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Deep brain stimulation of subthalamic nucleus (STN-DBS) became a standard therapeutic option in Parkinson's disease (PD), even though the underlying modulated network of STN-DBS is still poorly described. Probabilistic tractography and connectivity analysis as derived from diffusion tensor imaging (DTI) were performed together with modelling of implanted electrode positions and linked postoperative clinical outcome. Fifteen patients with idiopathic PD without dementia were selected for DBS treatment. After pre-processing, probabilistic tractography was run from cortical and subcortical seeds of the hypothesized network to targets represented by the positions of the active DBS contacts. The performed analysis showed that the projections of the stimulation site to supplementary motor area (SMA) and primary motor cortex (M1) are mainly involved in the network effects of STN-DBS. An involvement of the " hyperdirected pathway " and a clear delimitation of the cortico-spinal tract were demonstrated. This study shows the effects of STN-DBS in PD distinctly rely on the network connections of the stimulated region to M1 and SMA, motor and premotor regions.
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Abstract Deep brain stimulation of subthalamic nucleus (STN-
DBS) became a standard therapeutic option in Parkinson's disease
(PD), even though the underlying modulated network of STN-DBS
is still poorly described. Probabilistic tractography and
connectivity analysis as derived from diffusion tensor imaging
(DTI) were performed together with modelling of implanted
electrode positions and linked postoperative clinical outcome.
Fifteen patients with idiopathic PD without dementia were
selected for DBS treatment. After pre-processing, probabilistic
tractography was run from cortical and subcortical seeds of the
hypothesized network to targets represented by the positions of the
active DBS contacts. The performed analysis showed that the
projections of the stimulation site to supplementary motor area
(SMA) and primary motor cortex (M1) are mainly involved in the
network effects of STN-DBS. An involvement of the
“hyperdirected pathway” and a clear delimitation of the cortico-
spinal tract were demonstrated. This study shows the effects of
STN-DBS in PD distinctly rely on the network connections of the
stimulated region to M1 and SMA, motor and premotor regions.
High-frequency deep brain stimulation of the subthalamic
nucleus (STN-DBS) is an effective therapy option for
patients with Parkinson’s disease (PD) [1]. The effect on
major clinical motor symptoms as tremor, rigidity, and
bradykinesia is unequivocal. Furthermore DBS improve
non-motor symptoms of the disease, possibly through its
network effects [2]. Despite the clinical success of DBS, its
mechanisms at the local and systemic level have not been
fully elucidated. Furthermore there is no clear data on the
anatomical structures targeted. A complex modulation of
the basal ganglia loops or the cortico-subcortical networks
is hypothesised [3]. Early studies attested that high-
frequency stimulation might modulate the neuronal activity
within the STN [4]. However, DBS presumably does not
only change the neural activity in the nuclei but furthermore
targets the fibre tracts entering, exiting, or passing the
stimulation site [5]. Moreover an interaction with the
pathological oscillations in distinct brain networks might be
a critical feature of the DBS induced clinical response in PD
[7, 8].
*Koirala N, Fleischer V, Muthuraman M, Groppa S, are with the Johannes
Gutenberg university hospital, 55131, Mainz and Granert O,Deuschl G is with
University clinic Schleswig-Holstein, 24105,Kiel,Germany; corresponding e-
mail:,,,, o.granert@neurologie.uni-, .
Studies on primates and recent studies on humans attested
the existence of the so-called hyperdirect cortical STN
projections [6]. Furthermore this pathway might be of
special importance for the effects of STN-DBS [7].
Here we analyse the connections of the electrode regions
by the use of diffusion tensor imaging (DTI) and
probabilistic tractography. Therefore we focus on cortical
and subcortical projection to the electrode site that might be
involved in the clinical effect of STN-DBS. We hypothesise
that these connections play an important role for STN-DBS
and their characteristics are crucial for the clinical outcome
and stimulation parameters. Furthermore we consider the
connectivity data as possible predictors that relate to
postoperative clinical outcome scores such as UPDRS-III
(UPDRS motor score) or stimulation parameters for an
optimal clinical response.
A. Data Acquisition
Fifteen patients with idiopathic PD without dementia
selected for DBS treatment (11 males, age 63.3±8.2, Hoehn
and Yahr 3.5± 0.8) selected for DBS treatment were
randomly included in this study. All patients received, after
clinical and neuropsychological assessment, bilateral STN
electrodes. The UPDRS-III values in the medication OFF,
stimulation ON state have been used to calculate the
quotient to the preoperative UPDRS-III score in medication
ON state (mentioned further as qUPDRS) have been
selected for the parameter of clinical outcome and included
into further analysis. The surgical procedure has been
previously described in detail [8]. The study protocol used
was approved by the local ethics committee and all patients
have signed a written consent regarding the procedure.
