Reducing the side effectsfor
treatment of Parkinson Disease
Patients with Parkinson disease may
finally develop severe tremor. It is known that the origin of this uncontrolled
motor behaviour is
of the basal ganglia: the subthalamic nucleus (STN), deep in the brain. The
discovery of Deep Brain Stimulation (DBS) is attributed to Alim Benabid in
the late 1980s, who found that electrical stimulation of the basal ganglia
improved the symptoms of Parkinson's disease (but it has a complex history).
Continuous stimulation at 80 or 150 Hz is
accomplished by the operative placement of two electrodes in both STNs (left
and right), driven by an implanted brain pacemaker under the clavicula.
The goal of deep brain stimulation for Parkinson’s disease is to
stimulate the motor part of the subthalamic nucleus (blue) and to avoid
stimulation of the non-motor areas (green and red).
However severe side effects can develop: • In
50% of the cases a behavioral change is noticed in the patient; • In
14% of the cases the change is severe: • Depressions • Mania
hypersexuality, euphoria) • Agressiveness
The reason is the inaccurate positioning
of the stimulating electrode near the STN. The STN consists of three layers
(see figure), and stimulation should be done at the somatomotor
partition [Handbook on DBS, in
The project started with a feasibility
study by TU/e BME MSc student Ellen Brunenberg (supervised by dr. Bram Platel and
dr. Anna Vilanova). Ellen’s MSc
published at MICCAI, and she was rewarded a Dutch Top-Talent PhD scholarship
Before the operation: to image the small
STN (lens-shaped, ~ 7 x 6 x 3 mm) the patient is scanned by 3T MRI and
high-resolution CT, and the 3D volumes are co-registered.
A frame is mounted to
the patient’s skull, to aid the registration. It is quite difficult to locate
We were surprised how primitive the
location was determined (the classical method in literature):
11.5 mm lateral, 2.5 mm posterior and 4.1
mm inferior to the mid-point of the AC–PC line.
The DBS operation typically takes 5-6 hours.
The patient is awake, and his leg stiffness and pupil- and finger reflexes are
tested at frequent intervals.
skull is penetrated and a needle with 5 electrodes is painstakingly slow driven
towards the STN.
The proximity of the needle to the STN is signaled by (listening to) the high spiking activity of the STN.
The Substantia Nigra,
another brain basal ganglia structure, produces dopamine, a neurotransmitter.
In Parkinson Disease patients the cells
of the Substantia Nigra degenerate.
In a healthy person there is a good
balance between excitation and inhibition on the STN.
In Parkinson, the diminished dopamine
releases the inhibition on the STN, which starts firing in an uncontrolled
well can you see the STN on 3T MRI and CT scans?
To know the state-of-the-art in optimizing the localization and visualization of the STN on MRI images [Brunenberg
papers were reviewed with different targeting techniques, among which deformable atlas-mapping.
The results were not conclusive: the STN was not so well visible in many cases.So we
decided to investigate the brain with Diffusion-Weighted MRI,
a technique in which the motility (its diffusion) of
water molecules is measured, per voxel.
you subdivide the STN in its functional parts?
We hypothesized that this diffusion might
be different in the different parts of the STN due to possible differences in
cell shapes and local connections. We studied this in the rat (where the STN
has two subdivisions) with an excised brain in a small-bore 9.4 Tesla
AVANCE-III MRI scanner.
It turned out that the new DTI technique
with many more (132) orientations, called High
Angular Resolution Diffusion Imaging, gave good results. With a new geometric
separation technique (Sobolov norm) we could much better discriminate the
subdivisions than with conventional separation methods.
Diffusion glyphs in the STN region with anatomical context. (a) Normalized Q-ball
glyphs in the STN region (from Figure 5.3(b)), with atlas overlay based on  (ic = internal
capsule, ns = nigrostriatal bundle, stn = subthalamic nucleus, zid = dorsal zona incerta, ziv = ventral zona incerta). (b) Supposed subdivision of rat STN into the large lateral motor part (motor) and
the smaller medial associative and limbic part (a/l), indicated by the dashed line.
The dotted line in the lower figure indicates the subdivision.
is the STN structurally (with fiber connections) connected to its surroundings?
The next step was to find the ‘structural
connectivity’ of the STN. How are the different part fysically wired to its
the motor cortex?
3T DTI-MRI on 8 healthy subjects revealed
many afferent (in-going) and efferent (outgoing) connections to the surrounding
basal ganglia (see the tables in the PloS one publication [Brunenberg2012].
was quite spectacular that we could visualize a direct ‘hyperdirect
pathway’ from the STN to the motor cortex. [Figure source].
is the STN functionally (correlated activity) connected to its surroundings?
MRI is a
technique to measure brain’s activity by measuring tiny local differences in
oxygen flow. To establish the functional connectivity, we performed resting
state fMRI, assuming
functionally connected areas have a temporal correlation in activity.
It was found that the posterior lateral
part of the STN shows the highest functional connectivity to the motor areas,
while the anterior medial part yields the lowest values.
Ellen Brunenberg defended her TU/e BMIA PhD thesis on 08-09-2011.
