Name: Controlling Parkinsons Disease With Adaptive Deep Brain Stimulation (Video) | JoVE Journal
Uploaded: 2014-07-16T13:00:00.000+00:00
Duration: 11 min 12 s
Description: Learn how adaptive deep brain stimulation improves Parkinson's disease outcomes compared to conventional methods. This technique monitors beta oscillations in real time to optimize motor performance while reducing power consumption.

ai_agent_IP

ai_agent

maintenance

instantTrialDurationMinutes

isBiopharma

enableNewMyJoveSectionDesign

educationFeatures

seoMetaApi

ai_copilot_institution_blacklist

ai_chat_institution_blacklist

freeAccessWindow

ssoRoleCapture

scheduledMaintenanceBanner

joveLabsFeatures

disable_autoplay_for_bots

extended_trial_duration

5 minutes

playerTrialDesktop

This method was developed using funding from the Wellcome Trust, Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, and Rosetrees Trust. The UCL Unit of Functional Neurosurgery is supported by the UK Parkinson Appeal and the Monument Trust.

1. Consent and Biomarker Identification
This protocol has been reviewed and approved by the National Research Ethics Service Committee South Central - Oxford A.
<ol>
	<li>Identify appropriate subjects for study: subjects are those who are clinically identified as being suitable for deep brain stimulation (medically refractory Parkinson&#39;s disease). Note: Perform experiment after electrode implantation (day 1) and before battery/stimulator placement (day 7) whilst wires are externalized.</li>
	<li>Consent patient for stimulation testing and overnight&#160;Parkinsonian medication withdrawal.</li>
	<li>Following 12 hr&#160;withdrawal of Parkinsonian medication, connect externalized DBS electrodes to appropriate amplifier (amplifier must be designed, safety tested &#38; validated for intracranial neurophysiological use in humans)16.</li>
	<li>Record local field potential (LFP) at rest from all contacts bilaterally (L 0-3 &#38; R 0-3.)</li>
	<li>Create bipolar montages (0,2 and 1,3) by subtraction of recordings from adjacent contacts.</li>
	<li>Perform power spectral analysis to identify patient specific beta peak frequency and bipolar contact pair with highest beta amplitude for stimulation testing. Note: majority of PD patients off medication have a beta peak2. If no beta peak is discernible off medication, the patient should be excluded from further analysis as this may represent DBS targeting complications.</li>
	<li>Select contact for monopolar stimulation that is bridged by bipolar contact pair (0,2 or 1,3) with highest beta amplitude.</li>
</ol>
2. Connection of Patient to aDBS Setup
<ol>
	<li>Connect the DBS electrode to the analogue amplifier and filter. Note: band pass filter between 3 - 37 Hz with x 9,100 gain.</li>
	<li>Connect reference to patient. Note: Reference should be 5 cm x 5 cm neurostimulator gel electrode pad connected by a standard 2 mm monopolar electrode wire. Place the electrode over the left clavicle.</li>
	<li>Connect analogue amplifier to A/D converter and portable computer running signal analysis software. Second stage digitally filter the signal around the patient specific beta peak with a 4 Hz pass band. Monitor beta amplitude and use this to control stimulation with a pre-set threshold. Smooth beta amplitude with a smoothing window (400 msec was heuristically effective in this setup.)</li>
	<li>Connect D/A trigger to stimulator.</li>
	<li>Connect stimulator to patient through amplifier. Note: For safety, ensure charge densities are limited to &#60;30 &#956;Q/cm2 and stimulator has linear input - output function. Optically isolate all connections to patient. Stimulator should be designed and tested with EN60601-1 medical safety standard as reference.</li>
</ol>
3. Testing of Conventional Continuous Stimulation
<ol>
	<li>Turn on conventional high frequency stimulation, but initially at zero voltage (100 msec, 130 Hz, 0 V). Apply monopolar stimulation at contact bridged by bipolar contact pair with highest beta amplitude. Monitor stimulator readout continuously throughout experiment to ensure that stimulation delivered is as expected.</li>
	<li>Slowly increase stimulation voltage by 0.5 V increments every few minutes, looking for clinical effect threshold. Establish clinically useful stimulation voltage (generally 1.5-3.0 V) accompanied by minimal or no side-effects such as paresthesia.</li>
</ol>
4. Testing of Threshold with on/off Switching and Trigger Setting
<ol>
	<li>With the stimulation at the clinically effective voltage, switch the stimulator off with 250 msec ramping down.</li>
	<li>With the stimulation at the clinically effective voltage, switch the stimulator on with 250 msec ramping up.</li>
	<li>Enquire about paresthesia and any other possible side-effects experienced upon switching stimulation on and off.</li>
	<li>If side effects are present, reduce the voltage by 0.25 V and repeat steps 4.1 to 4.3 until below paresthesia upon on/off switching threshold.</li>
	<li>By titration find the threshold for paresthesia with on/off switching again and set the voltage just below (0.1 V) this threshold for further testing. If this is clinically ineffective then try other contact (choose contact 1 or 2). Note: switching stimulator on and off may also in some patients cause a spike artifact, possibly related to capacitance charging at the tissue electrode interface. As the signal was pass-band filtered in the beta band, before setting a trigger level, this artifact was greatly attenuated. Nevertheless, in a few instances this artifact was sufficient to cause self-triggering. To address this in these cases, we reduced the voltage of stimulation, and increased trigger threshold to escape self-triggering. Another way that this could be tackled in the future if necessary is through the incorporation of a lock out period after each trigger onset to avoid self-triggering.</li>
	<li>Turn on stimulation at voltage just under the on/off switching paresthesia threshold determined above.</li>
	<li>Increase beta amplitude trigger threshold to a level that results in the minimum time on stimulation whilst maintaining clinical effect. Aim for at least 50% reduction in time on stimulation.</li>
	<li>Turn off stimulation and leave patient without stimulation (following set up and between test blocks) for 10 min&#160;to washout stimulation effect.</li>
</ol>
5. Testing of Patient Across Different Stimulation Conditions
<ol>
	<li>Ensure blinding of patients to test conditions (adaptive DBS, conventional &#38; off).</li>
	<li>Apply each test condition for a minimum of a 5 min&#160;stabilization period with the condition running before clinical testing begins. Counterbalance test condition order across subjects. Fix the voltage, pulse width and stimulation frequency identically across test conditions so that the only difference relates to the timing of stimulation with regard to beta amplitude.</li>
	<li>At a predetermined fixed point after commencement of stimulation (e.g., as a minimum 300 sec), assess the patient clinically for effect through the UPDRS rating scale.</li>
	<li>Video record assessment and then blind&#160;rate by independent experts offline (excluding rigidity.)</li>
	<li>Perform clinical assessment using objective measures (accelerometry or actigraphy).</li>
</ol>

