outcomes from stimulation of the caudal zona incerta and pedunculopontine nucleus in patients with...

ORIGINAL ARTICLE

Outcomes from stimulation of the caudal zona incerta andpedunculopontine nucleus in patients with Parkinson’s disease

SADAQUATE KHAN1, LUCY MOONEY1, PUNEET PLAHA1, SHAZIA JAVED1,

PAUL WHITE2, ALAN L. WHONE3 & STEVEN S. GILL1

1Department of Neurosurgery, Institute of Neurosciences, Frenchay Hospital, Bristol, UK, 2Department of Mathematics and

Statistics, University of the West of England, Bristol, UK, and 3Department of Neurology, Institute of Neurosciences, Frenchay

Hospital, Bristol, UK

AbstractIntroduction. Axial symptoms including postural instability, falls and failure of gait initiation are some of the most disablingmotor symptoms of Parkinson’s disease (PD). We performed bilateral deep brain stimulation (DBS) of thepedunculopontine nucleus (PPN) in combination with the caudal zona incerta (cZi) in order to determine their efficacyin alleviating these symptoms.Methods. Seven patients with predominant axial symptoms in both the ‘on’ and ‘off’ medication states underwent bilateralcZi and PPN DBS. Motor outcomes were assessed using the motor component of the Unified Parkinson’s Disease RatingScale (UPDRS 3) and a composite axial subscore was derived from items 27, 28, 29 and 30 (arising from chair, posture, gaitand postural stability). Quality of life was measured using the PDQ39. Comparisons were made between scores obtained atbaseline and those at a mean follow-up of 12 months.Results. In both the off and on medication states, a statistically significant improvement in the UPDRS part 3 score wasachieved by stimulation of the PPN, cZi and both in combination. In the off medication state, our composite axial subscore ofthe UPDRS part 3 improved with stimulation of the PPN, cZi and both in combination. The composite axial subscore, in the‘on’ medication state, however, only showed a statistically significant improvement when a combination of cZi and PPNstimulation was used.Conclusions. This study provides evidence that a combination of PPN and cZi stimulation can achieve a significantimprovement in the hitherto untreatable ‘on’ medication axial symptoms of PD.

Key words: Parkinson’s disease, deep brain stimulation, functional neurosurgery, stereotaxy.

Introduction

Axial features of Parkinson’s disease (PD) such as

falls, postural instability and gait disturbance are the

motor symptoms with the greatest negative impact on

quality of life (QOL) in advanced PD. Indeed axial

symptoms are only surpassed by dementia and

depression in terms of reducing QOL.1 The impact

of axial symptoms on QOL reflects the limited

response of these symptoms to the currently available

pharmacological and surgical therapies.2–4

There have now been several clinical studies of

pedunculopontine nucleus (PPN) stimulation in hu-

mans showing variable results. Two initial case reports

described stimulation of this nucleus in isolation, and

an open label study reporting stimulation of the PPN

in conjunction with stimulation of the subthalamic

nucleus (STN) have reported positive outcomes.5–7

More recent publications describing PPN stimulation,

in patients blinded to their stimulation state, however,

have shown limited benefit from this therapy.8,9

In this article, we report on the 1-year follow-up of

seven patients with PD treated with dual site deep

brain stimulation (DBS) of the PPN and cZi. The

patients had not had previous surgery and presented

with poorly controlled limb symptoms (tremor,

rigidity and bradykinesia) as well as predominant

axial symptoms (failure of gait ignition, gait freezing

and falls) in the on medication state. All patients had

implantation of four electrodes, bilateral cZi electro-

des in order to alleviate their resistant limb symp-

toms,10 and bilateral PPN electrodes in order to

alleviate their axial symptoms. We focus on the

clinically relevant ‘On’ medication outcomes and

compare the effects of stimulating each site in

isolation and in combination.

Correspondence: Professor Steven Gill, Consultant Neurosurgeon, Department of Neurosurgery, Frenchay Hospital, Bristol BS16 1LE, UK.

Tel: þ44-117-9701212. Fax: þ44-117-9701161. E-mail: [email protected]

Received for publication 30 August 2010. Accepted 29 November 2010.

British Journal of Neurosurgery, April 2011; 25(2): 273–280

ISSN 0268-8697 print/ISSN 1360-046X online ª 2011 The Neurosurgical Foundation

DOI: 10.3109/02688697.2010.544790

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Methods

Patient population

The study population comprised seven patients (two

females, five males) who underwent bilateral DBS of

both the cZi and PPN and were assessed at a mean

follow-up of 12 months (range 10–13 months). The

main selection criteria were a diagnosis of PD as

defined by the UK PDS Brain Bank Diagnostic

Criteria for idiopathic PD. The patients symptoms

included significant falling, freezing or postural

instability in both the on and off medication states.

