Antonietta Romaniello

The lower limb flexion reflex in humans

The flexion or flexor reflex (FR) recorded in the lower limbs in humans (LLFR) is a widely investigated neurophysiological tool. It is a polysynaptic and multisegmental spinal response that produces a withdrawal of the stimulated limb and resembles (having several features in common) the hind-paw FR in animals. The FR, in both animals and humans, is mediated by a complex circuitry modulated at spinal and supraspinal level. At rest, the LLFR (usually obtained by stimulating the sural/tibial nerve and by recording from the biceps femoris/tibial anterior muscle) appears as a double burst composed of an early, inconstantly present component, called the RII reflex, and a late, larger and stable component, called the RIII reflex. Numerous studies have shown that the afferents mediating the RII reflex are conveyed by large-diameter, low-threshold, non-nociceptive A-beta fibers, and those mediating the RIII reflex by small-diameter, high-threshold nociceptive A-delta fibers. However, several afferents, including nociceptive and non-nociceptive fibers from skin and muscles, have been found to contribute to LLFR activation. Since the threshold of the RIII reflex has been shown to correspond to the pain threshold and the size of the reflex to be related to the level of pain perception, it has been suggested that the RIII reflex might constitute a useful tool to investigate pain processing at spinal and supraspinal level, pharmacological modulation and pathological pain conditions. As stated in EFNS guidelines, the RIII reflex is the most widely used of all the nociceptive reflexes, and appears to be the most reliable in the assessment of treatment efficacy. However, the RIII reflex use in the clinical evaluation of neuropathic pain is still limited. In addition to its nocifensive function, the LLFR seems to be linked to posture and locomotion. This may be explained by the fact that its neuronal circuitry, made up of a complex pool of interneurons, is interposed in motor control and, during movements, receives both peripheral afferents (flexion reflex afferents, FRAs) and descending commands, forming a multisensorial feedback mechanism and projecting the output to motoneurons. LLFR excitability, mediated by this complex circuitry, is finely modulated in a state- and phase-dependent manner, rather as we observe in the FR in animal models. Several studies have demonstrated that LLFR excitability may be influenced by numerous physiological conditions (menstrual cycle, stress, attention, sleep and so on) and pathological states (spinal lesions, spasticity, Wallenbergs syndrome, fibromyalgia, headaches and so on). Finally, the LLFR is modulated by several drugs and neurotransmitters. In summary, study of the LLFR in humans has proved to be an interesting functional window onto the spinal and supraspinal mechanisms of pain processing and onto the spinal neural control mechanisms operating during posture and locomotion.

Laser-evoked potentials: normative values.

OBJECTIVE Laser-evoked potentials (LEPs) currently represent the most reliable and widely agreed method of investigating the A delta-fibre pathways. Many studies dealt with the usefulness of LEPs in peripheral and central nervous system diseases. We aimed at gaining normative values for LEP data. METHODS Using a CO2 laser stimulator we recorded LEPs after face, hand, and foot stimulation in 100 normal subjects. We measured the perceptive threshold, latency and amplitude of the main vertex components, and their side-to-side differences. We also studied the correlations between LEP data and age and body height, as well as gender differences. RESULTS Laser perceptive threshold increased and LEP amplitude decreased from face to foot (P<0.0001). The latency of hand and foot-LEPs correlated significantly with body height (P<0.0001). The amplitude, though not the latency, correlated with age (P<0.0001). LEP data did not significantly differ between genders (P>0.1). CONCLUSIONS This study provides normative values for the main LEP data and their absolute and side-to-side limits, highlighting the physiological differences related to, body height, age, gender and stimulation site. SIGNIFICANCE Our data may help to improve the clinical reliability of LEPs as a diagnostic tool.

