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Toward defining deep brain stimulation targets in MNI space: A subcortical atlas based on multimodal MRI, histology and structural connectivity

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Three-dimensional atlases of subcortical brain structures are valuable tools to reference anatomy in neuroscience and neurology. For instance, they can be used to study the position and shape of the three most common deep brain stimulation (DBS) targets, the sub-thalamic nucleus (STN), internal part of the pallidum (GPi) and ventral intermediate nucleus of the thalamus (VIM) in stereotactic space and in spatial relationship to DBS electrodes. Here, we present a composite atlas that is based on manual segmentations of a multimodal high resolution brain template, histology and structural connectivity. In a first step, four key structures were defined on the template itself using a combination of multi-spectral image analysis and manual segmentation. Second, these structures were used as anchor points to coregister a detailed histological atlas into standard space. Results show that this approach significantly improved coregistration accuracy over previously published methods. Finally, a sub-segmentation of STN and GPi into functional zones was achieved based on structural connectivity. The result is a composite atlas that defines key nuclei on the template itself, fills the gaps between them using histology and further subdivides them using structural connectivity. We show that the atlas can be used to segment DBS targets in single subjects, yielding more accurate results compared to priorly published atlases. The atlas will be made publicly available and constitutes a resource to study DBS electrode localizations in combination with modern neuroimaging methods.
Which one is «correct»? Comparison of the ICBM 152 2009b NLIN template and various atlases of the STN available in standard space. Large panel: Overview showing selected section of the template. Small panels: First (upper middle) panel: The hy- pointense lentiform region of the STN defined by the template may clearly be identified. Subsequent panels show definitions of the STN based on various atlases overlaid to the template. Please note that some of the ATAG atlases have been estimated specifically to account for, e.g. age-related variance of the STN and are thus prone to vary from template anatomy (which is based on young subjects). *Also note that the Chakravarty 2006 histo- logical atlas was coregistered to the colin27 average T1 brain template (on which the STN is not visible; Holmes et al. 1998) but is overlaid to a different template here. Even though both templates represent similar versions of the MNI space, inaccuracies on subcortical structures are prone to happen. STN definition from the Talairach Demon as defined by WFU Pickatlas (Lancaster et al. 2000; Maldjian et al. 2003). The version of the MIDA mod- el was nonlinearly coregistered to standard space using a multimodal SyN deformation with Advanced Normalization Tools as implemented in Lead-DBS. The selected axial slice cuts through two of three functional zones of the atlas by Accolla and colleagues (motor: orange, associative: yellow). Bottom right panel shows all atlases overlaid to visualize their distribution. Axial sections displayed at z = -8 mm.
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... This helps to highlight the electrodes' relationship with different neuroanatomical substrates, such as the subthalamic nucleus (STN). In particular, the DISTAL atlas displays the STN and its subdivisions; the substantia nigra (SN), located ventrally to the STN; the thalamus and its subdivisions, as well as the zona incerta (ZI), both located dorsally to the STN (Ewert et al., 2018). This subcortical atlas was based on manual segmentations of high resolution brain template series, the Montreal Neurological Institute (MNI) 152 template series, to which a histological atlas and an atlas of structural connectivity were co-registered (Ewert et al., 2018). ...
... In particular, the DISTAL atlas displays the STN and its subdivisions; the substantia nigra (SN), located ventrally to the STN; the thalamus and its subdivisions, as well as the zona incerta (ZI), both located dorsally to the STN (Ewert et al., 2018). This subcortical atlas was based on manual segmentations of high resolution brain template series, the Montreal Neurological Institute (MNI) 152 template series, to which a histological atlas and an atlas of structural connectivity were co-registered (Ewert et al., 2018). ...
... To determine the location of each MER relative to the anatomical substrates, the reconstructed images were segmented using the DISTAL atlas (Ewert et al., 2018), bringing out all the relevant subcortical structures, including the STN subdivisions. This subcortical atlas was based on manual segmentations of multimodal (T1, T2, proton density, T2 relaxometry) high resolution brain template series, the Montreal Neurological Institute (MNI) 152 template series (http://www.bic.mni. ...
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Microelectrode recordings (MERs) are often used during deep brain stimulation (DBS) surgeries to confirm the position of electrodes in patients with advanced Parkinson’s disease. The present study focused on 32 patients who had undergone DBS surgery for advanced Parkinson’s disease. The first objective was to confront the anatomical locations of intraoperative individual MERs as determined electrophysiologically with those determined postoperatively by image reconstructions. The second aim was to search for differences in cell characteristics among the three subthalamic nucleus (STN) subdivisions and between the STN and other identified subcortical structures. Using the DISTAL atlas implemented in the Lead-DBS image reconstruction toolbox, each MER location was determined postoperatively and attributed to specific anatomical structures (sensorimotor, associative or limbic STN; substantia nigra [SN], thalamus, nucleus reticularis polaris, zona incerta [ZI]). The STN dorsal borders determined intraoperatively from electrophysiology were then compared with the STN dorsal borders determined by the reconstructed images. Parameters of spike clusters (firing rates, amplitudes – with minimum amplitude of 60 μV -, spike durations, amplitude spectral density of β-oscillations) were compared between structures (ANOVAs on ranks). Two hundred and thirty one MERs were analyzed (144 in 34 STNs, 7 in 4 thalami, 5 in 4 ZIs, 34 in 10 SNs, 41 others). The average difference in depth of the electrophysiological dorsal STN entry in comparison with the STN entry obtained with Lead-DBS was found to be of 0.1 mm (standard deviation: 0.8 mm). All 12 analyzed MERs recorded above the electrophysiologically-determined STN entry were confirmed to be in the thalamus or zona incerta. All MERs electrophysiologically attributed to the SN were confirmed to belong to this nucleus. However, 6/34 MERs that were electrophysiologically attributed to the ventral STN were postoperatively reattributed to the SN. Furthermore, 44 MERs of 3 trajectories, which were intraoperatively attributed to the STN, were postoperatively reattributed to the pallidum or thalamus. MER parameters seemed to differ across the STN, with higher spike amplitudes (H = 10.64, p < 0.01) and less prevalent β-oscillations (H = 9.81, p < 0.01) in the limbic STN than in the sensorimotor and associative subdivisions. Some cells, especially in the SN, showed longer spikes with lower firing rates, in agreement with described characteristics of dopamine cells. However, these probabilistic electrophysiological signatures might become clinically less relevant with the development of image reconstruction tools, which deserve to be applied intraoperatively.
... This tripartite organization has been reported by using tractography-based parcellation. 22,29,[53][54][55] In addition, we added a fourth segment based on SMA-related connectivity, located between the SMC and associative clusters. To date, few imaging-based STN atlases have explicitly parcellated the SMA-connected region, even though this cortico-STN projection is considered to play an important role in normal motor and behavioral control and in the pathophysiology of PD. 31,56 Previous studies using fluorodeoxyglucose-positron emission tomography suggested that long-range modulation of SMA metabolism underlies improvement of the motor score by both STN-DBS 57 and tcMRgFUS subthalamotomy, 58 and some evidence points to the border between the motor and associative clusters as the most effective target. ...
... 55 In contrast, probabilistic tractography provides robust and reliable results with high-quality large databases, but its sampling and reconstruction requirements may be prohibitive in a routine clinical context. 22,28,53,55 Conversely, GQI reconstruction outperforms other tractography techniques when applied to diffusion datasets with a standard signal-to-noise ratio, while reducing the processing time of probabilistic methods by several orders. 26 Therefore, analytic tractography may play an important role in incorporating tractography into STN targeting, particularly in tcMRgFUS subthalamotomy and direct MRI-based DBS, which are limited by the absence of neurophysiological feedback. ...
... 75,76 This explains the reported variability, ranging from approximately 70 to 140 mm 3 . 53,77,78 Furthermore, morphological discrepancies between histological and neuroimaging data introduce shortcomings in any atlas-guided segmentation, reducing the sensitivity and reproducibility of segmentation based on STN connectivity. ...
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Background: The subthalamic nucleus (STN) is considered a key structure in motor, behavioral, and emotional control. Although identification of the functional topography of the STN has therapeutic implications in the treatment of the motor features of Parkinson's disease (PD), the details of its functional and somatotopic organization in humans are not well understood. Objective: The aim of this study was to characterize the functional organization of the STN and its correlation with the motor outcomes induced by subthalamotomy. Methods: We used diffusion-weighted imaging to assess STN connectivity patterns in 23 healthy control subjects and 86 patients with PD, of whom 39 received unilateral subthalamotomy. Analytical tractography was used to reconstruct structural cortico-subthalamic connectivity. A diffusion-weighted imaging/functional magnetic resonance imaging-driven somatotopic parcellation of the STN was defined to delineate the representation of the upper and lower limb in the STN. Results: We confirmed a connectional gradient to sensorimotor, supplementary-motor, associative, and limbic cortical regions, spanning from posterior-dorsal-lateral to anterior-ventral-medial portions of the STN, with intermediate overlapping zones. Functional magnetic resonance imaging-driven parcellation demonstrated dual segregation of motor cortico-subthalamic projections in humans. Moreover, the relationship between lesion topography and functional anatomy of the STN explains specific improvement in bradykinesia, rigidity, and tremor induced by subthalamotomy. Conclusions: Our results support an interplay between segregation and integration of cortico-subthalamic projections, suggesting the coexistence of parallel and convergent information processing. Identifying the functional topography of the STN will facilitate better definition of the optimal location for functional neurosurgical approaches, that is, electrode placement and lesion location, and improve specific cardinal features in PD. © 2021 International Parkinson and Movement Disorder Society.
... We then generated linear models using volume overlap as dependent variable to explain variance in clinical outcome (total tremor improvement). This process was repeated for alternative diencephalic structures including VIM [18][19][20][21][22] and DRT, 2,23-25 as well as the previously generated probabilistic maps to compare overall model performance. Because patients were stimulated bilaterally, the percent overlap between ROIs and stimulation volumes was aggregated across both hemispheres in each patient. ...
... R 2 = 0.01, p = 0.657; DRT: Dembek et al, 2 R 2 = 0.02, p = 0.366; cerebellothalamic outflow tract [VIM + DRT]: R 2 = 0.06, p = 0.168; see Fig 3G-I).To investigate whether variability of segmentation approaches and diffusion MRI (dMRI) pipelines could explain the lower predictive ability of our models as compared to hypointensity overlap, we correlated clinical outcome with volume overlap using additional VIM[19][20][21][22] and DRT 23-25 atlases derived from Lead-DBS. Overlap with atlases, however, was again not able to explain an amount of variance comparable to the hypointensity (VIM: Ewert et al,19 R 2 = 0.01, p = 0.539; Ilinsky et al, 20 R 2 = 0.03, p = 0.301; Akram et al, 21 R 2 = 0.02, p = 0.422; ...
... R 2 = 0.01, p = 0.657; DRT: Dembek et al, 2 R 2 = 0.02, p = 0.366; cerebellothalamic outflow tract [VIM + DRT]: R 2 = 0.06, p = 0.168; see Fig 3G-I).To investigate whether variability of segmentation approaches and diffusion MRI (dMRI) pipelines could explain the lower predictive ability of our models as compared to hypointensity overlap, we correlated clinical outcome with volume overlap using additional VIM[19][20][21][22] and DRT 23-25 atlases derived from Lead-DBS. Overlap with atlases, however, was again not able to explain an amount of variance comparable to the hypointensity (VIM: Ewert et al,19 R 2 = 0.01, p = 0.539; Ilinsky et al, 20 R 2 = 0.03, p = 0.301; Akram et al, 21 R 2 = 0.02, p = 0.422; He et al, 22 R 2 = 0.02, p = 0.424; DRT: Lau et al, 23 R 2 = 0.03, p = 0.283; Petersen et al, 24 R 2 = 0.03, p = 0.332; Middlebrooks et al, 25 R 2 = 0.01, p = 0.536; decussating DRT: Middlebrooks et al, 25 R 2 = 0.02, p = 0.361; nondecussating DRT: Middlebrooks et al, 25 R 2 = 0.0, p = 0.874; all combinations of VIM + DRT: R 2 mean = 0.02 (range = 0.0007-0.03), ...
