close

Вход

Забыли?

вход по аккаунту

?

Changes in excitability of motor cortical circuitry in patients with parkinson's disease.

код для вставкиСкачать
Changes in Excitabdity of Motor Cortical
Circuitry in Patients with Parkmson’s Disease
M. C. Ridding, MSc,” R. Inzelberg, MD,? and J. C. Rothwell, PhD”
Using the technique of transcranial magnetic stimulation over the motor areas of cortex and recording electromyographic (EMG) responses from the first dorsal interosseous muscle, we measured the excitability of corticocortical
inhibitory circuits at rest using a double pulse paradigm, in 11 patients with Parkinson’s disease (PD) studied both
on (ON) and off (OFF) (after overnight withdrawal) their normal medication and in 10 age-matched control subjects.
There was a significant decrease in the amount of corticocortical inhibition at short (1-5 msec) interstimulus intervals
in patients relative to their controls, which improved after L-dopa intake. For comparison with previous reports using
transcranial magnetic stimulation we also measured the duration of the EMG silent period when stimuli were given
to voluntarily active muscle, and the threshold for evoking an EMG response in both the active and relaxed states.
There was no change in the threshold for evoking EMG responses whether muscles were active or relaxed. However,
the silent period was significantly prolonged when ON compared with OFF, although in neither state was the duration
significantly different from that seen in normals. We suggest that there may be abnormalities of motor cortical
inhibitory mechanisms in patients with Parkinson’s disease that are not readily detected using threshold or silent
period measurements alone.
Ridding MC, Inzelberg R, Rothwell JC. Changes in excitability of motor cortical circuitry
in patients with Parkinson’s disease. Ann Neurol 1995;17:181-188
T h e motor areas of the cerebral cortex are a primary
target for the output of the basal ganglia, so that the
deficits in movement control that occur in basal ganglia
disease should ultimately be reflected in the activity of
cortical cells. In monkeys, it has been reported that
both electrolytic lesions of the substantia nigra [l],
and treatment with l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) 12, 31 can produce substantial
changes in the activity of neurons in the motor areas
of the cortex. In the primary motor strip there is a
decrease in the phasic discharge and a slower buildup
of activity in cells with movement-related activity. In
addition, there is a decrease in the proportion of cells
that show reciprocal changes in their discharge in association with movements in opposite directions [?I.
Neurons in the supplementary motor area lose the
“set-related” activity that occurs before the onset of
movement in a known direction [4]. T h e aim of the
present experiments was to identify changes in the excitability of motor areas of the human cerebral cortex
in patients with Parkinson’s disease (PD).
Examination of motor cortical circuitry in humans is
necessarily indirect. Using transcranial electrical stimulation of the cortex, which activates corticospinal output axons in the white matter [ S ] , Dick and colleagues
[GI confirmed that the corticospinal projection was intact and readily accessible in patients wtih PD. More
recently magnetic stimulation has been used [?I. T h e
electromyographic (EMG) responses evoked by this
technique are more sensitive to the level of cortical
excitability than those evoked by electrical stimulation
[ 5 ] and may therefore reflect activity in corticocortical
connections as well as in the output pathway itself.
Cantello and associates [S] reported that the threshold
for magnetic stimulation was lower in patients with P D
than in normals, but they did not distinguish whether
this was caused by increased excitability of spinal motoneurons, which may have responded more readily to a
given corticospinal discharge, o r by an increase in the
excitability of motor cortex neurons. Indeed, later
studies have reported conflicting results, with some
groups supporting a decrease in threshold [8, 91 and
larger responses [lo], while others have reported an
increase in threshold but with larger responses at
suprathreshold intensities [ 111. T h e most recent study
by Valls-Sole and colleagues [ 121 has resolved some
of these discrepancies by showing that when relaxed,
the threshold for magnetic stimulation is the same in
patients and normals, while the responses evoked at
suprathreshold intensities are larger than normal. In
From fTel Aviv University and the Weizmann Institute of Science,
Tel Aviv, Isrdel; and “MRC Human Movement and Balance Unit,
Institute of Neurology. London, UK.
Address correspondence and reprint requests to Dr Rothwell, MRC
Human Movement and Balance Unit, Institute of Neurology, Queen
Square, London W C l N 3BG, UK.
Received Apr 26, 1994, and in revised form Jul S . Accepted tor
publication Aug 4 , 1904.
Copyright Q 1995 by the American Neurological Association 181
contrast, when subjects are active, the responses in patients are likely to be smaller than normal. Valls-Sole
and colleagues [12) conclude that the effects are likely
to be caused by changes in excitability of spinal cord
(increased relative to normal at rest, decreased relative
to normal when active) rather than cortical mechanisms.
