Neurophysiology of Atypical Parkinsonism 409extras.springer.com/2005/978-1-58829-331-2/PDF/24Valls...Neurophysiology of Atypical Parkinsonism 411 ological findings in IPD, such as

Neurophysiology of Atypical Parkinsonism 409

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From: Current Clinical Neurology: Atypical Parkinsonian DisordersEdited by: I. Litvan © Humana Press Inc., Totowa, NJ

24Role of Electrophysiology in Diagnosis and Research

in Atypical Parkinsonian Disorders

Josep Valls-Solé

INTRODUCTION

Correct clinical diagnosis of patients with parkinsonism is not always possible in spite of thecontinuous effort in defining diagnostic criteria (1). Parkinsonism, defined as the combination ofbradykinesia and rigidity (2), may be a predominant clinical feature of several diseases, includingidiopathic Parkinson’s disease (IPD) and several other entities commonly known as “Parkinson-plus”syndromes or atypical parkinsonian disorders (APDs). In these entities, parkinsonism is accompa-nied by other clinical signs, or red flags (3), that should warn the physician of the existence of adegenerative disorder. Even though rather specific clinical patterns have been described in patientswith APDs, such as predominantly autonomic failure, cerebellar, or pyramidal dysfunction, in mul-tiple system atrophy (MSA), axial rigidity, ocular motility disorders, and falls early in the course ofthe disease, in progressive supranuclear palsy (PSP), myoclonus and asymmetrical higher corticallimb dysfunction, in corticobasal degeneration (CBD), and fluctuating cognitive deficits, visual hal-lucinations, and REM sleep behavior disorder, in diffuse Lewy-body disease (LBD), these signs arenot always evident or they may pass unrecognized by nonspecialized neurologists. In some condi-tions, such as for instance CBD, similar clinical expressions may be common to different pathologies(4), and the same disease may encompass diverse clinical presentations (5). In others, such as MSAwith parkinsonian features (MSA-P), patients may behave like IPD until death (6), making it almostimpossible to establish a clinical separation between the two diseases. Nowadays, the definite clini-cal diagnosis still resides in the pathological postmortem examination (1,7,8).

When in doubt, the clinician may seek help in laboratory exams. Unfortunately, however, there arenot yet laboratory methods that can supply a diagnosis of certainty for APDs. Although single photonemission computer tomography (SPECT) and positron emission tomography (PET) have shownpostsynaptic dopaminergic deficits in APDs (9), these tests are not yet capable of differentiatingbetween the various degenerative syndromes featuring parkinsonism. Though electrophysiologicalstudies do not usually provide the diagnosis, they can be of great help in the recognition of patho-physiological mechanisms underlying the presentation of some symptoms and signs. In parkinsonism,pallidal hyperactivity might be responsible for reduced activation of thalamocortical projections, andfor an abnormal control of brainstem circuits (10–12). The situation might be slightly different inAPDs, in which the basal ganglia pathology is accompanied by neuronal loss and atrophy in manynuclei of the brainstem and cerebellum, and dysfunctions might be present in various circuits. It is

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therefore logical that, although some clinical neurophysiological manifestations are common to bothtypes of disorders, there are a few specific and distinctive features of each syndrome that may beclinically useful.

Neurophysiological studies are suited to demonstrate, document, and quantify clinical observa-tions. They are not expensive, and mainly noninvasive. They may occasionally bring information onneurological functions that is not obtainable with other means. One such example is, for instance, themeasure of excitability in neuronal structures or circuits. In this chapter, we describe the neurophysi-ological observations made in patients with the principal disorders grouped under the term APDs,and discuss how the results compare between different patient groups.

NEUROPHYSIOLOGICAL CORRELATE OF PARKINSONISM

Patients with APDs usually present with the main clinical signs characteristic of parkinsonism,i.e., bradykinesia and rigidity. Although clinicians identify bradykinesia and rigidity with no need forneurophysiological recordings, these are convenient for quantitation of the dysfunction. Bradykine-sia and, specially, rigidity are present with varying degree and localization in patients with parkin-sonism. They may not be observed at all in patients at early stages of the cerebellar variant of multiplesystem atrophy (MSA-C), though they will eventually appear during the course of the disease.

Hypokinesia and BradykinesiaHypokinesia and bradykinesia are abnormalities of movement, and the best way to quantify them

is with the use of reaction time task paradigms. Akinesia is defined as a delay in movement initiation,whereas bradykinesia is defined as the slowness of movement execution (13). There are many studieson reaction time in patients with IPD, but considerably less in APDs. Reaction time can be studiedusing different methods, ranging from the execution of a task (14,15), the release of a switch or alever (16,17), the onset of limb displacement (18,19), or the onset of electromyogram (EMG) activity(20,21). In paradigms of simple reaction time (SRT), the subject knows all details about the requestedmotor performance before the imperative signal is delivered. In paradigms of choice reaction time(CRT), subjects have to process some of the information contained in the imperative signal itself.When measuring SRT as the onset of EMG activity in wrist extensors in patients with IPD, PSP, andMSA, Valldeoriola et al. (22) found a significantly larger delay of reaction time in patients with PSPin comparison to the other groups of patients (Fig. 1). This is in fitting with previously reportedresults of an investigation of reaction time to progressively complex tasks in PSP patients (23). Theseauthors found an increased central processing time in patients with PSP compared with both IPD andcontrol subjects. PSP patients might have degraded cognition, with a delay in stimulus identificationand categorization processes (24).

