Investigation of threshold and magnitude criteria of the nociceptive blink reflex

ObjectiveThe nociceptive blink reflex is a trigeminofacial brain-stem reflex which is used in pain research to evaluate the modulation of pain processing. To standardize the analysis of the reflex we investigated which electromyographic parameters show the best correlation with subjective pain ratings and should therefore be used for scoring blink reflex magnitude. Furthermore we investigated which parameters show the highest accuracy and reliability to define the blink reflex threshold.MethodsForty-six subjects each received 54 electrical stimuli to the supraorbital nerve at nine different stimulus intensities, which corresponded to pain ratings between 0 and 70 (scale 0–100). Multilevel modeling was performed to determine which electromyographic blink reflex parameter showed the best correlation with subjective pain ratings. To define the blink reflex threshold ROC analyses were performed, comparing different electromyographic blink reflex parameters with the judgment of expert raters for 2500 blink reflex recordings from this study and 1400 from another.ResultsThe baseline-adjusted area under the curve showed the best correlation with subjective pain ratings. Seventy-six percent of the residual variance of the pain ratings could be explained by this parameter. The peak z score showed the highest accuracy in defining the blink reflex threshold and also the highest cut-point stability.ConclusionsWe recommend the baseline-adjusted area under the curve for scoring the magnitude of the nociceptive blink reflex and the peak z score to define the nociceptive blink reflex threshold.SignificanceThe here defined standardized criteria to score blink reflex magnitude and threshold improve the comparability and validity of blink reflex studies.     

Nociceptive R3 reflex in relapsing-remitting multiple sclerosis patients.

Pain in multiple sclerosis (MS) patients has only recently been recognised as a genuine symptom of this disease. It is important to determine whether this pain is the consequence of another symptom of MS or whether it is due to a demyelinating lesion affecting pain pathways. A close relationship has been found between the R3 component of the blink reflex and the pain threshold. The aim of this work was to carry out an objective evaluation of the nociceptive system in MS patients by means of the R3 component of the blink reflex. The study was performed on 20 healthy volunteers and on 20 clinically defined relapsing-remitting MS patients with EDSS not > 3.5, normal R1 and R2 components of the blink-reflex, personal and family anamnesis negative for migraine and trigeminal neuralgia; the patients were not taking drugs at the time of the test. A significant difference was found, between healthy volunteers and patients, for R3 threshold, pain threshold and R3 latency.     

A new method to increase nociception specificity of the human blink reflex.

OBJECTIVE: The medullary R2 response of the blink reflex can be elicited by innocuous and noxious stimuli. The purpose of this study was to elicit a nociception specific R2 response with a new surface electrode. METHODS: In 10 healthy subjects the blink reflex was elicited using a standard (10-15 mA) and a new concentric surface electrode type (0.6-1.6 mA) which produces a pin-prick-like pain. RESULTS: After topical local anaesthesia with lignocaine/prilocaine R1 was unchanged, R2 was attenuated by 12% after standard stimulation but was almost abolished (-91%) with the new electrode type. CONCLUSION: Stimulation with low stimulus intensities but electrode-dependent high current density allows preferential depolarization of superficial nociceptive A-delta fibres. This new method is less traumatic than others and is useful in the study of trigeminal nociception.     

Methodological considerations on the use of the blink reflex R3 component in the assessment of pain in man

We define the principal physiological properties of the nociceptive component R3 of the blink reflex (b.r.) on electrical stimulation of the supraorbital nerve, with the aim of supplying some rules for its use in the analysis of pain in man. We explore the relationship between the threshold (th) of R3 and that of pain on stimulation of the trigeminal nerve and the extent to which R3 is modulated by habituation and attentional levels. Both pain th and R3 th correlate significantly with age. The R3 th was always higher than the R2 th. Habituation definitely decreases the amplitude of R3, which easily disappears. Focusing of attention on the stimulus sharply inhibits R3 while distraction increases it. Our findings emphasize the need to take all these aspects into account when designing protocols for the study of pain mechanisms based on the R3 reflex component. This work was partly supported by a grant from the Italian Ministry for the Universities and for Scientific and Technological Research     

Effect of experimental posterior temporalis muscle pain on human brainstem reflexes.

