The role of the inferior parietal lobule in writer's cramp.

Humans have a distinguishing ability for fine motor control that is subserved by a highly evolved cortico-motor neuronal network. The acquisition of a particular motor skill involves a long series of practice movements, trial and error, adjustment and refinement. At the cortical level, this acquisition begins in the parieto-temporal sensory regions and is subsequently consolidated and stratified in the premotor-motor cortex. Task-specific dystonia can be viewed as a corruption or loss of motor control confined to a single motor skill. Using a multimodal experimental approach combining neuroimaging and non-invasive brain stimulation, we explored interactions between the principal nodes of the fine motor control network in patients with writer's cramp and healthy matched controls. Patients and healthy volunteers underwent clinical assessment, diffusion-weighted MRI for tractography, and functional MRI during a finger tapping task. Activation maps from the task-functional MRI scans were used for target selection and neuro-navigation of the transcranial magnetic stimulation. Single- and double-pulse TMS evaluation included measurement of the input-output recruitment curve, cortical silent period, and amplitude of the motor evoked potentials conditioned by cortico-cortical interactions between premotor ventral (PMv)-motor cortex (M1), anterior inferior parietal lobule (aIPL)-M1, and dorsal inferior parietal lobule (dIPL)-M1 before and after inducing a long term depression-like plastic change to dIPL node with continuous theta-burst transcranial magnetic stimulation in a randomized, sham-controlled design. Baseline dIPL-M1 and aIPL-M1 cortico-cortical interactions were facilitatory and inhibitory, respectively, in healthy volunteers, whereas the interactions were converse and significantly different in writer's cramp. Baseline PMv-M1 interactions were inhibitory and similar between the groups. The dIPL-PMv resting state functional connectivity was increased in patients compared to controls, but no differences in structural connectivity between the nodes were observed. Cortical silent period was significantly prolonged in writer's cramp. Making a long term depression-like plastic change to dIPL node transformed the aIPL-M1 interaction to inhibitory (similar to healthy volunteers) and cancelled the PMv-M1 inhibition only in the writer's cramp group. These findings suggest that the parietal multimodal sensory association region could have an aberrant downstream influence on the fine motor control network in writer's cramp, which could be artificially restored to its normal function.

The thermal grill illusion: unmasking the burn of cold pain.

In Thunberg's thermal grill illusion, first demonstrated in 1896, a sensation of strong, often painful heat is elicited by touching interlaced warm and cool bars to the skin. Neurophysiological recordings from two classes of ascending spinothalamic tract neurons that are sensitive to innocuous or noxious cold showed differential responses to the grill. On the basis of these results, a simple model of central disinhibition, or unmasking, predicted a quantitative correspondence between grill-evoked pain and cold-evoked pain, which was verified psychophysically. This integration of pain and temperature can explain the thermal grill illusion and the burning sensation of cold pain and may also provide a basis for the cold-evoked, burning pain of the classic thalamic pain syndrome.

Pain affect encoded in human anterior cingulate but not somatosensory cortex.

Recent evidence demonstrating multiple regions of human cerebral cortex activated by pain has prompted speculation about their individual contributions to this complex experience. To differentiate cortical areas involved in pain affect, hypnotic suggestions were used to alter selectively the unpleasantness of noxious stimuli, without changing the perceived intensity. Positron emission tomography revealed significant changes in pain-evoked activity within anterior cingulate cortex, consistent with the encoding of perceived unpleasantness, whereas primary somatosensory cortex activation was unaltered. These findings provide direct experimental evidence in humans linking frontal-lobe limbic activity with pain affect, as originally suggested by early clinical lesion studies.

Multiple representations of pain in human cerebral cortex.

The representation of pain in the cerebral cortex is less well understood than that of any other sensory system. However, with the use of magnetic resonance imaging and positron emission tomography in humans, it has now been demonstrated that painful heat causes significant activation of the contralateral anterior cingulate, secondary somatosensory, and primary somatosensory cortices. This contrasts with the predominant activation of primary somatosensory cortex caused by vibrotactile stimuli in similar experiments. Furthermore, the unilateral cingulate activation indicates that this forebrain area, thought to regulate emotions, contains an unexpectedly specific representation of pain.