On medication falls and postural instability had to

occur when the patients were not dyskinetic. (Patient

details are given in Table I.) Patients 1 and 4, with

young onset had undergone screening for genetic

forms of parkinsonism, which were negative. They

had also been reviewed by at least two neurologists

with a specialist interest in movement disorders who

had found no evidence of an atypical Parkinson’s

syndrome.

Informed consent was acquired from patients prior

to surgery and ethical approval was obtained from the

Frenchay hospital and local ethical committee gave

approval to perform the stereotactic procedures

under general anaesthesia using implantable guide

tubes to deliver the DBS leads.

Surgical procedure and target sites

The PPN is an elongated structure, the rostral aspect

of which lies on an axial plane formed from the upper

border of the pons to the mid collicular point. The

location of the PPN can de defined on this axial plane

from the medially placed decussation of the superior

cerebellar peduncle and the laterally placed medial

lemniscus.11 (Fig. 1) Atlases of the human brainstem

indicate the PPN extends approximately 5 mm

caudal from this point, running parallel with the

fourth ventricle and aqueduct.11,12

The surgical technique used by our group for

performing DBS surgery and targeting the cZi and

PPN has been described in detail in previous

publications. 10,13–15 However as various methods

for targeting of the PPN, a novel target have been

described in the recent literature,16,17 we have

included a brief description of our technique.

Following application of a Leksell frame (Elekta

Instrument AB, Stockholm, Sweden), pre-operative

MRI scanning was performed with general anaes-

thesia under stereotactic conditions to identify the

target sites.

For visualisation of the PPN, MR images are

acquired parallel (axial) to a plane formed by the

upper border of the pons and the mid-collicular

point. This allows direct comparison with the

Nieuwenhuys atlas (Springer, Berlin). In our experi-

ence the structures defining the boundaries of the

PPN are best visualised using a combination of high-

resolution T2-weighted (TR 4000, TE 120, TSE 11, TA

BL

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274 S. Khan et al.

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NSA 12, 2 mm slice, 0.4 mm gap, voxel size 0.45

mm6 0.45 mm) and proton density sequences (TR

4000, TE 15, TSE 7, NSA 8, 2 mm slice, 0.4mm

gap, voxel size 0.45 mm6 0.45mm) (Fig. 1).13

Zrinzo et al. have also published a detailed descrip-

tion of the anatomy and imaging of this structure.16

Intra-operatively a plastic guide tube (Electrode

Introducer Kit, Renishaw PLC, UK) is inserted short

of the target site and bonded into the skull, an

indwelling stylette was passed down the guide tube to

the target site. Separate burr holes were used for each

of the target sites. A repeat peri-operative MRI scan

was used to asses the position of the plastic stylette in

relation to the intended target site. (Fig. 2A and B

demonstrates the stylettes positions within the PPN.)

Upon confirmation of satisfactory placement, the

stylette was removed and replaced with a DBS lead

(model 3389, Medtronic Inc., Minneapolis, MN,

USA). This was performed bilaterally for both the

cZi/STN and PPN as a single surgical procedure,

and the leads were connected to DBS pulse

generators (Kinetra, Medtronic Inc., Minneapo-

lis).The DBS pulse generator supplying the PPN

electrodes was placed in the right infra-clavicular

region and the pulse generator supplying the cZi

electrodes in the left infra-clavicular region (Kinetra,

Medtronic Inc., Minneapolis, MN, USA). The first

five patients in this cohort had electrode trajectories

that avoided the lateral ventricle. In the last two

patients, we changed our targeting of the PPN and

now take a trajectory that traverses the lateral

ventricles as this approach optimises the placement

of active contacts within the target.14

All patients had successful implantation of bilateral

cZi and PPN electrodes on first pass. There were no

intra-operative complications.

Clinical evaluations

Evaluations were performed preoperatively and at 12

months postoperatively. Clinical evaluations were

based on the CAPIT protocol,18 and included the

Unified Parkinson’s Disease Rating Scale (UPDRS)

and the Hoehn and Yahr scale. Patients were

assessed off and on medication before and after

surgery.

The Kinetra generators were switched on imme-

diately following surgery for patients 1, 3, 4, 6 and 7,

and at 1 week for patient 2 and 5. A movement

disorder nurse (LM) under the supervision of the

lead surgeon (SSG) programmed the patients’

stimulators. Anti-Parkinsonian medications were

reviewed and changed as clinically indicated by the

movement disorder neurologist. (AW) Assessments

were performed by a trained movement disorder

nurse specialist (LM), but neither the patients nor

nurse was blinded to the stimulation settings. All

assessments were filmed, and reviewed by a second

blinded assessor (SK). In cases where the score for

any subsection differed by more than on point

between the assessors, the recordings were reviewed

by the neurologist (AW) in a blinded fashion, in

order to reach a consensus score. Assessments for the

conditions were performed in a randomised order,

allowing sufficient time for the patients to have no

residual effects from the previous settings.