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Objective: With a growing appreciation for interindividual anatomical variability and patient-specific brain connectivity, advanced imaging sequences offer the opportunity to directly visualize anatomical targets for deep brain stimulation (DBS). The lack of quantitative evidence demonstrating their clinical utility, however, has hindered their broad implementation in clinical practice. Methods: Using fast gray matter acquisition T1 inversion recovery (FGATIR) sequences, the present study identified a thalamic hypointensity that holds promise as a visual marker in DBS. To validate the clinical utility of the identified hypointensity we retrospectively analyzed 65 patients (26 female, mean age: 69.1 ± 12.7 years) who underwent DBS in the treatment of essential tremor. We characterized its neuroanatomical substrates and evaluated the hypointensity's ability to predict clinical outcome using stimulation volume modeling and voxel-wise mapping. Finally, we determined whether the hypointensity marker could predict symptom improvement on a patient-specific level. Results: Anatomical characterization suggested that the identified hypointensity constituted the terminal part of the dentato-rubro-thalamic tract. Overlap between DBS stimulation volumes and the hypointensity in standard space significantly correlated with tremor improvement (R2 = 0.16, p = 0.017) and distance to hotspots previously reported in the literature (R2 = 0.49, p = 7.9e-4). In contrast, the amount of variance explained by other anatomical atlas structures was reduced. When accounting for interindividual neuroanatomical variability, the predictive power of the hypointensity increased further (R2 = 0.37, p = 0.002). Interpretation: Our findings introduce and validate a novel imaging-based marker attainable from FGATIR sequences that has the potential to personalize and inform targeting and programming in DBS for essential tremor. This article is protected by copyright. All rights reserved.
... As the smallest nucleus of the basal ganglia, the STN predominantly receives input from the external pallidum, thalamus, and several brain stem nuclei (Parent and Hazrati, 1995) in addition to input from direct cortical projections (Nambu et al., 2002). Anterograde tracing work in animals (Haynes and Haber, 2013;Parent and Hazrati, 1995) and diffusion-weighted imaging studies in humans (Accolla et al., 2014;Ewert et al., 2018;Lambert et al., 2012) have revealed a topographic organisation of these structural connections that has motivated a partitioning of the STN into sensorimotor, cognitive/associative, and limbic subregions. Although such a tripartite subdivision forms an attractive hypothesis for the relation between the exact anatomical coordinates of implanted DBS electrodes and the observed effect of stimulation on motor and neuropsychiatric symptoms (Temel et al., 2005), it has also been met with scepticism due to inconsistent findings across studies regarding the number and location of subregions (Keuken et al., 2012) and the large degree of overlap in terminal fields from cortical projections (Alkemade et al., 2015). ...
... The MNI locations for the left hemisphere were projected towards the right hemisphere via non-linear registration to the mirrored template scan. The DISTAL atlas (Ewert et al., 2018) was used to visualize results with respect to sensorimotor, cognitive/associative, and limbic subregions that were informed by cortical-STN structural connectivity. ...
... Recordings ON medication are shown in the top row, recordings OFF medication in the bottom row. The STN is visualized according to the Distal atlas (Ewert et al., 2018) with its subregions as derived from human tractography data. All data points were projected and visualized onto the STN in the right hemisphere. ...
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The subthalamic nucleus (STN) is a primary target for deep brain stimulation in Parkinson's disease (PD). Although small in size, the STN is commonly partitioned into sensorimotor, cognitive/associative, and limbic subregions based on its structural connectivity profile to cortical areas. We investigated whether such a regional specialization is also supported by functional connectivity between local field potential recordings and simultaneous magnetoencephalography. Using a novel data set of 21 PD patients, we replicated previously reported cortico-STN coherence networks in the theta/alpha and beta frequency ranges, and looked for the spatial distribution of these networks within the STN region. Although theta/alpha and beta coherence peaks were both observed in on-medication recordings from electrode contacts at several locations within and around the STN, sites with theta/alpha coherence peaks were situated at significantly more inferior MNI coordinates than beta coherence peaks. Sites with only theta/alpha coherence peaks, i.e. without distinct beta coherence, were mostly located near the border of sensorimotor and cognitive/associative subregions as defined by a tractography-based atlas of the STN. Peak coherence values were largely unaltered by the medication state of the subject, however, theta/alpha peaks were more often identified in recordings obtained after administration of dopaminergic medication. Our findings suggest the existence of a frequency-specific topography of cortico-STN coherence within the STN, albeit with considerable spatial overlap between functional networks. Consequently, optimization of deep brain stimulation targeting might remain a trade-off between alleviating motor symptoms and avoiding adverse neuropsychiatric side effects.
... 38 One participant (Subject 8) experienced worsening of tremor at 6-months post-DBS implantation (−50% worsening) and was labelled a non-responder. Her connectivity profile demonstrated strong connectivity to the PMC (0.33) and weaker connectivity to the SMA (0.56). ...
... The active contacts for each lead are denoted in green. The thalamic nuclei are defined from the DISTAL.38 ...
... The spatial differences for the VIM-targeted (red) and VOp-targeted (yellow) VTAs are shown for the (A) non-responder subject and (B) super-responder subject at 6 months postimplantation. The VIM nucleus (blue) and VOp nucleus (orange) are defined from the DISTAL.38 ...
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Tremor is a common symptom in multiple sclerosis and can present as a severe postural and action tremor, leading to significant disability. Owing to the diffuse and progressive nature of the disease, it has been challenging to characterize the pathophysiology underlying multiple sclerosis tremor. Deep brain stimulation of the ventralis intermedius and the ventralis oralis posterior thalamic nuclei has been used to treat medically refractory multiple sclerosis tremors with variable results. The aim of this study was to characterize multiple sclerosis tremor at the network level by applying modern connectomic techniques to data from a previously completed single-centre, randomized, single-blind prospective trial of 12 subjects who were treated with unilateral dual-lead (ventralis intermedius + ventralis oralis posterior) thalamic deep brain stimulation. Preoperative T1-weighted MRI and postoperative head CTs were used, along with applied programming settings, to estimate the volume of tissue activated for each patient. The volumes of tissue activated were then used to make voxel-wise and structural connectivity correlations with clinically observed tremor suppression. The volume of the tissue-activated analyses identified the optimal region of stimulation at the ventralis oralis posterior ventralis intermedius border intersecting with the dentato-rubro-thalamic tract. A regression model showed strong connectivity to the supplemental motor area was positively associated with tremor suppression (r = 0.66) in this cohort, whereas connectivity to the primary motor cortex was negatively associated with tremor suppression (r = −0.69), a finding opposite to that seen in ventralis intermedius deep brain stimulation for essential tremor. Comparing the structural connectivity to that of an essential tremor cohort revealed a distinct network that lies anterior to the essential tremor network. Overall, the volumes of tissue activated and connectivity observations converge to suggest that optimal suppression of multiple sclerosis tremor will likely be achieved by directing stimulation more anteriorly toward the ventralis oralis posterior and that a wide field of stimulation synergistically modulating the ventralis oralis posterior and ventralis intermedius nuclei may be more effective than traditional ventralis intermedius deep brain stimulation at suppressing the severe tremors commonly seen in complex tremor syndromes such as multiple sclerosis tremor.
... cgi-bin/index.cgi) that segregated peri-electrode tissue by tissue type. 27 The FieldTrip-SimBio finite element model pipeline was then used to simulate the potential electric field distribution around each active contact (https://www. mrt.uni-jena.de/simbio/index.php/; ...
... A 3D reconstruction showing the electrode placement for the 8 patients in the connectomic analyses, using a high-resolution, high-fidelity brain template. 46 Renderings of the target structures are provided in 3D: NAcc in green 27 and pHyp in blue. 46 The DBS electrodes are identified in pairs, with the exception of patients D and F, who only received unilateral electrodes on the right. ...
Article
OBJECTIVE Individuals with autism spectrum disorder (ASD) may display extreme behaviors such as self-injury or aggression that often become refractory to psychopharmacology or behavioral intervention. Deep brain stimulation (DBS) is a surgical alternative that modulates brain circuits that have yet to be clearly elucidated. In the current study the authors performed a connectomic analysis to identify brain circuitry engaged by DBS for extreme behaviors associated with ASD. METHODS A systematic review was performed to identify prior reports of DBS as a treatment for extreme behaviors in patients with ASD. Individual patients' perioperative imaging was collected from corresponding authors. DBS electrode localization and volume of tissue activated modeling were performed. Volumes of tissue activated were used as seed points in high-resolution normative functional and structural imaging templates. The resulting individual functional and structural connectivity maps were pooled to identify networks and pathways that are commonly engaged by all targets. RESULTS Nine patients with ASD who were receiving DBS for symptoms of aggression or self-injurious behavior were identified. All patients had some clinical improvement with DBS. Connectomic analysis of 8 patients (from the systematic review and unpublished clinical data) demonstrated a common anatomical area of shared circuitry within the anterior limb of the internal capsule. Functional analysis of 4 patients identified a common network of distant brain areas including the amygdala, insula, and anterior cingulate engaged by DBS. CONCLUSIONS This study presents a comprehensive synopsis of the evidence for DBS in the treatment of extreme behaviors associated with ASD. Using network mapping, the authors identified key circuitry common to DBS targets.
... 11 When speaking of the sensorimotor/associative/ limbic functional zones of the structure, we apply the parcellation defined (based on structural connectivity) in Ewert and colleagues. 12 Here, we used data from the EARLYSTIM cohort 13 to investigate the relationship between the localization of the STN-DBS electrodes and improvement in clinical parameters, particularly QoL. The major advantage of this cohort over previously used (and mostly retrospective) cohorts 8,14-17 is the meticulous clinical characterization over a period of 2 years after stimulation. ...
... We must emphasize that in reality, the basal ganglia loops rather work along a gradient/continuum and loops are highly interconnected on multiple levels-but the applied model of three divisions would still serve as a useful simplified model here. Therefore, we used the tripartite separation of the STN into its subareas 12 and studied the correlation of the overlap of the individual stimulation volume with the anatomical target area (Supplementary Table S2). We found significant correlations between the extent of the overlap with the sensorimotor STN and the improvement along the UPDRS III (left: r = 0.32, P = 0.004; right: r = 0.29, P = 0.010) and the PDQ-39 SI (left: r = 0.23, P = 0.032; right: r = 0.43, P < 0.001). ...
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Background: Subthalamic nucleus deep brain stimulation (STN-DBS) effectively treats motor symptoms and quality of life (QoL) of advanced and fluctuating early Parkinson's disease. Little is known about the relation between electrode position and changes in symptom control and ultimately QoL. Objectives: The relation between the stimulated part of the STN and clinical outcomes, including the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS) and the quality-of-life questionnaire, was assessed in a subcohort of the EARLYSTIM study. Methods: Sixty-nine patients from the EARLYSTIM cohort who underwent DBS, with a comprehensive clinical characterization before and 24 months after surgery, were included. Intercorrelations of clinical outcome changes, correlation between the affected functional parts of the STN, and changes in clinical outcomes were investigated. We further calculated sweet spots for different clinical parameters. Results: Improvements in the UPDRS III and Parkinson's Disease Questionnaire (PDQ-39) correlated positively with the extent of the overlap with the sensorimotor STN. The sweet spots for the UPDRS III (x = 11.6, y = -13.1, z = -6.3) and the PDQ-39 differed (x = 14.8, y = -12.4, z = -4.3) ~3.8 mm. Conclusions: The main influence of DBS on QoL is likely mediated through the sensory-motor basal ganglia loop. The PDQ sweet spot is located in a posteroventral spatial location in the STN territory. For aspects of QoL, however, there was also evidence of improvement through stimulation of the other STN subnuclei. More research is necessary to customize the DBS target to individual symptoms of each patient. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
... DBS leads position reconstruction was performed using MATLAB-based software (Lead-DBS, RRID:SCR_002915) (Horn and Kuhn, 2015;Horn et al., 2019) in 11 patients who had both preoperative and postoperative 3D MRI. Final 3D rendering of the DBS leads was demonstrated relative to the sensorimotor, associative, and limbic subregions of STN defined using the DISTAL Atlas (Ewert et al., 2018). ...