The mechanisms underlying hypokinesia can be studied using EMG analysis of reaction timetasks. Hallett and Khoshbin (10) found that IPD patients were unable to appropriately scale the sizeof the first agonist burst to the requirements of a ballistic movement. They proposed that such defectrepresented a physiological mechanism of bradykinesia. It is likely that the increased pallidal inhibi-tion of thalamocortical excitatory connections accounts for such an abnormal “energization” of themotor cortex. A proper study of the triphasic pattern in patients with APDs has not been done so far.However, in a small group of PSP patients, Molinuevo et al. (25) observed abnormalities of thetriphasic pattern that were similar to those observed in IPD patients.

RigidityRigidity in patients with parkinsonism manifests as a difficulty of complete muscle relaxation,

with often permanent tonic background EMG activity (11). Several neurophysiological tests havebeen used to assess rigidity, although direct clinico-neurophysiological correlations have proven moredifficult than with bradykinesia. Rigidity has been considered to be the cause of some neurophysi-


ological findings in IPD, such as an increased size of the F wave (26), increased size of long loopreflex responses to stretch (27) or to electrical stimuli (28–30), abnormalities in the silent periodinduced by transcranial magnetic stimulation (31,32), reduced reciprocal inhibition (33,34), andreduced autogenic (Ib) inhibition of the soleus H reflex (35). However, none of those tests is spe-cific for rigidity, which continues to be assessed by clinical evaluation of the resistance to passivemovements.

Like with bradykinesia, most tests directed to the evaluation of rigidity have been proven inpatients with IPD, and more scarcely in patients with APDs. However, it is not unreasonable toadmit that when and where rigidity is present, patients with APDs would present similar abnormali-ties as those described for IPD. Direct surface electrophysiological recording of a muscle in rigidpatients in resting conditions may be enough to notice that there is increased muscle activity withrespect to normal subjects. Electrophysiological evidence for that can be found when testing therelaxation time after a sustained contraction (36). The stretch reflex, which is the most paradigmaticelectrophysiological test for limb rigidity, has not been properly tested in patients with APDs. Inthese patients, rigidity often predominates in axial muscles and is very mild in limb muscles, makingit more difficult for neurophysiological evaluation. The shortening reaction (37–40) is a relativelypoorly studied long latency reflex that occurs in the muscle shortened during a passive movement. Itsfrequent presence in patients with IPD could reflect the difficulties of these patients in modulatingsensory signals generated by either joint afferents (38), tendon organ afferents (39), or both. Unfortu-nately, however, there have not been recent studies on such an interesting phenomenon.

The pathophysiology of rigidity may be related to abnormalities in propriospinal reflexes. In theirstudy of IPD patients, Delwaide et al. (35) postulate that reduced autogenic inhibition mediated by Ibinterneurons would be a neurophysiological correlate of rigidity. Interestingly, however, in the solestudy published so far on spinal physiological mechanisms in APD patients, Fine et al. (41) reportedincreased Ib inhibition in patients with PSP. The observation of such an opposite behavior betweenIPD and PSP patients might be useful for differential diagnosis but points to the fact that neurophysi-

Fig. 1. Histograms of the mean and 1 standard deviation of simple reaction time values (expressed in ms)for EMG activity, onset of movement and task execution in healthy volunteers, and in patients with IPD,PSP, and MSA.

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ological observations might only be one manifestation of dysfunctional mechanisms. Further studiesare required to find out the mechanisms by which the Ib interneurons are modulated in a differentdirection in PSP and IPD, and what is the exact role of this dysfunction in the generation of rigidity.

NEUROPHYSIOLOGICAL TESTS IN THE ASSESSMENT OF ATYPICALPARKINSONIAN DISORDERS

Some neurophysiological features are specific or distinctive of patients with APDs. However, thisdoes not mean that the electrophysiological findings hold the key for the diagnosis, since sensitivityand specificity of the tests has not been properly examined yet. The most relevant of these observa-tions are described below, where they are grouped according to the neurophysiological method ortechnique in which the observation is based.

Brainstem ReflexesThe brainstem is a crucial structure for integration of reflexes and functions related to motor con-

trol. These structures receive modulatory inputs from more rostral centers, including the basal gan-glia. There are many nuclei and circuits of interest in the brainstem for neurophysiological studies.However, it is still difficult to assign the results of some neurophysiological observations to specificbrainstem centers or circuits. Therefore, most data gathered from the study of the brainstem in patientswith APDs have the value of an empirical finding, and the exact anatomical/pathological correlation inhumans is mainly based on hypothesis and theoretical knowledge from animal experiments.

Table 1 summarizes the observations made in patients with parkinsonism regarding facial move-ments and brainstem reflexes. Although many brainstem circuits are dysfunctional in patients withAPDs, the examination of brainstem reflexes and functions yields more interesting results in patientswith PSP than in any other form of parkinsonism.

Eye and Eyelid MovementsSome of the most striking features differentiating PSP from other disorders presenting with par-

kinsonism regard facial expression and gaze disturbances (42). A list of abnormalities reported so farregarding eye or eyelid movements in these patients is shown in Table 2. The resting blink rate, of 24per minute in normal controls, was found to be reduced in most patients with parkinsonism (43), butsignificantly more so in patients with PSP, whose mean blinking frequency can be reduced to as littleas 4 blinks per minute. Blinking rate may be an expression of the level of dopamine activity.

Clinical evidence of eye movement abnormalities is not always present in the initial phases of thedisease (42). If the possibility of PSP is suspected on the basis of some other clinical features, record-ing of eye movements by electro-oculography might be of some help. Surface electrodes are placedin the upper, lower, nasal, and temporal edges of the orbit and the subject is requested to makehorizontal and vertical eye movements (44). Electro-oculogram recordings may show characteristicabnormalities in patients with PSP (45), including slowness of vertical eye movements, absent Bell’sphenomenon, and square wave jerks (Fig. 2). In the study reported by Vidailhet and coworkers, 9 outof 10 patients with PSP had vertical-gaze paralysis with preserved reflex eye movements. Vidailhetet al. (46) also showed slowness of horizontal eye movement and microsaccades that would help indistinguishing patients with PSP from those with other parkinsonisms. Some eye movement abnor-malities are already apparent at simple inspection. A PSP patient exhibiting slowness of saccades andlimitation of vertical eye movement with preserved oculo-cephalic reflexes is shown in video segment 1.

