C-Fiber Loss as a Possible Cause of Neuropathic Pain in Schwannomatosis.

Schwannomatosis is the third form of neurofibromatosis and characterized by the occurrence of multiple schwannomas. The most prominent symptom is chronic pain. We aimed to test whether pain in schwannomatosis might be caused by small-fiber neuropathy. Twenty patients with schwannomatosis underwent neurological examination and nerve conduction studies. Levels of pain perception as well as anxiety and depression were assessed by established questionnaires. Quantitative sensory testing (QST) and laser-evoked potentials (LEP) were performed on patients and controls. Whole-body magnetic resonance imaging (wbMRI) and magnetic resonance neurography (MRN) were performed to quantify tumors and fascicular nerve lesions; skin biopsies were performed to determine intra-epidermal nerve fiber density (IENFD). All patients suffered from chronic pain without further neurological deficits. The questionnaires indicated neuropathic symptoms with significant impact on quality of life. Peripheral nerve tumors were detected in all patients by wbMRI. MRN showed additional multiple fascicular nerve lesions in 16/18 patients. LEP showed significant faster latencies compared to normal controls. Finally, IENFD was significantly reduced in 13/14 patients. Our study therefore indicates the presence of small-fiber neuropathy, predominantly of unmyelinated C-fibers. Fascicular nerve lesions are characteristic disease features that are associated with faster LEP latencies and decreased IENFD. Together these methods may facilitate differential diagnosis of schwannomatosis.

Acupuncture analgesia involves modulation of pain-induced gamma oscillations and cortical network connectivity.

Recent studies support the view that cortical sensory, limbic and executive networks and the autonomic nervous system might interact in distinct manners under the influence of acupuncture to modulate pain. We performed a double-blind crossover design study to investigate subjective ratings, EEG and ECG following experimental laser pain under the influence of sham and verum acupuncture in 26 healthy volunteers. We analyzed neuronal oscillations and inter-regional coherence in the gamma band of 128-channel-EEG recordings as well as heart rate variability (HRV) on two experimental days. Pain ratings and pain-induced gamma oscillations together with vagally-mediated power in the high-frequency bandwidth (vmHF) of HRV decreased significantly stronger during verum than sham acupuncture. Gamma oscillations were localized in the prefrontal cortex (PFC), mid-cingulate cortex (MCC), primary somatosensory cortex and insula. Reductions of pain ratings and vmHF-power were significantly correlated with increase of connectivity between the insula and MCC. In contrast, connectivity between left and right PFC and between PFC and insula correlated positively with vmHF-power without a relationship to acupuncture analgesia. Overall, these findings highlight the influence of the insula in integrating activity in limbic-saliency networks with vagally mediated homeostatic control to mediate antinociception under the influence of acupuncture.

Immediate Pain Relief in Adhesive Capsulitis by Acupuncture-A Randomized Controlled Double-Blinded Study.

OBJECTIVE: Primary adhesive capsulitis (AC), or frozen shoulder, is an insidious and idiopathic disease. Severe pain is predominant in the first two of the three stages of the condition, which can last up to 21 months. DESIGN, SETTING, AND SUBJECTS: Sixty volunteers with primary AC were randomly assigned to acupuncture with press tack needles compared with press tack placebos in a patient- and observer-blinded placebo-controlled study. The participants were subsequently offered classical needle acupuncture in an open follow-up clinical application. Thirty-four volunteers received conservative therapy, including 10 classical needle acupuncture treatments over 10 weeks, 13 volunteers received conservative therapy without classical needle acupuncture. All subjects agreed to follow-up after one year. METHODS: Acupuncture treatment was performed using a specific distal needling concept, using reflex areas on distant extremities avoiding local treatment. RESULTS: An immediate improvement of 3.3 ± 3.2 points in Constant-Murley Shoulder Score (CMS) pain subscore was seen in the press tack needles group and of 1.6 ± 2.8 points in the press tack placebos group (P <0.02). Conservative therapy including classical needle acupuncture significantly improved the pain subscore within 14.9 ± 15.9 weeks compared with 30.9 ± 15.8 weeks with only conservative therapy (P < 0.001). CONCLUSION: The efficiency of distal needling acupuncture on immediate pain reduction was demonstrated in patients with AC and confirmed the applicability of press tack needles and press tack placebos for double-blind studies in acupuncture. Subsequent clinical application observation proved that results obtained with press tack needles/press tack placebos can be transferred to classical needle acupuncture. Integrating acupuncture with conservative therapy showed superior effectiveness with respect to the time course of the recovery process in AC compared with conservative therapy alone.