OBJECTIVE: To study the modulation of jaw-stretch and blink reflexes by experimental posterior temporalis muscle pain. METHODS: Thirty healthy volunteers (15 males, 25.5+/-0.6 years and 15 females, 27.4 +/- 1.2 years) were included. Short-latency stretch reflex responses were evoked in the masseter and temporalis muscles by fast stretches (1 mm displacement, 10 ms ramp time) and the blink reflexes were evoked by painful electrical pulses (0.5 ms duration), delivered by a concentric electrode placed on the left lower forehead close to the supraorbital foramen before, during and 15 min after a period with experimentally induced muscle pain. RESULTS: The normalized peak-to-peak amplitude of the stretch reflex in the painful temporalis was significantly higher during pain in both males and females compared with pre- and post-pain conditions (P < 0.004). The R2 root mean square (RMS) of the blink reflex decreased significantly during muscle pain as compared to the pre-pain (P < 0.03) in both males and females. CONCLUSIONS: The present results indicated that experimental posterior temporalis muscle pain facilitates the jaw-stretch reflex, whereas the nociceptive specific blink reflex is inhibited. SIGNIFICANCE: Present study suggested that these reflexes are suitable models for probing pontine and medullary pain processing.     

The R3 component of the blink reflex in man: a reflex response induced by activation of high threshold cutaneous afferents

Ten successive experiments were carried out in 10 volunteers to compare the physiological properties of R2 and R3 components of the blink reflex. The electrical activation threshold of the R3 component was found to be significantly higher than that of the R2 response and was more susceptible to anaesthetic blocking of the peripheral afferents. This result suggests that the R3 component is induced by the activation of a different population of peripheral afferents from the R2 component. A recovery cycle study performed using a double stimulus showed that R3 is inhibited to a greater extent and for a longer time than R2. The temporal relationship of R3 to the voluntarily produced blink demonstrates that R3 is not a voluntary response to electrical stimulation. In conclusion, these experiments support the existence of an independent R3 component and its relationship with the activation of small diameter and higher threshold afferent fibres, perhaps nociceptive ones.     

Nociceptive-specific blink reflex and glyceryl trinitrate infusion in healthy volunteers

Glyceryl trinitrate (GTN) is known to induce early headache in healthy humans after intravenous infusion. Moreover, in animal models subcutaneous administration produces an increase in Fos expression in brainstem areas that are involved in trigeminal pain processing. In a double-blind crossover study, we tested the blink reflex before, during and immediately after GTN and placebo intravenous infusion in eight healthy volunteers using a new stimulation electrode that preferentially activates A-delta nociceptive afferent fibres. The initial hypothesis that GTN could induce an increase in the magnitude of the nociceptive blink reflex R2 component by stimulating activity of trigeminal nucleus caudalis wide dynamic range interneurones was not confirmed. Although mild headache was induced in six subjects, there was no significant change between the R2 area under the curve before and after drug vs. placebo.     

Pain increases during sympathetic arousal in patients with complex regional pain syndrome

OBJECTIVE: To investigate the effect of sympathetic arousal on pain and vasomotor responses in healthy control subjects and patients with complex regional pain syndrome (CRPS), and to determine whether pain increases in patients with particular symptoms. METHODS: In experiments 1 and 2, capsaicin was applied to the forearm of 24 healthy subjects to induce thermal hyperalgesia. Vascular responses were monitored and subjects rated thermal hyperalgesia before and after being startled (experiment 1), and before, during, and after mental arithmetic, breath holding, forehead cooling, the Valsalva maneuver, and a cold pressor test in experiment 2. In a third experiment, sensitivity to heat, cold, and mechanical stimulation was investigated in 61 patients with CRPS. Pain ratings and vascular and electrodermal responses were recorded after patients were startled and during forehead cooling. RESULTS: In experiment 1, thermal hyperalgesia decreased in healthy control subjects after they were startled, and digital blood vessels constricted symmetrically. In experiment 2, thermal hyperalgesia decreased during and after other forms of sympathetic arousal. However, in experiment 3, ratings of clinical pain increased during forehead cooling or after being startled in over 70% of patients with CRPS. Pain increased most consistently during forehead cooling in patients with cold allodynia or punctate allodynia. Digital blood vessels constricted more intensely on the symptomatic than the nonsymptomatic side in patients with CRPS during sympathetic arousal. CONCLUSIONS: Normal inhibitory influences on pain during sympathetic arousal are compromised in the majority of patients with CRPS. The augmented vasoconstrictor response in the symptomatic limb during sympathetic arousal is consistent with adrenergic supersensitivity. An adrenergic sensitivity in nociceptive afferents might contribute to pain and hyperalgesia during sympathetic arousal in certain patients with CRPS.     

