Mechanism of Action of Deep Brain Stimulation In Parkinson Disease

Mechanism of Action
of Deep Brain Stimulation
In Parkinson Disease
Samer D. Tabbal, M.D.
Associate Professor of Neurology
Washington University at St Louis
Department
p
of Neurology
gy
June 2011
Conflict of Interest Statement
No drug company pays
me any money
NIH, American Parkinson Disease Association (APDA),
Greater St. Louis Chapter of the APDA, McDonnell Center
for Higher Brain Function, Barnes-Jewish Hospital
Foundation
Bilateral STN DBS in PD
STN DBS iis effective
ff ti and
d safe
f iin advanced
d
d PD
patients with disabling motor fluctuations:
-
Improves UPDRS scores
Improves motor fluctuations:
z
z
-
Decreases OFF time
Improves dyskinesia
Decreases daily dose of levodopa and other PD
medications
(Improves sleep)
(Weight
(We
g gain)
g )
Improves quality of life measures
Deuschl at al NEJM, vol 355;pp 896896-908, August 31, 2006
Quality of Life in STN DBS
Deuschl at al NEJM, vol 355;pp 896
896--908, August 31, 2006
Why Do We Need to Learn About the
Mechanism
M h i off A
Action
ti off DBS?
If we know how it works, we may be able to
make it work better:
- To optimize motor benefit (“sweet spot”)
- To minimize adverse effects ((cognitive,
g
-
psychiatric, visual …)
To look for tentative new DBS targets for other
disorders (dystonia, tics, depression, obsessiveobsessivecompulsive disorders, seizure…)
Normal Basal Ganglia Circuitry
Striatum
PD Basal Ganglia Circuitry
Striatum
Direcct pathway (+)
Indirecct pathwayy (-)
Basal Ganglia Circuitry
Aft S
After
Subthalamic
bth l i L
Lesion
i
What Are We Stimulating
And/Or Inhibiting?
Likely stimulating axons
With monopolar
p
stimulation: ((Holsheimer 2000))
- Nearby axons may be blocked (by high
-
currents))
Distant axons are unlikely affected by
stimulation
Intermediately located axons may be activated
(“shell of activation”)
STN
S
N Efferent
ffe ent & Afferent
ffe ent Projections
ojections
Frontal Cortex
STN
Parafascicular
Nucleus of Thalamus
Substantia Nigra
(pars compacta)
Pedunculopontine
nucleus
External
E
t
l
Globus Pallidus
Substantia Nigra
g
(pars reticulata)
Internal Globus
Pallidus
Neurophysiology of STN DBS
in Animals & Humans
In MPTP monkeys: (Hashimoto 2003, Kita 2005)
- GPe and GPi: Increased firing
In
I PD patients:
ti t
- Following 500 msec: ½ of STN cells were inhibited
(Filali 2004)
- Following 20 seconds: all STN cells were inhibited
(Welter 2004)
Net Effects of DBS
on Basal
B l Ganglia
G
li Circuitry
Ci it
and Cortical Targets
If STN is inhibited by DBS
If STN is stimulated by DBS
cortical targets
activated
DBS
cortical
ti l targets
t
t
suppressed
DBS
thalamus
STN
GPi/SNpr
thalamus
STN
GPi/SN
GPi/SNpr
Bilateral STN DBS Reduces Blood Flow to
the Cortex ((measured byy H2O15 PET))
Decrease
Increase
STN output is
i
increased
d
cortical targets
g
STN
thalamus
GPi/SNpr
Hershey et al, 2003
Unilateral STN DBS Improves
Rigidity Bilaterally
DBS conditions
BOTH ON
CONTRA ON
IPSI ON
-10
-20
<0 03
<0.03
-30
-40
-50
<0 00005
<0.00005
<0.0005
NS
<0.05
% Change in Rig
gidity UPDR
RS
%C
Change in Impedance
e
0
DBS conditions
0
BOTH ON
CONTRA ON
