Patients with chronic orofacial pain pose a challenge for the

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1 Clinical Neurophysiology and Quantitative Sensory Testing in the Investigation of Orofacial Pain and Sensory Function Satu K. Jääskeläinen, MD, PhD Associate Professor Department of Clinical Neurophysiology Turku University Hospital Turku, Finland Correspondence to: Dr Satu K. Jääskeläinen Department of Clinical Neurophysiology Turku University Hospital PB 52, FI Turku Finland Fax: satu.jaaskelainen@tyks.fi Chronic orofacial pain represents a diagnostic and treatment challenge for the clinician. Some conditions, such as atypical facial pain, still lack proper diagnostic criteria, and their etiology is not known. The recent development of neurophysiological methods and quantitative sensory testing for the examination of the trigeminal somatosensory system offers several tools for diagnostic and etiological investigation of orofacial pain. This review presents some of these techniques and the results of their application in studies on orofacial pain and sensory dysfunction. Clinical neurophysiological investigation has greater diagnostic accuracy and sensitivity than clinical examination in the detection of the neurogenic abnormalities of either peripheral or central origin that may underlie symptoms of orofacial pain and sensory dysfunction. Neurophysiological testing may also reveal trigeminal pathology when magnetic resonance imaging has failed to detect it, so these methods should be considered complementary to each other in the investigation of orofacial pain patients. The blink reflex, corneal reflex, jaw jerk, sensory neurography of the inferior alveolar nerve, and the recording of trigeminal somatosensory-evoked potentials with near-nerve stimulation have all proved to be sensitive and reliable in the detection of dysfunction of the myelinated sensory fibers of the trigeminal nerve or its central connections within the brainstem. With appropriately small thermodes, thermal quantitative sensory testing is useful for the detection of trigeminal small-fiber dysfunction (A and C). In neuropathic conditions, it is most sensitive to lesions causing axonal injury. By combining different techniques for investigation of the trigeminal system, an accurate topographical diagnosis and profile of sensory fiber pathology can be determined. Neurophysiological and quantitative sensory tests have already highlighted some similarities among various orofacial pain conditions and have shown heterogeneity within clinical diagnostic categories. With the aid of neurophysiological recordings and quantitative sensory testing, it is possible to approach a mechanism-based classification of orofacial pain. J OROFAC PAIN 2004; 18: Key words: neurophysiological diagnostic techniques, neuropathy, orofacial pain, quantitative sensory testing, trigeminal nerve Patients with chronic orofacial pain pose a challenge for the clinician. With the exceptions of trigeminal neuralgia and temporomandibular disorders (TMD) related pain, chronic orofacial pain is typically continuous. It may last from several months to decades, often causing considerable suffering. Furthermore, the role of the face in everyday social life is extremely important and, thus, sensory symptoms within this area may lead Journal of Orofacial Pain 85

2 to severe disability with psychosocial handicap. 1 While the clinical diagnostic criteria for conditions such as trigeminal neuralgia 2 and TMD 2,3 are fairly well defined, other disorders, such as burning mouth syndrome (BMS), atypical odontalgia, and atypical facial pain (AFP), are still regarded as diagnoses of exclusion, with continuing discussion on the clinically relevant diagnostic criteria. 4 Even the diagnosis of neuropathic trigeminal pain after, eg, idiopathic neuritis or traumatic nerve injury, may be difficult if not impossible to confirm with clinical tools alone. 5 8 Nor do normal scans of the patient made using magnetic resonance imaging (MRI) mean that his or her trigeminal symptoms have no organic cause. 9,10 Yet correct diagnosis is the first step in studying the etiology and pathophysiological mechanisms of orofacial pain, with the final aim of mechanism-targeted interventions. Since the trigeminal nerve (TN) mediates somatosensory impulses, including nociceptive information, from most of the orofacial region, careful investigation of the trigeminal system is necessary for correct diagnosis of orofacial pain. Clinical neurophysiology offers several tools for detailed investigation of dysfunction within the trigeminal and facial system. Of these, the elicitation of brainstem reflexes such as the blink reflex, jaw jerk, and masseter inhibitory reflex recordings has been in clinical use for over years During the past 15 years, these tests have been further developed and modified for more accurate and comprehensive diagnosis of trigeminal lesions. 5,14 24 In addition, new techniques such as nerve conduction studies, trigeminal-evoked responses, 19,,31 and quantitative sensory testing (QST) of thermal thresholds 7,8,32 34 have emerged for the examination of the trigeminal system. Several of these techniques have been found to be more sensitive than clinical examination or magnetic resonance imaging of the brain in detecting trigeminal dysfunction. 5,6,8 10,20 One reason for this is that neurophysiological tests, especially when used in combination, evaluate the whole trigeminal and facial system, covering not only the brainstem complex but also the peripheral pathways, beginning from the skin receptors. With QST and laser-evoked reflex and somatosensory evoked potential recordings, even selective trigeminal small-fiber dysfunction can now be quantitatively measured. In addition, neurophysiological tests evaluate function; they may detect purely functional abnormalities behind the patients symptoms when macroscopic changes are minor or subclinical. Thus, the main focus of this article is the utility of neurophysiological and thermal QST in the investigation of the trigeminal sensory system in relation to pain and other sensory functions. Although TMD is the most common chronic orofacial pain condition, I will not describe the neurophysiological techniques and findings in musculoskeletal pain within the face because a review on the subject was previously published in this journal. 