# Dorsolateral Prefrontal Cortex: A Possible Target for Modulating Dyskinesias in Parkinson's Disease by Repetitive Transcranial Magnetic Stimulation

Authors: I. Rektorova; S. Sedlackova; S. Telecka; A. Hlubocky; I. Rektor
Journal: International Journal of Biomedical Imaging
 (2008)

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## Abstract

We studied whether five sessions of 10 Hz repetitive transcranial magnetic stimulation (rTMS treatment) applied over the dorsolateral prefrontal cortex (DLPFC) or the primary motor cortex (MC) in advanced Parkinson's disease (PD) patients would have any effect on L-dopa-induced dyskinesias and cortical excitability. We aimed at a randomised, controlled study. Single-pulse transcranial magnetic stimulation (TMS), paired-pulse transcranial magnetic stimulation, and the Unified Parkinson's Disease Rating Scale (UPDRS parts III and IV) were performed prior to, immediately after, and one week after an appropriate rTMS treatment. Stimulation of the left DLPFC induced a significant motor cortex depression and a trend towards the improvement of L-dopa-induced dyskinesias.


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## Body

## 1. Introduction

The neural mechanisms that underlie L-dopa-induced dyskinesias in
Parkinson’s disease (PD) remain poorly understood [1–4]. Dyskinesias have
been associated with pulsatile stimulation of dopamine receptors, downstream
changes in genes and proteins, and changes in nondopamine transmitter systems
[4–6]. All these changes lead to alterations in the firing patterns within the
basal ganglia, causing overactivations of the primary motor cortex and premotor
cortical areas [7, 8]. Activation studies in PD patients (H2 15O
positron emission tomography (PET) and 133Xe single photon emission
computed tomography (SPECT)) are in line with these results, and indicate that
L-dopa-induced dyskinesias are associated with inappropriate overactivity of
striatofrontal projections both at rest and during volitional actions [2, 9].
Comparison of rest with dyskinesias versus rest without dyskinesias showed a
relative activation of the motor cortex, the lateral and mesial premotor areas
including the supplementary motor area (SMA), the dorsal prefrontal cortex, and
the basal ganglia. The comparison of dyskinetic versus nondyskinetic states
during voluntary movement revealed additional activation of the same brain
regions [9]. Unfortunately, in the PET study of Brooks et al. [9] mentioned
above, regional cerebral blood flow (rCBF) in PD patients with and without
L-dopa induced dyskinesias was not compared to that of healthy subjects, and
therefore, it is difficult to speculate whether the relative increases in rCBF
observed in patients with dyskinesias were in fact above or still below that of
controls in all the reported areas including the DLPFC.Repetitive transcranial magnetic stimulation (rTMS) can produce
changes in excitability of cortical circuits that outlast the period of
stimulation, opening the possibility of intervening directly with the
mechanisms of cortical plasticity in the human cortex. rTMS is also a suitable tool to investigate plasticity