IPSI ON
-10
-20
<0.05
-30
-40
-50
-60
-70
<0.02
<0.00001
<0.00001
NS
<0.002
<0.00001
(N=24)
Unilateral STN DBS Improves
Bradykinesia
B d ki i Bilaterally
Bil t ll
NS
<0.05
<0.03
0.03
250
<0.005
200
150
100
NS
50
0
BOTH ON
CONTRA ON
DBS conditions
IPSI ON
% Chang
ge in Brady
ykinesia UP
PDRS
% Chang
ge in HRV
300
DBS conditions
<0.05
350
(N=25)
0
BOTH ON
CONTRA ON
-10
<0.03
-20
<0.001
-30
-40
IPSI ON
<0.00001
<0.03
NS
<0.00001
Effect of Unilateral STN DBS on Gait
BOTH ON
LEFT ON
RIGHT ON
<0.0005
<0.0001
% Chang
ge in Walking Tim
me
0
-10
-20
-30
<0.00001
NS
<0.0005
<0.005
(N=44)
Effect of Unilateral STN DBS on
Motor Function &Working Memory
Working memory:
- abilityy to maintain,, monitor and use internal information to guide
g
behavior
- essential for carrying more complex executive functions, affected in PD
- measured using Spatial Delayed Response (SDR) test
Mean
M
UPDRS and
dS
Spatial
ti l D
Delayed
l dR
Response (SDR) responses tto
Left DBS vs Right DBS did not differ
On the more affected side of the brain ((compared
p
to the less
affected side):
- contralateral UPDRS
-
improvement was greater
SDR performance was
more impaired (p=0.008)
Variability among patients
What Accounts For The Variability in
Motor
M t Benefit
B fit From
F
STN DBS?
Disease duration at surgery?
Age at surgery?
Disease
Di
severity?
it ?
Stimulation parameters?
p
Brain atrophy?
Ability
Abilit to
t generate
t
dyskinesia??
dyskinesia
Location of electrode?
Sites of
Neurodegeneration
in Parkinson
Disease
Substantia nigra
g p
pars
compacta
Substantia
innominata
Amygdala
Ventral tegmental
area
Locus ceruleus
Raphe
p nuclei
Dorsal motor nucleus
of vagus nerve
Intermediolateral
column/Sympathetic
ganglia
Lang AE et. al. NEJM, vol 339(15): p1047
Functional Sections off the STN
Dorsolateral: Sensori
Sensori--motor (SM)
- Afferents from motor and supplementary
motor cortex, thalamus, GPe
Efferents to putamen, GPe/GPi
Ventrolateral: Associative (AS)
- Afferents from prefrontal cortex
- Efferents to caudate, putamen, GPi/SNpr
Ventromedial: Limbic (Li)
- Afferents from GPm/GPv, caudate,
-
putamen thalamus,
putamen,
thalamus medial frontal,
frontal
orbitofrontal and anterior cingulate cortex Coronal view of the STN
Efferents to caudate, GPe/GPi, SNpr
(Parent & Hazrati 1995)
Is jjust dorsal of white matter tracts
connecting the amygdala and hypothalamus
STN
Substantia
Nigra
Active Contact Localization
AC--18.6
AC
18 6 mm
Th Uncertainty
The
U
i
off The
Th Zona
Z
Incerta
I
Post--Operative CT
Post
(Tom Videen, PhD)
Tip of
electrode
Intra--Operative MRI: Intensity Inverted
Intra
Overlap MRI/CT Images Using
AIR* (Roger Woods, UCLA)
*Automated Image Registration
Overlap Coronal MRI on Whole Brain
C -registered
CoCo
i t d MRI/CT
Overlap Active Contacts
on Coronal MRI
Active Contact Localization
Unilateral Dorsal vs Ventral STN DBS
No difference in motor function:
- Bradykinesia UPDRS and hand rotation velocity
- Rigidity UPDRS and impedance (rigidity analyzer)
- Gait
Ventral STN DBS caused definite
impairment of response inhibition
(G -No
(Go(Go
N -Go)
NoG )
Mentor
Best Friend
Best Squash
partner!
