stimulation

Deep Brain Stimulation for Post-Traumatic Stress Disorder

Deep Brain Stimulation for Post-Traumatic Stress Disorder

In 2018 the application of DBS for PTSD was still strictly investigational and animal models suggest that stimulation of the amygdala, ventral striatum, hippocampus, and prefrontal cortex may be effective in fear extinction and anxiety-like behavior 1).

Neuroimaging, preclinical, and preliminary clinical data suggested that the use of DBS for the treatment of PTSD may be practical 2).

PTSD is the only potential clinical indication for DBS that shows extensive animal research prior to human applications. Nevertheless, DBS for PTSD remains highly investigational. Despite several years of government funding of DBS research in view of treating severe PTSD in combat veterans, ethical dilemmas, recruitment difficulties, and issues related to use of DBS in such a complex and heterogenous disorder remain prevalent 3).

Hamani et al. treated four posttraumatic stress disorder (PTSD) patients with DBS delivered to the subgenual cingulum and the uncinate fasciculus. In addition to validated clinical scales, patients underwent neuroimaging studies and psychophysiological assessments of fear conditioning, extinction, and recall. They show that the procedure is safe and potentially effective (55% reduction in Clinical Administered PTSD Scale scores). Posttreatment imaging data revealed metabolic activity changes in PTSD neurocircuits. During psychophysiological assessments, patients with PTSD had higher skin conductance responses when tested for recall compared to healthy controls. After DBS, this objectively measured variable was significantly reduced. Last, they found that a ratio between recall of extinguished and nonextinguished conditioned responses had a strong correlation with clinical outcomes. As this variable was recorded at baseline, it may comprise a potential biomarker of treatment response 4).

Amygdala Deep Brain Stimulation for Post-Traumatic Stress Disorder

Functional neuroimaging studies have suggested that amygdala hyperactivity is responsible for the symptoms of PTSD. Deep brain stimulation (DBS) can functionally reduce the activity of a cerebral target by delivering an electrical signal through an electrode. We tested whether DBS of the amygdala could be used to treat PTSD symptoms. Rats traumatized by inescapable shocks, in the presence of an unfamiliar object, develop the tendency to bury the object when re-exposed to it several days later. This behavior mimics the symptoms of PTSD. 10 Sprague-Dawley rats underwent the placement of an electrode in the right basolateral nucleus of the amygdala (BLn). The rats were then subjected to a session of inescapable shocks while being exposed to a conspicuous object (a ball). Five rats received DBS treatment while the other 5 rats did not. After 7 days of treatment, the rats were re-exposed to the ball and the time spent burying it under the bedding was recorded. Rats treated with BLn DBS spent on average 13 times less time burying the ball than the sham control rats. The treated rats also spent 18 times more time exploring the ball than the sham control rats. In conclusion, the behavior of treated rats in this PTSD model was nearly normalized. We argue that these results have direct implications for patients suffering from treatment-resistant PTSD by offering a new therapeutic strategy 5)

1)

Lavano A, Guzzi G, Della Torre A, Lavano SM, Tiriolo R, Volpentesta G. DBS in Treatment of Post-Traumatic Stress Disorder. Brain Sci. 2018 Jan 20;8(1):18. doi: 10.3390/brainsci8010018. PMID: 29361705; PMCID: PMC5789349.
2)

Reznikov R, Hamani C. Posttraumatic Stress Disorder: Perspectives for the Use of Deep Brain Stimulation. Neuromodulation. 2016 Dec 19. doi: 10.1111/ner.12551. [Epub ahead of print] Review. PubMed PMID: 27992092.
3)

Meeres J, Hariz M. Deep Brain Stimulation for Post-Traumatic Stress Disorder: A Review of the Experimental and Clinical Literature. Stereotact Funct Neurosurg. 2022 Jan 3:1-13. doi: 10.1159/000521130. Epub ahead of print. PMID: 34979516.
4)

Hamani C, Davidson B, Corchs F, Abrahao A, Nestor SM, Rabin JS, Nyman AJ, Phung L, Goubran M, Levitt A, Talakoub O, Giacobbe P, Lipsman N. Deep brain stimulation of the subgenual cingulum and uncinate fasciculus for the treatment of posttraumatic stress disorder. Sci Adv. 2022 Dec 2;8(48):eadc9970. doi: 10.1126/sciadv.adc9970. Epub 2022 Dec 2. PMID: 36459550.
5)

Langevin JP, De Salles AA, Kosoyan HP, Krahl SE. Deep brain stimulation of the amygdala alleviates post-traumatic stress disorder symptoms in a rat model. J Psychiatr Res. 2010 Dec;44(16):1241-5. doi: 10.1016/j.jpsychires.2010.04.022. Epub 2010 May 26. PMID: 20537659.

Deep brain stimulation (DBS)

Deep brain stimulation (DBS)

General information

Deep brain stimulation (DBS): Neurosurgical procedure that uses electrical stimulation through surgically implanted electrodes to produce neuromodulation of electrical signals for the purpose of symptom improvement. For many indications, DBS has supplanted ablative procedures in the brain.

Deep brain stimulation (DBS) is a neurosurgical procedure introduced in 1987, involving the implantation of a medical device called a neurostimulator (sometimes referred to as a ‘brain pacemaker’), which sends electrical impulses, through implanted electrodes.

The system consists of a lead that is implanted into a specific deep brain target. The lead is connected to an implantable pulse generator (IPG), which is the power source of the system. The lead and the IPG are connected by an extension wire that is tunneled under the skin between both of them. This system is used to chronically stimulate the deep brain target by delivering a high-frequency current to this target.

Deep brain stimulation of different targets has been shown to drastically improve symptoms of a variety of neurological conditions. However, the occurrence of disabling side effects may limit the ability to deliver adequate amounts of current necessary to reach the maximal benefit. Computed models have suggested that reduction in electrode size and the ability to provide directional lead stimulation could increase the efficacy of such therapies 1).

Deep brain stimulation surgery, create an opportunity to conduct cognitive or behavioral experiments during the acquisition of invasive neurophysiology. Optimal design and implementation of intraoperative behavioral experiments require consideration of stimulus presentation, time and surgical constraints. Tekriwal et al., describe the use of a modular, inexpensive system that implements a decision-making paradigm, designed to overcome challenges associated with the operative environment.

They created an auditory, two-alternative forced choice (2AFC) task for intraoperative use. Behavioral responses were acquired using an Arduino based single-hand held joystick controller equipped with a 3-axis accelerometer, and two button presses, capable of sampling at 2 kHz. We include designs for all task relevant code, 3D printed components, and Arduino pin-out diagram.

They demonstrated feasibility both in and out of the operating room with behavioral results represented by three healthy control subjects and two Parkinson’s disease subjects undergoing deep brain stimulator implantation. Psychometric assessment of performance indicated that the subjects could detect, interpret and respond accurately to the task stimuli using the joystick controller. We also demonstrate, using intraoperative neurophysiology recorded during the task, that the behavioral system described here allows us to examine neural correlates of human behavior.

COMPARISON WITH EXISTING METHODS: For low cost and minimal effort, any clinical neural recording system can be adapted for intraoperative behavioral testing with our experimental setup.

CONCLUSION: Our system will enable clinicians and basic scientists to conduct intraoperative awake and behaving electrophysiologic studies in humans 2).

Indications

see Deep brain stimulation indications.

Targets

see Deep Brain Stimulation Targets.

Research has demonstrated that multi-target DBS shows some benefits over single target DBS.

Deep Brain Stimulation during Pregnancy and Delivery

Scelzo et al. report a retrospective case series of women, followed in two DBS centers, who became pregnant and went on to give birth to a child while suffering from disabling MD or psychiatric diseases [Parkinson’s disease, dystonia, Tourette’s syndrome (TS), Obsessive Compulsive Disorder (OCD)] treated by DBS. Clinical status, complications and management before, during, and after pregnancy are reported. Two illustrative cases are described in greater detail.

DBS improved motor and behavioral disorders in all patients and allowed reduction in, or even total interruption of disease-specific medication during pregnancy. With the exception of the spontaneous early abortion of one fetus in a twin pregnancy, all pregnancies were uneventful in terms of obstetric and pediatric management. DBS parameters were adjusted in five patients in order to limit clinical worsening during pregnancy. Implanted material limited breast-feeding in one patient because of local pain at submammal stimulator site and led to local discomfort related to stretching of the cable with increasing belly size in another patient whose stimulator was implanted in the abdominal wall.

Not only is it safe for young women with MD, TS and OCD who have a DBS-System implanted to become pregnant and give birth to a baby but DBS seems to be the key to becoming pregnant, having children, and thus greatly improves quality of life 3).