<ol><li>Schrag, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Dyskinesias+and+motor+fluctuations+in+Parkinson%27s+disease%3A+A+community-based+study%5BTitle%5D)+AND+%22Brain%22%5BJournal%5D)">Dyskinesias and motor fluctuations in Parkinson's disease: A community-based study.</a> Brain. 123 (11), 2297-2305 (2000).</li>
<li>Little, S., Brown, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((What+brain+signals+are+suitable+for+feedback+control+of+deep+brain+stimulation+in+Parkinson%27s+disease%5BTitle%5D)+AND+%22Annals+of+the+New+York+Academy+of+Sciences%22%5BJournal%5D)">What brain signals are suitable for feedback control of deep brain stimulation in Parkinson's disease.</a> Annals of the New York Academy of Sciences. 1265 (1), 9-24 (2012).</li>
<li>Chen, C. C., Brücke, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Deep+brain+stimulation+of+the+subthalamic+nucleus%3A+a+two-edged+sword%5BTitle%5D)+AND+%22Current+biology%22%5BJournal%5D)">Deep brain stimulation of the subthalamic nucleus: a two-edged sword.</a> Current biology. 16 (22), 952-953 (2006).</li>
<li>Modolo, J., Legros, A., Thomas, A. W., Beuter, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Model-driven+therapeutic+treatment+of+neurological+disorders%3A+reshaping+brain+rhythms+with+neuromodulation%5BTitle%5D)+AND+%22Interface+Focus%22%5BJournal%5D)">Model-driven therapeutic treatment of neurological disorders: reshaping brain rhythms with neuromodulation.</a> Interface Focus. (1), 61-74 (2011).</li>
<li>Priori, A., Foffani, G., Rossi, L., Marceglia, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Adaptive+deep+brain+stimulation+%28aDBS%29+controlled+by+local+field+potential+oscillations%5BTitle%5D)+AND+%22Experimental+neurology%22%5BJournal%5D)">Adaptive deep brain stimulation (aDBS) controlled by local field potential oscillations.</a> Experimental neurology. 245, 77-86 (2012).</li>
<li>Kühn, A. A., Kupsch, A., Schneider, G., Brown, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Reduction+in+subthalamic+8-35+Hz+oscillatory+activity+correlates+with+clinical+improvement+in+Parkinson%27s+disease%5BTitle%5D)+AND+%22The+European+journal+of+neuroscience%22%5BJournal%5D)">Reduction in subthalamic 8-35 Hz oscillatory activity correlates with clinical improvement in Parkinson's disease.</a> The European journal of neuroscience. 23 (7), 1956-1960 (2006).</li>
<li>Eusebio, A., Cagnan, H., Brown, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Does+suppression+of+oscillatory+synchronisation+mediate+some+of+the+therapeutic+effects+of+DBS+in+patients+with+Parkinson%27s+disease%5BTitle%5D)+AND+%22Frontiers+in+integrative+neuroscience%22%5BJournal%5D)">Does suppression of oscillatory synchronisation mediate some of the therapeutic effects of DBS in patients with Parkinson's disease.</a> Frontiers in integrative neuroscience. 6, (2012).</li>
<li>Giannicola, G., Rosa, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Subthalamic+local+field+potentials+after+seven-year+deep+brain+stimulation+in+Parkinson%27s+disease%5BTitle%5D)+AND+%22Experimental+neurology%22%5BJournal%5D)">Subthalamic local field potentials after seven-year deep brain stimulation in Parkinson's disease.</a> Experimental neurology. 237 (2), 312-317 (2012).</li>
