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Spontaneous asymmetric circling behavior in hemi-parkinsonism; a human equivalent of the lesioned-circling rodent behavior
Life Sciences, Vol. 40, pp. ]127-1130 Printed in the U.S.A.
Pergamon Journals
SPONTANEOUS ASYMMETRIC CIRCLING BEHAVIOR IN HEMI-PARKINSONISM; A HUMAN EQUIVALENT OF THE LESIONED-CIRCLING RODENT BEHAVIOR H. S. Bracha I
C. Shults 2, S
D. Glick 3, J
E. Kleinman 4
Ipsychiatry Service, San Diego VA Medical Center and Dept. of Psychiatry, UC San Diego~ La Jolla CA 92093 Neurology Service, San Diego VA Medical Center and Dept. of Neurosciences, UC San Diego, La Jolla CA 92093 3Department of Pharmacology and Toxicology, Albany Medical College, Albany, N.Y. 12208 4Neuropsychiatry Branch NIMH, WAS Bldg., St. Elizabeth's Hospital Washington, D.C. 20032 (Received in final form December i0, 1986) Summary When induced experimentally in rodents, hemispheric assymetry in basal ganglia dopamine results in spontaneous asymmetric circling toward the hemisphere with the lower level of dopamine. A similar asymmetry has long been thought to exist in the brains of hemiParkinsonian patients. Using an electronic turn counter, we demonstrated that, like unilaterally lesioned rats, and without being aware of it, five ambulating outpatients with hemi-Parkinson's disease exhibit spontaneous rotation toward the hemisphere containing less striatal dopaminergic activity.
Introduction In animals, a hemispheric imbalance of dopaminergic activity within the basal ganglia is associated with markedly asymmetric circling behavior (rotation, turning), as a rule toward the hemisphere with lower dopamine (1,2). The The dopaminergic imbalance has most commonly been produced with electrical stimulation or lesions (3,4), and subjects have included rats, mice, gerbils, and cats (5). A moderate to marked asymmetry in dopamine levels has long been noted to exist in the basal ganglia of patients with hemi-Parkinson's disease (8), a relatively rare and usually transient stage of Parkinson's disease in which the nigral lesion is believed to be asymmetric (6,7,8,9). In monkeys unlateral lesions of the ventral tegentum involving the substantia nigra induce tremor and hypotonia on the contralateral side. Such results tend to suggest that the basic efferent pathways from the basal ganglia of primates are similar to those of lower animals such as the dog, cat and rat (2). Furthermore, there are reports of Parkinsonian patients exhibiting a lateral posture who, when blindfolded and crawling on all fours, tend gradually to turn in the same direction (9,10). The question asked was whether such human rotation is purely the result of the curvature of the spine, as has been suggested by Martin (9), or is it the direct result of striatal dopamine 0024-3205/87
$3.00 + .00
1128
Asymmetric Circling in Hemi-Parkinsonism
Vol. 40, No. ii, 1987
imbalance making it directly comparable to Ungerstedt's rotating rat in a rotometer (i0). If the latter analogy is true then the rotating rat is truly a valuable model for hemi-Parkinsonism. We sought to determine whether ambulating outpatients with hemi-Parkinson's disease exhibit subtle abnormal circling behavior during a normal day's activities. For such studies we have developed an electronic device to measure in humans the kinds of rotational movements observed in rats (Ii). Methods As designed for humans, the "rotometer" is a lightweight, rechargeable beltmounted device consisting of a position sensor and an electronic processing circuit. The position sensor monitors changes in the orientation of the dorsal-ventral axis of the subject. Magnetic north is used as an external reference and is tracked by a compass. A compass transducer system moves with the subject relative to the needle. A microchip is programmed with algorithms for registering left and right full (360-degree) turns. If a subject enters four quadrants sequentially in the same direction (i.e., moves 360o), a full turn is counted for the respective direction. If, however, a subject enters three quadrants sequentially in the same direction, but then enters a quadrant from the opposite direction of the previous move, a new direction is begun. This is precisely the same logic employed with the analagous device commonly used for rodents (12). Percent clockwise rotation (% right preference), an activity-independent measure, is used as the index of asymmetry, and refers to the percentage of full turns in the right (clockwise) direction (11,12). Since we have previously shown that gender and to a lesser extent hemispheric dominance affect rotational preference (ii), all five patients and 50 control subjects studied were male and all were right handed right footed and