Reflex Responses of the Orbicularis OculiIn contrast to the reduced frequency of spontaneous blinking, reflex responses of the orbicularis

oculi to trigeminal nerve inputs are of normal latency (47). The normality of reflex responses totrigeminal nerve stimuli is in contrast to the absence or significant reduction of the responses toauditory inputs (48). Whether the response of the orbicularis oculi to loud auditory stimulus is part of


Table 1Characteristics of Some Brainstem Reflexes and Functions in Patients With Parkinsonism

Test IPD PSP MSA CBD

Spontaneous Reduced Extremely Reduced Enhanced Normalblinking frequency Normal Reduced

Excitability recovery Enhanced Enhanced Enhanced Normalcurve (paired pulses)

Blinking to loud auditory Normal Reduced Normal or Increased Normalstimuli

Blinking to median nerve Normal Reduced or Absent Normal Normalstimuli

Auditory prepulse Reduced Reduced ? ?inhibition

Somatosensory prepulse Normal Reduced ? ?inhibition

IPD, idiopathic Parkinson’s disease; PSP, progressive supranuclear palsy; MSA, multiple system atrophy(strionigral degeneration); CBD, corticobasal degeneration; ?, data unknown.

Table 2Eye and Eyelid Movement Abnormalities Observed in Patients With PSP

Reduced spontaneous blinking (43)Blepharospasm (42)Supranuclear palsy of eyelid opening (45)Supranuclear palsy of eyelid closing (42)Reduced voluntary suppression of vestibular ocular reflex (VOR) (42)Eyelid retraction (Cowper’s sign) (42)Square-wave jerks (46)Absent eyelid responses to acoustic stimuli (48)Absent eyelid responses to median nerve stimuli (47)

the generalized startle reaction or is an auditory blink reflex with separate physiological characteris-tics is still a matter of debate (49,50). In any case, the reduction of orbicularis oculi responses toauditory stimuli is indeed an important observation of some clinical utility in the differential diagno-sis of APDs.

The palmomental reflex is usually elicited by scratching the volar aspect of the thenar eminence orthe thumb. This leads to a reflex movement of the chin that is considered abnormal when it showsreduced habituation (51). Electromyographic recording of facial muscle responses during elicitationof the palmomental reflex permits the quantitation of the responses (52). The facial reflex response isnot limited to the mentalis muscle but is usually accompanied by an ipsilateral eyelid movement thatcan be apparent with simple inspection and readily demonstrated with surface electromyographicrecording (Fig. 3A). Interestingly, in patients with PSP, contraction of eyelid muscles is not presenteven when the mentalis response is evident (see the second part of video segment 1 on accompanyingDVD). In a protocolized study of facial reflexes in patients with parkinsonism, Valls-Solé et al. (47)analyzed the responses elicited simultaneously in the mentalis and orbicularis oculi muscles bymedian nerve electrical stimulation. The study included patients with IPD, PSP, MSA, CBD, andhealthy volunteers. Responses in the mentalis muscle were found in most patients and in 2 out of 10normal subjects. In all of them, whenever there were responses in the mentalis muscle, there were

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Fig. 2. Electro-oculogram in a healthy subject (A) and in a patient with PSP (B) during fixation to an object(upper traces) and voluntary saccades (lower traces). Note the presence of small eye movements during fixa-tion, and of a slow and staircase eyeball displacement during the saccadic movement.

Fig. 3. Facial reflex responses to median nerve stimulation in a patient with IPD (A), and in a patient withPSP (B). Note the absence of orbicularis oculi response in the patient with PSP even though the mentalis muscleresponse (lower traces) is similar in both patients.

also responses in the orbicularis oculi muscle. The exception were the patients with PSP, who had noorbicularis oculi responses even if the responses of the mentalis muscle were not different from thoseobserved in the other groups of patients (Fig. 3B). This abnormality probably reflects the activationof two different circuits by the median nerve afferent volley. The mentalis response could be con-veyed through the cortico-nuclear tract, since this tract innervates predominantly lower facial moto-neurons (53), and a transcortical loop has been suggested because of the contiguity between thumband chin areas in the brain sensorimotor region (52,54). The selective damage of the pontine reticular


formation in patients with PSP would be responsible for the absence of the orbicularis oculi response.Enhancement of mentalis response may occur because of disinhibition of thalamo-cortical connec-tions from their striatal control (54).

One of the earliest contributions of electromyography to the assessment of central nervous system(CNS) abnormalities in patients with parkinsonism was made by Kimura in 1973 (55). Kimura dem-onstrated in these patients the existence of an abnormal decrease of habituation of the blink reflex topaired supraorbital nerve electrical stimuli. The fact that the abnormalities occurred in the R2 but notin the R1 component of the blink reflex suggested that the disturbance lies in the interneurons ratherthan in the motoneurons. Since then, many authors have studied the blink reflex excitability recoverycurve to paired stimuli, by dividing the size of the response to the test stimulus by that of the responseto the conditioning stimulus. This sign has been reported not only in parkinsonism, but in many otherdisorders as well (56,57). It is therefore of little use for differential diagnosis between degenerativedisorders. In clinical practice, the assessment of enhanced trigemino-facial reflex excitability may beof interest for documenting the existence of an abnormal function of brainstem interneurons in patientsin whom clinical assessment is dubious or at early stages of their disease. We found similar interneu-ronal brainstem excitability enhancement in IPD, PSP, and MSA patients (47). Figure 4 shows theproposed circuit of basal ganglia control of trigemino-facial reflex excitability, according to Bassoand Evinger (58) and Basso et al. (59), and the dysfunction likely occurring in parkinsonism.