All patients underwent a preoperative high resolution
MRI (3T) using an 8-channel SENSE head coil. We
acquired diffusion sensitive MRI of the whole brain at 2
mm isometric voxel resolution covering a field of view of
224 x 224 mm. DTI included three acquisitions of 32
gradient directions plus 5 b0 images for each acquisition (b
value 1000 s/mm2, TE = 59 ms, TR = 11855 ms, fat
saturation “on”, 60 contiguous slices). Moreover we
obtained a high-resolution T1-weighted structural image of
the whole brain using a standard MPRAGE sequence (TR =
7.7 ms, TE = 3.6 ms, flip angle = 8°). The T1-scan
consisted of 160 contiguous sagittal slices with 1 mm
isometric voxels and a field of view = 240 x 240 mm. On
the first postoperative day a further recording was
Network effects and pathways in Deep brain stimulation in
Parkinson’s disease*
Koirala N, Fleischer V, Granert O, Deuschl G, Muthuraman M, Groppa S
performed on a 1.5 T scanner with a protocol consisting of a
T1-weighted structural image of the whole brain using a
standard MPRAGE sequence (TR = 10.7 ms, TE = 1.96 ms,
flip angle = 8°). The structural brain scan consisted of 160
contiguous coronal slices with 2 mm isometric voxel size
and a field of view = 256 x 256 mm.
B. Preprocessing
Electrode positions and electrode trajectory were
determined by performing the following image analysis
First step: Post-operative T1 images were used to determine
the position of the electrode lead. The lead was
mathematically modelled by a straight line and the position
was determined from a set of manually placed 3D space
points (markers) along the electrode trajectory. The
electrode trajectory was determined within the MRI T1
weighted images using all three orthogonal views (sagittal,
coronal and transversal). Markers were placed at the target
points, near the points of exit and uniformly along the
trajectory artefact. Finally, a three dimensional least square
optimization procedure was used to determine the exact
position of the trajectory. Based on the optimized lead
position the T1 intensity profile was extracted along the
trajectory. The exact electrode positions were then
determined by shifting the four contacts manually along the
lead such that the center of the intensity dip, apparent in the
extracted intensity profile, was in correspondence with the
lead contacts.
Second step: Geometrically determined electrode contact
positions were used to create spatially Gaussian weighting
masks. The masks were calculated by specifying the
following two standard deviations: I. along the lead to
model contact dimensions, known from manufacturer’s
annotations; II. in orthogonal directions to model
stimulation depth. The multivariate Gaussians were
centered at the contact positions determined as described in
the first step. We restricted our analysis to a mask with an
extension of two standard deviations along the lead and two
standard deviations in depth (isometric mask with 4.7 mm
full width at half maximum (FWHM), corresponding to a
radius of ~2.4 mm). These parameters were selected
considering existing literature that attests that neural
elements up to a distance of 2 mm from the active contact
might be excited by DBS [9]. The generated Gaussian
masks were then used for further analysis. To allow bias-
free definition of seed and target areas unaffected by
subjective judgments about anatomical correspondences, we
built masks for cortical seeds from anatomical coordinates
known from a meta-analysis for activation studies [10]. The
generated masks were spheres with a radius of 5 mm
centered at the following MNI coordinates: primary motor
cortex [M1 (-37 -21 58)], dorsal and ventral premotor
cortex [PMd (-30 -4 58), PMv (-50 5 22)] and SMA (-2 -7
55) [11]. The coordinates were transformed into MNI space
using GingerALE [12]. ROIs of Globus Pallidus internus
(GPi) and Globus Pallidus externus (GPe) were generated
from the MNI probability atlas by including the entire areas
C. Tractography analysis
The aim of our tractography analysis was to generate
voxel-based connectivity index maps in the regions of the
DBS electrodes. We used all voxels in the basal ganglia and
the midbrain structures as generated by the MNI atlas and
defined this area as target region [14]. A multi-fiber model
was fit to the diffusion data at each voxel, allowing for
tracing through regions of crossing fibers [15]. Here, we
drew 5,000 streamline samples from our seed voxels to form
an estimate of the probability distribution of connections
from each seed voxel using FSL (v 4.1). Tracts generated
are volumes wherein values at each voxel represent the
number of samples (or streamlines) that passed through that
voxel. For the elimination of spurious connections,
tractography in individual subjects was restricted to include
only voxels through which at least 10 percent of all
streamline samples had passed [16]. The probability of
connection to the target mask was obtained from the
proportion of samples that reached each of the voxels. The
individual maps were then normalized to calculate a tract
probability at each voxel of the target region for each tract
and subject. This connectivity values were then extracted
from the Gaussian masks and feed into further analysis.
Further we performed another tractography analysis to
generate a voxel-based connectivity index map to delimitate
the cortical connections to the electrode regions from the
cortico-spinal tract. The analyzed tract started as well from
the M1-mask but passed a conjunction mask of the
ipsilateral cerebral peduncle region and internal capsule
[17]. The connectivity values of the electrode regions have
been then extracted as described above.
D. Statistical analysis
The correlation analysis was performed using SPSS
software (Version 16.0, SPSS Inc, Chicago, IL, USA). To
improve the statistical power of the data analysis, we pooled
the data from both sides. Stimulation intensity amplitudes
and the quotient of the post- to preoperative UPDRS-III
(qUPDRS) were introduced into further analysis of
covariance (ANCOVA). T-test has been calculated for the
clinical outcome measurements. For the cortico-spinal
tractography analysis, we calculated two single linear
regression analyses with the connectivity data from the
cortico-spinal tract and “DBS intensity” and “qUPDRS”-
A. Tractography analysis
The analysis of covariance (ANCOVA) including the
continuous factor DBS stimulation intensity revealed a
significant main effect for the factor Seed [F(5, 140)=2.35,
p<0.05]. The interaction between the factors Seed and DBS
intensity was also significant [F(5, 140)=2.30, p<0.05].
Model correlation with the continuous factor DBS intensity
was significant for the variables of connectivity indices from
M1 (r=0.45, F=7.30, p<0.05) and SMA (r=0.39, F=5.28,
p<0.05, Figure 1A & 1B).