right eye dominant as determined by a 13-item laterality scale from the HalsteadReitan battery (13). Subjects wore the rotometer for 8 to 12 hrs starting at 8 a.m. and were completely unaware of the type of counts being registered. The control subjects were 50 students, physicians, and hospital employees at the University of California, San Diego. The patients were five outpatients with highly lateralized hemi-Parkinsonism (Hoehn and Yahr scale, Type i) who, although medicated with levodopa/carbidopa, exhibited marked symptoms on the right sides of their bodies. Although the patients were significantly older than controls (63 + 12 vs. 33 + 4 years; mean + S.D.), there was no correlation between age and the direction of turning for either group (r = -0.06; p > 0.5). The subjects were unaware of the purpose of the study. Results Relationships were readily apparent between turning preference and the side where tremor or rigidity were present. Four hemi-Parkinsonian patients had predominantly right-sided symptoms, suggesting severe left nigral dopamine deficits. While the handedness-matched normal controls rotated as a group equally to left or right, the patients with right-sided symptoms rotated preferentially and markedly to the left (i.e., had a low percentage of clockwise rotation). This difference was statistically significant ( p < 0.006, Kruskal-Wallis test) (Fi~. i). For two of the patients percent clockwise rotation was more than 2 S.D. below the mean for normal controls. In addition we have studied one right-handed hemi-Parkinsonian patient who had left-sided symptoms, suggesting severe right nigral dopamine deficits. This patient rotated mostly (67%) to the right. The patients and controls did not differ in total (left + right) turns per hours~ Retesting these outpatients was not feasible. However, we reported earlier good test-retest reliability of % right preference among 50 right-handed normal controls, Interclass Correlation
Vol. 40, No. ii, 1987
Coefficient = 0 . 6 6
Asymmetric Circiing in Hemi-Parkinsonism
1129
(II).
I00 LEFT HEMISPHERE DOMINANT MALE SUBJECTS
KRUSKAL-WALLtSTEST 80
P < O. 006 0 0 0 0 0 0
g
0
o Bo °
6o
o/o
o
+ROTATION /RIGHT
o o~0 0 o -o-
o
.
o
L>
4o LIJ O
.
.
.
.
.
.
.
.
.
.
ol
.
.
.
.
.
,,E,T
°|T
°I
°±°
O-
20
NORMAL CONTROLS
RIGHT HEMIPARKINSONISM (RIGHT SIDED SYMPTOMS)
( N =50)
(N=4)
FIG i. Percent clockwise rotation ~ r i g h t preference) of normal controls vs. hemi-Parkinsonian patients with markedly right-sided symptoms. Spontaneous circling behavior was monitored via a belt-mounted rotometer that registers left and right full (360-degree) turns.
Discussion The data indicate that without being aware of it, and not unlike unilaterally lesioned rodents, hemi-Parkinsonian patients spontaneously rotate toward the hemisphere believed to contain lower dopamine levels. Both patients who manifested primarily unilateral tremor and little asymmetry in tone and patients with predominant asymmetry in tone but little tremor demonstrated asymmetric turning. Monitoring with the rotometer for a full day may provide a more sensitive index of motor abnormalities than a single or occasional clinical examination, particularly for patients such as ours who have mild disease. None of these mildly affected patients had hemiparesis, nor was there a clinically apparent inability to turn to right or left. There have curiously only been relatively few reports on the subject of physiological mechanisms of circling behavior. Hitzig (14) attributed the phenomenon to a paralysis of muscles of the trunk on one side. More recently a body of authors have found that unilateral lesions placed within the
1130
Asymmetric Circling in Hemi-Parkinsonism
Vol. 40, No. ii, 1987
substantia nigra cause a profound sensory inattention. Such sensory inattention appears to be associated with loss of the contralateral ascending dopamine-containing axons (15,16,17). The degree of sensory inattention seems to correlate well with the severity of depletion of dopamine, although further work is required. This is the first evaluation of circling behavior for study patients with a brain disorder. Studies are in progress with hemi-Parkinson's patients offmedications, on lower or higher doses, as well as with patients who are affected bilaterally, and patients medicated with post synaptic dopamine agonists which are likely not to abolish, but to completely reverse the direction of the asymmetry in rotational preference in hemi-Parkinsonism. This initial study shows the possible usefulness of human rotation studies and helps validate the animal model of Parkinson's disease. Acknowledsement This work was supported in part by a grant to H. S. Bracha from the United States Veterans' Administration.