Following surgery patients were assessed in both

the off and on medication states with no stimulation,

FIG. 2. (A) Postoperative axial T2 MR image showing the implanted guide tubes and stylettes (arrowed) within the PPN. (B) Postoperative

coronal T2 MR image showing guide tubes and stylettes in the PPN.

FIG. 1. An axial inverted proton density image of the brainstem

with the PPN and surrounding structures labelled.

PPN and cZi stimulation 275

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PPN stimulation alone, cZi stimulation alone and

combined PPN and cZi stimulation. The practically

defined off state assessments were performed with the

patients having stopped their medication at least 12 h

beforehand, and had their stimulation switched off

overnight. The same assessments were then repeated

in the on medication state, at least on hour after

administration of 120% of the patient’s normal

morning L-dopa dose, with all patients having had

a protein-free breakfast on the morning of the

assessment.

Outcome measures and statistical analysis

The primary outcome measures were the motor

component of the UPDRS 3 and an axial subscore

derived from items 27, 28, 29 and 30 (arising from

chair, posture, gait and postural stability) as well as

QOL measured by the PDQ39. Secondary outcome

measures were the change in the tremor (items 20

and 21), rigidity (item 22) and bradykinesia (items

23–26) components of the UPDRS 3.

Changes in the motor UPDRS score and subscores

were analysed using repeated measures ANOVA with

a paired sample t-test. The change in L-dopa dose

was analysed using the paired Wilcoxon signed rank

test and non-parametric test. Changes in the QOL

(PDQ39 and PDSI) were analysed using the paired

Student t-test.

The level of significance was set at p50.05.

Results

Off medication motor UPDRS score and subscore

In the off medication state, the mean motor UPDRS

score off stimulation was 53.1+ 15.1. PPN stimula-

tion improved the motor UPDRS by 18.8% (a mean

score of 43.1+ 14.8 on PPN stimulation, p¼ 0.01).

cZi stimulation improved the motor UPDRS by

46.8% (a mean score of 28.3+ 8.9 on cZi stimula-

tion, p¼ 0.02). Combined PPN and Zi stimulation

improved the motor UPDRS by 47.3% (a mean score

of 28.0+ 10.5, p¼ 0.001).

In the off medication state, the mean motor

UPDRS axial subscore derived from items 27, 28,

29 and 30 (arising from chair, posture, gait and

postural stability) was 10.9+ 3.0. PPN stimulation

improved the motor UPDRS axial subscore by

26.3% (a mean score of 8.0+ 3.8 on PPN stimula-

tion, p¼ 0.02). cZi stimulation improved the motor

UPDRS axial subscore by 40.8% (a mean score of

6.4+ 3.2 on cZi stimulation, p¼ 0.004). Combined

PPN and cZi stimulation improved the motor

UPDRS axial subscore by 50.0% (a mean score of

5.4+ 4.3, p¼ 0.005).

In the off medication state, the combination of

PPN and cZi stimulation provided no additional

benefit in improving the total motor UPDRS over

cZi stimulation alone. Combined site stimulation

compared to cZi stimulation alone, achieved and

additional 9.2% improvement in the motor UPDRS

axial subscore, however this was not a statistically

significant change.

Improvements in the off medication tremor,

rigidity and bradykinesia are outlined in Table II.

On medication motor UPDRS score and axial subscore

In the on medication state, the mean motor UPDRS

score off stimulation was 30.3+ 8.7. PPN stimula-

tion improved the motor UPDRS by 17.9% (a mean

score of 24.9+ 11.6 on PPN stimulation, p¼ 0.03).

cZi stimulation improved the motor UPDRS by

31.1% (a mean score of 20.9+ 6.7, p¼ 0.003).

Combined PPN and cZi stimulation improved the

motor UPDRS by 42.0% (a mean score of

17.6+ 7.8, p50.001). In the on medication state,

the combination of PPN and cZi stimulation resulted

in a significant 10.9% additional improvement of the

motor UPDRS score compared to cZi stimulation

alone (p¼ 0.002).

The on medication mean motor UPDRS axial

subscore was 6.9+ 2.5. PPN stimulation improved

the axial subscore by 29.3%, but this was not

significant (a mean score of 4.1+ 3.8, p¼ 0.12).

cZi stimulation also improved the axial subscore by

29.3% but this was not significant (a mean score of

4.1+ 2.5, p¼ 0.10). Combined PPN and cZi stimu-

lation achieved a significant, 48.8% improvement in

the motor UPDRS axial subscore (a mean score of

3.0+ 2.2, p¼ 0.004).

In the on medication state, neither PPN nor cZi

stimulation alone achieved a statistically significant

improvement in the motor UPDRS axial subscore.