Technique

Deep brain stimulation technique.

see Short pulse deep brain stimulation.

Frameless deep brain stimulation

Postoperative evaluation

Recent developments in the postoperative evaluation of deep brain stimulation surgery on the group level warrant the detection of achieved electrode positions based on postoperative imaging. Computed tomography (CT) is a frequently used imaging modality, but because of its idiosyncrasies (high spatial accuracy at low soft tissue resolution), it has not been sufficient for the parallel determination of electrode position and details of the surrounding brain anatomy (nuclei). The common solution is rigid fusion of CT images and magnetic resonance (MR) images, which have much better soft tissue contrast and allow accurate normalization into template spaces. Here, we explored a deep-learning approach to directly relate positions (usually the lead position) in postoperative CT images to the native anatomy of the midbrain and group space.

Materials and methods: Deep learning is used to create derived tissue contrasts (white matter, gray matter, cerebrospinal fluid, brainstem nuclei) based on the CT image; that is, a convolution neural network (CNN) takes solely the raw CT image as input and outputs several tissue probability maps. The ground truth is based on coregistrations with MR contrasts. The tissue probability maps are then used to either rigidly coregister or normalize the CT image in a deformable way to group space. The CNN was trained in 220 patients and tested in a set of 80 patients.

Results: Rigorous validation of such an approach is difficult because of the lack of ground truth. We examined the agreements between the classical and proposed approaches and considered the spread of implantation locations across a group of identically implanted subjects, which serves as an indicator of the accuracy of the lead localization procedure. The proposed procedure agrees well with current magnetic resonance imaging-based techniques, and the spread is comparable or even lower.

Postoperative CT imaging alone is sufficient for accurate localization of the midbrain nuclei and normalization to the group space. In the context of group analysis, it seems sufficient to have a single postoperative CT image of good quality for inclusion. The proposed approach will allow researchers and clinicians to include cases that were not previously suitable for analysis 4).

Complications

see Deep brain stimulation complications.

Case series

Harmsen et al. assessed the state of DBS-related research by analyzing the DBS literature as well as active studies sponsored by the National Institutes of Health (NIH) or German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]).In total, 8,974 publications, 172 active NIH-funded projects, and 34 active DFG projects were identified. Records spanned 52 different disorders across 31 distinct brain targets and showed a shift toward studies examining conditions other than movement disorders. Most published works involved human research (80.6% of published studies), of which 10.2% were identified as clinical trials. Increasingly, studies focused on imaging or electrophysiological changes associated with DBS (69.8% NIH-active and 70.6% DFG-active vs. 25.8% published) or developing new stimulation techniques and adaptive technologies (37.8% NIH-active and 17.6% DFG-active vs. 6.5% published).

This overview in 2022 of past and present DBS-related studies provides insight into the status of DBS research and what we can anticipate in the future concerning new indications, improved/novel target selection and stimulation paradigms, closed-loop technology, and a better understanding of the mechanisms of action of DBS 5).

see Deep Brain Stimulation case series

Case reports

A 79-year-old woman with a history of coarse tremors effectively managed with deep brain stimulation presented with multiple intracranial metastases from a newly diagnosed lung cancer and was referred for whole-brain radiation therapy. She was treated with a German helmet technique to a total dose of 30 Gy in 10 fractions using 6 MV photons via opposed lateral fields with the neurostimulator turned off prior to delivery of each fraction. The patient tolerated the treatment well with no acute complications and no apparent change in the functionality of her neurostimulator device or effect on her underlying neuromuscular disorder. This represents the first reported case of the safe delivery of whole-brain radiation therapy in a patient with an implanted neurostimulator device. In cases such as this, neurosurgeons and radiation oncologists should have discussions with patients about the risks of brain injury, device malfunction or failure of the device, and plans for rigorous testing of the device before and after radiation therapy 6).

Books

see Deep Brain Stimulation Books.

1)

Pollo C, Kaelin-Lang A, Oertel MF, Stieglitz L, Taub E, Fuhr P, Lozano AM, Raabe A, Schüpbach M. Directional deep brain stimulation: an intraoperative double-blind pilot study. Brain. 2014 Jul;137(Pt 7):2015-26. doi: 10.1093/brain/awu102. Epub 2014 May 19. PubMed PMID: 24844728.
2)

Tekriwal A, Felsen G, Thompson JA. Modular auditory decision-making behavioral task designed for intraoperative use in humans. J Neurosci Methods. 2018 May 7. pii: S0165-0270(18)30134-1. doi: 10.1016/j.jneumeth.2018.05.004. [Epub ahead of print] PubMed PMID: 29746889.
3)

Scelzo E, Mehrkens JH, Bötzel K, Krack P, Mendes A, Chabardès S, Polosan M, Seigneuret E, Moro E, Fraix V. Deep Brain Stimulation during Pregnancy and Delivery: Experience from a Series of “DBS Babies”. Front Neurol. 2015 Sep 1;6:191. doi: 10.3389/fneur.2015.00191. eCollection 2015. PubMed PMID: 26388833.
4)

Reisert M, Sajonz BEA, Brugger TS, Reinacher PC, Russe MF, Kellner E, Skibbe H, Coenen VA. Where Position Matters-Deep-Learning-Driven Normalization and Coregistration of Computed Tomography in the Postoperative Analysis of Deep Brain Stimulation. Neuromodulation. 2022 Nov 21:S1094-7159(22)01330-7. doi: 10.1016/j.neurom.2022.10.042. Epub ahead of print. PMID: 36424266.
5)

Harmsen IE, Wolff Fernandes F, Krauss JK, Lozano AM. Where Are We with Deep Brain Stimulation? A Review of Scientific Publications and Ongoing Research. Stereotact Funct Neurosurg. 2022 Feb 1:1-14. doi: 10.1159/000521372. Epub ahead of print. PMID: 35104819.
6)

Kotecha R, Berriochoa CA, Murphy ES, Machado AG, Chao ST, Suh JH, Stephans KL. Report of whole-brain radiation therapy in a patient with an implanted deep brain stimulator: important neurosurgical considerations and radiotherapy practice principles. J Neurosurg. 2016 Apr;124(4):966-70. doi: 10.3171/2015.2.JNS142951. Epub 2015 Aug 28. PubMed PMID: 26315009.

Deep brain stimulation for Parkinson’s disease

Deep brain stimulation for Parkinson’s disease

Subthalamic deep brain stimulation for Parkinson’s disease.

Cramer et al. from the University of Minnesota, sought to determine whether racial and socioeconomic disparity in the utilization of deep brain stimulation (DBS) for Parkinson’s disease (PD) have improved over time. They examined DBS utilization and analyzed factors associated with placement of DBS. The odds of DBS placement increased across the study period while White PD patients were 5 times more likely than Black patients to undergo DBS. Individuals, regardless of racial background, with two or more comorbidities were 14 times less likely to undergo DBS. Privately insured patients were 1.6 times more likely to undergo DBS. Despite increasing DBS utilization, significant disparities persist in access to DBS 1).

Methods

Modified power-on programming method.

Traditional power-on programming method.

Indications

Deep brain stimulation for Parkinson’s disease Indications.

Outcome

Deep brain stimulation for Parkinson’s disease outcome.

Case series

Deep brain stimulation for Parkinson’s disease case series.

1)

Cramer SW, Do TH, Palzer EF, Naik A, Rice AL, Novy SG, Hanson JT, Piazza AN, Howard MA, Huling JD, Chen CC, McGovern RA. Persistent racial disparities in deep brain stimulation for Parkinson’s disease. Ann Neurol. 2022 Apr 19. doi: 10.1002/ana.26378. Epub ahead of print. PMID: 35439848.

Vagus nerve stimulation complications

Vagus nerve stimulation complications

The most common side effects associated with Vagus nerve stimulation are hoarseness, throat pain and coughing. Cardiac arrhythmia has been reported during lead tests performed during implantation of the device, but few cases during regular treatment.

After implanting vagus nerve electrodes to the cervical vagus nerve, side effects such as voice alterations and dyspnea or missing therapeutic effects are observed at different frequencies. Cervical vagus nerve branching might partly be responsible for these effects.

Adverse events (AEs) are generally associated with implantation or continuous on-off stimulation. Infection is the most serious implantation-associated AE. Bradycardia and asystole have also been described during implantation, as has vocal cord paresis, which can last up to 6 months and depends on surgical skill and experience. The most frequent stimulation-associated AEs include voice alteration, paresthesia, cough, headache, dyspnea, pharyngitis and pain, which may require a decrease in stimulation strength or intermittent or permanent device deactivation. Newer non-invasive VNS delivery systems do not require surgery and permit patient-administered stimulation on demand. These non-invasive VNS systems improve the safety and tolerability of VNS, making it more accessible and facilitating further investigations across a wider range of uses.