References i. 2. 3. 4. 5. 6.
7. 8. 9. I0. 11. 12. 13.
14. 15. 16. 17.
S. D. GLICK, T. P. JERUSSI, L. N., FLEISHER, Life Sci. 18 889-896. (1976). C. J. PYCOCK, Neuroscience 5 461-514. (1980). B. ZIM}fERBERG, S. D. GLICK, T. P. JERUSSI, Science 185 (623-625. (1974). S. D. GLICK and R. M. SHAPIRO, in Cerebral Lateralization in Nonhuman Species, S. D. Glick, ed., p. 157-183, Academic Press New Y o r ~ (1985). S. D. GLICK, L. M. WEAVER, and R. M. MEIBACH, Brain Res. 208 227-229. (1981). E. S. GARNETT, C. NAHMIAS, and G. FIRNAU, Can. J. Neurol. Sci. ii 174-179. (1984). L. HENRIKSEN and J . BOAS, A c t a N e u r o l . Scand. 71 257-266. ( 1 9 8 5 ) . G. BAROLIN, !I. BERNHEIMER & O. HORNIKIEWICZ. Archs Neurol. Neurochir. Psvchiat. 94 241-248. (1964). J. P. MARTIN. The Basal Ganglia and Posture, 100-105. Pittman, London. (1967). R. C. DUVOISIN & C. D. MARSDEN. Journal Neurol. Neurosurg. Psychiat. 8 787-793. (1975). H. S. BRACHA, D. SEITZ, J. OTEMAA, and S. D. GLICK, Brain Resesrch. in press (1987). S. GREENSTEIN and S. D. GLICK. Pharmacol. Biochem. Behav. 3 507-510. (1975). R . M . RIETAN, Manual for Administration of Neuropsychological Test Batteries for Adults and Children, Reitan Neuropsychology Labs., Inc., Tucson AZ (1979). E. HITZIG. In: Physiologische und Klinische Untersuchunger uber das Gehirn, 2 155-609. (1904). J. F. MARSHALL & P. J. TEITELBAUM. Comp. Physiol. Psychol. 86 375-395. (1974). U. UNGERSTEDT & T. J. LJUNGBERG. Psyciat. Res. 11 149-150. (1974). T. LJUNGBERG & U. UNGERSTEDT. Expl. Neurol. 53 585-600. (1976).
Pergamon Journals
SPONTANEOUS ASYMMETRIC CIRCLING BEHAVIOR IN HEMI-PARKINSONISM; A HUMAN EQUIVALENT OF THE LESIONED-CIRCLING RODENT BEHAVIOR H. S. Bracha I
C. Shults 2, S
D. Glick 3, J
E. Kleinman 4
Ipsychiatry Service, San Diego VA Medical Center and Dept. of Psychiatry, UC San Diego~ La Jolla CA 92093 Neurology Service, San Diego VA Medical Center and Dept. of Neurosciences, UC San Diego, La Jolla CA 92093 3Department of Pharmacology and Toxicology, Albany Medical College, Albany, N.Y. 12208 4Neuropsychiatry Branch NIMH, WAS Bldg., St. Elizabeth's Hospital Washington, D.C. 20032 (Received in final form December i0, 1986) Summary When induced experimentally in rodents, hemispheric assymetry in basal ganglia dopamine results in spontaneous asymmetric circling toward the hemisphere with the lower level of dopamine. A similar asymmetry has long been thought to exist in the brains of hemiParkinsonian patients. Using an electronic turn counter, we demonstrated that, like unilaterally lesioned rats, and without being aware of it, five ambulating outpatients with hemi-Parkinson's disease exhibit spontaneous rotation toward the hemisphere containing less striatal dopaminergic activity.