Sami Harik
Active
ctive Contact Localization
ocalization
ZI
ZI
STN
STN
Active Contact Localization
1 cm
Volume of Activation
Cameron McIntyre
Cleveland Clinic
Clinic, Dept of Biochemical Engineering
Spatial Delayed
elayed Response
esponse Task
ask
Cue
Delay
Response
STN DBS May Affect Higher
C
Cognitive
i i Function
F
i
Spatial Delayed Response
10
1.0
*
30
2
25
20
One Cue
Two Cues
0
p<0.05
Diiscriminabillity (Pr)
Mean Error (mm)
M
35
15
Response Inhibition
0.8
*
0.6
Medium Target Frequency
HighTarget Frequency
0.0
OFF
DBS
ON
OFF
DBS
ON
Hershey at al, 2004
p<0.05
Effect Of Active Contact Location On
Spatial Working Memory
Spatial working memory (rated by SDR performance):
-
improved on DBS when the active contact was located out of
the STN.
worsened when the active contact was located in the STN.
Left-sided UPDRS Motor Scale Score
Spatial Delayed Response Performance
45
30
40
35
20
OUT
15
IN
Motor S
Score
Mean Error (m
mm)
25
30
25
OUT
20
IN
15
10
10
5
0
5
OFF
ON
DBS
0
OFF
ON
DBS
Hershey at al, 2006
Unilateral STN DBS Improves
Bradykinesia
B d ki i Bilaterally
Bil t ll
<0.05
300
<0.01
NS
<0.05
200
<0.01
150
100
<0.05
50
0
BOTH ON
CONTRA ON
DBS conditions
(N=38)
IPSI ON
Mean
n Hand Rotation Velocity
(deg/sec) (DB
BS Off)
% Change
e in HRV
250
700
rs = - 0
0.57
57
600
p < 0.003
500
400
300
200
100
0
1.5
2.0
2.5
3.0
3.5
4.0
Mean UPDRS Bradykinsia (DBS Off)
(N=25)
Unilateral STN DBS Improves
Rigidity Bilaterally
DBS conditions
BOTH ON
CONTRA ON
IPSI ON
-10
-20
<0.001
-30
<0.00001
-40
<0.00001
-50
rS = 0.67
0.15
Impedance ((Nm/deg)
(DBS O
Off)
%C
Change in Impedance
0
p < 0.0003
0.10
0.05
0.00
NS
NS
<0.005
(N=42)
2.0
2.5
3.0
3.5
4.0
Mean UPDRS Rigidity (DBS Off)
(N=24)
Levodopa-Equivalents Reduction
Levodopaatt 6 Months
M th After
Aft STN DBS
Mean Levoodopa Equivaalents in milligrams
2200
2000
1800
1600
1400
1200
*
1000
800
600
400
200
0
Pre-surgery
g y
Follow-up
p
*p< 0.001
Effect of STN DBS
on UPDRS M
Motor
t S
Scores
6-Month Follow
Follow--Up
OFF Stimulation
UPDRS Score
6-Month Follow
Follow--Up
ON Stimulation
UPDRS Score
Average
Percent
Change*
Significance of
Change
(P value)
43.4 + 16.1
22.8 + 11.6
47%
< 0.001
Tremor ** (0(0- 28)
7.3 + 0.8
0.7 + 0.2
74%
< 0.001
Rigidity (0(0-20)
9.0 + 4.3
4.1 + 3.2
58%
< 0.001
Bradykinesia
(0--36)
(0
17.9 + 6.9
11.0 + 6.1
37%
< 0.001
Speech (0(0-4)
1.5 + 0.6
1.3 + 0.7
13%
= 0.002
Postural
Instability (0(0-4)
1.8 + 1.2
1.1 + 1.1
35%
< 0.001
Gait
(0--4)
(0
2.1 + 0.9
1.2 + 0.9
44%
< 0.001
Axial
(0--16)
(0
7.5 + 3.8
4.3 + 3.1
42%
< 0.001
Total (0(0-108)
Demographic
emog aphic Profile
ofile
All operated
patients
(N=110)
Outcome Analysis
Subgroup
(N=72)
66
44
41
31
Age at onset of symptoms
(in years)
47.9 + 10.2
(22-69)
48.4 + 9.8
(28-69)
g at time of surgery
g y
Age
(in years)
62.6 + 8.8
(31-84)
63. 0 + 8.2
(45-78)
Duration of Parkinson
disease at time of surgery
(in years)
14.5 + 6.3
(4-29)
(4
29)
14.5+ 6.5
(4-29)
(4
29)
Gender
Male
Female
Leading Author
Year of
publication
Number of
patients
Duration of
follow-up
(months)
Reduction in
motor UPDRS
score
