Less is more – Pulse width dependent therapeutic window in deep brain stimulation for essential tremor

Background

Shorter pulse widths than conventional pulse width settings may lead to reduction of side effects and therefore be a valuable therapeutic option for deep brain stimulation (DBS) in patients with essential tremor (ET).

Effect of stimulation frequency on tremor suppression in essential tremor.

We sought to determine the effect of deep brain stimulation (DBS) frequency on tremor suppression in essential tremor (ET) patients with deep brain stimulators implanted in the ventral intermediate nucleus (VIM) of the thalamus. A uniaxial accelerometer was used to measure tremor in the right upper extremity of subjects with a diagnosis of ET who had DBS electrodes implanted in the left VIM. The root-mean-square acceleration was used as the index of tremor magnitude and normalized to the OFF DBS condition. There was a highly significant inverse sigmoidal relationship between stimulation frequency and normalized tremor acceleration (X(2)/DoF = 0.42, r(2) = 0.997). Tremor acceleration had a nearly linear response to stimulation frequencies between 45 and 100 Hz with little additional benefit above 100 Hz. These findings have two important implications. Clinically, frequency of thalamic stimulation is an important variable for optimal tremor control with maximal benefit achieved with 100 to 130 Hz in most patients. Second, thalamic DBS provides tremor benefit in a graded manner and is not an all-or-nothing phenomenon.     

Postural tremor suppression is dependent on thalamic stimulation frequency.

Deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) reduces tremor in people with essential tremor (ET), yet the dependence of tremor suppression on stimulation frequency remains unclear. To address this issue, we tested tremor suppression for three 15-second measurements during a variety of stimulation frequencies in 11 ET patients treated with VIM DBS. Stimulation frequencies at or above 100 Hz produced maximal benefit; higher frequencies provided no additional benefit. If this short-term measure predicts long-term response in routine activities at home, then this stimulation frequency setting will prolong battery half-life compared to higher frequency settings. These findings suggest that ET patients treated with VIM DBS may receive adequate benefit from stimulation frequencies about 100 Hz and this setting compared to commonly used higher settings will prolong battery life of surgically implanted pulse generators.     

Thalamic deep brain stimulation: effects on the nontarget limbs.

Unilateral thalamic ventral intermediate (VIM) deep brain stimulation (DBS) is now accepted as an effective treatment for essential tremor (ET) and tremor related to Parkinson's disease (PD). The effects of unilateral placement on the side ipsilateral to the surgical site have not been carefully evaluated. To systematically assess the effects ipsilateral to the surgical side and to determine the effects of device inactivation on the baseline tremor, we evaluated tremor in 73 patients approximately 3 months after their unilateral thalamic placement. Assessment included blinded and unblinded ratings using the Unified Parkinson's Disease Rating Scale for PD patients and a modified Tremor Rating Scale in ET patients. All measures of tremor contralateral to the implantation site improved significantly and robustly in both PD and ET. Implantation did not worsen tremor by any measure on the ipsilateral side. There was mild ipsilateral improvement as measured by lower observed tremor scores in ET (6.0 +/- 1.8 to 5.0 +/- 1.9, P < 0.005), but not PD. There was no rebound augmentation of tremor in either hand after the devices were deactivated in either group. We conclude that VIM DBS may mildly improve ipsilateral ET, and that concerns about meaningful ipsilateral tremor augmentation after device deactivation are not warranted.     

Effect of lead trajectory on the response of essential head tremor to deep brain stimulation

BackgroundEssential tremor (ET) is one of the most common movement disorders. Normally ET affects the distal upper extremities, but it can also be accompanied by midline symptoms. Ventralis intermedius (VIM) thalamic deep brain stimulation (DBS) has been shown to be effective in reducing hand tremor, but its effects on head tremor have been inconsistent.MethodsTwenty-nine DBS patients with a diagnosis of ET met inclusion criteria. All implantations targeted VIM. The factors examined included age, gender, disease duration, presence or absence of head tremor, handedness, and the Fahn-Tolosa-Marin rating scale (TRS). This analysis specifically focused on TRS head tremor sub-scores at baseline, 6 months and 12 months post-DBS. Additionally, DBS lead entry angles were examined.ResultsTwenty-three ET patients underwent unilateral DBS and six underwent staged bilateral DBS. At both 6 and 12 months following DBS, stimulation resulted in diminished head tremor (ON vs OFF; p < 0.0001). The most important predictor of head tremor suppression was the entry angle of the DBS lead in the sagittal projection relative to the AC–PC axial plane (AC–PC angle). Head tremor reduction was greater among more vertical AC–PC angles.ConclusionA more vertical AC–PC angle of the DBS lead trajectory was associated with improved head tremor suppression. Further studies will be necessary to confirm this potentially important finding.     

