Clemens Forster

Brain processing during mechanical hyperalgesia in complex regional pain syndrome: a functional MRI study

&NA; Complex Regional Pain Syndromes (CRPS) are characterized by a triad of sensory, motor and autonomic dysfunctions of still unknown origin. Pain and mechanical hyperalgesia are hallmarks of CRPS. There are several lines of evidence that central nervous system (CNS) changes are crucial for the development and maintenance of mechanical hyperalgesia. However, little is known about the cortical structures associated with the processing of hyperalgesia in pain patients. This study describes the use of functional magnetic resonance imaging (fMRI) to delineate brain activations during pin‐prick hyperalgesia in CRPS. Twelve patients, in whom previous quantitative sensory testing revealed the presence of hyperalgesia to punctuate mechanical stimuli (i.e. pin‐prick hyperalgesia), were included in the study. Pin‐prick‐hyperalgesia was elicited by von‐Frey filaments at the affected limb. For control, the identical stimulation was performed on the unaffected limb. fMRI was used to explore the corresponding cortical activations. Mechanical stimulation at the unaffected limb was non‐painful and mainly led to an activation of the contralateral primary somatosensory cortex (S1), insula and bilateral secondary somatosensory cortices (S2). The stimulation of the affected limb was painful (mechanical hyperalgesia) and led to a significantly increased activation of the S1 cortex (contralateral), S2 (bilateral), insula (bilateral), associative‐somatosensory cortices (contralateral), frontal cortices and parts of the anterior cingulate cortex. The results of our study indicate a complex cortical network activated during pin‐prick hyperalgesia in CRPS. The underlying neuronal matrix comprises areas not only involved in nociceptive, but also in cognitive and motor processing.

Automatic classification and analysis of microneurographic spike data using a PC/AT

Using a standard PC-AT with a commercial analog data interface a system was designed which supports microneurographic experiments and which may also be used for other types of extracellular spike recordings. The signal is sampled on-line at 25 kHz and a spike is detected if the signal passes a certain threshold. The spikes are displayed on the screen and stored on disk. A second on-line mode records the responses of the examined unit to electrical stimulations, which are used to identify the type of fibre and to test the subsequent spike classification. The spikes are classified off-line using a template matching algorithm, which has unsupervised learning and discrimination phases. The results are displayed in a time-frequency plot and may be checked with the responses to electrical stimulations. Artifacts from EMG and other electrical fields are reliably sorted out. In recordings, which include more than one unit, their spikes are discriminated with a low error rate.

BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation

SummaryDirect vagus nerve stimulation (VNS) has proved to be an effective treatment for seizure disorder and major depression. However, since this invasive technique implies surgery, with its side-effects and relatively high financial costs, a non-invasive method to stimulate vagal afferences would be a great step forward. We studied effects of non-invasive electrical stimulation of the nerves in the left outer auditory canal in healthy subjects (n = 22), aiming to activate vagal afferences transcutaneously (t-VNS). Short-term changes in brain activation and subjective well-being induced by t-VNS were investigated by functional magnetic resonance imaging (fMRI) and psychometric assessment using the Adjective Mood Scale (AMS), a self-rating scale for current subjective feeling. Stimulation of the ear lobe served as a sham control.fMRI showed that robust t-VNS induced BOLD-signal decreases in limbic brain areas, including the amygdala, hippocampus, parahippocampal gyrus and the middle and superior temporal gyrus. Increased activation was seen in the insula, precentral gyrus and the thalamus. Psychometric assessment revealed significant improvement of well-being after t-VNS. Ear lobe stimulation as a sham control intervention did not show similar effects in either fMRI or psychometric assessment. No significant effects on heart rate, blood pressure or peripheral microcirculation could be detected during the stimulation procedure. Conclusions. Our study shows the feasibility and beneficial effects of transcutaneous nerve stimulation in the left auditory canal of healthy subjects. Brain activation patterns clearly share features with changes observed during invasive vagus nerve stimulation.

Neural activation during experimental allodynia: a functional magnetic resonance imaging study.