The combination of PPN and cZi stimulation

results in a statistically significant improvement of

the motor UPDRS axial subscore from both baseline

(48.8% improvement, p¼ 0.004) and Zi stimulation

alone (an additional 19.5% improvement, p¼ 0.05).

Improvements in the on medication tremor, rigidity

and bradykinesia scores are outlined in Table III.

TABLE II. UPDRS III tremor, rigidity and bradykinesia subscores scores off medication

Tremor – items 20 and 21

(% change from baseline)

Rigidity – item 22


Bradykinesia – items 23–26


Baseline 9.3 10.6 16.7

PPN stimulation 6.6 (29.2%, p¼0.03) 9.3 (12.2%, p¼0.23 ) 13.3 (20.5%, p¼0.02)

cZi stimulation 1.4 (84.6%, p¼0.01) 5.9 (44.6%, p¼0.02) 9.0 (46.2%, p¼0.003)

Combined stimulation 2.9 (69.2%, p¼0.01) 6.1 (41.9%, p¼0.02) 9.1 (45.3%, p¼0.001)

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Functional status (PDQ 39) and L-dopa dose

Four of the seven patients completed the PDQ 39

QOL, a QOL questionnaire pre and post operatively.

All patients were on chronic dual site (PPN and cZi)

stimulation at the time of completing the post-

operative questionnaire. Combined PPN and cZi

stimulation significantly improved global QOL by

32.6% as measured by the PDQ 39SI (mean pre-

operative score 35.6, mean postoperative score 24.0,

p¼ 0.003).

There was no statistically significant change in L-

dopa dose equivalent from the pre to postoperative

state (1021+ 435 to 872+ 322 mg).

Postoperative complications

In the immediate postoperative period, patients 2

and 5 had a prolonged period of global akinesia

despite restarting their normal anti Parkinson’s

medication. This was a complication we have not

observed in patients undergoing cZi DBS. The

akinesia resolved in patient 2 in the first postoperative

week. In patient 5, there was a gradual improvement

in the first postoperative month. All patients returned

to their pre-operative baseline with no new neurolo-

gical deficits.

Stimulation settings and stimulation-related side effects

Stimulation settings at which the patients had optimal

symptom control at 1 year were 2.6+ 0.7 V, 60 Hz,

60 ms for PPN stimulation alone and 3.3+ 0.4 V,

130 Hz, 60 ms for cZi stimulation alone. Combined

site stimulation was performed at 2.4+ 0.5 V, 60 Hz

and 60 ms for PPN and 3.2+ 0.4 V, 60 ms for cZi,

60 Hz frequency in patients 1–4, 6 and 7, and 120 Hz

in patient 5. At therapeutic voltages there were no

stimulation-related side effects with cZi stimulation.

cZi stimulation was bipolar, with stimulation from the

central two contacts. PPN stimulation was bipolar, on

the upper two contacts in patient 5, and tripolar using

the upper three contacts in the remaining patients.

The optimal frequencies for PPN stimulation were

determined by stimulating each contact at frequen-

cies varying from 5 to 210 Hz. Voltages were

increases at each frequency until the patient com-

plained of side effects. This process was repeated for

cZi stimulation. The frequency ranges had been

therapeutically beneficial for each target in isolation

were then trialled in combination. This process was

repeated in both the off and on medication states in

order to define the optimal stimulation parameters.

We found cZi stimulation to have the maximal

benefit instantaneously, whereas PPN stimulation

required up to 30 min to have the maximal beneficial

effect.

At the 1-year follow-up point the assessment order

was randomised, with a minimal delay of 1 h after

administering medication and switching on the

stimulators prior to assessing the patients. A washout

period of at least 3 h was allowed following cZi

stimulation and 12 h following PPN stimulation.

Indirect evidence of accurate targeting was ob-

tained by stimulating at supra-therapeutic voltages.

On the lowest contact higher voltages resulted in

upward gaze palsy which could be attributed to

current spreading to adjacent structures such as the

medial longitudinal fasciculus. Visual disturbance

with PPN stimulation has also been described by

Ferraye et al., and in their case was attributed to

current spread to the fibres of the occulomotor

nerve.19 Increased voltage on the higher contacts

resulted in parasthesia from current spread to the

laterally placed medial lemniscus.

Discussion

Clinical outcomes from L-dopa therapy and DBS

The postoperative clinical assessments in this patient

cohort proved challenging for both patients and the

assessor. A complete postoperative visit required

eight UPDRS assessments to cover all stimulation

combinations in both the on and off medication

states. In earlier postoperative evaluations we found

patients fatigued with repeated assessments, with the

later assessments resulting in worse clinical outcomes

irrespective of the medication and or stimulation

settings. We also found variability in the baseline

UPDRS scores between visits, and at different time

points in the day for the same patient. Both problems

have been previously reported by other groups. 9,20

At the 1-year follow-up, time between assessments

for each of the patients varied to allow full recovery

following changes in stimulation, prolonged periods

of being off medication and repeated UPDRS

assessments.

