Falk von Dincklage

Introduction of a continual RIII reflex threshold tracking algorithm

INTRODUCTION The RIII reflex is used in fundamental and clinical pain research. Here we introduce a continual reflex threshold tracking algorithm to facilitate investigations of the time courses of influences on the threshold. METHODS First we investigated the probability of reflex occurrence at the threshold estimated by the continual algorithm and the changes of the threshold over the time during continual recordings of 100 min duration in 10 subjects. Secondly we compared the threshold estimates of the continual algorithm with those of a standard algorithm of threshold estimation in 52 subjects and compared the differences between the two methods with the test-retest-variability of each method. RESULTS The average probability of reflex occurrence at the threshold estimated by the continual algorithm was 48.7% (SD = 3.2%). Changes of the RIII reflex threshold over the time were not significant (Friedman test, p>0.05). The variability between the thresholds determined by the different algorithms (test: SD = 2.50 mA, retest: SD = 1.80 mA) was lower than the variability between test and retest (standard algorithm: SD = 4.32 mA, continual algorithm: SD = 4.44 mA). DISCUSSION The continual algorithm can be used for a continuous estimation of the reflex threshold at the 50% probability of reflex-occurrence. No evidence of habituation was detected. This allows for investigations of the time courses of pharmacological and physiological influences on the reflex threshold by using this algorithm. The lower variability between the continual algorithm and the standard algorithm compared to the variability between tests and retests of the methods allows for interchangeable conclusions drawn from data obtained with both methods.

Effects of Sevoflurane and Propofol on the Nociceptive Withdrawal Reflex and on the H Reflex

Background:The predominant target of anesthetics to suppress movement responses to noxious stimuli is located in the spinal cord. Although volatile anesthetics appear to produce immobility by actions on the ventral rather than the dorsal horn, the site of action of propofol remains unclear. Methods:In a crossover design, the authors compared in 13 volunteers the effects of sevoflurane and propofol on the amplitudes of the H reflex, which is mediated exclusively in the ventral horn and a withdrawal reflex (RIII Reflex), which integrates dorsal and ventral horn function. The concentrations were adjusted according to a Dixon up-and-down approach, depending on movement responses to tetanic stimulation. Results:Sevoflurane and propofol concentrations ranged from 1.2 to 1.6 Vol% and 3 to 6 mg/l, respectively. Sevoflurane reduced the H reflex amplitude significantly to 66 ± 17% (mean ± SD) of its control values. Propofol did not significantly reduce the H reflex. The reductions under the two drugs differed significantly. The RIII reflex amplitude was significantly reduced to 19 ± 10% and 27 ± 12% (mean ± SD) of the control values by sevoflurane and propofol, respectively. The reductions did not differ between the drugs. Conclusions:Probably because of the polysynaptic relay, the attenuation of the withdrawal reflex exceeds the attenuation of the H reflex. Sevoflurane produces a larger inhibitory effect on the H reflex than propofol, which confirms that the ventral horn is a more important target for volatile anesthetics, whereas effects of propofol on this site of action are rather limited. Our findings indirectly suggest for propofol a relatively stronger effect within the dorsal horn.

Variability Comparison of the Composite Auditory Evoked Potential Index and the Bispectral Index During Propofol-fentanyl Anesthesia

BACKGROUND: Monitors of hypnotic depth help anesthesiologists to guide the anesthetic. The performance of different monitors depends on several factors, index variability at a steady state of hypnotic depth being one. We compared the recently introduced AAI1.6 with the established bispectral index (BIS), regarding index variability during stable values of propofol effect-site concentration. METHODS: After ethics committee approval and written informed consent, anesthesia was performed in 40 patients with propofol as the target controlled infusion and fentanyl. Variability of BIS and AAI1.6 was calculated during periods of constant predicted propofol effect compartment concentration and constant levels of surgical stimulation as the median absolute deviation (MAD) from the median value. A variability index was calculated as 1.48*MAD/(threshold − median value), with threshold being the division line between awake and asleep. Threshold crossing time was used to evaluate the performance in predicting return of consciousness. RESULTS: Variability index, however, was significantly larger for the AAI1.6, despite similar absolute variability measured as MAD. Lightening of anesthesia before recovery could be noticed earlier using the BIS than the AAI1.6, although consciousness was detected with a significantly higher Pk-value by the AAI1.6. CONCLUSION: Variability in relation to the difference between the median index value during anesthesia and the threshold necessary to detect consciousness with high sensitivity is higher for the AAI1.6 than for the BIS. This, as well as the steeper concentration–response function found for AAI1.6, impairs the performance of the AAI1.6 in predicting imminent return of consciousness during decreasing propofol concentrations. However, it makes AAI1.6 well suited to detect consciousness when it has occurred.