Pain induced by gentle stroking, i.e. dynamic–mechanical allodynia, is one of the most distressing symptoms of neuropathic pain. The underlying neuronal pathways are still a matter of debate. Here, we investigated the cortical activations associated with dynamic‐mechanical allodynia in an experimental human pain model by functional magnetic resonance imaging (fMRI). Large and stable areas of brush‐evoked allodynia were induced in 11 healthy subjects by topical capsaicin (2.5%, 30 min) application following local heating (45 °C for 5 min), thus combining both physical and chemical sensitization. During the fMRI experiments, allodynia was rekindled by local heat application (40 °C for 5 min) immediately before the allodynia testing. Brushing the untreated forearm (control condition) led to activations of the contralateral primary somatosensory cortex (S1), contralateral parietal association cortex (PA), bilateral secondary somatosensory cortices (S2) and insula (contralateral). Brushing the allodynic skin was painful and the cortical responses were partially overlapping with those induced by the nonpainful brush stimulation. Additionally, the contralateral inferior frontal cortex (IFC) and the ipsilateral insula were activated. Direct comparison between nonpainful brushing and brush‐evoked allodynia revealed significant increases in blood oxygenation level‐dependent (BOLD) signals in contralateral S1, PA, IFC and bilateral S2/insula during allodynia. This study highlights the importance of a cortical network comprising S1, PA, S2/insula and IFC in the processing of dynamic–mechanical allodynia in the human brain. Furthermore, it demonstrates that the combined heat/capsaicin model can be used successfully in the exploration of brain processes underlying stimulus‐evoked pain.

Effects of antihyperalgesic drugs on experimentally induced hyperalgesia in man

&NA; In a double‐blind, cross‐over study, ibuprofen (600 mg), a peripherally‐acting selective &kgr;‐opioid receptor agonist (7.5 mg), or placebo were given orally in experiments on healthy volunteers 1 h before assessment of pain thresholds to radiant heat and of pain ratings to controlled mechanical impact stimuli. Mechanical and thermal hyperalgesia had been induced 24 h before by irradiating skin patches on the ventral side of the upper leg. UVB irradiation induced mechanical and thermal hyperalgesia at radiation dosages of three times the minimal erythema dose. UVA irradiation resulted in an immediate erythema and a delayed tanning of the skin, however, no hyperalgesia was observed. For comparison another model of mechanical hyperalgesia was applied in the same experiments which has been previously proven sensitive to non‐steroidal anti‐inflammatory drugs (NSAIDs). In this model hyperalgesia was assessed, which develops during repetitive pinching of skin folds (pinch model). Ibuprofen significantly diminished heat and mechanical hyperalgesia induced by UVB, but had no effect on pain responses obtained from untreated skin. It also had an antihyperalgesic effect in the pinch stimulus paradigm. In contrast, the &kgr;‐agonist showed no antihyperalgesic efficacy in the chosen models. It is concluded that the UVB model, as the pinch model, is suitable for establishing antihyperalgesic effects of NSAIDs, but probably not of &kgr;‐receptor agonists, in healthy human volunteers. Compared to the pinch stimulus model, the UVB model offers additional advantages: (a) drugs may be tested after induction of the skin trauma by UV and this situation is more similar to the clinical use of antihyperalgesic drugs. (b) Since mechanical and thermal hyperalgesia is induced by UVB, drug effects can be tested upon both forms of hyperalgesia.

CNS BOLD fMRI Effects of Sham-Controlled Transcutaneous Electrical Nerve Stimulation in the Left Outer Auditory Canal – A Pilot Study