Measurements have also been made on the duration
of the silent period that occurs in an actively contracting muscle after cortical stimulation [12, 131. In
normal subjects, the latter part of the silence is probably produced by inhibition of cortical activity, since
spinal cord excitability as tested by H-reflexes recovers
more rapidly than the EMG silence C14, 151. At high
intensities of stimulation the silent period is slightly
shorter than normal in Parkinson’s diseae, which would
be compatible with a reduction in the activity of cortical inhibitory circuits. However, the rebound in EMG
activity that follows the silence also is larger in PD than
normal. This rebound may be the result of excitation
of muscle afferents during the relaxation phase of contraction. If this reflex is enhanced in PD it may reduce
the apparent duration of the silence E12).
We have recently described a technique that may
give direct information on the excitability of corticocortical inhibitory connections within motor areas of
cortex 1161. Two shocks are given through the same
coil. The first, conditioning shock is set to an intensity
that is subthreshold for producing EMG responses in
actively contracting muscles; in subjects at rest, this
implies that the shock evokes no descending corticospinal volley. The second shock is suprathreshold for
evoking an EMG response at rest. With intervals between the shocks of 1 to 6 msec, the test response is
substantially suppressed by the presence of the conditioning shock. Since the conditioning shock produces
no corticospinal volley, the inhibition is thought to be
the result of activity in corticocortical inhibitory circuits. If so, then the technique is a relatively simple
Patient
NO.
1
2
3
4
5
6
-
8
9
10
11
Sex
Age (yr)
F
M
F
M
M
M
F
F
F
F
M
49
77
64
74
59
55
57
72
69
Methods
Patients
Eleven nontremulous patients were selected from the outpatients clinic and their results compared with those from 10
neurologically healthy age-matched control subjects. The age
of the patients, the duration of their symptoms as well as
their clinical ratings during OFF and O N states are shown in
the Table. The mean age of the patients was 65.3 ? 9.6
years, while that of controls was 65.2 2 9 years. All subjects
were right handed and gave oral informed consent for participating in the study. The procedures were approved by the
local ethics committee.
Techrziqire
All experiments were performed using a figure-eight stimulating coil (external loop diameters, 9 cm) powered from a
highpower Magstim 200 magnetic stimulator (Magstim,
Dyfed, UK). The coil was oriented so that it induced electric
currents in the brain that flowed in a posterior-to-anterior
direction over the hand area of motor cortex. Silver/silver
chloride surface recording electrodes were used to record
responses from the contralateral first dorsal interosseous
(FDI). The active electrode was placed over the muscle belly
and the reference over the second metacarpophalangeal
joint. Responses were recorded onto a PC using a 1401 laboratory interface (Cambridge Electronic Design, Cambridge,
UK) for off-line analysis.
Hoehn & Yahr
Stage
Disease
Duration (yr)
Webster
Score OFF
Webster
Score O N
I11
I11
111
111
7
24
5
7
7
7
16
9
10
17
8
7
11
8
1
111
111
I11
I1
I11
5
6
29
9
19
15
8
78
I11
7
6
25
19
64
I1
6
6
10.0
8.3
13.6
6.3
Mean
SI)
182 Annals of Neurology
way of estimating the excitability of corticocortical circuits in conscious man.
The aim of the present experiments was to use the
conditioning-test technique to examine possible
changes in motor cortex excitability in patients with
PD on (ON) and off (OFF) their normal therapy. In
addition, we made measurements of both threshold
and silent period duration for comparison with previous results. We have found substantial changes in the
excitability of cortical circuits, in the absence of dramatic changes in threshold or silent period, that we
interpret as being due to a lack of basal ganglia input.
Vol 5’
No 2
February 1995
-
4
18
16
3
8.5
5.2
Threshold
Transcallosal Inhibition
Thresholds were determined for both relaxed and tonically
active muscle. Threshold was defined as being the stimulus
intensity needed to produce a clear response in at least 50%
of individual trials. The display gain of the EMG response
was adjusted to be 100 p,V/cm, so that a clear response would
have an amplitude of 20 to 30 kV. Initially the stimulus
intensity was adjusted in 5% steps, to gain a rough estimate
of the threshold. Once this was achieved the intensity was
then adjusted in 157 steps to allow precise determination of
thresholds. For threshold determination it is important to
have consistent levels of voluntary activity. For this to be
achieved the subjects were given audio-visual feedback. Relaxed threshold was determined during complete electrical
muscle silence; active threshold was determined during a
tonic contraction of approximately 5 qfi maximum voluntary
contraction (MVC). Because of the background activity in
the EMG, which obscures small evoked potentials, it is probable that our criterion for threshold was slightly larger than
that used at rest.