Introduction In animals, a hemispheric imbalance of dopaminergic activity within the basal ganglia is associated with markedly asymmetric circling behavior (rotation, turning), as a rule toward the hemisphere with lower dopamine (1,2). The The dopaminergic imbalance has most commonly been produced with electrical stimulation or lesions (3,4), and subjects have included rats, mice, gerbils, and cats (5). A moderate to marked asymmetry in dopamine levels has long been noted to exist in the basal ganglia of patients with hemi-Parkinson's disease (8), a relatively rare and usually transient stage of Parkinson's disease in which the nigral lesion is believed to be asymmetric (6,7,8,9). In monkeys unlateral lesions of the ventral tegentum involving the substantia nigra induce tremor and hypotonia on the contralateral side. Such results tend to suggest that the basic efferent pathways from the basal ganglia of primates are similar to those of lower animals such as the dog, cat and rat (2). Furthermore, there are reports of Parkinsonian patients exhibiting a lateral posture who, when blindfolded and crawling on all fours, tend gradually to turn in the same direction (9,10). The question asked was whether such human rotation is purely the result of the curvature of the spine, as has been suggested by Martin (9), or is it the direct result of striatal dopamine 0024-3205/87
$3.00 + .00
1128
Asymmetric Circling in Hemi-Parkinsonism
Vol. 40, No. ii, 1987
imbalance making it directly comparable to Ungerstedt's rotating rat in a rotometer (i0). If the latter analogy is true then the rotating rat is truly a valuable model for hemi-Parkinsonism. We sought to determine whether ambulating outpatients with hemi-Parkinson's disease exhibit subtle abnormal circling behavior during a normal day's activities. For such studies we have developed an electronic device to measure in humans the kinds of rotational movements observed in rats (Ii). Methods As designed for humans, the "rotometer" is a lightweight, rechargeable beltmounted device consisting of a position sensor and an electronic processing circuit. The position sensor monitors changes in the orientation of the dorsal-ventral axis of the subject. Magnetic north is used as an external reference and is tracked by a compass. A compass transducer system moves with the subject relative to the needle. A microchip is programmed with algorithms for registering left and right full (360-degree) turns. If a subject enters four quadrants sequentially in the same direction (i.e., moves 360o), a full turn is counted for the respective direction. If, however, a subject enters three quadrants sequentially in the same direction, but then enters a quadrant from the opposite direction of the previous move, a new direction is begun. This is precisely the same logic employed with the analagous device commonly used for rodents (12). Percent clockwise rotation (% right preference), an activity-independent measure, is used as the index of asymmetry, and refers to the percentage of full turns in the right (clockwise) direction (11,12). Since we have previously shown that gender and to a lesser extent hemispheric dominance affect rotational preference (ii), all five patients and 50 control subjects studied were male and all were right handed right footed and right eye dominant as determined by a 13-item laterality scale from the HalsteadReitan battery (13). Subjects wore the rotometer for 8 to 12 hrs starting at 8 a.m. and were completely unaware of the type of counts being registered. The control subjects were 50 students, physicians, and hospital employees at the University of California, San Diego. The patients were five outpatients with highly lateralized hemi-Parkinsonism (Hoehn and Yahr scale, Type i) who, although medicated with levodopa/carbidopa, exhibited marked symptoms on the right sides of their bodies. Although the patients were significantly older than controls (63 + 12 vs. 33 + 4 years; mean + S.D.), there was no correlation between age and the direction of turning for either group (r = -0.06; p > 0.5). The subjects were unaware of the purpose of the study. Results Relationships were readily apparent between turning preference and the side where tremor or rigidity were present. Four hemi-Parkinsonian patients had predominantly right-sided symptoms, suggesting severe left nigral dopamine deficits. While the handedness-matched normal controls rotated as a group equally to left or right, the patients with right-sided symptoms rotated preferentially and markedly to the left (i.e., had a low percentage of clockwise rotation). This difference was statistically significant ( p < 0.006, Kruskal-Wallis test) (Fi~. i). For two of the patients percent clockwise rotation was more than 2 S.D. below the mean for normal controls. In addition we have studied one right-handed hemi-Parkinsonian patient who had left-sided symptoms, suggesting severe right nigral dopamine deficits. This patient rotated mostly (67%) to the right. The patients and controls did not differ in total (left + right) turns per hours~ Retesting these outpatients was not feasible. However, we reported earlier good test-retest reliability of % right preference among 50 right-handed normal controls, Interclass Correlation
Vol. 40, No. ii, 1987
Coefficient = 0 . 6 6
Asymmetric Circiing in Hemi-Parkinsonism
1129
(II).
I00 LEFT HEMISPHERE DOMINANT MALE SUBJECTS
KRUSKAL-WALLtSTEST 80
P < O. 006 0 0 0 0 0 0
g
0
o Bo °
6o
o/o
o
+ROTATION /RIGHT
o o~0 0 o -o-
o
.
o
L>
4o LIJ O
.
.
.
.
.
.
.
.
.
.
ol
.
.
.
.
.
