Cellular responses in globus pallidus to GP-DBS during joint movement.

<p>A: Example of firing rate in two pallidal cells before, during (grey bar), and after DBS. Periods of joint articulation used for analysis are denoted by white bars. B: Population average firing rate change during therapeutic and sub-therapeutic DBS. Error bars indicate +/- 1 SEM (n=16 therapeutic DBS, n=10 sub-therapeutic DBS). C: Proportion of recorded cells with statistically significant changes in firing rate during therapeutic DBS. D: Corresponding PSTHs to the example pallidal neurons shown in part A, before (light grey), during (black) and after DBS (dark grey). E: Population average change in firing pattern during therapeutic (dark grey) and subtherapeutic (light grey - dashed) DBS. Filled areas indicate +/- 1 SEM. F: Proportion of recorded cells with statistically significant changes in their PSTHs during therapeutic DBS.</p

Effect of GP-DBS on kinematic tuning of VLo spike activity.

<p>A: Two examples of responses to joint movement during therapeutic DBS. B: Population analysis of cells that did and did not maintain tuning to joint movement during therapeutic DBS. C: (left) Proportion of the recorded population with partial or complete loss of tuning during therapeutic DBS whose PSTH was also modulated (grey hash) or unchanged (white hash); (right) Proportion that maintained tuning during therapeutic DBS and whose PSTH was modulated (grey) or unchanged (white) by therapeutic DBS.</p

Effect of GP-DBS on kinematic tuning of globus pallidus spike activity.

<p>A: Two examples of modulated responses to joint movement during therapeutic DBS (top: motion capture data of the joint movement; middle: corresponding raster plots triggered to the beginning of each movement cycle; bottom: peri-event time histograms showing responses before, during, and after DBS). B: Population analysis of cells that did and did not maintain tuning to joint movement during therapeutic DBS. Outer pie chart shows the proportion of the recorded population tuned in the DBS-OFF condition to aspects of the joint movement (i.e. position, velocity, acceleration, or a combination). Inner pie chart shows the fraction of cells in each group that maintained tuning during DBS (white), or lost some aspect of tuning during therapeutic DBS (hashed). C: (left) Proportion of the recorded population with partial or complete loss of tuning during therapeutic DBS in which the accompanying PSTH was also modulated (grey hash) or unchanged (white hash); (right) proportion that maintained tuning during therapeutic DBS and whose PSTH was modulated (grey) or unchanged (white) by therapeutic DBS.</p

Experimental design used to investigate the effects of GP-DBS on encoding of joint kinematics through the pallidofugal pathway.

<p>A: Microelectrode recordings were performed in regions of the globus pallidus and thalamus with spike activity that was responsive to passive joint movement. B: Results of experimenter-blinded muscle rigidity scoring for both monkeys at three DBS settings. C and D: Co-registration of pre-operative MRI and post-electrode implantation CT showing DBS electrode location for monkey R (C) and K (D). E and F: Localization of recorded cells obtained from stereotactic navigation software and overlaid on corresponding atlas plates for monkey R (top) and K (bottom) for both the pallidum (E) and the thalamus (F). G: A generalized linear model (GLM) accounting for position, velocity, and acceleration of the joint movement was applied to determine the correlation between kinematics of the joint movement (top row) and spike activity (2^nd row: spike raster, 3^rd row: corresponding rate histogram). Bottom row shows the GLM prediction of firing rate.</p

Neuronal encoding of joint movement during subtherapeutic and therapeutic DBS in globus pallidus.

<p>Shown is an example of the response of a cell to shoulder flexion/extension before, during and after subtherapeutic DBS (left) and therapeutic DBS (right) (top: motion capture data of the joint movement; middle: corresponding raster plots triggered to the beginning of each movement cycle; bottom: PETHs showing responses before, during, and after DBS).</p

<i>In Vivo</i> 7T MRI of the Non-Human Primate Brainstem

<div><p>Structural brain imaging provides a critical framework for performing stereotactic and intraoperative MRI-guided surgical procedures, with procedural efficacy often dependent upon visualization of the target with which to operate. Here, we describe tools for <i>in vivo</i>, subject-specific visualization and demarcation of regions within the brainstem. High-field 7T susceptibility-weighted imaging and diffusion-weighted imaging of the brain were collected using a customized head coil from eight rhesus macaques. Fiber tracts including the superior cerebellar peduncle, medial lemniscus, and lateral lemniscus were identified using high-resolution probabilistic diffusion tractography, which resulted in three-dimensional fiber tract reconstructions that were comparable to those extracted from sequential application of a two-dimensional nonlinear brain atlas warping algorithm. In the susceptibility-weighted imaging, white matter tracts within the brainstem were also identified as hypointense regions, and the degree of hypointensity was age-dependent. This combination of imaging modalities also enabled identifying the location and extent of several brainstem nuclei, including the periaqueductal gray, pedunculopontine nucleus, and inferior colliculus. These clinically-relevant high-field imaging approaches have potential to enable more accurate and comprehensive subject-specific visualization of the brainstem and to ultimately improve patient-specific neurosurgical targeting procedures, including deep brain stimulation lead implantation.</p></div

Brainstem tractography displayed with warped nuclei in four rhesus macaques.

<p>Tractography is shown for SCP (red), LL (purple), and ML (green). SCP is shown to course through PPN (grey) and around RN (gold).</p

Process for reconstructing brainstem nuclei and fiber tracts in 3D from 7T MRI.

<p>The brainstem region outlined in blue (A) was cropped (B) from each coronal 7T SWI MR image. (C) An affine deformation algorithm based on user-defined seed points was used to warp contours from a rhesus macaque brain atlas to the MRI of each subject. The PPN is outlined in white. (D) Algorithm-defined contours from nuclei and fiber tracts within brainstem were outlined on each slice and then (E, F) lofted to create surface renderings.</p

Imaging PAG with comparisons between MRI modalities and immunolabeled histology.

<p>Coronal SWI, T1, and T2 images were matched to corresponding histological slices stained with AChE from the same animal (M3 and M4). The corresponding warped atlas was overlaid on both the SWI and the histology. On the right, matched coronal SWI slices are shown for all other animals. Histograms for all coronal MRI slices were not altered, but stretched to encompass the entire spectrum (0–255).</p

Comparisons of SWI normalized pixel intensity across brainstem regions and rhesus macaques.

<p>(A) Analysis of three paired brainstem nuclei and adjacent fiber tracts, each corresponding to an investigational target for DBS therapy. Pixel intensity values were calculated by averaging pixel intensities for each region (0 = black, 255 = white) from the raw SWI scans and dividing by the average pixel intensity values of the anterior commissure about the midline. Columnar intensity values are plotted in age order with white being the youngest and black being the oldest subject. (B) Example of age-dependent SWI pixel intensity across basal ganglia, thalamus, and brainstem structures.</p