In our patient cohort, our main outcome measures

included the UPDRS part 3 and its subscores. There

TABLE III. UPDRS III tremor, rigidity and bradykinesia subscores on medication

Tremor – items 20 and 21


Rigidity – item 22


Bradykinesia – items 23–26


Baseline 3.6 7.1 9.4

PPN stimulation 3.0 (16.0%, p¼ 0.5) 5.9 (18.0%, p¼0.14 ) 7.6 (19.7%, p¼ 0.06)

cZi stimulation 0.6 (84.0%, p¼ 0.03 ) 5.0 (30.0%, p¼0.06) 7.1 (24.2.0%, p¼0.05)

Combined stimulation 0.6 (84.0%, p¼ 0.04 ) 3.9 (46.0%, p¼0.03) 6.0 (36.4%, p¼ 0.006)


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is also a poor correlation between the axial subscores

of the UPDRS and pathological findings such as axial

hypertonia, a significant contributing factor to

postural instability and falls.21 This is reflected in

our preoperative UPDRS data where the patients

clinically reported frequent episodes of gait freezing

and falls in the on medication state, however

continue to show a response on the axial components

of the motor UPDRS following L-dopa administra-

tion. The addition of QOL data in this patient cohort

was therefore essential. This demonstrates that the

extent of UPDRS part 3 improvements did match

the improvement in the QOL outcome measures as

well. In our more recent cohort of patients under-

going PPN DBS, we have included direct measures

of posture and gait including the Tinetti assessment

tool22 and gait freezing and falls diaries.

In the off medication state stimulation of PPN

and cZi in isolation and combination produced a

statistically significant improvement of the total

motor UPDRS score and axial subscore. However,

dual site stimulation did not produce a statistically

significant benefit over stimulation of cZi in isola-

tion for either the Axial subscore or total motor

UPDRS.

In the clinically more relevant on medication state,

stimulation of PPN and cZi in isolation and

combined produced a statistically significant im-

provement in the motor UPDRS from baseline.

However for the clinically significant on medication

motor UPDRS axial subscores, the improvement

with DBS was only statistically significant with

combined site PPN and cZi stimulation.

With PPN stimulation we found a variable

response of the different axial symptoms depending

on the frequency of stimulation. Postural stability

improved at frequencies as low as 10–20 Hz, whereas

initiation and maintenance of gait was optimal at a

higher frequency of 60 Hz. The introduction of high

frequency (4100 Hz) cZi stimulation in addition to

PPN stimulation resulted in a significant reduction in

the beneficial effects of PPN on axial symptoms. We

found stimulation of both sites at 60 Hz to be a

compromise position resulting in acceptable control

of both axial and limb symptoms. The use of lower

frequency STN stimulation for axial symptoms in

PD has previously been described.23 We also found

60 Hz stimulation of the cZi in isolation to improve

axial symptoms; however, it did not result in optimal

control of limb symptoms such as tremor, and the

improvement in axial symptoms was short lived.

The specific purpose of PPN DBS is to target on

medication axial symptoms which hitherto have been

resistant to both medical and surgical therapy. The

findings from our pilot study suggest that dual site

stimulation of the cZi and PPN is required to achieve

this.

At 1 year all patients chose to be on dual site

stimulation, and reported a significant improvement

in their QOL, measured using the PDQ39.

Although PPN DBS has attracted significant

interest in recent years there is limited clinical

outcome data available on the efficacy of this therapy.

Our on medication findings are similar to those

reported by Stefani et al., in an open label study of 6

patients with advanced PD. They concluded that

combined PPN and standard site STN DBS may be

useful in improving gait in the on medication state.6

In contrast, a more recent study by Ferraye et al.,

which assessed the efficacy of implanting PPN

electrodes into six patients with axial symptoms and

existing STN DBS showed disappointing results.

This patient cohort was assessed with the STN

stimulation remaining on, with and without PPN

stimulation. The assessments were carried out as

part of a double-blind cross-over study. At 1 year,

following surgery there was no improvement in the

on medication motor UPDRS, axial subscores of

the UPDRS, or QOL as measured by the PDQ-39.9

Lozano and coworkers have recently reported similar

findings, with no improvements in the motor

UPDRS at 3 or 12 months; however, patients did

report a significant reduction in falls.8 There remains

the need for further studies on patient selection,

targeting and outcomes for this therapy.

Mechanism of action of PPN stimulation

There are a number of possible mechanisms by

which PPN DBS results in improved axial control,

gait control and reduced fall frequency.