Figure 1. Correlation analysis of connectivity ratios for M1 (A) and SMA
(B) to stimulation intensity at the active contact.
The ANCOVA including the continuous factor qUPDRS
revealed a significant main effect for the factor Seed [F(5,
140=8.81, p<0.05] but showed no other significant
interactions between terms. No correlations with
connectivity values from other cortical (PMd, PMv) or
subcortical seeds (GPi or GPe) achieved statistical
significance in the above mentioned analyses.
B. Delimitation of the cortico-spinal tract
The two linear regression analyses for the connectivity
values from the cortico-spinal tract and “DBS intensity”
(t=-1.2, p>0.1) and “qUPDRS” (t=-0.4, p>0.1) were not
significant. On the visual inspection of the tract probability
maps and VTA (volume tissue activation) positions, the
corticospinal tract was positioned more laterally, while for
electrodes localised in the neighbourhood of the cortico-
spinal tract lower stimulation intensities have been chosen,
possibly to reduce the effects (Figure 2).
Figure 2. Probabilistic tractography results with schematic presentation of
the binarized cortico-spinal tract (blue) and electrode region. Color bar:
connectivity values represent the number of subjects with positive voxels and
current intensity at the effective electrode.
Using diffusion MRI, we show that the connectivity
pattern as derived from probabilistic tractography from M1
and SMA directly correlate with the applied voltage at the
active contact for an optimal clinical effect after STN-DBS.
The connectivity profile from these two cortical regions
might become important predictors for STN-DBS. The
main purpose of this study was to reconstruct the
anatomical network modulated by STN-DBS. So far little is
known about the systemic mechanisms of the STN-DBS.
Important data on possible network interactions was
obtained from animal studies, while direct translations to
human models are lacking [18].
The direct involvement and imperative role of the
primary motor cortex for the effects of the STN-DBS have
been demonstrated in two recent studies. They showed that
DBS induced antidromic spikes in Layer V pyramidal cells
triggered a dampened oscillation of local field potentials in
cortex with a resonant frequency around 120 Hz [19]. With
optogenetics and solid-state optics a direct activation of
cortical afferents from M1 projecting to the STN region was
observed and an explicitly associated with therapeutic
benefit was determined [20]. Seminal data on the role of the
motor cortex for the effects of the STN-DBS provided a
study on Parkinsonian rats, that showed that the corrective
action is upon the cortex, where stochastic antidromic
spikes originating from the STN directly modify the firing
probability of the corticofugal projection neurons, destroy
the dominance of beta rhythm [7]. In summary these studies
together with our probabilistic and structural data suggest
that STN-DBS specifically modulates the M1-STN and
SMA-STN connections via either the hyperdirect pathway
or possible loops, functionally related circuits in a way that
normalise the overall cortico-basal-ganglia-cortical network
and the circulating pathological activity.
In our view, the correlative evidence of the stimulation
parameters and connectivity values explains the fiber tract
integrity and the associated modifiability profile of the
connection to the motor and premotor areas through STN-
DBS. Our results are supported by existing effective
connectivity data too, showing an increased cortical output
to STN via hyperdirect tract area in the Parkinsonian
primates compared to the control group [21]. Stronger
structural connectivity in these circuits might be further the
basis for the oscillations that have to be counteracted by
An important point for the discussion of STN-DBS
effects in the light of these results is the possible direct
activation of the pyramidal tract fibers that might worsen
bradykinesia and akinesia and negatively influence the
clinical outcome [22]. Since both regions M1 and SMA
present wide corticospinal projections the importance of
these for the effects of STN-DBS could not be completely
ruled out. Nonetheless the adjacent studied premotor
cortical areas (PMd and PMv) are similarly to M1 and SMA
sources for dense corticospinal projections [23]. The
connectivity analysis of these regions to the electrode sites
did not depict any correlative relationships. Furthermore a
direct stimulation of the pyramidal tract would activate
cranial or spinal motoneurons and lead to muscle
contractions, which was not the case in all of our patients as
well. The performed analysis of the connectivity data of the
generated cortico-spinal tract and the lack of the correlation
to the stimulation parameters or clinical outcome make the
direct involvement of this pathway for the STN-DBS
In conclusion our data suggests that the effects of STN-
DBS in PD distinctly depend on the network connections of
the stimulated region to M1 and SMA, motor and premotor
regions. We observed no correlations with connectivity
values from other cortical (PMd, PMv) or subcortical seeds
(GPi or GPe). Furthermore we witnessed DTI and
probabilistic tractography as the important tools that can be
used to refine STN-DBS targeting and better elucidate the
achieved systemic effects.
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... We recorded the second CSP at a similar time on the following day (day 2) (Fig. 1). We also evaluated changes in the total UPDRS-III score and individual scores of rigidity (3-3), akinesia (3-4~8, and [3][4][5][6][7][8][9][10][11][12][13][14], and tremor (3-15~18). Twenty hours is enough time to assess the effect of the disappearance of short acting drugs, including levodopa, although the effect of long acting dopaagonist or other adjuvants would be residual. ...
... The direct activation of primary motor cortex during STN stimulation also was shown in primates (13). The network effect from STN-DBS to the primary motor cortex and supplementary motor area (14) could be a likely reason for the CSP changes, similar to the effects of anti-PD medications. Moreover, an activation of the motor cortex might induce a good environment for CSP generation. ...
