The physiology of rigidity in Parkinson's disease (PD) can be investigated by the study of reflexes. Cutaneous reflexes (CR) were measured in 10 patients with PD and in 10 age- and sex-matched normal volunteers. EMG activity was recorded from the first dorsal interosseous muscle with surface electrodes, rectified and averaged. The index finger was stimulated with an intensity four times the sensory threshold. The subjects abducted the index finger with 20% of maximal force. While the latencies of the different reflex components and the amplitudes of the excitatory peaks were not different in the two groups, the first inhibitory component was less pronounced in patients with PD as compared with normals. This effect is partially reversed with dopaminergic drug treatment. The results are compatible with the loss of an inhibitory spinal mechanism elicited by cutaneous afferents, and can be a partial explanation for increased tone in PD. Key words: cutaneous reflexes long latency reflexes cortical stirnulation L-dopa Parkinson's disease MUSCLE & NERVE 15~733-739 1992
CUTANEOUS REFLEXES IN PARKINSON'S DISEASE PETER FUHR, MD, THOMAS ZEFFIRO, MD, PhD, and MARK HALLElT,
Rigidity in Parkinson's disease (PD) is abolished by dorsal root ~ e c t i o n , ~and ' could therefore be generated or supported by reflex action. Since the monosynaptic reflex is not enhanced in this condition,2 it is conceivable that some kind of a long latency reflex is overactive or disinhibited and that its quantification might be a useful measure of rigidity in parkinsonism. Long latency reflexes in the upper extremities can be evoked in three different wa s: by stretching the muscle under investigation,' by stimulating its nerve carrying mixed a f f e r e n t ~ , ~or ' by stimulating cutaneous a f f e r e n t ~ . ~In' ~ ~several studies of long latency reflexes in Parkinson's disease the stretch paradigm was used. Mostly, an increase in the amplitude of the long latency reflex
From the Human Motor Control Section, MNB, NINDS, National Institutes of Health, Bethesda, Maryland Presented in part at the 1990 AAEM Annual Scientific Meeting in Chicago, Illinois. September. 1990. Acknowledgments: We are indebted to Ms.6.J. Hessie for editorial assistance; to Lisa McShane, PhD, for statistical advice, and to Nguyet Dang for technical support. Address reprint requests to Mark Hallett. MD, Clinical Director, NINDS, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 5N226. Bethesda, MD 20892. Dr. Fuhr's present address is Neurologische Universitatsklinik, Kantonsspital, CH-4031 Basel, Switzerland. Accepted for publication November 11, 1991 CCC 0148-639X/92/060733-07 $04.00 0 1992 John Wiley & Sons, Inc.
Cutaneous Reflexes in Parkinson's Disease
MD
was f o ~ n d . ~However, . ~ . ~ ~ this finding was controversial and has been demonstrated to depend on the exact methodology, since both an increase and no alteration of the long latency reflex could be demonstrated in identical patients.28 Studies with mixed nerve stimulation also yielded controversial results. 12.1926 In all of these studies, attention was focused on the increase in the long latency excitatory reflex component. However, it is equally conceivable that rigidity results from the loss of an inhibitory mechanism. Therefore, it is tempting to look at this issue using cutaneous stimulation, because the inhibitory component is so prominent in this paradigm. Moreover, cutaneous stimulation reduces the amplitude of motor-evoked potentials to cortical stimulation in normals, but not in patients with PD." MATERIALS AND METHODS
Studies were performed on 10 male patients with Parkinson's disease whose characteristics are listed in Table 1. Mean age was 61 15 years. All were studied while they were withdrawn from medication, and 9 of them were studied also when taking L-dopa or dopamine-receptor agonists. A second group consisted of patients with hemiparkinsonism, and side-to-side comparisons were done in those. The control group consisted of 10 normal volunteers who were matched for sex (1 female, 9 males) and age (mean 55 17
Subjects.
*
*
MUSCLE & NERVE
June 1992
733
Table 1. Patients with bilateral Parkinson's disease ~~
Patient
Sex
Age
UPDRS*
HlYt
SlE*
Delay5
Withdrawal''
1
M
42
29138 (5120)
2.5 (2.0)
80 (90)
70 d
5d
2
M
68
41139 (27126)
3.0 (3.0)
80 (80)
134 d
24 h
3
M
56
11I26 (12/22)
2.5 (2.0)
90 (90)
71 d
14 d
4
M
56
86/84 (69164)
4.0 (4.0)
30 (50)
11 d
6 d
5
M
76
34130 (33126)
2.5 (2.5)
80 (90)
7d
5d
6
M
66
36136 (25128)
2.5 (2.0)
80 (90)
77 d
24 h
7
M
74
74174 (71171)
4.0 (4.0)
30 (70)
63 d
12 h
8 9 10
M M M
76 56 35
30121 (44129) 37130 (37128) 14123
2.5 (3.0) 3.0 (3.0) 2.5
80 (80) 80 (90) 100
78 d 12 d
20 h 14 d
-
-
Medication Deprenyl 2 x 5 mg. bromocriptine 5 x 1 25 mg, propranolol 3 x 30 mg Amantadine 2 x 200 mg, acebutolol 1 x 100 mg CIL-dopa 101100 4 x 1, propranolol 2 x 40 mg CIL-dopa 251100 6 x 1, deprenyl4 x 5 mg ClL-dopa 101100 3 x 112, amantadine 2 x 200 mg, deprenyl2 x 5 mg CIL-dopa 251100 3 x 1, deprenyl2 x 5 mg CIL-dopa 251100 8 x 1, bromocriptine 4 x 2 5 mg, pergolide 2 x 0 5 mg, deprenyl 2 x 5 mg, arnitriptyline 1 x 5 mg, diazepam 1 x 5 mg CIL-dopa 251100 3 x 1 CIL-dopa 101100 4 x 1 None
'Unified Parkinson's Disease Rating Scale First number right-sided and generalized signs and symptoms, second number left-sided and generalized signs and symptoms Numbers in parentheses indicate the score when on medication tHoehniYahr Staging Numbers in parentheses indicate the score when on medication fSchwablEngland Activities of Daily Living Scale Numbers in parentheses indicate the score when on medication §Time delay, in days, between testing off and on medlcation Plain numbers first testing off, then on medication italic numbers, vice versa "Duration of complete withdrawal, in hours (h) or days id), from CarbidopalL-dopa andlor dopamine receptor agonrsts andlor MAO-B inhibitor
years). All subjects gave their written informed consent for the study, which was approved by the clinical research review committee. Experimental Proceedings. T h e severity of symptoms was assessed according to the Unified Parkinson's Disease Rating Scale (UPDRS, version 3.0).'" EMG activity was recorded from the first dorsal interosseous (FDI) muscle with surface electrodes using a DISA 15C01 amplifier, with low and high filters set at 20 Hz and 10 kHz, respectively. T h e signal was rectified and averaged. T h e sampling period was 200 ms, and 1024 samples were averaged three times on both sides. T h e curves were printed and analyzed off-line. The technique of recording the reflex was described in detail in an earlier study,15 and is summarized here only briefly. Stimuli of 0.2 ms duration were delivered at a rate of 3 Hz from a constant current stimulator (DISA 15E25) through ring electrodes to the digital nerves of the second finger. Stimulus intensity was four times the sensory threshold or the threshold of pain, whichever was lower. T h e reflexes were recorded