VNS battery replacement, revisions, and removals account for almost one-half of all VNS procedures. The findings suggest important long-term expectations for VNS including expected complications, battery life, and other surgical issues. Review of the literature suggests that the first large review of VNS revisions by a single center was done by Couch et al. The findings are important to better characterize long-term surgical expectations of VNS therapy. A significant portion of patients undergoing VNS therapy will eventually require revision 1).

In a retrospective study over an 8-year period, 13 patients underwent revision surgery due to lead failure. Lead failure was classified as either lead intrinsic damage or lead pin disengagement from the generator header. In the X-ray image, Zhou et al., defined an RC ratio that represented the portion of rear lead connector in the header receptacle. It was used to quantitatively evaluate the mechanical failure of the lead-header interface. Optimal procedures to identify and manage lead failure were established.

All 13 patients presented with high lead impedance ≥ 9 kOhms at the time of revision. Seven of ten patients with lead damage presented with increased seizure frequency after a period of seizure remission. In contrast to lead damages occurring relatively late (> 15 months), lead pin disengagement was usually found within the early months after device implantation. A significant association was found between an elevated RC ratio (≥ 35%) and lead pin disengagement. The microsurgical technique permitted the removal or replacement of the lead without adverse effects.

The method of measuring the RC ratio developed in this study is feasible for identifying lead disengagement at the generator level. Lead revision was an effective and safe procedure for patients experiencing lead failure 2).

Vocal cord paralysis

Main risk of surgery is transient or permanent vocal cord paralysis.

Endotracheal Tube Electrode Neuromonitoring represents a safe adjunctive tool that can help localize the vagus nerve, particularly in the setting of varying anatomy or hazardous dissections. It may help reduce the potential for vagal trunk damage or electrode misplacement and potentially improve clinical outcomes 3).

1)

Couch JD, Gilman AM, Doyle WK. Long-term Expectations of Vagus Nerve Stimulation: A Look at Battery Replacement and Revision Surgery. Neurosurgery. 2016 Jan;78(1):42-6. doi: 10.1227/NEU.0000000000000985. PubMed PMID: 26678088.
2)

Zhou H, Liu Q, Zhao C, Ma J, Ye X, Xu J. Lead failure after vagus nerve stimulation implantation: X-ray examination and revision surgery. World Neurosurg. 2018 Dec 26. pii: S1878-8750(18)32893-6. doi: 10.1016/j.wneu.2018.12.070. [Epub ahead of print] PubMed PMID: 30593965.
3)

Katsevman GA, Josiah DT, LaNeve JE, Bhatia S. Endotracheal Tube Electrode Neuromonitoring for Placement of Vagal Nerve Stimulation for Epilepsy: Intraoperative Stimulation Thresholds. Neurodiagn J. 2022 Feb 28:1-12. doi: 10.1080/21646821.2022.2022911. Epub ahead of print. PMID: 35226831.

Repetitive transcranial magnetic stimulation for Parkinson’s disease

Repetitive transcranial magnetic stimulation for Parkinson’s disease

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that has been closely examined as possible Parkinson’s disease treatment.

Data were acquired during resting state on 34 Parkinson’s disease patients and 25 controls. The ratio of standard uptake value for PET images and the subthalamic nucleus (STN) Dynamic functional connectivity (FC) maps for fMRI data were generated. The metabolic connectivity mapping (MCM) approach that combines PET and fMRI data was used to evaluate the direction of the connectivity. Results showed that PD patients exhibited both increased FDG uptake and STN-FC in the sensorimotor area (PFDR < 0.05). MCM analysis showed higher cortical-STN MCM value in the PD group (F = 6.63, P = 0.013) in the left precentral gyrus. There was a high spatial overlap between the increased glucose metabolism and increased STN-FC in the sensorimotor area in PD. The MCM approach further revealed an exaggerated cortical input to the STN in PD, supporting the precentral gyrus as a target for treatment such as the repetitive transcranial magnetic stimulation 1).

40 Parkinson’s disease patients with freezing of gait, 31 without freezing of gait, and 30 normal controls. A subset of 30 patients with freezing of gait (verum group: N = 20; sham group: N = 10) who participated the aforementioned rTMS study underwent another scan after the treatments. Using the baseline scans, the imaging biomarkers for freezing of gait and Parkinson’s disease were developed by contrasting the connectivity profiles of patients with freezing of gait to those without freezing of gait and normal controls, respectively. These two biomarkers were then interrogated to assess the rTMS effects on connectivity patterns. Results showed that the freezing of gait biomarker was negatively correlated with Freezing of Gait Questionnaire score (r = -0.6723, p < 0.0001); while the Parkinson’s disease biomarker was negatively correlated with MDS-UPDRS motor score (r = -0.7281, p < 0.0001). After the rTMS treatment, both the freezing of gait biomarker (0.326 ± 0.125 vs. 0.486 ± 0.193, p = 0.0071) and Parkinson’s disease biomarker (0.313 ± 0.126 vs. 0.379 ± 0.155, p = 0.0378) were significantly improved in the verum group; whereas no significant biomarker changes were found in the sham group. The findings indicate that high-frequency rTMS over the supplementary motor area confers the beneficial effect jointly through normalizing abnormal brain functional connectivity patterns specifically associated with freezing of gait, in addition to normalizing overall disrupted connectivity patterns seen in Parkinson’s disease 2).

In 2017 a study aimed to review the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for Parkinson’s disease (PD). Randomized, double-blind, sham-controlled, multicenter studies on rTMS for PD have been conducted three times in Japan (in 2003, 2008, and 2013). These studies revealed that 5-Hz rTMS over the supplementary motor area (SMA) is the most effective modality for improving motor symptoms. Several functional imaging studies showed reduced SMA excitability in patients with PD, probably secondary to basal ganglia dysfunction. Therefore, 5-Hz rTMS is assumed to normalize SMA excitability and amend basal ganglia function secondarily. Currently, a phase III trial is being conducted in Japan. Therefore, in the near future, 5-Hz rTMS can be used as a therapeutic modality for PD treatment. In addition, several powerful rTMS have been developed recently, including quadripulse stimulation (QPS), which most potently induces neural plasticity. QPS is also expected to be a potential therapeutic tool to treat patients with PD 3).

In 2015 Twenty studies with a total of 470 patients were included. Random-effects analysis revealed a pooled SMD of 0.46 (95% CI, 0.29-0.64), indicating an overall medium effect size favoring active rTMS over sham rTMS in the reduction of motor symptoms (P<.001). Subgroup analysis showed that the effect sizes estimated from high-frequency rTMS targeting the primary motor cortex (SMD, 0.77; 95% CI, 0.46-1.08; P<.001) and low-frequency rTMS applied over other frontal regions (SMD, 0.50; 95% CI, 0.13-0.87; P=.008) were significant. The effect sizes obtained from the other 2 combinations of rTMS frequency and rTMS site (ie, high-frequency rTMS at other frontal regions: SMD, 0.23; 95% CI, -0.02 to 0.48, and low primary motor cortex: SMD, 0.28; 95% CI, -0.23 to 0.78) were not significant. Meta-regression revealed that a greater number of pulses per session or across sessions is associated with larger rTMS effects. Using the Grading of Recommendations, Assessment, Development, and Evaluation criteria, we characterized the quality of evidence presented in this meta-analysis as moderate quality.

The pooled evidence suggests that rTMS improves motor symptoms for patients with PD. Combinations of rTMS site and frequency as well as the number of rTMS pulses are key modulators of rTMS effects. The findings of our meta-analysis may guide treatment decisions and inform future research 4).

Randomized, double-blind, sham-controlled, multicenter studies on rTMS for PD have been conducted three times in Japan (in 2003, 2008, and 2013). These studies revealed that 5-Hz rTMS over the supplementary motor area (SMA) is the most effective modality for improving motor symptoms. Several functional imaging studies showed reduced SMA excitability in patients with PD, probably secondary to basal ganglia dysfunction. Therefore, 5-Hz rTMS is assumed to normalize SMA excitability and amend basal ganglia function secondarily. Currently, a phase III trial is being conducted in Japan. Therefore, in the near future, 5-Hz rTMS can be used as a therapeutic modality for PD treatment. In addition, several powerful rTMS have been developed recently, including quadripulse stimulation (QPS), which most potently induces Neuroplasticity. QPS is also expected to be a potential therapeutic tool to treat patients with PD 5).