Other Facial ReflexesNeurophysiological abnormalities have been reported in other brainstem reflexes in parkinsonism,

although they have not been investigated specifically in APDs (60–62). It has been shown that thesecond inhibitory period of the masseteric exteroceptive inhibitory reflex has an enhanced excitabil-ity recovery cycle, similar to that of the blink reflex in patients with IPD. The same excitabilityrecovery abnormalities have been reported in parkinsonism and dystonia (60).

The Startle Reaction and the Startle-Induced Modulation of Reaction TimeThe startle reaction in experimentation animals is known to be generated in the nucleus reticularis

pontis caudalis (nRPC), which activates the reticulospinal tract inducing muscle responses in facialand spinal motoneurons (63). In humans, the startle reaction is also thought to originate in corre-sponding nuclei of the brainstem, and spread caudally and rostrally to limb and facial muscles.

Abnormalities in the startle reaction can be related to enhancement or reduction of the responsesize. One example of abnormal startle response enhancement is hyperkeplexia (64), whereas anabnormal startle response reduction takes place in patients with PSP (48). The decrease of thestartle reaction in PSP patients should not be surprising, since neuronal loss in these patients involvesspecifically the cholinergic neurons of the lower pontine reticular formation, where the startle reac-tion is generated. Neuronal loss has been reported in the pedunculo-pontine tegmental nucleus andthe nucleus reticularis pontis caudalis (65–67). In the study carried out by Vidailhet et al. (48), theresponse was absent in three out of eight patients, and it was small and delayed in the other fivepatients. The same finding was later replicated by Valldeoriola et al. (22), who carried out a compara-tive study of PSP and other APDs.

Whereas response enhancement is easy to identify because of reactions of larger size and decreasedhabituation, assessment of an abnormal reduction of the response may be more difficult because of thefact that the response habituates easily in healthy subjects (49). For this reason, the observationsmade in experiments in which the startling stimulus was applied together with the imperative signalin the context of a reaction time task paradigm should be helpful for clinical purposes. Using suchmethods, Valls-Solé and coworkers (68–70) made a few interesting observations in healthy subjects:

1. The startling stimulus applied together with the imperative signal of a reaction time task induces a signifi-cant acceleration in the execution of the intended movement. The ballistic movement is executed withoutany distortion but at a significantly faster speed (70).

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Fig. 4. Basal ganglia control of trigemino-facial reflex excitability. The basal ganglia modulate the excit-ability of the blink reflex through the output signals arising from the globus pallidus pars interna (GPi) and thesubstantia nigra pars reticulata (SNr). According to Basso et al. (58) and Basso and Evinger (59), the GPi/SNrcomplex sends inhibitory inputs to the superior colliculus (SC), which is excitatory for the nucleus raphe magnus(nRM). This, in turn, inhibits the trigeminal neurons of the spinal nucleus. In PD, there is increased GPi/SNrinhibition of the SC which, as a consequence, reduces its excitatory inputs to the nRM. The less active nRMinduces less inhibition of the spinal trigeminal nucleus, which becomes dis-inhibited (hyperexcitable). As withbradykinesia, it is difficult to know whether the same mechanisms apply to APDs. I, inhibitory; E, excitatory ofstimulus.

2. The response to the startling stimulus is enhanced. The same startling stimulus that would give rise to arelatively small and inconsistent response when given alone induce a significantly larger response when isapplied during motor preparation (68).

3. Habituation of the response to the startling stimulus is significantly reduced. In a study in which auditorystimuli were applied at the same rate in different experimental conditions, Valls-Solé et al. (69) found thathabituation of the response to the startling stimulus was reduced in facial and cervical muscles whensubjects were engaged in preparation for a ballistic reaction.

Clinical application of the collision between a startle reaction and the voluntary activity in a reac-tion time task paradigm (the StartReact effect) was reported by Valldeoriola et al. (22). These authorsfound that patients with PSP not only had absent startle reaction but they were also not able to accel-erate their voluntary reaction when the startling stimulus was applied together with the imperativesignal.

In contrast to patients with PSP, patients with MSA have normal auditory startle reaction in facialand cervical muscles (71). Furthermore, when the responses of cranial and limb muscles are analyzedtogether, MSA patients had enhanced probability of a response, shortened onset latency, and enlargedresponse magnitude compared to normal controls (72,73). In the only analysis of the startle response inpatients with LBD, Kofler et al. (73) reported fewer and abnormally delayed ASR of low amplitude andshort duration in extremity muscles in comparison to healthy controls. Two more details of the studiesof Kofler and coworkers (72,73) are relevant for the discussion of the contribution of the startlereaction to the differential diagnosis of APD patients. One is the fact that three patients with MSAhad no response to the startle reaction, indicating that absence of the startle reaction is not a featureexclusive to PSP patients (48). A particularly high density of oligodendroglial cytoplasmatic inclu-


sions in the brainstem area responsible for the generation of the reticulospinal tract was assumed tobe the cause of absent startle response in those MSA patients. Another observation made by Kofleret al. (72) was the existence of subtle differences in the characteristics of the response betweenMSA-P and MSA-C patients. Whereas MSA-P patients had a higher startle probability and a largerarea and shorter latency of the motor response, patients with MSA-C had less habituation. Differ-ences between the two groups in the inhibitory effect of the cerebellum over the motor cortex may beresponsible for such neurophysiological observation (72).