This technique is described in detail elsewhere [17]. Magnetic stimuli were given through two figure-eight coils placed
over both motor cortices. Again, the first stimulus was the
conditioning and the second the test. Interstimulus intervals
(conditioning-test) of 6 to 16 msec (in 2 msec steps) were
investigated. Two blocks of 40 trials were recorded for each
subject. Each block consisted of four different conditions,
i.e., test alone and test
conditioning at three different
ISIs. The order in which the conditions were presented was
pseudorandomly generated by computer. Both conditioning
and test stimulus intensities were adjusted so that when given
alone they produced EMG responses of approximately 1 mV
in relaxed, contralateral, FDI muscles. Individual responses
were recorded and measured. The area of the conditioned
responses were expressed as a percentage of the area of the
test response alone. Relaxation of both FDI muscles was
maintained throughour with rhe aid of audio-visual feedback.
+
Statistical Analysis
Silent Period
The silent period was elicited while subjects held a tonic
voluntary contraction of approximately 5% MVC. Trials consisted of 10 stimuli. For the first five, cortical stimulation was
given at an intensity equal to relaxed threshold, while in the
second five it was given at a stimulator output of 20% above
relaxed threshold. Stimuli were delivered at the optimal scalp
site for producing responses in FDI. Audio-visual feedback
was used to assist subjects in maintaining the correct level of
activity throughout the trials. The onset of the silent period
was taken as being the end of the M wave; the end of the
silent period taken as the point where the first burst of EMG
activity was seen following the period of EMG silence.
Ipsilateral Corticocortical Inhibition
This technique is described in detail elsewhere [16}. In brief,
two magnetic stimuli were given through the same stimularing coil over the motor cortex and the effect of the first
(conditioning) stimulus on the second (test) stimulus investigated. The conditioning stimulus was set at an intensity of
5% (of stimulator output) below active threshold. The second, test, shock intensity was adjusted to evoke a muscle
response in relaxed FDI with an amplitude of approximately
1 mV peak-to-peak. The timing of the conditioning shock
was altered in relation to the test shock. Interstimulus intervals (ISIS) between 1 and 15 msec were investigated. Three
blocks of 40 trials were recorded for each subject. Each block
consisted of four different conditions; test alone and test +
conditioning at three different ISIS. The order of the presentation was generated pseudo randomly by means of a 1401
laboratory interface (Cambridge Electronic Design). For
these recordings muscle relaxation is very important and subjects were given audio-visual feedback at high gain to assist
in maintaining complete relaxation. If EMG activity became
apparent during data collection, responses were rejected.
Measurements were made on individual responses and the
area of the conditioned response, at each ISI, was expressed
as a percentage of the area of the test response alone.
The experiments were designed to consider two comparisons: between patients and normals and within individual
patients ON and OFF therapy. For ipsilateral corticocortical
inhibition, the different ISIs were divided into the following
two groups: IS1 = 1-6 and IS1 = 7, 10, 15 msec as previous
work has shown that conditioning stimuli using short ISIs
have an inhibitory effect on the test response, while longer
ISIS produce a facilitation [16]. The effect of group
(GROUP) (PD/control), ISI, and the interaction between
GROUPYSI were analyzed using Multivariate Analysis of
Variance (MANOVA) for short and long ISls separately.
When the GROUP'ISI interaction was found to be statistically significant, the difference between the groups for each
IS1 was analyzed individually using Student's t test. For transcallosal inhibition the effect of G R O U P (PD OFF/control),
ISI, and the interaction between GROUP"IS1 were analyzed
using MANOVA. The difference between OFF and O N
states for different ISls were analyzed using MANOVA
where the effects of ON-OFF, ISI, and the interaction bew e e n ON-0FF"ISI were considered. Similar MANOVA
models were used for analyzing the GROUP differences for
the silent period and the effect of stimulus intensity (INTENSITY) as well as ON-OFF effects.
For the comparison of ON-OFF differences of Webster
scores within P D patients, the paired Student's t test was
used. The correlation between several variables was evaluated using Spearman's correlation analysis.
Results
The clinical details of the patients are summarized in
the Table. N i n e of t h e 11 patients were H o e h n &
Y a h r grade 111, cwo w e r e grade 11. The Webster scores
decreased significantly (paired t test, p < 0.001) when
patients were ON compared with OFF therapy.