35 Various brainstem reflexes will be described because their elicitation is useful for investigation of the sensory and motor functions of the trigeminal and facial nerves, and because these techniques have most often been systematically applied in studies on the orofacial pain conditions described in this article. Useful neurophysiological methods for the examination of cranial motor nerve function also include needle electromyography of the cranial muscles, and motor nerve conduction studies with electrical or transcranial magnetic stimulation. Transcranial magnetic stimulation has been systematically applied only in the study of experimental or TMD pain. Consequently, it is beyond the scope of this article. Readers interested in these techniques may wish to consult textbooks of clinical neurophysiology. 36,37 In this review, a short overview of the anatomy of the trigeminal system is presented first, followed by present techniques for the examination of the trigeminal system with emphasis on the investigation of sensory function, and finally, a summary is given of the findings of neurophysiological and quantitative thermal sensory tests in trigeminal neuralgia, symptomatic neurogenic trigeminal pain, AFP, and BMS. Anatomy of the TN The motor root of the TN supplies the masticatory muscles, and the sensory root innervates the skin of the face (with the exception of the skin overlying the angle of the jaw) and the forehead up to the vertex as well as the oral cavity. Figure 1 depicts the peripheral anatomy of the TN and its central connections in the brainstem. The cells of origin of the trigeminal sensory afferents are located in the trigeminal sensory ganglion (gasserian or semilunar ganglion) within the middle cranial fossa. The sensory trigeminal root connects the ganglion cells to the principal sensory nucleus of the TN in the pons and to the spinal nucleus of the TN, which extends down to the level of the second cervical segment. The peripheral branches of the ophthalmic, maxillary, and mandibular divisions of the TN (the supraorbital, infraorbital, inferior alveolar, mental, buccal, and lingual 86 Volume 18, Number 2, 2004

3 nerves) conduct signals related to vibrotactile, thermal, and nociceptive sensory modalities to the central nervous system. Tactile information is transmitted mainly via the principal sensory trigeminal nucleus in the pons, while most thermal and nociceptive input is relayed by the subnucleus caudalis of the spinal nucleus of the TN. However, these pathways also send collateral branches to other levels of the trigeminal brainstem complex. The mandibular branch of the TN also contains the Ia muscle spindle afferents that have their cell bodies within the mesencephalic nucleus of the TN in the midbrain. These proprioceptive muscle afferents make direct monosynaptic connections with motoneurons within the ipsilateral trigeminal motor nucleus that send their efferent axons to masticatory muscles (the temporal, the masseter, and the pterygoids). In addition, via polysynaptic circuits within the dorsolateral brainstem that contain both excitatory and inhibitory interneurons, the TN fibers make numerous collateral connections to ipsilateral and contralateral brainstem motor nuclei (eg, trigeminal, facial, and accessory nerves). This rich collateral network serves as the anatomic basis for various brainstem reflexes. From the brainstem, the second-order somatosensory neurons project to the ventroposteriormedial nucleus of the contralateral thalamus, the thirdorder neurons of which connect to the primary somatosensory cortex (SI) of the face. Somatosensory information, including nociceptive information relayed through the subnucleus caudalis of the spinal trigeminal nucleus, can also travel via additional connections, in part via nonspecific thalamic nuclei such as the reticular thalamic nucleus, to several other cortical areas including the secondary somatosensory (SII), insular, cingulate, and prefrontal cortexes. 38,39 Techniques for Investigation of the Trigeminal System Brainstem Reflexes Blink Reflex (Orbicularis Oculi Reflex, Trigeminofacial Reflex). Reflex eye closure occurs after various sudden stimuli, especially when these appear in the head region. The blink reflex can be elicited, eg, with a flashlight, a loud noise, or a tap on the skin of the face. It is considered the most constant part of the generalized startle reflex. Although auditory 41 and visually 42 evoked blink reflexes offer interesting possibilities for the scientific investigation of sensory integration and its Fig 1 Anatomy of the TN. AI = inferior alveolar nerve, B = buccal nerve, I = infraorbital nerve, L = lingual nerve, M = mental nerve, Ma = mandibular division of the trigeminal nerve, Mx = maxillary division, O = ophthalmic division, G = gasserian ganglion, S = supraorbital nerve, V MES = mesencephalic nucleus of the TN, V PRINC = principal or main nucleus of the TN in the pons, V SPIN = spinal nucleus of the TN in the medulla oblongata. modulation in pain, and may help in the localization of brainstem lesions, they are less constant than the electrically evoked responses that are most often used in clinical practice. 11 The trigeminal distributions are stimulated electrically in a standardized manner at random intervals. The blink reflex is recorded with surface electrodes placed bilaterally on the orbicularis oculi muscles. In clinical practice, the intensity of stimulation is gradually increased from 3 to 5 ma up to 10 to 20 ma and is adjusted to obtain stable responses. 11,43 45 In scientific investigative protocols, the stimulus intensity may be more precisely defined as multiples of the perception threshold. When the supraorbital nerve (SON) is stimulated, the resulting reflex response consists of an early ipsilateral response (R1) with a latency of 10 to 12 ms on the side of the stimulation, and late ipsilateral (R2i) and contralateral (R2c) components with latencies between and ms. 11,46 The threshold of the R2 components is equal to or only slightly higher than the perception threshold, 47 while a somewhat higher intensity is needed to evoke the R1 component. The early component is frequently missing when other trigeminal branches (the infraorbital nerve [ION] and the mental nerve [MN]) are stimulated. The R2 components have similar latencies with SON and ION Journal of Orofacial Pain 87