... Among these 11 patients, 12 HICs were detected. The reconstructions showed that two HICs involved the motor subregion, one passed through the associative subregion, two involved the border between the motor (Ewert et al., 2018). The sensorimotor subregion of the STN is represented in the orange, associative subregion in blue, and the limbic subregion in yellow. ...
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Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective treatment for the motor impairments of patients with advanced Parkinson's disease. However, mood or behavioral changes, such as mania, hypomania, and impulsive disorders, can occur postoperatively. It has been suggested that these symptoms are associated with the stimulation of the limbic subregion of the STN. Electrophysiological studies demonstrate that the low-frequency activities in ventral STN are modulated during emotional processing. In this study, we report 22 patients with Parkinson's disease who underwent STN DBS for treatment of motor impairment and presented stimulation-induced mood elevation during initial postoperative programming. The contact at which a euphoric state was elicited by stimulation was termed as the hypomania-inducing contact (HIC) and was further correlated with intraoperative local field potential recorded during the descending of DBS electrodes. The power of four frequency bands, namely, θ (4–7 Hz), α (7–10 Hz), β (13–35 Hz), and γ (40–60 Hz), were determined by a non-linear variation of the spectrogram using the concentration of frequency of time (conceFT). The depth of maximum θ power is located approximately 2 mm below HIC on average and has significant correlation with the location of contacts ( r = 0.676, p < 0.001), even after partializing the effect of α and β, respectively ( r = 0.474, p = 0.022; r = 0.461, p = 0.027). The occurrence of HIC was not associated with patient-specific characteristics such as age, gender, disease duration, motor or non-motor symptoms before the operation, or improvement after stimulation. Taken together, these data suggest that the location of maximum θ power is associated with the stimulation-induced hypomania and the prediction of θ power is frequency specific. Our results provide further information to refine targeting intraoperatively and select stimulation contacts in programming.
... Briefly, all images were nonlinearly normalized to standard space [27], after which DBS electrodes were manually localized on the post-operative images and normalized to standard space using the above transform and correcting for post-operative brain shift when necessary [28]. Bilateral VTAs were modelled using the 12-months stimulation settings [29]. ...
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Background: Obsessive-compulsive disorder (OCD) is a debilitating disease with a lifetime prevalence of 2-3%. Neuromodulatory treatments have been successfully used in severe cases. Deep brain stimulation (DBS) targeting the inferior thalamic peduncle (ITP) has been shown to successfully alleviate symptoms in OCD patients; however, the brain circuits implicated remain unclear. Here, we investigate the efficacious neural substrates following ITP-DBS for OCD. Methods: High-quality normative structural and functional connectomics and voxel-wise probabilistic mapping techniques were applied to assess the neural substrates of OCD symptom alleviation in a cohort of 5 ITP-DBS patients. Results: The region of most efficacious stimulation was located in the regions of the ITP and bed nucleus of the stria terminalis. Both functional and structural connectomics analyses demonstrated that successful symptom alleviation involved a brain network encompassing the bilateral amygdala and prefrontal regions. Limitations: The main limitation is the small size of the ITP-DBS cohort. While the findings are highly consistent and significant, these should be validated in larger studies. Conclusions: These results identify a tripartite brain network - composed of the bilateral amygdala and prefrontal regions 24 and 46 - whose engagement is associated with greater symptom improvement. They also provide information for optimizing targeting and identifying network components critically involved in ITP-DBS treatment response. Amygdala engagement in particular seems to be a key component for clinical benefits and could constitute a biomarker for treatment optimization.
... Some studies used histology atlases, such as the Schaltenbrand-Wahren atlas (Nowinski et al., 2005) and Morels atlas (Åström et al., 2010;Fytagoridis et al., 2013), or atlases more specific to the basal ganglia, such as the one from Mai et al. (2015), Dembek et al. (2017), andHorn et al. (2017a). Another approach is integrating segmentations from histology atlases into a probabilistic MRI atlas (Ewert et al., 2018) to obtain the delineations of the anatomical structures. Both types of atlases bring in the known shortcomings of histological atlases . ...
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Deep brain stimulation (DBS) is a well-established neurosurgical procedure for movement disorders that is also being explored for treatment-resistant psychiatric conditions. This review highlights important consideration for DBS simulation and data analysis. The literature on DBS has expanded considerably in recent years, and this article aims to identify important trends in the field. During DBS planning, surgery, and follow up sessions, several large data sets are created for each patient, and it becomes clear that any group analysis of such data is a big data analysis problem and has to be handled with care. The aim of this review is to provide an update and overview from a neuroengineering perspective of the current DBS techniques, technical aids, and emerging tools with the focus on patient-specific electric field (EF) simulations, group analysis, and visualization in the DBS domain. Examples are given from the state-of-the-art literature including our own research. This work reviews different analysis methods for EF simulations, tractography, deep brain anatomical templates, and group analysis. Our analysis highlights that group analysis in DBS is a complex multi-level problem and selected parameters will highly influence the result. DBS analysis can only provide clinically relevant information if the EF simulations, tractography results, and derived brain atlases are based on as much patient-specific data as possible. A trend in DBS research is creation of more advanced and intuitive visualization of the complex analysis results suitable for the clinical environment.
... Lead locations are shown in A, oblique and B, axial 3-dimensional projections from a representative subject. Reconstructions were created in lead deep brain stimulation using available Montreal Neurological Institute (MNI)-space subcortical atlases.26,27 Globus pallidus externa (blue), globus pallidus interna (green), subthalamic nucleus (orange), and red nucleus (maroon) are highlighted as volumes, and active contacts are shaded in red. ...
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Background: Deep brain stimulation (DBS) is an effective therapy in advanced Parkinson disease (PD). Although both subthalamic nucleus (STN) and globus pallidus (GP) DBS show equivalent efficacy in PD, combined stimulation may demonstrate synergism. Objective: To evaluate the clinical benefit of stimulating a combination of STN and GP DBS leads and to demonstrate biomarker discovery for adaptive DBS therapy in an observational study. Methods: We performed a pilot trial (n = 3) of implanting bilateral STN and GP DBS leads, connected to a bidirectional implantable pulse generator (Medtronic Summit RC + S; NCT03815656, IDE No. G180280). Initial 1-year outcome in 3 patients included Unified PD Rating Scale on and off medications, medication dosage, Hauser diary, and recorded beta frequency spectral power. Results: Combined DBS improved PD symptom control, allowing >80% levodopa medication reduction. There was a greater decrease in off-medication motor Unified PD Rating Scale with multiple electrodes activated (mean difference from off stimulation off medications -18.2, range -25.5 to -12.5) than either STN (-12.8, range -20.5 to 0) or GP alone (-9, range -11.5 to -4.5). Combined DBS resulted in a greater reduction of beta oscillations in STN in 5/6 hemispheres than either site alone. Adverse events occurred in 2 patients, including a small cortical hemorrhage and seizure at 24 hours postoperatively, which resolved spontaneously, and extension wire scarring requiring revision at 2 months postoperatively. Conclusion: Patients with PD preferred combined DBS stimulation in this preliminary cohort. Future studies will address efficacy of adaptive DBS as we further define biomarkers and control policy.
... The definitions of the nuclei were partly taken from publicly available atlases but were also drawn manually. Definitions of the red nucleus were based on (Ewert et al., 2018); definitions of the sub thalamic nucleus and its subdivision is taken from Ilinsky et al. (2018). The VTA and the mamillary bodies were manually delineated by an experienced neuroscientist based on the T1 and T2 weighted MR images. ...
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Background We here report two cases of stimulation induced pathological laughter (PL) under thalamic deep brain stimulation (DBS) for essential tremor and interpret the effects based on a modified neuroanatomy of positive affect display (PAD).Objective/HypothesisThe hitherto existing neuroanatomy of PAD can be augmented with recently described parts of the motor medial forebrain bundle (motorMFB). We speculate that a co-stimulation of parts of this fiber structure might lead to a non-volitional modulation of PAD resulting in PL.Methods We describe the clinical and individual imaging workup and combine the interpretation with normative diffusion tensor imaging (DTI)-tractography descriptions of motor connections of the ventral tegmental area (VTA) (n = 200 subjects, HCP cohort), [[18F] fluorodeoxyglucose (18FDG)] positron emission tomography (PET), and volume of activated tissue simulations. We integrate these results with literature concerning PAD and the neuroanatomy of smiling and laughing.ResultsDBS electrodes bilaterally co-localized with the MB-pathway (“limiter pathway”). The FDG PET activation pattern allowed to explain pathological PAD. A conceptual revised neuroanatomy of PAD is described.Conclusion Eliciting pathological PAD through chronic thalamic DBS is a new finding and has previously not been reported. PAD is evolution driven, hard wired to the brain and realized over previously described branches of the motorMFB. A major relay region is the VTA/mammillary body complex. PAD physiologically undergoes conscious modulation mainly via the MB branch of the motorMFB (limiter). This limiter in our cases is bilaterally disturbed through DBS. The here described anatomy adds to a previously described framework of neuroanatomy of laughter and humor.
... The applications of the procedure described here are various, but the atlas can be efficiently applied to in vivo MRI data sets, either for post-operative analysis (Fonoff et al. 2012;Martinez et al. 2013) or to clinical voxel-based morphometry (VBM) studies (Kilimann et al. 2014;Teipel et al. 2014). Normalization of high-resolution histology-to-MNI space has clinical importance, since it is the standard stereotactic space in neuroimaging literature and has gained attention recently in the neurosurgical literature in the context of DBS (Horn and Kühn 2015;Ewert et al. 2017). ...
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Fluorescence intensity of embedding foam in paraffin blocks can be used to measure the thickness of histological microsections. We embedded samples of embedding foam and produced several microsections of varying thicknesses using routine processing and staining. Fluorescence intensity in the blue area of the embedding foam detected with a slide scanner was compared to absolute thickness as measured using confocal microscopy. Correlation analysis displayed a clear linear correlation with convincingly low prediction interval. The concept of measuring thickness of histological microsections by detecting fluorescence intensity of embedding foam is suggested as an approach to high-throughput measuring of histological sections applicable for a fully digitized pathology department. No acquisition of dedicated equipment is required and the method can be applied as a fully automated technique requiring no time consumption.
... Conductivity values were set according to standard parameters then the VAT was binarised at a threshold of 0.2 Volts/mm. Finally, electrode locations and VATs were visualised on the DISTAL atlas [27]. ...