52 Parkinson’s disease (PD) patients were randomly classified into two groups. The first group received 20 Hz and the 2nd group received 1 Hz Repetitive Transcranial Magnetic Stimulation (rTMS) with a total of 2000 pulses over M1of each hemisphere for ten days. Effects were assessed with the Unified Parkinson’s Disease Rating Scale part III (UPDRS), Instrumental Activity of Daily Living (IADL), and a self-assessment score (SA) before, after the last session, and one month later. Cortical excitability was measured before and after the end of sessions.

There was a significant improvement on all rating scales after either 1 Hz or 20 Hz rTMS, but the effect persisted for longer after 20 Hz (treatment X time interaction for UPDRS and IADL (P = 0.075 and 0.04, respectively). Neither treatment affected motor thresholds, but 20 Hz rTMS increased MEP amplitude and the duration of transcallosal inhibition. In an exploratory analysis, each group was subdivided into akinetic-rigid and tremor dominant subgroups and the effects of 1 Hz and 20 Hz treatment recalculated. There was weak evidence that patients with an akinetic-rigid presentation may respond better than those with predominant tremor.

Both 20 Hz and 1 Hz rTMS improve motor function in PD, but 20 Hz rTMS is more effective 6).

1)

Zang Z, Song T, Li J, Nie B, Mei S, Zhang C, Wu T, Zhang Y, Lu J. Simultaneous PET/fMRI revealed increased motor area input to subthalamic nucleus in Parkinson’s disease. Cereb Cortex. 2022 Feb 23:bhac059. doi: 10.1093/cercor/bhac059. Epub ahead of print. PMID: 35196709.
2)

Mi TM, Garg S, Ba F, Liu AP, Liang PP, Gao LL, Jia Q, Xu EH, Li KC, Chan P, McKeown MJ. Repetitive transcranial magnetic stimulation improves Parkinson’s freezing of gait via normalizing brain connectivity. NPJ Parkinsons Dis. 2020 Jul 17;6:16. doi: 10.1038/s41531-020-0118-0. PMID: 32699818; PMCID: PMC7368045.
3)

Matsumoto H, Ugawa Y. [Repetitive Transcranial Magnetic Stimulation for Parkinson’s Disease: A Review]. Brain Nerve. 2017 Mar;69(3):219-225. Japanese. doi: 10.11477/mf.1416200730. PMID: 28270631.
4)

Chou YH, Hickey PT, Sundman M, Song AW, Chen NK. Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease: a systematic review and meta-analysis. JAMA Neurol. 2015 Apr;72(4):432-40. doi: 10.1001/jamaneurol.2014.4380. Review. PubMed PMID: 25686212; PubMed Central PMCID: PMC4425190.
5)

Matsumoto H, Ugawa Y. [Repetitive Transcranial Magnetic Stimulation for Parkinson’s Disease: A Review]. Brain Nerve. 2017 Mar;69(3):219-225. doi: 10.11477/mf.1416200730. Review. Japanese. PubMed PMID: 28270631.
6)

Khedr EM, Al-Fawal B, Wraith AA, Saber M, Hasan AM, Bassiony A, Eldein AN, Rothwell JC. The Effect of 20 Hz versus 1 Hz Repetitive Transcranial Magnetic Stimulation on Motor Dysfunction in Parkinson’s Disease: Which Is More Beneficial? J Parkinsons Dis. 2019 Mar 21. doi: 10.3233/JPD-181540. [Epub ahead of print] PubMed PMID: 30909248.

Multitarget deep brain stimulation

Multitarget deep brain stimulation

Deep brain stimulation (DBS) surgery for movement disorder treatments usually employs stimulation at a single site in one or both hemispheres. However, research has demonstrated that Multitarget deep brain stimulation shows some benefits over single target DBS 1) 2) 3).

Dinget al. proposed a novel stereotaxic system used for implanting a curved lead to any two targets of the brain, and used the theoretical “curved lead method”. First, a customized novel stereotaxic system was fabricated, and a solid cranial model with six fixed internal targets was made; second, CT scan was performed to locate the fixed internal targets; third, five curved leads were implanted to five selected pairs of targets, each following the calculated parameters of “curved lead pathway” with the novel stereotaxic system, respectively. Finally, CT scans were performed again to determine the exact locations of the curved leads.

Results: The five curved leads accurately passed through the five pairs of combined targets, respectively, and the average vector error of curved lead implantation was 0.70±0.24mm.

Comparison with existing method(s): In most situations, performing a multiple-target DBS procedure with the current stereotaxic systems means increased number of implanted leads, increased incidence of operative complications, and increased medical costs. However, the novel stereotaxic system could guide a single lead to reach two selected targets of the brain with high accuracy.

Conclusions: The novel stereotaxic system enables curved lead implantation with high accuracy, and can be considered as a useful complement to the current stereotaxic system 4).

Case series

Chang et al. reviewed patients who had undergone unilateral DBS targeting the GPi and ventralis oralis (Vo).

Five patients diagnosed with medically refractory upper extremity dystonia (focal or segmental) underwent DBS. Two DBS electrodes each were inserted unilaterally targeting the ipsilateral GPi and Vo. Clinical outcomes were evaluated using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Disability Rating Scale.

BFMDRS scores decreased by 55% at 1-month, 56% at 3-month, 59% at 6-month, and 64% at 12-month follow up. Disability Rating Scale scores decreased 41% at 1-month, 47% at 3-month, 50% at 6-month, and 60% at 12-month follow up. At 1 month after surgery, stimulating both targets improved clinical scores better than targeting GPi or Vo alone.

Unilateral thalamic and pallidal dual electrode DBS may be as effective or even superior to DBS of a single target for dystonia. Although the number of patients was small, our results reflected favorable clinical outcomes 5).

Parker et al. report a series of cases: midbrain cavernoma hemorrhage with olivary hypertrophy, spinocerebellar ataxia-like disorder of probable genetic origin, Holmes tremor secondary to brainstem stroke, and hemiballismus due to traumatic thalamic hemorrhage, all treated by dual pallidal and thalamic DBS. All patients demonstrated robust benefit from DBS, maintained in long-term follow-up. This series demonstrates the flexibility and efficacy, but also the limitations, of dual thalamo-pallidal stimulation for managing axial and limb symptoms of tremors, dystonia, chorea, and hemiballismus in patients with complex movement disorders 6).

Kobayashi et al. implanted 2 DBS electrodes (one at the nucleus ventralis oralis/nucleus ventralis intermedius and the other at the SA) in 4 patients with HT. For more than 2 years after implantation, each patient’s tremor was evaluated using a tremor rating scale under the following 4 conditions of stimulation: “on” for both thalamus and SA DBS; “off” for both thalamus and SA DBS; “on” for thalamus and “off” for SA DBS; and “on” for SA and “off” for thalamus DBS.

The tremor in all patients was improved for more than 2 years (mean 25.8 ± 3.5 months). Stimulation with 2 electrodes exerted greater effect on the tremor than did 1-electrode stimulation. Interestingly, in all patients progressive effects were observed, and in one patient treated with DBS for 1 year, tremor did not appear even while stimulation was temporarily switched off, suggesting irreversible improvement effects. The presence of both resting and intentional/action tremor implies combined destruction of the pallidothalamic and cerebellothalamic pathways in HT. A larger stimulation area may thus be required for HT patients. Multitarget, dual-lead stimulation permits coverage of the wide area needed to suppress the tremor without adverse effects of stimulation. Some reorganization of the neural network may be involved in the development of HT because the tremor appears several months after the primary insult. The mechanism underlying the absence of tremor while stimulation was temporarily off remains unclear, but the DBS may have normalized the abnormal neural network.

They successfully treated patients with severe HT by using dual-electrode DBS over a long period. Such DBS may offer an effective and safe treatment modality for intractable HT 7).

Case reports

A 33-year-old male PD patient with onset at the age of 12 years. The onset of the disease is presented with bradykinesia and progressively developed severe choreic dyskinesia with the use of medications. We then performed a thorough evaluation of the patient and decided to perform bilateral globus pallidus interna combined with subthalamic nucleus variable frequency DBS (bSGC-DBS) implantation, and after 2 years of follow-up the patient’s bradykinesia and dyskinesia symptoms and quality of life improved significantly. Conclusions: This is the first case of bSCG-DBS in a PD patient with refractory dyskinesia, and the first report of encouraging results from this clinical condition. This important finding explores multi-electrode and multi-target stimulation for the treatment of dystonia disorders 8).