4 Fig 2 The blink reflex arc. The circuit for the oligosynaptic R1 component is depicted with a broken line, and the polysynaptic pathways for the R2i and R2c components with a continuous line. SON = supraorbital nerve, GG = gasserian ganglion, V PRINC = principal or main nucleus of the TN in the pons, FN = facial nerve, VII MOT = motor nucleus of the facial nerve in the lower pons. stimulation, whereas stimulation of the MN elicits R2 components with longer latencies, between and ms. 11,15 Stimulation of the lingual nerve (LN) distribution at high stimulus intensities (20 to ma) elicits the blink reflex R2 components bilaterally in only about % of healthy adults; eye closure may facilitate the LN blink reflex. When high-intensity, subjectively painful stimuli are used, later R3 components occur bilaterally with latencies between 60 and 80 ms, 48 although in a more recent study, the threshold of the R3 component was found to be within the activation range of tactile A afferents. 49 The same motor units fire during the R1 and the R2 responses, but lid closure coincides with the beginning of the R2 response. 51 Figure 2 shows schematically the anatomy of the blink reflex arc. The sensory afferents involved in both the R1 and the R2 components are mediumsized myelinated tactile A fibers, 44,52 although A fibers also contribute to the generation of these components when higher stimulus intensities are used in experimental settings. 53 Some authors have suggested that nociceptive A fibers are mainly responsible for mediating the R3 component, 48 whereas others assign the main role to tactile A fibers. 49 In the author s own experience, it seems that the R3 components normally show significantly higher thresholds than the R2 components, but their occurrence is also susceptible to higher modulating influences (such as state anxiety and apprehension). The R3 components are elicited with low stimulus intensities in conditions showing increased excitability of the blink reflex. 6,7,54 The R1 component is mediated via an oligosynaptic pontine circuit with the sensory root and principal sensory nucleus of the TN as the afferent part of the reflex arc and the facial motoneurons as the efferent part. Collateral connections crossing the midline in the pons may sometimes give rise to a contralateral R1 component. 55 The afferent impulses for the R2 components travel from the trigeminal sensory root entry zone down to the caudal brainstem along the spinal tract of the TN and through a polysynaptic network in the lower medulla oblongata. 20,45 From there on, the ascending impulses project both ipsilaterally and contralaterally in the lateral tegmental field (dorsolateral reticular formation) to the facial motor nuclei within the pons. 56 Experimentally, it has been shown that the same interneurons in the medullary and pontine reticular formation participate in both the R1 and the R2 components as premotor relay neurons. 57 The medullary wide dynamic range neurons are suggested to participate in the R2 response components, and the pontine low-threshold mechanoreceptive neurons to mediate the R1 component. 58 This extensive brainstem network, and the possibility of stimulating the various peripheral branches of the TN, make blink reflex recording a useful diagnostic tool that often enables accurate localization of a lesion or dysfunction within the trigeminal system, even when MRI and clinical testing fail to detect it. In TN dysfunction, the the blink reflex can show abnormal conduction of the afferent pathway. In this case, all blink reflex components are abnormal (either with prolonged latencies and diminished amplitudes or totally absent responses) when the side of the lesion is stimulated and normal with stimulation of the healthy side. In neuropathies of 1 peripheral branch of the TN, the blink reflex responses are abnormal only with stimulation of that particular division, whereas stimulation of other trigeminal distributions on the same side produces normal reflex responses. An efferent pattern of the abnormal blink reflex is seen in conditions with a facial nerve lesion such as Bell s palsy, in which the responses recorded from the side with the palsy are abnormal, irrespective of the side of stimulation. In brainstem lesions, a variety of distinct patterns can be encountered, depending on the level and 88 Volume 18, Number 2, 2004

5 extent of the lesion. In particular, in patients with small unilateral pontine lesions located near the principal sensory nucleus of the TN, such as a lacunar infarct or multiple sclerosis plaque, the R1 component is frequently absent. 59 The R1 may be missing in up to % of normal adults when single stimuli are used. Its true absence must be checked by means of paired stimuli with a short interstimulus interval (eg, 5 ms), or repeated stimulation at 1 to 5 Hz. Habituation of the Blink Reflex. The R2 responses habituate easily, ie, the amplitude and area under the response diminish rapidly when repeated stimuli are given rapidly ( 0.1 Hz) and steadily. The habituation of the R2 components of the blink reflex can be used to study the excitability of the blink reflex. Experimentally, it has been shown that the midbrain dopaminergic circuitry and the nigrostriatal dopaminergic system are involved in the inhibitory control of the late components of the blink reflex. 60,61 It has been suggested that the dopamine-controlled GABAergic nigrotectal projection from the substantia nigra pars reticularis to the superior colliculus is especially critical in mediating the hyperexcitability of the blink reflex that occurs in Parkinson s disease, with the tecto-reticular projection as the final pathway to the brainstem. 62 Clinical evidence for the role of the striatal dopaminergic system in the control of the R2 components comes from studies on Huntington s chorea, Parkinson s disease, and other extrapyramidal syndromes The tendency of R2 components to habituate is decreased in diseases with dopamine depletion. Figure 3 shows normal and deficient habituation of the blink reflex. The neurophysiological recording of the habituation phenomenon can be carried out with repeated stimulation, eg, at 1 Hz frequency, measuring the amplitude or, preferably, the area decrement between consecutive R2 responses. 