<li>López-Azcárate, J., Tainta, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Coupling+between+beta+and+high-frequency+activity+in+the+human+subthalamic+nucleus+may+be+a+pathophysiological+mechanism+in+Parkinson%27s+disease%5BTitle%5D)+AND+%22The+Journal+of+Neuroscience%22%5BJournal%5D)">Coupling between beta and high-frequency activity in the human subthalamic nucleus may be a pathophysiological mechanism in Parkinson's disease.</a> The Journal of Neuroscience. 30 (19), 6667-6677 (2010).</li>
<li>Ozkurt, T. E., Butz, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((High+frequency+oscillations+in+the+subthalamic+nucleus%3A+A+neurophysiological+marker+of+the+motor+state+in+Parkinson%27s+disease%5BTitle%5D)+AND+%22Experimental+neurology%22%5BJournal%5D)">High frequency oscillations in the subthalamic nucleus: A neurophysiological marker of the motor state in Parkinson's disease.</a> Experimental neurology. 229 (2), 324-331 (2011).</li>
<li>Pogosyan, A., Yoshida, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Parkinsonian+impairment+correlates+with+spatially+extensive+subthalamic+oscillatory+synchronization%5BTitle%5D)+AND+%22Neuroscience%22%5BJournal%5D)">Parkinsonian impairment correlates with spatially extensive subthalamic oscillatory synchronization.</a> Neuroscience. 171 (1), 245-257 (2010).</li>
<li>Chen, C. C., Hsu, Y. T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Complexity+of+subthalamic+13-35+Hz+oscillatory+activity+directly+correlates+with+clinical+impairment+in+patients+with+Parkinson%27s+disease%5BTitle%5D)+AND+%22Experimental+neurology%22%5BJournal%5D)">Complexity of subthalamic 13-35 Hz oscillatory activity directly correlates with clinical impairment in patients with Parkinson's disease.</a> Experimental neurology. 224 (1), 234-240 (2010).</li>
<li>Rosin, B., Slovik, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Closed-loop+deep+brain+stimulation+is+superior+in+ameliorating+parkinsonism%5BTitle%5D)+AND+%22Neuron%22%5BJournal%5D)">Closed-loop deep brain stimulation is superior in ameliorating parkinsonism.</a> Neuron. 72 (2), 370-384 (2011).</li>
<li>Little, S., Pogosyan, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Adaptive+Deep+Brain+Stimulation+in+Advanced+Parkinson+Disease%5BTitle%5D)+AND+%22Annals+of+neurology%22%5BJournal%5D)">Adaptive Deep Brain Stimulation in Advanced Parkinson Disease.</a> Annals of neurology. 74 (3), 449-457 (2013).</li>
<li>Afshar, P., Khambhati, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((A+translational+platform+for+prototyping+closed-loop+neuromodulation+systems.+Frontiers+in+neural+circuits%5BTitle%5D)+AND+%22%22%5BJournal%5D)">A translational platform for prototyping closed-loop neuromodulation systems. Frontiers in neural circuits.</a> 6, (2012).</li>
<li>Eusebio, A., Thevathasan, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Deep+brain+stimulation+can+suppress+pathological+synchronisation+in+parkinsonian+patients%5BTitle%5D)+AND+%22Journal+of+neurology%2C+neurosurgery%2C+and+psychiatry%22%5BJournal%5D)">Deep brain stimulation can suppress pathological synchronisation in parkinsonian patients.</a> Journal of neurology, neurosurgery, and psychiatry. 82 (5), 569-573 (2011).</li>
<li>Little, S., Pogosyan, A., Kuhn, A. A., Brown, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Beta+band+stability+over+time+correlates+with+Parkinsonian+rigidity+and+bradykinesia%5BTitle%5D)+AND+%22Experimental+neurology%22%5BJournal%5D)">Beta band stability over time correlates with Parkinsonian rigidity and bradykinesia.</a> Experimental neurology. 236 (2), 383-388 (2012).</li>
</ol>