within a distributed functional network since conditioning effects of rTMS are
not limited to the stimulated area but give rise to functional changes in
interconnected cortical areas. The magnitude and the direction of rTMS-induced
plasticity depend on extrinsic factors (i.e., the variables of stimulation such
as intensity, frequency, and total number of stimuli) and intrinsic factors
(i.e.,  the functional state of the cortex targeted by rTMS). High frequencies
of rTMS applied over the motor cortex lead to facilitatory aftereffects on
corticospinal excitability while low-frequency stimulations
lead to opposite (i.e., inhibitory) aftereffects (for review, see 10).  The main
problem remains, that the basic mechanisms mediating the effects of rTMS are
still poorly understood.Recenly, several studies have suggested the therapeutic efficacy of
rTMS in PD while other studies have found no clinical improvement of motor
performance in PD  [11–15]. Using rTMS over the SMA, an Italian group [4]
showed that 900 pulses of 1 Hz rTMS with an intensity set at 90% of the resting
motor excitability threshold markedly reduced drug-induced dyskinesias in 8
advanced PD patients. In spite of this promising result, a year later the same
group [16] discovered that 5 repeated sessions of the 1 Hz rTMS failed to
enhance and/or prolong the beneficial effects of the procedure, and thus could
not be considered clinically useful. Very similar results were reported by a Toronto
group [17] who
used the same stimulation parameters but targeted the primary motor cortex
contralateral to the side with more severe dyskinesias in 6 PD patients.
Although the benefit was evident at day 1 after a two-week course of rTMS,
the authors have not managed to obtain more sustained clinical improvement
after the treatment.We recently reported the results of a pilot study that investigated
whether 5 repeated sessions of high frequency rTMS at 10 Hz applied over the
motor cortex (MC) of the relevant leg or over the left dorsolateral prefrontal
cortex (DLPFC) might result in a modification of “off”-related freezing of
gait and motor symptoms of PD in 6 advanced PD patients [18]. The selection of
MC and DLPFC targets for rTMS was based on dopamine release in the putamen and
caudate, respectively [19, 20]. The target selection was further supported by
the results of Lomarev et al. [14] who had reported positive cumulative benefit
of high-frequency rTMS applied over the same targets for improving gait, as
well as reducing upper limb bradykinesia in PD patients. In our study, rTMS was
well tolerated. Despite a reported trend towards improvement of the Stroop test
interference after rTMS over the left DLPFC, freezing of gait and motor
symptoms of PD remained unchanged by rTMS.Interestingly, patients who had undergone the DLPFC treatment
reported a subjective improvement of their dyskinesias. Therefore, in this
paper, we present a post hoc analysis of the data from the same group of
patients that focuses on cortical excitability and on the possible modification
of L-dopa-induced dyskinesias by repeated sessions of rTMS over the DLPFC.