16,44,66 Habituation of the R2 component to repeated stimulation of the SON does not occur with stimulus frequencies slower than 0.1 Hz. 16,66 According to the reference values of our laboratory, upon electrical stimulation of the SON at 1 Hz, the area under the R2i component decreases at least % between the first and the third response in a series of 8. Alternatively, a paired pulse paradigm in which 2 electrical stimuli, a conditioning and a test shock, are given with different interstimulus intervals (classically, from 100 to 1,0 ms, increasing by 100-ms steps) can be used for stimulation, and the recovery curve of the R2 amplitude or area is measured. 11 In clinical situations, checking all Fig 3 (a) Normal and (b) deficient habituation of the R2i component of the blink reflex with 1 Hz electrical stimulation (square wave pulses, 0.2 ms, 10 ma for normal habituation and 8 ma for deficient habituation) of the right SON. Eight consecutive ipsilateral responses recorded from the right orbicularis oculi muscle are shown. In (a), a large R1 component is seen at the beginning of most traces, and the onset and offset of the normally diminishing R2i component are marked on the first 2 traces as well as on the sixth and eighth traces. In (b), there is some facilitation of the initially missing R1 component toward the fourth trace, but no habituation of the R2i component, the area of which is still % of that of the first response on the eighth trace. The abnormal habituation was recorded in a 54-year-old woman who had suffered from AFP within the supraorbital and infraorbital distributions on the right side for 7 years. these steps is not necessary for diagnostic purposes. 20 The R2 test response is virtually absent up to 200-ms intervals, and then gradually recovers to % of the unconditioned response at the 0-ms interval, 20 and to 70% at the 800-ms interval 64 in healthy subjects. Nociceptive Blink Reflexes. Two new stimulation techniques utilizing the blink reflex have recently been developed for studying the trigeminal nociceptive system. One of these techniques adopts Journal of Orofacial Pain 89

6 a specially constructed concentric electrode with a small stimulating surface that gives high focal current density with low stimulus intensities. 23 It generates a pinprick-like sensation and evokes a blink reflex through specific activation of the nociceptive A fibers in all cutaneous distributions of the TN. The other technique adopts high-intensity laser stimuli that specifically activate the mechano-thermal nociceptive skin afferents 19,21,24 and elicit bilateral blinklike responses with long latencies (around 70 ms and 1 ms) in the eye-closing muscles, whether directed to perioral or supraorbital regions. The long latencies are caused by the long activation time of the nociceptors in the skin and slow conduction in the A fibers. It seems that the laser blink reflex is a purely nociceptive reflex, sharing part of the same interneuron chain within the medullary reticular formation as the R2 component of the blink reflex. 19,21,24 Both these nociceptive-specific blink reflex tests have yet to be applied to the clinical diagnosis of orofacial pain. Corneal Reflex. Clinically, the corneal reflex resembles the blink reflex but they are, in fact, 2 separate reflexes. 45,52,67 The corneal reflex is considered a purely nociceptive brainstem reflex. It is elicited with electrical or mechanical (air puff) stimulation of the cornea, and the simultaneous late reflex responses from both orbicularis oculi muscles are recorded with surface electrodes, as in the blink reflex test. The early R1 component of the blink reflex is absent in the corneal reflex. The corneal reflex has a longer latency and duration than the late components of the blink reflex. 67 The afferent impulses of the corneal reflex are mediated via small myelinated A pain fibers of the ciliary branch of the ophthalmic division of the TN. 20,45,52,68 These afferents project to neurons of the subnucleus caudalis of the spinal nucleus of the TN. 20 Although the bilateral late components evoked by corneal stimulation vary between subjects, intraindividual latency times show a high degree of constancy, and the corneal reflex does not habituate with repeated stimuli. 45 In addition, it is far less influenced by suprasegmental descending modulations. 20 The is fairly sensitive in detecting extra-axial and brainstem lesions. 20 These features should make the corneal reflex a good tool for evaluation of the trigeminal small-fiber function and nociceptive system, but so far it has only rarely been adopted in the study of orofacial pain conditions 5 or headache. 69,70 Jaw Jerk (Masseteric Reflex). The jaw jerk is a monosynaptic tendon reflex. In clinical practice, the jaw jerk is used for diagnosis of upper motoneuron disorders within the trigeminal system, as its increased excitability is often obvious on clinical examination. Clinically, however, it is not possible to detect reliably a decreased or unilaterally absent reflex response. The jaw jerk is elicited with a tap to the chin. The resulting extension of the muscle spindles evokes a contraction of the ipsilateral jaw-closing muscles (eg, masseter and temporalis). The afferent part of the reflex arc consists of large myelinated Ia muscle spindle afferents that have their cell bodies in the mesencephalic nucleus of the TN. As noted above, these afferent fibers project to the motor nucleus of the TN, where they may activate motoneurons supplying the jaw-closing muscles. There are no crossing connections to the contralateral side in the brainstem. Because the fibers mediating the jaw jerk are large myelinated Ia afferents and efferents, the test is especially sensitive to extra-axial lesions causing compression along the reflex arc. In humans, the jaw jerk is the first reflex to develop intrauterinely, and it can be consistently recorded already in preterm babies. 12,20,45,71 75 In a neurophysiological examination, the jaw jerk can be elicited with a reflex hammer that triggers a recording device on contact with the skin of the chin. The hammer may be operated either manually or automatically; automation and standardization of the tap force, direction, and magnitude of jaw displacement, as well as monitoring of the tension in the jaw-closing muscles, all help to decrease the variability of the responses. 