Pallidal stimulation as treatment for camptocormia in Parkinson’s disease

Abstract

Camptocormia is a common and often debilitating postural deformity in Parkinson’s disease (PD). Few treatments are currently effective. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) shows potential in treating camptocormia, but evidence remains limited to case reports. We herein investigate the effect of GPi-DBS for treating camptocormia in a retrospective PD cohort. Thirty-six consecutive PD patients who underwent GPi-DBS were reviewed. The total and upper camptocormia angles (TCC and UCC angles) derived from video recordings of patients who received GPi-DBS were used to compare camptocormia alterations. Correlation analysis was performed to identify factors associated with the postoperative improvements. DBS lead placement and the impact of stimulation were analyzed using Lead-DBS software. Eleven patients manifested pre-surgical camptocormia: seven had lower camptocormia (TCC angles ≥ 30°; TCC-camptocormia), three had upper camptocormia (UCC angles ≥ 45°; UCC-camptocormia), and one had both. Mean follow-up time was 7.3 ± 3.3 months. GPi-DBS improved TCC-camptocormia by 40.4% (angles from 39.1° ± 10.1° to 23.3° ± 8.1°, p = 0.017) and UCC-camptocormia by 22.8% (angles from 50.5° ± 2.6° to 39.0° ± 6.7°, p = 0.012). Improvement in TCC angle was positively associated with pre-surgical TCC angles, levodopa responsiveness of the TCC angle, and structural connectivity from volume of tissue activated to somatosensory cortex. Greater improvement in UCC angles was seen in patients with larger pre-surgical UCC angles. Our study demonstrates potential effectiveness of GPi-DBS for treating camptocormia in PD patients. Future controlled studies with larger numbers of patients with PD-related camptocormia should extend our findings.

Full text

ARTICLE OPEN
Pallidal stimulation as treatment for camptocormia in
Parkinson’s disease
Yijie Lai
1
, Yunhai Song
1,2
, Daoqing Su
3
, Linbin Wang
1
, Chencheng Zhang
1
, Bomin Sun
1
, Jorik Nonnekes
4
, Bastiaan R. Bloem
5
and
Dianyou Li
1
✉
Camptocormia is a common and often debilitating postural deformity in Parkinson’s disease (PD). Few treatments are currently
effective. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) shows potential in treating camptocormia, but evidence
remains limited to case reports. We herein investigate the effect of GPi-DBS for treating camptocormia in a retrospective PD cohort.
Thirty-six consecutive PD patients who underwent GPi-DBS were reviewed. The total and upper camptocormia angles (TCC and
UCC angles) derived from video recordings of patients who received GPi-DBS were used to compare camptocormia alterations.
Correlation analysis was performed to identify factors associated with the postoperative improvements. DBS lead placement and
the impact of stimulation were analyzed using Lead-DBS software. Eleven patients manifested pre-surgical camptocormia: seven
had lower camptocormia (TCC angles ≥30°; TCC-camptocormia), three had upper camptocormia (UCC angles ≥45°; UCC-
camptocormia), and one had both. Mean follow-up time was 7.3 ± 3.3 months. GPi-DBS improved TCC-camptocormia by 40.4%
(angles from 39.1° ± 10.1° to 23.3° ± 8.1°, p=0.017) and UCC-camptocormia by 22.8% (angles from 50.5° ± 2.6° to 39.0° ± 6.7°,
p=0.012). Improvement in TCC angle was positively associated with pre-surgical TCC angles, levodopa responsiveness of the TCC
angle, and structural connectivity from volume of tissue activated to somatosensory cortex. Greater improvement in UCC angles
was seen in patients with larger pre-surgical UCC angles. Our study demonstrates potential effectiveness of GPi-DBS for treating
camptocormia in PD patients. Future controlled studies with larger numbers of patients with PD-related camptocormia should
extend our findings.
npj Parkinson’s Disease (2021) 7:8 ; https://doi.org/10.1038/s41531-020-00151-w
INTRODUCTION
Camptocormia, an abnormal uncontrollable forward flexion of the
spine while standing or walking, is a common type of postural
deformity with an overall incidence of 5–19% in patients with
Parkinson’s disease (PD)
1–3
. This deformity is often debilitating and
can hinder patients during walking or performing activities of daily
living
4
. Currently, few treatments are available for camptocormia in
PD. Levodopa or botulinum toxin injection may be partially
effective but the efficacy varies, and the majority of the patients
are not helped satisfactorily by these approaches
1,2
. Dopamine
agonists can even aggravate or induce camptocormia
2,5
.