The basal ganglia play a key role in the planning

and execution of volitional behaviour by synchronis-

ing the oscillatory frequency of relevant thalamic,

midbrain and in turn cortical neurons to facilitate

information-processing in a direction that is deter-

mined by procedural learning.24–26 Different types of

information are processed at particular frequencies,

for example, information concerning maintenance of

posture occurs at a and b frequency ranges (9–14 Hz

and 15–35 Hz) and limb movement within the grange (60–80 Hz).27,28

The execution of a planned motor task involves the

basal ganglia setting up coherent synchronous

oscillations in the motor cortex via the ventral

anterior (VA) thalamus and in the brainstem and

spinal cord motor generators via the MEA (PPNd).

In this way, an instruction from the pre-motor cortex

can be processed in the motor cortex and spinal cord

concurrently to integrate the axial and distal aspects

of the movement repertoire.24,25,28–31

In PD, reduced dopamine delivery to the basal

ganglia impairs their ability to generate appropriate

patterns of synchronised oscillations and transmit

them to the motor cortex and spinal cord. The

persisting low frequency noise or in some cases

pathological low frequency synchronicity will disrupt

the execution of motor tasks.31,32

Therapeutic interventions such as the administra-

tion of L-dopa and high frequency DBS of the

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conventional target sites has been shown to augment

physiological oscillatory activity in the basal ganglia –

thalamo – cortical loop.33 Clinically this results in a

reduction of the classical distal limb symptoms of PD

such as tremor, bradykinesia and rigidity, however

has limited benefit on axial symptoms.2,34,35 Stimu-

lation of the STN at a lower frequency of 60 Hz, will,

via its descending output to the PPNd/MEA,

partially improve some of the axial symptoms of

PD.23 In our experience this effect is transient.

The failure to control axial symptoms with L-dopa

therapy and conventional site DBS, with its efferent

modulation of the PPNd indicated that the loss of the

cholinergic neurones of the PPNc are a significant

contributor to axial disturbance in PD. This is

supported by post-mortem data showing degenera-

tion of this cell group in patients with PD with gait

disturbance and postural instability.36,37 The loss of

ascending cholinergic projections in PD has also

been correlated to frontal lobe dysfunction, specifi-

cally impaired executive function and attention

which closely correlates with the risk of falling in

PD.38 These patients typically fall when faced with a

distraction or attempt to multitask whilst walking.39

Therefore direct targeting is required in order to

drive the cholinergic neurones in PPNc. Physiologi-

cally this is in the range of 20–60 Hz.40 However

because of the immediate proximity of PPNd

neurones the imposed oscillatory frequency will also

be transmitted to brainstem and motor effectors.

Thus we found that at stimulation frequencies of

10 Hz and 20 Hz postural instability was improved

but gait was impaired. Increasing stimulation to

60 Hz improved gait but postural stability was less

optimal. In our patients, the best compromise

frequency for PPN stimulation was 60 Hz. In this

patient, cohort we stimulated cZi in conjunction with

PPN because our patients had a combination of axial

and peripheral symptoms of PD.

When stimulating cZi at high frequency (130 Hz)

in combination with PPN stimulation at 60 Hz or

below we found postural stability became impaired.

This is presumably because these high frequencies are

transmitted to PPNd, disrupting its ability to oscillate

in the 10–20 Hz range which would be optimal for

posture maintenance. Reducing cZi stimulation to

40 Hz or below would worsen Parkinsonism, increas-

ing tremor, rigidity and bradykinesia. Consequently a

compromise setting of 60 Hz at both targets was

selected. In the on medication state, stimulation of

cZi and PPN together at 60 Hz showed greater

improvement in the axial motor UPDRS subscores

than stimulation of PPN alone (25% versus 50%,

p¼ 0.042). This is presumably because dual stimula-

tion will impose the same 60 Hz oscillatory frequency

throughout the motor pathways facilitating more

coherent information processing in the cortex,

brainstem and spinal cord. In contrast to our findings,

Ferraye et al. report no improvement in axial

symptoms with dual stimulation of the STN and

PPN, however they maintained high frequency

stimulation of STN during their assessments.9

There remains questions regarding patient selec-

tion, surgical technique and programming para-

meters. Obtaining optimal benefit from this

procedure requires the implantation of four DBS

leads which is not without risk and this may outweigh

the benefits in more advanced cases of PD who have

little cholinergic reserve with associated cognitive

decline. The selection of younger onset patients with

a predominance of axial problems would be appro-

priate but one has to be cautious that they do not have

an alternative diagnosis such as Progressive Supra-

nuclear Palsy or Multisystem Atrophy, where bulbar

and autonomic disturbance soon become the pre-

dominant disabling features.

Conclusion

Axial symptoms including postural instability, failure of

gait initiation and gait freezing have the greatest impact

on QOL after depression and dementia in patients with

PD and are refractory to current medical treatment.

PPN stimulation has the potential to make a

significant impact on these aspects of the disease.

The surgery is complex and not without risk and

patient selection is not straightforward.

