Deep Brain Stimulation 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 in one 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.
Without DBS.
With DBS.
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 (e.g. 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 Dutch].
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 thesis was published at MICCAI, and she was rewarded a Dutch Top-Talent PhD scholarship (2007-2011).
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 the STN.
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.
The 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 manner.
Q1.How 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 2011]. 70 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.
Q2.Can 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 Bruker-Biospec 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 [240] (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.
Q3.How 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 environment, in particular to 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].
It was quite spectacular that we could visualize a direct ‘hyperdirect pathway’ from the STN to the motor cortex. [Figure source].
4.How is the STN functionally (correlated activity) connected to its surroundings?
Functional 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 that 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.
We started a collaboration with prof. Tianzi Jiang [Google Scholar], 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 committee request’.
These questions were tackled in Birgit Plantinga’s PhD thesis (2012-2016).
Q1: Can 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 and Wahren atlas (Schaltenbrand and Wahren , 2005): (a) caudate nucleus, (b) anterior limb of internal capsule, (c) putamen, (d) lamina pallidi lateralis, (e) external globus pallidus, (f) lamina pallidi medialis, (g) pallidum mediale externum, (h) lamina pallidi incompleta, (i) pallidum mediale internum, (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).
Q2.Can 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.
Q3.Can 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.
Q4.Can we do really high 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.
Unilateral human post mortem sample including the globus pallidus, subthalamic nucleus, and substantia nigra.
(A–C) 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, subthalamic nucleus.
Fiber tracks of the SNc and SNr.(A,B) Fiber direction within the SNc (A) and SNr (B) color coded for orientation.
(C) Fibers tracked between the GPi and SNr (brown tracks) and SNc (green tracks). (D) Fibers tracked between the GPe and SNr (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.
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