Kakusa B, Saluja S, Tate WJ, Espil FM, Halpern CH, Williams NR. Robust clinical benefit of multi-target deep brain stimulation for treatment of Gilles de la Tourette syndrome and its comorbidities. Brain Stimul. 2019 May-Jun;12(3):816-818. doi: 10.1016/j.brs.2019.02.026. Epub 2019 Mar 4. PMID: 30878341.

DBS leads were implanted in the GPi and Vim/Vop and each stimulation combination (GPi, Vim/Vop, and both) was tested for three months in a single patient. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Short-Form 36 (SF-36) were completed at the end of each trial period.

Results: Multitarget (GPi+Vim/Vop) stimulation was clinically the most effective treatment and resulted in the most improvement in function and quality of life. The patient’s hemidystonia improved by 25% as measured by the BFMDRS during the multitarget stimulation trial period and at the 6-month follow-up. The patient’s quality of life improved by 86% and 59% during the multitarget stimulation trial period and at the 6 month follow-up respectively.

Conclusion: Multitarget thalamic and pallidal DBS proved to be the most effective therapy for this patient with secondary hemidystonia due to a putaminal stroke. A single-lead approach may not be sufficient in neuromodulating a highly disorganized motor network seen in hemidystonia. Multitarget DBS should be further explored in post-stroke dystonia and may offer improved outcome in other forms of secondary dystonia with limited response to GPi DBS 9).

1)

Oropilla JQL, Diesta CCE, Itthimathin P, Suchowersky O, Kiss ZHT: Both thalamic and pallidal deep brain stimulation for myoclonic dystonia. J Neurosurg 112:1267–1270, 2010
2)

Stefani A, Peppe A, Pierantozzi M, Galati S, Moschella V, Stanzione P, et al: Multi-target strategy for Parkinsonian patients: the role of deep brain stimulation in the centromedianparafascicularis complex. Brain Res Bull 78:113–118, 2009
3)

Stover NP, Okun MS, Evatt ML, Raju DV, Bakay RAE, Vitek JL: Stimulation of the subthalamic nucleus in a patient with Parkinson disease and essential tremor. Arch Neurol 62:141–143, 2005
4)

Ding CY, Yu LH, Lin YX, Chen F, Wang WX, Lin ZY, Kang DZ. A novel stereotaxic system for implanting a curved lead to two intracranial targets with high accuracy. J Neurosci Methods. 2017 Nov 1;291:190-197. doi: 10.1016/j.jneumeth.2017.08.017. Epub 2017 Aug 20. PMID: 28834693.
5)

Chang KW, Kim MJ, Park SH, Chang WS, Jung HH, Chang JW. Dual Pallidal and Thalamic Deep Brain Stimulation for Complex Ipsilateral Dystonia. Yonsei Med J. 2022 Feb;63(2):166-172. doi: 10.3349/ymj.2022.63.2.166. PMID: 35083902.
6)

Parker T, Raghu ALB, FitzGerald JJ, Green AL, Aziz TZ. Multitarget deep brain stimulation for clinically complex movement disorders. J Neurosurg. 2020 Jan 3:1-6. doi: 10.3171/2019.11.JNS192224. Epub ahead of print. PMID: 31899879.
7)

Kobayashi K, Katayama Y, Oshima H, Watanabe M, Sumi K, Obuchi T, Fukaya C, Yamamoto T. Multitarget, dual-electrode deep brain stimulation of the thalamus and subthalamic area for treatment of Holmes’ tremor. J Neurosurg. 2014 May;120(5):1025-32. doi: 10.3171/2014.1.JNS12392. Epub 2014 Mar 7. PMID: 24605838.
8)

Chang B, Mei J, Xiong C, Chen P, Jiang M, Niu C. Bilateral Globus Pallidus Interna Combined With Subthalamic Nucleus Variable Frequency Deep Brain Stimulation in the Treatment of Young-Onset Parkinson’s Disease With Refractory Dyskinesia: A Case Report. Front Neurosci. 2021 Nov 25;15:782046. doi: 10.3389/fnins.2021.782046. PMID: 34899174; PMCID: PMC8656942.
9)

Slotty PJ, Poologaindran A, Honey CR. A prospective, randomized, blinded assessment of multitarget thalamic and pallidal deep brain stimulation in a case of hemidystonia. Clin Neurol Neurosurg. 2015 Nov;138:16-9. doi: 10.1016/j.clineuro.2015.07.012. Epub 2015 Jul 29. PMID: 26241157.

Low-frequency deep brain stimulation

Low-frequency deep brain stimulation

Patients with Parkinson’s disease can develop axial symptoms, including speech, gait, and balance difficulties. Chronic high-frequency deep brain stimulation (>100 Hz) can contribute to these impairments while low-frequency stimulation (<100 Hz) may improve symptoms but only in some individuals.

DBS at frequencies below 100 Hz is a therapeutic option in select cases of Parkinson’s disease with freezing of gait and other axial symptoms, and in select patients with dystonia and other hyperkinetic movements, particularly those requiring an energy-saving strategy 1).

Comprehensive literature review and meta-analysis

In ten studies with 132 patients, the pooled results showed no significant difference in the total Unified Parkinson Disease Rating Scale part III (UPDRS-III) scores (mean effect, -1.50; p = 0.19) or the rigidity subscore between HFS and LFS. Compared to LFS, HFS induced a greater reduction in the tremor subscore within the medication-off condition (mean effect, 1.01; p = 0.002), while no significance was shown within the medication-on condition (mean effect, 0.01; p = 0.92). LFS induced greater reduction in akinesia subscore (mean effect, -1.68, p = 0.003), the time to complete the stand-walk-sit (SWS) test (mean effect, -4.84; p < 0.00001), and the number of freezing of gait (FOG) (mean effect, -1.71; p = 0.03). These results suggest that two types of frequency settings may have different effects, that is, HFS induces better responses for tremor and LFS induces greater response for akinesia, gait, and FOG, respectively, which are worthwhile to be confirmed in a future study, and will ultimately inform the clinical practice in the management of PD using STN-DBS 2).

Case series

Vijiaratnam et al. from the Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Unit of Functional Neurosurgery, the National Hospital for Neurology and Neurosurgery, London, Unit of Neurology of Ospedale “M. Bufalini” of Cesena, Cesena, Italy Department of Neurology, the Walton Centre NHS Foundation Trust, Liverpool recruited patients who developed axial motor symptoms while using high-frequency stimulation and objectively assessed the short-term impact of low-frequency stimulation on axial symptoms, other aspects of motor function and quality of life. A retrospective chart review was then conducted on a larger cohort to identify which patient characteristics were associated with not only the need to trial low-frequency stimulation but also those which predicted its sustained use. Among 20 prospective patients, low-frequency stimulation objectively improved mean motor and axial symptom severity and quality of life in the short term. Among a retrospective cohort of 168 patients, those with less severe tremor and those in whom axial symptoms had emerged sooner after subthalamic nucleus deep brain stimulation were more likely to be switched to and remain on long-term low-frequency stimulation. These data suggest that low-frequency stimulation results in objective mean improvements in overall motor function and axial symptoms among a group of patients, while individual patient characteristics can predict sustained long-term benefits. Longer follow-up in the context of a larger, controlled, double-blinded study would be required to provide definitive evidence of the role of low-frequency deep brain stimulation 3).

To investigate whether LF-SNr-DBS combined with standard HF stimulation of the subthalamic nucleus (STN) is clinically relevant in improving gait disorders that no longer respond to levodopa in PD patients, compared with HF-STN or LF-SNr stimulation alone.

Methods: Patients received LF-SNr or HF-STN stimulation alone or combined (COMB) stimulation of both nuclei (crossover design). The nucleus to be stimulated was randomly assigned and clinical evaluations performed by a blinded examiner after three months follow-up for each. Clinical assessment included the Freezing of Gait questionnaire, Tinetti Balance and Walking Assessing tool, and Unified Parkinson’s Disease Rating.

Results: We included six patients (mean age 59.1 years, disease duration 16.1 years). All patients suffered motor fluctuations and dyskinesias. The best results were obtained with COMB in four patients (who preferred and remained with COMB over 3 years of follow-up) and with HF-STN in two patients. SNr stimulation alone did not produce better results than COMB or STN in any patient.

Conclusion: COMB and HF-STN stimulation improved PD-associated gait disorders in this preliminary case series, sustained over time. Further multicenter investigations are required to better explore this therapeutic option 4).