Unmyelinated tactile afferents signal touch and project to insular cortex.

There is dual tactile innervation of the human hairy skin: in addition to fast-conducting myelinated afferent fibers, there is a system of slow-conducting unmyelinated (C) afferents that respond to light touch. In a unique patient lacking large myelinated afferents, we found that activation of C tactile (CT) afferents produced a faint sensation of pleasant touch. Functional magnetic resonance imaging (fMRI) analysis during CT stimulation showed activation of the insular region, but not of somatosensory areas S1 and S2. These findings identify CT as a system for limbic touch that may underlie emotional, hormonal and affiliative responses to caress-like, skin-to-skin contact between individuals.

Tactile functions after cerebral hemispherectomy.

Patients that were hemispherectomized due to brain lesions early in life sometimes have remarkably well-preserved tactile functions on their paretic body half. This has been attributed to developmental neuroplasticity. However, the tactile examinations generally have been fairly crude, and subtle deficits may not have been revealed. We investigated monofilament detection and three types of tactile directional sensibility in four hemispherectomized patients and six healthy controls. Patients were examined bilaterally on the face, forearm and lower leg. Normal subjects were examined unilaterally. Following each test of directional sensibility, subjects were asked to rate the intensity of the stimulation. On the nonparetic side, results were almost always in the normal range. On the paretic side, the patients' capacity for monofilament detection was less impaired than their directional sensibility. Despite the disturbed directional sensibility on their paretic side the patients rated tactile sensations evoked by the stimuli, on both their paretic and nonparetic body halves, as more intense than normals. Thus, mechanisms of plasticity seem adequate for tactile detection and intensity coding but not for more complex tactile functions such as directional sensibility. The reason for the high vulnerability of tactile directional sensibility may be that it depends on spatially and temporally precise afferent information processed in a distributed cortical network.

Feelings of warmth correlate with neural activity in right anterior insular cortex.

The neural coding of perception can differ from that for the physical attributes of a stimulus. Recent studies suggest that activity in right anterior insular cortex may underlie thermal perception, particularly that of cold. We now examine whether this region is also important for the perception of warmth. We applied cutaneous warm stimuli on the left leg (warmth) in normal subjects (n = 7) during functional magnetic resonance imaging (fMRI). After each stimulus, subjects rated their subjective intensity of the stimulus using a visual analogue scale (VAS), and correlations were determined between the fMRI signal and the VAS ratings. We found that intensity ratings of warmth correlated with the fMRI signal in the right (contralateral to stimulation) anterior insular cortex. These results, in conjunction with previous reports, suggest that the right anterior insular cortex is important for different types of thermal perception.

Effect of environment on the long-term consequences of chronic pain.

Much evidence from pain patients and animal models shows that chronic pain does not exist in a vacuum but has varied comorbidities and far-reaching consequences. Patients with long-term pain often develop anxiety and depression and can manifest changes in cognitive functioning, particularly with working memory. Longitudinal studies in rodent models also show the development of anxiety-like behavior and cognitive changes weeks to months after an injury causing long-term pain. Brain imaging studies in pain patients and rodent models find that chronic pain is associated with anatomical and functional alterations in the brain. Nevertheless, studies in humans reveal that lifestyle choices, such as the practice of meditation or yoga, can reduce pain perception and have the opposite effect on the brain as does chronic pain. In rodent models, studies show that physical activity and a socially enriched environment reduce pain behavior and normalize brain function. Together, these studies suggest that the burden of chronic pain can be reduced by nonpharmacological interventions.

A model of transient hyperalgesia in the behaving monkey induced by topical application of capsaicin.