734
Cutaneous Reflexes in Parkinson's Disease
while the subjects performed an isometric contraction of the FDI at 20% of the maximal force. Force was kept constant with visual feedback displayed to both the subject and the experimenter by using a digital scale connected to the load cell. T h e cutaneous reflex (CR) consists of a triphasic modulation of ongoing EMG activity, with two excitatory components ( E l and E2) divided by an inhibitory one (11) (Fig. 1). The latencies were measured from the stimulus artifact to the peak of the reflex components and normalized for arm length. l 5 T h e amplitudes were measured from the baseline to the peak of the reflex components, and the amplitude of the baseline of ongoing EMG activity was measured from the zero-line. The absolute data rather than the amplitudes divided by the baseline are presented, because normalization was done in force. Although there was a correlation in individuals of the amplitude of I1 with the force level, none was found between the amplitude of the baseline and the amplitude of I 1 in individuals applying the same force (20% of the maximum). T h e average of the three individual measure-
MUSCLE & NERVE
June 1992
STIMULUS
I
E2
_I 25PV 20 MS
FIGURE 1. Example of a normal cutaneous reflex, consisting of two excitatory components (El and E2) and an inhibitory component (11) between them. The recording was taken from the FDI muscle during an isometric contraction of 20% of the maximal force after rectifying and averaging the raw EMG over 1024 cycles. The index finger was stimulated with ring electrodes with an intensity four times the sensory threshold. Amplitudes were measured at the arrows, 1 representing the amplitude of the baseline EMG; and 2, 3, and 4 the amplitudes of the rectified EMG during the peak of the three reflex components. The amplitudes of the reflex components were calculated by subtracting the amplitude of the baseline.
ments on each arm was used in the further analysis. For group comparisons (patients versus normal subjects; patients off therapy versus patients on medication), the average of the values from both arms was taken as the representative value for the individual patient. Two additional experiments were carried out to test the spinal motoneuron excitability during the inhibitory period I1 of the CR. These studies were performed on 4 normal male volunteers, ages 35 to 42 years. H-reflexes were recorded from the FDI muscle during voluntary contraction by stimulating the ulnar nerve at the The H-reflex was averaged 1024 times with (test condition) and without (control condition) concurrent stimulation of the index finger by alternating the condition every 50 cycles. Force of the FDI muscle and characteristics of the index finger stimulation were identical to those in the experiment with PD patients. Relative timing of the stimulus to the ulnar nerve and to the index finger was so that the H-reflex appeared during the peak of the I1 component of the CR. T h e amplitudes of the averaged Hreflexes obtained in the control and in the test condition were compared. H-reflexes were also recorded from the flexor carpi radialis (FCR) muscle at rest by stimulating the median nerve at the elbow with different intensities. l7,*' At each level of stimulus intensity, the H-reflex of the FCR was recorded alternately with (test condition) and without (control condi-
Additional Experiments.
Cutaneous Reflexes in Parkinson's Disease
tion) concurrent stimulation of the index finger. Intensity of the index finger stimulation was identical to that in the experiment with PD patients. Relative timing of the stimulus to the median nerve and to the index finger was so that the H-reflex appeared during the previously determined peak of the 11 component of the CR of the FCR muscle. The mean amplitudes of 20 H-reflexes obtained in the control and in the test condition were compared. Statistical Analysis. Interindividual comparisons were tested with the Mann-Whitney U test, and intraindividual comparisons were tested with the Wilcoxon signed rank test. The level of significance was set at 0.05. RESULTS
Patients and normal subjects did not differ with respect to the latencies of the reflex components, which were normalized for arm length. The mean 1 SD of the normalized latencies in the patients (values of the normal subjects in parentheses) were 61.8 4.2 ms (61.2 ? 4.5 ms) for E l , 76.5 5 5.2 ms (76.2 ? 4.7 ms) for 11, and 92.2 ? 5.8 ms (96.0 6.0 ms) for E2. All the individual latencies were within the normal limits determined in an earlier study. I 5 The amplitudes of the excitatory reflex components E l and E2 did not differ significantly in the two groups of subjects. The mean ? 1 SD (values of the normal subjects in parentheses) for E l were 10.4 +- 4.0 pV (11.9 2 6.6 pV), and for E2 they were 20.9 ? 14.8 pV (30.4 2 10.9 pV). However, the amplitude of the inhibitory component I1 was different in both groups. It was -15.4 2 6.0 FV in the patient group, and was -30.0 _t 13.1 PV in the group of normal subjects ( P = 0.0041) (Fig. 2). N o correlation between the amplitude of I1 and the clinical assessment of the severity of the disease could be found. However, medication (L-dopa in 8 patients, bromocriptine in 1) enlarged the amplitude of I1 (from -15.4 ? 6.4 pV to -28.4 5 16.7 kV, P = 0.0077) (Fig. 3). Side-to-side comparisons in 3 patients with hemiparkinsonism showed a clear, although not statistically significant, tendency toward smaller amplitudes on the symptomatic side ( P = 0.1088) (Fig. 4). In additional experiments to evaluate whether the mechanism of the inhibitory component of the CR was a direct inhibition of the excitability of the a-motoneuron pool, H-reflexes were recorded during the I1 component of the CR.
*
*
MUSCLE & NERVE
June 1992
735
a
“1 120
0
c
8 8
w
0
-30
0 0
3
0 0
-“I
-20. -40.
El
11
EZ
PATIENTS OFF THERAPY
BASELINE
FIGURE 2. Mean 4 1 SD of the amplitudes of the first excitatory (El), the inhibitory (Il), and the second excitatory component (E2)of the cutaneous reflex. To the far right is the amplitude of the baseline. Open circles represent the values of the normals, filled circles represent those of the patients. The amplitude of I1 is reduced by 50% in the patient group ( P = 0.0013),while the other reflex components and the baseline are not significantly different in the two groups.
From the analysis of the CR in the FDI muscle, an inhibition of 18.5% and 23% was expected in the 2 subjects, respectively. However, no diminution of the H-reflexes recorded from the FDI muscle during the I1 Component of the CR was observed. H-reflexes were also recorded during the I1 component of the C R evoked in the FCR muscle after index finger stimulation in 2 other subjects. I n this muscle, it is possible to record H-reflexes without voluntary background activity. Again, no diminution of the H-reflexes recorded from the FCR muscle during the I 1 component of the CR was observed (Fig. 5).