Threshold Values
T h e threshold stimulus intensity needed to e v o k e a
minimal EMG response in t h e FDI muscle varied considerably (range: normals, relaxed FDI 4 1-83%, active
Ridding et al: Motor Cortex in PD
183
2s0
1
1
loo!
80
% of maximum
qtimulator output
I
r
‘ p<o
0s
T
T
60 -
40 -
A
20 -
ON
OFF
Control
%oftest
alone
A
”
2
4
8
h
I?
IU
1-1
16
18
In~cr\titnulurinterval i m \ )
200
I50
i1f
I
1
OFF/controls p<O.US
ONlcontrols p>0.05
i
T
maximum
outpui
\t tmiilator
0
1
2
3
4
5
6
7
8
Inter\fimulu\ interval (ms)
-,-Parkinson’s
OFF
-.-Parkinson‘$
ON
-o-
Controls
B
ON
OFF
Control
B
Fig I . Bar chart shouing thresholdsfor eooking electromyographic responses in (A)relaxed and ( B ) tonically active first
dorsal interosseous (FDI) muscle t o transcranial magnetic stimulation. Thresholds (y-axis) are in percentage of stimulator output. The stimulation was pevfrmed with a figure-eight coil
placed over the hand area. Mean t SD are given for the patients in both the OFF and ON states as weell as controls. In neither the active nor relaxed states was the threshold significantly
different in patients when compared with the controls (p >
0.05).
30-65%; patients, relaxed 47-75%, active 30-57%)
from one individual to another. O n average, it was the
same in patients (ON or OFF therapy) as in normals,
whether the measurement was made with the muscle
relaxed or active (see Fig 1). As expected, the threshold was significantly higher in relaxed than in active
muscle (MANOVA, condition efect, p < 0.001).
Ipsilateral Corticocortical Inhibition
Ipsilateral corticocortical inhibition was investigated
over interstimulus intervals from 1 to 15 msec. A comparison of the mean data from the patients studied
OFF their therapy and normals is shown in Figure 2A.
184 Annals of Neurology
Vol 37
No 2
February 1995
Fig 2. Time course of ipsilateral corticocortical inhibition in the
relaxed first dorsal interosseous muscle. The x-axis is the interstimulus interval (ISI) between the conditioning and the test
shock; the y-axis is the size of the conditioned response expressed
as a percentage of the response size produced by the test shock
given alone. The dotted line at 100% represents the size of the
test response given alone. (A)Data obtained at ISIs I to I 5
msec from normal subjects and from patients in the O F F state.
*Intervals at which there was a signifcant difference (p <
0.05 t-test) between the percentage inhibition in patients and
normals. (B) Detailed data obtained for ISIs from 1 to 6 msec
in patients OFF and ON therapy and in the nortnal control
subjects. Each point represents the mean area ( t SEI ofthe conditioned response in all subjects expressed as a percentage of the
test alone response at that ISI. Across ISIs from 1 t o 6 msec
there was significantly less inhibition in the patients in the
OFF state compared with normal (MANOVA, GROUP effect3
p < 0.05). When ON the difference was not significant (p >
0.05).
Analysis of variance showed that the time course of
the initial period of inhibition was different in the patients OFF from that in controls (IS1 1-6 msec; interaction term between group comparisons, p < 0.05) with
significantly less (t-test, p < 0.05) inhibition at ISIs of
2, 4, and 5 msec. The behavior of the patients was
the same as that of normal subjects in the period of
facilitation (IS1 = 7-15 msec). When ON therapy, the
patients’ data at IS1 1-6 msec seemed to become closer
250 ;
200 % of rest
alone
150 '
6
8
10
I
12
14
16
50ms
Interstimulu!, iritrrval (ms)
-A-
Parkinson's
-O-
Controls
PD ON
OFF
hSm\
Fig 3. Comparison of the time course of transcallosal inhibition
in riomial subjects and i n 4 patientJ. with Parkinson's disease
studied OFF therapy. The x-axis plots the interstimulus interi'al (conditioning shock befre test shock) and the y-ax% plot5 the
size of the conditioned response expressed as a percentage of the
size of the response t o a test gizien alone. Magnetic stimuli were
gizien oiler both hand areas u i t h figure-eight coils. There is no
significant dif/erenre in the time course betuleen the patients and
the normals. Points represent mean 2 SE.
I
t
4
?SO
20
to normal (Fig 2B). There was no longer any significant
difference between the amount of inhibition in patients
ON versus normal ( p > 0.05); but neither was there
any significant difference between patients ON versus
OFF ( p > 0.05).