In Maastricht my colleague prof. Rainer Goebel had
acquired a major funding to acquire a 3T, a 7T and a 9.4T MRI, and founded the Maastricht
Brain Imaging Center.
The next phase of our DBS research
focused on 7T MRI.
started a collaboration with prof. Tianzi Jiang [Google
founder of the Brainnetome
Brain Atlas Project at the Chinese Academy of Science in Beijing (see here how
we met). In April 2012 we submitted a joint proposal to the Sino-Dutch Joint
Science & Technology Program (JSTP) and
were rewarded a 4-year PhD grant, and I hired Birgit Plantinga.
7T and 9.4T are amazingly powerful
magnets. I remember, during a guided tour to the 9.4 scanner, that we could
stand on a platform on top of the magnet, and felt the forces on a small key that we
had taken with us. It reminded me on a little accident we had in Utrecht, when
one day one of our image processing desktop PCs on a rolling cart got caught
against the 3T MRI magnet, and how much trouble we had to remove it …
7T is also expensive: € 1000 per hour. Luckily we
were awarded a grant of € 20,000.- of the Limburg
University Fund/SWOL to do these experimental 7T scans. We also submitted an extensive ‘ethical
These questions were tackled in Birgit Plantinga’s
PhD thesis (2012-2016).
the STN be better visualized and delineated on 7T MRI?
The first task was an extensive
literature study. A list of
all available (61 at the time) clinical 7T scanners was compiled, and with the
visualization results published in this Frontierspaper.
Here is an example of how well you can discriminate the STN:
Ultra-high field (7T)
axial (A,B,E,F) and coronal (C,D,G,H) T2*-weighted images (A–D) and R2*-maps
(E–H).Panels (B,D,F,H) show
the anatomical structures that can be identified with the Schaltenbrand
(a) caudate nucleus, (b) anterior limb of internal capsule, (c) putamen, (d)
lateralis, (e) external globus pallidus, (f) lamina pallidi
medialis, (g) pallidum mediale
(h) lamina pallidi
(i) pallidum mediale
(j) inferior thalamic peduncle, (k) anterior commissure, (l) prothalamus,
(m) fornix, (n) third ventricle, (o) hypothalamus, (p) posterior limb of
internal capsule, (q) subthalamic nucleus, (r) red nucleus, (s) substantia
nigra, (t) internal globus pallidus. (Courtesy D. Ivanov).
7T see quantitative differences in healthy and Parkinson basal ganglia?
We measured several quantitative MRI
parameters:- T1 relaxation time- T2* relaxation time - Mean diffusivity
In the figure the differences are shown
between 9 controls and 5 PD.
It was a major effort to write the Ethical Committee request
in order to do experimental measurements on PD patients.
we parcellate the subdivisions of the STN at 7T?
It turned out to parcellate the STN by
means of its structural connectivity (fibre connections) to the motor, limbic and
associative cortical areas.
The STN is parcellated based on
its connections to the limbic, associative, motor, and remaining cortical
areas. A-B) Division of the cortex into limbic (red), associative (green),
motor (blue) and remaining (yellow) cortical areas. C-D) Visualization of the
hypointense STNs in the axial (C) and coronal (D) planes.
E-H) Example of the
parcellation of the STNs of one subject in axial (E,G) and coronal (F,H) views.
Examples of the subdivisions of
the left (A,C,E) and right (B,D,F) subthalamic
nuclei of three subjects into a
limbic (red), associative (green), and motor (blue) zone. Intermediate colors
show overlap between the motor and associative zones (light blue) and between
the associative and limbic zones (brown).
Examples of the electrode
position in five STNs as defined during the post-operative programming. The
active contacts (red) lie within the pre-operatively computed motor areas.
From February till August 2015 Birgit visited prof. Noam Harel, at the Center for Magnetic Resonance Research (CMRR) of the University of Minnesota. Prof. Harel is known for developing high-field fMRI capabilities for mapping columnar and laminar organization in cerebral cortex both in human and animal models.
we do really
resolution tractography with 7T?
To get the ultimate in spatial
resolution, we were able to scan a post-mortem sample for 42 hours. This gave
0.5 x 0.5 x 0.5 mm resolution, and excellent fibre tracking.
sample including the globus pallidus, subthalamic nucleus, and substantia
Axial GRE images through the SNc and SNr, STN, and GPi and GPe, at three different levels ordered from
the most inferior level (A) to the most superior level (C). (D) 3D
Visualization of the segmented structures. A, anterior; ac, anterior
commissure; cp, cerebral peduncle; fx, fornix; GPe, external globus pallidus; GPi,
internal globus pallidus; I, inferior; ic, internal capsule; L, lateral; MB,
mammillary body; M, medial; ot, optic tract; P, posterior; RN, red
nucleus; S, superior; SNc,
substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN,
Fiber tracks of the SNc
and SNr.(A,B) Fiber
direction within the SNc (A) and
SNr (B) color
coded for orientation.
tracked between the GPi
(brown tracks) and SNc
(green tracks). (D) Fibers
tracked between the GPe
(orange tracks) and SNc
(blue tracks). A, anterior; L, lateral; M, medial; P,
Birgit Plantinga defended her TU/e BMIA PhD thesis on 17-11-2016 in Eindhoven.