Short latency activation of cortex by clinically effective thalamic brain stimulation for tremor

Deep brain stimulation (DBS) relieves disabling symptoms of neurologic and psychiatric diseases when medical treatments fail, yet its therapeutic mechanism is unknown. We hypothesized that ventral intermediate (VIM) nucleus stimulation for essential tremor activates the cortex at short latencies, and that this potential is related to the suppression of tremor in the contralateral arm. We measured cortical activity with electroencephalography in 5 subjects (seven brain hemispheres) across a range of stimulator settings, and reversal of the anode and cathode electrode contacts minimized the stimulus artifact, allowing visualization of brain activity. Regression quantified the relationship between stimulation parameters and both the peak of the short latency potential and tremor suppression. Stimulation generated a polyphasic event‐related potential in the ipsilateral sensorimotor cortex, with peaks at discrete latencies beginning less than 1 ms after stimulus onset (mean latencies 0.9 ± 0.2, 5.6 ± 0.7, and 13.9 ± 1.4 ms, denoted R1, R2, and R3, respectively). R1 showed more fixed timing than the subsequent peaks in the response (P < 0.0001, Levene's test), and R1 amplitude and frequency were both closely associated with tremor suppression (P < 0.0001, respectively). These findings demonstrate that effective VIM thalamic stimulation for essential tremor activates the cerebral cortex at approximately 1 ms after the stimulus pulse. The association between this short latency potential and tremor suppression suggests that DBS may improve tremor by synchronizing the precise timing of discharges in nearby axons and, by extension, the distributed motor network to the stimulation frequency or one of its subharmonics. © 2012 Movement Disorder Society     

On-demand deep brain stimulation for essential tremor: a report on four cases.

Deep brain stimulation (DBS) is an established therapy for essential tremor (ET), but loss of efficacy due to tolerance can occur. Our objective was to evaluate if it is feasible to use DBS only on-demand and if this would prevent tolerance. We report on the effects of left-side thalamic DBS in 4 ET patients who were instructed to switch on stimulation only when using their right hand for motor tasks and were followed-up to 30 months after surgery. The patients were capable of using DBS only on-demand (DBS use of 22.0+/-13.5%/day). DBS led to a stable suppression of right arm tremor throughout the follow-up. No problems associated with tolerance such as tremor rebound or late therapy failure occurred. In comparison to publications stating that ET patients had been using DBS continuously during the daytime, the use of on-demand DBS saves battery life, which delays surgical replacement of the stimulator. Thus, on-demand DBS saves money, may help to prevent tolerance, and should be adopted for the long-term treatment of ET patients.     

Deep brain stimulation of the ventral intermediate thalamic nucleus in the treatment of essential tremor

Essential tremor (ET) is the most common movement disorder. In most patients the course of ET is mild and pharmacological therapy controls postural and kinetic components of tremor. The first-line treatment of ET is pharmacotherapy with propranolol, primidone and gabapentin. In patients with marked head and voice tremor, local botulinum toxin injections have been found to be very effective. Despite optimal drug therapies it is estimated that approximately 50% of patients with ET have medication-resistant tremor. ET can cause more functional impairment than parkinsonian resting tremor because most prominent components of ET are postural and kinetic ones. For patients with drug-resistant debilitating tremor, surgical therapy (thalamotomy) and more recently deep brain stimulation (DBS) of the ventral intermediate thalamic nucleus (VIM) is a viable treatment modality. Several long-term studies have confirmed the high effectiveness rate of ablative surgery and thalamic DBS in the treatment of ET. The most striking advantage of thalamic DBS is the possibility of performing bilateral surgery in one operative session with a significantly lower rate of side effects. Nowadays the bilateral staged thalamotomy is performed rarely because of unacceptable side effects. Moreover, many authors have observed that in bilaterally stimulated patients the head and voice tremor have diminished in postoperative course. Thalamic DBS is a very efficacious and safe procedure in the treatment of ET.     