Top-down and bottom-up modulation of pain-induced oscillations.

Attention is an important factor that is able to strongly modulate the experience of pain. In order to differentiate cortical mechanisms underlying subject-driven (i.e., top-down) and stimulus-driven (bottom-up) modes of attentional pain modulation, we recorded electric brain activity in healthy volunteers during painful laser stimulation while spatial attention and stimulus intensity were systematically varied. The subjects' task was to evaluate the pain intensity at the attended finger, while ignoring laser stimuli delivered to the other finger. Top-down (attention) and bottom up (intensity) influences differed in their effects on oscillatory response components. Attention towards pain induced a decrease in alpha and an increase in gamma band power, localized in the insula. Pain intensity modulated delta, alpha, beta and gamma band power. Source localization revealed stimulus driven modulation in the cingulate gyrus (CG) and somatosensory areas for gamma power changes. Our results indicate that bottom-up and top-down modes of processing exert different effects on pain-induced slow and fast oscillatory activities. Future studies may examine pain-induced oscillations using this paradigm to test for altered attentional pain control in patients with chronic pain.

Two-year follow-up after decompressive surgery with and without implantation of an interspinous device for lumbar spinal stenosis: a prospective controlled study.

STUDY DESIGN: Two-arm prospective controlled study. OBJECTIVE: The aim of our study was to prospectively assess the outcome of symptomatic lumbar spinal stenosis (LSS) treated with decompressive surgery alone in comparison with additional implantation of the Coflex interspinous device. SUMMARY OF BACKROUND DATA: In symptomatic LSS, decompression surgery is an established treatment. Recently, a number of interspinous devices have been introduced as an alternative to conventional surgical procedures. The theoretical aim of the Coflex device is to unload the facet joints, restore foraminal height, and provide stability to improve the clinical outcome. Published information is limited, and there are no data that prove the superiority of the implant in comparison with traditional surgical approaches. METHODS: Sixty-two patients with symptomatic LSS were treated with decompressive surgery; 31 of these patients received an additional Coflex device. Preoperatively and postoperatively, disability and pain scores were measured using the Oswestry Disability Index, the Roland-Morris Disability Questionnaire, the Visual Analog Scale, and the pain-free walking distance. Patients underwent postoperative assessments at 3, 6, 12, and 24 month including the above-mentioned scores and patient satisfaction. RESULTS: There was a significant improvement (P<0.001) in the clinical outcome assessed in the Oswestry Disability Index, the Roland-Morris Disability Questionnaire, the Visual Analog Scale, and the pain-free walking distance at all times of reinvestigation compared with the base line in both groups. Up to 2 years after surgery, there were no significant differences between both groups in all ascertained parameters, including the patient satisfaction and subjective operation decision. CONCLUSIONS: The results of this first prospective controlled study indicate that the additional placement of a Coflex interspinous device does not improve the already good clinical outcome after decompressive surgery for LSS in the 24-month follow-up interval.

Spectral signatures of viewing a needle approaching one's body when anticipating pain.

When viewing the needle of a syringe approaching your skin, anticipation of a painful prick may lead to increased arousal. How this anticipation is reflected in neural oscillatory activity and how it relates to activity within the autonomic nervous system is thus far unknown. Recently, we found that viewing needle pricks compared with Q-tip touches increases the pupil dilation response (PDR) and perceived unpleasantness of electrical stimuli. Here, we used high-density electroencephalography to investigate whether anticipatory oscillatory activity predicts the unpleasantness of electrical stimuli and PDR while viewing a needle approaching a hand that is perceived as one's own. We presented video clips of needle pricks and Q-tip touches, and delivered spatiotemporally aligned painful and nonpainful intracutaneous electrical stimuli. The perceived unpleasantness of electrical stimuli and the PDR were enhanced when participants viewed needle pricks compared with Q-tip touches. Source reconstruction using linear beamforming revealed reduced alpha-band activity in the posterior cingulate cortex (PCC) and fusiform gyrus before the onset of electrical stimuli when participants viewed needle pricks compared with Q-tip touches. Moreover, alpha-band activity in the PCC predicted PDR on a single trial level. The anticipatory reduction of alpha-band activity in the PCC may reflect a neural mechanism that serves to protect the body from forthcoming harm by facilitating the preparation of adequate defense responses.