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Introduction Accurate placement of deep brain stimulation electrodes within the intended target is believed to be a key variable related to outcomes. However, methods to verify electrode location are not universally established. Research Question The aim of this study was to determine the feasibility of post-op lead localisation in clinical practice and its utility to audit our own DBS accuracy. Material and Methods A retrospective cohort study was performed of a consecutive series of patients with Parkinson’s disease who underwent deep brain stimulation of either the globus pallidus internus (GPi) or subthalamic nucleus (STN) between 2016 and 2019. Image processing was performed using the Lead-DBS toolbox. Institutional ethical approval was granted as a review of service. Results In total 38 participants met the inclusion criteria. Electrode localisation was completed in 79%. Clinical outcomes included improvement in UPDRS III of 46% and PDQ39 of 32%. Overall electrode accuracy was 0.22 +/- 0.4mm for all electrodes to the main nucleus with 9 (12%) outliers but only 3 (4%) electrodes out with 2mm from the intended target. Accuracy was worse for the second electrode implanted and in the GPi but was not affected by pneumocephalus or brain shift. Neither clinical outcomes nor the volume of activated tissue was affected by electrode accuracy. Discussion and Conclusions A neuroimaging approach to electrode localisation allows qualitative appraisal of targeting accuracy and is feasible with routine clinical data. Such methods are complimentary to traditional co-ordinate approaches and lend themselves to developing large, collaborative, and quantitative projects. HIGHLIGHTS Overall electrode accuracy was 0.22 +/- 0.4mm with only 3 (4%) electrodes out with 2mm from the intended target Accuracy was significantly worse in the GPi versus the STN and on the second side implanted Inaccuracy occurred in the X (lateral) plane but was not related to pneumocephalus or brain shift
... Electrode contacts were automatically pre-reconstructed using the TRAC/CORE approach and manually refined using a tool specifically designed for this task in Lead-DBS [11]. 3D electrode reconstructions were rendered in Lead-DBS using anatomic segmentation defined by the DISTAL Atlas [14]. (Figure 2c). ...
Article
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Background: Deep Brain Stimulation (DBS) for dystonia is usually targeted to the globus pallidus internus (GPi), though stimulation of the ventral-intermediate nucleus of the thalamus (Vim) can be an effective treatment for phasic components of dystonia including tremor. We report on a patient who developed a syndrome of bilateral upper limb postural and action tremor and progressive cervical dystonia with both phasic and tonic components which were responsive to Vim DBS. We characterize and quantify this effect using markerless-3D-kinematics combined with accelerometry. Methods: Stereo videography was used to record our subject in 3D. The DeepBehavior toolbox was applied to obtain timeseries of joint position for kinematic analysis [1]. Accelerometry was performed simultaneously for comparison with prior literature. Results: Bilateral Vim DBS improved both dystonic tremor magnitude and tonic posturing. DBS of the hemisphere contralateral to the direction of dystonic head rotation (left Vim) had greater efficacy. Assessment of tremor magnitude by 3D-kinematics was concordant with accelerometry and was able to quantify tonic dystonic posturing. Discussion: In this case, Vim DBS treated both cervical dystonic tremor and dystonic posturing. Markerless-3D-kinematics should be further studied as a method of quantifying and characterizing tremor and dystonia.
... Multispectral normalization to ICBM 2009b MNI space was carried out by applying the ANTs SyN Diffeomorphic Mapping 20 . This method was shown to segment the STN region with high precision comparable to manual expert segmentations in a recent comparative study 21 . DBS electrodes were automatically prereconstructed using the phantom-validated and fully-automated PaCER method 22 ...
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Objective: To obtain individual clinical and neuroimaging data of patients undergoing Deep Brain Stimulation for essential tremor from five different European centers to identify predictors of outcome and to identify an optimal stimulation site. Methods: We analysed retrospectively baseline covariates, pre- and postoperative clinical tremor scores (12-month) as well as individual imaging data from 119 patients to obtain individual electrode positions and stimulation volumes. Individual imaging and clinical data was used to calculate a probabilistic stimulation map in normalized space using voxel-wise statistical analysis. Finally, we used this map to train a classifier to predict tremor improvement. Results: Probabilistic mapping of stimulation effects yielded a statistically significant cluster that was associated with a tremor improvement greater than 50%. This cluster of optimal stimulation extended from the posterior subthalamic area to the ventralis intermedius nucleus and coincided with a normative structural-connectivity-based cerebello-thalamic tract (CTT). The combined features "distance between the stimulation volume and the significant cluster" and "CTT activation" were used as a predictor of tremor improvement. This correctly classified a greater than 50% tremor improvement with a sensitivity of 89% and a specificity of 57%. Interpretation: Our multicentre ET probabilistic stimulation map identified an area of optimal stimulation along the course of the CTT. The results of this study are mainly descriptive until confirmed in independent datasets, ideally through prospective testing. This target will be made openly available and may be used to guide surgical planning and for computer-assisted programming of deep brain stimulation in the future. This article is protected by copyright. All rights reserved.
... Several new atlases for thalamic and basal ganglia structures have also been more recently developed, including atlases based on histology (50-53), structural or functional connectivity (54,55), and postmortem or in vivo high-field 7T MRI (56)(57)(58). Multimodal approaches to atlas construction have also been beneficial for detailed anatomical visualization, as shown in the DISTAL atlas (59). Although the majority of atlases have been developed based on data from healthy controls, population-specific atlases may also provide advantages for capturing specific pathologies, such as the PD25 atlas or the ParkMedAtlas for PD (60,61). ...
Article
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Deep brain stimulation (DBS) has advanced treatment options for a variety of neurologic and neuropsychiatric conditions. As the technology for DBS continues to progress, treatment efficacy will continue to improve and disease indications will expand. Hardware advances such as longer-lasting batteries will reduce the frequency of battery replacement and segmented leads will facilitate improvements in the effectiveness of stimulation and have the potential to minimize stimulation side effects. Targeting advances such as specialized imaging sequences and “connectomics” will facilitate improved accuracy for lead positioning and trajectory planning. Software advances such as closed-loop stimulation and remote programming will enable DBS to be a more personalized and accessible technology. The future of DBS continues to be promising and holds the potential to further improve quality of life. In this review we will address the past, present and future of DBS.
... In tinnitus patients, the maps have the potential to aid future neurosurgical planning for deep-brain stimulation (Smit et al., 2016;van Zwieten et al., 2021). The latter already benefits from the development of multimodal deep-brain stimulation atlases (Ewert et al., 2018) to which our metathalamic probability maps can contribute. ...
Article
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The human metathalamus plays an important role in processing visual and auditory information. Understanding its layers and subdivisions is important to gain insights in its function as a subcortical relay station and involvement in various pathologies. Yet, detailed histological references of the microanatomy in 3D space are still missing. We therefore aim at providing cytoarchitectonic maps of the medial geniculate body (MGB) and its subdivisions in the BigBrain – a high-resolution 3D-reconstructed histological model of the human brain, as well as probabilistic cytoarchitectonic maps of the MGB and lateral geniculate body (LGB). Therefore, histological sections of ten postmortem brains were studied. Three MGB subdivisions (MGBv, MGBd, MGBm) were identified on every 5th BigBrain section, and a deep-learning based tool was applied to map them on every remaining section. The maps were 3D-reconstructed to show the shape and extent of the MGB and its subdivisions with cellular precision. The LGB and MGB were additionally identified in nine other postmortem brains. Probabilistic cytoarchitectonic maps in the MNI “Colin27” and MNI ICBM152 reference spaces were computed which reveal an overall low interindividual variability in topography and extent. The probabilistic maps were included into the Julich-Brain atlas, and are freely available. They can be linked to other 3D data of human brain organization and serve as an anatomical reference for diagnostic, prognostic and therapeutic neuroimaging studies of healthy brains and patients. Furthermore, the high-resolution MGB BigBrain maps provide a basis for data integration, brain modeling and simulation to bridge the larger scale involvement of thalamocortical and local subcortical circuits.
... For this, we employed an additional connectome, as connectivity to the brainstem has not been modelled in the BG-IC connectome. Instead, we used a whole-brain patient-specific group connectome derived from high-resolution dMRI in 90 patients from the Parkinson Progression Marker Initiative (PPMI) [39] that has previously been used to study effects of STN-DBS in PD [40]. Additionally, we employed an anatomical atlas that focusses on brainstem nuclei based on histology-guided tractography findings [41] to determine connectivity of the patient's stimulation sites to mesencephalic locomotor nuclei. ...
Article
Background: Freezing of gait (FOG) is among the most common and disabling symptoms of Parkinson's disease (PD). Studies show that deep brain stimulation (DBS) of the subthalamic nucleus (STN) can reduce FOG severity. However, there is uncertainty about pathways that need to be modulated to improve FOG. Objective: To investigate whether STN-DBS effectively reduces FOG postoperatively and whether structural connectivity of the stimulated tissue explains variance of outcomes. Methods: We investigated 47 patients with PD and preoperative FOG. Freezing prevalence and severity was primarily assessed using the Freezing of Gait Questionnaire (FOG-Q). In a subset of 18 patients, provoked FOG during a standardized walking course was assessed. Using a publicly available model of basal-ganglia pathways we determined stimulation-dependent connectivity associated with postoperative changes in FOG. A region-of-interest analysis to a priori defined mesencephalic regions was performed using a disease-specific normative connectome. Results: Freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. Optimal stimulation volumes for improving FOG structurally connected to motor areas, the prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of FOG. This connectivity profile was robust in a leave-one-out cross-validation. Subcortically, stimulation of fibers crossing the pedunculopontine nucleus and the substantia nigra correlated with postoperative improvement. Conclusion: STN-DBS can alleviate FOG severity by modulating specific pathways structurally connected to prefrontal and motor cortices. More differentiated FOG assessments may allow to differentiate pathways for specific FOG subtypes in the future.
... org, RRID:SCR_002915) (Horn and Kühn, 2015). Subsections of the STN colored in orange (motor), blue (associative) and yellow (limbic) as well as fiber tracts of HDP (orange) and CST (green) were visualized with subcortical atlases pre-installed in Lead-DBS (Ewert et al., 2018;Meola et al., 2016;Middlebrooks et al., 2020). All structures are overlaid an axial section of the BigBrain dataset (Amunts et al., 2013) at z = − 12 mm. ...
Article
The subthalamic nucleus (STN) receives input from various cortical areas via hyperdirect pathway (HDP) which bypasses the basal-ganglia loop. Recently, the HDP has gained increasing interest, because of its relevance for STN deep brain stimulation (DBS). To understand the HDP's role cortical responses evoked by STN-DBS have been investigated. These responses have short (<2 ms), medium (2–15 ms), and long (20–70 ms) latencies. Medium-latency responses are supposed to represent antidromic cortical activations via HDP. Together with long-latency responses the medium responses can potentially be used as biomarker of DBS efficacy as well as side effects. We here propose that the activation sequence of the cortical evoked responses can be conceptualized as high frequency oscillations (HFO) for signal analysis. HFO might therefore serve as marker for antidromic activation. Using existing knowledge on HFO recordings, this approach allows data analyses and physiological modeling to advance the pathophysiological understanding of cortical DBS-evoked high-frequency activity.
... Conductivity values were set according to standard parameters then the VAT was binarised at a threshold of 0.2 V/mm. Finally, electrode locations and VATs were visualised on the DISTAL atlas (Ewert et al., 2018). All results for UPDRS are off medication. ...
... A refined affine transform restricted to our subcortical area of interest to account for brain-shift was implemented if visual inspection revealed improved results. Final localization in MNI template space was applied to the DISTAL minimal atlas [45]. With monopolar stimulation, coordinates utilized were that of the active (cathode) contact. ...
