Journal: Brain stimulation
Article Title: Closed-loop deep brain stimulation effects on parkinsonian motor symptoms in a non-human primate -- is beta enough?
doi: 10.1016/j.brs.2016.06.051
Figure Lengend Snippet: Closed-loop DBS (CL-DBS) that delivers STN stimulation based on the level of beta activity in the STN has comparable therapeutic effect on rigidity compared to traditional DBS (tDBS) but does not improve performance on a cued reaching task. A) In the parkinsonian (MPTP) macaque used in this study, a peak (~14Hz) in the low beta range is present in the normalized power spectral density calculated from LFPs recorded from STN DBS electrode contacts 1–3. This plot was derived from LFPs recording during one of the 3 minute baseline recording sessions. B) Schematic of the system used to implement real-time CL-DBS, which incorporates Tucker Davis Technologies (TDT) hardware. LFPs were recorded from DBS contacts 1 and 3, subtracted to achieve a bipolar LFP signal and bandpass filtered (9–20Hz) to extract what we are defining as beta LFP (i). The beta amplitude envelope was calculated by rectifying and low-pass filtering by means of a 400ms moving average filter (ii). The threshold level for stimulation was fixed at the median of the beta amplitude envelope calculated from the baseline LFP recording acquired at the start of each experimental session. During CL-DBS, a trigger that was switched on/off whenever the beta amplitude was greater/less than the threshold (iii) controlled stimulation (Monopolar C2, 133Hz, 700μA, 80μs/phase, (iv)). An on/off ramp time (250ms) was employed to reduce potential paresthesias induced by switching on stimulation. C) Experiment design. Following the 3 min. baseline recording session, from which the CL-DBS trigger level was defined, an experiment block consisting of a control or stimulation (CL-DBS or tDBS) period, clinical rigidity assessment, behavior assessment, and washout; experiment blocks were repeated for each experimental condition: Off-DBS, tDBS, CL-DBS. The order of blocks was randomized each day. D) Schematic showing the cued reach behavior task. E) Rigidity scores for arm and leg joints based on blinded assessment during each condition (mean ± SE; P<0.05). F) Total movement time (left) and peak speeds during reach and return task epochs (middle,right) for each condition (mean and 95% C.I.; P<0.05). The “normal” condition reflects data collected when the animal was in the normal state before MPTP administration. G) Top: beta amplitude envelope averaged over all trials in each condition, aligned to reach onset (Time = 0 s). Bottom: DBS stimulus level (as a percentage of the maximum level) averaged over all trials in the CL-DBS condition, aligned to reach onset (Time = 0 s). a: mean reach duration, b: mean return duration
Article Snippet: Data were collected from one female rhesus macaque (25 yr.) rendered parkinsonian by two intra-carotid and two systemic injections of the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and implanted in the STN with a 4-contact scaled version of a human DBS lead (NuMed) using standard approaches described elsewhere [ 19 ].
Techniques: Activity Assay, Derivative Assay, Blocking Assay, Control
![The effects of parkinsonism on oscillatory activity and phase-amplitude coupling (PAC) across all recorded structures in each subject. A and E: location of Utah array in the motor cortex (M1; top) and location of deep brain stimulation <t>(DBS)</t> leads in the subthalamic nucleus and internal and external segments of the globus pallidus [subthalamic <t>nucleus</t> <t>(STN),</t> internal segment of the globus pallidus (GPi), and external segment of the globus pallidus (GPe); bottom]. In animal J, contact pairs C2–3, C3–4, and C4–5 are estimated to be in the GPi, and the most dorsal usable contact pair, C5–6, straddled the border between GPe and GPi. Also shown are PSDs (left) and PAC comodulograms (right) in the M1 (B and F), STN (C and G), and globus pallidus (GP; D and H). Power spectral density (PSD) plots reflect median values, and shaded regions contain the 25th and 75th percentiles of the PSDs at each frequency. The white dashed boxes in the PAC comodulograms indicate regions associated with an observed increase in PAC in the parkinsonian condition.](https://pub-med-central-images-cdn.bioz.com/pub_med_central_ids_ending_with_2540/pmc05672540/pmc05672540__z9k0111743640001.jpg)
![Strength of antidromic firing in M1 diminishes over time. A, Heat map illustrating the time course of the population PSTH of M1 cells that were antidromically activated during the first 50 s of STN DBS for both subjects. Before averaging, the PSTH of each cell was aligned to the time bin in the PSTH where firing was maximal, and firing rate normalized to the firing rate calculated over the first three time bins. Zero on the x-axis represents the time point of peak antidromic firing. PSTH were calculated in 2 s bins and for visualization a 5-point linear interpolation both x and y axes was performed. B, The percentage of cells with significant change in their peak PSTH firing rate [first 10 s vs the last 10 s, Wilcoxon rank sum (WRS) test, p < 0.05]. C, Time course of the population PSTH of cells whose responses to 15 and 80 Hz stimulation were tested in addition to 130 Hz.](https://pub-med-central-images-cdn.bioz.com/pub_med_central_ids_ending_with_5133/pmc07055133/pmc07055133__zns9992023470003.jpg)
![The strength of antidromic activation of M1 cells was progressively diminished over 4 h of continuous STN. A, C, Composite scores based on the mUPDRS (y-axis) for Subjects K and J, respectively. X-axis represents the time of stimulation. mUPDRS scores are shown for Hours 1–3 but were not taken in Hour 4. Detailed scores for individual motor signs are presented in Table 2. B, D, Time course of cell population PSTH over 4 h of STN DBS in each animal is shown in the heat map (left). The percentage of cells with significant change in their peak PSTH firing rate [DBS onset vs 4 h DBS duration, Wilcoxon rank sum (WRS) test, p < 0.05] is shown in the pie charts (right). PSTH were calculated in 2 s bins and grouped into DBS onset (first 50 s of recording) and 1, 2, 3, and 4 h DBS time bins. Before averaging, the PSTH of each cell was aligned to the time bin in the PSTH where firing was maximal, and firing rate normalized to the firing rate calculated over the first three time bins.](https://pub-med-central-images-cdn.bioz.com/pub_med_central_ids_ending_with_5133/pmc07055133/pmc07055133__zns9992023470004.jpg)