The influence of music and music therapy on pain-induced neuronal oscillations measured by magnetencephalography.

Modern forms of music therapy are clinically established for various therapeutic or rehabilitative goals, especially in the treatment of chronic pain. However, little is known about the neuronal mechanisms that underlie pain modulation by music. Therefore, we attempted to characterize the effects of music therapy on pain perception by comparing the effects of 2 different therapeutic concepts, referred to as receptive and entrainment methods, on cortical activity recorded by magnetencephalography in combination with laser heat pain. Listening to preferred music within the receptive method yielded a significant reduction of pain ratings associated with a significant power reduction of delta-band activity in the cingulate gyrus, which suggests that participants displaced their focus of attention away from the pain stimulus. On the other hand, listening to self-composed "pain music" and "healing music" within the entrainment method exerted major effects on gamma-band activity in primary and secondary somatosensory cortices. Pain music, in contrast to healing music, increased pain ratings in parallel with an increase in gamma-band activity in somatosensory brain structures. In conclusion, our data suggest that the 2 music therapy approaches operationalized in this study seem to modulate pain perception through at least 2 different mechanisms, involving changes of activity in the delta and gamma bands at different stages of the pain processing system.

Crossmodal bias of visual input on pain perception and pain-induced beta activity.

In our environment, acute pain is often accompanied by input from other sensory modalities, like visual stimuli, which can facilitate pain processing. To date, it is not well understood how these inputs influence the perception and processing of pain. Previous studies on integrative processing between sensory modalities other than pain have shown that multisensory response gains are strongest when the constituent unimodal stimuli are minimally effective in evoking responses. This finding has been termed the principle of inverse effectiveness (IE). In this high-density electroencephalography study, we investigated the influence of Gabor patches of low and high contrast levels on the perception and processing of spatially and temporally aligned painful electrical stimuli of low and high intensities. Subjective pain ratings, event-related potentials (ERPs) and oscillatory responses served as dependent measures. In line with the principle of IE, stronger crossmodal biasing effects of visual input on subjective pain ratings were found for low compared to high intensity painful stimuli. This effect was paralleled by stronger bimodal interactions in right-central ERPs (150-200ms) for low compared to high intensity pain stimuli. Moreover, an enhanced suppression of medio-central beta-band activity (12-24Hz, 200-400ms) was found for low compared to high intensity pain stimuli. Our findings possibly reflect a facilitation of stimulus processing that serves to enhance response readiness of the sensorimotor system following painful stimulation. Taken together, our study demonstrates that multisensory processing between visual and painful stimuli follows the principle of IE and suggests a role for beta-band oscillations in the crossmodal modulation of pain.

Viewing a needle pricking a hand that you perceive as yours enhances unpleasantness of pain.

"Don't look and it won't hurt" is commonly heard advice when receiving an injection, which implies that observing needle pricks enhances pain perception. Throughout our lives, we repeatedly learn that sharp objects cause pain when penetrating our skin, but situational expectations, like information given by the clinician prior to an injection, may also influence how viewing needle pricks affects forthcoming pain. How both previous experiences and acute situational expectations related to viewing needle pricks modulate pain perception is unknown. We presented participants with video clips of a hand perceived as their own being either pricked by a needle or touched by a Q-tip, while concurrently applying painful or nonpainful electrical stimuli. Intensity and unpleasantness ratings, as well as pupil dilation responses, were monitored. Effects of situational expectations about the strength of electrical stimuli were investigated by manipulating the contingency between clips and electrical stimuli across experimental blocks. Participants were explicitly informed about the contingency. Intensity ratings of electrical stimuli were higher when a clip was associated with expectation of painful compared to nonpainful stimuli, suggesting that situational expectations about forthcoming pain bias perceived intensity. Unpleasantness ratings and pupil dilation responses were higher when participants viewed a needle prick, compared to when they viewed a Q-tip touch, suggesting that previous experiences with viewing needle pricks primarily act upon perceived unpleasantness. Thus, remote painful experiences with viewing needle pricks, together with information given prior to an injection, differentially shape the impact of viewing a needle prick on pain perception.