Objectives: We sought to evaluate whether the cutaneous silent period (CSP) could be an electrophysiological indicator reflective of the effects of therapy for Parkinson's disease (PD), including anti-PD medications or deep brain stimulation (DBS). Material and methods: We recorded the CSP in 43 patients with PD prior to and following the administration of medication during a pre-DBS evaluation (30 cases) and the "on" and "off" states of subthalamic nucleus DBS (13 cases). The CSP was elicited from the abductor pollicis brevis muscle by an electrical stimulation of the index finger that was 2, 4, and 15 times stronger than the sensory threshold (ST). We measured changes in latencies, including the onset, duration, and end of CSP, and waveform scores from 0 to 3. The correlation between the CSP score and unified PD rating score part III (UPDRS-III) also was assessed. Results: The onset latency and duration of CSP were significantly different between high (15ST) and low-strength stimulations (2ST and 4ST). However, there were no significant latency changes (onset, duration, end of CSP) before and after receiving medication, or during the on and off state of the DBS. Anti-PD medications substantially increased the CSP waveform score only in the 4ST state. However, the waveform score significantly increased in all stimuli states during the DBS-on state. Both medication and the DBS-on state decreased the UPDRS-III. Nevertheless, there was no statistically significant correlation between the UPDRS-III and CSP waveform scores. Conclusion: Different onset latencies and the duration of CSP between low- and high-strength stimuli support the hypotheses proposing two different reflex pathways. Despite being independent from the UPDRS-III, the CSP may be an electrophysiological indicator reflective of the changes in inhibitory activity to the spinal α-motoneuron in response to anti-PD medications and DBS.
... Here, noninvasive evaluation of connecting white matter (WM) fiber tracts that are in direct contact with the DBS leads, based on diffusion-weighted magnetic resonance imaging (DWI), is key to advancing individualized DBS planning and therapy [16]. In this direction, even though a considerable amount of work has been conducted regarding the identification of WM pathways from DBS electrode locations and DBS-modulated gray matter (GM) regions as well as their relationship to clinical outcomes [17][18][19][20], previous work has lacked a detailed examination of the microstructural properties of the reconstructed pathways and the integrity of their connected GM terminals as derived from available morphometric and diffusion magnetic resonance imaging (MRI) metrics. ...
Full-text available
IntroductionDeep brain stimulation of the subthalamic nucleus (STN-DBS) is an established therapy for Parkinson's disease (PD). However, a more detailed characterization of the targeted network and its grey matter (GM) terminals that drive the clinical outcome is needed. In this direction, the use of MRI after DBS surgery is now possible due to recent advances in hardware, opening a window for the clarification of the association between the affected tissue, including white matter fiber pathways and modulated GM regions, and the DBS-related clinical outcome. Therefore, we present a computational framework for reconstruction of targeted networks on postoperative MRI.Methods We used a combination of preoperative whole-brain T1-weighted (T1w) and diffusion-weighted MRI data for morphometric integrity assessment and postoperative T1w MRI for electrode reconstruction and network reconstruction in 15 idiopathic PD patients. Within this framework, we made use of DBS lead artifact intensity profiles on postoperative MRI to determine DBS locations used as seeds for probabilistic tractography to cortical and subcortical targets within the motor circuitry. Lastly, we evaluated the relationship between brain microstructural characteristics of DBS-targeted brain network terminals and postoperative clinical outcomes.ResultsThe proposed framework showed robust performance for identifying the DBS electrode positions. Connectivity profiles between the primary motor cortex (M1), supplementary motor area (SMA), and DBS locations were strongly associated with the stimulation intensity needed for the optimal clinical outcome. Local diffusion properties of the modulated pathways were related to DBS outcomes. STN-DBS motor symptom improvement was highly associated with cortical thickness in the middle frontal and superior frontal cortices, but not with subcortical volumetry.Conclusion These data suggest that STN-DBS outcomes largely rely on the modulatory interference from cortical areas, particularly M1 and SMA, to DBS locations.
... Recently, it has been proposed to study Parkinson's disease on a systems or network-level, considering the anatomical and functional interactions of the basal ganglia with the cortex, cerebellum (CER), and brainstem (Helmich et al., 2013;Caligiore et al., 2016). Since effective DBS simultaneously affects multiple regions that are connected with the stimulation site (Koirala et al., 2016(Koirala et al., , 2018Muthuraman et al., 2017), our understanding is that we must study the effects of DBS on a wide network instead of (pre-) selected regions. Recent advances in EEG source reconstruction have made it possible to non-invasively reveal cortical and subcortical sources with an improved spatial resolution, adding to the advantage of having a good temporal resolution (Litvak et al., 2011;Muthuraman et al., 2012Muthuraman et al., , 2018bTamas et al., 2018;Seeber et al., 2019). ...