PATIENTS ON THERAPY
NORMAL VOLUNTEERS
FIGURE 3. The amplitude of the I1 component of the reflex is shown as a function of the treatment. On the left are patients withdrawn from medication, in the middle are the same patients on dopaminergic medication; and on the right are the values of the normal control group. Mean f 1 SD are given to the side of the individual values. The baseline is at the top, and larger amplitudes correspond to points lower on the graph. The amplitude of the I1 component is smaller in the untreated than in the treated state of the same patients ( P 5 0.05).
sions in the central nervous system support this hypothesis.22 Much less data is available as to the mechanism of the first inhibitory component. If it were generated in a transcortical loop, enough time for ner-
0
-10.
-20.
DISGUSSlON
The CR is composed of a first excitatory response followed by an inhibitory phase, and then by a second excitatory response. After these, more responses may be observed, but they are much less The first excitatory reflex component has a latency similar to that of the H-reflex and a central delay of 4.6 ms, and thus it can involve only a relatively simple spinal pathway.22 As for the second excitatory component, its latency leaves enough time for a transcortical loop via the dorsal columns and the corticospinal tract, and observations made in patients with anatomically well-defined lePhysiology of the Cutaneous Reflex.
736
Cutaneous Reflexes in Parkinson’s Disease
zW
n 3
-30
z
& -40.
-50.
NORMAL SIDE
SYMPTOMATIC SIDE
FIGURE 4. Comparison of the two sides in three patients with hemiparkinsonism. The baseline is at the top and larger amplitudes correspond to points lower on the graph.
MUSCLE & NERVE
June 1992
STIMULUS TO INDEX FINGER
I1
A.
CUTANEOUS REFLEX AVERAGED RECTIFIED
*10 ms
H-REFLEX ALONE
500 pv
H-REFLEX AT LATENCY OF INHIBITORY PERIOD OF CUTANEOUS REFLEX
10 ms
B.
4504 4000
5 3500
pi
2 3000 AMPLITUDES OF W H-REFLEXES (pV) n WITH AND WITHOUT 2 2500 CUTANEOUS STIMULATION 2000
2
3
1500 loo0 500
a STIMULUS INTENSITY FIGURE 5. H-reflex recorded at rest in the FCR muscle at the previously determined peak of the inhibitory phase of the cutaneous reflex in this muscle. (A) Cutaneous reflex recorded in the FCR muscle after index finger stimulation. (Middle) H-reflexes with and without preceding stimulation of the index finger. (B) Mean ~fr1 SD of the amplitudes of H-reflexes with (filled circles) and without (open circles) preceding stimulation of the index finger. The abscissa represents different intensities of the stimulus to the median nerve at the elbow so as to produce H-reflexes with different amplitudes. The stimulus intensities are indicated as multiples of the threshold for the ti-reflex. Over the whole range of the recorded part of the H-reflex recruitment curve, there is no significant amplitude reduction during the inhibitory phase of the cutaneous reflex.
vous conduction would be a necessary requirement. In a study of 70 normal volunteers, the mean onset latency for the inhibitory component of the CK, which coincides with the latency of the peak of the first excitatory component, was 40.3 ms, and that of the first negative peak of the somatosensory-evoked potential to identical stimulation of index finger, representing the arrival of the volley at the sensory cortex, was 21.9 ms.15 The difference between these two latencies, 18.4 ms, less the time for central processing, would be
Cutaneous Reflexes in Parkinson’s Disease
available for efferent conduction from cortex to hand muscle. T h e mean onset latency of the motor-evoked potential in voluntarily activated hand muscles, however, is 19.6 ms,18 and this is the minimal estimate because only activation of the center of the motor representation area of a muscle can elicit a motor response at minimal latencies. l4 Therefore, there is not sufficient time for a transcortical loop, and the cutaneous inhibition of voluntary activity likely originates subcortically.
MUSCLE & NERVE
June 1992
737
In a study with magnetic cortical stimulation, the amplitudes of motor-evoked responses in hand muscles (APB) at rest were reduced if the index finger was stimulated 18 to 20 ms (maximal effect at 18 ms) before the cortical stimulation with an intensity four times the sensory threshold."' Since the mean latency of the fastest conduction of this stirnulus to the sensory cortex is longer than that, the cutaneous inhibition of the motor-evoked potential to cortical stimulation must also be located on a subcortical level. T h e delay of the motor-evoked response after the cutaneous stimulation can be calculated by adding 22.6 2 1.2 ms for the onset-latency of motorevoked responses to magnetic cortical stimulation in the same hand muscle (APB) at rest4 to the 18-ms delay between cutaneous and cortical stimulus. The result, about 40 ms, corresponds well to the onset-latency of the inhibitory component of the CK (40.3 ms). It is likely, therefore, that the mechanism for the cutaneous inhibition of motorevoked potentials and that of voluntary activity is the same, arid that it is located on a subcortical level. To determine further the site of interaction of the cutaneous input with the voluntary activity, we measured the H-reflex during the inhibitory phase of the CK in the FDI and FCR muscles. N o diminution of the amplitude of the H-reflexes was apparent. 'This indicates that the inhibitory activity brought about by cutaneous afferents does not have a direct effect on the a motoneuron, nor does it affect the presynaptic terminals of the Ia afferents. 'I'hus, the site of inhibitory action lies above the a motoneuron. Cutaneous Inhibition in PD. While the amplitudes of the excitatory components and all the latencies are not different in the patient and normal groups, the inhibition of voluntary muscle activity during the first inhibitory component of the CK is diminished in PD. This effect can also be demonstrated in a side-to-side comparison in patients with hemiparkinsonism, and it is partially reversed with drug therapy. Similar to the present results, no cutaneous inhibition of the motor-evoked potential to cortical stimulation was found in patients with PD; instead, it was replaced by facilitation. When the patients were treated with [*-dopa, this facilitation was reduced and sometimes replaced by inhibition.") T h e impact of PD on the cutaneous inhibition of ongoing voluntary activity is not as dramatic as on motor-evoked potentials to cortical stimulation, but the changes go in the same direc-
738
Cutaneous Reflexes in Parkinson's Disease
tion. T h e difference is probably due to the more complex way in which voluntary effort activates the spinal niotoneuron pool. I t is clear, however, that the reduction of cutaneous inhibition in PD not only affects an artificially evoked potential but also the voluntary muscle activity of the patients. A possible explanation is an alteration of excitability of spinal interneurons upon which cutaneous afferents and pyramidal fibers converge.'" Their role is important in both the control of voluntary movement and in determining the shape and amplitude of the motor-evoked potential, because the majority of the corticospinal neurons terminate on spinal inter neuron^.^ There is also a selective malfunction of other inhibitory spinal mechanisms in PD. It has been shown recently that reciprocal Ia" and autogenic Ib inhibition' is diminished, while recurrent inhibition'3 is normal in PD. There are two potential explanations for the alterations of spinal reflexes in PD. The spinal networks themselves are abnormal. A considerable loss of tyrosine-hydroxylase immunoreactive neurons and fibers has been demonstrated in the human spinal cord of patients with PD." Intravenous injection of [.-dopa has been shown to inhibit transmission in some pathways from the FRA, thereby releasing alternative mechanisms.' On the other hand, overactivity in PD of the reticulospinal pathways originating in the lower brainstem may be the cause. These pathways have been shown to inhibit a variety of spinal reflexes, including those of the Ia afferents2* The reticular nuclei of the lower brainstem get input from the basal ganglia,8 and it is therefore likely that the activity in the reticulospinal projections is altered in PD and can be modified by dopaminergic drugs. In conclusion, our results demonstrate that a reduction of an inhibitory mechanism in Parkinson's disease, which is activated by cutaneous input, depends on the integrity of a subcortical catechokdminergic mechanism above the level of the (Y motoneuron. While the decrease in cutaneous inhibition o f voluntary activity can be demonstrated in the patients as a group, there is considerable overlap between the patients and the normal subjects, which renders the CR insensitive for diagnostic purposes in individuals with questionable Parkinson's disease.