In recent years, deep brain stimulation (DBS) has attracted
increasing attention as a potential treatment of postural
deformities in PD patients. Subthalamic nucleus (STN) and globus
pallidus internus (GPi) are the two main targets of DBS for PD
6
.
Various studies have reported the clinical effectiveness of STN-DBS
in treating PD postural deformities. Recently, results from studies
with large sample sizes showed that STN-DBS had a relatively
small but significant therapeutic effect on abnormal posture
7,8
and
could especially bring about large improvement to those who
were complicated with camptocormia
9
. Based on its efficacy in the
treatment of primary dystonia, GPi-DBS has also been proposed to
be effective for dystonic posture in PD
10
. However, compared to
STN-DBS, the evidence for any efficacy of GPi-DBS for treating
PD-related camptocormia has been limited to case reports with
incongruent results
4,11–13
. Besides, the methods for measuring
postural deformities varied between studies and the international
consensus for determining patients’flexion angle was not reached
until recently
3,9,14
. Larger studies with consensus-based methods
are therefore required to determine the effectiveness of GPi-DBS
on camptocormia in PD patients.
Here we report the effectiveness of GPi-DBS on camptocormia
in patients with PD based on a retrospective cohort of thirty-six
consecutive subjects who underwent GPi-DBS. The effect of pre-
surgical medication on total camptocormia or upper camptocor-
mia (TCC/UCC) angles, as defined in the recent consensus for the
measurement of the camptocormia angle
3
, was investigated by
comparing the angles during the medication-OFF state (med-OFF)
with angles during the medication-ON state (med-ON) before
surgery. The benefit of DBS surgery was determined by comparing
these angles during the pre-surgical med-OFF state with the
angles during post-surgical med-OFF and stimulation-ON (med-
OFF/DBS-ON) state. We also looked for factors that were
potentially associated with post-surgical camptocormia angle
improvements.
RESULTS
Characteristics of included patients
Thirty-six consecutive patients were included in this retrospective
study. The demographical data are presented in Table 1and the
results of motor assessment are presented in Table 2. Eleven
1
Center for Functional Neurosurgery, Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2
Neurosurgery
Department, Shanghai Children’s Medical Center Affiliated to the Medical School of Shanghai Jiao Tong University, Shanghai, China.
3
Department of Neurosurgery, Liaocheng
People’s Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, China.
4
Department of Rehabilitation, Radboud University Medical Center,
Donders Institute for Brain Cognition and Behavior, Nijmegen, The Netherlands.
5
Department of Neurology, Radboud University Medical Center, Donders Institute for Brain
Cognition and Behavior, Nijmegen, The Netherlands. ✉email: ldy11483@rjh.com.cn
www.nature.com/npjparkd
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(30.6%) of these 36 patients had camptocormia, in whom 7
(19.4%) patients were diagnosed with TCC-camptocormia (or
lower camptocormia) as presenting with a TCC angle of ≥30° and
3 (8.3%) patients were diagnosed with UCC-camptocormia (or
UCC) as presenting with a UCC angle of ≥45°. One (2.8%) patient
presented with both TCC-camptocormia and UCC-camptocormia.
Effect of levodopa treatment on posture angles in the overall
population and in patients with/without camptocormia
Pre-surgically, small but significant improvement was observed in
the TCC angles (from 21.7° ± 11.6° to 18.4° ± 8.3°, p=0.0185) and
the UCC angles (from 36.4° ± 7.1° to 33.4° ± 5.6°, p=0.0012) in
response to levodopa treatment (Fig. 1). In patients with TCC-
camptocormia, both the TCC angles (from 39.1° ± 10.1° to 27.8° ±
8.3°, p=0.0566) and the UCC angles (from 38.2° ± 9.2° to 34.0° ±
7.1°, p=0.0905) showed a nonsignificant reduction after admin-
istration of levodopa. In patients with UCC-camptocormia, a
significant improvement was seen in the UCC angles (from 50.5° ±
2.6° to 36.3° ± 8.5°, p=0.0317) but not with the TCC angles (from
25.4° ± 5.7° to 22.7° ± 9.1°, p=0.4114). In patients without
camptocormia, improvement in the TCC angles (from 15.9° ± 5.4°
to 14.9° ± 5.1°, p=0.0689) was not significant, whereas a small but
significant reduction was seen in the UCC angles (from 34.2° ± 4.5°
to 32.8° ± 4.5°, p=0.0032).