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The disruption of pathologically enhanced beta oscillations is considered one of the key mechanisms mediating the clinical effects of deep brain stimulation on motor symptoms in Parkinson’s disease. However, a specific modulation of other distinct physiological or pathological oscillatory activities could also play an important role in symptom control and motor function recovery during deep brain stimulation. Finely tuned gamma oscillations have been suggested to be prokinetic in nature, facilitating the preferential processing of physiological neural activity. In this study, we postulate that clinically effective high-frequency stimulation of the subthalamic nucleus imposes cross-frequency interactions with gamma oscillations in a cortico-subcortical network of interconnected regions and normalizes the balance between beta and gamma oscillations. To this end we acquired resting state high-density (256 channels) EEG from 31 patients with Parkinson’s disease who underwent deep brain stimulation to compare spectral power and power-to-power cross-frequency coupling using a beamformer algorithm for coherent sources. To show that modulations exclusively relate to stimulation frequencies that alleviate motor symptoms, two clinically ineffective frequencies were tested as control conditions. We observed a robust reduction of beta and increase of gamma power, attested in the regions of a cortical (motor cortex, supplementary motor area, premotor cortex) and subcortical network (subthalamic nucleus and cerebellum). Additionally, we found a clear cross-frequency coupling of narrowband gamma frequencies to the stimulation frequency in all of these nodes, which negatively correlated with motor impairment. No such dynamics were revealed within the control posterior parietal cortex region. Furthermore, deep brain stimulation at clinically ineffective frequencies did not alter the source power spectra or cross-frequency coupling in any region. These findings demonstrate that clinically effective deep brain stimulation of the subthalamic nucleus differentially modifies different oscillatory activities in a widespread network of cortical and subcortical regions. Particularly the cross-frequency interactions between finely tuned gamma oscillations and the stimulation frequency may suggest an entrainment mechanism that could promote dynamic neural processing underlying motor symptom alleviation.
... Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunctions including, among others, tremor, difficulty in initiating and executing voluntary movements (akinesia/freezing/bradykinesia) and muscular rigidity (Caligiore et al., 2016). These deficits are believed to arise from the dysfunction within the dopaminergic system and alterations in the integrity of distributed brain neural networks (Brooks and Pavese, 2011;Koirala et al., 2016). A positive modulation of this network might be critical for therapeutic efficacy. ...
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Parkinson’s disease (PD) is a neurodegenerative disease, neuropathologically characterised by progressive loss of neurons in distinct brain areas. We hypothesize that quantifiable network alterations are caused by neurodegeneration. The primary motivation of this study was to assess the specific network alterations in PD patients that are distinct but appear in conjunction with physiological aging. 178 subjects (130 females) stratified into PD patients, young, middle-aged and elderly healthy controls (age- and sex-matched with PD patients), were analysed using 3D-T1 magnetization-prepared rapid gradient-echo (MPRAGE) and diffusion weighted images acquired in 3T MRI scanner. Diffusion modelling and probabilistic tractography analysis were applied for generating voxel-based connectivity index maps from each seed voxel. The obtained connectivity matrices were analysed using graph theoretical tools for characterization of involved network. By network-based statistic (NBS) the interregional connectivity differences between the groups were assessed. Measures evaluating local diffusion properties for anisotropy and diffusivity were computed for characterization of white matter microstructural integrity. The graph theoretical analysis showed a significant decrease in distance measures - eccentricity and characteristic path length - in PD patients in comparison to healthy subjects. Both measures as well were lower in PD patients when compared to young and middle-aged healthy controls. NBS analysis demonstrated lowered structural connectivity in PD patients in comparison to young and middle-aged healthy subject groups, mainly in frontal, cingulate, olfactory, insula, thalamus and parietal regions. These specific network differences were distinct for PD and were not observed between the healthy subject groups. Microstructural analysis revealed diffusivity alterations within the white matter tracts in PD patients, predominantly in the body, splenium and tapetum of corpus callosum, corticospinal tract and corona radiata, which were absent in normal aging. The identified alterations of network connectivity presumably caused by neurodegeneration indicate the disruption in global network integration in PD patients. The microstructural changes identified within the white matter could endorse network reconfiguration. This study provides a clear distinction between the network changes occurring during aging and PD. This will facilitate a better understanding of PD pathophysiology and the direct link between white matter changes and their role in the restructured network topology.
OBJECTIVE Deep brain stimulation (DBS) for Parkinson disease (PD) is traditionally performed with awake intraoperative testing and/or microelectrode recording. Recently, however, the procedure has been increasingly performed under general anesthesia with image-based verification. The authors sought to compare structural and functional networks engaged by awake and asleep PD-DBS of the subthalamic nucleus (STN) and correlate them with clinical outcomes. METHODS Levodopa equivalent daily dose (LEDD), pre- and postoperative motor scores on the Movement Disorders Society–Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS III), and total electrical energy delivered (TEED) at 6 months were retroactively assessed in patients with PD who received implants of bilateral DBS leads. In subset analysis, implanted electrodes were reconstructed using the Lead-DBS toolbox. Volumes of tissue activated (VTAs) were used as seed points in group volumetric and connectivity analysis. RESULTS The clinical courses of 122 patients (52 asleep, 70 awake) were reviewed. Operating room and procedure times were significantly shorter in asleep cases. LEDD reduction, MDS-UPDRS III score improvement, and TEED at the 6-month follow-up did not differ between groups. In subset analysis (n = 40), proximity of active contact, VTA overlap, and desired network fiber counts with motor STN correlated with lower DBS energy requirement and improved motor scores. Discriminative structural fiber tracts involving supplementary motor area, thalamus, and brainstem were associated with optimal clinical improvement. Areas of highest structural and functional connectivity with VTAs did not significantly differ between the two groups. CONCLUSIONS Compared to awake STN DBS, asleep procedures can achieve similarly optimal targeting—based on clinical outcomes, electrode placement, and connectivity estimates—in more efficient procedures and shorter operating room times.