Reduction in daily
levodopa-equivalent
dose
Limousin
1998
24
12
60 %
50 %
Kumar
1998
7
6-12
58 %
40 %
Moro
1999
7
16
42 %
65 %
Burchiel
1999
5
12
44 %
51 %
Pinter
1999
9
3-12
45 %
-
Bejjani
2000
12
6
64 %
70 %
Houeto
2000
23
6
67 %
61 %
g
Rodriguez-Oroz
2000
15
6
60 %
-
Molinuevo
2000
15
6
66 %
80 %
DBS for PD Study Group
2001
91
6
51 %
37 % *
Lopiano
2001
16
3
56 %
72 %
V lk
Volkmann
2001
16
12
67 %
65 %
Ostergaard
2002
26
12
64 %
19 %
Simuni
2002
12
12
47 %
55 %
Starr
2002
10
12
45 %
-
Thobois
2002
18
6
55 %
66 %
Vesper
2002
38
12
52 %
53 %
Voges
2002
15
6-12
61 %
59 % **
Pahwa
2003
33
12
28 %
57 %
Herzog
2003
48
6
51 %
49 %
Ford
2004
30
12
30 %
30 %
Tabbal
2006
72
3-12
47 %
45 %
First 110 STN DBS Patients
at Washington University in St Louis
Retrospective analysis:
-
First 110 patients assessed at around 6 months postpost-DBS
surgery
47% improvement in UPDRS motor score ON vs OFF DBS
(OFF medication)
45% mean reduction in daily levodopa-equivalent dose
Average
A
weight
i ht gain
i 55.1
1 + 0.7
0 7 kg
k
-
median 3.7 kg ; range -3.6 kg to +23.9 kg
Operating room time (from the mounting of the
stereotactic frame to its removal):
-
Median 5 hours 25 minutes
Mild and transient adverse events
STN DBS Studies from 1998 to 2006:
UPDRS & L
Levodopa
Levodopad
-Equivalent
E i l
% Reduction
R d i
80
Peercent Changge (%)
70
60
50
40
30
20
10
UPDRS % Reduction
Levodopa % Reduction
STN DBS Studies from 1998 to 2006:
UPDRS vs L
Levodopa
Levodopad
-Equivalent
E i l
% Reduction
R d i
15
Levodop
pa-Equivalen
nt % Reductiion
80
16
18
70
7
60
16
23
15
33
50
766
5
12 38
48
72
40
91
30
12
24
7
30
20
26
10
20
30
40
50
UPDRS % Reduction
60
70
STN DBS Parameters
DBS parameter programming
-
Voltage (volts)
Pulse width (μ
(μsec)
Pulse
P l frequency
f
(Hz)
(H )
Electric contacts combination
Stimulation pattern:
p
-
Monopolar in 74%
Multipolar in 26%
None were set in bipolar pattern
3
Optimal contact:
-
contact #2 in 58%
contact #1 in 34%
contact #3 in 27%
2
STN
1
0
Post--Operative DBS Programming
Post
Programming starts 22--4 weeks after
electrode implantation
OFF medication
di ti
Frequency: 130 to 185 Hz
Pulse width: 60
60,, 90 or 120 μsec
Voltage: 2.5 to 4 volts
Contact configuration: usually monopolar
or multipolar
Decrease medication gradually
STN
S
N Spans
No significant correlation between the STN
span and improvement of UPDRS motor
scores
Average STN span:
- on the right 4.5 + 0.9 mm (range 2.0 to 6.8 mm)
- on the left 4.9 + 0.8 mm (range 3.2 to 7.4 mm)
Overlap Atlas on MRI/CT
Fiducials used to stretch the atlas images:
- Anterior commissure
- Posterior commissure
- Optic chiasm
- Optic tract (in midmid-commisural plane)
- Anterior tip of the putamen (in commisural plane)
- Red nucleus
- Brain edge (in commisural plane)
Using reformatted MRI images:
- Transverse:
z
z
-
3D windowed sinc (sharpest but artifacts near optic chiasm)
trilinear interpolation
C
Coronal:
l
z
z
nearest neighbor (sharpest but abrupt jumps between planes)
trilinear interpolation

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