The aim of this study was to develop a model of transient hyperalgesia in the awake monkey performing operant tasks. An adult male rhesus monkey was trained to press a lever to receive food reward for detecting a light or to escape mechanical or thermal stimuli applied in the maxillary region of the face. A small contact thermode was positioned on one side of the face and a mechanical stimulator was placed on the other side. Noxious and innocuous thermal (43, 47 and 51 degrees C) or mechanical (245, 490, 736 and 1472 mN) stimuli of 4.5-s duration were presented in a pseudo-random order. The animal was tested before, 1 h and 24 h after topical capsaicin application (0.3 ml; 0.004 M). At the site of capsaicin application, the monkey escaped more thermal and mechanical stimuli 1 h after than before capsaicin, suggestive of thermal and mechanical hyperalgesia. At 24 h post-capsaicin, mechanical escape behavior had returned to baseline, but thermal escapes were still slightly elevated. Capsaicin had no significant effect on either mechanical or thermal escape behavior for stimuli presented to the contralateral site. Seven human subjects tested with these procedures reported higher pain intensity for similar stimuli after capsaicin application, in accordance with the monkey escape behavior. It is concluded that topical application of capsaicin on the maxillary face of the awake behaving monkey produces a transient thermal and mechanical hyperalgesia. The procedure is repeatable and produces no overt signs of distress. Thus it could provide an important tool for studying neural mechanisms of hyperalgesia and for testing analgesic treatments in primates.

The effects of dorsal column stimulation on measures of clinical and experimental pain in man.

Despite the extensive use of dorsal column stimulation (DCS) for the control of various chronic pain conditions, most clinicians report only modest success rates. Surprisingly, there has been little placebo-controlled investigation of its efficacy for altering either clinical or experimental pain perception. The current study compared the effects of DCS to placebo stimulation on clinical pain perception, perceived intensity of painful heat stimuli and visual stimuli, and the discrimination of small changes in noxious heat intensity and in light intensity. We found that DCS, but not placebo stimulation, significantly altered ratings of spontaneous clinical pain as well as those of painful cutaneous heat. In addition, heat discrimination thresholds were increased by DCS, but not placebo. On the other hand, DCS had no effect on ratings of visual stimulus intensity nor on visual discrimination, suggesting that the DCS modulation of pain perception was not due to a general change in attention. These data indicate that DCS significantly alters pain transmission in humans. Nevertheless, the relatively small reduction in clinical pain (less than 30%) must be weighed against the invasive nature of electrode implantation.

Representation of acute and persistent pain in the human CNS: potential implications for chemical intolerance.

The study of pain may be relevant to the study of chemical intolerance (CI) in many ways. Pain is often reported as a symptom of CI and it is defined as a subjective experience similar to many other symptoms of CI, making its objectification difficult. Furthermore, the CNS plastic changes that underlie the development of persistent pain states and abnormal pain responses may share some similarities with those involved in the sensitization to environmental chemicals. Functional brain imaging studies in humans demonstrate that acute pain evoked by nociceptive stimulation is accompanied by the activation of a widely distributed network of cerebral structures, including the thalamus and the somatosensory, insular, and anterior cingulate cortices. Abnormal activity within these regions has been associated with the experience of pain following damage to the peripheral or central nervous system (neuropathic pain) in a number of clinical populations. In normal individuals, activity within this network is correlated with subjective pain perception, is highly modifiable by cognitive interventions such as hypnosis and attention, and has been associated with emotions. Other cognitive mediators such as expectations can also produce robust changes in pain perception (e.g., in placebo analgesia). These effects likely depend on both higher-order cerebral structures and descending mechanisms modulating spinal nociceptive activity. These psychological processes can be solicited to reduce clinical pain and we speculate that they may further attenuate or promote central mechanisms involved in the transition from acute to persistent pain states. The investigation of central determinants of subjective experience is essential to assess the possibility that higher-order brain/psychological processes modulate and/or mediate the development of persistent pain states. These factors may contribute to the development of symptoms in CI.

A primate model for the study of tonic pain, pain tolerance and diffuse noxious inhibitory controls.

A primate model of cold pressor pain is described in which the animal itself initiates all trials, may terminate painful stimuli at any time, and controls the duration of the experimental session, thus avoiding the inadvertent administration of intolerable pain stimuli. Pain tolerance time varies directly with stimulus intensity and is sensitive to motivational factors. This model will facilitate the study of endogenous pain-modulatory pathways and the assessment of analgesic treatments in animals.