35,76 The reflex responses are recorded bilaterally with surface electrodes placed on the masseter or temporalis muscles. If the jaw jerk is difficult to elicit, voluntary activation by closing the jaws lightly, extension of the head by 15 degrees, or Jendrassik s maneuver (activation of other muscles, eg, finger flexion) may help in the recording. The latencies and amplitudes of repeated responses vary widely, but the difference in latencies between the sides at each trial is fairly constant, and this can be utilized in diagnosis. This difference is normally under 1.0 ms in adults and under 0.8 ms in children, according to the reference values of our laboratory. Amplitude asymmetry is common and, in general, only a totally absent response is considered abnormal when a handheld reflex hammer is used. However, because dental occlusion has a strong effect on the jaw-jerk amplitude, this reflex should be tested in different positions of the mandible and during voluntary clenching before it is judged to be definitely absent. 20 The latency values, measured from the best simultaneous bilateral responses from several trials, are normally between 6 and 9 ms in adults, 12,20,45 and between 4 and 7.5 ms in children 90 Volume 18, Number 2, 2004

7 from 2 to 15 years of age. 75 The jaw jerk may be missing in healthy individuals after 60 years of age. Figure 4 shows normal jaw-jerk recordings. When the jaw jerk is abnormal, the lesion can be anywhere within the reflex arc: in the afferent fibers of the mandibular division; at the level of the gasserian ganglion; in the motor root of the TN; intra-axially, in, or between the mesencephalic nucleus or the motor nucleus of the TN; between the mesencephalic nucleus and the motor nucleus of the TN; or in the masseter nerve. Further localization to the afferent or efferent part of the reflex arc is possible with the aid of transcranial magnetic stimulation of the trigeminal motor root or electromyographic (EMG) examination of the jaw-closing muscles. If the EMG examination shows signs of denervation or the evoked motor response is abnormal, the efferent part (trigeminal motor nucleus or motoneurons) is involved. An abnormal jaw jerk with normal EMG findings indicates a lesion of the Ia muscle spindle afferents either peripherally or in the trigeminal brainstem complex in the mesencephalon and upper pons cranial to the trigeminal motor nucleus. 72,74 A myotatic stretch reflex similar to the jaw jerk can be evoked in the medial pterygoid muscle by chin tapping. This reflex can be recorded with needle electrodes inserted from below the mandibular angle. According to some preliminary observations, the myotatic reflex of the pterygoid muscle may aid in the diagnosis of intra-axial lesions at the level of the midbrain and upper pons, as it seems to be mediated by structures partly separated from the jaw-jerk pathway. 46 Masseter Inhibitory Reflex (Masseter Silent Period, Exteroceptive Suppression). Electrical or mechanical (chin tap) stimulation within the ION and MN distributions evokes a reflex inhibition of ongoing muscle activity in the jaw-closing muscles bilaterally ( silent period [SP] or exteroceptive suppression [ES]). This reflex usually consists of an early (SP1/ES1) and a late (SP2/ES2) suppression period, 20,35,77 but patterns with only 1 long suppression or with 3 suppression periods have been reported. 45 Stimulation of the MN distribution gives more constant responses than stimulation of the 2 upper trigeminal divisions. 46 In the literature, the term exteroceptive suppression refers to suppression of masticatory muscle activity with cutaneous electrical stimulation, whereas the term silent period often has been used for both electrically and mechanically (chin tap) induced masseter inhibitory reflexes. The duration of the inhibition varies widely among subjects. The SP2 response Fig 4 Normal jaw-jerk responses of (a) a preterm baby at 29 weeks postconception and (b) a 54-year-old woman with AFP. Upper traces show recordings from the right masseter muscle, lower traces from the left. Note the different amplitude and time scales. may even be absent in healthy subjects. 78 Intraindividually, however, the onset latencies are fairly constant, and the interside latency differences are small; these variables may be utilized in the neurophysiological diagnosis. 5,13,20,45,46 Recent advances in the standardization and automation of the stimulation protocols, in the control of background EMG activity, and in the analysis of the recordings have led to more consistent findings in healthy subjects and in experimental pain (for a recent review, see De Laat et al 35 ), and it is hoped that these advances will eventually lead to more reliable results in clinical studies as well. With electrical stimulation, the afferent impulses are mediated mainly via A -afferent fibers. 20,77 The nociceptive afferents may also contribute to the reflex responses. 21 The early SP1 component is mediated via the sensory root of the TN and the mid-pontine oligosynaptic circuit with a connection to the contralateral side. The afferent impulses related to the late SP2 response travel via a polysynaptic medullary pathway along the spinal tract of the TN and the lateral reticular formation, and then ascend, medial to the spinal nucleus of the TN, to the trigeminal motor neurons bilaterally. The last interneurons of the chains connecting to the motor nuclei of the TN are inhibitory. 20,45,79,80 Journal of Orofacial Pain 91