Sidiropoulos et al. studied the effects of low-frequency stimulation (LFS) (≤80 Hz) for improving speech, gait, and balance dysfunction in the largest patient population to date. PD patients with bilateral STN-DBS and resistant axial symptoms were switched from chronic 130 Hz stimulation to LFS and followed up to 4 years. Primary outcome measures were total motor UPDRS scores, and axial and gait subscores before and after LFS. Bivariate analyses and correlation coefficients were calculated for the different conditions. Potential predictors of therapeutic response were also investigated. Forty-five advanced PD patients who had high-frequency stimulation (HFS) for 39.5 ± 27.8 consecutive months were switched to LFS. LFS was kept on for a median period of 111.5 days before the assessment. There was no significant improvement in any of the primary outcomes between HFS and LFS, although a minority of patients preferred to be maintained on LFS for longer periods of time. No predictive factors of response could be identified. There was overall no improvement from LFS in axial symptoms. This could be partly due to some study limitations. Larger prospective trials are warranted to better clarify the impact of stimulation frequency on axial signs 5).

1)

Baizabal-Carvallo JF, Alonso-Juarez M. Low-frequency deep brain stimulation for movement disorders. Parkinsonism Relat Disord. 2016 Oct;31:14-22. doi: 10.1016/j.parkreldis.2016.07.018. Epub 2016 Jul 30. PMID: 27497841.
2)

Su D, Chen H, Hu W, Liu Y, Wang Z, Wang X, Liu G, Ma H, Zhou J, Feng T. Frequency-dependent effects of subthalamic deep brain stimulation on motor symptoms in Parkinson’s disease: a meta-analysis of controlled trials. Sci Rep. 2018 Sep 27;8(1):14456. doi: 10.1038/s41598-018-32161-3. PMID: 30262859; PMCID: PMC6160461.
3)

Vijiaratnam N, Girges C, Wirth T, Grover T, Preda F, Tripoliti E, Foley J, Scelzo E, Macerollo A, Akram H, Hyam J, Zrinzo L, Limousin P, Foltynie T. Long-term success of low-frequency subthalamic nucleus stimulation for Parkinson’s disease depends on tremor severity and symptom duration. Brain Commun. 2021 Jul 28;3(3):fcab165. doi: 10.1093/braincomms/fcab165. PMID: 34396114; PMCID: PMC8361419.
4)

Valldeoriola F, Muñoz E, Rumià J, Roldán P, Cámara A, Compta Y, Martí MJ, Tolosa E. Simultaneous low-frequency deep brain stimulation of the substantia nigra pars reticulata and high-frequency stimulation of the subthalamic nucleus to treat levodopa unresponsive freezing of gait in Parkinson’s disease: A pilot study. Parkinsonism Relat Disord. 2019 Mar;60:153-157. doi: 10.1016/j.parkreldis.2018.09.008. Epub 2018 Sep 5. PMID: 30241951.
5)

Sidiropoulos C, Walsh R, Meaney C, Poon YY, Fallis M, Moro E. Low-frequency subthalamic nucleus deep brain stimulation for axial symptoms in advanced Parkinson’s disease. J Neurol. 2013 Sep;260(9):2306-11. doi: 10.1007/s00415-013-6983-2. Epub 2013 Jun 9. PMID: 23749331.

Subthalamic deep brain stimulation for Parkinson’s disease outcome

The bilateral effects of deep brain stimulation (DBS) on motor and non-motor symptoms of Parkinson’s disease (PD) have been extensively studied and reviewed. However, the unilateral effects-in particular, the potential lateralized effects of left- versus right-sided DBS-have not been adequately recognized or studied.

Lin et al. summarized the current evidence and controversies in the literature regarding the lateralized effects of DBS on motor and non-motor outcomes in PD patients. Publications in the English language before February 2021 were obtained from the PubMed database and included if they directly compared the effects of unilateral versus contralateral side DBS on the motor or non-motor outcomes in PD. The current literature is overall of low-quality and is biased by various confounders. Researchers have investigated mainly PD patients receiving subthalamic nucleus (STN) DBS while the potential lateralized effects of globus pallidus internus (GPi) DBS have not been adequately studied. Evidence suggests potential lateralized effects of STN DBS on axial motor symptoms and deleterious effects of left-sided DBS on language-related functions, in particular, the verbal fluency, in PD. The lateralized DBS effects on appendicular motor symptoms as well as other neurocognitive and neuropsychiatric domains remain inconclusive. Future studies should control for varying methodological approaches as well as clinical and DBS management heterogeneities, including symptom laterality, stimulation parameters, location of active contacts, and lead trajectories. This would contribute to improved treatment strategies such as personalized target selection, surgical planning, and postoperative management that ultimately benefit patients 1).

The surgical and clinical outcomes of asleep DBS for Parkinson’s disease are comparable to those of awake DBS 2).

Suboptimal targeting within the STN can give rise to intolerable sensorimotor side effects, such as dysarthria, contractions and paresthesias 3) 4) 5). eye movement perturbations, and psychiatric symptoms 6) 7) 8), limiting the management of motor symptoms. The small size of the STN motor territory and the consequences of spreading current to immediately adjacent structures obligate precise targeting. Neurosurgeons therefore rely on a combination of imaging, electrophysiology, kinesthetic responses, and stimulation testing to accurately place the DBS lead into the sensorimotor domain of STN 9) 10) 11).

Deep Brain Stimulation has been associated with post-operative neuropsychology changes, especially in verbal memory.

Deep brain stimulation (DBS) of subthalamic nucleus (STN) is widely accepted to treat advanced Parkinson disease (PD). However, published studies were mainly conducted in Western centers 12).

High frequency subthalamic nucleus (STN) deep brain stimulation (DBS) improves the cardinal motor signs of Parkinson’s disease (PD) and attenuates STN alpha/beta band neural synchrony in a voltage-dependent manner. While there is a growing interest in the behavioral effects of lower frequency (60 Hz) DBS, little is known about its effect on STN neural synchrony.

Low-frequency stimulation of the subthalamic nucleus via the optimal contacts is effective in improving overall motor function of patients with Parkinson Disease 13). In Parkinson’s disease significantly improved important aspects of QoL as measured by PDQ-39. The improvements were maintained at 2 years follow-up except for social support and communication. Sobstyl et al., demonstrated a positive correlation between changes in the off condition of motor UPDRS scores and Unified Dyskinesia Rating Scale in several PDQ-39 dimensions, whereas fluctuation UPDRS scores were negatively correlated with PDQ-39 mobility scores 14).

The degree of clinical improvement achieved by deep brain stimulation (DBS) is largely dependent on the accuracy of lead placement.

A study reports on the evaluation of intraoperative MRI (iMRI) for adjusting deviated electrodes to the accurate anatomical position during DBS surgery and acute intracranial changes 15).

Although dementia is a contraindication in deep brain stimulation for Parkinson’s disease, the concept is supported by little scientific evidence. Moreover, it is unclear whether PD with mild cognitive impairment (PD-MCI) or domain-specific cognitive impairments affect the outcome of DBS in non-demented PD patients.

Baseline cognitive levels of patients with PD who underwent DBS were classified into PD with dementia (PDD) (n = 15), PD-MCI (n = 210), and normal cognition (PD-NC) (n = 79). The impact of the cognitive level on key DBS outcome measures [mortality, nursing home admission, progression to Hoehn&Yahr (HY) stage 5 and progression to PDD] were analyzed using Cox regression models. Park et al. also investigated whether impairment of a specific cognitive domain could predict these outcomes in non-demented patients.

Results: Patients with PDD showed a substantially higher risk of nursing home admission and progression to HY stage 5 compared with patients with PD-MCI [hazard ratio (HR) 4.20, P = .002; HR = 5.29, P < .001] and PD-NC (HR 7.50, P < .001; HR = 7.93, P < .001). MCI did not alter the prognosis in patients without dementia, but those with visuospatial impairment showed poorer outcomes for nursing home admission (P = .015), progression to HY stage 5 (P = .027) and PDD (P = .006).

Conclusions: Cognitive profiles may stratify the pre-operative risk and predict long-term outcomes of DBS in PD 16).