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Diffusion magnetic resonance imaging (dMRI) datasets are susceptible to several confounding factors related to data quality, which is especially true in studies involving young children. With the recent trend of large-scale multicenter studies, it is more critical to be aware of the varied impacts of data quality on measures of interest. Here, we investigated data quality and its effect on different diffusion measures using a multicenter dataset. dMRI data were obtained from 691 participants (5–17 years of age) from six different centers. Six data quality metrics—contrast to noise ratio, outlier slices, and motion (absolute, relative, translation, and rotational)—and four diffusion measures—fractional anisotropy, mean diffusivity, tract density, and length—were computed for each of 36 major fiber tracts for all participants. The results indicated that four out of six data quality metrics (all except absolute and translation motion) differed significantly between centers. Associations between these data quality metrics and the diffusion measures differed significantly across the tracts and centers. Moreover, these effects remained significant after applying recently proposed harmonization algorithms that purport to remove unwanted between-site variation in diffusion data. These results demonstrate the widespread impact of dMRI data quality on diffusion measures. These tracts and measures have been routinely associated with individual differences as well as group-wide differences between neurotypical populations and individuals with neurological or developmental disorders. Accordingly, for analyses of individual differences or group effects (particularly in multisite dataset), we encourage the inclusion of data quality metrics in dMRI analysis.
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Alongside stereotactic magnetic resonance imaging, microelectrode recording (MER) is frequently used during the deep brain stimulation (DBS) surgery for optimal target localization. The aim of this study is to optimize subthalamic nucleus (STN) mapping using MER analytical patterns. 16 patients underwent bilateral STN-DBS. MER was performed simultaneously for 5 microelectrodes in a setting of Ben's-gun pattern in awake patients. Using spikes and background activity several different parameters and their spectral estimates in various frequency bands including low frequency (2-7 Hz), Alpha (8-12 Hz), Beta (sub-divided as Low_Beta (13-20 Hz) and High_Beta (21-30 Hz)) and Gamma (31 to 49 Hz) were computed. The optimal STN lead placement with the most optimal clinical effect/ side-effect ratio accorded to the maximum spike rate in 85% of the implantation. Mean amplitude of background activity in the low beta frequency range was corresponding to right depth in 85% and right location in 94% of the implantation respectively. MER can be used for STN mapping and intraoperative decisions for the implantation of DBS electrode leads with a high accuracy. Spiking and background activity in the beta range are the most promising independent parameters for the delimitation of the proper anatomical site.
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DBS is an effective neuromodulatory therapy that has been applied in various conditions, including PD, essential tremor, dystonia, Tourette syndrome, and other movement disorders. There have also been recent examples of applications in epilepsy, chronic pain, and neuropsychiatric conditions. Innovations in neuroimaging technology have been driving connectomics, an emerging whole‐brain network approach to neuroscience. Two rising techniques are functional connectivity profiling and structural connectivity profiling. Functional connectivity profiling explores the operational relationships between multiple regions of the brain with respect to time and stimuli. Structural connectivity profiling approximates physical connections between different brain regions through reconstruction of axonal fibers. Through these techniques, complex relationships can be described in various disease states, such as PD, as well as in response to therapy, such as DBS. These advances have expanded our understanding of human brain function and have provided a partial in vivo glimpse into the underlying brain circuits underpinning movement and other disorders. This comprehensive review will highlight the contemporary concepts in brain connectivity as applied to DBS, as well as introduce emerging considerations in movement disorders. © 2020 International Parkinson and Movement Disorder Society
Objective: Deep brain stimulation (DBS) has demonstrated to be an advanced therapy for selected patients with Parkinson disease (PD) from numerous clinical trials, while its maximal therapeutic effect is capped by the inadequate understanding of precise neuronal mechanisms underlying PD. Recordings from multi-channel electrodes placed in subcortical and cortical regions of the basal ganglia-thalamocortical (BGTC) motor network during DBS surgical procedures can provide rich physiologic information from accessible network nodes. However, most investigations focus on presumed spatio-spectral points of interest, neither fully utilizing the richness of spatial, spectral and temporal aspects of the multivariate signals nor making discoveries in the context of all possible candidates. In addition, aggregated network-level information has been missed out. Approach: We use complex network analysis to characterize functional network characteristics of the pallidocortical subcircuit of the BGTC motor network in PD at rest and with movement. The network matrix was constructed using distinct frequency bands at each anatomic recording site as virtual nodes and spectral connectivity (through phase-amplitude coupling and coherence) as network edges. Main results: We confirm the critical roles of beta bands and provide additional evidence on their differential functional roles in the pallidocortical motor network. Moreover, significant changes (p<0.05) in network functional segregation and integration between rest and movement conditions are revealed for the first time. More importantly, movement-dependent modulation of these network metrics are significantly correlated with hemi-body Unified Parkinson Disease Rating Scales (UPDRS), providing network-level perspectives of pallidocortical motor network pertaining to PD symptoms (p<0.05). Significance: Findings in the present study provide network-level understanding of neuronal mechanisms in the pallidocortical motor network underlying PD. The demonstrated approach is also highly plausible to be applied in other important subcircuits towards comprehensive understanding of the BGTC motor network.