Effect of GPi-DBS on posture angles in the overall population and
in patients with/without camptocormia
At a mean follow-up of 7.3 ± 3.3 months, both the TCC angles
(from 21.7° ± 11.6° to 18.8° ± 7.1°; p=0.0976; Fig. 1a) and the UCC
angles (from 36.4° ± 7.1° to 35.4° ± 7.1° (p=0.4198; Fig. 1b)
showed a nonsignificant decrease in all patients treated with
bilateral GPi-DBS. In patients with TCC-camptocormia, the TCC
angles significantly decreased from 39.1° ± 10.1° to 23.3° ± 8.2°
(p=0.0168; Fig. 2a), whereas no significant improvement was
seen in the UCC angles (from 38.2° ± 9.2° to 40.4° ± 8.5° p=0.3715;
Fig. 2b); in the UCC-camptocormia group, significant improvement
was seen in the UCC angles (50.5° ± 2.6° to 39.0° ± 6.7°, p=0.0124;
Fig. 2b) but not in the TCC angles (from 25.4° ± 5.7° to 17.6° ± 2.2°,
p=0.1073; Fig. 2a); in patients without camptocormia, a slight but
significant deterioration was seen in the TCC angles (from 15.9° ±
5.4° to 17.3° ± 6.6°, p=0.0308; Fig. 2a), whereas a nonsignificant
improvement was found in the UCC angles (from 34.2° ± 4.5° to
33.5° ± 5.9°, p=0.6261; Fig. 2b). In addition, the levodopa
equivalent daily dosage (LEDD) significantly decreased from
675.1 ± 275.3 mg to 534.0 ± 221.7 mg (p< 0.001) after surgery in
the whole population.
Factors associated with DBS effectiveness
In the univariate analysis of the whole population, greater
improvement in the TCC angles was found in patients with larger
pre-surgical TCC angles during the med-OFF state (p=0.0001;
Fig. 3a) and better levodopa responsiveness of the TCC angle (p=
0.0043; Fig. 3b); improvement of the UCC angles were positively
Table 1. Characteristics of included patients.
Characteristics Value
n36
Age at surgery (years) 63.7 ± 8.6
Gender 15 F/21 M
Age at PD onset 52.9 ± 9.2
Duration of PD (years) 10.8 ± 4.4
Follow-up time (months) 7.3 ± 3.3
LEDD (mg) 675.1 ± 275.3
Stimulation parameters
Amplitudes (V) L 3.1 ± 0.5/R 3.0 ± 0.6
Frequency (Hz) L 134.1 ± 30.5/R 134.9 ± 30.6
Pulse width (μsec) L 71.3 ± 13.0/R 72.3 ± 12.7
Table 2. Pre-surgical examinations at med-OFF state.
Items Overall Without CC TCC-CC UCC-CC
n36 25 8 4
MDS-UPDRS III
Total 54.0 ± 18.3 49.5 ± 16.0 69.9 ± 19.2 48.8 ± 11.7
Tremor 7.1 ± 5.9 6.6 ± 5.8 9.5 ± 5.5 5.8 ± 6.8
Rigidity 11.7 ± 5.3 11.1 ± 5.0 14.8 ± 5.8 8.0 ± 3.9
Bradykinesia 24.6 ± 8.6 22.5 ± 8.3 31.3 ± 7.1 24.0 ± 6.5
Axial 10.6 ± 4.7 9.2 ± 4.2 14.4 ± 5.4 11.0 ± 3.2
Posture 2.1 ± 1.3 1.6 ± 1.3 3.3 ± 0.7 2.8 ± 0.5
Camptocormia angles
TCC angle 21.7 ± 11.6 15.9 ± 5.4 39.1 ± 10.1 25.4 ± 5.7
UCC angle 36.4 ± 7.1 34.2 ± 4.5 38.2 ± 9.2 50.5 ± 2.6
TCC-camptocormia 7 0 7 –
UCC-
camptocormia
30 –3
Both camptocormia
a
10 11
TCC total camptocormia angle, TCC-camptocormia group of patients with a
clinically diagnosed camptocormia as defined by a TCC angle ≥30°, UCC
upper camptocormia angle, UCC-camptocormia group of patients with a
clinically diagnosed camptocormia as defined by a UCC angle ≥45°.
a
Both camptocormia means presenting with both TCC- and UCC-
camptocormia.
Fig. 1 Effect of levodopa and surgery on camptocormia angles in
the whole population. Pre- and post-surgical total- (a) and upper (b)
camptocormia angles (TCC/UCC angles) were shown for individual
PD patient. *p< 0.05; **p< 0.01; n.s.: not significant.