L.Z., M.H.: consultancy, travel support, speaking fees, Medtronic, St Jude. T.F.: consultancy, AbbVie Pharmaceuticals, St Jude, Medtronic; P.L.: consultancy, speaking fees, Medtronic, St Jude. P.B.: consultancy, Medtronic, Sapiens.

This article outlines a new method for the study and validation of adaptive deep brain stimulation in post-operative patients. DBS treatment is part of standard treatment for PD, essential tremor and dystonia and is being introduced and tested in a range of other conditions including cluster headache, epilepsy, Gilles de la Tourette syndrome, obsessive compulsive disorder and depression. At present, all clinical stimulation paradigms employ continuous, open-loop stimulation and although these simple stimulation paradigms are often effective, it is hoped that they can be significantly improved by making them responsive to disease appropriate biomarkers and thereby optimizing stimulation in an informed, patient specific manner. The method, outlined here, allows the testing of aDBS in patients externalized after their first surgery (electrode implantation), prior to internalization and implantation of the battery and stimulator. Using this method, it is hoped therefore that researchers can investigate the efficacy of aDBS using a range of biomarkers across the spectrum of disorders for which DBS is used. This may then lead to trials in the chronically implanted clinical setting.
The protocol that we have used and found to be successful is outlined above. We discerned a number of critical steps for fine-tuning the process in order to achieve successful aDBS. Parameters that can be controlled in this simple aDBS setup include voltage, trigger threshold, stimulation contact and ramping duration. These must all be balanced against the side effects of switching stimulation on and off (paresthesia), technical problems (recurrent &#8216;self&#39; triggering) and clinical efficacy. Switching stimulation on and off causes a voltage dependent artifact in the LFP that, despite filtering, can potentially leak into the frequency range of interest. If this is severe, it can cause the system to self-trigger even in the absence of an elevation in the biomarker signal, -here beta activity in the local field potential. This does not represent a safety issue as it effectively results in the aDBS being on all the time and therefore mimicking cDBS which is known to be safe. However, it does result in a lack of reactivity to beta amplitude and the loss therefore of any potential benefit of aDBS over cDBS. We found that, if necessary, self-triggering could be avoided by reducing the stimulation voltage, raising the threshold or changing the stimulation contact. The 250 msec ramping of stimulation on and off was found to be satisfactory compromise with regard to preventing paresthesias whilst maintaining responsiveness of aDBS. At present parameters have to be adjusted heuristically in order to achieve the best response profile in individual patients and we have not yet identified consistent rules that are applicable at the group level to achieve this reliably. Nevertheless, in all patients studied thus far, we have found that heuristic adjustment of voltage, trigger threshold and stimulation contact enabled efficacious aDBS, and optimal parameters were identified in less than 30 min. It is hoped that the management of side effects (paresthesias from on/off switching) and artifact contamination (possibly related to tissue-electrode capacitance) can be further investigated and better understood to derive more generalized rules regarding their minimization.
The potential parameter space for exploration will also become larger and more complicated as the complexity of biomarkers and stimulation algorithms grow. For instance, high frequency power ratios, phase amplitude coupling and beta variability have all been shown to relate to Parkinsonian state9,10,12,17. The method described in this paper should enable the systematic investigation of such parameters and their effect on the clinical efficacy of stimulation in addition to their side effect profile. However, the thorough optimization of all parameters in the future is likely to be facilitated once DBS models and algorithmic optimization routines that focus on the response of the biomarker rather than clinical effects allow limitation of the parameter ranges to be searched empirically.
This method has demonstrated improved power consumption and clinical efficacy when compared to conventional DBS and has the potential to be further improved in PD with advancement in our understanding regarding biomarkers and stimulation patterning. In other conditions where DBS is used, much less is known regarding underlying pathophysiology and therefore corresponding biomarkers are yet to be fully determined. Significant further research is required to fully harness the potential of aDBS in Parkinsonism, and to explore its feasibility in a number of other potential neurological and neuropsychiatric conditions in which severity and impairment fluctuate over time.