Prepulse InhibitionA weak stimulus preceding by about 100 ms the startling stimulus has an effect of inhibition upon

the startle reaction (prepulse inhibition). The prepulse stimulus may be of the same or a differentsensory modality as the stimulus inducing the startle (50). In the blink reflex, an auditory prepulsecauses enhancement of the R1 and depression of the R2 to electrical supraorbital nerve stimuli (74).In a study of prepulse inhibition in patients with IPD, Nakashima et al. (75) found that auditoryprepulse stimuli induced an abnormally reduced inhibition of the R2 response of the blink reflex, andLozza et al. (76) reported an abnormally reduced blink reflex inhibition after index finger stimula-tion. However, some patients with IPD have an abnormal auditory prepulse inhibition and a normalsomatosensory prepulse inhibition (77). The different behavior of auditory and somatosensoryprepulse stimuli in IPD patients could be owing to differences in the prepulse effectiveness of thesame vs different sensory modality, differences in the arrival time of prepulse inputs to the brainstemcenters, or to selective impairment of reticular formation neurons activated by auditory inputs. Patientswith PSP have also absent or significantly reduced prepulse inhibition to both auditory and somatosen-sory prepulses (Fig. 5), revealing an even more striking dysfunction of the prepulse circuit in PSPcompared to IPD. No data are available so far regarding prepulse inhibition in MSA patients.

Spinal ReflexesA variety of tests determining the excitability of propriospinal interneurons (78,79) have been

applied to patients with IPD, demonstrating reduced reciprocal (33,34) and autogenetic (Ib) inhibi-tion (35), possibly related to the clinical expression of rigidity. These exams have not been done inpatients with APDs, except for a single study of autogenetic inhibition (Ib inhibition) in patients withPSP (41). In such a study, the authors showed enhancement of the inhibition, the exact opposite ofwhat was reported in patients with IPD. The explanation why opposite results have been found inthese two groups of patients is, up to now, not clear.

Audiospinal facilitation is known as the effect of an auditory stimulus on spinal reflexes, specifi-cally the soleus H reflex. The methods for audiospinal facilitation were developed by Rossignol andJones (80) and Delwaide et al. (81). The stimulus to the posterior tibial nerve to induce the H reflex isapplied between 0 and 110 ms after a loud acoustic stimulus. Healthy subjects have H reflex facilita-tion beginning at intervals between 60 and 80 ms, and lasting until the intervals of 100 or 110 ms.However, audiospinal facilitation is abnormally reduced in patients with IPD (12,81). Our own pre-liminary observations in patients with the clinical diagnosis of probable PSP is that they exhibit thesame abnormality (82).

Surface EMG Recording of Abnormal MovementsThe recording of abnormal movements by means of surface EMG recording yields interesting

information for the analysis of tremor, such as in patients with IPD (82). Tremor has also been reportedin up to 74% of MSA patients (83). However, this figure included several types of tremor, with only afew patients exhibiting the resting tremor typical of IPD, and a large proportion of unclassifiablehands and finger “jerky” tremors, such as those shown in video segment 2. Electrophysiologicalstudies of these latter movements have shown that their characteristics are closer to myoclonus thanto tremor (84). A piezoelectric accelerometer was used to record finger movements and analyze the

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Fig. 5. Prepulse inhibition of the blink reflex in a healthy volunteer and in a patient with PSP. The traces ofthe upper row show the responses to a stimulus to the supraorbital nerve applied at the vertical line. Ipsilateralrecordings (ipsi) show R1 and R2 responses whereas contralateral recordings show only the R2. The traces ofthe lower row show the responses to the same stimulus when a prepulse is applied 100 ms before (arrows).(A) Normal auditory prepulse inhibition in a healthy volunteer; (B) Absent auditory prepulse inhibition in apatient with PSP. (C) Absent somatosensory prepulse inhibition in the same patient.

frequency spectrum of the signal through fast Fourier transformation. This procedure showed thatmovements of MSA patients were rather non-rhythmic in comparison to those of patients with otherforms of tremor (Fig. 6). Salazar et al. (84) suggested the term minipolymyoclonus to be used todescribe these small amplitude, irregular, jerklike abnormal movements. Other forms of myoclonushave been also reported in a few MSA patients (30,85), which might have their origin in a reducedinhibition of the strio-palido-thalamo-cortical circuit (86). Table 3 shows a list of disorders in whichactivity defined as minipolymyoclonus has been encountered, together with some of the most rel-evant neurophysiological findings.

Myoclonus is also an apparent feature in patients with CBD (87), in whom they are thought to beof cortical origin in spite of lacking neurophysiological evidence. The expected findings of corticalmyoclonus, such as giant somatosensory evoked potentials and jerk-locked EEG potentials, are incon-sistent in CBD. The cortical response is occasionally absent, which is attributed to the marked frontopa-rietal cortical atrophy and neuronal degeneration characteristic of these patients (88,89). Corticalatrophy of inhibitory neurons could lead to the enhanced (disinhibited) motor cortex excitability.

The “C” wave, or focal reflex myoclonus (90), is a response seen in forearm muscles after electri-cal stimulation of ipsilateral cutaneous nerves of the hand. This response is thought to be mediated byfast-conducting afferent and efferent pathways and might have a latency as short as 43.1+/–3.2 ms(87). In some patients, focal reflex myoclonus might be elicited by stimuli of an intensity belowperception threshold, which suggests a direct connection from the thalamic nuclei to the motor cortex(91). The “C” response should not be mistaken for the long latency excitatory response of the cutaneo-muscular reflexes (92,93). The cutaneo-muscular reflex can be elicited during a sustained tonic vol-untary contraction of the forearm muscles. The long latency excitatory component of thecutaneo-muscular reflex is abnormally enhanced in patients with IPD or MSA (30). However, thelatency of such a response is longer than that of the “C” reflex.


Fig. 6. Surface EMG recording from wrist extensors (A), accelerometric recording of finger movements(B), and FastFourier analysis of the movement recording (C) in a patient with MSA and minipolymyoclonus.See the absence of a dominant frequency peak.