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Patients with psychiatric symptoms, such as depression, anxiety, and visual hallucinations, may be at increased risk for adverse effects following deep brain stimulation of the subthalamic nucleus for Parkinson’s disease, but there have been relatively few studies of associations between locations of chronic stimulation and neuropsychological outcomes. We sought to determine whether psychiatric history modulates associations between stimulation location within the subthalamic nucleus and postoperative affective and cognitive changes. We retrospectively identified 42 patients with Parkinson’s disease who received bilateral subthalamic nucleus deep brain stimulation and who completed both pre- and postoperative neuropsychological testing. Active stimulation contacts were localized in MNI space using Lead-DBS software. Linear discriminant analysis identified vectors maximizing variance in postoperative neuropsychological changes, and Pearson’s correlations were used to assess for linear relationships. Stimulation location was associated with postoperative change for only 3 of the 18 neuropsychological measures. Variation along the superioinferior (z) axis was most influential. Constraining the analysis to patients with a history of depression revealed 10 measures significantly associated with active contact location, primarily related to location along the anterioposterior (y) axis and with worse outcomes associated with more anterior stimulation. Analysis of patients with a history of anxiety revealed 5 measures with location-associated changes without a predominant axis. History of visual hallucinations was not associated with significant findings. Our results suggest that a history of depression may influence the relationship between active contact location and neuropsychological outcomes following subthalamic nucleus deep brain stimulation. These patients may be more sensitive to off-target (nonmotor) stimulation.
... Berlin, Germany) (Horn and Kühn, 2015;Horn et al., 2019) was used for postoperative lead reconstruction analyses, allowing the determination of the specific lead position and orientation on an individual hemispheric level. We then calculated the distance between the center of each electric field and the closest voxel of certain brain regions using the Distal atlas (Ewert et al., 2018). ...
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Background Deep brain stimulation (DBS) is an effective neuromodulation therapy to treat people with medication-refractory Parkinson’s disease (PD). However, the neural networks affected by DBS are not yet fully understood. Recent studies show that stimulating on different DBS-contacts using a single current source results in distinct EEG-based evoked potentials (EPs), with a peak at 3 ms (P3) associated with dorsolateral subthalamic nucleus stimulation and a peak at 10 ms associated with substantia nigra stimulation. Multiple independent current control (MICC) technology allows the center of the electric field to be moved in between two adjacent DBS-contacts, offering a potential advantage in spatial precision.Objective Determine if MICC precision targeting results in distinct neurophysiological responses recorded via EEG.Materials and Methods We recorded cortical EPs in five hemispheres (four PD patients) using EEG whilst employing MICC to move the electric field from the most dorsal DBS-contact to the most ventral in 15 incremental steps.ResultsThe center of the electric field location had a significant effect on both the P3 and P10 amplitude in all hemispheres where a peak was detected (P3, detected in 4 of 5 hemispheres, p < 0.0001; P10, detected in 5 of 5 hemispheres, p < 0.0001). Post hoc analysis indicated furthermore that MICC technology can significantly refine the resolution of steering.Conclusion Using MICC to incrementally move the center of the electric field to locations between adjacent DBS-contacts resulted in significantly different neurophysiological responses that may allow further precision of the programming of individual patients.
... Fibers were extracted from a normative atlas of 28 pathways of the basal ganglia (Petersen et al., 2019). Red mesh structure represents the right hemispherical red nucleus (RN), light blue mesh structure the right VIM, orange mesh represents the subthalamic nucleus (STN) and green and turquoise mesh structures represent internal (GPi) and external globus pallidus (GPe) as defined by the DISTAL atlas (Ewert et al., 2018) superimposed on a section of 7 Tesla MRI of ex vivo human brain at 100 μm resolution (Edlow et al., 2019). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) ...
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Background Gait disturbances are frequent side effects related to chronic thalamic deep brain stimulation (DBS) that may persist beyond cessation of stimulation. Objective We investigate the temporal dynamics and clinical effects of an overnight unilateral withdrawal of DBS on gait disturbances. Methods 10 essential tremor (ET) patients with gait disturbances following thalamic DBS underwent clinical and kinematic gait assessment ON DBS, after instant and after an overnight unilateral withdrawal of DBS of the hemisphere corresponding to the non-dominant hand. The effect of stimulation withdrawal on gait performance was quantitatively assessed using clinical rating and inertial sensors and compared to gait kinematics from 10 additional patients with ET but without subjective gait impairment. DBS leads were reconstructed and active contacts were visualized in relation to surrounding axonal pathways and nuclei. Results Patients with gait deterioration following DBS exhibited greater excursion of sagittal trunk movements and greater variability of stride length and shank range of motion compared to ET patients without DBS and without subjective gait impairment. Overnight but not instant withdrawal of unilateral DBS resulted in significant reduction of SARA axial subscore and stride length variability, while tremor control of the dominant hand was preserved. Cerebellothalamic, striatopallidofugal and corticospinal fibers were in direct vicinity of transiently deactivated contacts. Conclusion Non-dominant unilateral cessation of VIM DBS may serve as a therapeutic option as well as a diagnostic tool to detect stimulation-induced gait disturbances that is applicable in ambulatory settings due to preserved functionality of the dominant hand.
... The locations of active contacts in STN were located with Lead-DBS software [7,9]. Normalization to the MNI space (Montreal Neurological Institute), and the VTA of STN were calculated in MNI defined by the DISTAL atlas [10,11]. ...
Article
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Objectives: our group explored the correlation between postoperative coordinates of the electrode contacts, VTA, and anxiety and depression symptoms in Parkinson's disease (PD) patients after subthalamic nucleus deep brain stimulation (STN-DBS). Methods: STN-DBS was conducted on PD patients (n = 57) for six months with follow-up. Clinical outcomes were explored using the unified Parkinson's disease rating scale Part III (UPDRS-III), the Hamilton Anxiety Rating Scale (HAM-A), and the Hamilton Depression Rating Scale (HAM-D) before and after surgery. At the Montreal Neurological Institute (MNI), the location of active contacts and the volume of tissue activated (VTA) were calculated. Results: patient evaluations took place preoperatively and follow-ups took place at 1 month, 3 months, and 6 months. The average patient improvement rates for HAM-A and HAM-D scores at the 6-month follow-up were 41.7% [interquartile range (IQR) 34.9%] and 37.5% (IQR 33.4%), respectively (both p < 0.001). In medication-off, there were negative correlations between the HAM-A improvement rate and the Z-axis coordinate of the active contact (left side: r = -0.308, p = 0.020; right side: r = -0.390, p = 0.003), and negative correlations between the HAM-D improvement rate and the Z-axis coordinate of the active contact (left side: r = -0.345, p = 0.009; right side: r = -0.521, p = 0.001). There were positive correlations between the HAM-A and HAM-D scores improvement rate at 6 months after surgery and bilateral VTA in the right STN limbic subregion (HAM-A: r = 0.314, p = 0.018; HAM-D: r = 0.321, p = 0.015). Conclusion: bilateral STN-DBS can improve anxiety and depression symptoms in PD patients. The closer the stimulation to the ventral limbic region of the STN, the more significant the improvement in anxiety and depression symptoms of PD patients.
... We chose not to fully limit analysis to within anatomical borders of the nucleus to retain a larger sample and since prior studies Kühn et al., 2005) have shown beta extending from the dorsolateral border. Using a scattered interpolant to estimate power values in between data points, heatmaps for each frequency band were smoothed with fullwidth-half-maximum Gaussian kernel of 0.7 mm and visualised in MNI space with subcortical parcellations integrated in Lead-DBS (DISTAL atlas; Ewert et al., 2018) in front of a high-resolution postmortem MRI backdrop (Edlow et al., 2019). To enhance the number of data points and for visualisation purposes, coordinates from left hemisphere were flipped non-linearly to the right. ...
Article
Current efforts to optimize subthalamic deep brain stimulation in Parkinson's disease patients aim to harness local oscillatory activity in the beta frequency range (13–35 Hz) as a feedback-signal for demand-based adaptive stimulation paradigms. A high prevalence of beta peak activity is prerequisite for this approach to become routine clinical practice. In a large dataset of postoperative rest recordings from 106 patients we quantified occurrence and identified determinants of spectral peaks in the alpha, low and high beta bands. At least one peak in beta band occurred in 92% of patients and 84% of hemispheres off medication, irrespective of demographic parameters, clinical subtype or motor symptom severity. Distance to previously described clinical sweet spot was significantly related both to beta peak occurrence and to spectral power (rho −0.21, p 0.006), particularly in the high beta band. Electrophysiological landscapes of our cohort's dataset in normalised space showed divergent heatmaps for alpha and beta but found similar regions for low and high beta frequency bands. We discuss potential ramifications for clinicians' programming decisions. In summary, this report provides robust evidence that spectral peaks in beta frequency range can be detected in the vast majority of Parkinsonian subthalamic nuclei, increasing confidence in the broad applicability of beta-guided deep brain stimulation.
... Fourth, we corrected these reconstructions for brainshift in post-operative acquisitions by applying a refined affine transform calculated between pre-and post-operative scans that were restricted to a subcortical area of interest (as implemented in the Lead-DBS software). Lastly, we visually confirmed the positions of the contacts using the DISTAL Atlas 63 . Full details of electrode positioning can be found in Supplementary Table 1. ...
Article
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The thalamus is much more than a simple sensory relay. High-order thalamic nuclei, such as the mediodorsal thalamus, exert a profound influence over animal cognition. However, given the difficulty of directly recording from the thalamus in humans, next-to-nothing is known about thalamic and thalamocortical contributions to human cognition. To address this, we analysed simultaneously-recorded thalamic iEEG and whole-head MEG in six patients (plus MEG recordings from twelve healthy controls) as they completed a visual detection task. We observed that the phase of both ongoing mediodorsal thalamic and prefrontal low-frequency activity was predictive of perceptual performance. Critically however, mediodorsal thalamic activity mediated prefrontal contributions to perceptual performance. These results suggest that it is thalamocortical interactions, rather than cortical activity alone, that is predictive of upcoming perceptual performance and, more generally, highlights the importance of accounting for the thalamus when theorising about cortical contributions to human cognition. How the thalamus and the cortex interact in the context of perception remains largely unclear. Here, the authors show that rhythmic activity in the human mediodorsal thalamus and prefrontal cortex interact to predict whether a near-threshold visual stimulus will be seen, contradicting the traditional view that the thalamus is a simple relay.
... Here, we used a PCA on the individual STN masks to identify the ventromedial-dorsolateral axis, along we divided the STNs in three segments of equal volume. Some other studies suggest more complex shapes of subregions (e.g., Ewert et al., 2018;Horn et al., 2017; but see Lambert et al., 2012), but there is considerable variability in the reported shapes and even number of hypothesized subdivisions (for review, see Keuken et al., 2012). Other work suggests the STN is organized along a gradient of changes with no clear boundaries De Hollander et al., 2014). ...
Article
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The subthalamic nucleus (STN) is a small, subcortical brain structure. It is a target for deep brain stimulation, an invasive treatment that reduces motor symptoms of Parkinson’s disease. Side effects of DBS are commonly explained using the tripartite model of STN organization, which proposes three functionally distinct subregions in the STN specialized in cognitive, limbic, and motor processing. However, evidence for the tripartite model exclusively comes from anatomical studies and functional studies using clinical patients. Here, we provide the first experimental tests of the tripartite model in healthy volunteers using ultra-high field 7 Tesla (T) functional magnetic resonance imaging (fMRI). Thirty-four participants performed a random-dot motion decision-making task with a difficulty manipulation and a choice payoff manipulation aimed to differentially affect cognitive and limbic networks. Moreover, participants responded with their left and right index finger, differentially affecting motor networks. We analysed BOLD signal in three subregions of the STN along the dorsolateral-ventromedial axis, identified using manually delineated high resolution anatomical images and based on a previously published atlas. Using these paradigms, all segments responded equally to the experimental manipulations, and the tasks did not provide evidence for the tripartite model.
Article
Deep Brain Stimulation (DBS) is a therapy for various neurological movement disorders. It acts predominantly on motor symptoms, but may unfold a number of mostly subtle cognitive effects. In this regard, reports on particular language-related DBS sequels are comparably frequent, but difficult to overlook, given the heterogeneity of targeted structures in the brain, treated diseases, assessment methods and results reported. Accordingly, available knowledge was organized with respect to important aspects, such as the main DBS loci and surgical versus neuromodulatory therapy actions. Current views of biolinguistic underpinnings of the reviewed data, their clinical relevance and potential implications are discussed.