Parkinson&#39;s disease is a common severely disabling degenerative movement disorder for which long term medical treatment is unsatisfactory1. DBS is effective for advanced medically refractory PD but is limited in terms of efficacy, side effects and cost2. Conventional stimulation is set heuristically by a movement disorders specialist and left running continuously without change until the next clinic visit. Typical stimulation parameters are 60 msec pulse width, 3 V intensity, and 130 Hz repetition. However, this continuous high voltage stimulation may interfere with normal motor functioning3. Much as cardiac pacing has successfully transitioned from simple open loop systems to complex responsive closed loop systems, with an associated improvement in outcome, it is hoped that DBS can similarly be improved by making it responsive to underlying brain rhythms - adaptive DBS (aDBS)4,5.
In order to realize aDBS, it is firstly critical to identify reliable biomarkers of disease. Parkinson&#39;s disease is characterized by prominent beta (13-33 Hz) oscillations recorded throughout the basal ganglia circuit2. These beta oscillations are suppressed by levodopa and DBS in proportion to improvement in clinical state6,7. They are stable and robust in the long term and can be recorded from the same electrodes used for clinical DBS making them attractive targets for biomarkers8. In addition to beta oscillations, a range of other, more complex, potential biomarkers have been identified that have been shown to relate to severity of symptoms2,9-12.
Proof of principle of aDBS has now been demonstrated in a non - human primate model of PD13. This used a single cortical motor neuron to control stimulation with firing of the neuron triggering DBS stimulation after a fixed delay. The study reported that adaptive stimulation was more efficacious than conventional DBS. Recent work has since successfully extended aDBS to humans, the method for which is presented in this JoVE article14. This study investigated patients with PD in the immediate post-operative period prior to internalization of their wires and connection to their battery pack / stimulator. Beta oscillations were monitored in real time online and used to control the timing of high frequency stimulation. This led to a &#62;50% reduction in power consumption and a 25% improvement in motor impairment compared to standard stimulation. These results will need to be replicated in the chronically implanted state where thresholds and effective stimulation parameters can change as well as drug levels. As such, biomarkers and control algorithms may need to be adjusted and matched accordingly and indeed may well require further complexity to adapt to this different parameter landscape. Devices that are equipped for longer term stimulation and recording are currently being developed and trialed in a research setting15. Meanwhile there is a need for a platform that will allow the possible benefits of adaptive DBS and the algorithms that underpin its performance to be further evaluated and refined. This is an important step, as errors and sub-optimal approaches are more difficult to reverse once systems are internalized for chronic use. Moreover, acute studies are necessary to motivate efforts in overcoming the challenges implicit in developing chronic internalized adaptive DBS system.
The goal of this methods report is to enable researchers to explore a range of different biomarkers and stimulation paradigms in DBS patients and to optimize parameters so as to maximize efficacy and minimize side effects / power consumption. It is the first method of its kind to be effective in patients with Parkinsonism and yet is relatively simple and easy to apply. The method is designed to investigate any DBS patient for whom there is a known LFP biomarker and who has a period of externalization post-operatively (up to 1 week period when electrode wires are extra-cranial and available for experimentation prior to battery/stimulator insertion).

<table><tbody><tr><td>StimRecord Amplifier (3-37 Hz)</td><td>In house</td><td>NA</td><td>Common mode rejection, 3-37 Hz (bandpass), x9500 amplifier. See - Eusebio, A &lt;i&gt;et al&lt;/i&gt;&lt;sup&gt;16&lt;/sup&gt;.</td></tr><tr><td>1401 Digital acquisition unit</td><td>CED</td><td>Micro 1401-3</td><td></td></tr><tr><td>Spike 2 software</td><td>CED</td><td>NA</td><td></td></tr><tr><td>Stimulator</td><td>In house</td><td>NA</td><td>Biphase, variable, ramped stimulator. See - Little &lt;i&gt;et al&lt;/i&gt;&lt;sup&gt;14&lt;/sup&gt;.</td></tr><tr><td>Gel electrode reference pad</td><td>Axelgaard</td><td>895220</td><td>5 x 5 cm PALS platinum gel electrode pad</td></tr></tbody></table>