Correlation between pain thresholds and polysynaptic components of blink reflex in essential arterial hypertension

An interaction between pain modulation and arterial pressure control has been proposed on the basis of experimental data in man and animal. Eight hypertensive patients and eight normotensive volunteers were investigated by electrical stimulation of the first trigeminal branch and dental pulp, to evaluate nociceptive sensation and reflex responses. A significant threshold increase of pain sensation and R2, R3 polysynaptic components of the blink reflex, has been found in hypertensive patients.     

Influence of stimulus control on the excitability of the electrically elicited blink reflex in patients with schizophrenia.

BACKGROUND: In humans, the excitability of the electrically evoked blink reflex is influenced by the subject's attention to the stimulus. The early reflex component R1 has been found to be facilitated in conditions of increased selective attention, whereas the late components R2 and R3 exhibited a marked suppression. Distraction from the stimulus leads to enhanced R2 and R3 magnitudes. METHODS: We investigated the excitability of the distinct reflex components in 19 patients with schizophrenia and 19 healthy control subjects. In the control condition (EE), stimulation was elicited by the experimenter; in a second condition (SE), subjects released a key to evoke the reflex themselves. RESULTS: The SE patients with schizophrenia exhibited an abnormally increased R1 facilitation and an impaired R2 inhibition in comparison with normal control subjects. An R3 component could be registered in EE in 13 of 19 patients but only in one control subject; SE resulted in a complete suppression of this component in all but two patients with schizophrenia. CONCLUSIONS: The abnormal R1 facilitation and the impaired R2 inhibition may be regarded as neurophysiological markers of defective information processing in a condition of increased selective attention to a self-controlled stimulus in patients with schizophrenia. The enhanced excitability of the R3 component under standard conditions indicates defective attentional mechanisms in patients with schizophrenia in an uninstructed passive condition attending a stimulus triggered by the experimenter.     

Blink reflex in patients with hemispheric cerebrovascular accident (CVA). Blink reflex in CVA

A blink reflex consists of an early unilateral component, R1, and a late bilateral component, R2. During an acute phase of hemispheric cerebrovascular accident, R1 and R2 were abnormal in 30 and 50 of 66 patients, respectively. Paired stimuli usually corrected R1 but not R2, which was profoundly suppressed. The discrepancy between polysynaptic R2 and oligosynaptic R1 indicates a greater disfacilitation at the level of interneurons than at the motoneuron, which serves as the final common path. Abnormality of R2 occurred bilaterally with stimulation on the affected side of face and contralaterally after stimulation on the normal side in 31 patients. This finding suggests a diffuse loss of internuncial excitability, contralateral to the hemispheric lesion. Changes of R2 implicated the brainstem pathways forming the afferent and efferent arc of the reflex in 7 and 8 patients, respectively. The remaining 4 comatose patients had no R2 irrespective of stimulus sites. Clinical localization of the hemispheric lesion showed no consistent correlation with the type of blink reflex abnormalities. The CT scans revealed widely scattered changes in 29 patients with abnormal blink reflex but with a tendency to overlap in the inferior Rolandic area. This contrasted with conspicuous sparing of the inferior post-central region in 10 patients with normal blink reflex. These findings suggest the presence of crossed facilitation to this reflex from wide areas of the cortex but most prominently from the sensory representation of the face.     

Modulation of electrically induced pain by paired pulse transcranial magnetic stimulation of the medial frontal cortex.

