Dear Editor,
Deep brain stimulation (DBS) has been utilized to treat adult and childhood dystonia for several decades. While efficacy in primary dystonia has been well proven, the results in secondary dystonia and other movement disorders have been variable and often incomplete [
[1]
]. Once optimal stimulation sites are identified, the stimulation parameters must be adjusted to optimize efficacy for individuals [[2]
]. In some, adjustment of parameters limited by patient-reported side effects [- Isaias I.U.
- Tagliati M.
Deep brain stimulation programming for movement disorders.
Deep Brain Stimul Neurol Psychiatr Disord. 2008; (Published online): 361-397https://doi.org/10.1007/978-1-59745-360-8_20
[3]
]. Therefore, there remains a need to identify additional adjustable parameters that could potentially increase efficacy or decrease side effects in patients with incomplete response.DBS is predominantly used with continuous regular pulse trains without breaks, with the hypothesized goal of blocking or attenuating abnormal signaling. While the mechanism of action of DBS remains unknown, recent research has suggested the temporal pattern of stimulation pulses may be an important determinant of efficacy [
[4]
]. Cycling of DBS, or intermittent deep brain stimulation (iDBS) for variable on/off periods has been utilized in affective disorders and tremor [[5]
]. In Parkinson's, there has been an effect on motor symptoms with change in temporal stimulation patterns [[6]
]. It has been hypothesized these benefits are due to the cycling pattern allowing desynchronization of neuronal activity beyond a simple excitatory or inhibitory modulation [[7]
]. Despite these considerations and exploration in other disorders, iDBS has had limited utilization in the treatment of dystonia [- Herrington T.M.
- Cheng J.J.
- Eskandar E.N.
Mechanisms of deep brain stimulation.
J Neurophysiol. 2016; 115: 19-38https://doi.org/10.1152/JN.00281.2015/ASSET/IMAGES/LARGE/Z9K0011634190006.JPEG
[8]
].Here, we test a particular form of iDBS that we refer to as "theta-burst iDBS". This pattern is inspired by results from experiments in transcranial magnetic stimulation. Theta-burst stimulation describes a pattern in which bursts of stimulation are given at 100msec intervals of 50Hz stimulation alternating with 100msec pauses, to mimic previously seen improvement in plasticity in hippocampal slices [
[9]
]. There have been few trials [[6]
] of high frequency cycling stimulation in DBS, and no prior reported testing in dystonia. We describe an initial open-label pilot observational study of children and young adults with implanted neurostimulators who are tested for clinical response to theta-burst iDBS.1. Methods
All subjects had previously undergone DBS lead placement for secondary dystonia and were seen for regular scheduled programming visits. All subjects had implanted Medtronic Activa™ neurostimulators (Medtronic, Minneapolis, Minnesota). Subjects with other DBS systems were excluded as their neurostimulators did not allow for this pattern. Location of leads was confirmed for all subjects by review of post-operative imaging (typically a post-operative CT scan co-registered to a pre-operative MRI to allow simultaneous visualization of lead location and brain structures). All patients had leads placed utilizing a previously described staged procedure [
[10]
] to identify optimal lead location for treatment of their secondary dystonia.Subjects were selected if they had incomplete response to continuous DBS (cDBS.) Incomplete response was defined as persistent dystonia interfering with motor function. Informed consent was obtained from all subjects, or their guardians, as applicable.
iDBS was trialed with observation by trained clinician. The cycling pattern was set at 100msec with stimulation on and 100msec with stimulation off, henceforth referred to as iDBS theta-burst. A complete on/off cycle thus occurred every 200msec, yielding a 5Hz burst frequency. Within each 100msec on period, stimulus pulses were delivered at the frequency previously seen to have optimal benefit in cDBS for the subject. When benefit was not seen at follow-up, or if worsening occurred at any time, subjects were returned to previous cDBS settings.
Benefits, lack of response, or worsening were noted by subject, parent, and clinician both within 30 minutes of initial change as well as at follow-up appointment. Data was utilized only if clinicians, subjects, and parents were all in agreement. No other changes to parameters were made to limit confounding effects. Retrospective chart review was utilized to assess response, with confirmation by video review when available. Responses were recorded on a 3-point Likert scale, as "better", "same", or "worse".
2. Results
Detailed results and demographics of each subject can be seen in Table I. No adverse events occurred. Of the 22 subjects, 20 received benefit and elected to continue with iDBS theta-burst in at least one lead location, while 2 received no benefit or worsened and were returned to their previous settings. Benefits were variable, with differing responses in dystonic postures and hyperkinetic movements.
