured subjects.

STUDY DESIGN: Measurement of sympathetic effector organ responses to selective activation of muscle and skin nociceptors below lesion in spinal cord-injured (SCI) subjects. OBJECTIVES: To test whether selective noxious stimulation below lesion causes exaggerated sympathetic responses in human SCI. SETTING: Prince of Wales Medical Research Institute, Australia. METHODS: Twelve subjects (C5-T10, ASIA A-C), none of whom had sensation below the lesion, were included in the study. Selective stimulation of muscle or cutaneous nociceptors was produced by bolus injection of hypertonic (5%) saline into the tibialis anterior muscle or overlying skin and compared with non-noxious electrical stimulation of the abdominal wall. Cutaneous vasoconstrictor (photoelectric plethysmography) and sudomotor (skin conductance) responses, in addition to respiration, heart rate and continuous arterial pressure were monitored. RESULTS: Electrical stimulation of the abdominal wall caused a significant increase in arterial pressure (31.8+/-6.1%). Conversely, intramuscular or subcutaneous injection of hypertonic saline caused no significant changes in blood pressure (-3.0+/-2.4%; -1.4+/-3.4%) heart rate, skin blood flow or sweat release. CONCLUSIONS: While hypertonic saline injected into muscle or skin induces strong pain, cutaneous vasoconstriction and sweat release in able-bodied subjects, we saw no evidence of exaggerated sympathoexcitation when these same noxious stimuli were delivered below lesion in subjects with SCI. This suggests that certain types of somatic noxious input may not trigger autonomic dysreflexia, and questions the concept that any painful stimuli originating below lesion can reliably trigger dysreflexia.

Vestibular inputs do not influence the fusimotor system in relaxed muscles of the human leg.

Descending vestibular pathways have been shown to influence recruitment thresholds of alpha motoneurones in both human and cat. However, whereas parallel connections to the fusimotor system have been shown in the cat, such connections have not yet been demonstrated in humans. In the present study we investigated whether vestibular inputs can influence the firing of spontaneously active muscle spindles in the leg via activation of gamma motoneurones. Unitary recordings were made from 30 muscle spindle afferents via tungsten microelectrodes inserted percutaneously into the common peroneal nerve of seated awake human subjects. Sinusoidal bipolar binaural galvanic vestibular stimulation (GVS; frequency 0.2, 0.5, 0.8 Hz, amplitude +/-2 mA, 100 cycles) was applied to the mastoid processes. This continuous stimulation produced a sustained frequency-dependent illusion of "rocking in a boat" or "swinging in a hammock". Despite these robust illusions none of the spontaneously active muscle spindles exhibited phase-locked modulation of firing during sinusoidal GVS. We conclude that this dynamic vestibular input was not sufficient to recruit gamma motoneurones, which are known to have little spontaneous activity in relaxed human muscles.

Somatotopic organization of the processing of muscle and cutaneous pain in the left and right insula cortex: a single-trial fMRI study.

The insula is involved in processing noxious information. It is consistently activated by acute noxious stimuli, can elicit pain on stimulation, and lesions encompassing the insula can alter pain perception. Anatomical tracing, electrophysiological and functional brain imaging investigations have suggested that the insula is somatotopically organized with respect to noxious cutaneous inputs. It has also recently been revealed that the anterior insula displays differential activation during cutaneous compared with muscle pain. Given this difference, it is important to determine if an insula somatotopy also exists for muscle pain. Using high-resolution functional magnetic resonance imaging (fMRI) we compared insula activation patterns in 23 subjects during muscle and cutaneous pain induced in the right leg and forearm. Group and frequency analyses revealed somatotopically organized signal increases in the posterior contralateral (left) and ipsilateral (right) anterior insula. Within the posterior contralateral insula, signal increases during both cutaneous and muscle forearm pain were located lateral and anterior to those evoked by leg pain, whereas in the ipsilateral anterior insula the pattern was reversed. Furthermore, within the ipsilateral anterior insula, muscle pain activated a region anterior to that activated by cutaneous pain. This somatotopic organization may be crucial for pain localization or other aspects of the pain experience that differ depending on both stimulation site and type of tissue activated. This study reveals that the insula is organized somatopically with respect to muscle and cutaneous pain and that this organization is further separated according to the tissue in which the pain originates.

Distinct forebrain activity patterns during deep versus superficial pain.

All pain is unpleasant, but different perceptual and emotional qualities are characteristic of pain originating in different structures. Pain of superficial (cutaneous) origin usually is sharp and restricted, whereas pain of deep origin (muscle/viscera) generally is dull and diffuse. Despite the differences it has been suggested previously that all pain is mediated by an invariant set ("neuromatrix") of brain structures. However, we report here, using functional magnetic resonance imaging (fMRI), that striking regional differences in brain activation patterns were the rule. Signal differences were found in regions implicated in emotion (perigenual cingulate cortex), stimulus localization and intensity (somatosensory cortex) and motor control (motor cortex, cingulate motor area). Further, most fMRI signal changes matched perceived changes in pain intensity. These findings clearly indicate that distinct neural activity patterns in distinct sets of brain structures are evoked by pain originating from different tissues of the body. Further, we suggest that these differences underlie the different perceptual and emotional reactions evoked by deep versus superficial pain.

Neural sites involved in the sustained increase in muscle sympathetic nerve activity induced by inspiratory capacity apnea: a fMRI study.

A maximal inspiratory breath hold (inspiratory capacity apnea) against a closed glottis evokes a large and sustained increase in muscle sympathetic nerve activity (MSNA). Because of its dependence on a high intrathoracic pressure, it has been suggested that this maneuver causes unloading of the low-pressure baroreceptors, known to increase MSNA. To determine the central origins of this sympathoexcitation, we used functional magnetic resonance imaging to define the loci and time course of activation of different brain areas. We hypothesized that, as previously shown for the Valsalvsa maneuver, discrete but widespread regions of the brain would be involved. In 15 healthy human subjects, a series of 90 gradient echo echo-planar image sets was collected during three consecutive 40-s inspiratory capacity apneas using a 3-T scanner. Global signal intensity changes were calculated and subsequently removed by using a detrending technique, which eliminates the global signal component from each voxel's signal intensity change. Whole brain correlations between changes in signal intensity and the known pattern of MSNA during the maneuver were performed on a voxel-by-voxel basis, and significant changes were determined by using a random-effects analysis procedure (P < 0.01, uncorrected). Significant signal increases emerged in multiple areas, including the rostral lateral medulla, cerebellar nuclei, anterior insula, dorsomedial hypothalamus, anterior cingulate, and lateral prefrontal cortexes. Decreases in signal intensity occurred in the dorsomedial and caudal lateral medulla, cerebellar cortex, hippocampus, and posterior cingulate cortex. Given that many of these sites have roles in cardiovascular control, the sustained increase in MSNA during an inspiratory capacity apnea is likely to originate from a distributed set of discrete areas.