## 2. Patients and Methods

We studied 6
patients (5 men and 1 woman, mean age67.3±7.7 years) with advanced PD
according to the UK Parkinson’s Disease brain bank criteria [21, 22],
a Hoehn-Yahr stage [23] between 2.5 and 4 while in the “off” state, and
without dementia (Mini-Mental State Examination [24] score >24). A Montgomery-Asberg Depression
Rating Scale [25] cut-off score of 14 was used to exclude patients with
depression. Patients with a predominant tremor form of PD were also excluded
from the study. All patients had dyskinesias, motor fluctuations, and “off”-related
freezing of gait. The disease duration was 11.3±3.1 years. The daily L-dopa
dose equivalent was 1145.8±413.2 mg; all patients were on L-dopa ± entacapone plus a dopamine
receptor agonist. The antiparkinsonian medication was stable for at least 4
weeks prior to the study commencement and during the study. All patients signed
the informed consent form, which was approved by the Ethics Committee of Saint Anne’s Hospital in
Brno.rTMS was applied
over the left DLPFC (5 cm anterior to the optimum scalp position for activation
of the contralateral first dorsal interosseus muscle [26]) or over the optimal
position for the tibialis anterior muscle contralateral to the foot which was
most frequently used by the patient to make the first step after freezing of
gait (i.e., MC), using the Magstim Super Rapid stimulator and a figure-of-eight
coil with a mean diameter of 7 cm. The coil was placed tangentially to the
scalp with the handle pointing backwards and laterally at 45° angle away from
the midline inducing a posterior-anterior current in the brain. Nowadays,
the frameless stereotaxy has been used in order to target the region of brain
corresponding to cytoarchitectonic area 9/46 as defined by Petrides and Pandya
[27]. Nevertheless, this part of the brain was found to overlap with the region
targeted by the standard procedure (Rektorova and Paus, unpublished data), used
in most studies.rTMS was
delivered in the “on” state (i.e., when PD medication was working and
providing benefit) without dyskinesias according to the individual patients’
diaries, at the same time of day. One treatment consisted of 5 sessions over 5
consecutive days. We chose a repeated sessions design,
and our patients were stimulated while being in their “on” state since both
conditions have been associated with better rTMS outcomes in literature [12, 14]. One
session consisted of 1350 pulses delivered at 10 Hz frequency, at an intensity
of 90% of the resting motor excitability threshold (for the right
first dorsal interosseus muscle when stimulating the left DLPFC, and the
appropriate tibialis anterior muscle when stimulating the MC). Each patient
completed at least one rTMS treatment. The order of stimulation sites was
randomized using closed envelopes. Although we aimed at a crossover design,
only two patients completed both treatments (with a one-month interval between
them).In order to
ensure the method was safe with regard to cognitive functions, a brief
neuropsychological battery of tests was administered prior to, immediately
after, and one week after each rTMS treatment. The results have been published
elsewhere [18].Experienced neurologists who were
blinded to the stimulation site performed a neurological evaluation prior to,
immediately after, and one week after appropriate rTMS treatment. The
evaluation was conducted during the patients’ relative “off” state (i.e.,
when PD medication was not improving PD symptoms resulting in a lack of
mobility) according to the individual patients’ diaries, at the same time of
day. It consisted of the UPDRS, part III
(motor examination) and part
IV (treatment complications) [28]. A more detailed evaluation and analysis of
gait and “off”-related freezing of gait has been reported elsewhere [18].Single-pulse and paired-pulse TMS
was performed while the patient was “on” to study the effects of rTMS
treatments on cortical excitability. We used the paired-pulse TMS paradigm of
Ridding et al. [29] at interstimulus intervals (ISI) of 1, 3, 7, and 15 milliseconds
[30]. We evaluated motor evoked potentials (MEPs) elicited by single and
paired-pulse TMS pulses over the MC contralateral to either the right first dorsal interosseus muscle (prior to, immediately after, and one week after the rTMS
treatment over the left DLPFC) or the appropriate tibialis anterior muscle
(prior to, immediately after, and one week after the rTMS treatment over the
appropriate MC).  The motor cortical sites were chosen to specifically
accommodate the primary goal of our freezing of gait protocol design. A
circular coil was used. MEP size reflects more globally the corticospinal
input-output balance, excitatory inputs from high-threshold glutamatergic
pathways to the motor cortex lead to intracortical facilitation, whereas
inhibitory inputs from low-threshold GABA-A-mediated pathways lead to
intracortical inhibition at short ISI [13].


## 3. Statistical Analysis

The effects of
rTMS treatments on single MEP amplitudes and UPDRS before and after the rTMS
treatments were analysed by a two-tailed paired-samplet test. A
two-factor repeated measures ANOVA, with the factors of “TIME” (3 levels:
baseline, immediately after the rTMS treatment, and 1 week after the rTMS
treatment) and “ISI” (3 levels: averaged data from the inhibiting ISI (1 and
3 milliseconds), the facilitating ISI (15 milliseconds), and the intermediate
ISI (7 milliseconds)) was performed to evaluate the effects of the rTMS
treatment applied over the MC and the DLPFC, respectively.


