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(1) Background: OnabotulinumtoxinA (BoNT-A) is a commonly used prophylactic treatment for chronic migraine (CM). Although randomized placebo studies have shown its clinical efficacy, the mechanisms by which it exerts its therapeutic effect are still incompletely understood and debated. (2) Methods: We studied in 15 CM patients the cephalic and extracephalic nociceptive and lemniscal sensory systems using electrophysiological techniques before and 1 and 3 months after one session of pericranial BoNT-A injections according to the PREEMPT protocol. We recorded the nociceptive blink reflex (nBR), the trigemino-cervical reflex (nTCR), the pain-related cortical evoked potential (PREP), and the upper limb somatosensory evoked potential (SSEP). (3) Results: Three months after a single session of prophylactic therapy with BoNT-A in CM patients, we found (a) an increase in the homolateral and contralateral nBR AUC, (b) an enhancement of the contralateral nBR AUC habituation slope and the nTCR habituation slope, (c) a decrease in PREP N-P 1st and 2nd amplitude block, and (d) no effect on SSEPs. (4) Conclusions: Our study provides electrophysiological evidence for the ability of a single session of BoNT-A injections to exert a neuromodulatory effect at the level of trigeminal system through a reduction in input from meningeal and other trigeminovascular nociceptors. Moreover, by reducing activity in cortical pain processing areas, BoNT-A restores normal functioning of the descending pain modulation systems. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The aims of this study were to evaluate the pattern of the nociceptive withdrawal reflex (NWR) of the upper limb at rest and after injection of Botulinum toxin type A (BoNT‐A) in poststroke subacute hemiparetic patients. Methods: Fourteen patients with poststroke subacute hemiparesis underwent clinical and instrumental evaluation and BoNT‐A injection. Painful electrical stimulation was applied to induce the NWR. Baseline EMG activity and NWR recordings (EMG and kinematic response) were performed at T0, one month (T1), and three months (T2) after the BoNT‐A injection, as were Modified Ashworth Scale (MAS) and Functional Independence Measure (FIM) scores. Results: Comparison of results at T0, T1, and T2 revealed significant changes in the MAS score for the elbow (p < 0.001) and wrist joints (p < 0.001) and in the FIM score at T0 and T2. BoNT‐A injection had a significant effect on both NWR amplitude and baseline EMG activity in the posterior deltoid (PD) and flexor carpi radialis (FCR) muscles as well as in all averaged muscles. Analysis of elbow kinematics before and after treatment revealed that the reflex probability rates were significantly higher at T1 and T2 than at T0. Conclusion: Injection of BoNT‐A in the subacute phase of stroke can modify both the baseline EMG activity and the NWR‐related EMG responses in the upper limb muscles irrespective of the site of injection; furthermore, the reflex‐mediated defensive mechanical responses, that is, shoulder extension and abduction and elbow flexion, increased after treatment. BoNT‐A injection may be a useful treatment in poststroke spasticity with a potential indirect effect on spinal neurons. [ABSTRACT FROM AUTHOR]

Objective To examine the viscerosomatic interaction between bladder afferents and somatic nociception we evaluated the effect of bladder filling on the nociceptive withdrawal reflex (NWR) in 21 healthy subjects. Methods NWR was evoked in the lower and upper limbs by stimulating the sural and index finger digital nerves, respectively, while simultaneously recording EMG activity in the biceps femoris and biceps brachialis. NWR pain-related perception was quantified on a 10-point pain scale. Bladder filling was evaluated with suprapubic bladder sonography. Subjects were examined during empty bladder, medium and high level of bladder filling sessions. Results NWR magnitude in both upper and lower limbs and perceived pain for the upper limb were significantly decreased at higher levels of bladder filling compared to empty bladder sessions. Conclusions Reduced NWR magnitude in both upper and lower limbs during bladder filling strongly indicates that bladder control and nociception share common modulatory descending pathways. Bladder afferents may activate these pathways to suppress the micturition reflex, but they may also inhibit spinal reflexes to maintain continence during pain stimuli. Significance The effect of bladder filling on the NWR may represent a useful tool to investigate interactions between the neural pathways controlling the bladder and pain. [ABSTRACT FROM AUTHOR]