8 With mechanical chin tapping, the evoked masseter SP responses are mediated via proprioceptive afferents. 81 The masseter inhibitory reflexes are generally recorded with surface electrodes on the masseter or anterior temporal muscles on both sides. The subject is asked to maintain a steady contraction of the jaw-closing muscles; forces of between % and 100% of the maximal voluntary biting force have been used. The background EMG activity is monitored either via the loudspeakers of the EMG equipment or by means of more sophisticated automated techniques. 82,83 In addition to electrical stimulation of the perioral skin and chin tapping, mechanical (tooth tap) or electrical stimulation of the teeth may be used to elicit the masseter inhibitory reflex. Besides this inhibitory reflex, tooth stimulation induces an active jaw-opening reflex that can be recorded in the digastric muscles also in humans. 84 Noxious electrical, mechanical (air puff, drilling), or thermal (heating) stimulation of the tooth pulp A and C fiber afferents induces a nociceptive jawopening reflex that has been recorded in the digastric muscles and tongue of experimental animals. 35,85 The nociceptive jaw-opening reflex has been widely applied in experimental studies on antinociception and the trigeminal system, but not to my knowledge in clinical studies on orofacial pain. With electrical stimulation of the perioral skin, the normal onset latency of the bilateral SP1 is between 10 and 14 ms, and that of the SP2 is between and ms. The recovery cycle of the masseter inhibitory reflex can be studied with a paired pulse technique similar to that described for the blink reflex, enabling quantitative evaluation of the excitability of the trigeminal motor system. 86,87 Recent methodological refinement of the masseter inhibitory reflex technique with single motor unit recordings now allows detailed quantification of the trigeminal motoneuron excitability. 88 This study also showed a strong relation between stimulus intensity and the inhibition of reflexive masseter motor unit firing: The inhibitory period of a single unit was longer with a stronger stimulus. High-intensity laser stimuli delivered to the perioral area also evoke reflex suppression of voluntary activity of masticatory muscles bilaterally, the so-called laser silent period (LSP) response. 21,78,83 However, noxious laser stimulation of the perioral area fails to evoke a jaw-opening reflex in the suprahyoid muscles in man. 78 The LSP response occurs with mean onset latencies between and 80 ms, the high variation probably reflecting the differences in the stimulus intensity and the force of voluntary muscle contraction in different studies. 21,78,83 The LSP is thought to be a nociceptive reflex mediated by A fibers via a polysynaptic ponto-medullary interneuronal network, that in part may be identical to that of the late SP2 pathway. 21,78 Although experimental pain influences the LSP, 83 this potentially interesting tool for investigation of the trigeminal nociceptive system has not yet been applied to clinical studies on orofacial pain. Recording of Sensory Nerve Conduction Velocity (Neurography) Direct recording of sensory conduction of the TN in awake humans is possible for the mandibular division of the TN, and several studies have reported techniques for inferior alveolar nerve (IAN) neurography. 25,26,29,89 An intraoral recording site at the mandibular foramen has been used, which seems to give inconsistent results even in healthy subjects. 29,89 Recently, a method for orthodromic recording of the sensory action potential of the IAN has been developed by applying a percutaneous route for the insertion of the recording needles. 25,26 The action potentials can be recorded either with a silver wire electrode coated with Teflon (DuPont) (except for the tip) threaded inside a hypodermic needle, or a disposable monopolar needle electrode, as the active recording electrode. This electrode is inserted beneath the zygomatic arch in front of the temporomandibular joint about 3 cm anterior to the tragus. The point of the needle is directed upwards and backwards after penetration of the skin and advanced to a depth of about 4 to 4.5 cm to lie in the vicinity of the mandibular nerve trunk at its exit from the foramen ovale. Electrical stimuli are applied at the mental foramen via a small bipolar surface electrode. Figure 5 illustrates the neurography of the IAN. In most patients, single responses are clear enough for analysis, but in cases with severe axonal damage and small response amplitudes, averaging may be necessary. The normal upper reference limit for the onset latency is 2.0 ms, and the interside difference normally does not exceed 0.3 ms. The variation in the amplitude of the negative peak is wide; the lower reference limit for the amplitude is 2.6 µv. 26 Percutaneous neurography is generally well tolerated by patients; eg, most of the patients (n = 20) participating in a 1-year follow-up study 90 allowed 5 repeated tests on both sides. The pain is usually described as equal to needle prick pain, with radiating pain sometimes to the lower molars if the needle tip comes near the mandibular trunk. The 92 Volume 18, Number 2, 2004

9 observed side effects have included 3 subcutaneous hematomas due to venous bleeding that resolved within 1 week in the approximately 100 patients investigated so far in our laboratory; there have been no infections. This recording technique has also been modified for intraoperative monitoring of the function of the IAN during mandibular sagittal split osteotomy surgery, 25,27,90 and for investigation of LN injuries. 28 QST Quantitative thermal thresholds have been shown to be valuable in the examination of patients with sensory symptoms of both peripheral 91,92 and central origin, 93 and their wider use in clinical practice has been encouraged. 92,94 97 QST may enable verification and quantification of sensory dysfunction even when the results of nerve conduction studies are normal. 92,96 98 Thermal QST allows the assessment of the function of small myelinated A and unmyelinated sensory C fibers that cannot be studied with traditional neurophysiological techniques. Irrespective of the applied testing algorithm, QST is a psychophysical test and, for reliable and reproducible results, good concentration ability and the cooperation of the patient are necessary. However, a recent study using an automated method of levels algorithm for QST suggested that the reproducibility of the thresholds may not be an adequate measure to separate patients with sensory neuropathy from healthy subjects instructed to simulate sensory loss. 99 In combination with other electrophysiological tests and clinical data, QST allows a determination of the profile and extent of sensory dysfunction, both in clinical practice and scientific research, 97,100 since the sensory fiber populations have differential susceptibility to various types of nerve injury. In addition, QST is the only clinically available method for measuring the positive sensory symptoms often encountered in neuropathic pain, eg, hyperalgesia and allodynia. 