Many studies suggest that Parkinson's disease (PD) is associated with changes in neuronal activity patterns throughout the basal ganglia-thalamocortical motor circuit. There are limited electrophysiological data, however, describing how parkinsonism impacts the pre-supplementary motor area (pre-SMA) and SMA proper (SMAp), cortical areas known to be involved in movement planning and motor control. In this study, local field potentials (LFPs) were recorded in the pre-SMA/SMAp of a non-human primate during a visually cued reaching task. Recordings were made in the same subject in both the naive and parkinsonian state using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. We found that in the naive animal, well before a go cue providing instruction of reach onset and direction was given, LFP activity was dynamically modulated in both high (20-30 Hz) and low-beta (10-20 Hz) bands, and the magnitude of this modulation correlated linearly with reaction time (RT) on a trial-to-trial basis, suggesting it may predictively encode for RT. Consistent with this hypothesis, we observed that this activity was more prominent within the pre-SMA compared to SMAp. In the parkinsonian state, however, pre-SMA/SMAp beta band modulation was disrupted, particularly in the high-beta band, such that the predictive encoding of RT was significantly diminished. In addition, the predictive encoding of RT preferentially within pre-SMA over SMAp was lost. These findings add to our understanding of the role of pre-SMA/SMAp in motor behavior and suggest a fundamental role of these cortical areas in early preparatory and pre-movement processes that are altered in parkinsonism.
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Dystonia is a brain disorder characterized by sustained involuntary muscle contractions. It is typically inherited as an autosomal dominant trait with incomplete penetrance. While lacking clear degenerative neuropathology, primary dystonia is thought to involve microstructural and functional changes in neuronal circuitry. In the current study, we used magnetic resonance diffusion tensor imaging and probabilistic tractography to identify the specific circuit abnormalities that underlie clinical penetrance in carriers of genetic mutations for this disorder. This approach revealed reduced integrity of cerebellothalamocortical fiber tracts, likely developmental in origin, in both manifesting and clinically nonmanifesting dystonia mutation carriers. In these subjects, reductions in cerebellothalamic connectivity correlated with increased motor activation responses, consistent with loss of inhibition at the cortical level. Nonmanifesting mutation carriers were distinguished by an additional area of fiber tract disruption situated distally along the thalamocortical segment of the pathway, in tandem with the proximal cerebellar outflow abnormality. In individual gene carriers, clinical penetrance was determined by the difference in connectivity measured at these two sites. Overall, these findings point to a novel mechanism to explain differences in clinical expression in carriers of genes for brain disease.
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Deep brain stimulation (DBS) is a therapeutic option for intractable neurological and psychiatric disorders, including Parkinson's disease and major depression. Because of the heterogeneity of brain tissues where electrodes are placed, it has been challenging to elucidate the relevant target cell types or underlying mechanisms of DBS. We used optogenetics and solid-state optics to systematically drive or inhibit an array of distinct circuit elements in freely moving parkinsonian rodents and found that therapeutic effects within the subthalamic nucleus can be accounted for by direct selective stimulation of afferent axons projecting to this region. In addition to providing insight into DBS mechanisms, these results demonstrate an optical approach for dissection of disease circuitry and define the technological toolbox needed for systematic deconstruction of disease circuits by selectively controlling individual components.
An automated coordinate-based system to retrieve brain labels from the 1988 Talairach Atlas, called the Talairach Daemon (TD), was previously introduced [Lancaster et al., 1997]. In the present study, the TD system and its 3-D database of labels for the 1988 Talairach atlas were tested for labeling of functional activation foci. TD system labels were compared with author-designated labels of activation coordinates from over 250 published functional brain-mapping studies and with manual atlas-derived labels from an expert group using a subset of these activation coordinates. Automated labeling by the TD system compared well with authors' labels, with a 70% or greater label match averaged over all locations. Author-label matching improved to greater than 90% within a search range of +/-5 mm for most sites. An adaptive grey matter (GM) range-search utility was evaluated using individual activations from the M1 mouth region (30 subjects, 52 sites). It provided an 87% label match to Brodmann area labels (BA 4 & BA 6) within a search range of +/-5 mm. Using the adaptive GM range search, the TD system's overall match with authors' labels (90%) was better than that of the expert group (80%). When used in concert with authors' deeper knowledge of an experiment, the TD system provides consistent and comprehensive labels for brain activation foci. Additional suggested applications of the TD system include interactive labeling, anatomical grouping of activation foci, lesion-deficit analysis, and neuroanatomy education. (C) 2000 Wiley-Liss, Inc.
Much recent discussion about the origin of Parkinsonian symptoms has centered around the idea that they arise with the increase of beta frequency waves in the EEG. This activity may be closely related to an oscillation between subthalamic nucleus (STN) and globus pallidus. Since STN is the target of deep brain stimulation, it had been assumed that its action is on the nucleus itself. By means of simultaneous recordings of the firing activities from populations of neurons and the local field potentials in the motor cortex of freely moving Parkinsonian rats, this study casts doubt on this assumption. Instead, we found evidence that the corrective action is upon the cortex, where stochastic antidromic spikes originating from the STN directly modify the firing probability of the corticofugal projection neurons, destroy the dominance of beta rhythm, and thus restore motor control to the subjects, be they patients or rodents.