OBJECTIVE: Aim of this study was to investigate whether paired pulse transcranial magnetic stimulation (ppTMS) applied over the medial frontal cortex (MFC) affects acute Adelta fiber-mediated electrically induced pain. In addition, we investigated whether this effect depends on the time course of the stimulation, on the noxious stimulus intensity or on the ppTMS intensity. METHODS: For painful stimulation, the electrical stimulus for the nociceptive flexion reflex (NFR) was used. PpTMS (ISI: 50 ms) was applied over the medial frontal cortex at different intervals ranging from 0 to 1,000 ms following the previous elicited NFR in 10 healthy volunteers. Three sequences at 3 different NFR stimulus intensities (at NFR threshold, 1.3 x and 1.6 x NFR threshold) with a ppTMS stimulus intensity at 1.2 x resting motor threshold (RMT) and one sequence with elevated ppTMS at 1.6 x RMT stimulus intensity were performed. Pain intensity and pain unpleasantness were assessed by visual analogue scales. RESULTS: Pain ratings differed in dependence of the interstimulus interval between NFR and ppTMS. Post-hoc t-tests revealed an increased verbal pain report within interstimulus intervals from 25 to 75 ms at NFR threshold as well as for 25 ms at 1.3 x NFR threshold when ppTMS was applied at 1.2 x RMT and from 0 to 75 ms at 1.6 x NFR threshold when ppTMS was applied at 1.6 x RMT. CONCLUSIONS: The present data suggest that ppTMS over MFC-applied in a certain time window-can enhance pain perception of acute Adelta fiber-mediated electrically induced pain. We hypothesize that the increase of pain is due to interference between ppTMS and the incoming nociceptive input. Further pain processing might be modulated by direct effects on MFC or indirect effects on anterior cingulate cortex (ACC) or spinal nociception. SIGNIFICANCE: Brain areas involved in cognitive and emotional adaptation to pain can be used, in place of primary motor areas, as cortical targets in TMS trials of experimental or ongoing pain.     

The corneal reflex and the R2 component of the blink reflex

A reflex contraction of the human orbicularis oculi muscles can be evoked by stimulation of either the supraorbital region ("blink reflex") or the cornea ("corneal reflex"). We found that the latency of the corneal reflex was longer, and the duration was longer than the R2 component of the blink reflex. The absolute refractory period of the R2 component of the blink reflex was longer after supraorbital than after corneal conditioning stimulation. When the R2 component of the blink reflex was habituated by repetitive stimuli, stimulation of the cornea still evoked a reflex, but supraorbital stimulation produced only a depressed R2 response. These findings suggest that the two reflexes do not have identical neural connections.     

The blink reflex in "chronic migraine".

OBJECTIVES: Activation of the trigeminovascular system and sensitisation of brainstem trigeminal nuclei are thought to play an important role in migraine. The aim of this study was to investigate the blink reflex and its habituation in patients with "chronic migraine". METHODS: We studied 35 patients suffering from "chronic migraine" (IHS classification criteria) outside and during a spontaneous attack, and 35 control subjects. An EMG device with a specific habituation test program was used to elicit and record blink reflex responses and to randomly repeat stimulations at different time intervals so as to induce habituation. RESULTS: The R(1) and R(2) latencies, amplitudes and areas of the basal blink reflex were similar in patients studied both outside and during an attack as well as in control subjects, whereas the blink reflex habituation responses were markedly reduced in patients studied outside an attack. The percent changes in the R(2) areas from the baseline values, obtained when stimuli were delivered at time intervals of 10, 5, 4, 3, 2 and 1s, were statistically different (p<0.01-p<0.001) from those of the same patients studied during a migraine attack and of those of control subjects. There was a significant correlation between decreased habituation of the blink reflex and a higher frequency of attacks. The stimulus intensities of the blink reflex (multiples of the detection threshold intensities) were significantly lower (p<0.001) on the side affected, or more severely affected, by headache in patients studied during a migraine attack. CONCLUSIONS: The decreased habituation of the blink reflex outside an attack reflects abnormal excitability in "chronic migraine", which normalizes during the attacks. The inverse correlation between the frequency of attacks and habituation responses confirms the abnormal excitability induced by the high frequency of attacks. Central sensitisation mechanisms (allodynia) may explain the lower detection thresholds observed on the side affected by headache in patients during the attacks. SIGNIFICANCE: The blink reflex and its habituation may help shed light on the subtle neurophysiological changes that occur in migraine patients between and during attacks.     