Abstract: The nociceptive withdrawal reflex (NWR), a defensive response that allows withdrawal from a noxious stimulus, is a reliable index of spinal nociception in humans. It has been shown that various kinds of stimuli (emotional, visual, auditory) can modulate the transmission and perception of pain. The aim of the present study was to evaluate, by means of the NWR, the modulatory effect on the spinal circuitry of olfactory stimuli with different emotional valence. The magnitude of the NWR elicited by electrical stimulation of the sural nerve was measured while 18 subjects (9 women, 9 men) smelled pleasant, unpleasant, or neutral odors. The NWR was conditioned by odor probe with interstimulus intervals (ISIs) of 500 ms and 1,500 ms. The magnitude of NWR was significantly greater after the unpleasant odor probe (P <.001) and reduced following the pleasant odor probe (P <.001) at both ISIs. A significant effect of olfactory stimuli on subjective pain ratings were found at both ISIs for pleasant vs unpleasant odors (P <.000), and for both pleasant and unpleasant odors vs neutral and basal conditions (P <.000). No statistical differences in subjective pain ratings at different ISIs were found. Consistent with the notion that NWR magnitude and pain perception can be modulated by stimuli with different emotional valence, these results show that olfactory stimuli, too, can modulate spinal nociception in humans. [Copyright &y& Elsevier]

Abstract: Objectives: To investigate the behavior of the nociceptive withdrawal reflex (NWR) in the upper limb during reaching and grasping movements in post-stroke hemiparetic patients. Methods: Eight patients with chronic stroke and moderate motor deficits were included. An optoelectronic motion analysis system integrated with a surface EMG machine was used to record the kinematic and EMG data. The NWR was evoked through a painful electrical stimulation of the index finger during a movement which consisted of reaching out, picking up a cylinder, and returning it to the starting position. Results: We found that: (i) the NWR is extensively rearranged in hemiparetic patients, who were found to present different kinematic and EMG reflex patterns with respect to controls; (ii) patients partially lose the ability to modulate the reflex in the different movement phases; (iii) the impairment of the reflex modulation occurs at single-muscle, single-joint and multi-joint level. Conclusions: Patients with chronic and mild-moderate post-stroke motor deficits lose the ability to modulate the NWR dynamically according to the movement variables at individual as well as at multi-muscle and joint levels. Significance: The central nervous system is unable to use the NWR substrate dynamically and flexibly in order to select the muscle synergies needed to govern the spatio–temporal interaction among joints. [Copyright &y& Elsevier]

In the present study we investigated the probability, latency and duration of the inhibitory component of the withdrawal reflex elicited by painful electrical stimulation of the index finger in humans. The stimulus consisted of a train of high-intensity pulses. The investigation was carried out in several upper limb muscles during isometric contractions of different strengths and during a motor sequence consisting of reaching, picking up and transporting an object. We used a new algorithm to detect and characterize the inhibitory reflex. The reflex was found in all muscles except the brachioradialis at all the isometric contraction strengths, and showed a distal-to-proximal gradient of latency and duration. Conversely, during movement the reflex probability was high (> 80%) in the anterior deltoid and triceps muscles during reaching, in the extensor carpi radialis muscle during transporting of the object, and in the first interosseous muscle during both picking up and transporting of the object. This modulation of inhibitory reflex transmission in the upper limb muscles suggests that the motor response is organized in such a way as to inhibit the overall ongoing motor task by interrupting motion during reaching and by releasing the object during transporting. This pattern of modulation appears to differ markedly from that previously reported for the excitatory component of the withdrawal reflex. Study of the nociceptive inhibitory reflexes during movement offers new and more profound insights into the functional anatomical organization of the spinal interneuronal network mediating sensory–motor integration. [ABSTRACT FROM AUTHOR]