94,101 However, it should be taken into account that these phenomena related to sensitization are not specific to a neuropathic pain condition, but frequently occur in experimental nociceptive or musculoskeletal clinical pain conditions. 102 However, increased thresholds indicating thermal hypoesthesia have been reported outside of neuropathic pain conditions in only a single case. 102 QST Within the TN Distribution. In contrast to the fairly abundant literature on QST within the extremities, less data are available on its clinical use Fig 5 Neurography of the IAN. Point of entry of the active recording needle electrode is marked a few cm anterior to tragus; reference electrode is placed subdermally on the zygomatic arch. Stimulation site at the mental foramen is marked with 2 points. The ground electrode is on the skin of the throat. within the trigeminal distribution Only a few studies give some normal values for the thermal thresholds within the SON or ION distributions. 32,95,108 In these previous studies, large or medium-sized (eg, 25 mm, 5 25 mm, 3.6 cm 2 ) thermodes were applied to the skin, but electrodes of this size may not be suitable for studying the small innervation areas of the terminal branches of the TN. With a large thermode, the stimulus may inadvertently spread to the neighboring distributions or across the midline, and it is difficult to obtain complete contact with the skin along the contours of the face. In addition, the sensitivity of thermal detection and pain threshold measurements depends on the relationship between the thermode size and the small fiber density of the skin. Smaller thermodes are more sensitive for testing C-fibermediated threshold than larger ones, 109,110 especially when densely C-fiber-innervated areas, such as the facial skin, are investigated. This is due to spatial summation: The warmth and heat pain thresholds directly correlate with local C-fiber density. 94,110 In 1 earlier study 111 and in a few more recent ones, 7,8,33,34 smaller thermodes (8 16 mm and 9 9 mm) have been applied with promising results in the examination of TN small-fiber function within the narrow MN and LN distributions. In almost all studies on trigeminal thermal QST, the classical method of limits 112,113 has been applied. Although this paradigm tends to overestimate the absolute detection threshold because it includes the reaction time delay, 113 it nevertheless gives reliable results within reasonable examination times if proper reference values are available. 7,8,32 Journal of Orofacial Pain 93

10 In our laboratory, the trigeminal thermal thresholds are measured with a small handheld rectangular probe (9 9 mm) specially constructed for stimulating the face area. The thermode consists of Peltier elements that either cool or warm up linearly, depending on the direction of the applied electric current, which is changed by a subjectoperated switch button. The baseline temperature is set to C, and the rate of temperature change to 1 C/s. If the cold pain threshold is measured, the lower limit of temperature range is set to 1 C (although even this may be painless in some healthy subjects). The method of limits is applied for detection threshold tracking. For each threshold, 5 series of increasing intensities are given, and after deleting the highest and the lowest value, the mean of the remaining 3 values is calculated to be used as the detection threshold. The prepain range (the difference between heat pain and warmth detection thresholds) is also calculated. The subjects are instructed to press the switch button immediately when they perceive a change in temperature (cooling or warming), and when they feel the warm stimulus becoming painful. Before placing the thermode, the skin is wiped with alcohol or the tongue mucosa dried with a cotton compress. Within the face, testing sites near the midline give more repeatable results than more lateral sites, 32 obviously because of higher small-fiber density of the skin near the midline. The recorded threshold values, the prepain range, and their interside differences are compared to the reference values for the SON, ION, MN, and LN distributions. When performing QST, each laboratory should gather its own reference values from a large enough reference population, with all age ranges represented and an equal sex distribution, to enable reliable clinical diagnoses. In addition, as the level of dysfunction cannot be determined by means of QST alone, additional tests are required to help in the localization of dysfunction. These include the various neurophysiological techniques described in this review and, in addition, measurement of intraepidermal small-fiber densities of skin biopsy samples 98 or, in experimental studies, the use of microneurography. 114 Both of these approaches can directly show the possible small-fiber involvement in the case of abnormal QST results. Trigeminal-Evoked Responses Electrical Stimulation. Recording of trigeminal somatosensory-evoked potentials (TSEPs) has been used to diagnose TN lesions. 5, In this technique, electrical stimuli are given to the different branches of the TN, and the cortical responses are recorded with surface electrodes on the scalp. The responses are small, and several hundred trials must be averaged to extract the TSEP waveform from the surrounding noise. There is, however, great discrepancy in the literature concerning the normal TSEP response, which makes the interpretation of the previous reports on the clinical application of TSEPs problematic. Even in normal control subjects, the TSEP results in different studies are extremely variable as regards wavelet composition, latencies, and proposed neural generators of the waveforms. 5, For clinical purposes, many studies have applied TSEP waveforms appearing after 10 ms of the stimulus 115,116,123,124 although these components have convincingly been shown to consist of muscle artifacts and unstable middlelatency and long-latency responses. 125,126 In addition, somatosensory-evoked potentials in general may be insensitive in detecting peripheral nerve damage because central amplification of the response may obscure the effects of a partial peripheral nerve injury. 