Assessment of trigeminal small‐fiber function: brain and reflex responses evoked by CO2‐laser stimulation

Laser pulses selectively excite mechano‐thermal nociceptors and evoke brain potentials that may reveal small‐fiber dysfunction. We applied CO2‐laser pulses to the perioral and supraorbital regions and recorded the scalp laser‐evoked potentials (LEPs) and reflex responses in the orbicularis oculi, masticatory, and neck muscles in 30 controls and 10 patients with facial sensory disturbances. Low‐intensity pulses readily evoked scalp potentials consisting of a negative component with a latency of 165 ms followed by a positive component at 250 ms. In vertex recordings, the amplitude of LEPs exceeded 30 μV. Although only high‐intensity pulses evoked reflex responses, some subjects showed—even to low‐intensity pulses—an orbicularis oculi (blink‐like) response that markedly contaminated the scalp recording. Scalp LEPs were abnormal in patients with hypalgesia and normal trigeminal reflexes and normal in patients with normal pain sensitivity and abnormal trigeminal reflexes. Possibly because of the high receptor density in this area and the short conduction distance, laser stimulation of the trigeminal territory yields low‐threshold and large LEPs, which are useful for detecting dysfunction in peripheral and central pain pathways.

Small-fiber dysfunction in trigeminal neuralgia: Carbamazepine effect on laser-evoked potentials

Background: In patients with trigeminal neuralgia, results of clinical examination of sensory function are normal. Reflex and evoked potential studies have already provided information on large-afferent (non-nociceptive) function. Using laser-evoked potentials (LEP), the authors sought information on small-afferent (nociceptive) function. Methods: The brain potentials evoked by CO2–laser pulses directed to the perioral and supraorbital regions were studied in 67 patients with idiopathic or symptomatic trigeminal neuralgia and 30 normal subjects. Of the 67 patients, 49 were receiving carbamazepine. Results: All patients with symptomatic and 51% of those with idiopathic trigeminal neuralgia had frankly abnormal LEP on the painful side. The mean latency was significantly higher and mean amplitude lower on the painful than the nonpainful side. However, even on the nonpainful side, the mean latency was significantly longer than that of the age-matched controls. The nonpainful-side latency correlated significantly with the carbamazepine dose. Conclusions: LEP detect severe impairment of the nociceptive afferent system on the painful side of patients with idiopathic as well as symptomatic trigeminal neuralgia. A dysfunction of small-myelinated afferents may play an important role in the pathophysiology of neuralgic pain. Carbamazepine markedly dampens these brain potentials. The authors propose that this effect may result from inhibition of nociceptive transmission in the cingulate gyrus.

Cortical mechanisms mediating the inhibitory period after magnetic stimulation of the facial motor area

We studied the silent period (SP) that interrupts voluntary electromyographic activity (EMG) in facial muscles, after transcranial magnetic stimulation (TMS), in normal subjects. High‐intensity magnetic stimulation with a 12‐cm round coil centered at the vertex induced a long‐lasting SP (215 ms), whereas supramaximal stimulation of the facial nerve only induced a short (< 20 ms) and incomplete EMG suppression, and cutaneous stimuli had no inhibitory effect at all. Cutaneous trigeminal stimulation delivered after TMS evoked blink‐like reflexes, showing that facial motoneurons were not inhibited during the SP. Simultaneous recordings from perioral muscles (large cortical representation) and from orbicularis oculi and masseter muscles (small cortical representation) showed SPs of identical duration. Focal stimuli with a figure‐of‐eight coil showed that positioning of the coil was critical and that the optimal scalp sites for evoking the largest motor potentials and longest SPs coincided. Low‐intensity stimulation occasionally elicited short SPs without a preceding motor potential. We conclude that the SP induced in facial muscles by TMS results from the excitation of cortical inhibitory interneurons surrounding the upper motoneurons.

Shortened cortical silent period in facial muscles of patients with cranial dystonia.

Objective: To study the cortical silent period (SP) in the orbicularis oculi and perioral muscles in 23 patients with cranial dystonia and 10 age-matched control subjects. Methods: High-intensity magnetic stimuli were delivered with a round coil centered at the vertex during a maximal muscle contraction. Electromyographic (EMG) responses were recorded from surface electrodes placed over the orbicularis oculi and perioral muscles. Results: SPs elicited in upper and lower facial muscles had a similar duration. Facial muscle SPs were significantly shorter in patients than in control subjects. Patients with blepharospasm plus oromandibular dystonia had shorter SPs than patients with blepharospasm alone. Although patients’ recordings showed reduced voluntary and evoked EMG activity, neither activities correlated with the duration of the SP. Conclusions: Silent period (SP) shortening depends neither on the level of electromyographic activity nor on segmentary mechanisms. The shortened SP in facial muscles reflects hypoexcitability of cortical inhibitory neurons in cranial dystonia.