Propofol increases presynaptic inhibition of Ia afferents in the intact human spinal cord

Background: In vitro studies indicate that the primary molecular targets of propofol in the spinal cord are γ-aminobutyric acid (GABA) type A receptors. Because of the complexity of the central nervous system, specific GABA-mediated effects have not yet been isolated in humans. Here, the authors used heteronymous Ia facilitation of the soleus H-reflex from the femoral nerve as a specific pathway involving GABA to demonstrate a presynaptic GABA-mediated effect of propofol in humans. Methods: The study was performed in 10 volunteers aged 23–32 yr. The soleus H-reflex was evoked by stimulation of the tibial nerve in the popliteal fossa. The stimulation current was adjusted to yield an unconditioned H-reflex of 15% of the maximal muscle response to electric stimulation of the tibial nerve. The soleus H-reflex was conditioned by stimulating Ia afferents from the quadriceps femoris in the femoral triangle. The stimulus was applied 0.3–0.4 ms after the onset of facilitation, to assure a purely monosynaptic excitatory postsynaptic potential from quadriceps Ia afferents to the soleus motoneuron. At least 45 conditioned (femoral and tibial) and unconditioned (only tibial) stimuli were applied in random order. The authors compared the amount of heteronymous H-reflex facilitation under a concentration of 2 μg/ml propofol with control values obtained before and after the propofol infusion. Results: H-reflex facilitation due to the conditioning stimulus during propofol administration was significantly (P < 0.05, t test) decreased by an average of 43% in all patients in comparison with the control values. Conclusions: Although alternative explanations such as supraspinal effects cannot be ruled out completely, the findings of this study are most likely explained by a specific presynaptic effect of propofol. Strong evidence form neurophysiologic studies indicates that this effect is mediated by the GABA type A receptors.

Habituation of the nociceptive flexion reflex is dependent on inter-stimulus interval and stimulus intensity

The nociceptive flexion reflex (NFR) has become a popular tool in experimental and clinical pain research. However, the gradual decrease of the reflex size during repeated application of stimuli, which is termed habituation, may reduce its validity and the comparability of studies. We investigated the degree of habituation at different inter-stimulus intervals (ISI) commonly used in clinical studies and the dependency of habituation on stimulus intensity. Thirty subjects each received 12 sets of 50 stimuli to elicit the NFR at ISI of 1, 3, 6 and 10s, each at stimulus intensities of 1 ×, 1.5 × and 2 × the individual NFR-threshold. For each of the sets, the habituation was calculated as the relative size of the average of the last 10 reflexes compared to the average of the first 10 reflexes. The influence of the factors ISI and stimulus intensity, as well as the factor interaction, was tested using a two-way analysis of variance (ANOVA). Analysis proved that influences of ISI and stimulus intensity on reflex habituation were significant (p < 0.01, two-way ANOVA), while the interaction between the two factors had no significant influence (p = 0.99). We conclude that habituation of the NFR is dependent on ISI and stimulus intensity. Lower stimulus intensities and shorter ISI lead to stronger habituation. Therefore, to ensure habituation is avoided during repeated elicitation of the NFR, stimulation should be conducted according to the ISI for the respective stimulus intensities presented here.

Comparison of Trigeminal and Spinal Modulation of Pain and Nociception

ABSTRACT Modulation of pain and nociception by noxious counterstimulation, also called “diffuse noxious inhibitory controls” or DNIC-like effect, is often used in studies of pain disorders. It can be elicited in the trigeminal and spinal innervation areas, but no study has previously compared effects in both innervation areas. Therefore, we performed a study comparing DNIC-like effects on the nociceptive flexion reflex (NFR) and the nociceptive blink reflex as well as the respective pain sensations. In 50 healthy volunteers, the blink reflex elicited with a concentric electrode and the NFR were recorded before and after immersion of the contralateral hand in cold water. Responses were recorded as the subjective pain sensation and the reflex size. The cold water immersion of the contralateral hand elicited a reduction of both subjective pain sensation and reflex amplitude following the stimulation of both reflexes. However, there were no strong correlations between the individual reductions of both subjective pain sensation and reflex amplitude for both reflexes, and neither when results of the two reflexes were compared with each other. The dissociation between DNIC-like effects on pain and on nociception, which had been found previously already for the NFR, implies that both effects need to be studied separately.

Ethanol reduces motoneuronal excitability and increases presynaptic inhibition of Ia afferents in the human spinal cord.