BACKGROUND It has recently been shown that electrical stimulation of sensory afferents within the outer auditory canal may facilitate a transcutaneous form of central nervous system stimulation. Functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) effects in limbic and temporal structures have been detected in two independent studies. In the present study, we investigated BOLD fMRI effects in response to transcutaneous electrical stimulation of two different zones in the left outer auditory canal. It is hypothesized that different central nervous system (CNS) activation patterns might help to localize and specifically stimulate auricular cutaneous vagal afferents. METHODOLOGY 16 healthy subjects aged between 20 and 37 years were divided into two groups. 8 subjects were stimulated in the anterior wall, the other 8 persons received transcutaneous vagus nervous stimulation (tVNS) at the posterior side of their left outer auditory canal. For sham control, both groups were also stimulated in an alternating manner on their corresponding ear lobe, which is generally known to be free of cutaneous vagal innervation. Functional MR data from the cortex and brain stem level were collected and a group analysis was performed. RESULTS In most cortical areas, BOLD changes were in the opposite direction when comparing anterior vs. posterior stimulation of the left auditory canal. The only exception was in the insular cortex, where both stimulation types evoked positive BOLD changes. Prominent decreases of the BOLD signals were detected in the parahippocampal gyrus, posterior cingulate cortex and right thalamus (pulvinar) following anterior stimulation. In subcortical areas at brain stem level, a stronger BOLD decrease as compared with sham stimulation was found in the locus coeruleus and the solitary tract only during stimulation of the anterior part of the auditory canal. CONCLUSIONS The results of the study are in line with previous fMRI studies showing robust BOLD signal decreases in limbic structures and the brain stem during electrical stimulation of the left anterior auditory canal. BOLD signal decreases in the area of the nuclei of the vagus nerve may indicate an effective stimulation of vagal afferences. In contrast, stimulation at the posterior wall seems to lead to unspecific changes of the BOLD signal within the solitary tract, which is a key relay station of vagal neurotransmission. The results of the study show promise for a specific novel method of cranial nerve stimulation and provide a basis for further developments and applications of non-invasive transcutaneous vagus stimulation in psychiatric patients.

Delayed responses to electrical stimuli reflect C-fiber responsiveness in human microneurography

The slowing of impulse conduction during the relative refractory period has often been used to assess activation of C-fibers, in particular, in human microneurography. This study aimed to evaluate the sensitivity of this method and the factors affecting it. Thirty cutaneous C-fibers were recorded from the peroneal nerves of healthy human subjects. Intracutaneous electrical stimulation in the receptive field at 4 s intervals, after some minutes of adaptation, induced spike discharges at constant latency. One or more conditioning stimulus pulses were interpolated at different intervals and the increase in latency after the subsequent regular pulse was assessed. The latency shift was found to depend on the number of interposed pulses, on the time interval between conditioning and conditioned stimulus, and on the conduction velocity of the C-unit. The increase in latency was larger with greater distance between stimulating and recording electrodes, indicating a contribution of the conductile membrane over its whole length. On the other hand, slowing was more pronounced, on average, in slower conducting C-units and conduction velocities were slower when recordings were performed more distally. These findings indicate that the slower terminal nerve branches contribute most to the latency increases. Even a single additional spike in between two regular pulses caused a reliable latency shift of 1.2±0.2 ms (mean ±SEM) and additional pulses lead to an approximately linear latency increase (2 pulses: 2.3±0.3 ms; 4 pulses: 5.9±0.7 ms). In contrast to the number of interposed stimuli, different intervals between interposed and regular stimuli had only a minor impact on the latency shifts. It is concluded that latency shifts are reliable indicators of C-fiber activation, being sensitive enough to detect even single spike responses. Furthermore, latency increases may be used as a relative measure of C-fiber activation, e.g., when comparing responses to stimuli of different strength.

Inflammatory models of cutaneous hyperalgesia are sensitive to effects of ibuprofen in man