Y. Lai et al.
2
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correlated with pre-surgical UCC angles (p=0.0065; Fig. 3c). No
significant correlation was found between percent improvement
of TCC/UCC angles after surgery and the rest of the variables,
including age at surgery, duration of PD, length of follow-up,
baseline Movement Disorder Society-Sponsored Revision of the
Unified Parkinson’s Disease Motion Assessment Scale Part III (MDS-
UPDRS-III) total scores, percent improvement in MDS-UPDRS-III
total scores in response to levodopa and levodopa responsiveness
of the UCC angle (all ps > 0.05). In addition, in patients presented
with TCC-camptocormia, values of pre-surgical TCC/UCC angles or
levodopa responsiveness of TCC/UCC angles were not significantly
correlated with the post-surgical improvements in TCC/UCC
angles (all ps > 0.05). In the multivariate analysis incorporating
aforementioned variables, pre-surgical TCC angles (β=0.61,
p=0.0020) were identified as the independent predictor of
post-surgical improvement in the TCC angles, whereas none of the
rest of the variables remained predictive of the TCC/UCC angle
improvements (all ps > 0.05).
To investigate the impact of different stimulation parameters on
the outcome of GPi-DBS, a total of 28 patients (10 in 11
camptocormia patients) with available imaging and stimulation
data were analyzed to reconstruct the location of DBS electrodes
and model the stimulation impact. No significant outliers among
the electrodes were identified through the manual examination
(Fig. 4). In volume of tissue activated (VTA) analysis, although
significant correlation was found between VTA overlap with GPi
and percent improvements in axial subscores (R=0.38, p=
0.0300; Fig. 5a), improvements in the TCC/UCC angles were not
correlated with the volume of VTA intersection with GPi (all p>
0.05; Fig. 5b, c). By analyzing the possible fibers traversing through
the VTA and projected to the volumetric space of the vast brain
areas, we found the structural connectivity from VTA to right
somatosensory cortex (S1) was significantly correlated with
improvements in TCC angles (R=0.39, p=0.0380; Fig. 6).
DISCUSSION
This cohort study focused on the effectiveness of GPi-DBS for
treating postural deformities in PD patients and its possible
predictors. Pre-surgically, levodopa provided a small but significant
Fig. 2 Improvements in camptocormia angles after surgery.
Colored dots represent pre- and post-surgical total (a) and upper
(b) camptocormia angles (TCC/UCC angles) in patients with lower
camptocormia (blue symbols and lines), upper camptocormia (red
symbols and lines) and without camptocormia (green symbols and
lines). *p< 0.05; n.s.: not significant.
Fig. 3 Relation between improvement in camptocormia angles and clinical variables. The improvement in TCC angles was significantly
correlated with pre-surgical values of TCC angles (a) and its responsiveness to levodopa (b); improvement in UCC angles was found correlated
with pre-surgical UCC angles. Gray areas represent the 95% CI. PD: Parkinson’s disease; TCC: total camptocormia; UCC: upper camptocormia;
pre-surg: pre-surgical.
Fig. 4 Reconstruction of the DBS electrodes. The electrodes of 10
patients with camptocormia (marked in orange) and 18 patients
without camptorcormia (maked in blue) were shown on the T1-
weighted Montreal Neurological Institute (MNI) template. Active
contacts were marked in red. Masses with yellow described the
location of the STN, red for the red nucleus, and green for the GPi.
Y. Lai et al.
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improvement of bending angles in the whole population of PD
patients, with an approximately equal effect on the measurement
of TCC and UCC angles. The follow-up results showed that GPi-DBS
can significantly improve postural alignments in PD patients with
camptocormia, and the correlation analysis suggests that patients
with larger pre-surgical TCC/UCC angles, better levodopa respon-
siveness of the TCC angle and higher connectivity from VTA to
right S1 cortex could possibly gain greater benefits following
surgery. These findings add to and extends previously published
data in the aspect of clinical effectiveness and candidate selection
of GPi-DBS for the treatment of camptocormia in PD
15,16
.
The effect of GPi-DBS on camptocormia could be described as a
mean of 40.4% improvement seen for TCC-camptocormia and 22.8%
for UCC-camptocormia; this marked improvement (around 16° in TCC
and 11° in UCC on average) in patients with severe postural
deformities showed important clinical utility (an example of patient
with TCC-camptocormia before and after surgery can be seen in
Fig. 7). This beneficial effect were comparable with previous reports
on the treatment effect of GPi-DBS for PD-related camptocormia: in
2005, Micheli et al.