Objective.—To evaluate trigemino-cervical-spinal reflexes (TCSRs) in a group of migraine patients during the pain-free period. Background.—TCRSs are part of a complex nocifensive response involving the cervical and the upper limb muscles, and are modulated by supraspinal inhibitory pathways; it may, thus, be possible to use TCRSs to explore the trigeminal system in migraineurs. Methods.—A total of 43 migraine patients without aura (MWoA, 32 patients) or with typical aura (MWA, 11 patients) and 30 age- and sex-matched healthy subjects took part in the study. TCRSs were obtained by stimulating the supraorbital nerve and recorded from the semispinalis capitis muscle and the biceps brachii. The latency (L, msec), area (A, mVms) and recovery cycle of the reflexes were recorded. The effects of heterotopic painful stimulation on the neurophysiological parameters were studied by a validated cold pressor test (CPT). Results.—No significant changes were found between either migraine patients and controls or MWoA and MWA patients in the mean values in the L and A of TCRSs ( t-test, P > .05). The recovery curve of the trigemino-cervical reflexes (TCRs) was significantly faster in migraine patients than in controls, while no differences were found in the trigemino-spinal reflexes (TSRs) ( t-test, P < .01). Activation of the diffuse inhibitory controls through the CPT induced a significant reduction in the TCRs and TSRs area in both migraine patients and controls (paired t-test, P < .01), though the extent of this reduction did not differ significantly between migraineurs and controls ( t-test, P > .05). Comments.—Our data suggest that the pain-free period in migraine patients is characterized by a hyperexcitability of the trigeminal pathways and of their anatomical and functional connections with the upper cervical cord neurons, and that this abnormal hyperexcitability does not appear to be due to a lack of a supraspinal inhibitory modulation. ( Headache 2005;45:1061-1068) [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to investigate the effects of diffuse noxious inhibitory controls (DNICs) on the temporal summation of the nociceptive flexion reflex (RIII reflex) in humans. Recordings were obtained from 36 healthy adults (16 M, 20 F), and the area and temporal summation threshold (TST) of the RIII reflex were measured. The subjective intensity of the painful sensation was rated on an 11-point visual analogue scale (VAS). Neurophysiological and VAS measurements were recorded after activation of DNICs by means of the cold pressor test (CPT), which involved immersing the hand in cold water (2–4°C). A slight significant lower TST was found in the females versus the males. In all the subjects, the CPT induced a significant TST increase and RIII area reduction compared with the control session. The VAS results paralleled those of the RIII reflex area and TST. During the CPT, a significant difference in the percentage TST increase emerged between females and males, being lower in the former. Similarly, we found a significantly lower percentage reduction of the RIII area in women than in men during the CPT. To summarize, activation of DNICs through the CPT significantly increased the TST of the RIII reflex in healthy subjects. This inhibitory effect was gender-specific. Whereas other findings are based on psychophysical evaluations, the results of this experimental study provide an objective neurophysiological demonstration that DNICs attenuate temporal summation in humans and confirm the presence of significant differences in pain modulation mechanisms between men and women. [Copyright &y& Elsevier]

Introduction: Electrical stimulation of the supraorbital nerve (SON) induces late reflex responses in the neck muscles; these responses are hypothesised to be polysynaptic reflexes participating in a defensive withdrawal retraction of the head from facial nociceptive stimuli. Such responses may extend to the proximal muscle of the arms.Objective: (1) to investigate reflexes in the upper limb muscles (trigemino-spinal responses, TSR) and their relationship with trigemino-cervical responses (TCR); and (2) to identify the nociceptive component of such reflexes and their functional significance.Methods: Reflex responses were registered from the semispinalis capitis and biceps brachii muscles after electrical stimulation of the SON in 12 healthy subjects. The sensory (ST), painful (PT) and reflex thresholds, the latency and area of the responses, the effect of heterotopic painful stimulation (HTP), the recovery cycle as well as the effect of the expected and unexpected stimuli were measured.Results: Stable reproducible TCR and TSR responses were identified at 2.5±0.4 ×ST, which corresponded exactly to the PT in all the subjects. The TCR and TSR areas were markedly reduced after HTP. The recovery cycle of the TSR area was faster than that of the TCR. Repeated rhythmic stimulation failed to induce progressive reflex suppression.Conclusions: These results confirm the nociceptive nature of the TCR and indicate that the biceps brachii response (TSR) has the same nocifensive significance as the posterior neck muscle responses. TCR and TSR are mediated different polysynaptic pathways The presence of trigemino-cervical-spinal responses in our study clearly indicates that there is a reflex interaction between nociceptive trigeminal afferents and both upper and lower cervical spinal cord motoneurons. [Copyright &y& Elsevier]