Table 3Disorders Featuring Minipolymyoclonus

Disorder Dominant Clinical Sign EMG Bursts EEG “C” wave

Motoneuron disease Fasciculation atrophy Asynchronous (1–20 Hz) Not described Not described

Polyneuropathy Absent tendon jerks Slow and asynchronous Not described Not describedSevere sensory deficit

Alzheimer’s disease Dementia Multifocal Slow waves PresentEpileptiform

activityNegative

frontal wave

Myoclonic epilepsy Seizures Synchronized or irregular Slow negative Presentfrontal wave

Syringomyelia Weakness. Spasticity Asynchronous and Not described Not describedSensory deficit irregular

MSA-P Rigid-akinetic syndrome Synchronous (1–12 Hz) Normal Present

Autonomic Reflexes and FunctionsAutonomic nervous system dysfunction is the key to the diagnosis in patients with MSA who

present with parkinsonism or cerebellar syndromes (3), and is presently a required criterion for thediagnosis of probable MSA (94). Clinically relevant autonomic dysfunctions in these patients areorthostatic hypotension, urinary and fecal incontinence, erectile dysfunction in males, sudomotordisregulation, and abnormalities in respiratory control during sleep. Autonomic dysfunction, i.e.,urinary incontinence (97%) and constipation (83%), has also been reported in patients with LBD (95).

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Orthostatic hypotension may result from the inability to increase sympathetic activity when stand-ing. This can be shown as an abnormal regulation of baroreflex responses to different stimuli (96).Using readily available electrophysiological equipment, it is also possible to monitor heartbeat fre-quency. Recording the R-R interval variation by means of the signal trigger and the delay line unit ofan electromyograph shows graphically the reduced adaptation of the heart beat rate to a posturalchange or to the Valsalva maneuver (77). The main drawback of this test is that patients with severebradykinesia might be unable to perform adequately the maneuvers, and reduced R-R interval varia-tion could actually be owing to insufficient stimulation. One of the possibilities to test R-R intervalvariation using methods that do not require the patient’s cooperation is based on the fact that thestartle response is normal in MSA patients (71,72), and on the observation that a startle acceleratesheartbeat frequency in normal subjects (97). In a group of six MSA patients, a startling acousticstimulus induced the normal motor component of the startle reaction but a significantly smaller changeof the R-R interval in comparison to healthy volunteeers (98).

The sympathetic sudomotor skin response, or SSR (99), may reveal dysfunctions in the autonomiccontrol of sudomotor reflexes. Loss of sympathetic neurons of the intermediolateral column mightexplain the finding of frequently abnormal SSRs in patients with MSA (100). Other tests of sudomo-tor function, such as the evaluation of the amount of sweat production to direct gland stimulationwith intradermal methacholine, have also demonstrated a decreased sweat response in patients withMSA (101).

Sleep disorders are frequent in patients with MSA and in those with LBD. Some of these disordersmight be related to autonomic dysfunction. In the study of Plazzi et al. (102), 35 out of 39 patientswith MSA had REM sleep behavior disorders. These preceded the diagnosis in 44% of the cases.Polysomnographic studies revealed subclinical obstructive sleep apnea in 6 patients, laryngeal stri-dor in 8 patients, and periodic leg movements during sleep in 10 patients. Laryngeal stridor, owing tovocal cord abductor paralysis during sleep, is probably caused by selective denervation atrophy ofthe cricoarytenoid muscle resulting from selective loss of neurons in the nucleus ambiguous (103),and may lead to chocking and death in advanced stages of MSA. This can be prevented with tracheo-stomy (104) or with continuous positive air pressure (105). REM sleep behavior disorder has alsobeen considered a sign heralding LBD (106) and, in a more recent study, it is considered as a possiblehallmark of a synucleinopathy in the setting of a cognitive dementia or parkinsonism (107).

Needle EMG Recording of the Sphincter MusclesIn MSA patients, manifestations of autonomic dysfunctions such as erectile impotence are usually

accompanied by increased urinary frequency and urgency, leading soon to incontinence, associatedwith large residual urine volumes (108). The severity of urinary symptoms is one main red flag thatshould warn the neurologist of the possibility that the parkinsonian patient thought to have IPD isactually facing the diagnosis of probable MSA (3). Urinary incontinence in MSA patients might bebecause of autonomic dysfunction, loss of pontine control of micturition, striatal sphincter denerva-tion, or a combination of them all. Striatal sphincter denervation is attributed to the selective loss ofmotoneurons in the nucleus of Onuff at the S2-S3 medullary segments. Needle electromyographyof the external anal sphincter, therefore, is considered an important neurophysiological test in theassessment of patients with parkinsonism, as most patients with MSA show denervation-reinnerva-tion signs (109,110). We and others have confirmed that anal sphincter denervation is prominent inpatients with MSA, although similar types of abnormalities have been found in a large proportion ofpatients with PSP as well as in some patients with IPD (111,112). Therefore, the utility of anal orvesical sphincter needle EMG in the diagnosis of MSA is still under debate (113,114). Chronic con-stipation, local trauma related to delivery, and other pudendal nerve long-standing lesions may giverise also to sphincter denervation (115,116), which may diminish the validity of the sign as a truemarker of motoneuronal loss. In the consensus statement for the diagnosis of MSA (94), sphincterEMG abnormalities are considered as a supportive laboratory finding.


Transcranial Magnetic Stimulation

There are not many studies published on the use of transcranial magnetic stimulation (TMS) inpatients with APDs in comparison to the large body of literature published in patients with IPD.However, finding an abnormality in central conduction time in a patient with parkinsonism should beconsidered as a red flag to warn of the likely existence of a degenerative disorder different from IPD.Central motor conduction time has been found slightly delayed in a number of patients with MSA, inboth the parkinsonian (117) and cerebellar variants (118).