11
reported a sustained improvement in
camptocormia 6 months after GPi-DBS in a 62-year-old man with
early PD symptoms; a 33% reduction in the Burke–Fahn–Marsden
motor trunk subscore was observed 36 months after surgery in a
patient with PD-related camptocormia
17
; Thani et al.
13
utilized high-
frequency neuromodulation of the GPi to successfully achieve relief
of camptocormia in a 57-year-old womanwithPD.However,despite
a number of successful cases, treatment failure was also reported: in
a patient whose camptocormia only minimally responded to
dopaminergic medications, the immediate post-surgical alleviation
after bilateral GPi-DBS did not sustained at the longer follow-up
(15 months)
4
. In our study, improvements in the TCC/UCC angles
ranged from −0.3% to 69.6% (mean 33.4%) in the subgroup of 11
patients with camptocormia, and similarly, a wide range of post-
surgical improvements was also seen in the whole population. These
findings suggest that the therapeutic effect of DBS on postural
abnormalities could be promisingingeneral,buttheoutcomemay
differ from person to person.
To date, much of the knowledge about the factors influencing
the effectiveness of DBS on camptocormia were from studies on
STN-DBS
7,9,18
. In 2018, a meta-analysis pooled the efficacy measures
of five bilateral STN-DBS studies with an overall decrease in the
mean sagittal plane bending angles from 56.6° ± 5.1° to 38.4° ± 6.6°
after surgery and proposed duration of camptocormia of 2 years or
less as predictive of better outcomes
9
.However,duetothe
retrospective nature of our study, we were not able to include
duration of camptocormia as a covariate because the accurate time
of camptocormia onset could not be retrieved
19
. Instead, we
investigated the impact of PD disease duration on surgery outcome
and found it was not correlated with the treatment effect of GPi-
DBS. Preoperative levodopa responsiveness was another important
factor suggested to be predictive of DBS effect on camptocor-
mia
7,18
, although, as discussed in previous literature, the correlation
between preoperative levodopa responsiveness and benefitfrom
STN-DBS may be the result of methods used in statistical analysis
and was not always congruent between studies
19–22
.Inour
univariate analysis of factors associated with improvements in
camptocormia angles, the results showed that levodopa respon-
siveness of the TCC angle was positively correlated to DBS benefit.
This suggests that the occurrence of camptocormia could be a type
of off-period dystonia, in which favorable outcomes after DBS can
be expected
18
. However, the above association found in our study
still needs further validation as it did not reach significance in the
following multivariate analysis. In both the univariate and multi-
variate analysis, larger pre-surgical TCC angles were suggested to
predict higher post-surgical improvements. Similar findings were
also reported in STN-DBS, which showed that patients with
camptocormia were more likely to have a substantial improvement
Fig. 5 Correlation between percentage of VTA overlap with GPi and outcomes. The overlap volume significantly correlated with
improvements in subscores for axial symptoms (a), but not with improvements in TCC angles (b) and UCC angles (c). Gray areas represent the
95% CI. PD: Parkinson’s disease; VTA: volume of tissue activated; TCC: total camptocormia; UCC: upper camptocormia.
Fig. 6 Significant correlation was found between structural
connectivity from VTA to right S1 and percent improvement in
TCC angles. Gray areas represent the 95% CI. PD: Parkinson’s
disease; S1: somatosensory cortex; PD: Parkinson’s disease; TCC: total
camptocormia; UCC: upper camptocormia.
Y. Lai et al.
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after STN-DBS compared to those with normal camptocormia
angles
8
.Thesefindings suggest that patients with better respon-
siveness to levodopa can be expected to gain larger improvements
after DBS and camptocormia should not be a contraindication for
DBS, but it might even benefit from the surgery.
It is important to note that, unlike tremor and rigidity, which are
supposed to improve within minutes to hours, axial symptoms,
such as postural abnormalities, usually require days and even
months to improve after electrodes were turned on
23
.Asa
consequence, repeat programming is expected in order to achieve
optimal relief and the stimulation parameters could therefore be
highly influential in improvements in postural alignments
23
.
However, despite brief documentation of stimulation parameters
in some of the studies, few researchers investigated the effect of
different sets of stimulation parameters on camptocormia
7,18
.