Wide-dynamic-range dorsal horn neurons participate in the encoding process by which monkeys perceive the intensity of noxious heat stimuli.

The role of dorsal horn wide-dynamic-range (WDR) and nociceptive-specific (NS) neurons in the encoding of the perceived intensity of noxious stimuli was determined while monkeys detected near-threshold changes in the intensity of noxious heat stimuli. Behavioral detection latencies were a reliable measure of the perceived intensity of these stimuli. There was a significant correlation between behavioral detection latency and neuronal discharge of WDR, but not NS neurons. In addition, WDR neurons exhibited greater activity on correctly detected vs non-detected trials, whereas NS neurons did not. We conclude that WDR neurons are involved in the encoding process by which monkeys perceive the intensity of noxious heat stimuli near detection threshold.

Dorsal horn opiate administration attenuates the perceived intensity of noxious heat stimulation in behaving monkey.

In monkeys trained to detect and discriminate noxious heat stimuli, morphine microinjected into the medullary dorsal horn attenuated the perceived intensity of noxious heat in a dose- and stimulus-dependent fashion. These data demonstrate a pharmacologically specific effect of opiates on the sensory intensity component of pain at the earliest central relay pathway transmitting noxious information.

Central pain in a hemispherectomized patient.

We have examined a hemispherectomized patient who complained of touch-evoked pricking and burning pain in her paretic hand, especially when the hand was cold. Psychophysical examination showed that for the paretic side she confused cool and warm temperatures, and confirmed that she had a robust allodynia to brush stroking that was enhanced at a cold ambient temperature. Functional magnetic resonance imaging (fMRI) showed that during brush-evoked allodynia, brain structures implicated in normal pain processing (viz. posterior part of the anterior cingulate cortex, secondary somatosensory cortex, and prefrontal cortices) were activated. The fMRI findings thus indicate that the central pain in this patient was served by brain structures implicated in normal pain processing. Possible pathophysiological mechanisms include plasticity as well as thalamic disinhibition.

Primary afferent and sacral dorsal horn neuron responses to vaginal probing in the cat.

An analysis was made of primary afferent and dorsal horn neuron responses to stimulation of genitalia of female cats. Three types of primary afferents responded to vaginal probing. The most common type responded maximally to the on- and off-ramps of non-noxious pressure applied directly to the clitoris. A second type responded similar but to surrounding labia mucosa. The third type showed a tonic discharge during deep vaginal-cervical probing. None of the primary afferents that responded to vaginal probing exhibited after-responses to any stimulus. However, a majority (76%) of wide dynamic range dorsal horn neurons showed increased rates of firing that outlasted the duration of vaginal probing by at least 28 sec. No other type of dorsal horn neuron responded in this manner. It appears that after-responses of wide dynamic range neurons to vaginal stimulation cannot be attributed to after-responses of primary afferents or to supraspinal mechanisms but are produced by mechanisms within the spinal cord.

Preoperative flurbiprofen in oral surgery: a method of choice in controlling postoperative pain.

The analgesic efficacy of a single 50-mg preoperative dose of flurbiprofen was compared with ACC-30 (aspirin 375 mg, codeine 30 mg, caffeine 30 mg) and a placebo. Forty patients scheduled for the surgical removal of impacted maxillary third molars were enrolled in a double-blind, randomized study. Using a within-subject design we compared the analgesic efficacy of (1) preoperative flurbiprofen 50 mg with placebo in 20 patients, and (2) preoperative ACC-30 with placebo in 20 other patients. Using a between-group design, we then compared the analgesic efficacy of (3) each drug given preoperatively and postoperatively, and (4) each drug given postoperatively only. Patients rated 2 pain dimensions, intensity and unpleasantness, hourly for 8 hours after the presurgical dose. The results of this study indicate that better analgesia was obtained when flurbiprofen was given preoperatively compared to only after surgery. Conversely, preoperative administration of ACC-30 did not demonstrate any significant influence on postsurgical analgesia. When comparing the 2 drugs, flurbiprofen proved to be superior in providing pain relief only when it was given prior to surgery. There was no difference between them when given only after surgery. Side effects were moderate and not significantly different between patients receiving flurbiprofen and those receiving ACC-30.