## 4. Results

### 4.1. Clinical Effects

Despite our aim to perform a
randomised crossover design, the study was stopped prematurely as several
patients withdrew the consent form before completing both treatments. A
subjective lack of treatment effect on freezing of gait (i.e., the primary
outcome) was the reason for the study withdrawal. This study presents the
results from four patients that completed the rTMS treatment over the MC and
four patients that completed the treatment over the DLPFC. Despite the lack of
effect of rTMS on freezing of gait and motor symptoms of PD [18], the patients reported
a decreased frequency and intensity of dyskinesias after 5 consecutive sessions
of rTMS targeted over the left DLPFC. These changes were reflected by the mean
UPDRS IV decrease immediately after 5 sessions of the stimulation as compared
with the baseline scores (see Table 1). The result did not reach statistical
significance (P=.06) but could be suggestive of a mild improvement of
dyskinesias. No such changes were observed after rTMS of the MC.Table 1
Effects of rTMS treatments on motor symptoms of PD and treatment complications
as assessed by the UPDRSs III and IV. UPDRS III: Unified Parkinson’s
Disease Rating Scale, part III, motor examination; UPDRS IV: Unified
Parkinson’s Disease Rating Scale, part IV, treatment complications;
Pre-rTMS/MC: prior to the repetitive transcranial magnetic stimulation
treatment applied over the motor cortex; Post-rTMS/MC: immediately after the
repetitive transcranial magnetic stimulation treatment applied over the motor
cortex; Pre-rTMS/PFC: prior to the repetitive transcranial magnetic stimulation
treatment applied over the prefrontal cortex; Post-rTMS/PFC: immediately after
the repetitive transcranial magnetic stimulation treatment applied over the
prefrontal cortex.
Pre-rTMS/MC scoresPost-rTMS/MC scoresPre-rTMS/PFC scoresPost-rTMS/PFC scoresUPDRS III “on”21.25±13.4321.75±13.6720.75±12.8720.00±14.12UPDRS IV6.00±1.837.00±2.506.25±1.714.75±0.96


### 4.2. Effects on Cortical Excitability

There was no cumulative effect of
the rTMS treatment over the MC on corticospinal excitability as measured by MEP
responses produced by single TMS pulses over the left MC contralateral to the
appropriate tibialis anterior muscle (see Table2). However, we found that 5
consecutive sessions of high frequency rTMS of the left DLPFC produced a
significant decrease in the amplitude of MEP responses produced by single TMS
pulses over the left MC contralateral to the right first
dorsal interosseus
muscle (see Table 2).Table 2
Effects of rTMS treatments on the amplitude of MEP responses produced by single TMS pulses. MEP: motor evoked
potential; Pre-rTMS/MC: prior to the repetitive transcranial magnetic
stimulation treatment applied over the motor cortex; Post-rTMS/MC: immediately
after the repetitive transcranial magnetic stimulation treatment applied over
the motor cortex; Pre-rTMS/PFC: prior to the repetitive transcranial magnetic
stimulation treatment applied over the prefrontal cortex; Post-rTMS/PFC:
immediately after the repetitive transcranial magnetic stimulation treatment
applied over the prefrontal cortex.
Pre-rTMS/MCPost-rTMS/MCPre-rTMS/PFCPost-rTMS/PFCMEP amplitudeμV)1.60±0.791.52±0.682.02±0.10*1.22±0.32**P=.03 (paired samples t test).There
were no effects of any rTMS treatments on the time course of intracortical inhibition or intracortical facilitation in the
appropriate motor cortex; this was verified with a two-factor repeated measures
ANOVA with the factors “TIME” and “ISI”: F(4,26)=0.72, P=.6 for rTMS
treatment over the DLPFC; F(4,10) =2.4, P=.1 for rTMS treatment over the MC.