Through the stimulation analysis, we modeled the effect of various
stimulation settings on local regions. When correlating stimulation
volume on GPi to clinical outcomes, in contrast to the axial
subscore improvements, the overlap volume of VTA with GPi was
not found significantly associated with improvement in campto-
cormia angles, which resembles recent findings that suggest the
volume of VTA-GPi overlap may not positively related to outcomes
of pallidal stimulation in dystonic symptoms
24
. Aside from its local
effects on stimulated brain targets, DBS is also proposed to exert
its therapeutic effect by modulating remote structures and the
distributed brain networks
25
. In connectivity analysis, we found
that the structural connectivity from VTA to right somatosensory
cortex was significantly correlated with improvements in TCC
angles, suggesting the role of somatosensory cortex and
proprioceptive integration in mediating the effect of DBS
treatment for camptocormia. In previous studies, proprioceptive
disintegration was found highly related to postural deformities in
PD and in patients with camptocormia
26,27
. Although the
pathophysiology of camptocormia remains unclear, our findings
indirectly lend support to the theory that postural control could
require a complex system involving the integration of vestibular,
visual, and proprioceptive sensory information
26
.
At the time of the study, there was no strong evidence for the
superiority of STN-DBS over the GPi-DBS, or vice versa
28
. In our
study, camptocormia was not the primary indication for surgery.
The main motivation of choosing GPi as the preferred target was
based on the concern of a possible cognitive impact of STN-DBS
and also, due to the relatively low doses of levodopa administra-
tion in our current cohort (mean LEDD of 675.1 mg, 31 patients
<1000 mg), the benefit of reducing medications, which is a key
advantage for STN-DBS, was not a top priority
28,29
. Additional
considerations were the need for less intensive monitoring of
medication and stimulation adjustments, as previously suggested
for most patients received GPi-DBS
29,30
. Therefore, the selection of
the GPi as target was largely a pragmatic one. According to
previous systematic reviews, there was also not enough evidence
to adequately compare STN and GPi as the target for parkinsonian
camptocormia or any of the postural deformities, e.g., Pisa
syndrome and anterocollis, particularly because of the relatively
small sample sizes
9,15
. Although compared to STN-DBS, impressive
outcome (improvement of 50–100%) was seen in patients with
dystonic camptocormia after GPi-DBS, this finding may not be
easily replicated in PD, as dystonic camptocormia patients were
younger, had shorter disease duration, and longer camptocormia
duration
15
. Studies utilizing randomized designs are now required
to provide stronger evidence for optimal target selection
8
.
There are several limitations of our study. First, the length of
follow-up in the overall population was restricted to within
12 months after surgery. Though this narrowed follow-up period
was adopted to prevent substantial disease progression during
the study, it may not allow full improvement in dystonic
symptoms, which can sometimes take months after optimal
settings are found
23,31
. Also, as there are studies indicating that
DBS might lost its initial beneficial effect at long term
4,22
,
longitudinal studies with repeated assessments at longer follow-
ups, e.g., 5 years post surgery, were needed to assess the effect of
DBS on camptocormia taking the fact of disease progression into
consideration
32
. Second, due to the potential for overfitting of the
data, the relatively small number of participants limited our power
in making inference based on the multivariate analysis
33
. Also, the
mere four patients presented with UCC-camptocormia makes it
difficult to draw firm conclusion on the effect of GPi-DBS in
patients with UCC-camptocormia. To deal with this issue, multi-
center studies could be expected for not only enlarging the
sample size but also contributing in validating the reproducibility
of results across datasets. Third, our study was retrospective in
nature. Prospective and controlled studies therefore remain useful
in investigating other predictive factors, including the duration of
camptocormia
19
and features in the electromyogram recordings
of flexor and extensor muscles of the trunk
34
.
Our study demonstrates effectiveness of GPi-DBS in improving
camptocormia in PD patients. Specifically, patients present with
larger pre-surgical TCC/UCC angles, better pre-surgical respon-
siveness of TCC angles to levodopa, and higher VTA to
S1 structural connectivity may experience larger improvement in
Fig. 7 Measurement of the camptocormia angles angle in a
patient with TCC-camptocormia pre- and post surgery. a Pre-
surgical UCC angle; bUCC angle at 12 month post-surgery; cpost-
surgical TCC angle; dTCC angle at 12 months post-surgery. Written
consent was obtained for publication of the photographs. C7:
spinous process of vertebra C7; L5: suspected location of the
spinous process of vertebra L5; LM: lateral malleolus; FC: vertebral
fulcrum, the point with the greatest distance from the spine.
Y. Lai et al.
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posture. These findings suggest that camptocormia should not be
a contraindication for DBS, but it might even improve following
GPi-DBS. Further randomized controlled studies with repeat
measurement and multicenter data could help determine the
long-term effects of DBS, identify predictors of outcome, and
validate the reproducibility of results across datasets.