Modulation of heat pain perception by high frequency transcutaneous electrical nerve stimulation (TENS).

Although many studies have indicated that high frequency nonpainful transcutaneous electrical nerve stimulation (TENS) reduces clinical pain, controlled studies of the modulation of experimental pain by TENS have produced conflicting results. This study evaluated the effect of high frequency nonpainful TENS on heat pain perception using a model that we have previously shown to be sensitive to other nonpharmacological analgesic treatments. We found that TENS significantly reduced subjects' ratings of painful and near painful heat stimuli (43-51 degrees C) (p = 0.01) and increased the pain threshold from 46.7 to 47.9 degrees C (p = 0.002). Placebo stimulation had no effect on the subjects' ratings or on their pain thresholds. Furthermore, TENS did not alter subjects' ratings of visual stimuli, indicating that the analgesic effect was not due to a nonspecific distraction. These data suggest that TENS alters the perception of experimentally produced natural pain stimuli. The TENS related modulation also appears to be comparable to that produced by other nonpharmacological analgesic manipulations such as counterirritation and changes in attention.

The effect of reinforcement differences on choice and response distribution during stimulus compounding.

In Experiments I and II, rats were trained to respond on one lever during light and another during tone. The absence of tone and light controlled response cessation. In the multiple schedule of Experiment I, all reinforcements were received for responding in tone or light; in the chain schedule of Experiment II, all reinforcements were received in no tone + no light for not responding. Experiment I subjects, for which tone and light were associated with response and reinforcement increase, responded significantly more to tone-plus-light than to tone or light alone (additive summation). Experiment II subjects, for which tone and light were associated with response increase and reinforcement decrease, responded comparably to tone, light, and tone + light. Thus, additive summation was observed when stimulus-response and stimulus-reinforcer associations in tone and light were both positive, but not when they were conflicting. All subjects in both experiments responded predominantly on the light-correlated lever during tone + light, even when light intensity was reduced in testing. Furthermore, when a light was presented to a subject engaged in tone-associated responding, all subjects immediately switched the locus of responding to the light-correlated lever. No change in locus occurred when a tone was presented to a subject engaged in light-associated responding, irrespective of the stimulus-reinforcer association conditioned to tone. The light-lever preference in tone + light indicates that the heightened responding observed in Experiment I was not the summation of tone-associated behavior with light-associated behavior. Rather, it appears to be the result of a facilitation of one operant (light-associated responding) by the reinforcement-associated cue for the other.

An investigation of peak shift and behavioral contrast for autoshaped and operant behavior.

Instrumental treadle press and nonreinforced key peck responses were monitored during discrimination training and generalization testing in pigeons on positive and negative reinforcement schedules. In Experiment 1, six pigeons pressed a treadle for food on a multiple variable-interval extinction schedule. In Experiment 2, three pigeons pressed a treadle to avoid shock on a multiple free-operant avoidance extinction schedule. Different color keylights signaled S+ and S- components. Some positive behavioral contrast occurred during discrimination training, but the effect was small. Pecking occurred to the S+ keylight in Experiment 1 but not in Experiment 2. On stimulus generalization tests, all subjects displayed a positive peak shift when pressing the treadle for food or to avoid shock. However, peak shift was not found for nonreinforced "autopecks" on the stimulus key, although an area shift was observed in Experiment 1. This is the first demonstration of peak shift for pigeons pressing treadles and the only reliable demonstration of peak shift when negative reinforcement maintained responding. These results, in combination with previous demonstrations of peak shift for rats pressing levers and pigeons pecking keys, indicate that peak shift is a general by-product of operant discrimination learning, since it occurs across a variety of the organisms, responses, and reinforcers.