Tremor induced by thalamic deep brain stimulation in patients with complex regional facial pain.

We report on two patients who developed a new postural and action tremor after chronic stimulation of the contralateral thalamus (VPM nucleus) during treatment of a complex regional facial pain syndrome. The tremor was only present during deep brain stimulation (DBS) and was suppressed with adjustment of the stimulation parameters. Tremor was seen only with low frequency stimulation (50 Hz or lower) and disappeared with higher stimulation frequencies. In addition to being an unusual side effect of thalamic DBS, we believe that this phenomenon affords insight into one possible mechanism underlying essential tremor (ET). A central oscillatory mechanism involving the olivocerebellar complex and the thalamus, which is a part of the cerebro-cerebello-cerebral circuit, is thought to play an important role in the genesis of ET. Induction of a tremor resembling ET in our patients indicates an active role for low frequency stimulation. A plausible explanation for this is that low frequency stimulation in the thalamic area enhances the output of the tremor-producing network. This leads credence to the concept of central oscillations in a "tremor circuit," of which the thalamus is a part, as being important in ET.     

Fulfilment of patients' goals after thalamic deep brain stimulation: a follow-up study

Deep brain stimulation (DBS) in the ventrolateral thalamus (VIM) is shown to reduce tremor in essential tremor (ET) and Parkinson's disease (PD). Our aim was to evaluate the results of VIM DBS from the patients' perspective. Sixteen consecutively included patients (8 ET and 8 PD) described their own outcome goals preoperatively and evaluated the fulfillment 1, 6 and 12 months postoperatively. We conclude that the patients could do specific activities that are of importance to them such as eating, drinking and socializing, and perceived either partial or total fulfillment of their goals.     

A pilot study: Microlesion effects and tremor outcome in the ventrointermediate deep brain stimulation (VIM-DBS)

Objectives

To perform a pilot study to investigate the relationship between the microlesion effect (MLE) seen in deep brain stimulation (DBS) of the ventralis intermedius nucleus (VIM) and subsequent tremor response and DBS parameter settings.

Patients and methods

Nineteen thalami in 12 patients (11 essential tremor and 1 Parkinson's disease), who underwent unilateral (n = 5) and bilateral VIM-DBS (n = 7) were assessed at pre- and 24-h post-operation, at their initial DBS activation, and at 6-month follow-up. The severity of tremor was rated (from 0 to 4) for each activity including hand at rest, outstretched, wing beating, finger–nose–finger, dot approximation and spiral drawing (total score ranging from 0 to 24). The difference of total tremor score before and 24-h after electrode implants (MLE) was segregated into 3 groups based on immediate (24 h) post-operative tremor improvement: (1) minimal (none or mild, 0–2), (2) moderate (>2–4), and (3) marked (>4). At the initial activation (23.4 ± 3.7 days post-operation), the mean OFF tremor scores were still marginally better in marked than the minimal and moderate MLE groups.

Results

At 6 months, 14 of 19 thalami (74%) were eligible for follow-up analysis. The “OFF” stimulation MLE disappeared in all groups. There was no significant difference of mean ON tremor scores among the groups; however, DBS parameter settings, including amplitude and pulse width, trended to be mildly lower in those with a marked MLE.

Conclusion

MLE has minimal long term clinical effect except for possibly allowing for lower DBS settings.     

Frameless deep brain stimulation surgery: A community hospital experience

Objective

Frame-based stereotaxy has regularly been utilized for deep brain stimulation (DBS) surgery. More recently, frameless neuronavigation has revealed similar outcomes for functional neurosurgical operations. Such comparable outcomes have been described by tertiary referral centers, but whether such excellent surgical outcomes are attainable in a community setting has yet to be reported.

Methods

Eighteen patients received frameless DBS surgery, 11 with subthalmic nucleus (STN) implantation for Parkinson's disease (PD) and 7 with ventral intermediate nucleus (Vim) implantation for essential tremor (ET). Their data was collected and analyzed, including the Unified Parkinson's Disease Rating Scale (UPDRS) and tremor scores.