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Objectives Deep brain stimulation (DBS) delivered via multicontact leads implanted in the basal ganglia is an established therapy to treat Parkinson disease (PD). However, the different neural circuits that can be modulated through stimulation on different DBS contacts are poorly understood. Evidence shows that electrically stimulating the subthalamic nucleus (STN) causes a therapeutic effect through antidromic activation of the hyperdirect pathway—a monosynaptic connection from the cortex to the STN. Recent studies suggest that stimulating the substantia nigra pars reticulata (SNr) may improve gait. The advent of directional DBS leads now provides a spatially precise means to probe these neural circuits and better understand how DBS affects distinct neural networks. Materials and Methods We measured cortical evoked potentials (EPs) using electroencephalography (EEG) in response to low-frequency DBS using the different directional DBS contacts in eight patients with PD. Results A short-latency EP at 3 milliseconds originating from the primary motor cortex appeared largest in amplitude when stimulating DBS contacts closest to the dorsolateral STN (p < 0.001). A long-latency EP at 10 milliseconds originating from the premotor cortex appeared strongest for DBS contacts closest to the SNr (p < 0.0001). Conclusions Our results show that at the individual patient level, electrical stimulation of different nuclei produces distinct EP signatures. Our approach could be used to identify the functional location of each DBS contact and thus help patient-specific DBS programming. Clinical Trial Registration The ClinicalTrials.gov registration number for the study is NCT04658641.
Article
Analysis of the basal ganglia has been important in investigating the effects of Parkinson's disease as well as treatments for Parkinson's disease. One method of analysis has been using MRI for non-invasively segmenting the basal ganglia, then investigating significant parameters that involve the basal ganglia, such as fiber orientations and positional markers for deep brain stimulation. Following enhancements to optimizations and improvements to 3T and 7T MRI acquisitions, we utilized Lead-DBS on human connectome project data to automatically segment the basal ganglia of 49 human connectome project subjects, reducing the reliance on manual segmentation for more consistency. We generated probabilistic tractography streamlines between each segmentation pair using 3T and 7T human connectome diffusion data to observe any major differences in tractography streamline patterns that can arise due to tradeoffs from different field strengths and acquisitions. Tractography streamlines generated between basal ganglia structures using 3T images showed less standard deviation in streamline count than using 7T images. Mean tractography streamline counts generated using 3T diffusion images were all higher in count than streamlines generated using 7T diffusion images. We illustrate a potential method for analyzing the structural connectivity between basal ganglia structures, as well as visualize possible differences in probabilistic tractography that can arise from different acquisition protocols.
Article
Objective Blindsight is a disorder where brain injury causes loss of conscious but not unconscious visual perception. Prior studies have produced conflicting results regarding the neuroanatomical pathways involved in this unconscious perception. Methods We performed a systematic literature search to identify lesion locations causing visual field loss in patients with blindsight (n=34) and patients without blindsight (n=35). Resting state functional connectivity between each lesion location and all other brain voxels was computed using a large connectome database (n=1000). Connections significantly associated with blindsight (versus no blindsight) were identified. Results Functional connectivity between lesion locations and the ipsilesional medial pulvinar was significantly associated with blindsight (FWE p=0.029). No significant connectivity differences were found to other brain regions previously implicated in blindsight. This finding was independent of methods (e.g. flipping lesions to the left or right) and stimulus type (moving versus static). Interpretation Connectivity to the ipsilesional medial pulvinar best differentiates lesion locations associated with blindsight versus those without blindsight. Our results align with recent data from animal models and provide insight into the neuroanatomical substrate of unconscious visual abilities in patients. This article is protected by copyright. All rights reserved.
Conference Paper
Deep brain stimulation is an effective neurosurgical intervention for movement disorders such as Parkinson's disease. Despite its success, the underlying mechanisms are still debated. One tool to better understand them is the Volume of Tissue Activated (VTA), that estimates the region activated by electrical stimulation. Different estimation approaches exist, these typically assume isotropic tissue properties and modelling of anisotropy is often lacking.The present work was aimed at developing and testing a method for patient-specific VTA estimation that incorporated an anisotropic conduction model. Our method was implemented within the open-source toolbox Lead-DBS and is accessible to the public.The present method was further tested with two patient cases and compared to a standard Lead-DBS pipeline for VTA estimation. This showed encouraging similarities in one test scenario and expected differences in another test scenario. Further validation with a wider cohort is warranted.
Article
The subthalamic nucleus (STN) is commonly used as a surgical target for deep brain stimulation in movement disorders such as Parkinson's Disease. Tractography-derived connectivity-based parcellation (CBP) has been recently proposed as a suitable tool for non-invasive in vivo identification and pre-operative targeting of specific functional territories within the human STN. However, a well-established, accurate and reproducible protocol for STN parcellation is still lacking. The present work aims at testing the effects of different tractography-based approaches for the reconstruction of STN functional territories. We reconstructed functional territories of the STN on the high-quality dataset of 100 unrelated healthy subjects and on the test-retest dataset of the Human Connectome Project (HCP) repository. Connectivity-based parcellation was performed with a hypothesis-driven approach according to cortico-subthalamic connectivity, after dividing cortical areas into three groups: associative, limbic and sensorimotor. Four parcellation pipelines were compared, combining different signal modeling techniques (single-fiber vs multi-fiber) and different parcellation approaches (winner takes all parcellation vs fiber density thresholding). We tested these procedures on STN regions of interest obtained from three different, commonly employed, subcortical atlases. We evaluated the pipelines both in terms of between-subject similarity, assessed on the cohort of 100 unrelated healthy subjects, and of within-subject similarity, using a second cohort of 44 subjects with available test-retest data. We found that each parcellation provides converging results in terms of location of the identified parcels, but with significative variations in size and shape. All pipelines obtained very high within-subject similarity, with tensor-based approaches outperforming multi-fiber pipelines. On the other hand, higher between-subject similarity was found with multi-fiber signal modeling techniques combined with fiber density thresholding. We suggest that a fine-tuning of tractography-based parcellation may lead to higher reproducibility and aid the development of an optimized surgical targeting protocol.
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Lead-DBS is an open-source, semi-automatized and widely applied software tool facilitating precise localization of deep brain stimulation electrodes both in native as well as in standardized stereotactic space. While automatized preprocessing steps within the toolbox have been tested and validated in previous studies, the interrater reliability in manual refinements of electrode localizations using the tool has not been objectified so far. Here, we investigate the variance introduced in this processing step by different raters when localizing electrodes based on postoperative CT or MRI. Furthermore, we compare the performance of novel trainees that received a structured training and more experienced raters with an expert user. We show that all users yield similar results with an average difference in localizations ranging between 0.52- 0.75 mm with 0.07-0.12 mm increases in variability when using postoperative MRI and following normalization to standard space. Our findings may pave the way toward formal training for using Lead-DBS and demonstrate its reliability and ease-of-use for imaging research in the field of deep brain stimulation.
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Dystonia is a debilitating disease with few treatment options. One effective option is deep brain stimulation (DBS) to the internal pallidum. While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations regarding optimal stimulation sites and potential network effects have not been carried out. Here, we retrospectively studied clinical results following DBS for cervical and generalized dystonia in a multicenter cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce an approach to map optimal stimulation sites to anatomical space. Second, we investigate which tracts account for optimal clinical improvements, when modulated. Third, we investigate distributed stimulation effects on a whole-brain functional connectome level. Our results show marked differences of optimal stimulation sites that map to the somatotopic structure of the internal pallidum. While modulation of the striatopallidofugal axis of the basal ganglia accounted for optimal treatment of cervical dystonia, modulation of pallidothalamic bundles did so in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in the form of connectivity to the cerebellum and somatomotor cortex. Our results suggest a brief divergence of optimal stimulation networks for cervical vs. generalized dystonia within the pallidothalamic loop that merge again on a thalamo-cortical level and share a common whole-brain network.
Article
To explore whether the thalamus participates in lexical status (word vs. nonword) processing during spoken word production, we recorded local field potentials from the ventral lateral thalamus in 11 essential tremor patients (three females) undergoing thalamic deep brain stimulation lead implantation during a visually cued word- and nonword-reading aloud task. We observed task-related beta (12-30 Hz) activity decreases that were preferentially time-locked to stimulus presentation, and broadband gamma (70-150 Hz) activity increases, which are thought to index increased multi-unit spiking activity, occurring shortly before and predominantly time-locked to speech onset. We further found that thalamic beta activity decreases bilaterally were greater when nonwords were read, demonstrating bilateral sensitivity to lexical status that likely reflects the tracking of task effort; in contrast, greater nonword-related increases in broadband gamma activity were observed only on the left, demonstrating lateralization of thalamic broadband gamma selectivity for lexical status. In addition, this lateralized lexicality effect on broadband gamma activity was strongest in more anterior thalamic locations, regions which are more likely to receive basal ganglia than cerebellar afferents and have extensive connections with prefrontal cortex including Brodmann's areas 44 and 45, regions consistently associated with grapheme-to-phoneme conversions. These results demonstrate active thalamic participation in reading aloud and provide direct evidence from intracranial thalamic recordings for the lateralization and topography of subcortical lexical status processing.SIGNIFICANCE STATEMENTDespite the cortico-centric focus of most experimental work and accompanying models, there is increasing recognition of the role of subcortical structures in speech and language. Using local field potential recordings in neurosurgical patients, we demonstrated that the thalamus participates in lexical status (word vs. nonword) processing during spoken word production, in a lateralized and region-specific manner. These results provide direct evidence from intracranial thalamic recordings for the lateralization and topography of subcortical lexical status processing.
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How the basal ganglia participate in the uniquely human behavior of speech is poorly understood, despite their known role in modulating critical aspects of cognitive and motor behavior. The subthalamic nucleus (STN) is well positioned to facilitate basal ganglia functions critical for speech. Using electrocorticography in patients undergoing awake deep brain stimulation (DBS) surgery, evidence is reported for a left opercular hyperdirect pathway in humans via stimulating the STN and examining antidromic-evoked activity in the left temporal, parietal, and frontal opercular cortex. These high-resolution cortical and subcortical mapping data provide evidence for hyperdirect connectivity between the inferior frontal gyrus and the STN. In addition, evoked potential data are consistent with the presence of monosynaptic projections from areas of the opercular speech cortex that are primarily sensory, including the auditory cortex, to the STN. These connections may be unique to humans, evolving alongside the ability for speech.
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Background Essential tremor (ET) is one of the most common movement disorders, and continuous deep brain stimulation (DBS) is an established treatment for medication-refractory cases. However, the need for increasing stimulation intensities, with unpleasant side effects, and DBS tolerance over time can be problematic. The advent of novel DBS devices now provides the opportunity to longitudinally record LFPs using the implanted pulse generator, which opens up possibilities to implement adaptive DBS algorithms in a real-life setting. Methods Here we report a case of thalamic LFP activity recorded using a commercially available sensing-enabled DBS pulse generator (Medtronic Percept PC). Results In the OFF-stimulation condition, a peak tremor frequency of 3.8 Hz was identified during tremor evoking movements as assessed by video and accelerometers. Activity at the same and supraharmonic frequency was seen in the frequency spectrum of the LFP data from the left vim nucleus during motor tasks. Coherence analysis showed that peripherally recorded tremor was coherent with the LFP signal at the tremor frequency and supraharmonic frequency. Conclusion This is the first report of recorded tremor-related thalamic activity using the electrodes and pulse generator of an implanted DBS system. Larger studies are needed to evaluate the clinical potential of these fully implantable systems, and ultimately pulse generators with sensing-coupled algorithms driving stimulation, to really close the loop.