Emotional facial expressions modulate pain-induced beta and gamma oscillations in sensorimotor cortex.

Painful events in our environment are often accompanied by stimuli from other sensory modalities. These stimuli may influence the perception and processing of acute pain, in particular when they comprise emotional cues, like facial expressions of people surrounding us. In this whole-head magnetoencephalography (MEG) study, we examined the neuronal mechanisms underlying the influence of emotional (fearful, angry, or happy) compared to neutral facial expressions on the processing of pain in humans. Independent of their valence, subjective pain ratings for intracutaneous inputs were higher when pain stimuli were presented together with emotional facial expressions than when they were presented with a neutral facial expression. Source reconstruction using linear beamforming revealed pain-induced early (70-270 ms) oscillatory beta-band activity (BBA; 15-25 Hz) and gamma-band activity (GBA; 60-80 Hz) in the sensorimotor cortex. The presentation of faces with emotional expressions compared to faces with neutral expressions led to a stronger bilateral suppression of the pain-induced BBA, possibly reflecting enhanced response readiness of the sensorimotor system. Moreover, pain-induced GBA in the sensorimotor cortex was larger for faces expressing fear than for faces expressing anger, which might reflect the facilitation of avoidance-motivated behavior triggered by the concurrent presentation of faces with fearful expressions and painful stimuli. Thus, the presence of emotional cues, like facial expressions from people surrounding us, while receiving acute pain may facilitate neuronal processes involved in the preparation and execution of adequate protective motor responses.

Somatotopy of placebo analgesia is independent of spatial attention.

Placebo analgesia is being increasingly appraised as an effective support of pharmacological and surgical treatments of pain. The understanding of its neurobiological and psychological basis is therefore of high clinical relevance. It has been shown that placebo analgesia is somatotopically organized and relies on endogenous opioids. However, it is not clear whether temporal fluctuations of cue-dependent spatial attention account for the site specificity of placebo analgesia or whether a somatotopic placebo effect is possible without an attentional focus on the respective location. To address this issue we induced placebo expectations for one specific foot in healthy subjects, the other foot serving as a control location. The feet were stimulated in random order by painful laser stimuli. Half of the pulses were cued for stimulus location, whereas in the other half of trials the subjects were naïve about the location. We found that about half of the subjects exhibited a somatotopic placebo effect that was statistically independent of the spatial cue. We suggest that, after the induction of an initial expectation, placebo analgesia is spatially specific but does not necessarily depend on momentary fluctuations of spatial attention. This result rather suggests that the somatotopy of placebo analgesia relies on the creation of spatially guided expectations or conditioning, but can be maintained without ongoing monitoring of the affected body part.

Does an interspinous device (Coflex) improve the outcome of decompressive surgery in lumbar spinal stenosis? One-year follow up of a prospective case control study of 60 patients.