Results

There was a 58% reduction in UPDRS III and a 47% reduction in overall levodopa dose in those with STN DBS (p < 0.0001 and p < 0.0005, respectively) and those with Vim DBS had a 76% improvement in their overall tremor rating score (p < 0.002) at mean follow-up (8.2 and 10.1 months, respectively). No intraoperative complications occurred. Two subjects developed wound dehiscence post-operatively and another had fall-induced lead fracture, all treated with uncomplicated hardware replacement.

Conclusions

Frameless DBS for PD and ET can be safely performed in a community setting with similar excellent outcomes as those of larger academic centers as well as clinical results comparable to frame-based surgery. Patients living in community or rural areas may not need to travel across city or even state lines to receive this surgical option, especially if they have the opportunity to receive it closer to home.     

Determining an efficient deep brain stimulation target in essential tremor - Cohort study and review of the literature

IntroductionDeep brain stimulation (DBS) is a highly efficacious treatment for essential tremor (ET). Still, the optimal anatomical target in the (sub)thalamic area is a matter of debate. The aim of this study was to determine the optimal target of DBS for ET regarding beneficial clinical outcome and impact on activities of daily living as well as stimulation-induced side effects and compare it with previously published coordinates.MethodsIn 30 ET patients undergoing bilateral DBS, severity of tremor was assessed by blinded video ratings before and at 1-year follow-up with DBS ON and OFF. Tremor scores and reported side effects and volumes of tissue activated were used to create a probabilistic map of DBS efficiency and side effects.ResultsDBS was effective both in tremor suppression as well as in improving patient reported outcomes, which were positively correlated. The “sweet spot” for tremor suppression was located inferior of the VIM in the subthalamic area, close to the superior margin of the zona incerta. The Euclidean distance of active contacts to this spot as well as to 10 of 13 spots from the literature review was predictive of individual outcome. A cluster associated with the occurrence of ataxia was located in direct vicinity of the “sweet spot”.ConclusionOur findings suggest the highest clinical efficacy of DBS in the posterior subthalamic area, lining up with previously published targets likely representing the dentato-rubro-thalamic tract. Side effects may not necessarily indicate lead misplacement, but should encourage clinicians to employ novel DBS programing options.     

Thalamic deep brain stimulation: comparison between unilateral and bilateral placement

BACKGROUND: Unilateral thalamic deep brain stimulation (DBS) is accepted as an effective treatment for essential tremor (ET) and the tremor of Parkinson disease (PD). There are, however, relatively little data concerning bilateral thalamic DBS and no thorough comparisons between the 2 methods. METHODS: To assess the relative benefit of a staged second contralateral DBS placement in patients with PD and ET, we compared preoperative baseline assessments with those at 3 months after the initial implantation, and again at 3 months after the second contralateral implantation. The assessments included the Unified Parkinson's Disease Rating Scale for patients with PD (n = 8) and a modified Unified Tremor Rating Assessment for patients with ET (n = 13). The design included open and blinded (unknown activation status) assessments. RESULTS: Overall, after the second implantation, all specific measures assessing tremor contralateral to that side improved in patients with PD and ET, generally without sacrificing those contralateral to the first side implantation. Midline tremors (face and head) improved only after the second side implantation. In patients with ET, functional and subjective scores tended to further improve after the second placement; however, patients with PD had less subjective improvement. Hand tremor scores in patients with ET randomized to "on" stimulation improved from 6.7 +/- 0.9 to 1.3 +/- 1.2 (P<.005). The scores of patients with PD randomized to on stimulation improved from 9.3 +/- 1.0 to 1.0 +/- 0.5. (Data are given as mean +/- SD.) Tremor scores did not change from baseline in those patients randomized to "off" stimulation in either group. Adverse events related to stimulation increased after the second implantation in both groups. CONCLUSIONS: Bilateral thalamic DBS is more effective than unilateral DBS at controlling bilateral appendicular and midline tremors of ET and PD. Despite this, overall functional disability only improved in patients with ET, possibly secondary to more problematic adverse events in patients with PD, especially balance problems. Bilateral DBS should be considered when unilateral DBS does not offer satisfactory benefit, especially in patients with ET.     