,,E,T
°|T
°I
°±°
O-
20
NORMAL CONTROLS
RIGHT HEMIPARKINSONISM (RIGHT SIDED SYMPTOMS)
( N =50)
(N=4)
FIG i. Percent clockwise rotation ~ r i g h t preference) of normal controls vs. hemi-Parkinsonian patients with markedly right-sided symptoms. Spontaneous circling behavior was monitored via a belt-mounted rotometer that registers left and right full (360-degree) turns.
Discussion The data indicate that without being aware of it, and not unlike unilaterally lesioned rodents, hemi-Parkinsonian patients spontaneously rotate toward the hemisphere believed to contain lower dopamine levels. Both patients who manifested primarily unilateral tremor and little asymmetry in tone and patients with predominant asymmetry in tone but little tremor demonstrated asymmetric turning. Monitoring with the rotometer for a full day may provide a more sensitive index of motor abnormalities than a single or occasional clinical examination, particularly for patients such as ours who have mild disease. None of these mildly affected patients had hemiparesis, nor was there a clinically apparent inability to turn to right or left. There have curiously only been relatively few reports on the subject of physiological mechanisms of circling behavior. Hitzig (14) attributed the phenomenon to a paralysis of muscles of the trunk on one side. More recently a body of authors have found that unilateral lesions placed within the
1130
Asymmetric Circling in Hemi-Parkinsonism
Vol. 40, No. ii, 1987
substantia nigra cause a profound sensory inattention. Such sensory inattention appears to be associated with loss of the contralateral ascending dopamine-containing axons (15,16,17). The degree of sensory inattention seems to correlate well with the severity of depletion of dopamine, although further work is required. This is the first evaluation of circling behavior for study patients with a brain disorder. Studies are in progress with hemi-Parkinson's patients offmedications, on lower or higher doses, as well as with patients who are affected bilaterally, and patients medicated with post synaptic dopamine agonists which are likely not to abolish, but to completely reverse the direction of the asymmetry in rotational preference in hemi-Parkinsonism. This initial study shows the possible usefulness of human rotation studies and helps validate the animal model of Parkinson's disease. Acknowledsement This work was supported in part by a grant to H. S. Bracha from the United States Veterans' Administration.
References i. 2. 3. 4. 5. 6.
7. 8. 9. I0. 11. 12. 13.
14. 15. 16. 17.
S. D. GLICK, T. P. JERUSSI, L. N., FLEISHER, Life Sci. 18 889-896. (1976). C. J. PYCOCK, Neuroscience 5 461-514. (1980). B. ZIM}fERBERG, S. D. GLICK, T. P. JERUSSI, Science 185 (623-625. (1974). S. D. GLICK and R. M. SHAPIRO, in Cerebral Lateralization in Nonhuman Species, S. D. Glick, ed., p. 157-183, Academic Press New Y o r ~ (1985). S. D. GLICK, L. M. WEAVER, and R. M. MEIBACH, Brain Res. 208 227-229. (1981). E. S. GARNETT, C. NAHMIAS, and G. FIRNAU, Can. J. Neurol. Sci. ii 174-179. (1984). L. HENRIKSEN and J . BOAS, A c t a N e u r o l . Scand. 71 257-266. ( 1 9 8 5 ) . G. BAROLIN, !I. BERNHEIMER & O. HORNIKIEWICZ. Archs Neurol. Neurochir. Psvchiat. 94 241-248. (1964). J. P. MARTIN. The Basal Ganglia and Posture, 100-105. Pittman, London. (1967). R. C. DUVOISIN & C. D. MARSDEN. Journal Neurol. Neurosurg. Psychiat. 8 787-793. (1975). H. S. BRACHA, D. SEITZ, J. OTEMAA, and S. D. GLICK, Brain Resesrch. in press (1987). S. GREENSTEIN and S. D. GLICK. Pharmacol. Biochem. Behav. 3 507-510. (1975). R . M . RIETAN, Manual for Administration of Neuropsychological Test Batteries for Adults and Children, Reitan Neuropsychology Labs., Inc., Tucson AZ (1979). E. HITZIG. In: Physiologische und Klinische Untersuchunger uber das Gehirn, 2 155-609. (1904). J. F. MARSHALL & P. J. TEITELBAUM. Comp. Physiol. Psychol. 86 375-395. (1974). U. UNGERSTEDT & T. J. LJUNGBERG. Psyciat. Res. 11 149-150. (1974). T. LJUNGBERG & U. UNGERSTEDT. Expl. Neurol. 53 585-600. (1976).