PD
OFF
€3
Tvanscallosal Inhibition
Transcallosal inhibition between the hemispheres was
examined in the OFF condition in 4 patients. The time
course of inhibition was the same as that in normals
(Fig 3 ) (MANOVA, GROUP effect, p > 0.5). When
treated as a separate small group, the ipsilateral corticocortical inhibition (IS1 1-6 msec) in these 4 patients
was significantly less than that in controls (MANOVA,
GROUP effect, p < 0.05).
The Silent Period
The silent period was elicited at TWO intensities of stimulation, relaxed threshold and 209% of the stimulator
intensity output above that value. An example of the
silent period in 1 patient ON and OFF therapy is
shown in Figure 4A. The mean duration of the silence
is shown for all subjects in Figure 4B and C.
The duration of the silent period increased with increasing stimulus intensity by similar amounts in all
three groups of subjects (MANOVA, INTENSITY
effect, p < 0.001; INTENSITY-GROUP interaction,
p > 0.05). The duration tended to be shorter in patients OFF therapy than in normals and longer than
normal in patients when they were ON therapy, although neither effect was significant. Paired comparisons in individual patients showed that there was a
PD
ON
Controls
250
OFF /controls p>O. I
200
C
OFF / ON p=0 06
PD
OFF
PD
Control,
ON
F i g 4. (A) Superimposed rau, data traces rfizie trials) showing
elertromyographic silent periods in the contracting (5% maximum roluntary contraction)first dorsal interosseou~.of a patient
with Parkinson's disease. Cortical stimulation using a figureeight coil uas gisen at an intensity equal to relaxed threshold.
In the OFF state the silent period duration is shorter than in
the ON state. (B)Mean data i?
SE) in the patients OFF and
ON therapy aj well as in the normal controls uhen the stimulus
intensity was equal t o relaxed threshold, and ( C ) umhen the stiniulus intensity was equal t o 20% of the stimulator output above
relaxed threshold. With both stimulus intensities the silent period
in the patients appears slightb shorter than in normals wheti
OFF and J-lightly longer than in nornials when ON. However,
these changes are not significant. There is a signjficant (p <
0.05. paired t-test) lengthening of the silent period when ON
compared u'ith OFF when stimulating at threshold intensities.
Ridding et al: Mocor Cortex in PD
185
significant ( p < 0.05) increase in duration (25 msec)
ON versus OFF when threshold intensities were used.
T h e effect was not significant when stimulating at the
higher intensities ( p = 0.06).There was no correlation
between any of the individual clinical scores (rigidity,
tremor, bradykinesia) or the global Webster score and
silent period duration in the patients ON and OFF
therapy.
Disiusslo rr
T h e present results show that there is a reduction in
the amount of corticocortical inhibition, as tested using
transcranial magnetic stimulation, in the cortical motor
areas of patients with P D studied after overnight withdrawal of their normal medication. In our study, there
was no signifcant difference between patients and control subjects in either (1) the threshold for eliciting
EMG responses (whether active o r relaxed), o r ( 2 ) in
the duration of the EMG silent period seen after cortical stimulation. In patients, L-dopa improved the
amount of inhibition and lengthened the duration of
the silent period.
Ipsihtrval Covtii.oiortlid Itrhlbition
Kujirai and colleagues [ 161 provided strong evidence
that the suppression of test responses with paired stimulation at short intervals was the result of activity in
cortical inhibitory circuits. In brief, they showed (1)
that the conditioning shock given on its own did not
inhibit spinal H-reflexes; indeed, it often facilitated
them, and ( 2 )that anodal electrical conditioning stimuli
were much less effective in producing suppression than
magnetic conditioning shocks. T h e latter point was explained in the following way. Anodal stimulation at low
intensities tends to activate axons of the corticospinal
tract in the white matter, while magnetic stimulation
acts either directly at the initial segment o r transsynaptically within the cortex IS]. Since both forms of stimulation are thought to activate the same population of
descending fibers, the greater effectiveness of magnetic
stimulation in producing suppression seems likely to
be due to its activation of cortical mechanisms.
Kujirai and colleagues El61 usually used a conditioning stimulus that had an intensity of 0.8 to 0.9 times
the threshold for producing activity in relaxed subjects.
Such intensities can evoke a descending corticospinal
volley that can be detected by its facilitatory effect o n
spinal H-reflexes. Thus, in their experiments, the conditioning stimulus had two effects, spinal facilitation
and cortical inhibition. Any change in the amount of
suppression could, under these circumstances, be d u e
to change in the amount of either cortical or spinal
excitability. In the present experiments, we wished to
avoid any spinal cord effect, so that we could be sure
that any changes occurred within the cerebral cortex.