Dysfunction of small myelinated afferents in diabetic polyneuropathy, as assessed by laser evoked potentials

OBJECTIVE To verify whether laser evoked potentials are useful in assessing the function of small afferent fibers and to compare dysfunction of large and small afferent fibers in patients with diabetic polyneuropathy. METHODS The brain potentials evoked by CO2 laser stimulation of the hand and foot were studied in diabetic patients (n = 45) with various degrees of peripheral nerve damage. Laser evoked potentials (which assess the function of small myelinated afferents) were also compared with ulnar and sural nerve sensory action potentials (which assess the function of large myelinated afferents) by scoring the abnormalities of the two neurophysiological tests with similar criteria. RESULTS Laser evoked potentials were often absent; the mean latency was normal and mean amplitude decreased, as expected in axonopathies. Although clinical examination showed more frequent impairment of vibratory than pinprick sensation, laser evoked potentials and sensory action potentials yielded similar abnormality scores and showed a strong intra-individual correlation. CONCLUSIONS Laser evoked potentials, possibly better than standard clinical examination for assessing the abnormalities of small-diameter afferents, indicate that diabetic polyneuropathy induces large- and small-afferent dysfunction in parallel.

Excitability of the central masticatory pathways in patients with painful temporomandibular disorders

&NA; Much is unclear about the pathophysiological mechanisms underlying painful temporomandibular disorders. In addition to various other theories, masticatory muscle dysfunction and pain have also been attributed to primary central nervous system hyperactivity. We assessed this possibility in a study using recent neurophysiological techniques. From among outpatients whose diagnosis of temporomandibular disorders had been obtained in stomatognathic facilities, we studied 10 patients with bilateral pain and 15 patients with unilateral pain, in whom electromyographic examination of the trigeminal reflexes disclosed normal findings except for absence or amplitude asymmetry of the jaw jerk. Transcranial magnetic stimulation yielded masseter motor evoked potentials of normal latency and amplitude, but five patients had to exert a near‐maximum contraction to obtain their responses. The masseter silent periods elicited by the double‐shock technique recovered normally. Because these tests measure the excitability of the masticatory system (including motor cortex, corticobulbar and corticoreticular connections, reticular interneurones and lower motoneurones), the lack of facilitation in these patients’ responses excluded central hyperactivity as the primary cause of their masticatory dysfunction and pain.

Mandibular nerve involvement in diabetic polyneuropathy and chronic inflammatory demyelinating polyneuropathy

Sensory complaints in the area of the mandible and mouth often escape notice or remain undiagnosed. Using electromyographic recording of the trigeminal reflexes and motor responses, we sought trigeminal dysfunction in 50 patients with peripheral neuropathy, and tried to gain pathophysiological information on the mechanisms provoking trigeminal damage. Trigeminal reflex recordings (early and late blink reflex after supraorbital stimulation, early and late masseter inhibitory reflex after mental stimulation, and jaw jerk) disclosed abnormalities caused by sensory trigeminal neuropathy in 8 out of 15 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 13 out of 23 patients with severe diabetic polyneuropathy, and in none of 12 patients with mild diabetic polyneuropathy. Six patients had abnormal motor responses in facial or masseter muscles. The response affected most frequently was the masseter early inhibitory reflex (also called first silent period, SP1) after mental nerve stimulation, its latency being strongly delayed. We found these long delays not only in patients with CIDP, but also in diabetic patients with severe polyneuropathy. We conclude that peripheral polyneuropathies often cause subclinical damage to the trigeminal nerve, especially to its mandibular branch. We believe that the nerve fibers running along the alveolar–mandibular pathway are more exposed to damage because of their cramped anatomical route in the mandibular canal and below the internal pterygoid muscle and fascia.

Topographical distribution of pinprick and warmth thresholds to CO2 laser stimulation on the human skin

We studied the topographical distribution of laser sensory thresholds on the human hairy skin, using a small laser beam for pinprick and a large beam for warmth sensations. The threshold for pinprick sensation correlated positively with the distance from the brain, suggesting that Adelta nociceptors, the fibers which convey pinprick sensation, are more dense at proximal than at distal body sites. This finding adds information to skin biopsy studies of epidermal free nerve endings which showed a similar gradient, but could not differentiate small myelinated from unmyelinated fiber afferents. Possibly because of a diffuse low density of warmth receptors, laser warmth thresholds showed no trend.