References

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Lin Z, Zhang C, Li D, Sun B. Lateralized effects of deep brain stimulation in Parkinson’s disease: evidence and controversies. NPJ Parkinsons Dis. 2021 Jul 22;7(1):64. doi: 10.1038/s41531-021-00209-3. PMID: 34294724.
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Wang J, Ponce FA, Tao J, Yu HM, Liu JY, Wang YJ, Luan GM, Ou SW. Comparison of Awake and Asleep Deep Brain Stimulation for Parkinson’s Disease: A Detailed Analysis Through Literature Review. Neuromodulation. 2019 Dec 12. doi: 10.1111/ner.13061. [Epub ahead of print] Review. PubMed PMID: 31830772.
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Benabid AL, Chabardes S, Mitrofanis J, Pollak P: Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol 8:67–81, 2009
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Groiss SJ, Wojtecki L, Südmeyer M, Schnitzler A: Deep brain stimulation in Parkinson’s disease. Ther Adv Neurol Disorder 2:20–28, 2009
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Zhang S, Zhou P, Jiang S, Wang W, Li P: Interleaving subthalamic nucleus deep brain stimulation to avoid side effects while achieving satisfactory motor benefits in Parkinson disease: a report of 12 cases. Medicine (Baltimore) 95:e5575, 2016
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Kulisevsky J, Berthier ML, Gironell A, Pascual-Sedano B, Molet J, Parés P: Mania following deep brain stimulation for Parkinson’s disease. Neurology 59:1421–1424, 2002
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Mallet L, Schüpbach M, N’Diaye K, Remy P, Bardinet E, Czernecki V, et al: Stimulation of subterritories of the subthalamic nucleus reveals its role in the integration of the emotional and motor aspects of behavior. Proc Natl Acad Sci U S A 104:10661–10666, 2007
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Raucher-Chéné D, Charrel CL, de Maindreville AD, Limosin F: Manic episode with psychotic symptoms in a patient with Parkinson’s disease treated by subthalamic nucleus stimulation: improvement on switching the target. J Neurol Sci 273:116–117, 2008
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Abosch A, Timmermann L, Bartley S, Rietkerk HG, Whiting D, Connolly PJ, et al: An international survey of deep brain stimulation procedural steps. Stereotact Funct Neurosurg 91:1–11, 2013
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Chiou SM, Lin YC, Huang HM. One-year Outcome of Bilateral Subthalamic Stimulation in Parkinson Disease: An Eastern Experience. World Neurosurg. 2015 Jun 10. pii: S1878-8750(15)00709-3. doi: 0.1016/j.wneu.2015.06.002. [Epub ahead of print] PubMed PMID: 26072454.
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Khoo HM, Kishima H, Hosomi K, Maruo T, Tani N, Oshino S, Shimokawa T, Yokoe M, Mochizuki H, Saitoh Y, Yoshimine T. Low-frequency subthalamic nucleus stimulation in Parkinson’s disease: A randomized clinical trial. Mov Disord. 2014 Jan 21. doi: 10.1002/mds.25810. [Epub ahead of print] PubMed PMID: 24449169.
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Sobstyl M, Ząbek M, Górecki W, Mossakowski Z. Quality of life in advanced Parkinson’s disease after bilateral subthalamic stimulation: 2 years follow-up study. Clin Neurol Neurosurg. 2014 Sep;124:161-5. doi: 10.1016/j.clineuro.2014.06.019. Epub 2014 Jun 23. PubMed PMID: 25051167.
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Cui Z, Pan L, Song H, Xu X, Xu B, Yu X, Ling Z. Intraoperative MRI for optimizing electrode placement for deep brain stimulation of the subthalamic nucleus in Parkinson disease. J Neurosurg. 2016 Jan;124(1):62-9. doi: 10.3171/2015.1.JNS141534. Epub 2015 Aug 14. PubMed PMID: 26274983.
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Park KW, Jo S, Kim MS, et al. Cognitive profile as a predictor of the long-term outcome after deep brain stimulation in Parkinson’s disease [published online ahead of print, 2020 Jul 28]. J Neurol Sci. 2020;417:117063. doi:10.1016/j.jns.2020.117063

Electrical stimulation for peripheral nerve injury treatment

Electrical stimulation for peripheral nerve injury treatment

Peripheral nerve injury afflicts individuals from all walks of life. Despite the peripheral nervous system’s intrinsic ability to regenerate, many patients experience incomplete functional recovery. Surgical repair aims to expedite this recovery process in the most thorough manner possible. However, full recovery is still rarely seen especially when nerve injury is compounded with polytrauma where surgical repair is delayed. Pharmaceutical strategies supplementary to nerve microsurgery have been investigated but surgery remains the only viable option 1).

Electrical stimulation is regarded pivotal to promote repair of nerve injury, however, failed to get extensive application in vivo due to the challenges in noninvasive electrical loading accompanying with construction of biomimetic cell niche.

Building on decades of experimental evidence in animal models, several recent, prospective, randomized clinical trials have affirmed electrical stimulation as a clinically translatable technique to enhance functional recovery in patients with peripheral nerve injuries requiring surgical treatment 2).

Implantable wireless stimulators can deliver therapeutic electrical stimulation to injured peripheral nerve tissue. Implantable wireless nerve stimulators might represent a novel means of facilitating therapeutic electrical stimulation in both intraoperative and postoperative settings 3).

Zhang et al. demonstrated a new concept of magneto responsive electric 3D matrix for remote and wireless electrical stimulation. By the preparation of magnetoelectric core/shell structured Fe3 O4 @BaTiO3 NPs-loaded hyaluronan/collagen hydrogels, which recapitulate considerable magneto-electricity and vital features of native neural extracellular matrix, the enhancement of neurogenesis both in cellular level and spinal cord injury in vivo with external pulsed magnetic field applied is proved. The findings pave the way for a novel class of remote controlling and delivering electricity through extracellular niches-mimicked hydrogel network, arising prospects not only in neurogenesis but also in human-computer interaction with higher resolution 4).

The frequency of stimulation is an important factor in the success of both quality and quantity of axon regeneration as well as growth of the surrounding myelin and blood vessels that support the axon. Histological analysis and measurement of regeneration showed that low frequency stimulation had a more successful outcome than high frequency stimulation on regeneration of damaged sciatic nerves.

The use of autologous nerve grafting procedures that involve redirection of regenerative donor nerve fibers into the graft conduit has been successful in restoring target muscle function. Localized delivery of soluble neurotrophic factors may help promote the rate of axon regeneration observed within these graft conduits.

An expanding area of nerve regeneration research deals with the development of scaffolding and bio-conduits. Scaffolding developed from biomaterial would be useful in nerve regeneration if they successfully exhibit essentially the same role as the endoneurial tubes and Schwann cell do in guiding regrowing axons.

The surgeon, who treats nerve injuries, should have knowledge about how peripheral nerves react to trauma, particularly an understanding about the extensive pathophysiological alterations that occur both in the peripheral and in the central nervous system. A large number of factors influence the functional outcome, where the surgeon only can affect a few of them. In view of the new knowledge about the delicate intracellular signaling pathways that are rapidly initiated in neurons and in nonneuronal cells with the purpose to induce nerve regeneration, the timing of nerve repair and reconstruction after injury has gained more interest. It is crucial to understand and to utilize the inborn mechanisms for survival and regeneration of neurons and for activation, survival, and proliferation of the Schwann cells and other cells that are acting after a nerve injury. Thus, experimental and clinical data clearly point toward the advantage of early nerve repair and reconstruction of injuries. Following an appropriate diagnosis of a nerve injury, the nerve should be promptly repaired or reconstructed, and new rehabilitation strategies should early be initiated. Considering nerve transfers in the treatment arsenal can shorten the time of nerve reinnervation of muscle targets. Timing of nerve repair and reconstruction is crucial after nerve injury 5).

1)

Willand MP, Nguyen MA, Borschel GH, Gordon T. Electrical Stimulation to Promote Peripheral Nerve Regeneration. Neurorehabil Neural Repair. 2016 Jun;30(5):490-6. doi: 10.1177/1545968315604399. Epub 2015 Sep 10. PMID: 26359343.
2)

Zuo KJ, Gordon T, Chan KM, Borschel GH. Electrical stimulation to enhance peripheral nerve regeneration: Update in molecular investigations and clinical translation. Exp Neurol. 2020 Oct;332:113397. doi: 10.1016/j.expneurol.2020.113397. Epub 2020 Jul 3. PMID: 32628968.
3)

MacEwan MR, Gamble P, Stephen M, Ray WZ. Therapeutic electrical stimulation of injured peripheral nerve tissue using implantable thin-film wireless nerve stimulators. J Neurosurg. 2018 Feb 9:1-10. doi: 10.3171/2017.8.JNS163020. Epub ahead of print. PMID: 29424647.
4)

Zhang Y, Chen S, Xiao Z, Liu X, Wu C, Wu K, Liu A, Wei D, Sun J, Zhou L, Fan H. Magnetoelectric Nanoparticles Incorporated Biomimetic Matrix for Wireless Electrical Stimulation and Nerve Regeneration. Adv Healthc Mater. 2021 Jun 27:e2100695. doi: 10.1002/adhm.202100695. Epub ahead of print. PMID: 34176235.
5)

Dahlin LB. The role of timing in nerve reconstruction. Int Rev Neurobiol. 2013;109:151-64. doi: 10.1016/B978-0-12-420045-6.00007-9. Review. PubMed PMID: 24093611.