To do this we reduced the intensity of the conditioning
186 Annals of Neurology Vol
-37
No 2
February 1995
stimulus so that it was below the threshold for evoking
any response in active (rather than relaxed) muscles.
W e then performed the main experiments at rest.
W e reasoned that during activity, the excitability of
the spinal motoneurons should be high, such that at
any instant some motoneurons would be close enough
to their firing threshold to be discharged by minimal
descending excitatory input. Lack of a response to cortical stimulation therefore implies that there is virtually
no descending volley. In practice, it is difficult to be
sure, without averaging very many trials, that there is
definitely no response to stimulation when subjects are
active. Because of this, we reduced the stimulus intensity Sfi;, below threshold to minimize the chance of
producing any descending volley. In addition, as stated
already, experiments were then carried out at rest.
With magnetic stirnulation, the threshold for producing
any descending activity is higher at rest than it is during
activity 1181. Thus, the combination of a subthreshold
(in the active state) shock and a relaxed subject should
effectively have ruled out any possibility that the conditioning shock produces a descending corticospinal volley. W e conclude that not only does the suppression
of the test response occur at a cortical level, but that
the changes seen in patients with PD also reflect
changes in cortical, not spinal excitability.
I t is possible that many different cortical circuits,
both excitatory and inhibitory, are tested using the
paired pulse technique. Reduced suppression of the
test response at short ISIs is consistent with either a
decreased inhibition or an excess of excitation. However, since the net effect at short intervals is inhibition,
we have suggested previously [ 161 that an important
component may be d u e to activity in intracortical yaminobutyric acid (GABA)ergic inhibitory connections. If so, then the results in PD would be compatible
with a decrease in excitability of these GABAergic
pathways.
T w o details of the results deserve discussion. First,
why is reJuced suppression not evident at all the
ISIs studied between 1 and 5 msec? W e can only speculate on the possible reasons for this behavior, and,
given the limited number of subjects that we studied,
it is probably best to be circumspect in o u r theorizing.
O n e possibility is that the differences reflect varying
interaction between excitatory and inhibitory circuits
at the different ISIs. T h e second point concerns the
normal transcallosal inhibition that we described in the
patients. This result has two important implications.
First, it suggests that the mechanism of transcallosal
and ipsilateral inhibition are different, and second, that
the changes in PD are specific to the latter. Precisely
which neural pathways are involved is, at the present
time, unknown.
We can only speculate o n how deranged basal ganglia output in P D might affect excitability of the intrin-
sic connections within the motor areas of cortex. One
clue comes from the changes in motor cortical cell discharges seen in monkeys after administration of
MPTP. In intact animals, approximately half of the cells
that change their firing during flexiodextension movements of the wrist have a reciprocal pattern of activity
for the two directions of movement. After MPTP treatment, this directional selectivity is reduced. Only 18%
of cells have a reciprocal firing pattern. As a result,
many neurons whose activity might have been expected to decrease during movement in one direction
continue to discharge [ 2 ] . A similar effect is seen after
local injection of the GABA antagonist bicuculline into
the motor cortex. There is a decrease in the selectivity
of neuronal discharge, so that neurons that normally
discharge during active movement of a joint in only
one direction begin to discharge during movements
made in either direction {lS]. Again, there is a net
increase in the cortical activity accompanying movement in either direction. I t seems possible, therefore,
that the changes in cell firing after MPTP could be
due, in part, to abnormal basal ganglia input to cortical
inhibitory circuits. If so, then the results from neural
recordings in monkeys provide a direct link with the
present data. Basal ganglia dysfunction in PD may decrease the excitability of cortical inhibitory circuits and
result in reduced ipsilateral corticocortical suppression
as tested by magnetic stimulation.
The results from experiments with local injection
of bicuculline [l9] suggest that one role of inhibitory
connections within the motor areas of cortex is to “focus’’ activity onto appropriate groups of corticospinal
neurons. The present data lead us to suggest that basal
ganglia output may be one important factor that regulates this “shaping” process. Such a role would be compatible with other studies that have shown that basal
ganglia output is unlikely to be the source of the initial
command to move, but is more likely involved in preparing cortical motor areas for a forthcoming movement. In essence we propose that one role of the basal
ganglia is to preset excitability in cortical circuitry so
that the movement is executed as efficiently as possible.
