Supplementary material
Deep brain stimulation of the nucleus basalis of Meynert
in Alzheimer’s dementia
Prof Kuhn Jens*, MSc Hardenacke Katja*, Dr Lenartz Doris, Dr Gruendler Theo, Prof
Ullsperger Markus, MSc Bartsch Christina, Prof Mai Jürgen Konrad, Prof Zilles Karl, Prof
Bauer Andreas, Dr Matusch Andreas, Prof Schulz Ralf-JoachimJ, Dr Noreik Michaela, Dr
Bührle Christian Philipp, Prof Maintz David, Prof Woopen Christiane, Dr Häussermann Peter,
Dr Hellmich Martin, Prof Klosterkötter Joachim, Prof Wiltfang Jens, Dr Maarouf Mohammad,
Prof Freund Hans-Joachim#, Prof Sturm Volker#.
Methods
Target selection (further information)
In AD, CH4-p shows the most severe cell loss1 and volume reduction of CH4 is already
present in cases of mild cognitive impairment. In its major projection field, i. e. the entorhinal
cortex, up to 80% of the cholinergic axons will eventually degenerate or be lost as a result of
AD1. Hence, Ch4-p is of considerable importance for influencing memory and mood2. It may
be assumed that stimulation of Ch4-p has a quite pronounced effect, since the
electromagnetic field generated by the electrode also encompasses the (cholinergic) axons
forming the lateral pathway of the NBM. These axons concentrate within the external capsule
to reach the neocortex3, but evidence from ACh-esterase histochemistry also suggests a
ventral projection towards the amygdaloid area4. The electrode may also modify additional
fiber systems, such as the uncinate fascicle and the MFB, but not of the extended amygdala
as in case of Ch4-im stimulation.
For Ch4-im stimulation we oriented the electrode trajectory along the anteromedial border of
the anterior commissure, close to the transition between Ch4-im and CH4-p, i. e. below the
approximate level of the border between the putamen and globus pallidus (Fig. 2 and Fig.
S1). Here, the NBM is thickest and thus provides the best opportunity to affect a
considerable cluster of the surviving cholinergic neurons/axons. In this region, the extended
amygdala, the amygdalofugal pathway and other sublenticular fibers (inferior thalamic
peduncle) are potentially targeted. These might also be severely affected by Alzheimerinduced degeneration5. Alternatively, i. e. by stimulating Ch4-p, we intended to target the
area caudolateral to the anterior commissure (Ch4-p). This subdivision contains fewer
cholinergic neurons as supported by nerve growth factor receptor (NGFR) - immunoreactivity
(not shown), arranged along the subputaminal border. Of great interest are the fibers that
emerge from this region and form a dense and circumscribed bundle/sheet of NGFR-positive
axons that can be outlined as part of the external capsule. These axons are most reliably
targeted in the area which was defined by acetylcholinesterase (AChE) staining as
'substriatal terminal island (SSTI)4. These fibers are believed to separate at the SSTI for
innervating pallial (frontoparietal and temporal cortices) and subpallial (amygdaloid) regions,
respectively. The sublenticular amygdaloid structures are spared in this lateral location. As
optimal target we selected the constricted area where the cells and axons of NBM become
encroached between the base of the putamen and the anterior commissure; alternatively the
SSTI region (patients four and five).
Neurocognitive functioning (statistical procedure):
Continuous data were summarized by mean ± standard deviation. Moreover, linear mixed
models for repeated measures (Autoregressive1 covariance structure) were used to evaluate
changes over time. Mean differences due to crossover of conditions, i.e. from OFF to ON or
vice versa, were compared by paired t-tests. Calculations and figures were done in
SigmaPlot (Systat Software Inc., Chicago, IL, U.S.A) and SPSS Statistics (IBM Corp.,
Armonk, NY, U.S.A.).