A number of interspinous process devices have recently been introduced to the lumbar spinal market as an alternative to conventional surgical procedures in the treatment of symptomatic lumbar stenosis. One of those "dynamic" devices is the Coflex device which has been already implanted worldwide more than 14,000 times. The aim of implanting this interspinous device is to unload the facet joints, restore foraminal height and provide stability in order to improve the clinical outcome of surgery. Published information is limited, and there are so far no data of comparison between the implant and traditional surgical approaches such as laminotomy. The purpose of our prospective study is to evaluate the surgical outcome of decompressive surgery in comparison to decompressive surgery and additional implantation of the Coflex interspinous Device. 60 patients who were all treated in the Spine Center of Klinikum Neustadt, Germany for a one or two level symptomatic LSS with decompressive surgery were included. Two groups were built. In Group one (UD) we treated 30 patients with decompression surgery alone and group two (CO) in 30 patients a Coflex device was additional implanted. Pre- and postoperatively disability and pain scores were measured using the Oswestry disability index (ODI), the Roland-Morris score (RMS), the visual analogue scale (VAS) and the pain-free walking distance (WD). Patients underwent postoperative assessments 3, 6 and 12 month including the above-mentioned scores as well as patient satisfaction. In both groups we could see a significant improve (p < 0.001) in the clinical outcome assessed in the ODI, in the RMS for evaluation of back pain, in the VAS and in the pain-free WD at all times of reinvestigation compared to base line. At 1-year follow up there were no statistically differences between both groups in all ascertained parameters including patient satisfaction and subjective operation decision. Because there is no current evidence of the efficacy of the Coflex device we need further data from randomized controlled studies for defining the indications for theses procedures. To the best of our knowledge this is the first prospective controlled study which compares surgical decompression of lumbar spinal stenosis with additional implanting of an interspinous Coflex device in the treatment of symptomatic LSS.

Laser-evoked potentials: prognostic relevance of pain pathway defects in patients with acute radiculopathy.

The radicular pain syndrome is a major problem in public health care that can lead to chronic back and leg pain in 30%. Ischalgia and back pain are the most prominent signs of dorsal root affection. Until now, no clinical or neurophysiological test procedure exists that evaluates the function of the dorsal root and predicts the prognosis of patients suffering from RPS. We have recently demonstrated that laser-evoked potentials (LEP) are able to demonstrate dorsal root damage. With this study, we investigated 54 patients with acute radicular symptoms and compared LEP parameters (side to side difference of latency and amplitude, transformed to a z-score) with their state of health after 3 months to calculate their predictive value for outcome prognosis. Most significantly, the latency difference between the LEP of the affected dermatome relative to the contralateral healthy dermatome was able to predict the prognosis. Latency z score above two demonstrates a 91% specificity (33% sensitivity) for a poor outcome at 3 months. A significant relation between amplitude changes and the main outcome measure could not be shown. Only extreme changes (z score >10) in amplitude show a high specificity for the persistence of ischialgia in particular (specificity 0.94; sensitivity 0.35). All other parameters, such as clinical scores or other LEP parameters, were not able to predict the outcome of patients. We propose that clinical testing using LEP with latency analysis is a useful tool for estimating the course of disease, so that patients with poor predictive parameters can be treated more invasively at early disease stages to avoid persistence of radiculopathy.

C-fiber-related EEG-oscillations induced by laser radiant heat stimulation of capsaicin-treated skin.

Nociceptive input reaches the brain via two different types of nerve fibers, moderately fast A-delta and slowly conducting C-fibers, respectively. To explore their distinct roles in normal and inflammatory pain we used laser stimulation of normal and capsaicin treated skin at proximal and distal arm sites in combination with time frequency transformation of electroencephalography (EEG) data. Comparison of phase-locked (evoked) and non-phase-locked (total) EEG to laser stimuli revealed three significant pain-related oscillatory responses. First, an evoked response in the delta-theta band, mediated by A-fibers, was reduced by topical capsaicin treatment. Second, a decrease of total power in the alpha-to-gamma band reflected both an A- and C-nociceptor-mediated response with only the latter being reduced by capsaicin treatment. Finally, an enhancement of total power in the upper beta band was mediated exclusively by C-nociceptors and appeared strongly augmented by capsaicin treatment. These findings suggest that phase-locking of brain activity to stimulus onset is a critical feature of A-delta nociceptive input, allowing rapid orientation to salient and potentially threatening events. In contrast, the subsequent C-nociceptive input exhibits clearly less phase coupling to the stimulus. It may primarily signal the tissue status allowing more long-term behavioral adaptations during ongoing inflammatory events that accompany tissue damage.

Role of synchronized oscillatory brain activity for human pain perception.