controlling parkinson's disease with adaptive deep brain stimulation

Controlling Parkinson's Disease With Adaptive Deep Brain Stimulation

Adaptive deep brain stimulation (aDBS) has the potential to improve the treatment of Parkinson&#39;s disease by optimizing stimulation in real time according to fluctuating disease and medication state. In the present realization of adaptive DBS we record and stimulate from the DBS electrodes implanted in the subthalamic nucleus of patients with Parkinson&#39;s disease in the early post-operative period. Local field potentials are analogue filtered between 3 and 47 Hz before being passed to a data acquisition unit where they are digitally filtered again around the patient specific beta peak, rectified and smoothed to give an online reading of the beta amplitude. A threshold for beta amplitude is set heuristically, which, if crossed, passes a trigger signal to the stimulator. The stimulator then ramps up stimulation to a pre-determined clinically effective voltage over 250 msec and continues to stimulate until the beta amplitude again falls down below threshold. Stimulation continues in this manner with brief episodes of ramped DBS during periods of heightened beta power.
Clinical efficacy is assessed after a minimum period of stabilization (5 min) through the unblinded and blinded video assessment of motor function using a selection of scores from the Unified Parkinson&#39;s Rating Scale (UPDRS). Recent work has demonstrated a reduction in power consumption with aDBS as well as an improvement in clinical scores compared to conventional DBS. Chronic aDBS could now be trialed in Parkinsonism.

Results using this method have recently been published using this protocol for beta amplitude (Figure 1)14. This study showed that clinically efficacious stimulation can be achieved despite a &gt;50% reduction in time on stimulation (p &lt; 0.001). It was also noted that time on stimulation tended to progressively drop despite a constant trigger threshold (2-tailed, 1-sample t test, t7 = 3.2, p = 0.01). Motor scores were improved by 66% and 50% during aDBS in the unblinded and blinded conditions, respectively. Despite the reduced amount of total stimulation - clinical outcome was 29% (p=0.03) and 27% (p=0.005) better in the aDBS group compared with the conventional DBS group (unblinded and blinded respectively, Figure 2).
<img alt="Neuroscience experiment diagram; EEG recording, data unit, digital filtering, signal analysis." fo:content-width="5in" fo:src="/files/ftp_upload/51403/51403fig1highres.jpg" src="/files/ftp_upload/51403/51403fig1.jpg" data-altupdatedat="1787630408000" data-alt="Figure 1"> 
Figure 1. Experimental setup. Experimental setup for adaptive deep brain stimulation in externalized subjects. Bipolar local field potential (LFP) is passed through a custom built StimRecord amplifier that filters (3-37 Hz) and amplifies (x9,100). The analogue (A) output is passed to a data acquisition unit, which converts it to a digital (D) signal that is displayed on a portable computer. The signal is digitally filtered around the beta peak in real time and converted to beta amplitude by rectifying and smoothing. A threshold is set that triggers stimulation in a monopolar montage between the 2 bipolar recording electrodes when beta power crosses the threshold. Stimulation terminates when beta power drops again below threshold. (Reprinted with permission from Annals of Neurology.) <a href="https://www.jove.com/files/ftp_upload/51403/51403fig1highres.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Clinical motor improvement graph; session vs. video ratings; statistical comparison noted." fo:content-width="5in" fo:src="/files/ftp_upload/51403/51403fig2highres.jpg" src="/files/ftp_upload/51403/51403fig2.jpg" data-altupdatedat="1787630408000" data-alt="Figure 2"> 
Figure 2. Clinical improvements. Mean ± SEM % change in hemibody UPDRS scores (items 20, 22, and 23) with different stimulation conditions as assessed unblinded during the experimental sessions (A) or from video recordings by blinded experts (B). Asterixes denote significant differences following correction for multiple comparisons by the false discovery rate procedure. All changes were significant from the unstimulated state, with the exception of the blinded score for random stimulation (Reprinted with permission from Annals of Neurology.) <a href="https://www.jove.com/files/ftp_upload/51403/51403fig2highres.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Adaptive deep brain stimulation (aDBS) is effective for Parkinson&#8217;s disease, improving symptoms and reducing power consumption compared to conventional deep brain stimulation (cDBS). In aDBS we track a local field potential biomarker (beta oscillatory amplitude) in real time and use this to control the timing of stimulation.

Adaptive deep brain stimulation (aDBS) has the potential to improve the treatment of Parkinson&#39;s disease by optimizing stimulation in real time ...