EEG analysis
The EEG was recorded at baseline (prior to stimulation) and 52 weeks after surgery (during
stimulation OFF). At least 120 sec artifact free EEG time series, recorded with 62 Ag/AgCl
electrodes (BrainAmp and Easycap, Garching Germany) according to the international 10-20
system and sampled at 1000 Hz was subjected to the analysis. Shifts in power spectral
distribution were examined using custom MATLAB (The MathWorks, Natrick/MA, U.S.A
scripts and subjected to a reliable change index6 assessing normalized amplitude changes in
the frequency bands at the frontocentral electrode FCz. An absolute reliable change index
(RCI) value equal or greater than 1.96 indicates a significant change at p < 0.05.
Positron emission tomography (PET)
Patients 3, 4, 5 and 6 underwent pre- and postoperative [18F]FDG PET scans. All patients
were asked to fast for at least 8 h before the investigation. Accordingly, initial blood glucose
levels were below 6.7 mmol/l. At least 10 min before tracer administration, patients were
positioned in the PET scanner (Siemens ECAT HR+) with their eyes closed, ambient
illumination dimmed and acoustical interferences largely reduced. 189 ±16 MBq [18F]FDG
was injected i.v.. Thirty min later a 10 min transmission scan for attenuation correction and a
subsequent emission scan of 30 min duration were acquired. Data were Fourier rebinned
into 2-dimensional sinograms, corrected for randoms, scatter, and attenuation and
reconstructed using the OSEM-3D algorithm. A voxel-wise comparison to a control collective
(n = 22) of the same age range (55 – 91 yrs.) was obtained using the 3D iSSP software7.
Furthermore, PET data were coregistered to individual MRI. Regions of interest defined
according to macroanatomical criteria were delineated onto individual MRI and the average
uptake was read out using pmod3.0. In both modes, the cerebellum served as reference
region.
For PET analyses, within subject comparisons of rCMRGlc were performed with nonparametric Wilcoxon tests and the Spearman rank correlation coefficient was determined for
both PET and neuropsychological data.
Quality of life
The modus operandi for interview evaluation was guided by a pre-defined set of categories
containing multiple qualitative variables. A detailed description of the method can be found
elsewhere8. Due to the complexity of the method and its resulting multitude of qualitative
statements, only topics concerning the quality of life estimated by the patients and their
relatives prior to and one year after the operation were analyzed.
Results
Serious Adverse Events
After uncomplicated implantation of the stimulation system only high impedance values were
accessed in two patients suggesting a discontinuity of the electric circuit. In one case the
plug-in connection of the extension lead as well as the stimulation generator were technically
faulty and incorrectly assembled in the second case. A surgical revision and replacement of
the defect parts lead to normal impedance values for both systems.
Nutritional status
The body mass index was within normal range for all patients (20.2 – 28.1 kg/m², mean
23.8 kg/m²). Response to DBS and energy intake were negatively related. Body weight
increased in five patients; only patient one showed a decrease in body weight of 1.6 %
(range -1.6 – 8.0 %, mean 3.8 % change). Three patients (patient three, four, and five)
showed a decline in nutritional status measured by modified-Mini-Nutritional-Assessment
(mean change = 0.3 points). Patient three and five had a strong decrease in energy intake (617 kcal/day, -645 kcal/day), whereas the remaining patients showed an increase in energy
intake (226 – 1620 kcal/day).
Table S1
Change of FDG in a sphere of 3 mm radius around the respective active contact of the electrode
Patient
Center for volume
of interest
-27, -4, -7
28, -4, -6
Change in [18F]FDG uptake
preOP – 1y postOP
-6.4 %
-10.2 %
4
-28, -6, -7
33, -8, -5
4.1 %
-2.0 %
5
-27, -6. -7
25, -8, -5
0.8 %
-10.7 %
6
-27, -7, -6
32, -7, -5
-6.2 %
-6.6 %
left hemisphere
right hemisphere
-1.9 %
-6.6 %
3
Mean
For patients 3, 4, and 5 the spheric volumes of interest were defined in the post-operative MRI scan.
For patient 6 no post-operative MRI was available and volumes of interest were centered onto the
theoretical coordinates as planned beforehand.
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