METHODS
This study has been carried out in accordance with The Code of Ethics of
the World Medical Association (Declaration of Helsinki). The ethics
committee of the Ruijin Hospital Shanghai Jiao Tong University School
of Medicine approved this retrospective clinical research. Written informed
consent was obtained from all patients. The authors affirm that human
research participants provided informed consent, for publication of the
images in Fig. 7.
Study population
PD patients who were treated with bilateral GPi-DBS at Ruijin Hospital from
January 2017 to January 2019 with video-taped pre- and post-surgical
assessments were retrospectively analyzed. A lateral view was obtained
from the video for each assessed condition.
Inclusion and exclusion criteria
The inclusion criteria were as follows: (a) PD in Hoehn and Yahr stages 2–4,
(b) 40–75 years old, (c) available video-taped motor examinations for pre-
surgical (med-ON and med-OFF) and post-surgical (med-OFF/DBS-ON)
conditions within 1-year follow-up after surgery, and (d) bilateral GPi- DBS
treatment.
The exclusion criteria were as follows: (a) other neurological disease or
injuries which could affect gait and posture, (b) history of lesions or DBS of
other brain targets or spinal surgery, (c) severe orthopedic spine injuries or
diseases (such as vertebral fracture, severe osteoporosis, Pott’s disease,
etc.), and (d) postural abnormalities caused by trauma or disease after DBS.
Surgical procedure
Preoperatively, the location of the GPi was determined using a stereotactic
computed tomography (CT) scan [with the Leksell (Elekta, Inc.) head frame]
coregistered to high-resolution 3.0 T T1- and T2-weighted magnetic
resonance imaging (MRI) images with Leksell SurgiPlan (Elekta, Stockholm,
Sweden). In general, the target was defined directly under the guidance of
coregistered image and the location was about 2–4mm anterior to the
midpoint of the anterior commissure–posterior commissure line (AC–PC),
18–22 mm lateral to the AC–PC line, and 2–4 mm below the AC–PC line. The
procedure was performed under general anesthesia. After confirmation of
location of the electrodes (Model 3387, Medtronic, Inc., Minneapolis, MN,
USA; or Model L302, PINS, Inc., Beijing, China) with intraoperative CT, the
impulse generator was implanted. A CT or MRI scan was performed 1 week
after the surgery to confirm the location of the electrodes.
Symptom assessment and computational methods
Pre-surgical evaluation was conducted 1–2 days before surgery and post-
surgical evaluation was conducted during the corresponding follow-ups.
The length of follow-up was restricted to within 12 months after surgery
(median: 6 months; range: 1–12 months), during which a marked disease
progression was unlikely to happen.
Posture analysis. Based on the method recommended in the consensus
statement by Margraf et al.
3
, postural angles were determined by two
blinded physicians with an analysis of lateral view pictures of each patient
standing still with the camera lens at approximately waist level;
discrepancies were solved during a consensus meeting. The photographs
were marked as follows
3
: C7 (spinous process of vertebra C7), L5
(suspected location of the spinous process of vertebra L5), LM (lateral
malleolus), and FC (vertebral fulcrum, the point with the greatest distance
from the spine).
According to the above points, the camptocormia angles were
calculated as follows: (a) TCC angle =the angle between the line from
the LM to L5 and the line between L5 and C7, (b) UCC angle =the angle
between the line from L5 to FC and the line from FC to C7. An online tool
was used to calculate the angles (https://www.neurologie.uni-kiel.de/de/
axial-posturale-stoerungen/camptoapp)
3
. Using the cut-off for severity of
postural angles in previous studies (TCC angle ≥30° for lower campto-
cormia, or TCC-camptocormia and UCC angle ≥45° for UCC or UCC-
camptocormia)
3,14
, whether TCC-camptocormia or UCC-camptocormia was
present was determined. In addition, a clinical posture score using the item
“posture”in the MDS-UPDRS-III was obtained.
Motor examination: MDS-UPDRS-III was used to assess the patients’
motor symptoms. Preoperatively, the evaluation was carried out in med-
OFF state (12 hours’discontinuation of levodopa and 72 h of other anti-
Parkinson medication) and med-ON state (1.5 times routine drug use and
45 min after administration); after surgery, the evaluation was carried out
at med-OFF/DBS-ON state.
Collection of clinical information: Age at surgery, gender, duration of
PD, medication, stimulation parameters, and other medical histories were
collected.