Article
Objective Advanced therapies in neurosurgery, such as deep brain stimulation (DBS), would benefit from improved patient education materials. 3D printed anatomical models represent one recent development in improving patient education for neurosurgical procedures. Methods This study randomized 40 patients undergoing DBS surgery consultation to one of two groups: 1) experimental: received demonstration of DBS therapeutic neuroanatomical targets in a 3D printed brain model plus standard patient education (PE) or 2) control: received standard PE alone. Results Patients in the DBS model + PE group showed a significant increase in patient confidence and understanding of the brain structures targeted during a DBS procedure compared to the PE-only group (p < 0.01). There was no difference in the perceived risk, comfort, or anxiety related to the procedure. Conclusions As the first randomized controlled study of 3D printed models for DBS consultation, our results demonstrate that patients have improved understanding of their therapy. However, the models alone did not affect risk evaluation or comfort with surgery. A 3D printed DBS brain model may help improve patient understanding of DBS surgery.
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We present the first three-dimensional (3D) concordance maps of cyto-and fiber architecture of the human brain, combining histology, immunohistochemistry, and 7-T quantitative magnetic resonance imaging (MRI), in two individual specimens. These 3D maps each integrate data from approximately 800 microscopy sections per brain, showing neuronal and glial cell bodies, nerve fibers, and interneuronal populations, as well as ultrahigh-field quantitative MRI, all coaligned at the 200-m scale to the stacked blockface images obtained during sectioning. These unprecedented 3D multimodal datasets are shared without any restrictions and provide a unique resource for the joint study of cell and fiber architecture of the brain, detailed anatomical atlasing, or modeling of the microscopic underpinnings of MRI contrasts.
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Primary 4-repeat tauopathies are characterized by deposition of the 4-repeat isoform of the microtubule binding protein, tau. The two most common sporadic 4-repeat tauopathies are progressive supranuclear palsy and corticobasal degeneration. Because tau PET tracers exhibit poor binding affinity to 4-repeat pathology, determining how well in vivo MRI findings relate to underlying pathology is critical to evaluating their utility as surrogate markers to aid in diagnosis and as outcome measures for clinical trials. We studied the relationship of cross-sectional imaging findings, such as MRI volume loss and diffusion tensor imaging white matter tract abnormalities, to tau histopathology in 4-repeat tauopathies. Forty-seven patients with antemortem 3 T MRI volumetric and diffusion tensor imaging scans plus postmortem pathological diagnosis of a 4-repeat tauopathy (28 progressive supranuclear palsy; 19 corticobasal degeneration) were included in the study. Tau lesion types (pretangles/neurofibrillary tangles, neuropil threads, coiled bodies, astrocytic lesions) were semiquantitatively graded in disease-specific cortical, subcortical and brainstem regions. Antemortem regional volumes, fractional anisotropy, and mean diffusivity were modelled using linear regression with postmortem tau lesion scores considered separately, based on cellular type (neuronal vs glial), or summed (total tau). Results: showed that greater total tau burden was associated with volume loss in the subthalamic nucleus (P = 0.001), midbrain (P < 0.001), substantia nigra (P = 0.03), and red nucleus (P = 0.004), with glial lesions substantially driving the associations. Decreased fractional anisotropy and increased mean diffusivity in the superior cerebellar peduncle correlated with glial tau in the cerebellar dentate (P = 0.04 and P = 0.02, respectively) and red nucleus (P < 0.001 for both). Total tau and glial pathology also correlated with increased mean diffusivity in the midbrain (P = 0.02 and P < 0.001, respectively). Finally, increased subcortical white matter mean diffusivity was associated with total tau in superior frontal and precentral cortices (each, P = 0.02). Overall, results showed clear relationships between antemortem MRI changes and pathology in 4-repeat tauopathies. Our findings show that brain volume could be a useful surrogate marker of tau pathology in subcortical and brainstem regions, while white matter integrity could be a useful marker of tau pathology in cortical regions. Our findings also suggested an important role of glial tau lesions in the pathogenesis of neurodegeneration in 4-repeat tauopathies. Thus, development of tau PET tracers selectively binding to glial tau lesions could potentially uncover mechanisms of disease progression.
Article
Deep brain stimulation (DBS) for Tourette syndrome (TS) is an evolving therapy for severely affected patients. However, there is still ambiguity about the ideal target and networks that need to be modulated for optimal results. Recently, Johnson et al. demonstrated that tic reductions depend on normative structural connectivity seeding from stimulation sites, highlighting the utility of probing optimal fiber pathways, rather than focal targets. Connectivity estimates derived from resting-state functional magnetic resonance imaging may extend these findings by deciphering polysynaptic, functionally linked networks that are not necessarily structurally connected. Pursuing this approach, we performed an analysis of stimulation-dependent functional connectivity to derive a network that, if modulated by thalamic DBS, explains tic reduction in severe TS.
Article
Introduction: Selecting the ideal contact to apply subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease is time-consuming and reliant on clinical expertise. The aim of this cohort study was to assess whether neuronal signals (beta oscillations and evoked resonant neural activity (ERNA)), and the anatomical location of electrodes, can predict the contacts selected by long-term, expert-clinician programming of STN-DBS. Methods: We evaluated 92 hemispheres of 47 patients with Parkinson's disease receiving chronic monopolar and bipolar STN-DBS. At each contact, beta oscillations and ERNA were recorded intraoperatively, and anatomical locations were assessed. How these factors, alone and in combination, predicted the contacts clinically selected for chronic deep brain stimulation at 6 months postoperatively was evaluated using a simple-ranking method and machine learning algorithms. Results: The probability that each factor individually predicted the clinician-chosen contact was as follows: ERNA 80%, anatomy 67%, beta oscillations 50%. ERNA performed significantly better than anatomy and beta oscillations. Combining neuronal signal and anatomical data did not improve predictive performance. Conclusion: This work supports the development of probability-based algorithms using neuronal signals and anatomical data to assist programming of deep brain stimulation.
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Background: Deep Brain Stimulation (DBS) electrode implant trajectories are stereotactically defined using preoperative neuroimaging. To validate the correct trajectory, microelectrode recordings (MER) or local field potential recordings (LFP) can be used to extend neuroanatomical information (defined by magnetic resonance imaging) with neurophysiological activity patterns recorded from micro- and macroelectrodes probing the surgical target site. Currently, these two sources of information (imaging vs. electrophysiology) are analyzed separately, while means to fuse both data streams have not been introduced. Methods: Here we present a tool that integrates resources from stereotactic planning, neuroimaging, MER and high-resolution atlas data to create a real-time visualization of the implant trajectory. We validate the tool based on a retrospective cohort of DBS patients (𝑁 = 52) offline and present single use cases of the real-time platform. Results: We establish an open-source software tool for multimodal data visualization and analysis during DBS surgery. We show a general correspondence between features derived from neuroimaging and electrophysiological recordings and present examples that demonstrate the functionality of the tool. Conclusions: This novel software platform for multimodal data visualization and analysis bears translational potential to improve accuracy of DBS surgery. The toolbox is made openly available and is extendable to integrate with additional software packages. Funding: Deutsche Forschungsgesellschaft (410169619, 424778381), Deutsches Zentrum für Luftund Raumfahrt (DynaSti), National Institutes of Health (2R01 MH113929), Foundation for OCD Research (FFOR).
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Brain signal decoding promises significant advances in the development of clinical brain computer interfaces (BCI). In Parkinson's disease (PD), first bidirectional BCI implants for adaptive deep brain stimulation (DBS) are now available. Brain signal decoding can extend the clinical utility of adaptive DBS but the impact of neural source, computational methods and PD pathophysiology on decoding performance are unknown. This represents an unmet need for the development of future neurotechnology. To address this, we developed an invasive brain-signal decoding approach based on intraoperative sensorimotor electrocorticography (ECoG) and subthalamic LFP to predict grip-force, a representative movement decoding application, in 11 PD patients undergoing DBS. We demonstrate that ECoG is superior to subthalamic LFP for accurate grip-force decoding. Gradient boosted decision trees (XGBOOST) outperformed other model architectures. ECoG based decoding performance negatively correlated with motor impairment, which could be attributed to subthalamic beta bursts in the motor preparation and movement period. This highlights the impact of PD pathophysiology on the neural capacity to encode movement vigor. Finally, we developed a connectomic analysis that could predict grip-force decoding performance of individual ECoG channels across patients by using their connectomic fingerprints. Our study provides a neurophysiological and computational framework for invasive brain signal decoding to aid the development of an individualized precision-medicine approach to intelligent adaptive DBS.
Preprint
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Attention is a core cognitive function that lters and selects behaviourally relevant information in the environment. The cortical mapping of attentional systems identi ed two segregated networks that mediate stimulus-driven and goal-driven processes, the Ventral and the Dorsal Attention Networks (VAN, DAN). Deep brain electrophysiological recordings, behavioural data from phylogenetic distant species and observations from human brain pathologies challenge purely corticocentric models. Here, we used advanced methods of functional alignment applied to resting-state functional connectivity analyses to map the subcortical architecture of the Ventral and the Dorsal Attention Networks. Our investigations revealed the involvement of the pulvinar, the superior colliculi, the head of caudate nuclei, and a cluster of brainstem nuclei relevant for both networks. These nuclei are densely connected structural network hubs as revealed by diffusion-weighted imaging tractography and establish interrelations with the acetylcholine nicotinic receptor as well as dopamine and serotonin transporters systems. This convergence of functional, structural, and neurochemical evidence provides a novel framework to comprehensively understand the neural basis of attention across different species and brain diseases.
Article
Subcortical nuclei and other deep brain structures are known to play an important role in the regulation of the central and peripheral nervous systems. It can be difficult to identify and delineate many of these nuclei and their finer subdivisions in conventional MRI due to their small size, buried location, and often subtle contrast compared to neighboring tissue. To address this problem, we applied a multi-modal approach in ex vivo non-human primate (NHP) brain that includes high-resolution mean apparent propagator (MAP)-MRI and five different histological stains imaged with high-resolution microscopy in the brain of the same subject. By registering these high-dimensional MRI data to high-resolution histology data, we can map the location, boundaries, subdivisions, and micro-architectural features of subcortical gray matter regions in the macaque monkey brain. At high spatial resolution, diffusion MRI in general, and MAP-MRI in particular, can distinguish a large number of deep brain structures, including the larger and smaller white matter fiber tracts as well as architectonic features within various nuclei. Correlation with histology from the same brain enables a thorough validation of the structures identified with MAP-MRI. Moreover, anatomical details that are evident in images of MAP-MRI parameters are not visible in conventional T1-weighted images. We also derived subcortical template “SC21” from segmented MRI slices in three-dimensions and registered this volume to a previously published anatomical template with cortical parcellation (Reveley et al., 2017; Saleem and Logothetis, 2012), thereby integrating the 3D segmentation of both cortical and subcortical regions into the same volume. This newly updated three-dimensional D99 digital brain atlas (V2.0) is intended for use as a reference standard for macaque neuroanatomical, functional, and connectional imaging studies, involving both cortical and subcortical targets. The SC21 and D99 digital templates are available as volumes and surfaces in standard NIFTI and GIFTI formats.
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Computational modeling and simulations are increasingly being used to complement experimental testing for analysis of safety and efficacy of medical devices. Multiple voxel- and surface-based whole- and partial-body models have been proposed in the literature, typically with spatial resolution in the range of 1-2 mm and with 10-50 different tissue types resolved. We have developed a multimodal imaging-based detailed anatomical model of the human head and neck, named "MIDA". The model was obtained by integrating three different magnetic resonance imaging (MRI) modalities, the parameters of which were tailored to enhance the signals of specific tissues: i) structural T1- and T2-weighted MRIs; a specific heavily T2-weighted MRI slab with high nerve contrast optimized to enhance the structures of the ear and eye; ii) magnetic resonance angiography (MRA) data to image the vasculature, and iii) diffusion tensor imaging (DTI) to obtain information on anisotropy and fiber orientation. The unique multimodal high-resolution approach allowed resolving 153 structures, including several distinct muscles, bones and skull layers, arteries and veins, nerves, as well as salivary glands. The model offers also a detailed characterization of eyes, ears, and deep brain structures. A special automatic atlas-based segmentation procedure was adopted to include a detailed map of the nuclei of the thalamus and midbrain into the head model. The suitability of the model to simulations involving different numerical methods, discretization approaches, as well as DTI-based tensorial electrical conductivity, was examined in a case-study, in which the electric field was generated by transcranial alternating current stimulation. The voxel- and the surface-based versions of the models are freely available to the scientific community.