In our patients, decreased corticocortical suppression may be related to two common features of parkinsonian pathophysiology, enhanced long-latency stretch
reflexes and ON-dose dyskinesias. Both may result
from activity in inappropriate populations of cortical
cells in response to somatosensory and motor inputs.
In effect, dyskinesias might result from an overflow of
activity within motor cortex after restoration of motor
command signals from other sources. Long-latency
stretch reflexes, if they involve activity in a transcortical
pathway [20), may be increased because of a similar
increase in the population of cells responding to the
sensory input. In contrast, slowness of movement in
P D is unlikely to result solely from these changes in
motor cortical organization. Perhaps it relates to a separate “energizing” function of the basal ganglia in other
cortical motor areas.
L-dopa treatment improved the suppression produced by paired magnetic stimuli. The most likely explanation for this is that improved striatal function normalized basal ganglia output. However, we cannot
dismiss the possibility that there was an additional direct effect on dopaminergic input to superficial cortical
layers.
Coniparison with Previous Work
Data on the threshold for cortical stimulation in patients with P D is rather confused, with some groups
claiming a decrease [S, 91 in threshold and larger responses [lo], others an increase in threshold but with
larger responses at suprathreshold intensities [ 1 11, and
others no change [12). The present results support the
latter view.
A probable reason for the lack of consistency in the
results from different groups is that there is a very
wide range of threshold values in the normal population. With such an intrinsically variable measurement,
it is difficult to prove that definite changes occur unless
the differences are very large (as, for example, in patients treated with antiepileptic drugs [2 l ]), or if very
large numbers of subjects are studied. So far, relatively
small numbers of patients have been studied, so that
the question for P D must remain open. Our conclusion
is that if threshold changes do occur, then they are
likely to be quite minor.
A lack of change in threshold does not necessarily
conflict with the present observations on the reduction
in corticocortical suppression. The interaction between
the two depends critically on the tonic level of activity
in these inhibitory circuits in subjects at rest. Our results show only that the excitability of these circuits
(to external stimuli) is decreased in PD. They do not
necessarily relate to the tonic level of activity in them.
It may well be that inhibitory activity is low at rest and
only changes during or in preparation for movement.
If so, then excitatory thresholds would be unaffected
by changes in the excitability of inhibitory circuitry.
Indeed, inhibition of GABAergic transmission in monkey motor cortex produces little change in the background activity of cells when the monkey is not performing any task, even though the discharge during
activity is increased considerably [ 191.
Our present results showing that the duration of the
cortically evoked silent period is increased by L-dopa
therapy are similar to those reported by others [ 2 2 ) .
Many factors contribute to this silence. There is good
evidence, from the use of H-reflex testing, that the
latter part of the silent period is the result of a lack
of corticospinal input to the spinal cord rather than a
h d d i n g et al: Motor Cortex in PD
187
decrease in excitability of spinal motoneurons 114, 1S } .
In view of this, it may be that the changes that occur
are related to the reduced suppression detected in the
paired stimulus experiments. However, the stimulus
intensities used to elicit the silent period are far larger
than those used to test ipsilateral corticocortical inhibition, so that the question must remain unresolved at
the present time. Cantello and associates [S} originally
reported that the silent period was shorter in patients
with PD than in age-matched normal controls. This
was not the case in the present study. The probable
reason for this is that we used a smaller range of stimulus intensities and a smaller coil than Cantello and associates IS}. In fact, they only found shorter silent period
durations when high stimulus intensities were used.
When they used lower intensities, probably similar to
those employed by us, there was no difference in duration. Similar results have recently been reported by
Valls-Sole and colleagues [ 12).
In conclusion, we have shown that it is possible to
demonstrate changes in motor cortex excitability in patients with PD. The principal effect was a reduction in
the amount of ipsilateral corticocortical suppression as
tested with paired magnetic stimulation. We have suggested that this is due to a decrease in excitability of
intrinsic inhibitory circuits of the cortex, caused by abnormal output from the basal ganglia. Such changes
may result in decreased selectivity of cortical discharge
during movement as reported previously in monkeys
treated with the neurotoxin MFTP.
M. C. Ridding was supported by Action Research. R. lnzelberg was
suppurted by the British Council and the Clore Foundation.
We are grateful to Professor C. D. Marsden and D r N. Quinn for
allowing us to study their patients.