Stimulation-induced side effects in the posterior subthalamic area: Distribution,characteristics and visualization

Objective

The posterior subthalamic area (PSA) is an emerging but relatively unexplored target for DBS treatment of tremor. The aim of the study was to explore the area further by evaluating the spatial distribution and the characteristics of stimulation-induced side effects in this area.

Methods

Twenty-eight patients with essential tremor (ET) implanted with 33 DBS electrodes were evaluated concerning stimulation-induced side effects by testing each contact separately one year after surgery. The location of the side effects were plotted on axial slides of the Morel Stereotactic Atlas and a 3-dimensional model of the area for visualization was created.

Results

Visualization of the contacts eliciting stimulation-induced side effects demonstrated that identical responses can be elicited from various points in the PSA and its vicinity. The majority of contacts inducing muscular affection and cerebellar symptoms, including dysarthria, could not be attributed to an effect on the internal capsule. Paresthesias, affecting various body parts were elicited throughout the area without a clear somatotopic pattern.

Conclusion

Stimulation-induced side effects in the PSA and its vicinity were difficult to attribute to certain anatomical areas as the same response was induced from various locations. Therefore, this study could not provide a meaningful somatotopic map with regard to stimulation-induced side effects in the PSA.     

Multiparametric laryngeal assessment of the effect of thalamic deep brain stimulation on essential vocal tremor

ObjectiveEVT is a refractory voice disorder that significantly affects quality of life. This work aims to conduct a multiparametric assessment of the effect of deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (VIM) on essential vocal tremor (EVT) and investigate the relation between DBS lead location and EVT outcomes.MethodsNine participants underwent DBS for essential tremor and were diagnosed with co-occurring EVT in this prospective cohort study. Objective measurements including acoustic evaluation of vocal fundamental frequency (F0) and intensity modulation and subjective measurements including physiologic evaluation of the oscillatory movement of the laryngeal muscles and vocal tract and perceptual ratings of tremor severity were collected PRE and POST DBS. Finally, we investigated the relation between DBS lead location and EVT outcomes.ResultsAcoustic modulations of F0 and intensity were significantly improved POST DBS. Physiologic assessment showed a POST DBS reduction of oscillatory movement in the laryngeal muscles and vocal tract, but not significantly. Listener and participant perception, of EVT severity was also significantly reduced. Finally, our results indicate better EVT control with increased distance to midline of left VIM thalamic stimulation.ConclusionsBy employing a battery of objective and subjective measures, our study supports the benefit of DBS for the treatment of EVT and specifies the acoustic and physiologic mechanisms that mediate its positive effect. We further provide preliminary results on the relation between lead location and EVT outcomes, laying the foundation for future studies to clarify the optimal DBS target for the treatment of EVT.     

Directional Deep Brain Stimulation of the Thalamic Ventral Intermediate Area for Essential Tremor Increases Therapeutic Window

ObjectivesDeep brain stimulation (DBS) of the posterior subthalamic area (PSA) and the ventral intermediate thalamic nucleus (VIM) is a well-established therapy for essential tremor (ET), but it is frequently associated with side effects like dysarthria or gait ataxia. Directional DBS (dDBS) may be a way to activate fiber tracts more selectively. Is dDBS for ET superior to omnidirectional DBS (oDBS) regarding therapeutic window and clinically as effective as oDBS?Materials and MethodsTen patients with ET treated with PSA/VIM-DBS were recruited. Therapeutic window served as primary outcome parameter; clinical efficacy, volume of neuronal activation, and total electrical energy delivered (TEED) served as secondary outcome parameters. Therapeutic window was calculated for all three dDBS directions and for oDBS by determining therapeutic thresholds and side effect thresholds. Clinical efficacy was assessed by comparing the effect of best dDBS and oDBS on tremor and ataxia rating scales, and accelerometry. Volume of neural activation and TEED were also calculated for both paradigms.ResultsFor best dDBS, therapeutic window was wider and therapeutic threshold was lower compared to oDBS. While side effect threshold did not differ, volume of neural activation was larger for dDBS. In terms of clinical efficacy, dDBS was as effective as oDBS.ConclusionsdDBS for ET widens therapeutic window due to reduction of therapeutic threshold. Larger volume of neural activation for dDBS at side effect threshold supports the notion of persistent directionality even at higher intensities. dDBS may compensate for slightly misplaced leads and should be considered first line for PSA/VIM-DBS.     