Based on the postoperative CT or MRI images: Position of the electrodes
in the nucleus was reconstructed using the lead-DBS toolbox (version 2.2.3)
on Matlab according to the methods described by Horn et al.
35
.TheVTAwas
estimated with Lead-DBS based on finite element models. Conductivity
values for white matter were set to 0.14S/mm and for gray matter to 0.33 S/
mm. Thresholding of the potential gradient at 0.2 V/mm then determined
activated tissue
36
. GPi were located on the DISTAL atlas, as this atlas was
designed for surgical targets in basal ganglia and was proved to be of high
accuracy of localization
37
. Overlaps between VTAs and the GPi were
calculated for both hemispheres and summed up and normalized with the
total volume of GPi. For structural connectivity, the normative group
connectome from 32 subjects of the Human Connectome Project at
Massachusetts General Hospital (https://ida.loni.usc.edu/login.jsp) was used.
These data were acquired on a specially designed MRI scanner with more
powerful gradients than available on conventional MRI scanners. The
processing steps were described previously
36
. In each subject, 200,000 fibers
were sampled and transformed into MNI space. Structural connectivity was
calculated as fibers traversing through the VTA and projected to the
volumetric space of the brain in 2 mm isotropic resolution, denoting the
portion of fibers (connected to the VTA) that traversed through each
voxel
35,36
. Parcellation of motor cortices was based on the Human Motor
Area Template atlas, in which primary motor cortex (M1), somatosensory
cortex (S1), supplementary motor area (SMA), pre-SMA, lateral premotor
cortex along the dorsal and ventral plane (PMd and PMv) were defined
38
.
Statistical analysis
Data were described using means and SDs for continuous variables and
frequencies for categorical variables. A two-tailed paired t-test was used to
analyze the changes in TCC and UCC angles before and after operation.
Univariate and multivariate analysis were used to evaluate the association
between clinical/demographic characteristics and the extent of the effect
of GPi-DBS on camptocormia angles, which was measured using the
percentage changes (pre-surgical med-OFF vs. post-surgical med-OFF/DBS-
ON evaluation) of the TCC and UCC angles. Age at surgery, gender,
duration of PD, follow-up time, pre-surgical motor score (MDS-UPDRS-III) at
med-OFF, relative response to levodopa in motor score, and TCC/UCC
angles (pre-surgical med-OFF vs. pre-surgical med-ON evaluation) were
explored as covariates of interest. Two-sided p-values < 0.05 were
considered significant. STATA 14.0 was used to analyze the data.
Reporting summary
Further information on research design is available in the Nature Research
Reporting Summary linked to this article.
DATA AVAILABILITY
The data that support the findings of this study are available from the corresponding
author upon reasonable request.
Received: 26 June 2020; Accepted: 8 December 2020;
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ACKNOWLEDGEMENTS
B.S. received research support from DBS industry SceneRay and PINS (donated
devices); D.L. and C.Z. received honoraria and travel expenses from Medtronic,
SceneRay, and PINS. B.R.B. currently serves as co-Editor in Chief for the Journal of
Parkinson’s Disease; serves on the editorial board of Practical Neurology; has received
honoraria for serving on the scientific advisory board for Abbvie, Biogen, and UCB;
has received fees for speaking at conferences from AbbVie, Zambon, and Bial; and
has received research support from the Netherlands Organization for Scientific
Research, the Michael J Fox Foundation, UCB, Abbvie, the Stichting Parkinson Fonds,
the Hersenstichting Nederland, the Parkinson’s Foundation, Verily Life Sciences,
Horizon 2020, the Topsector Life Sciences and Health, and the Parkinson Vereniging.
Other authors report no disclosures. This study was supported by the grant from the
National Natural Science Foundation of China (81971294).
AUTHOR CONTRIBUTIONS
D.L., Y.L., and Y.S. conceived the study, collected and interpreted the data, and wrote
the manuscript. B.R.B. and J.S. conceived the study, interpreted the data, and
contributed to writing of the manuscript. Y.L. and Y.S. did statistical analysis and
visualization. D.L., D.S., and B.S. did the surgery. All authors contribut ed to data
collection and critical revision of the manuscript. Y.L. and Y.S. contributed equally as
first authors.
COMPETING INTERESTS
The authors declare no competing interests.
ADDITIONAL INFORMATION
Supplementary information is available for this paper at https://doi.org/10.1038/
s41531-020-00151-w.
Correspondence and requests for materials should be addressed to D.L.
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© The Author(s) 2021
Y. Lai et al.
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Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2021) 8