The overall goal of the following experiment is to observe and quantify the clinical effect of adaptive deep brain stimulation and compare it to standard stimulation. This is achieved by performing a passive recording from the deep brain stimulation or DBS electrodes of postoperative Parkinson's patients and performing spectral analysis on bipolar montages to identify the optimal contacts for simultaneous stimulation and recording. As a second step standard, continuous clinical monopolar stimulation is performed at the identified contact to determine the parameters that confer clinical improvements such as tremor suppression.Next intermittent stimulation is performed according to beta amplitude in order to identify trigger thresholds appropriate for adaptive stimulation, which can then be tested against standard continuous stimulation. The results show improvements in clinical outcome with adaptive stimulation compared with standard high frequency stimulation, despite significant reductions in electrical charge delivery and time on stimulation. The main advantage of this technique over existing methods like conventional high frequency simulation is that in acute studies, it reduces overall stimulation and therefore saves the battery as well as improving motor performance.The implications of this technique extend towards therapy of other neurological and neuropsychiatric disorders treated with DBS because other conditions such as tremor also fluctuate and therefore may be amenable to an adaptive stimulation approach. The idea for this method has developed slowly over time as a number of groups have recognized the importance of excessive synchronization, particularly beta oscillations in the pathophysiology of Parkinson's disease. Begin by obtaining informed consent for the experiment from a patient with medically refractory Parkinson's disease.Following the implantation of DBS electrodes, there are 2D BS electrodes each having four contacts. A stimulus can be delivered to one contact, and recordings can be obtained from the two adjacent contacts. The contact being used to deliver the stimulus can be changed as desired the night before the experimental procedure stopped the patient's Parkinsonian medication the following morning when the patient arrives for testing, start by washing your hands.Then gently remove the electrode wires from their protected cover. Next, connect the externalized DBS electrodes to the connector cable. Then connect the electrode to the amplifier.Finally, connect the reference electrode over the patient's left clavicle. Then record the bipolar local field potential or LFP from contact zero and two contralateral to the worst affected side whilst the patient is at rest. Next, repeat the bipolar recording from contacts one and three.Perform a power spectral analysis to identify the patient specific beta peak frequency and the bipolar contact pair with the highest beta amplitude for stimulation testing, which are the L zero L two electrodes. In this example, after determining the bipolar contact pair with the highest beta amplitude, which in this case would be zero and two, select the contact that is bridged by those two as the contact for monopolar stimulation. To connect the patient to the adaptive DBS setup.Connect the analog amplifier to the A to D converter and to the portable computer running the signal analysis software. Second stage digitally filter the signal around the patient's specific beta peak with the four hertz pass band. The software monitors the beta amplitude and uses this to control the stimulation With a preset threshold, the beta amplitude is smooth with a smoothing window of 400 milliseconds.Next, connect the D to a trigger to the stimulator. The next step is to turn on conventional high frequency stimulation with an initial voltage of zero. Then connect the stimulator to the patient through the amplifier optically, isolate all connections to the patient.Apply the monopolar stimulation at the contact identified earlier. Monitor the stimulator readout continuously throughout the experiment to ensure that the expected stimulation is delivered slowly. Increase the stimulation voltage by 0.5 volt increments every few minutes.Looking for the clinical effect threshold. For example, an improvement in tremor, stiffness, or slowness. Establish the clinically useful stimulation voltage, which is generally between 1.5 and three volts and has minimal or no side effects such as paresthesia with the stimulation at the clinically effective voltage.Switch the stimulator off with a 250 millisecond ramp down. Then with the stimulation still at the clinically effective voltage, switch the stimulator on with a 250 millisecond ramp up. Ask the patient about paresthesia or any other side effects experienced upon switching off and on the stimulation if side effects are present.Continue to reduce the voltage in steps of 0.25 volts and test for paresthesia by switching the stimulation off and on when no more paresthesia is reported. Set the voltage 0.1 volts below this threshold and turn on the stimulation. Next, increase the beta amplitude trigger threshold and ensure that the clinical effect remains continue to gradually increase the beta amplitude trigger threshold to a level that results in the minimum time on stimulation.Whilst maintaining a clinical effect, aim for stimulation to be on at most 50%of the time. Adjusting the trigger threshold and stimulation parameters to ensure appropriate adaptive DBS without self triggering is a crucial step. Achieving this requires careful and slow titration of the threshold and stimulation voltages whilst closely monitoring the patient.Once the trigger threshold and stimulation parameters are set, turn off the stimulation for 10 minutes to wash out the stimulation effect. Being sure to blind the patients to the test conditions. Begin to deliver adaptive DBS conventional DBS or no stimulation.Allow the test condition to run for a five minute stabilization period. After five minutes, begin the clinical testing. Assess the patient using the unified Parkinson's Disease Rating Scale.Objective assessment measures such as accelerometry or actigraphy could also be used. After finishing one test condition, turn off stimulation for another 10 minute rest period. Then trigger the next type of stimulation Again, beginning with a five minute stabilization period prior to performing the assessment.Fix the voltage pulse width and stimulation frequency identically across test conditions so that the only difference relates to the timing of stimulation. With regard to beta amplitude throughout the clinical testing video, record the task so that an independent expert can perform a blinded assessment at a later time. The percent motor improvement from the unstimulated state as assessed by an unblinded observer during the experimental session is shown here for conventional DBS adaptive DBS and random stimulation Blinded assessments were also done by evaluating videos of the motor performance.The motor scores were improved by 66%and 50%during adaptive DBS in the unblinded and blinded conditions respectively. Despite the reduced amount of total stimulation, the clinical outcome was 29%better unblinded and 27%better blinded in the adaptive DBS group compared with the conventional DBS group. While attempting this procedure, it's important to remember to continuously observe the patient for potential side effects or changes in clinical state Following this procedure.Other approaches like triggering of different potential biomarkers or with different triggering levels or forms can be performed in order to explore the large variety of possible adaptive DBS paradigms.