Mechanisms and predictors of chronic facial pain in lateral medullary infarction

The purpose of this study was to identify clinical predictors and anatomical structures involved in patients with pain after dorsolateral medullary infarction. Eight out of 12 patients (67%) developed poststroke pain within 12 days to 24 months after infarction. The pain occurred in the ipsilateral face (6 patients) and/or the contralateral limbs and trunk (5 patients, 3 of whom also had facial pain). Ipsilateral facial pain was significantly correlated with lower medullary lesions, including those of the spinal trigeminal tract and/or nucleus, as documented by magnetic resonance imaging. The R2 blink reflex component was abnormal only in patients with facial pain. Likewise, pain and temperature sensation in the ipsilateral face was decreased in all patients with facial pain but not in patients without pain. Ipsilateral touch sensation in the face was also decreased in all patients with facial pain, but the lesions revealed on magnetic resonance imaging did not involve the principal sensory nucleus of the fifth cranial nerve, and the R1 blink reflex latencies were normal. Although facial pain was correlated with lesions of the spinal trigeminal tract and/or nucleus, none of the lesions involved the subnucleus caudalis, which contains most nociceptive neurons. These findings suggest that facial pain after medullary infarction is due to lesions of the lower spinal trigeminal tract (axons of primary afferent neurons), leading to deafferentation of spinal trigeminal nucleus neurons.     

Pain-evoked blink reflex

The electrically evoked blink reflex (BR) consists of an ipsilateral R1 component (R1) at 11 ms and two bilateral components R2 at 33 ms and R3 at 83 ms. It is still unclear whether the R2 is mediated by activation of tactile or nociceptive afferents. For testing the nociceptive hypothesis, nociceptors of the supraorbital nerve were selectively activated by infrared laser stimuli in 10 subjects. Only painful laser stimuli evoked a bilateral early polyphasic BR response (LR2) at 71 ms. Stimulation of infraorbital and mental nerve dermatomes was equally effective. A late bilateral reflex response at 130 ms was occasionally observed. Regarding the nociceptor activation time of about 40 ms, onset latencies were within the range of the electrically evoked R2 and R3, respectively. The good accordance of R2 and LR2 may be due to activation of identical nociceptive fibers or to convergence of electrically evoked tactile and laser-elicited nociceptive input onto common multireceptive neurons. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 265–270, 1997.     

Fear conditioned potentiation of the acoustic blink reflex in patients with cerebellar lesions

OBJECTIVE: To investigate whether the human cerebellum takes part in fear conditioned potentiation of the acoustic blink reflex. METHODS: A group of 10 cerebellar patients (eight patients with lesions involving the medial cerebellum, two patients with circumscribed lesions of the cerebellar hemispheres) was compared with a group of 16 age and sex matched healthy control subjects. The fear conditioned potentiation paradigm consisted of three phases. During the first, habituation phase subjects received 20 successive acoustic blink stimuli. In the subsequent fear conditioning phase, subjects passed through 20 paired presentations of the unconditioned fear stimulus (US; an electric shock) and the conditioned stimulus (CS; a light). Thereafter, subjects underwent the potentiation phase, which consisted of a pseudorandom order of 12 trials of the acoustic blink stimulus alone, 12 acoustic blink stimuli paired with the conditioned stimulus, and six conditioned stimuli paired with the unconditioned stimulus. The EMG of the acoustic blink reflex was recorded at the orbicularis oculi muscles. The potentiation effect was determined as the difference in normalised peak amplitude of the blink reflex evoked by pairs of CS and acoustic blink stimuli and evoked by the acoustic stimulus alone. RESULTS: In the habituation phase, short term habituation of the acoustic blink reflex was preserved in all cerebellar patients. However, in the potentiation phase, the potentiation effect of the blink reflex was significantly reduced in patients with medial cerebellar lesions compared with the controls (mean (SD) potentiation effect (%), patients: -6.4 (15.3), controls: 21.6 (35.6)), but was within normal limits in the two patients with lateral lesions. CONCLUSIONS: The present findings suggest that the human medial cerebellum is involved in associative learning of non-specific aversive reactions-that is, the fear conditioned potentiation of the acoustic blink reflex.     