INTRODUCTION Already low blood concentrations of ethanol acutely impair motor control and coordination. In vitro experiments have given evidence that spinal effects of ethanol contribute to this by reducing spinal excitability and enhancing presynaptic inhibition of Ia fibers. In this study, we investigated the influence of 0.7 g per kilogram of bodyweight ethanol on motoneuronal excitability and presynaptic inhibition in humans. METHODS The study was performed in 10 volunteers. Spinal excitability was measured by the maximal H-reflex of the soleus muscle normalized to the maximal muscular response (Hmax/Mmax). Presynaptic inhibition was measured by changes in heteronymous Ia-facilitation of the soleus H-reflex, which is achieved by stimulation of the femoral nerve. A decrease in facilitation can be ascribed to an increase in presynaptic inhibition. Changes of these parameters under the influence of 0.7 g per kilogram of bodyweight ethanol were assessed in comparison to control measurements before ethanol application. RESULTS Both parameters, Hmax/Mmax and Heteronymous facilitation, were significantly reduced under the influence of ethanol (Wilcoxon signed-rank test with Bonferroni correction for each, p<0.01). DISCUSSION The increase in presynaptic inhibition by ethanol is probably caused by an increase in GABAA receptor-mediated Cl-conductance, which has been shown in spinal cord cultures. The role of presynaptic inhibition in movement is assumed to be there to control the afferent input of muscle spindles and tendon organs as a mechanism of specific input-selection. This study demonstrated that ethanol reduces spinal excitability and increases GABAergic presynaptic inhibition on Ia afferent fibers in humans.

H-reflex depression by propofol and sevoflurane is dependent on stimulus intensity

OBJECTIVE The H-reflex has been widely used to investigate effects of drugs on motoneuron excitability in humans. However, up to now no systematic investigation has been done to examine the effects at different stimulus intensities. Here, the M. soleus recruitment curves were compared under influence of propofol and sevoflurane with control conditions to investigate these stimulus intensity dependent effects. METHODS The study was performed in 10 volunteers for propofol and sevoflurane each, aged 23-32 years. The M. soleus H-reflex was evoked by stimulation of the tibial nerve. Recruitment curves were gained by increasing the stimulation current stepwise from below the threshold of a minimal H-reflex up to a maximal (m-response. Measurements were performed under the influence of the respective drug (2mg/l propofol, 0.8 vol% sevoflurane) and compared to control measurements before and after drug administration. RESULTS The relative amount of depression of the H-reflex at high stimulus intensities is for both drugs significantly (p<0.001, Friedmans test) lower than at low stimulus intensities. CONCLUSIONS Stimulus dependent effects have to be taken into consideration when experimental settings to investigate the effects of drugs on the H-reflex are being designed. According to the size principle of motoneuron excitation, it can also be assumed that under the influence of propofol and sevoflurane larger motoneurons are not depressed in the same amount as smaller motoneurons. SIGNIFICANCE Different drug effects on the H-reflex at different stimulus intensities are not only of methodological importance, but also indicate different drug effects on motoneurons of different sizes.

Introduction and validation of a less painful algorithm to estimate the nociceptive flexion reflex threshold.

The nociceptive flexion reflex (NFR) is a widely used tool to investigate spinal nociception for scientific and diagnostic purposes, but its clinical use is currently limited due to the painful measurement procedure, especially restricting its applicability for patients suffering from chronic pain disorders. Here we introduce a less painful algorithm to assess the NFR threshold. Application of this new algorithm leads to a reduction of subjective pain ratings by over 30% compared to the standard algorithm. We show that the reflex threshold estimates resulting from application of the new algorithm can be used interchangeably with those of the standard algorithm after adjusting for the constant difference between the algorithms. Furthermore, we show that the new algorithm can be applied at shorter interstimulus intervals than are commonly used with the standard algorithm, since reflex threshold values remain unchanged and no habituation effects occur when reducing the interstimulus interval for the new algorithm down to 3s. Finally we demonstrate the utility of the new algorithm to investigate the modulation of nociception through different states of attention. Taken together, the here presented new algorithm could increase the utility of the NFR for investigation of nociception in subjects who were previously not able to endure the measurement procedure, such as chronic pain patients.

Investigation of threshold and magnitude criteria of the nociceptive blink reflex

OBJECTIVE The 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. METHODS Forty-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. RESULTS The 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. CONCLUSIONS We 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. SIGNIFICANCE The here defined standardized criteria to score blink reflex magnitude and threshold improve the comparability and validity of blink reflex studies.