Acknowledgements

We wish to thank Dr. Peter Heywood for his assistance

in the management of our patients and our movement

disorder nurse specialist Mrs Karen O’ Sullivan, for

assisting in the clinical assessments. We also wish to

thank Ms Becky Durham for the illustrations.

Competing interests

Steven Gill and Shazia Javed are consultants to

Renishaw PLC. None of the other authors have

conflicts of interest to declare.

Author roles

Sadaquate Khan – (1) Research project: (A) Con-

ception, (B) Organization, (C) Execution; (2) Statis-

tical Analysis: (A) Design, (C) Review and Critique;

(3) Manuscript: (A) Writing of the first draft

Lucy Mooney – (1) Research project: (A) Concep-

tion, (B) Organization, (C) Execution; (3) Manu-

script: (A) Review and critique

Puneet Plaha – (1) Research project: (A) Concep-



Shazia Javed – (1) Research project: (A) Concep-



Paul White – (2) Statistical analysis: (A) Design,

(C) Review and critique, (3) Manuscript: (A) Review

and critique


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Alan L. Whone – (1) Research project: (C)

Execution; (2) Statistical analysis: (A) Design, (C)

Review and critique; (3) manuscript: (B) Review and

critique

Steven S. Gill – (1) Research project: (A) Con-

ception, (B) Organization, (C) Execution; (2) Sta-

tistical analysis: (A) Design, (C) Review and critique;

(3) Manuscript: (A) Writing of the first draft, (B)

Review and critique

References

1. Schrag A, Jahanshahi M, Quinn N. What contributes to

quality of life in patients with Parkinson’s disease? J Neurol

Neurosurg Psychiatry 2000;69:308–12.

2. Bonnet AM, Loria Y, Saint-Hilaire MH, Lhermitte F, Agid Y.

Does long-term aggravation of Parkinson’s disease result from

nondopaminergic lesions? Neurology 1987;37:1539–42.

3. Deuschl G, Schade-Brittinger C, Krack P, et al. A randomized

trial of deep-brain stimulation for Parkinson’s disease. N Engl

J Med 2006;355:896–908.

4. Guehl D, Cuny E, Benazzouz A, et al. Side-effects of

subthalamic stimulation in Parkinson’s disease: clinical

evolution and predictive factors. Eur J Neurol 2006;13:

963–71.

5. Plaha P, Gill SS. Bilateral deep brain stimulation of the

pedunculopontine nucleus for Parkinson’s disease. Neuroreport

2005;16:1883–7.

6. Stefani A, Lozano AM, Peppe A, et al. Bilateral deep brain

stimulation of the pedunculopontine and subthalamic nuclei

in severe Parkinson’s disease. Brain 2007;130:1596–607.

7. Mazzone P, Lozano A, Stanzione P, et al. Implantation of

human pedunculopontine nucleus: a safe and clinically

relevant target in Parkinson’s disease. Neuroreport 2005;16:

1877–81.

8. Moro E, Hamani C, Poon YY, et al. Unilateral pedunculo-

pontine stimulation improves falls in Parkinson’s disease.

Brain 2010;133:215–24.

9. Ferraye MU, Debu B, Fraix V, et al. Effects of pedunculo-

pontine nucleus area stimulation on gait disorders in

Parkinson’s disease. Brain 2008;79:514–21.

10. Plaha P, Ben-Shlomo Y, Patel NK, Gill SS. Stimulation of the

caudal zona incerta is superior to stimulation of the

subthalamic nucleus in improving contralateral parkinsonism.

Brain 2006;129:1732–47.

11. Nieuwenhuys R, Voogd J, van Huijzen C. The human central

nervous system. 4th ed. Berlin: Springer, 2008.

12. Paxinos G, Huang X. Atlas of the human brainstem. San Diego:

Academic Press, 1995.

13. Khan S, Javed S, Patel NK, Plaha P, Gill S. Pedunculo-

pontine DBS in advanced Parkinson’s disease. In: Bain P,

Aziz T, Liu X, Nandi D, eds. Deep brain stimulation. 1st ed.

Oxford: Oxford University Press, 2009: 27–34.

14. Khan S, Javed S, Park N, Gill SS, Patel NK. A magnetic

resonance imaging-directed method for transventricular

targeting of midline structures for deep brain stimulation

using implantable guide tubes. Neurosurgery 2010;66:234–7;

discussion 37.

15. Patel NK, Plaha P, Gill SS. Magnetic resonance

imaging-directed method for functional neurosurgery using

implantable guide tubes. Neurosurgery 2007;61:358–65; dis-

cussion 65–6.

16. Zrinzo L, Zrinzo LV, Tisch S, et al. Stereotactic localization of

the human pedunculopontine nucleus: atlas-based coordi-

nates and validation of a magnetic resonance imaging protocol

for direct localization. Brain 2008;131:1588–98.