Axonal pathways linked to therapeutic and nontherapeutic outcomes during psychiatric deep brain stimulation

Objective:

The underlying hypothesis of our work is that specific clinical neuropsychiatric benefits can be achieved by selective activation of specific axonal pathways during deep brain stimulation (DBS). As such, the goal of this study was to develop a method for identifying axonal pathways whose activation is most likely necessary for achieving therapeutic benefits during DBS.

Experimental design:

Our approach combined clinical data, diffusion tensor tractography, and computer models of patient‐specific neurostimulation to identify particular axonal pathways activated by DBS and determine their correlations with individual clinical outcome measures. We used this method to evaluate a cohort of seven treatment‐resistant depression patients treated with DBS of the ventral anterior internal capsule and ventral striatum (VC/VS).

Principal observations:

Clinical responders exhibited five axonal pathways that were consistently activated by DBS. All five pathways coursed lateral and medial to the VS or dorsal and lateral to the nucleus accumbens; however, details of their specific trajectories differed. Similarly, one common pathway was identified across nonresponders.

Conclusions:

Our method and preliminary results provide important background for studies aiming to expand scientific characterization of neural circuitry associated with specific psychiatric outcomes from DBS. Furthermore, identification of pathways linked to therapeutic benefit provides opportunities to improve clinical selection of surgical targets and stimulation settings for DBS devices. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.

     

Thalamic DBS with a constant-current device in essential tremor: A controlled clinical trial

IntroductionThis study of thalamic deep brain stimulation (DBS) investigated whether a novel constant-current device improves tremor and activities of daily living (ADL) in patients with essential tremor (ET).MethodsA prospective, controlled, multicenter study was conducted at 12 academic centers. We investigated the safety and efficacy of unilateral and bilateral constant-current DBS of the ventralis intermedius (VIM) nucleus of the thalamus in patients with essential tremor whose tremor was inadequately controlled by medications. The primary outcome measure was a rater-blinded assessment of the change in the target limb tremor score in the stimulation-on versus stimulation-off state six months following surgery. Multiple secondary outcomes were assessed at one-year follow-up, including motor, mood, and quality-of-life measures.Results127 patients were implanted with VIM DBS. The blinded, primary outcome variable (n = 76) revealed a mean improvement of 1.25 ± 1.26 points in the target limb tremor rating scale (TRS) score in the arm contralateral to DBS (p < 0.001). Secondary outcome variables at one year revealed significant improvements (p ≤ 0.001) in quality of life, depression symptoms, and ADL scores. Forty-seven patients had a second contralateral VIM-DBS, and this group demonstrated reduction in second-sided tremor at 180 days (p < 0.001). Serious adverse events related to the surgery included infection (n = 3), intracranial hemorrhage (n = 3), and device explantation (n = 3).ConclusionUnilateral and bilateral constant-current VIM DBS significantly improves upper extremity tremor, ADL, quality of life, and depression in patients with severe ET.     

Effects of thalamic stimulation frequency on intention and postural tremor

Deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of the thalamus improves essential tremor. Suppression of the amplitude of the postural tremor component with VIM DBS depends on stimulation frequency. The purpose of this study was to determine the effect of DBS frequency on the intention tremor component, that is, tremor that is enhanced by target-directed movement, and to compare it to the effect of DBS frequency on postural tremor in people with essential tremor. We measured tremor frequency and amplitude during trials of postural holding and voluntary reaching between two targets at 10 different stimulation frequency settings between 0 and 185 Hz. Tremor frequency did not change with changes in stimulation frequency. Amplitude suppression of both intention and postural tremor depended on stimulation frequency. Maximal tremor reduction occurred at approximately 130 Hz for both forms of tremor. However, at optimal frequencies, the percent reduction in tremor amplitude relative to the DBS OFF condition was greater for postural than for intention tremor. These results suggest that VIM DBS stimulation frequencies near 130 Hz may provide maximal control of intention and postural tremor. Identification of optimal stimulation settings should consider assessment of intention tremor, not just postural tremor, as intention tremor may not be as well controlled as postural tremor but may be a better gauge for functional benefit.