Anterior Thalamic Stimulation

Anterior Thalamic Stimulation

Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) is a novel and promising treatment method for patients with drug-resistant epilepsy.

Clinical efficacy

More than 70% of patients implanted with ANT-DBS benefit significantly from this method, i.e., they report seizure-reduction rates higher than 50%

The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p < 0.001).

Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population.

Classification of evidence: This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years. 1).

Adverse events

When focusing on the adverse events reported in a study of stimulation of the anterior nuclei of thalamus (SANTE study), the patients reported paresthesia (18% patients), pain in the implant side (10.9% patients), and infection at the implant site (9.1% patients) 2)

Literature search

Sobstyl et al. performed a literature search regarding the clinical efficacy of ANT DBS. They discussed the surgical technique of the implantation of DBS electrodes with special attention paid to the targeting methods of the ANT. Moreover, they present in detail the clinical efficacy of ANT DBS, with a special emphasis on the stimulation parameters, a stimulation mode, and polarity. They also report all adverse events and present the current limitations of ANT DBS.

In general, the safety profile of DBS in intractable epilepsy patients is good, with a low rate of surgery, hardware-related, and stimulation-induced adverse events. No significant cognitive declines or worsening of depressive symptoms was noted. At long-term follow-up, the quality-of-life scores have improved. The limitations of ANT DBS studies include a limited number of patients treated and mostly open-label designs with only one double-blind, randomized multicenter trial. Most studies do not report the etiology of intractable epilepsy or they include nonhomogeneous groups of patients affected by intractable epilepsy. There are no guidelines for setting initial stimulation parameters. All the variables mentioned may have a profound impact on the final outcome.

ANT DBS appears to be a safe and efficacious treatment, particularly in patients with refractory partial seizures (three-quarters of patients gained at least 50% seizure reduction after 5 years). ANT DBS reduces most effectively the seizures originating in the temporal and frontal lobes. The published results of ANT DBS highlight promise and hope for patients with intractable epilepsy 3).

A literature review discusses the rationale, mechanism of action, clinical efficacy, safety, and tolerability of ANT-DBS in drug-resistant epilepsy patients. A review using systematic methods of the available literature was performed using relevant databases including Medline, Embase, and the Cochrane Library pertaining to the different aspects ANT-DBS. ANT-DBS for drug-resistant epilepsy is a safe, effective and well-tolerated therapy, where a special emphasis must be given to monitoring and neuropsychological assessment of both depression and memory function. Three patterns of seizure control by ANT-DBS are recognized, of which a delayed stimulation effect may account for an improved long-term response rate. ANT-DBS remotely modulates neuronal network excitability through overriding pathological electrical activity, decrease neuronal cell loss, through immune response inhibition or modulation of neuronal energy metabolism. ANT-DBS is an efficacious treatment modality, even when curative procedures or lesser invasive neuromodulative techniques failed. When compared to VNS, ANT-DBS shows slightly superior treatment response, which urges for direct comparative trials. Based on the available evidence ANT-DBS and VNS therapies are currently both superior compared to non-invasive neuromodulation techniques such as t-VNS and rTMS. Additional in-vivo research is necessary in order to gain more insight into the mechanism of action of ANT-DBS in localization-related epilepsy which will allow for treatment optimization. Randomized clinical studies in search of the optimal target in well-defined epilepsy patient populations, will ultimately allow for optimal patient stratification when applying DBS for drug-resistant patients with epilepsy 4).

Case series

Bilateral ANT electrodes were implanted into 18 patients suffering from focal, pharmacoresistant epilepsy. Antiepileptic treatment was kept unchanged from three months prior to operation. The Liverpool seizure severity scale (LSSS) was used to measure the burden of epilepsy.

Results: There was no significant difference between the 2 groups at the end of the blinded period at 6 months. However, when considering all patients and comparing 6 months of stimulation with baseline, there was a significant, 22% reduction in the frequency of all seizures (P = 0.009). Four patients had ≥50% reduction in total seizure frequency and 5 patients ≥50% reduction in focal seizures after 6 months of stimulation. No increased effect over time was shown. LSSS at 6 months compared to baseline showed no significant difference between the 2 groups, but a small, significant reduction in LSSS was found when all patients had received stimulation for 6 months.

Conclusions: Our study supports results from earlier studies concerning DBS as a safe treatment option, with effects even in patients with severe, refractory epilepsy. However, our results are not as encouraging as those reported from many other, mainly unblinded, and open studies 5).

Case reports

A case of relapsing herpes simplex encephalitis (HSE) as a newly reported and potentially fatal stimulation-related adverse effect following stimulation of the anterior thalamic nucleus (ANT-DBS) accompanied by fever, confusion, and cognitive impairment in a 32-year-old epileptic patient with a history of herpes meningoencephalitis 31 years earlier. The T2-weighted/FLAIR high-signal intensity in the temporal lobe developed at a “distance” from the stimulation target. The positive polymerase chain reaction of herpes virus deoxyribonucleic acid in the cerebrospinal fluid confirmed the diagnosis. The condition improved partially on acyclovir and stimulation stopped. Seizures disappeared and then returned after few months. The unique case report presents a rationale for considering history of herpes encephalitis as a relative contraindication for ANT-DBS, and HSE relapse should be suspected in patients with post-stimulation fever and/or altered consciousness 6).

1)

Salanova V, Witt T, Worth R, Henry TR, Gross RE, Nazzaro JM, Labar D, Sperling MR, Sharan A, Sandok E, Handforth A, Stern JM, Chung S, Henderson JM, French J, Baltuch G, Rosenfeld WE, Garcia P, Barbaro NM, Fountain NB, Elias WJ, Goodman RR, Pollard JR, Tröster AI, Irwin CP, Lambrecht K, Graves N, Fisher R; SANTE Study Group. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology. 2015 Mar 10;84(10):1017-25. doi: 10.1212/WNL.0000000000001334. Epub 2015 Feb 6. PMID: 25663221; PMCID: PMC4352097.
2)

Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, Oommen K, Osorio I, Nazzaro J, Labar D, Kaplitt M, Sperling M, Sandok E, Neal J, Handforth A, Stern J, DeSalles A, Chung S, Shetter A, Bergen D, Bakay R, Henderson J, French J, Baltuch G, Rosenfeld W, Youkilis A, Marks W, Garcia P, Barbaro N, Fountain N, Bazil C, Goodman R, McKhann G, Babu Krishnamurthy K, Papavassiliou S, Epstein C, Pollard J, Tonder L, Grebin J, Coffey R, Graves N; SANTE Study Group. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia. 2010 May;51(5):899-908. doi: 10.1111/j.1528-1167.2010.02536.x. Epub 2010 Mar 17. PMID: 20331461.
3)

Sobstyl M, Stapińska-Syniec A, Iwański S, Rylski M. Clinical Efficacy and Safety Profile of Anterior Thalamic Stimulation for Intractable Epilepsy. J Neurol Surg A Cent Eur Neurosurg. 2021 Jun 14. doi: 10.1055/s-0041-1725954. Epub ahead of print. PMID: 34126641.
4)

Bouwens van der Vlis TAM, Schijns OEMG, Schaper FLWVJ, Hoogland G, Kubben P, Wagner L, Rouhl R, Temel Y, Ackermans L. Deep brain stimulation of the anterior nucleus of the thalamus for drug-resistant epilepsy. Neurosurg Rev. 2019 Jun;42(2):287-296. doi: 10.1007/s10143-017-0941-x. Epub 2018 Jan 6. PMID: 29306976; PMCID: PMC6502776.
5)

Herrman H, Egge A, Konglund AE, Ramm-Pettersen J, Dietrichs E, Taubøll E. Anterior thalamic deep brain stimulation in refractory epilepsy: A randomized, double-blinded study. Acta Neurol Scand. 2019 Mar;139(3):294-304. doi: 10.1111/ane.13047. Epub 2018 Dec 11. PMID: 30427061.
6)

Hamdi H, Robin E, Stahl JP, Doche E, Azulay JP, Chabardes S, Bartolomei F, Regis J. Anterior Thalamic Stimulation Induced Relapsing Encephalitis. Stereotact Funct Neurosurg. 2019;97(2):132-136. doi: 10.1159/000499072. Epub 2019 May 3. PMID: 31055582.