Many other cortical and subcortical functional measures can be determined with single-pulse TMS,including resting and active threshold, stimulus-response curves, silent period duration, or corticalmaps, but only a few studies of this kind have been carried out in patients with APDs. Most of themhave been performed in patients with CBD, a disorder featuring clinical signs of asymmetrical sen-sorimotor cortex involvement. Recording from muscles of the more affected side, Lu et al. (119)reported shortened TMS-induced silent period, and Strafella et al. (120) reported enhanced facilita-tion and reduced inhibition of MEPs modulated by digital nerve stimulation. These findings are likelyreflecting motor cortical excitability enhancement.

Patients with CBD exhibit lack of voluntary control of limb movements (video segment 3), or“alien-hand” syndrome, which suggests a cortical dysfunction (121,122). In normal subjects, unilat-eral TMS, applied with the figure of “8” coil, induces hand muscle responses restricted to the con-tralateral side. However, in 6 out of 10 patients with CBD, Valls-Solé et al. (123) found bilateralresponses to focal, unilateral, TMS applied to the side contralateral to the alien hand (Fig. 7). Ipsilat-eral responses were delayed with respect to the contralateral ones by a mean of 7.7 ± 2.2 ms, a timeallowing for conduction through the corpus callosum. Such abnormality was not found in any of 10normal subjects, 8 patients with Alzheimer’s disease, or 6 patients with IPD presenting with pre-dominantly unilateral rigidity. This finding points again to an enhanced motor cortex excitability inthe hemisphere contralateral to the alien hand, which may be unable to inhibit transcallosal excitatoryinputs from the other hemisphere.

Paired-pulse TMS has been also used in the study of corticospinal tract functions in patients withAPD. Intrahemispheric cortico-cortical inhibition was found abnormally reduced in patients with MSA-P, but not in patients with MSA-C (124). It has also been abnormal in the study of patients with CBD(125,126), suggesting the possibility of its clinical utility in the early phases of the disease (126).

TMS is an important tool not only for the assessment of cortical motor function but also for theanalysis of the modulatory effects that descending pathways might have on segmental reflexes.Using methods similar to those proposed by Delwaide and collaborators with auditory stimuli (81),we examined the effects of TMS on the soleus H reflex in normal subjects and in patients withparkinsonism. In healthy volunteers, TMS induced early (5–30 ms) and late (60–100 ms) phases ofsignificant facilitation of the soleus H reflex (127). The second phase is absent or significantlyreduced in about 50% of patients with IPD (82), and in all eight patients with PSP examined so far(unpublished results).

Evoked PotentialsThe early components of the somatosensory evoked potentials in patients with IPD are normal,

except for the N30 recorded at the frontal lobe, which shows reduced amplitude (128). According toRossini and collaborators, the reduced amplitude of the N30 might be owing to an abnormal sen-sorimotor integration (129). A different kind of abnormality has been reported in patients with PSP.In these patients, Kofler and collaborators (130) reported an enhancement of the amplitude of theearly components of the somatosensory evoked potentials, which was considered to be the conse-quence of cortical disinhibition. More recently, Miwa and Mizuno (131) confirmed the finding andproposed that the observation of enlarged somatosensory evoked potentials can be useful in the dif-ferentiation of PSP patients from other patients with movement disorders.

422 Valls-Solé

Fig. 7. Recordings from bilateral thenar muscles to focal, unilateral, transcranial magnetic stimulation (TMS)in a healthy control subject (A), and in a patient with CBD (B). Upper traces result from left-hemisphere TMS,and lower traces from right-hemisphere TMS. Note the presence of a delayed ipsilateral MEP in the patient.

The premotor evoked potentials are abnormal in patients with IPD, likely reflecting a disturbancein preparation of the motor act. Deecke et al. (132) showed that there was a delay and reduction of thebereitschaftpotential, and abnormalities in event-related potentials have been also published. How-ever, there are no studies of the premotor potentials in patients with APDs.

NEUROPHYSIOLOGICAL TESTS MOST USEFULFOR DIFFERENTIAL DIAGNOSIS IN PATIENTS WITH APD

There is no single clinical neurophysiology test that can be used to distinguish with certitudebetween patients with APD at an individual level. This situation of clinical neurophysiology is com-mon to many other conditions. In practicing clinical neurophysiology, the examiner is constantlylooking for data that can bring more cues to confirm or refute an hypothesis made on the basis ofclinical exam. The selection of tests useful for differential diagnosis in patients with APD can only beorientative or suggestive, but conclusive. One of the roles of those whose work is devoted to clinicalneurophysiology should be to search for new methods and technical improvements to bring furtherunderstanding on pathophysiological mechanisms of the disease process.

From the author’s point of view, the neurophysiological tests that better characterize parkinsonismand, specifically, the APDs, are listed in Table 4. Performance of ballistic movements within a reac-tion time task paradigm is useful to test the mechanisms of motor preparation and execution, eventhough very much should still be learned on the physiology of motor preparation for the test to pro-vide its full potential of information. Brainstem and spinal reflexes have to be conveniently modu-lated by the descending motor commands for them to be integrated in the subject’s normal motorbehavior. Although many tests have given interesting information on the abnormal brainstem andspinal reflex modulation in patients with parkinsonism, a good clinical correlate of these abnormali-ties is still pending. The evaluation of autonomic reflexes and the sphincter EMG provides informa-tion on specific abnormalities that can be predominant in certain groups of patients. They reflect theinvolvement of specific groups of neurons, well correlated with pathologic findings. However, theyare not useful for the diagnosis on an individual patient basis since similar abnormalities can be


present in other groups of patients. TMS, short latency evoked potentials, and event-related poten-tials, are all offering many possibilities for the study of motor and sensory pathways as well as brainsensorimotor integration and high level processing of information. Although many studies have beencarried out in patients with parkinsonism, very few reports on APDs have been published so far. Alarge amount of research is under way regarding the physiological mechanisms of TMS and event-related potentials. Many of them are already available for clinical application and more will be in thenear future, allowing for better characterization of the abnormalities involving sensory and motorfunctions of patients with APDs.