Subthalamic nucleus (STN) stimulation is a popular treatment for Parkinson's disease; however, its effect on neuronal activity is unclear. We performed simultaneous multi-electrode recordings in the STN and its targets, the globus pallidus internus (GPi) and externus (GPe) in the parkinsonian non-human primate during high frequency STN macro-stimulation. Our results indicate that in the parkinsonian state the abnormal neuronal oscillatory activity in the 10-15 Hz range is coherent within and between nuclei. We further show that STN macro-stimulation results in a reduction of oscillatory activity in the globus pallidus. In addition, a functional decoupling of the STN from its pallidal targets is evidenced by the reduced STN-GPi coherence, that effectively removes the STN synchronous oscillatory drive of basal ganglia output. This decoupling results in reduced coherence between neurons within the GPi which resume an independent neuronal activity pattern. This decorrelation of the basal ganglia output may result in a reduction of the fluctuations of the basal ganglia inhibitory control over thalamic neurons which may potentially contribute to the beneficial effects of deep brain high-frequency stimulation.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can be an effective treatment for the motor symptoms of Parkinson's disease. The therapeutic benefits are voltage-dependent and, in many cases, limited by the appearance of side effects, including muscle contractions. We have observed a number of clinical cases where improvements in rigidity were accompanied by a worsening of bradykinesia. Considering the anatomic position of STN and current approaches to implantation of the DBS lead, we hypothesized that this dissociation of motor symptoms arises from activation of pyramidal tract fibers in the adjacent internal capsule. The objective of this study was to assess the physiological basis for this dissociation and to test our hypothesis that the underlying etiology of this paradox is activation of fibers of the internal capsule. The effect of STN DBS at 80% of motor threshold for each of the four contacts was evaluated for its effect on rigidity, bradykinesia, and akinesia in a single primate with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Consistent with our observations in humans, this near-threshold stimulation was found to improve rigidity while bradykinesia and akinesia worsened. Worsening bradykinesia in the face of improvement of other motor signs in Parkinson's disease (PD) patients is suggestive of activation of pyramidal tract (PT) fibers during stimulation. This phenomenon may occur without overt muscle contraction and improved rigidity.
Deep brain stimulation (DBS) is an established medical therapy for the treatment of movement disorders and shows great promise for several other neurological disorders. However, after decades of clinical utility the underlying therapeutic mechanisms remain undefined. Early attempts to explain the mechanisms of DBS focused on hypotheses that mimicked an ablative lesion to the stimulated brain region. More recent scientific efforts have explored the wide-spread changes in neural activity generated throughout the stimulated brain network. In turn, new theories on the mechanisms of DBS have taken a systems-level approach to begin to decipher the network activity. This review provides an introduction to some of the network based theories on the function and pathophysiology of the cortico-basal-ganglia-thalamo-cortical loops commonly targeted by DBS. We then analyze some recent results on the effects of DBS on these networks, with a focus on subthalamic DBS for the treatment of Parkinson's disease. Finally we attempt to summarize how DBS could be achieving its therapeutic effects by overriding pathological network activity.
A widely used technique for coordinate-based meta-analyses of neuroimaging data is activation likelihood estimation (ALE). ALE assesses the overlap between foci based on modeling them as probability distributions centered at the respective coordinates. In this Human Brain Project/Neuroinformatics research, the authors present a revised ALE algorithm addressing drawbacks associated with former implementations. The first change pertains to the size of the probability distributions, which had to be specified by the used. To provide a more principled solution, the authors analyzed fMRI data of 21 subjects, each normalized into MNI space using nine different approaches. This analysis provided quantitative estimates of between-subject and between-template variability for 16 functionally defined regions, which were then used to explicitly model the spatial uncertainty associated with each reported coordinate. Secondly, instead of testing for an above-chance clustering between foci, the revised algorithm assesses above-chance clustering between experiments. The spatial relationship between foci in a given experiment is now assumed to be fixed and ALE results are assessed against a null-distribution of random spatial association between experiments. Critically, this modification entails a change from fixed- to random-effects inference in ALE analysis allowing generalization of the results to the entire population of studies analyzed. By comparative analysis of real and simulated data, the authors showed that the revised ALE-algorithm overcomes conceptual problems of former meta-analyses and increases the specificity of the ensuing results without loosing the sensitivity of the original approach. It may thus provide a methodologically improved tool for coordinate-based meta-analyses on functional imaging data.
(1) There are data on the amount of current necessary to stimulate a myelinated fiber or cell body and/or its axon a given distance away from a monopolar electrode over the entire range of practical interest for intracranial stimulation. Data do not exist for other electrode configurations. (2) Currents from a monopolar cathode of more than 8 times threshold may block action potentials in axons. Therefore, only axons lying in a shell around the electrode are stimulated. Elements very close to the electrode may not be stimulated. Close to an electrode small diameter axons may be stimulated and larger ones may not be. (3) Most, and perhaps all, CNS myelinated fibers have chronaxies of 50-100 musec. When gray matter is stimulated, the chronaxie is often 200-700 musec. It is not clear what is being stimulated in this case. Current-duration relations should be determined for many more responses. (4) There are no current-distance or current-duration data for central finely myelinated or unmyelinated fibers. (5) It takes less cathodal current than anodal to stimulate a myelinated fiber passing by a monopolar electrode. When a monopolar electrode is near a cell body, on the opposite side from the axon, often the lowest threshold is anodal, but sometimes cathodal. Stimulation of a neuron near its cell body is not well understood, but in many cases the axon is probably stimulated. (6) Orientation of cell body and axons with respect to current flow is important. For an axon it is the component of the voltage gradient parallel to the fiber that is important. (7) The pia has a significant resistance and capacitance. Gray matter, white matter, and cerebrospinal fluid have different resistivities, which affect patterns of current flow. (8) More is known about stimulation of mammalian CNS than most workers are aware of. Much of what is unknown seems solvable with current methods.