## 4.1. Clinical Effects

Despite our aim to perform a
randomised crossover design, the study was stopped prematurely as several
patients withdrew the consent form before completing both treatments. A
subjective lack of treatment effect on freezing of gait (i.e., the primary
outcome) was the reason for the study withdrawal. This study presents the
results from four patients that completed the rTMS treatment over the MC and
four patients that completed the treatment over the DLPFC. Despite the lack of
effect of rTMS on freezing of gait and motor symptoms of PD [18], the patients reported
a decreased frequency and intensity of dyskinesias after 5 consecutive sessions
of rTMS targeted over the left DLPFC. These changes were reflected by the mean
UPDRS IV decrease immediately after 5 sessions of the stimulation as compared
with the baseline scores (see Table 1). The result did not reach statistical
significance (P=.06) but could be suggestive of a mild improvement of
dyskinesias. No such changes were observed after rTMS of the MC.Table 1
Effects of rTMS treatments on motor symptoms of PD and treatment complications
as assessed by the UPDRSs III and IV. UPDRS III: Unified Parkinson’s
Disease Rating Scale, part III, motor examination; UPDRS IV: Unified
Parkinson’s Disease Rating Scale, part IV, treatment complications;
Pre-rTMS/MC: prior to the repetitive transcranial magnetic stimulation
treatment applied over the motor cortex; Post-rTMS/MC: immediately after the
repetitive transcranial magnetic stimulation treatment applied over the motor
cortex; Pre-rTMS/PFC: prior to the repetitive transcranial magnetic stimulation
treatment applied over the prefrontal cortex; Post-rTMS/PFC: immediately after
the repetitive transcranial magnetic stimulation treatment applied over the
prefrontal cortex.
Pre-rTMS/MC scoresPost-rTMS/MC scoresPre-rTMS/PFC scoresPost-rTMS/PFC scoresUPDRS III “on”21.25±13.4321.75±13.6720.75±12.8720.00±14.12UPDRS IV6.00±1.837.00±2.506.25±1.714.75±0.96


## 4.2. Effects on Cortical Excitability

There was no cumulative effect of
the rTMS treatment over the MC on corticospinal excitability as measured by MEP
responses produced by single TMS pulses over the left MC contralateral to the
appropriate tibialis anterior muscle (see Table2). However, we found that 5
consecutive sessions of high frequency rTMS of the left DLPFC produced a
significant decrease in the amplitude of MEP responses produced by single TMS
pulses over the left MC contralateral to the right first
dorsal interosseus
muscle (see Table 2).Table 2
Effects of rTMS treatments on the amplitude of MEP responses produced by single TMS pulses. MEP: motor evoked
potential; Pre-rTMS/MC: prior to the repetitive transcranial magnetic
stimulation treatment applied over the motor cortex; Post-rTMS/MC: immediately
after the repetitive transcranial magnetic stimulation treatment applied over
the motor cortex; Pre-rTMS/PFC: prior to the repetitive transcranial magnetic
stimulation treatment applied over the prefrontal cortex; Post-rTMS/PFC:
immediately after the repetitive transcranial magnetic stimulation treatment
applied over the prefrontal cortex.
Pre-rTMS/MCPost-rTMS/MCPre-rTMS/PFCPost-rTMS/PFCMEP amplitudeμV)1.60±0.791.52±0.682.02±0.10*1.22±0.32**P=.03 (paired samples t test).There
were no effects of any rTMS treatments on the time course of intracortical inhibition or intracortical facilitation in the
appropriate motor cortex; this was verified with a two-factor repeated measures
ANOVA with the factors “TIME” and “ISI”: F(4,26)=0.72, P=.6 for rTMS
treatment over the DLPFC; F(4,10) =2.4, P=.1 for rTMS treatment over the MC.