FURTHER RESEARCH IN NEUROPHYSIOLOGY OF APD

There is a large amount of possibilities for research in neurophysiology of parkinsonism and ofmovement disorders in general. Neurophysiology offers the advantage of a good temporal resolutionof events and should bring further understanding of what is wrong in the CNS that leads to motordsyfunction. The research in clinical neurophysiology will probably continue until the pathophysi-ological mechanisms of the diseases are well understood. However, meaningful information can onlybe obtained if a careful neurological examination is followed by an imaginative albeit meticulousneurophysiological study. Undoubtedly, the most rewarding situation would be the one in whichneurologists and clinical neurophysiologists join their efforts. Relevant and interesting informationderived from neurophysiological studies should stir up the interest of clinicians, whereas challengingquestions arising from clinical exams should stimulate the imagination of the clinical neurophysiolo-gist in devising new techniques for more careful documentation of the signs.

Although the cooperation between clinical and neurophysiological experts is the first conditionfor the development of future lines of research, the second one is the development of better methodsfor clinical diagnosis of the diseases. Neurophysiology would be able to provide accurate informa-tion on the pathophysiology of movement disorders only if the diagnostic uncertainty is reduced tonegligible levels. A thorough neurophysiological characterization of patients with APDs, appropri-ately classifed into well-differentiated groups, would certainly bring information that may be usefulin the future to improve the diagnostic accuracy but, most of all, the pathophysiology of the diseases.

Suggestions for future research lines are listed in Table 5. Some of them are based on clinicalfeatures that should be the focuss of neurophysiological studies. However, some techniques may be

Table 4Selection of Neurophysiological Findings Allowing for Characterization of Specific DisordersPresenting With Parkinsonism

Disorder Results of Neurophysiological Tests

IPD Mild delay of reaction time in performance of ballistic movementsReduced prepulse inhibition of the blink reflex to auditory stimuli, with normal prepulse

inhibition to somatosensory stimuliRegular alternating tremor at rest

PSP Absent startle reaction to auditory stimuliAbsent orbicularis oculi response to a median nerve electrical stimulus eliciting a response

in the mentalis muscleReduced prepulse inhibition of the blink reflex to both auditory and somatosensory stimuli

MSA Signs of denervation-reinnervation in sphincter musclesSigns of autonomic dysfunctionMinipolymyoclonus

CBD Spontaneous and reflex myoclonusAsymmetry in cortical maps of representation of hand muscles

LBD REM sleep behavior disorder

424 Valls-Solé

Table 5Lines of Future Research in Neurophysiology of APD

Clinical Feature Research Lines

Motor systems Documentation of bradykinesia when performing natural tasksMethods for enhancing energization of the motor tractReadiness and premotor potentialsRelationship between mental processes and motor actionsRole of external cues and rhythms on movement performanceDysfunction of subcortical motor pathwaysSource of rest and action tremor oscillations

Sensory systems Multilevel sensorimotor integrationLong latency and event-related evoked potentialsIntersensory facilitation vs collision between sensory stimuli

Spinal cord reflexes Alpha motoneuronal excitabilityThe role of propriospinal inhibitory circuits in rigidity

Brainstem physiology Relationship between basal ganglia and brainstem nucleiRecording pedunculopontine tegmental nucleus functionsPhysiology of automatic movementsSpontaneous and reflex blinks

Cortical stimulation Modulation of cortical responses with sensory inputsIpsilateral effects of TMSRepetitive transcranial magnetic stimulation

able to demonstrate features of the disease that point to the dysfunction of certain nervous systemcenters or structures. Among those techniques, TMS and event-related potentials are probably themost promising ones. Since their implantation, TMS and especially repetitive TMS (rTMS) haveopened a large avenue of research in parkinsonism and other movement disorders. They will cer-tainly bring more possibilities for neurophysiological interventions in the near future, including thera-peutic actions. It has been demonstrated that the introduction of a variable amount of electrical currentin brain tissues by applying rTMS of different intensities and frequencies induces excitability changesthat can in turn be measured by conventional TMS or other methods (133). Since 1994 (134), rTMShas been used as a therapy in patients with IPD. Although there has been contradictory observationsup to the most recently published papers (135,136), researchers will certainly keep trying until thetechnique finds its position among the armamentarium of neurophysiological interventions in patientswith APDs. Recording event-related brain potentials should provide information on structures that maybe dysfunctional in parkinsonism. Cognitive negative variation has been reported to be improvedafter subthalamic nucleus stimulation (137), indicating the sensitivity of the test to basal ganglia–cortical loop function. A variety of other neurophysiological techniques could be in the list of sug-gestions for future studies. The reader may find helpful information regarding many of thoseprocedures in the specialized literature. However, apart from knowing technical details, the researcherinterested in neurophysiology of parkinsonism should exercise imagination to find new ways to dem-onstrate specific features of the disease.

LEGENDS FOR THE VIDEO SEGMENTS

Video segment 1. Two patients with PSP featuring slow and limited voluntary eye movements.The second patient shows responses of the lower facial muscles, but not of the periocular muscles, toa scratch stimulus to the thenar eminence.

Video segment 2. Two patients with MSA-P showing minipolymyoclonus. Note the irregularmovements, sometimes limited to one finger


Video segment 3. Two patients with corticobasal degeneration. The first patient shows some fea-tures of alien limb. The second patient had asymmetrical upper limb appraxia.

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