REFERENCES 1. Anden N E , Jukes MGM, Lundberg A, Vyklicky L: T h e ef-
fect of DOPA on the spinal cord. 1. Influence on transmis-
MUSCLE & NERVE
June 1992
sion from primary afferents. Acta Physivl Scand 1966;67: 373-386. 2. Angel RW, Hofmann WW: The H reflex in normal, spastic, and rigid subjects. Arch Neurvl 1963;8:591-596. 3. Asanuma H: T h e pyramidal tract, in Handbook vf Physivlvgy. Bethesda, MD, American Physiological Society, 1981, vol 11, pp 703-733. 4. Barker AT, Freeston B, Jalinous R, Jarratt JA: Magnetic stimulation of the human brain and peripheral nervous system: An introduction and the results of an initial clinical evaluation. Neurosurgery 1987;20:100- 109. 5. Berardelli A, Sabra AF, Hallett M: Physiological mechanisms of rigidity in Parkinson’s disease. J Neurol Neurvsurg Psychiatly 1983;46:45- 53. 6. Burke D, Adams RW, Skuse NF: T h e effects of‘ voluntary contraction on the H reHex of human limb muscles. Brain 1989;112:417-433. 7. Caccia MR, McComas AJ, Upton ARM, Blogg T : Cutaneous reflexes in small muscles of the hand. J Neurul Neurv.surg Psychiatry 1973;36:960- 977. 8. Chronister RB, Walding JS, Aldes LD, Marco LA: Interconnections between substantia nigra reticulata and medullary reticular formation. Brain Res Bull 1988;21:313-317. 9. Cody FWJ, MacDermott N, Matthews PBC, Richardson HC: Observations on the genesis of the stretch reflex in Parkinson’s disease. Brain 1986;109:2229-249. 10. Delwaide PJ, Olivier E: Conditioning transcortical stimulation (TCCS) by exteroceptive stimulation in Parkinsonian patients. An approach to pathophysiology of rigidity, in Streifler M (ed): Parkinson’s Disease: Anatomy, Pathology and Therapy. New York, Raven Press, pp 175- 182. 1 1 . Delwaide PJ, Pepin JL, Maertens der Noordhout A: Shortlatency autogenic inhibition in patients with Parkinsonian rigidity. Ann Neurvl 1991;30:83-89. 12. Deuschl G, Schenck E, Lucking CH: Electrically elicited long latency reflexes in thenar muscles: Abnormal patterns in central movement disorders. J Neurvl 1985;232(suppl): 255. 13. Fahn S, Elton RL, Members of the UPDRS Development Committee: Unified Parkinson’s Disease rating scale, in Fahn S, Marsden CD, Goldstein M, et al. (eds): Recent Developments in Parkinson’s Diseuse II. New York, Macmillan, 1987, pp 153- 163. 14. Fuhr P, Cohen LG, Roth BJ, Hallett M: Latency of motor evoked potentials to focal transcranial stimulation varies as a function of scalp positions stimulated. Electrvencephalvgr Clin Neurvphysivl 1991;81:81-89.
Cutaneous Reflexes in Parkinson’s Disease
15. Fuhr P, Friedli WG: Electrocutaneous reHexes in upper limbs-reliability and normal values in adults. Eur N’eurol 1987:27:231 - 238. 16. Fuhr.P, Hallett M: Cutaneous reflexes in hand muscles in Parkinson’s disease. Muscle Nerve 1990;13:876. 17. Fuhr P, Hallett M: H-Reflex studies in muscles innervated by the median nerve, in Desmedt J (ed): Recommendulions f v r the Practice vf Clinical Neurvphysivlogy (to appear). 18. Hess CW, Mills KR, Murray NMF: Measurement of central motor conduction in multiple sclerosis by magnetic brain stimulation. Lancet 1986;ii:355-358. 19. Hunter JP, Ashby P, Lang AE: Afferents contributing to the exaggerated long latency reflex response to electrical stimulation in Parkinson’s disease. J Neurvl Neurosurg Psychiat? 1988;51: 1405- 141 0. 20. Jabre JF: Surface recording of the H reflex of the Hexor carpi radialis. Muscle Nerve 1981;4:435-438. 21. Jellinger K: T h e pathology of Parkinsonism, in Marsden CD and Fahn S (eds): Movement Disorders, 2. Butterworths, London, 1987, pp 124- 165. 22. Jenner JR, Stephens JA: Cutaneous reflex responses and their central nervous pathways studied in man. J Phy.rio1 1982;333:405-419. 23. Lelli S, Panizza M, Hallett M: Spinal cord inhibitory mechanisms in Parkinson’s disease. Neurology 1991;41:553-556. 24. Lundberg A: Control of spinal mechanisms from the brain, in Tower DB (ed): The Nervous System. The Basic NFUrosciences. New York, Raven Press, 1975, vol 1 , pp 253- 265. 25. Marsden CD, Merton PA, Morton HB: Servo action in human voluntary movement. Nature 1972;238:140- 143. 26. Noth J , Schurmann M, Podoll K, Schwarz M: Reconsidel-ation of the concept of enhanced static fusimotor drive in rigidity in patients with Parkinson’s disease. Neurvsci Lett 1988;84:239-243. 27. Pollock LJ, Davis L: Muscle tone in Parkinsonian rigidity. Arch Neurvl Psychiatry 1930;23 :303 - 3 19. 28. Rothwell JC, Obeso JA, Traub MM, Marsden CD: The behavior of the long latency stretch reflex in patients with Parkinson’s disease. J Neurvl Neurosurg Psychiatry 1983;46: 35-44. 29. Tatton WG, Lee RG: Evidence for abnormal long-loop reHexes in rigid Parkinsonian patients. Bruin Res 1975; 100:671-676. 30. Upton ARM, McComas AJ, Sica REP: Potentiation of. ‘‘late’’ responses evoked in muscles during effort. J Nrurvl Neurvsurg Psychiatry 1971;34:699-71 1 .