controlling-parkinson-s-disease-with-adaptive-deep-brain-stimulation

Research

JoVE Journal

Medicine

Deep brain stimulation surgery offers a unique opportunity to examine information encoding in the awake human brain.  This article will describe intra-operative methods used to perform cognitive and behavioral tasks while simultaneously acquiring physiological data such as EMG, single-unit neuronal activity and/or local field potentials.

Intra-Operative Behavioral Tasks in Awake Humans Undergoing Deep Brain Stimulation Surgery

The mechanism underlying the therapeutic effects of Deep Brain Stimulation (DBS) surgery needs investigation. The methods presented in this manuscript describe an experimental approach to examine the cellular events triggered by DBS by analyzing the gene expression profile of candidate genes that can facilitate neurogenesis post DBS surgery.

Analysis of Gene Expression Changes in the Rat Hippocampus After Deep Brain Stimulation of the Anterior Thalamic Nucleus

A method for implanting electrodes into the subthalamic nucleus (STN) of rats is described. Better localization of the STN was achieved by using a microrecording system. Furthermore, a stimulation set-up is presented that is characterized by long-lasting connections between the head of the animal and the stimulator.

Microelectrode Guided Implantation of Electrodes into the Subthalamic Nucleus of Rats for Long-term Deep Brain Stimulation

This article describes the delivery of intracranial electrical stimulation that is temporally and spatially separate from the drug-use environment for the treatment of IV methamphetamine dependence.

A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration

The present protocol aims at assessing cognitive-emotional functions in the basal ganglia by simultaneous neurophysiological recording of local field potentials and non-invasive brain cortical activity (EEG). The procedure is exemplified by the use of paradigms involving speech stimuli with emotional connotation or the Flanker task involving cognitive control.

Combined Invasive Subcortical and Non-invasive Surface Neurophysiological Recordings for the Assessment of Cognitive and Emotional Functions in Humans

This paper describes the use of quantitative measurement of eye movements in conjunction with stimulation of focal areas of the deep brain in order to study physiology, pathophysiology, and the mechanisms of deep brain stimulation.

Using Saccadometry with Deep Brain Stimulation to Study Normal and Pathological Brain Function

Deep brain stimulation (DBS) is an effective treatment option for Parkinson's disease. We established a study design to screen novel stimulation paradigms in rats. The protocol describes the use of the staircase test and cylinder test for motor outcome assessment in DBS treated hemiparkinsonian rats.

A Novel Approach to Assess Motor Outcome of Deep Brain Stimulation Effects in the Hemiparkinsonian Rat: Staircase and Cylinder Test

The goal of this project is to develop an interactive, patient-specific modeling pipeline to simulate the effects of deep brain stimulation in near real-time and provide meaningful feedback as to how these devices influence neural activity in the brain.

Targeting Neuronal Fiber Tracts for Deep Brain Stimulation Therapy Using Interactive, Patient-Specific Models

The protocol shows a prototype of the at-home multi-modal data collection platform that supports research optimizing adaptive deep brain stimulation (aDBS) for people with neurological movement disorders. We also present key findings from deploying the platform for over a year to the home of an individual with Parkinson's disease.

Bringing the Clinic Home: An At-Home Multi-Modal Data Collection Ecosystem to Support Adaptive Deep Brain Stimulation

Here, we describe a protocol for ex vivo high-density microelectrode array recordings from acute cerebellar brain slices of a dystonic hamster model that received in vivo. continuous pallidal deep brain stimulation for 11 days.

Investigating The Network-Wide Mechanisms of Pallidal Deep Brain Stimulation Using High-Density Microelectrode Arrays

Learn how adaptive deep brain stimulation improves Parkinson's disease outcomes compared to conventional methods. This technique monitors beta oscillations in real time to optimize motor performance while reducing power consumption.

Controlling Parkinson's Disease With Adaptive Deep Brain Stimulation

Explore More Videos