The understanding of cortical pain processing in humans has significantly improved since the development of modern neuroimaging techniques. Non-invasive electrophysiological approaches such as electro- and magnetoencephalography have proven to be helpful tools for the real-time investigation of neuronal signals and synchronous communication between cortical areas. In particular, time-frequency decomposition of signals recorded with these techniques seems to be a promising approach because different pain-related oscillatory changes can be observed within different frequency bands, which are likely to be linked to specific sensory and motor functions. In this review we discuss the latest evidence on pain-induced time-frequency signals and propose that changes in oscillatory activity reflect an essential communication mechanism in the brain that is modulated during pain processing. The importance of synchronization processes for normal and pathological pain processing, such as chronic pain states, is discussed.

Noxious counterirritation in patients with advanced osteoarthritis of the knee reduces MCC but not SII pain generators: A combined use of MEG and EEG.

CHRONIC PAIN IS MAINLY A RESULT OF TWO PROCESSES: peripheral and central sensitization, which can result in neuroplastic changes. Previous psychophysical studies suggested a decrease of the so-called pain-inhibiting-pain effect (DNIC) in chronic pain patients. We aimed to study the DNIC effect on the neuronal level using magnetoencephalography and electroencephalography in 12 patients suffering from advanced unilateral knee osteoarthritis (OA). DNIC was induced in patients by provoking the typical OA pain by a slightly hyperextended joint position, while they received short electrical pain stimuli. Although the patients did not report a reduction of electrical pain perception, the cingulate gyrus showed a decrease of activation during provoked OA pain, while activity in the secondary somatosensory cortex did not change. Based on much stronger DNIC induction at comparable intensities of an acute counterirritant pain in healthy subjects this result suggests a deficit of DNIC in OA patients. We suggest that the strength of DNIC is subject to neuronal plasticity of descending inhibitory pain systems and diminishes during the development of a chronic pain condition.

Attention to painful stimulation enhances gamma-band activity and synchronization in human sensorimotor cortex.

A number of cortical regions are involved in processing pain-related information. The SI and SII somatosensory cortices process mainly sensory discriminative attributes but also play an important role in recognition and memory of painful events. Regions such as SII and the posterior insula appear to be the first stations that house processes by which attention profoundly shapes both behavioral responses and subjective pain experience. We investigated the influence of directed attention on pain-induced oscillations and synchronization processes using magnetoencephalogram in combination with an oddball paradigm in 20 healthy subjects. The subject's task was to count rare painful electrical stimuli applied to one finger, while ignoring frequent stimuli at a different finger. A high detection ratio was observed for all blocks and subjects. Early evoked oscillations in the delta-band increased with higher stimulus intensity and directed attention, most prominently at contralateral sensorimotor sites. Furthermore, suppression and rebound of beta activity were observed after painful stimulation. Moreover, induced oscillatory activity in the high gamma-band increased with directed attention, an effect being significantly stronger for high compared with low stimulus intensity. Coupling analysis performed for this high gamma response revealed stronger functional interactions between ipsilateral and contralateral sites during attention. We conclude that pain-induced high-frequency activity in sensorimotor areas may reflect an attentional augmentation of processing, leading to enhanced saliency of pain-related signals and thus to more efficient processing of this information by downstream cortical centers.

Duration of the cue-to-pain delay increases pain intensity: a combined EEG and MEG study.

Expectation of pain is an important adaptive process enabling individuals to avoid bodily harm. It reflects the linking of past experience and environmental cues with imminent threat. In the present study, we examined changes in perceived pain contingent upon variation of the interval between an auditory cue and a subsequent painful laser stimulus. The duration of the cue-to-stimulus delay was systematically varied between 2, 4 and 6 s. Pain intensity and evoked brain responses measured by EEG and MEG recordings were analysed. Pain ratings from 15 subjects increased with longer cue-to-pain delays, accompanied by an increase in activity of the midcingulate cortex (MCC), as modelled from evoked EEG potential maps. On the other hand, MEG-based source activity in secondary somatosensory (SII) cortex remained unaffected by manipulation of the cue-to-stimulus interval. We conclude that activity in limbic structures such as MCC play a key role in the temporal dynamics of recruitment of expectation towards pain. Although this reaction is adaptive if the individual is able to avoid the stimulus, it is maladaptive if such opportunity is not present.