MUSCLE & NERVE
June 1992
739
CUTANEOUS REFLEXES IN PARKINSON'S DISEASE PETER FUHR, MD, THOMAS ZEFFIRO, MD, PhD, and MARK HALLElT,
Rigidity in Parkinson's disease (PD) is abolished by dorsal root ~ e c t i o n , ~and ' could therefore be generated or supported by reflex action. Since the monosynaptic reflex is not enhanced in this condition,2 it is conceivable that some kind of a long latency reflex is overactive or disinhibited and that its quantification might be a useful measure of rigidity in parkinsonism. Long latency reflexes in the upper extremities can be evoked in three different wa s: by stretching the muscle under investigation,' by stimulating its nerve carrying mixed a f f e r e n t ~ , ~or ' by stimulating cutaneous a f f e r e n t ~ . ~In' ~ ~several studies of long latency reflexes in Parkinson's disease the stretch paradigm was used. Mostly, an increase in the amplitude of the long latency reflex
From the Human Motor Control Section, MNB, NINDS, National Institutes of Health, Bethesda, Maryland Presented in part at the 1990 AAEM Annual Scientific Meeting in Chicago, Illinois. September. 1990. Acknowledgments: We are indebted to Ms.6.J. Hessie for editorial assistance; to Lisa McShane, PhD, for statistical advice, and to Nguyet Dang for technical support. Address reprint requests to Mark Hallett. MD, Clinical Director, NINDS, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 5N226. Bethesda, MD 20892. Dr. Fuhr's present address is Neurologische Universitatsklinik, Kantonsspital, CH-4031 Basel, Switzerland. Accepted for publication November 11, 1991 CCC 0148-639X/92/060733-07 $04.00 0 1992 John Wiley & Sons, Inc.
Cutaneous Reflexes in Parkinson's Disease
MD
was f o ~ n d . ~However, . ~ . ~ ~ this finding was controversial and has been demonstrated to depend on the exact methodology, since both an increase and no alteration of the long latency reflex could be demonstrated in identical patients.28 Studies with mixed nerve stimulation also yielded controversial results. 12.1926 In all of these studies, attention was focused on the increase in the long latency excitatory reflex component. However, it is equally conceivable that rigidity results from the loss of an inhibitory mechanism. Therefore, it is tempting to look at this issue using cutaneous stimulation, because the inhibitory component is so prominent in this paradigm. Moreover, cutaneous stimulation reduces the amplitude of motor-evoked potentials to cortical stimulation in normals, but not in patients with PD." MATERIALS AND METHODS
Studies were performed on 10 male patients with Parkinson's disease whose characteristics are listed in Table 1. Mean age was 61 15 years. All were studied while they were withdrawn from medication, and 9 of them were studied also when taking L-dopa or dopamine-receptor agonists. A second group consisted of patients with hemiparkinsonism, and side-to-side comparisons were done in those. The control group consisted of 10 normal volunteers who were matched for sex (1 female, 9 males) and age (mean 55 17
Subjects.
*
*
MUSCLE & NERVE
June 1992
733
Table 1. Patients with bilateral Parkinson's disease ~~
Patient
Sex
Age
UPDRS*
HlYt
SlE*
Delay5
Withdrawal''
1
M
42
29138 (5120)
2.5 (2.0)
80 (90)
70 d
5d
2
M
68
41139 (27126)
3.0 (3.0)
80 (80)
134 d
24 h
3
M
56
11I26 (12/22)
2.5 (2.0)
90 (90)
71 d
14 d
4
M
56
86/84 (69164)
4.0 (4.0)
30 (50)
11 d
6 d
5
M
76
34130 (33126)
2.5 (2.5)
80 (90)
7d
5d
6
M
66
36136 (25128)
2.5 (2.0)
80 (90)
77 d
24 h
7
M
74
74174 (71171)
4.0 (4.0)
30 (70)
63 d
12 h
8 9 10
M M M
76 56 35
30121 (44129) 37130 (37128) 14123
2.5 (3.0) 3.0 (3.0) 2.5
80 (80) 80 (90) 100
78 d 12 d
20 h 14 d
-
-
Medication Deprenyl 2 x 5 mg. bromocriptine 5 x 1 25 mg, propranolol 3 x 30 mg Amantadine 2 x 200 mg, acebutolol 1 x 100 mg CIL-dopa 101100 4 x 1, propranolol 2 x 40 mg CIL-dopa 251100 6 x 1, deprenyl4 x 5 mg ClL-dopa 101100 3 x 112, amantadine 2 x 200 mg, deprenyl2 x 5 mg CIL-dopa 251100 3 x 1, deprenyl2 x 5 mg CIL-dopa 251100 8 x 1, bromocriptine 4 x 2 5 mg, pergolide 2 x 0 5 mg, deprenyl 2 x 5 mg, arnitriptyline 1 x 5 mg, diazepam 1 x 5 mg CIL-dopa 251100 3 x 1 CIL-dopa 101100 4 x 1 None
'Unified Parkinson's Disease Rating Scale First number right-sided and generalized signs and symptoms, second number left-sided and generalized signs and symptoms Numbers in parentheses indicate the score when on medication tHoehniYahr Staging Numbers in parentheses indicate the score when on medication fSchwablEngland Activities of Daily Living Scale Numbers in parentheses indicate the score when on medication §Time delay, in days, between testing off and on medlcation Plain numbers first testing off, then on medication italic numbers, vice versa "Duration of complete withdrawal, in hours (h) or days id), from CarbidopalL-dopa andlor dopamine receptor agonrsts andlor MAO-B inhibitor
years). All subjects gave their written informed consent for the study, which was approved by the clinical research review committee. Experimental Proceedings. T h e severity of symptoms was assessed according to the Unified Parkinson's Disease Rating Scale (UPDRS, version 3.0).'" EMG activity was recorded from the first dorsal interosseous (FDI) muscle with surface electrodes using a DISA 15C01 amplifier, with low and high filters set at 20 Hz and 10 kHz, respectively. T h e signal was rectified and averaged. T h e sampling period was 200 ms, and 1024 samples were averaged three times on both sides. T h e curves were printed and analyzed off-line. The technique of recording the reflex was described in detail in an earlier study,15 and is summarized here only briefly. Stimuli of 0.2 ms duration were delivered at a rate of 3 Hz from a constant current stimulator (DISA 15E25) through ring electrodes to the digital nerves of the second finger. Stimulus intensity was four times the sensory threshold or the threshold of pain, whichever was lower. T h e reflexes were recorded
734
Cutaneous Reflexes in Parkinson's Disease
while the subjects performed an isometric contraction of the FDI at 20% of the maximal force. Force was kept constant with visual feedback displayed to both the subject and the experimenter by using a digital scale connected to the load cell. T h e cutaneous reflex (CR) consists of a triphasic modulation of ongoing EMG activity, with two excitatory components ( E l and E2) divided by an inhibitory one (11) (Fig. 1). The latencies were measured from the stimulus artifact to the peak of the reflex components and normalized for arm length. l 5 T h e amplitudes were measured from the baseline to the peak of the reflex components, and the amplitude of the baseline of ongoing EMG activity was measured from the zero-line. The absolute data rather than the amplitudes divided by the baseline are presented, because normalization was done in force. Although there was a correlation in individuals of the amplitude of I1 with the force level, none was found between the amplitude of the baseline and the amplitude of I 1 in individuals applying the same force (20% of the maximum). T h e average of the three individual measure-
MUSCLE & NERVE
June 1992
STIMULUS
I
E2
_I 25PV 20 MS
FIGURE 1. Example of a normal cutaneous reflex, consisting of two excitatory components (El and E2) and an inhibitory component (11) between them. The recording was taken from the FDI muscle during an isometric contraction of 20% of the maximal force after rectifying and averaging the raw EMG over 1024 cycles. The index finger was stimulated with ring electrodes with an intensity four times the sensory threshold. Amplitudes were measured at the arrows, 1 representing the amplitude of the baseline EMG; and 2, 3, and 4 the amplitudes of the rectified EMG during the peak of the three reflex components. The amplitudes of the reflex components were calculated by subtracting the amplitude of the baseline.