&NA; A new experimental procedure was developed to quantify the analgesic actions of non‐steroidal anti‐inflammatory drugs (NSAIDs) in healthy human subjects. In order to mimic the clinical situation, the drug was ‘therapeutically’ administered 1 day after induction of inflammation by freezing a small skin area. The procedure was easily tolerated and led to a marked hyperalgesia without ongoing pain which was tested using mechanical impact stimulation and magnitude estimation. For comparison, we used a previously established model of repeated noxious pinching of an interdigital skin web which induces a hyperalgesia to pressure (rated via visual analogue scale), and topical application of capsaicin which leads to quantifiable flare and allodynia responses. The effects of a cumulative drug regime of ibuprofen in 2 different doses (3 × 400 mg and 3 × 800 mg at 2‐h intervals) were tested versus placebo using a double‐blind cross‐over design with 24 volunteers of either gender. Ibuprofen caused a significant suppression of the hyperalgesia to repeated pinching and of the hyperalgesia to impact stimulation following freeze trauma. In contrast, there was no effect on the areas of flare and allodynia induced by capsaicin application and on the impact evoked sensations from untreated skin. The two dosages of ibuprofen, however, appeared to be equally effective in a way that suggests a plateauing of the antihyperalgesic effect. The two models in which hyperalgesia is affected by ibuprofen, i.e., repeated pinching and impact stimulation after freeze trauma, seem to provide comparable sensitivity. The freeze model may in the future have the advantage to allow for a better temporal resolution of the drugs action profile.

Limitation of sensitization to injured parts of receptive fields in human skin C-nociceptors

Unmyelinated cutaneous mechano-heat fibers (CMH) in the peroneal nerve of healthy human volunteers were studied by means of a “marking” technique which allows stable recordings from identified single units over extended periods. Mechanoreceptive field sizes were 105±13 mm2 in 25 units. These large receptive fields indicate extensive terminal branching of C fibers in the skin of foot and lower leg. Sensitization of CMHs was tested by assessment of thresholds for mechanical (von Frey hair) and heat stimuli before and after topical application of mustard oil (allyl isothiocyanate) and capsaicin (8-methyl-N-vanillyl-6-noneamide). While in a group of 14 CMHs the entire receptive field was treated with these irritant substances, in another group of 11 CMH units only parts of the receptive field were treated to check for signs of spreading sensitization through axon collaterals. Mustard oil application did not change mechanical thresholds, regardless of whether parts of or complete receptive fields were treated. However, mean heat thresholds dropped by 5.6° C to 36.5±1.5°C in completely treated receptive fields and by 5.7° C to 37.3±3.4° C in treated parts of receptive fields (“primary sensitization”). In contrast, heat thresholds in the non-treated parts did not change significantly (42.1±3.4° C vs 41.2±3.9° C), i.e. “secondary sensitization” to heat was lacking. The absence of primary sensitization to probing with von Frey hairs indicates that sensitization of insensitive C fibers and recruitment of insensitive axon collaterals may be more important for mechanical hyperalgesia than sensitization of conventional CMH units — apart from the contribution of central mechanisms. The lack of spread of sensitization to untreated parts of the receptive fields o CMHs (“secondary sensitization”) indicates that this fiber group is probably not involved in any form of secondary hyperalgesia to heating.

Cortical representation of experimental tooth pain in humans

&NA; Cortical processing of electrically induced pain from the tooth pulp was studied in healthy volunteers with fMRI. In a first experiment, cortical representation of tooth pain was compared with that of painful mechanical stimulation to the hand. The contralateral S1 cortex was activated during painful mechanical stimulation of the hand, whereas tooth pain lead to bilateral activation of S1. The S2 and insular region were bilaterally activated by both stimuli. In S2, the center of gravity of the activation during painful mechanical stimulation was more medial/posterior compared to tooth pain. In the insular region, tooth pain induced a stronger activation of the anterior and medial parts. The posterior part of the anterior cingulate gyrus was more strongly activated by painful stimulation of the hand. Differential activations were also found in motor and frontal areas including the orbital frontal cortex where tooth pain lead to greater activations. In a second experiment, we compared the effect of weak with strong tooth pain. A significantly greater activation by more painful tooth stimuli was found in most of those areas in which tooth pain had induced more activation than hand pain. In the medial frontal and right superior frontal gyri, we found an inverse relationship between pain intensity and BOLD contrast. We concluded that tooth pain activates a cortical network which is in several respects different from that activated by painful mechanical stimulation of the hand, not only in the somatotopically organized somatosensory areas but also in parts of the ‘medial’ pain projection system.