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Detailed anatomical understanding of the human brain is essential for unraveling its functional architecture, yet current reference atlases have major limitations in terms of lack of whole-brain coverage, relatively low image resolution, and sparse structural annotation. We present the first digital human brain atlas to incorporate neuroimaging, high-resolution histology, and chemoarchitecture across a complete adult female brain, consisting of MRI, DWI, and 1356 large-format cellular resolution (1 µm/pixel) Nissl and immunohistochemistry anatomical plates. The atlas is comprehensively annotated for 862 structures, including 117 white matter tracts and several novel cyto- and chemoarchitecturally defined structures, and these annotations were transferred onto the matching MRI dataset. Neocortical delineations were done for sulci, gyri, and modified Brodmann areas to link macroscopic anatomical and microscopic cytoarchitectural parcellations. Correlated neuroimaging and histological structural delineation allowed fine feature identification in MRI data and subsequent structural identification in MRI data from other brains. This interactive online digital atlas is integrated with existing Allen Institute for Brain Science gene expression atlases and is publicly accessible as a resource for the neuroscience community. This article is protected by copyright. All rights reserved.
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View largeDownload slide The use of subthalamic nucleus deep brain stimulation in Parkinson’s disease is limited in some patients by behavioural side-effects. Using perioperative electrophysiological recordings and presurgical neuroimaging, Accolla et al . characterize the anatomical networks modulated by deep brain stimulation, and reveal the existence of overlapping functional areas within the nucleus. View largeDownload slide The use of subthalamic nucleus deep brain stimulation in Parkinson’s disease is limited in some patients by behavioural side-effects. Using perioperative electrophysiological recordings and presurgical neuroimaging, Accolla et al . characterize the anatomical networks modulated by deep brain stimulation, and reveal the existence of overlapping functional areas within the nucleus.
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Despite the constant improvement of algorithms for automated brain tissue classification, the accurate delineation of subcortical structures using magnetic resonance images (MRI) data remains challenging. The main difficulties arise from the low grey-white matter contrast of iron rich areas in T1-weighted (T1w) MRI data and from the lack of adequate priors for basal ganglia and thalamus. The most recent attempts to obtain such priors were based on cohorts with limited size that included subjects in a narrow age range, failing to account for age-related grey-white matter contrast changes. Aiming to improve the anatomical plausibility of automated brain tissue classification from T1w data, we have created new tissue probability maps for subcortical grey matter regions. Supported by atlas-derived spatial information, raters manually labelled subcortical structures in a cohort of healthy subjects using magnetization transfer saturation and R2* MRI maps, which feature optimal grey-white matter contrast in these areas. After assessment of inter-rater variability, the new tissue priors were tested on T1w data within the framework of voxel-based morphometry. The automated detection of grey matter in subcortical areas with our new probability maps was more anatomically plausible compared to the one derived with currently available priors. We provide evidence that the improved delineation compensates age-related bias in the segmentation of iron rich subcortical regions. The new tissue priors, allowing robust detection of basal ganglia and thalamus, have the potential to enhance the sensitivity of voxel-based morphometry in both healthy and diseased brains.
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Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an established treatment in patients with severe dystonia. However, factors predicting outcome are largely unknown and motor improvement in DYT6 patients after DBS has been reported to be poorer as compared to, e.g., DYT1 patients. Here, we report the course of clinical improvement for up to 11 years of pallidal DBS in three male patients belonging to the same family with early-onset generalized or segmental dystonia due to a heterozygous THAP1 gene mutation (DYT6). All patients showed an initial effective response to pallidal DBS with a mean of 56.9 ± 11.7 % improvement in the Burke-Fahn-Marsden Dystonia motor and 45.5 ± 22.4 % in the disability score at 1-year follow-up. The long-term outcome of pallidal DBS was favorable in two patients (39, 67 % motor improvement, respectively). Our findings demonstrate that motor improvement is variable and may depend on disease severity, disease duration, and clinical presentation. Overall, our observation supports pallidal DBS as an important treatment option in patients with DYT6 dystonia.
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OBJECT The dentatorubrothalamic tract (DRTT) is the major efferent cerebellar pathway arising from the dentate nucleus (DN) and decussating to the contralateral red nucleus (RN) and thalamus. Surprisingly, hemispheric cerebellar output influences bilateral limb movements. In animals, uncrossed projections from the DN to the ipsilateral RN and thalamus may explain this phenomenon. The aim of this study was to clarify the anatomy of the dentatorubrothalamic connections in humans. METHODS The authors applied advanced deterministic fiber tractography to a template of 488 subjects from the Human Connectome Project (Q1–Q3 release, WU-Minn HCP consortium) and validated the results with microsurgical dissection of cadaveric brains prepared according to Klingler’s method. RESULTS The authors identified the “classic” decussating DRTT and a corresponding nondecussating path (the nondecussating DRTT, nd-DRTT). Within each of these 2 tracts some fibers stop at the level of the RN, forming the dentatorubro tract and the nondecussating dentatorubro tract. The left nd-DRTT encompasses 21.7% of the tracts and 24.9% of the volume of the left superior cerebellar peduncle, and the right nd-DRTT encompasses 20.2% of the tracts and 28.4% of the volume of the right superior cerebellar peduncle. CONCLUSIONS The connections of the DN with the RN and thalamus are bilateral, not ipsilateral only. This affords a potential anatomical substrate for bilateral limb motor effects originating in a single cerebellar hemisphere under physiological conditions, and for bilateral limb motor impairment in hemispheric cerebellar lesions such as ischemic stroke and hemorrhage, and after resection of hemispheric tumors and arteriovenous malformations. Furthermore, when a lesion is located on the course of the dentatorubrothalamic system, a careful preoperative tractographic analysis of the relationship of the DRTT, nd-DRTT, and the lesion should be performed in order to tailor the surgical approach properly and spare all bundles.
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Objectives: Recent studies suggest that oscillatory beta activity could be used as a state biomarker in patients with Parkinson's disease for subthalamic closed-loop stimulation with the intention of improving clinical benefit. Here we investigate the feasibility of subthalamic recordings via a novel chronically implanted pulse generator. Methods: Subthalamic local field potential recordings were obtained from eight patients before and during deep brain stimulation (DBS). All data were analyzed in the frequency domain using Fourier transform-based methods and compared between ON and OFF stimulation conditions. Results: Distinct peaks of oscillatory beta band activity were found in 12 of 15 electrodes. DBS induced a significant frequency specific suppression of oscillatory beta activity (p = 0.002). Conclusion: The results of the study suggest that oscillatory beta band synchronization and its modulation by DBS is recordable with a system suitable for chronic implantation and may serve as a biomarker for subthalamic closed-loop stimulation in patients with Parkinson's disease.
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Deep brain stimulation (DBS) is a promising approach in treatment-resistant depression (TRD). TRD is associated with problems in interpersonal relationships, which might be linked to impaired empathy. Here, we investigate the influence of DBS in the subgenual anterior cingulate cortex (sgACC) on empathy in patients with TRD and explore the pattern of oscillatory sgACC activity during performance of the multifaceted empathy test. We recorded local field potential activity directly from sgACC via DBS electrodes in patients. Based on previous behavioral findings, we expected disrupted empathy networks. Patients showed increased empathic involvement ratings toward negative stimuli as compared with healthy subjects that were significantly reduced after 6 months of DBS. Stimulus-related oscillatory activity pattern revealed a broad desynchronization in the beta (14-35 Hz) band that was significantly larger during patients' reported emotional empathy for negative stimuli than when patients reported to have no empathy. Beta desynchronization for empathic involvement correlated with self-reported severity of depression. Our results indicate a "negativity bias" in patients that can be reduced by DBS. Moreover, direct recordings show activation of the sgACC area during emotional processing and propose that changes in beta-band oscillatory activity in the sgACC might index empathic involvement of negative emotion in TRD. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Primary dystonia has been associated with an underlying dysfunction of a wide network of brain regions including the motor cortex, basal ganglia, cerebellum, brainstem and spinal cord. Dystonia can be effectively treated by pallidal deep brain stimulation although the mechanism of this effect is not well understood. Here, we sought to characterize cortico-basal ganglia functional connectivity using a frequency-specific measure of connectivity-coherence. We recorded direct local field potentials from the human pallidum simultaneously with whole head magnetoencephalography to characterize functional connectivity in the cortico-pallidal oscillatory network in nine patients with idiopathic dystonia. Three-dimensional cortico-pallidal coherence images were compared to surrogate images of phase shuffled data across patients to reveal clusters of significant coherence (family-wise error P < 0.01, voxel extent 1000). Three frequency-specific, spatially-distinct cortico-pallidal networks have been identified: a pallido-temporal source of theta band (4-8 Hz) coherence, a pallido-cerebellar source of alpha band (7-13 Hz) coherence and a cortico-pallidal source of beta band (13-30 Hz) coherence over sensorimotor areas. Granger-based directionality analysis revealed directional coupling with the pallidal local field potentials leading in the theta and alpha band and the magnetoencephalographic cortical source leading in the beta band. The degree of pallido-cerebellar coupling showed an inverse correlation with dystonic symptom severity. Our data extend previous findings in patients with Parkinson's disease describing motor cortex-basal ganglia oscillatory connectivity in the beta band to patients with dystonia. Source coherence analysis revealed two additional frequency-specific networks involving the temporal cortex and the cerebellum. Pallido-cerebellar oscillatory connectivity and its association with dystonic symptoms provides further confirmation of cerebellar involvement in dystonia that has been recently reported using functional magnetic resonance imaging and fibre tracking.
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Deep brain stimulation of the globus pallidus internus alleviates involuntary movements in patients with dystonia. However, the mechanism is still not entirely understood. One hypothesis is that deep brain stimulation suppresses abnormally enhanced synchronized oscillatory activity within the motor cortico-basal ganglia network. Here, we explore deep brain stimulation-induced modulation of pathological low frequency (4-12 Hz) pallidal activity that has been described in local field potential recordings in patients with dystonia. Therefore, local field potentials were recorded from 16 hemispheres in 12 patients undergoing deep brain stimulation for severe dystonia using a specially designed amplifier allowing simultaneous high frequency stimulation at therapeutic parameter settings and local field potential recordings. For coherence analysis electroencephalographic activity (EEG) over motor areas and electromyographic activity (EMG) from affected neck muscles were recorded before and immediately after cessation of high frequency stimulation. High frequency stimulation led to a significant reduction of mean power in the 4-12 Hz band by 24.8 ± 7.0% in patients with predominantly phasic dystonia. A significant decrease of coherence between cortical EEG and pallidal local field potential activity in the 4-12 Hz range was revealed for the time period of 30 s after switching off high frequency stimulation. Coherence between EMG activity and pallidal activity was mainly found in patients with phasic dystonic movements where it was suppressed after high frequency stimulation. Our findings suggest that high frequency stimulation may suppress pathologically enhanced low frequency activity in patients with phasic dystonia. These dystonic features are the quickest to respond to high frequency stimulation and may thus directly relate to modulation of pathological basal ganglia activity, whereas improvement in tonic features may depend on long-term plastic changes within the motor network.
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