Table 1Subject Characteristics and response to iDBS thetaburst
| Subject | Diagnosis | Age at Programming | Area of Stimulation | Hyperkinetic movements | Dystonic posturing |
|---|---|---|---|---|---|
| 1 | ADEM | 15 | Gpi | None | + |
| 2 | Cerebral palsy | 19 | Gpi | None | + |
| 3 | Cerebral palsy | 18 | Gpi | None | + |
| 4 | Cerebral palsy | 23 | Gpi | None | + |
| VoSTN | + | + | |||
| 5 | Cerebral palsy | 17 | Gpi | None | + |
| 6 | Cerebral palsy | 20 | Gpi | None | None |
| Vo | None | – | |||
| 7 | Kernicterus | 12 | VIM | + | None |
| 8 | Cerebral palsy | 21 | Gpi | + | + |
| 9 | Cerebral palsy | 18 | Gpi | + | + |
| VIM | None | + | |||
| 10 | Lesch-Nyhan | 16 | NA | + | None |
| 11 | Cerebral palsy | 12 | Gpi | + | + |
| VIM | None | – | |||
| 12 | Huntington's Disease | 14 | Gpi | None | + |
| 13 | Cerebral Palsy | 14 | Gpi | None | None |
| Vo | + | + | |||
| 14 | Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) | 14 | Gpi | None | + |
| 15 | Hypoxic Ischemic Injury | 20 | Gpi | + | + |
| 16 | Cerebral palsy | 15 | Gpi | – | None |
| VIM | None | – | |||
| 17 | Unknown | 18 | Gpi | None | + |
| 18 | Stroke | 11 | Gpi | None | + |
| VL | + | + | |||
| 19 | Cerebral palsy | 18 | VIM | + | + |
| 20 | Cerebral Folate Deficiency | 11 | Gpi | – | + |
| 21 | Post-pump chorea | 9 | Gpi | None | None |
| Vo | + | None | |||
| 22 | Stroke | 22 | Gpi | None | + |
| VIM | – | None |
VA: ventralis anterior nucleus; Vo: ventralis oralis anterior and posterior nucleus; VIM: ventralis intermediate nucleus; STN: subthalamic nucleus; NA: Nucleus Accumbens; VPL: ventral posterolateral nucleus; VL: ventral lateral nucleus; VoSTN: lead with proximal contacts in Vo and distal contacts in STN; + beneficial effect; -negative effect.
Positive "better" response in dystonic posturing was noted in 15 of the 19 subjects in which iDBS theta-burst was trialed in the Gpi. The remainder of subjects had no change. Hyperkinetic movement was noted to be improved in 4 subjects, worsened in 2, and unchanged in the remainder.
Trials of iDBS theta-burst in thalamic leads, implanted in various nuclei, were performed in a smaller sample of 12 subjects. A positive response in dystonic posturing was seen in 5 subjects, a negative in 3 and no response in 3. A positive response in hyperkinetic movements was also noted in 6 subjects, worsening was noted in 1, and 4 had no change.
In one subject cycling was trialed in the nucleus accumbens, with improvement in hyperkinetic movements noted.
3. Discussion
Here, we have shown that theta-burst iDBS in pallidum and thalamus on clinically efficacious settings can improve motor symptoms in a subset of pediatric secondary dystonia subjects who had previous suboptimal response. We have not yet identified predictors of beneficial response to iDBS theta-burst, and therefore we recommend a trial of iDBS theta-burst in subjects who have incomplete response to cDBS. Trials of rapid cycling should be performed with close clinician oversight, so non-responders may be rapidly returned to their previous parameter settings.
This study is limited by the small sample. Examination of benefit by retrospective chart review based on subjective clinician, participant, and parent report also introduces concerns of possible bias and difficulty quantifying benefit. These limitations need to be addressed in a future blinded trial in a larger group of subjects, utilizing quantitative outcome measures. We note that current approved implantable stimulation devices are limited in the available variation in temporal patterns. Our results may support future changes in device software to allow a variety of temporal stimulation patterns that will further expand options for programming and optimization of efficacy in patients treated with DBS.
Author roles
Jennifer MacLean: Conceptualization, Analysis, Writing- original draft, Writing-review and editing; Terence Sanger: Methodology, Writing-review and editing, Supervision, Project Administration.
Data availability statement
The data presented in this study are available on request from the corresponding author, subject to subject consent to privacy. The data are not publicly available due to subject privacy.
Funding sources and conflict of interest
No specific funding was received for this work. The authors declare no conflicts of interest relevant to this work.
Ethical compliance statement
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Boards of Children's Hospital of Orange County. Written informed consent was obtained from all subjects involved in the study, and HIPAA authorization for use of protected health information was obtained. All authors confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Acknowledgments
We are appreciative of the significant efforts of Amanda Salisbury and Cindy Malvaez, as well as the nursing staff at Children's Hospital Orange County in care for these subjects. We are also appreciative of the efforts of Mark Liker and Joffre Olaya in neurosurgical care and management.
References
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Kupsch A, Tagliati M, Vidailhet M, et al. Early postoperative management of DBS in dystonia: programming, response to stimulation, adverse events, medication changes, evaluations, and troubleshooting. doi:10.1002/mds.23624.
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Article info
Publication history
Published online: March 01, 2023
Accepted:
February 24,
2023
Received:
February 3,
2023
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© 2023 The Authors. Published by Elsevier Inc.
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