17. Mazzone P, Sposato S, Insola A, Dilazzaro V, Scarnati E.

Stereotactic surgery of nucleus tegmenti pedunculopontine

[corrected]. Br J Neurosurg 2008;22(Suppl 1):S33–40.

18. Langston JW, Widner H, Goetz CG, et al. Core assessment

program for intracerebral transplantations (CAPIT). Mov

Disord 1992;7:2–13.

19. Ferraye MU, Gerardin P, Debu B, et al. Pedunculopontine

nucleus stimulation induces monocular oscillopsia. J Neurol


20. Monge A, Viselli F, Stocchi F, et al. Variation in the

dopaminergic response during the day in Parkinson disease.

Clin Neuropharmacol 2004;27:116–8.

21. Wright WG, Gurfinkel VS, Nutt J, Horak FB, Cordo PJ. Axial

hypertonicity in Parkinson’s disease: direct measurements of

trunk and hip torque. Exp Neurol 2007;208:38–46.

22. Tinetti ME. Performance-oriented assessment of mobility

problems in elderly patients. J Am Geriatr Soc 1986;34:

119–26.

23. Moreau C, Defebvre L, Destee A, et al. STN-DBS frequency

effects on freezing of gait in advanced Parkinson disease.

Neurology 2008;71:80–4.

24. Bruno RM, Sakmann B. Cortex is driven by weak but

synchronously active thalamocortical synapses. Science

2006;312:1622–7.

25. Schoffelen JM, Oostenveld R, Fries P. Neuronal coherence as

a mechanism of effective corticospinal interaction. Science

2005;308:111–3.

26. Brown P, Marsden CD. What do the basal ganglia do? Lancet

1998;351:1801–4.

27. Gilbertson T, Lalo E, Doyle L, et al. Existing motor state is

favored at the expense of new movement during 13–35 Hz

oscillatory synchrony in the human corticospinal system. J

Neurosci 2005;25:7771–9.

28. Cassidy M, Mazzone P, Oliviero A, et al. Movement-related

changes in synchronization in the human basal ganglia. Brain

2002;125:1235–46.

29. Williams D, Tijssen M, Van Bruggen G, et al. Dopamine-

dependent changes in the functional connectivity between

basal ganglia and cerebral cortex in humans. Brain

2002;125:1558–69.

30. Womelsdorf T, Schoffelen JM, Oostenveld R, et al. Modula-

tion of neuronal interactions through neuronal synchroniza-

tion. Science 2007;316:1609–12.

31. Plaha P, Filipovic S, Gill SS. Induction of parkinsonian resting

tremor by stimulation of the caudal zona incerta nucleus: a

clinical study. J Neurol Neurosurg Psychiatry 2007;133: 205–14.

32. Brown P, Williams D. Basal ganglia local field potential

activity: character and functional significance in the human.

Clin Neurophysiol 2005;116:2510–9.

33. Hammond C, Bergman H, Brown P. Pathological synchroni-

zation in Parkinson’s disease: networks, models and treat-

ments. Trends Neurosci 2007;30:357–64.

34. Allert N, Volkmann J, Dotse S, et al. Effects of bilateral

pallidal or subthalamic stimulation on gait in advanced

Parkinson’s disease. Mov Disord 2001;16:1076–85.

35. Rodriguez-Oroz MC, Obeso JA, Lang AE, et al. Bilateral deep

brain stimulation in Parkinson’s disease: a multicentre study

with 4 years follow-up. Brain 2005;128:2240–9.

36. Bohnen NI, Muller ML, Koeppe RA, et al. History of falls in

Parkinson disease is associated with reduced cholinergic

activity. Neurology 2009;73:1670–6.

37. Jellinger K. The pedunculopontine nucleus in Parkinson’s

disease, progressive supranuclear palsy and Alzheimer’s

disease. J Neurol Neurosurg Psychiatry 1988;51:540–3.

38. Asahina M, Suhara T, Shinotoh H, et al. Brain muscarinic

receptors in progressive supranuclear palsy and Parkinson’s

disease: a positron emission tomographic study. J Neurol


39. Hausdorff JM, Doniger GM, Springer S, et al. A common

cognitive profile in elderly fallers and in patients with

Parkinson’s disease: the prominence of impaired executive

function and attention. Exp Aging Res 2006;32:411–29.

40. Garcia-Rill E, Skinner RD, Miyazato H, Homma Y.

Pedunculopontine stimulation induces prolonged activation

of pontine reticular neurons. Neuroscience 2001;104:455–65.

280 S. Khan et al.

Br

J N

euro

surg

201

1.25

:273

-280

.D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Mel

bour

ne o

n 09

/16/

13. F

or p

erso

nal u

se o

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outcomes from stimulation of the caudal zona incerta and pedunculopontine nucleus in patients with...

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