References
1. Gross C, Feger J, Seal J , et al. Neuronal activity in area 4 and
movement parameters recorded in trained monkeys after unilateral lesions o f t h e substanria nigra. Exp Brain Res 1983;7(suppl):
181-193
2. Doudet DJ. Gross C , Arluison M. Bioulac B. Modifications of
precentral cortex discharge and EMG activity in monkeys with
MPTP-induced lesions of D A nigral neurons. Exp Brain Res
l990;80:l77-188
-3. Mandir AS, Watts RL. Changes in primary motor cortex neuronal activity associatrd with increased reaction rime and movement time in MFTP parkinsonism. Mov Disord 1990;5(suppl
1 ):77 (Abstract)
4. Watts RL, Mandir AS. Abnormalities of supplementary motor
area (SMA) task-related neuronal activity in MPTP parkinsonism. Move Disord 1990;5(suppl 1).78 (Abstract)
188 Atinals of Neurology
Vol 37
No 2
February 1995
5 . Rothwell JC, ’rhompson PD, Day BL, er al. Stimulation o f the
human motor cortex through the scalp. Exp Physiol 1991;76:
159-200
6. Dick JPR, Cowan JMA, Day BL, et al. The corticomotoneurone
connection is normal in Parkinson’s disease. Nature 1 9 8 4 3 10:
407-409
7 . Kandler R H , Jarratt JA, S a g a HJ, et al. Abnormalities of central
motor conduction in Parkinson’s disease. J Neurol Sci 1990;
100:94-97
8. Cantello R, Gianelli M, Bettuci D, et al. Parkinson’s disease
rigidity: magnetic motor evoked potentials in a small hand muscle. Neurology 1991;4l: 1149-1456
9. Maerrens d e Noordhout A, Pepin JL, Delwaide PJ. Motor cortex hyperexcitability in Parkinson’s disease. Neurology 1992;
42(suppl 3):285 (Abstract)
0. Eisen A, Siejka S, Schulzer M , et al. Age-dependent decline in
motor evoked potential (MEP) amplitude: with a comment on
changes in Parkinson’s disease. Electroencephalogr Clin Neurophysiol 1991;81:209-2 15
1. Davey NJ, Dick JPR, Ellaway PH, et d. Raised motor cortical
threshold associated with bradykinesia as rcvcaled by transcranial magnetic stimulation in normal man and Parkinson’s disease.
J Physiol 1991;438:35P (Abstract)
2. Valls-Sole J, Pascual-Leone A. Brasil-Neto 1, er al. Abnormal
facilitation of the response to transcranial magnetic stimulation
in patients with Parkinson’s disease. Neurology l994;44:735741
3. Haug BA, Schonle PW. Knobloch C. Kohne M. Silent period
measurements revives as a valuable diagnostic tool with transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol 1902,85: 158- 160
14. Ziemann U, Netz J, Szelenyi A, Homberg V. Spinal and supra
spinal mechanisms contribute to the silent period in the contracting soleus muscle after transcranial magnetic stimulation of
human motor cortex. Neurosci Lett 1993;1i6:167-171
15. Fuhr P, Agostino R, Hallett M. Spinal motor neuron excitability
during the silent period afrer cortical stimulation. Electroencephalogr Clin Neurophysiol 1991;81:157-262
10. Kujirai T. Caramia M D , Rothwell JC, et al. Corticocortical inhibition in human motor cortex. J Physiol 1993;471:501-519
1’. Ferbert A, Priori A, RothwellJC, et al. lnterhernisphcric inhibition of the human motor cortex. J Physiol 1992;453:525-546
18. Mazzocchio R, Rothwell JC. Day BL, Thompson PD. Effect of
tonic voluntary acdvity on the excitability of human motor cortex. J Physiol 1994;474:261-267
19. Matsuniura M, Sawaguchi T, Kubora K. GABAergic inhibition
of neuronal activity in the primate motor and premotor cortex
during voluntary movement. J Neurophysiol 1992;68:692-702
20. Marsden CD. Rothwell JC, Day BL. Long-larency automatic
responses to muscle stretch in man: origin and function. In:
Desmedt JE, ed. Motor control mechanisms i n hedlth and disease. N K WYork: Raven Press. 1983:509-539
2 1. Hufnagel A, Elger E. Marx W. king A. Magnetic motor evoked
potentials in tpilepsy: Effects of the disrase and of anriconvulsant medication. Ann Neurol 1990;28:6XO-h86
22. Irighilleri M, Priori A, Restante R, Berddeh A. Drug induced
modifications of t h e silent period after magnetic brain stimulation in normal subjects. Elecrroencephalogr Clin Nrurophysiol
1993;87:S124 (Ahstract)
Документ
Категория
Без категории
Просмотров
0
Размер файла
792 Кб
Теги
motor, patients, change, cortical, circuitry, disease, parkinson, excitability
1/--страниц
Пожаловаться на содержимое документа