127 The most reliable recordings of subcortical and primary cortical TSEPs have been made with an invasive stimulation technique that requires the insertion of 2 thin stimulating needle electrodes near the ION,,119,126 MN, 121 or SON 128 at the exit from the foramen. This near-nerve technique allows the use of very low current intensities (1 to 3 ma), thus minimizing the stimulus artifact that might obscure the first 10 ms of the recording containing the main wavelets of the TSEP. The TSEP is recorded with a scalp electrode at the vertex referenced to the skin overlying the spinous process of the seventh cervical vertebra. Averaging of at least 1,000 responses is needed. The first 3 early scalp-recorded wavelets (W1, W2, W3) of presynaptic origin with mean latencies of 0.9 ms, 1.8 ms, and 2.5 ms with ION stimulation are considered the most stable components of the TSEP and, thus, are useful in clinical practice. They are thought to arise from the maxillary nerve at the foramen rotundum (W1), at the trigeminal root about 10 mm before it enters the pons (W2), and in the presynaptic portion of the trigeminal spinal tract in the medulla (W3). 125,128 The following later negative and positive components are postsynaptic in nature, and more variable among subjects. The negative N10 component with a mean latency of 10 ms is thought to be generated in the primary cortical representation area of the TN. 126 Laser Stimulation. Low-intensity laser stimulation of the peri- or intraoral regions constantly elicits large-amplitude laser-evoked potentials 94 Volume 18, Number 2, 2004

11 (LEPs). 19,83,129,1 Laser stimulation activates the intradermal A and C mechano-heat nociceptors and evokes a pure nociceptive cortical response. 131 With trigeminal stimulation, the LEP consists of a vertex negative component with a latency of 1 to 170 ms, with a following positive wave at 2 to 270 ms. The negative-positive peak-to-peak amplitude increases with increasing stimulus intensity, being in the range of 10 to µv. 19,31,83 Because of the large response amplitude, averaging of 10 to 20 single responses is sufficient. As the trigeminal LEPs are modulated by experimental pain, 83 and they have also proved to be efficient in the evaluation of trigeminal small-fiber dysfunction in peripheral diabetic neuropathy, 31 this method offers an interesting new neurophysiological tool for the study of orofacial pain. Findings in Clinical Orofacial Pain Conditions Trigeminal Neuralgia The brainstem reflex responses in classical trigeminal neuralgia are generally normal. 5,11,12,20,73,132 These include the jaw jerk, the corneal reflex, and the blink and masseter inhibitory reflexes with electrical stimulation of the symptomatic as well as asymptomatic divisions of the TN. Among our patients, the habituation of the R2 component of the blink reflex also has been normal in idiopathic trigeminal neuralgia. Only rarely may patients show slight delays in the R1 component of the blink reflex, the jaw jerk, or the SP1 of the masseter inhibitory reflex. 20 This is so unusual, however, that an abnormal result in reflex recordings warrants further MRI for the detection of possible underlying structural pathology. In addition, the brainstem reflex recordings have been applied successfully to the study of treatment effects after various surgical procedures for trigeminal neuralgia. 68,74 In 2 large studies on patients with trigeminal neuralgia, the tactile and thermal sensibility was found by means of QST to be altered in the symptomatic distribution 133 and, in addition, in the unaffected neighboring divisions. 106 In both studies, the differences between group means were small but statistically significant. In line with this, in 1 of these studies, 106 abnormal thermal thresholds were found in only one third of the patients. This may also explain the incongruous findings of another study showing normal tactile and thermal sensibility with quantitative tests in a small number (n = 6) of previously untreated trigeminal neuralgia patients. 104 When abnormal, the thermal detection thresholds are slightly increased, indicating thermal hypoesthesia in trigeminal neuralgia, most often to warming, but also to other thermal stimuli (cooling, heat pain). 106,133 However, it should be noted that in none of these studies were thermodes appropriately small for the study of the lower trigeminal distributions used, and proper reference values for individual patient diagnoses have not been available. Other methodological problems include the use of the contralateral side as the normal reference point. 106 It has been shown that in posttraumatic neuropathic pain of the hand, the thermal sensibility is altered also in the homologous area contralaterally, 134 which cannot thus be regarded as an unaffected point for comparisons. In conclusion, slight alterations in thermal somatosensory perception may occur in trigeminal neuralgia, but further studies are needed to clarify the extent of possible small-fiber involvement in trigeminal neuralgia. In clinical settings, clearly elevated thermal sensory thresholds in an individual patient with trigeminal neuralgia are an indication for further investigation of a possible structural abnormality. The diagnostic accuracy for the primary site of pathology in trigeminal neuralgia may be improved with recording of TSEP with the near-nerve stimulation technique. This has been shown to be more sensitive than the brainstem reflex recordings in detecting subtle, subclinical trigeminal dysfunction in trigeminal neuralgia. 5,135 With this technique, the early scalp-recorded TSEP responses (W2 and/or W3) evoked by stimulation of the ION are abnormal in 25% to % of the patients with idiopathic trigeminal neuralgia, which indicates pathological changes at the level of the trigeminal sensory root either before or just after it enters the pons. The site coincides with the commonly reported pathology in trigeminal neuralgia, namely a blood vessel compressing the TN root at its entry to the pons. This is thought to cause focal demyelination leading to ephaptic transmission of action potentials between the uninsulated nerve fibers, which is believed to elicit the paroxysmal pain in trigeminal neuralgia. 136 The incidence of abnormal TSEP findings in trigeminal neuralgia may further increase if the most severely clinically affected branch is stimulated. 135 This technique has also been applied in the intraoperative monitoring of the effectiveness of surgical treatment for trigeminal neuralgia. 135 Journal of Orofacial Pain 95