Corneal reflex in normal and pathological subjects

The orbicularis oculi response can be evoked both by mechanical stimulation of the cornea (corneal reflex) and by electrical stimulation of the skin overlying the supraorbital nerve (blink reflex). Mechanical stimuli to the cornea activate A delta and C free nerve endings of the corneal mucosa. Electrical stimuli to the supraorbital nerve activate A beta, A delta and C fibers of the nerve trunk. Both reflexes present a bilateral late response, but the blink reflex shows in addition an early ipsilateral component (R1), which has never been observed with the corneal stimulation in man. We have developed a simple technique of electrical stimulation of the cornea which provides stable responses and allows precise measurements of threshold and latency of the reflex. In normal subjects, the threshold ranged from 50 to 350 microA, and the maximal stimulus that the subject could bear (tolerance level) ranged from 1000 to 2500 microA. The minimal latency to tolerance level stimuli was 39 +/- 3 msec. The latency difference between the direct responses evoked from the two opposite corneas never exceeded 8 msec and the difference between the direct and consensual responses elicited from the same cornea never exceeded 5 msec. An early ipsilateral component similar to the R1 response of the blink reflex was not observed, even with supramaximal stimulation. The electrically evoked corneal reflex was normal in 10 cases of essential trigeminal neuralgia, while the responses showed significant abnormalities in 18 subjects submitted to thermocoagulation of the Gasserian ganglion as a treatment of neuralgic pain, as well as in 2 cases of symptomatic neuralgia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blink reflex abnormalities in Tourette syndrome.

OBJECTIVE: Tourette syndrome (TS) is a not uncommon disorder which represents the most complex manifestation of the spectrum of tic disorders, with onset during childhood or early adolescence. There are no definitive tests for diagnosis of TS. The objective of this study has been to demonstrate whether neurophysiological abnormalities of the blink reflex can be observed in patients affected with TS and correlate with the severity of TS. METHODS: We enrolled 17 patients with Tourette syndrome, diagnosed according to DSM IV Diagnostic Criteria, and 10 healthy volunteers. Tic severity was assessed using a self rating scale (Tourette Syndrome Symptom List, TSSL) and examiner ratings (Yale Global Tic Severity Scale (YGTSS), and Tourette-Syndrome Global Scale (TSGS)). The blink reflex was elicited by stimulating the supraorbital nerve in order to measure the early response (R1), homolateral and contralateral R2 (late) responses, amplitude of R1 and duration of R2. RESULTS: We observed a mean duration of R2 significantly longer in the patient group than in the control group (P<0.01, Student t test), without any statistically significant differences of R1 and R2 latencies and of R1 amplitude between the patient group and the control group. Correlations between changes in clinical rating scores and R2 duration were tested by simple linear regression analysis, which has not demonstrated a significant correlation between TSSL scores, clinical rating scores (measured by TSGS and YGTSS) and duration of R2. CONCLUSIONS: A pattern as to excitability of the blink reflex can be a frequent abnormality in TS patients, not correlated with its severity.     

Comparative study of the nociceptive reflex and late components of the evoked somatosensory potential during stimulation of the sural nerve in healthy subjects

A study was carried out with 10 normal volunteers in order to find a correlation between nociceptive flexion reflexes from the biceps femoris muscle and the amplitude of the late component (N150-P220) of the vertex evoked potential elicited by sural nerve stimulations at various intensities randomly delivered. The range of stimulus varied from the perception threshold (usually 1 mA) to 2 times the reflex threshold. This latter parameter was usually found between 8 and 11 mA. While the nociceptive flexion reflex increased linearly as a function of stimulation intensity, the amplitude of N150-P220 was maximum at pain threshold and remained in plateau at this level or even slightly decreased as a function of stimulus intensity. No significant correlation was found between the recruitment curve of the nociceptive reflex and that of the late component of the evoked potential as a function of stimulus intensity. Functional implications of these data are discussed.