Objective To investigate how the nociceptive withdrawal reflex (NWR) is modulated during gait initiation. Methods The NWR was elicited in ten subjects using electrical stimulation at four sites in the right foot during symmetrical stance (50% of body weight on each foot) or while performing the first step during gait initiation: either during heel off (HO, 20% of body load on the starting leg) or heel contact (HC, 80% of body load on the starting leg in the first step). Kinematics and EMG responses from major muscles of the ipsilateral leg were recorded. Results The NWR was modulated by stimulation site in all muscles except Soleus. The NWR responses elicited after stimulation of the arch were significantly larger than those evoked at all other sites in Tibialis Anterior, Rectus Femoris, and Vastus Lateralis. At the hip joint, the largest flexion was obtained during HO, whereas the smallest flexion was observed during HC, both following stimulation on the arch of the foot. Conclusions The NWR responses were modulated to maintain balance and continue the development of the gait initiation process. Significance The NWR modulation followed a functional principle, which might allow a functional use in rehabilitation strategies. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to shed light on the neurochemical modulatory mechanisms of the noxious spinal inhibitory cutaneous silent period (CSP). We study the effects of 100mg of oral tramadol in 11 healthy volunteers. Tramadol has low affinity for opioid receptors and has the ability to inhibit serotonin and noradrenaline reuptake. We elicited CSPs in the first dorsal interosseus muscle and noxious withdrawal flexor reflexes (NWR) in the right biceps femoris muscle before, 30min and each hour up to the 6th after tramadol. Subjective pain sensation was checked on an 11-point numerical scale. Tramadol increased duration of CSP, and reduced the NWR area under the curve maximally 2h after tramadol and paralleled the reduction of subjective pain perception. We suggest that the monoaminergic action of tramadol reinforces the activity of spinal inhibitory interneurons on α-motoneurons for the hand muscles. [Copyright &y& Elsevier]

Objective: To evaluate the effect of heterotopic painful stimulation (HPS) on the cutaneous silent period (CSP) and the withdrawal flexor reflex (WFR) in the upper limbs, in an attempt to better identify the nociceptive component of the CSP and its functional relationship with the flexor reflex.Methods: The CSP at different stimulus intensities, the WFR and the H/M ratio were studied in 12 healthy adults. Neurophysiological measurements were recorded in the following 4 conditions: (1) control session; (2) non-painful session (dipping hand in water at 25 °C); (3) painful (cold pressor test, CPT); and (4) after-effect (3–8 min after taking hand out of water at 5–6 °C).Results: During the CPT, the duration of the high-threshold CSP was approximately 23% shorter than the baseline value, the high-threshold CSP latency was approximately 10% longer than the baseline value, and the mean RIII reflex area was approximately 40% smaller than the baseline reflex area (all P<0.05). A significant correlation was found between the percentage decrease in the CSP duration and the WFR area (r=0.61, P<0.05).Conclusions: Our findings indicate that the HPS specifically inhibits both the high-threshold CSP and the WFR, thereby providing further evidence that these cutaneous reflexes are functionally and anatomically related, and that they represent different aspects of a complex nocifensive response. [Copyright &y& Elsevier]