ments on each arm was used in the further analysis. For group comparisons (patients versus normal subjects; patients off therapy versus patients on medication), the average of the values from both arms was taken as the representative value for the individual patient. Two additional experiments were carried out to test the spinal motoneuron excitability during the inhibitory period I1 of the CR. These studies were performed on 4 normal male volunteers, ages 35 to 42 years. H-reflexes were recorded from the FDI muscle during voluntary contraction by stimulating the ulnar nerve at the The H-reflex was averaged 1024 times with (test condition) and without (control condition) concurrent stimulation of the index finger by alternating the condition every 50 cycles. Force of the FDI muscle and characteristics of the index finger stimulation were identical to those in the experiment with PD patients. Relative timing of the stimulus to the ulnar nerve and to the index finger was so that the H-reflex appeared during the peak of the I1 component of the CR. T h e amplitudes of the averaged Hreflexes obtained in the control and in the test condition were compared. H-reflexes were also recorded from the flexor carpi radialis (FCR) muscle at rest by stimulating the median nerve at the elbow with different intensities. l7,*' At each level of stimulus intensity, the H-reflex of the FCR was recorded alternately with (test condition) and without (control condi-
Additional Experiments.
Cutaneous Reflexes in Parkinson's Disease
tion) concurrent stimulation of the index finger. Intensity of the index finger stimulation was identical to that in the experiment with PD patients. Relative timing of the stimulus to the median nerve and to the index finger was so that the H-reflex appeared during the previously determined peak of the 11 component of the CR of the FCR muscle. The mean amplitudes of 20 H-reflexes obtained in the control and in the test condition were compared. Statistical Analysis. Interindividual comparisons were tested with the Mann-Whitney U test, and intraindividual comparisons were tested with the Wilcoxon signed rank test. The level of significance was set at 0.05. RESULTS
Patients and normal subjects did not differ with respect to the latencies of the reflex components, which were normalized for arm length. The mean 1 SD of the normalized latencies in the patients (values of the normal subjects in parentheses) were 61.8 4.2 ms (61.2 ? 4.5 ms) for E l , 76.5 5 5.2 ms (76.2 ? 4.7 ms) for 11, and 92.2 ? 5.8 ms (96.0 6.0 ms) for E2. All the individual latencies were within the normal limits determined in an earlier study. I 5 The amplitudes of the excitatory reflex components E l and E2 did not differ significantly in the two groups of subjects. The mean ? 1 SD (values of the normal subjects in parentheses) for E l were 10.4 +- 4.0 pV (11.9 2 6.6 pV), and for E2 they were 20.9 ? 14.8 pV (30.4 2 10.9 pV). However, the amplitude of the inhibitory component I1 was different in both groups. It was -15.4 2 6.0 FV in the patient group, and was -30.0 _t 13.1 PV in the group of normal subjects ( P = 0.0041) (Fig. 2). N o correlation between the amplitude of I1 and the clinical assessment of the severity of the disease could be found. However, medication (L-dopa in 8 patients, bromocriptine in 1) enlarged the amplitude of I1 (from -15.4 ? 6.4 pV to -28.4 5 16.7 kV, P = 0.0077) (Fig. 3). Side-to-side comparisons in 3 patients with hemiparkinsonism showed a clear, although not statistically significant, tendency toward smaller amplitudes on the symptomatic side ( P = 0.1088) (Fig. 4). In additional experiments to evaluate whether the mechanism of the inhibitory component of the CR was a direct inhibition of the excitability of the a-motoneuron pool, H-reflexes were recorded during the I1 component of the CR.
*
*
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June 1992
735
a
“1 120
0
c
8 8
w
0
-30
0 0
3
0 0
-“I
-20. -40.
El
11
EZ
PATIENTS OFF THERAPY
BASELINE
FIGURE 2. Mean 4 1 SD of the amplitudes of the first excitatory (El), the inhibitory (Il), and the second excitatory component (E2)of the cutaneous reflex. To the far right is the amplitude of the baseline. Open circles represent the values of the normals, filled circles represent those of the patients. The amplitude of I1 is reduced by 50% in the patient group ( P = 0.0013),while the other reflex components and the baseline are not significantly different in the two groups.
From the analysis of the CR in the FDI muscle, an inhibition of 18.5% and 23% was expected in the 2 subjects, respectively. However, no diminution of the H-reflexes recorded from the FDI muscle during the I1 Component of the CR was observed. H-reflexes were also recorded during the I1 component of the C R evoked in the FCR muscle after index finger stimulation in 2 other subjects. I n this muscle, it is possible to record H-reflexes without voluntary background activity. Again, no diminution of the H-reflexes recorded from the FCR muscle during the I 1 component of the CR was observed (Fig. 5).