## 5. Discussion

The results of our study point to a
possible impact of repeated sessions of rTMS applied over the left DLPFC on L-dopa-induced
dyskinesias in advanced PD patients. The mean change in the UPDRS IV scores did
not reach a statistical significance, but we did not evaluate dyskinesias by
more appropriate standardized scales since the assessment of dyskinesias was
not the primary outcome of our pilot study. On the other hand, UPDRS IV was
used to test dyskinesias in a PET study by Brooks et al. [9]. There are a
number of hypothetical mechanisms that might underlie the possible effects of
rTMS of the DLPFC on L-dopa-induced dyskinesias in advanced PD.It appears that changes of the
excitability of the primary motor cortex may be more efficiently performed
through stimulation of premotor and/or other more anterior brain regions, for
review, see [31]. We found that 5 consecutive sessions of high frequency rTMS
of the left DLPFC produced a significant decrease in the amplitude of MEP
responses produced by single TMS pulses over the left MC for the right first
dorsal interosseus muscle (i.e., decrease of the cortico-spinal excitability).
These results are in accord with the results of Rollnick et al. [32] who also
demonstrated that stimulation of the DLPFC via subthreshold 5 Hz rTMS induces
motor cortex depression in healthy subjects. It was posited by the authors that
this finding might be explained by the fact that prefrontal brain areas
contribute to motor cortex inhibition through antagonisms between frontal and
parietal lobes [32, 33] but the exact mechanisms are not fully understood.
Primary motor cortex “overactivity” in rather advanced PD patients was found
by means of PET and functional magnetic resonance imaging (fMRI) while studying
simple or complex motor hand tasks [34, 35]. It was also observed in SPECT and
PET studies of PD patients with L-dopa-induced dyskinesias [2, 9].
Electrophysiological data furhter support this notion: increased MEP aplitudes
at rest were found in PD patients with L-dopa induced dyskinesias [36, 37].
Neuroimaging studies have shown that subthalamic nucleus stimulation acts
through the reduction of abnormal overactivity in the motor system at rest  [34, 38]. Even though dyskinesias were not systematically monitored in
these studies, it has been well known that subthalamic nucleus stimulation
surgery is able to reduce L-dopa-induced dyskinesias [39]. Taken together,
normalizing (i.e., reducing) the excitability of the primary motor cortex, for
example, by rTMS of the DLPFC might be one possible factor in improving L-dopa-induced
dyskinesias in advanced PD patients.rTMS applied over the left DLPFC can
induce significant increases of rCBF in the stimulated area [40]. Functional
imaging studies (PET and fMRI) report decreases in rCBF and MRI signal in the
DLPFC and the rostral SMA in advanced PD patients compared to controls [35, 41–45]. The DLPFC is connected with the rostral SMA [46]. Pallidotomy [44] and
subthalamic nucleus stimulation [47] reversed such a hypoactivation. After
unilateral pallidotomy, glucose metabolism increased in the DLPFC, in addition
to metabolic changes in other cortical and subcortical areas [48]. rCBF
increases were reported in the DLPFC and the rostral SMA during apomorphine
pumps [49]. Again, pallidotomy, subthalamic nucleus stimulation and continuous
apomorphine are able to reverse dyskinesias [39, 49–51].
Therefore, the direct involvement of the DLPFC and the degeneration of
mesofrontal dopaminergic afferents might also be hypothesized to play some role
in the development of dyskinesias.Finally,
involvement of the dorsolateral “prefrontal” circuit may well be possible.
The prefrontal circuit encompasses the dorsal prefrontal cortex, the dorsal
caudate nucleus, the dorsal medial globus pallidus, and the ventral anterior
nucleus of the thalamus. Strafella et al. have shown that high frequency rTMS
of the DLPFC leads to dopamine release in the ipsilateral caudate nucleus [19, 20]. We used the same parameters as Strafella et al. with regard to frequency
and intensity of stimulation. Therefore, subcortical mechanisms cannot be
excluded either.Taken
together, we have shown for the first time that repeated sessions of
subthreshold 10 Hz rTMS of the DLPFC induced significant reductions of the
ipsilateral motor cortex excitability in advanced PD population, and might
possibly be suggestive of an improvement of L-dopa-induced dyskinesias. It has
to be pointed out that this was a small observational study not specifically
designed to assess dyskinesias in PD. DLPFC stimulation was not controlled by
the placebo rTMS and therefore a possible placebo effect cannot be excluded
either [15]. On the other hand, the DLPFC stimulation was controlled by yet
another active stimulation over the MC. Improvement of dyskinesia could not
have been expected by patients since changes in the motor complications score
were not included in the primary outcomes of our pilot study.Further
research is warranted to explore more precisely whether the unilateral or
bilateral stimulation of the DLPFC via repeated sessions of high frequency rTMS
induces beneficial effects on L-dopa-induced dyskinesias in advanced PD
patients, and whether it could be considered clinically useful.



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