PATIENTS ON THERAPY
NORMAL VOLUNTEERS
FIGURE 3. The amplitude of the I1 component of the reflex is shown as a function of the treatment. On the left are patients withdrawn from medication, in the middle are the same patients on dopaminergic medication; and on the right are the values of the normal control group. Mean f 1 SD are given to the side of the individual values. The baseline is at the top, and larger amplitudes correspond to points lower on the graph. The amplitude of the I1 component is smaller in the untreated than in the treated state of the same patients ( P 5 0.05).
sions in the central nervous system support this hypothesis.22 Much less data is available as to the mechanism of the first inhibitory component. If it were generated in a transcortical loop, enough time for ner-
0
-10.
-20.
DISGUSSlON
The CR is composed of a first excitatory response followed by an inhibitory phase, and then by a second excitatory response. After these, more responses may be observed, but they are much less The first excitatory reflex component has a latency similar to that of the H-reflex and a central delay of 4.6 ms, and thus it can involve only a relatively simple spinal pathway.22 As for the second excitatory component, its latency leaves enough time for a transcortical loop via the dorsal columns and the corticospinal tract, and observations made in patients with anatomically well-defined lePhysiology of the Cutaneous Reflex.
736
Cutaneous Reflexes in Parkinson’s Disease
zW
n 3
-30
z
& -40.
-50.
NORMAL SIDE
SYMPTOMATIC SIDE
FIGURE 4. Comparison of the two sides in three patients with hemiparkinsonism. The baseline is at the top and larger amplitudes correspond to points lower on the graph.
MUSCLE & NERVE
June 1992
STIMULUS TO INDEX FINGER
I1
A.
CUTANEOUS REFLEX AVERAGED RECTIFIED
*10 ms
H-REFLEX ALONE
500 pv
H-REFLEX AT LATENCY OF INHIBITORY PERIOD OF CUTANEOUS REFLEX
10 ms
B.
4504 4000
5 3500
pi
2 3000 AMPLITUDES OF W H-REFLEXES (pV) n WITH AND WITHOUT 2 2500 CUTANEOUS STIMULATION 2000
2
3
1500 loo0 500
a STIMULUS INTENSITY FIGURE 5. H-reflex recorded at rest in the FCR muscle at the previously determined peak of the inhibitory phase of the cutaneous reflex in this muscle. (A) Cutaneous reflex recorded in the FCR muscle after index finger stimulation. (Middle) H-reflexes with and without preceding stimulation of the index finger. (B) Mean ~fr1 SD of the amplitudes of H-reflexes with (filled circles) and without (open circles) preceding stimulation of the index finger. The abscissa represents different intensities of the stimulus to the median nerve at the elbow so as to produce H-reflexes with different amplitudes. The stimulus intensities are indicated as multiples of the threshold for the ti-reflex. Over the whole range of the recorded part of the H-reflex recruitment curve, there is no significant amplitude reduction during the inhibitory phase of the cutaneous reflex.
vous conduction would be a necessary requirement. In a study of 70 normal volunteers, the mean onset latency for the inhibitory component of the CK, which coincides with the latency of the peak of the first excitatory component, was 40.3 ms, and that of the first negative peak of the somatosensory-evoked potential to identical stimulation of index finger, representing the arrival of the volley at the sensory cortex, was 21.9 ms.15 The difference between these two latencies, 18.4 ms, less the time for central processing, would be
Cutaneous Reflexes in Parkinson’s Disease
available for efferent conduction from cortex to hand muscle. T h e mean onset latency of the motor-evoked potential in voluntarily activated hand muscles, however, is 19.6 ms,18 and this is the minimal estimate because only activation of the center of the motor representation area of a muscle can elicit a motor response at minimal latencies. l4 Therefore, there is not sufficient time for a transcortical loop, and the cutaneous inhibition of voluntary activity likely originates subcortically.
MUSCLE & NERVE
June 1992
737
In a study with magnetic cortical stimulation, the amplitudes of motor-evoked responses in hand muscles (APB) at rest were reduced if the index finger was stimulated 18 to 20 ms (maximal effect at 18 ms) before the cortical stimulation with an intensity four times the sensory threshold."' Since the mean latency of the fastest conduction of this stirnulus to the sensory cortex is longer than that, the cutaneous inhibition of the motor-evoked potential to cortical stimulation must also be located on a subcortical level. T h e delay of the motor-evoked response after the cutaneous stimulation can be calculated by adding 22.6 2 1.2 ms for the onset-latency of motorevoked responses to magnetic cortical stimulation in the same hand muscle (APB) at rest4 to the 18-ms delay between cutaneous and cortical stimulus. The result, about 40 ms, corresponds well to the onset-latency of the inhibitory component of the CK (40.3 ms). It is likely, therefore, that the mechanism for the cutaneous inhibition of motorevoked potentials and that of voluntary activity is the same, arid that it is located on a subcortical level. To determine further the site of interaction of the cutaneous input with the voluntary activity, we measured the H-reflex during the inhibitory phase of the CK in the FDI and FCR muscles. N o diminution of the amplitude of the H-reflexes was apparent. 'This indicates that the inhibitory activity brought about by cutaneous afferents does not have a direct effect on the a motoneuron, nor does it affect the presynaptic terminals of the Ia afferents. 'I'hus, the site of inhibitory action lies above the a motoneuron. Cutaneous Inhibition in PD. While the amplitudes of the excitatory components and all the latencies are not different in the patient and normal groups, the inhibition of voluntary muscle activity during the first inhibitory component of the CK is diminished in PD. This effect can also be demonstrated in a side-to-side comparison in patients with hemiparkinsonism, and it is partially reversed with drug therapy. Similar to the present results, no cutaneous inhibition of the motor-evoked potential to cortical stimulation was found in patients with PD; instead, it was replaced by facilitation. When the patients were treated with [*-dopa, this facilitation was reduced and sometimes replaced by inhibition.") T h e impact of PD on the cutaneous inhibition of ongoing voluntary activity is not as dramatic as on motor-evoked potentials to cortical stimulation, but the changes go in the same direc-
738
Cutaneous Reflexes in Parkinson's Disease
tion. T h e difference is probably due to the more complex way in which voluntary effort activates the spinal niotoneuron pool. I t is clear, however, that the reduction of cutaneous inhibition in PD not only affects an artificially evoked potential but also the voluntary muscle activity of the patients. A possible explanation is an alteration of excitability of spinal interneurons upon which cutaneous afferents and pyramidal fibers converge.'" Their role is important in both the control of voluntary movement and in determining the shape and amplitude of the motor-evoked potential, because the majority of the corticospinal neurons terminate on spinal inter neuron^.^ There is also a selective malfunction of other inhibitory spinal mechanisms in PD. It has been shown recently that reciprocal Ia" and autogenic Ib inhibition' is diminished, while recurrent inhibition'3 is normal in PD. There are two potential explanations for the alterations of spinal reflexes in PD. The spinal networks themselves are abnormal. A considerable loss of tyrosine-hydroxylase immunoreactive neurons and fibers has been demonstrated in the human spinal cord of patients with PD." Intravenous injection of [.-dopa has been shown to inhibit transmission in some pathways from the FRA, thereby releasing alternative mechanisms.' On the other hand, overactivity in PD of the reticulospinal pathways originating in the lower brainstem may be the cause. These pathways have been shown to inhibit a variety of spinal reflexes, including those of the Ia afferents2* The reticular nuclei of the lower brainstem get input from the basal ganglia,8 and it is therefore likely that the activity in the reticulospinal projections is altered in PD and can be modified by dopaminergic drugs. In conclusion, our results demonstrate that a reduction of an inhibitory mechanism in Parkinson's disease, which is activated by cutaneous input, depends on the integrity of a subcortical catechokdminergic mechanism above the level of the (Y motoneuron. While the decrease in cutaneous inhibition o f voluntary activity can be demonstrated in the patients as a group, there is considerable overlap between the patients and the normal subjects, which renders the CR insensitive for diagnostic purposes in individuals with questionable Parkinson's disease.
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fect of DOPA on the spinal cord. 1. Influence on transmis-
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sion from primary afferents. Acta Physivl Scand 1966;67: 373-386. 2. Angel RW, Hofmann WW: The H reflex in normal, spastic, and rigid subjects. Arch Neurvl 1963;8:591-596. 3. Asanuma H: T h e pyramidal tract, in Handbook vf Physivlvgy. Bethesda, MD, American Physiological Society, 1981, vol 11, pp 703-733. 4. Barker AT, Freeston B, Jalinous R, Jarratt JA: Magnetic stimulation of the human brain and peripheral nervous system: An introduction and the results of an initial clinical evaluation. Neurosurgery 1987;20:100- 109. 5. Berardelli A, Sabra AF, Hallett M: Physiological mechanisms of rigidity in Parkinson’s disease. J Neurol Neurvsurg Psychiatly 1983;46:45- 53. 6. Burke D, Adams RW, Skuse NF: T h e effects of‘ voluntary contraction on the H reHex of human limb muscles. Brain 1989;112:417-433. 7. Caccia MR, McComas AJ, Upton ARM, Blogg T : Cutaneous reflexes in small muscles of the hand. J Neurul Neurv.surg Psychiatry 1973;36:960- 977. 8. Chronister RB, Walding JS, Aldes LD, Marco LA: Interconnections between substantia nigra reticulata and medullary reticular formation. Brain Res Bull 1988;21:313-317. 9. Cody FWJ, MacDermott N, Matthews PBC, Richardson HC: Observations on the genesis of the stretch reflex in Parkinson’s disease. Brain 1986;109:2229-249. 10. Delwaide PJ, Olivier E: Conditioning transcortical stimulation (TCCS) by exteroceptive stimulation in Parkinsonian patients. An approach to pathophysiology of rigidity, in Streifler M (ed): Parkinson’s Disease: Anatomy, Pathology and Therapy. New York, Raven Press, pp 175- 182. 1 1 . Delwaide PJ, Pepin JL, Maertens der Noordhout A: Shortlatency autogenic inhibition in patients with Parkinsonian rigidity. Ann Neurvl 1991;30:83-89. 12. Deuschl G, Schenck E, Lucking CH: Electrically elicited long latency reflexes in thenar muscles: Abnormal patterns in central movement disorders. J Neurvl 1985;232(suppl): 255. 13. Fahn S, Elton RL, Members of the UPDRS Development Committee: Unified Parkinson’s Disease rating scale, in Fahn S, Marsden CD, Goldstein M, et al. (eds): Recent Developments in Parkinson’s Diseuse II. New York, Macmillan, 1987, pp 153- 163. 14. Fuhr P, Cohen LG, Roth BJ, Hallett M: Latency of motor evoked potentials to focal transcranial stimulation varies as a function of scalp positions stimulated. Electrvencephalvgr Clin Neurvphysivl 1991;81:81-89.
Cutaneous Reflexes in Parkinson’s Disease
15. Fuhr P, Friedli WG: Electrocutaneous reHexes in upper limbs-reliability and normal values in adults. Eur N’eurol 1987:27:231 - 238. 16. Fuhr.P, Hallett M: Cutaneous reflexes in hand muscles in Parkinson’s disease. Muscle Nerve 1990;13:876. 17. Fuhr P, Hallett M: H-Reflex studies in muscles innervated by the median nerve, in Desmedt J (ed): Recommendulions f v r the Practice vf Clinical Neurvphysivlogy (to appear). 18. Hess CW, Mills KR, Murray NMF: Measurement of central motor conduction in multiple sclerosis by magnetic brain stimulation. Lancet 1986;ii:355-358. 19. Hunter JP, Ashby P, Lang AE: Afferents contributing to the exaggerated long latency reflex response to electrical stimulation in Parkinson’s disease. J Neurvl Neurosurg Psychiat? 1988;51: 1405- 141 0. 20. Jabre JF: Surface recording of the H reflex of the Hexor carpi radialis. Muscle Nerve 1981;4:435-438. 21. Jellinger K: T h e pathology of Parkinsonism, in Marsden CD and Fahn S (eds): Movement Disorders, 2. Butterworths, London, 1987, pp 124- 165. 22. Jenner JR, Stephens JA: Cutaneous reflex responses and their central nervous pathways studied in man. J Phy.rio1 1982;333:405-419. 23. Lelli S, Panizza M, Hallett M: Spinal cord inhibitory mechanisms in Parkinson’s disease. Neurology 1991;41:553-556. 24. Lundberg A: Control of spinal mechanisms from the brain, in Tower DB (ed): The Nervous System. The Basic NFUrosciences. New York, Raven Press, 1975, vol 1 , pp 253- 265. 25. Marsden CD, Merton PA, Morton HB: Servo action in human voluntary movement. Nature 1972;238:140- 143. 26. Noth J , Schurmann M, Podoll K, Schwarz M: Reconsidel-ation of the concept of enhanced static fusimotor drive in rigidity in patients with Parkinson’s disease. Neurvsci Lett 1988;84:239-243. 27. Pollock LJ, Davis L: Muscle tone in Parkinsonian rigidity. Arch Neurvl Psychiatry 1930;23 :303 - 3 19. 28. Rothwell JC, Obeso JA, Traub MM, Marsden CD: The behavior of the long latency stretch reflex in patients with Parkinson’s disease. J Neurvl Neurosurg Psychiatry 1983;46: 35-44. 29. Tatton WG, Lee RG: Evidence for abnormal long-loop reHexes in rigid Parkinsonian patients. Bruin Res 1975; 100:671-676. 30. Upton ARM, McComas AJ, Sica REP: Potentiation of. ‘‘late’’ responses evoked in muscles during effort. J Nrurvl Neurvsurg Psychiatry 1971;34:699-71 1 .
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