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.     

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.     

Successful thalamic deep brain stimulation for orthostatic tremor

We report a patient with severe orthostatic tremor (OT) unresponsive to pharmacological treatments that was successfully controlled with thalamic (Vim, ventralis intermedius nucleus) deep brain stimulation (DBS) over a 4‐year period. Cortical activity associated with the OT revealed by EEG back‐averaging and fluoro‐deoxi‐glucose PET were also suppressed in parallel with tremor arrest. This case suggests that Vim‐DBS may be a useful therapeutic approach for patients highly disabled by OT. © 2008 Movement Disorder Society     

VIM thalamic stimulation for tremor in a patient with IgM paraproteinaemic demyelinating neuropathy.

We demonstrate the effect of deep brain stimulation of the ventral intermediate thalamic nucleus on intractable action tremor, in a 72-year-old man suffering from neuropathy associated with monoclonal gammopathy.     

Gait and balance in essential tremor: Variable effects of bilateral thalamic stimulation

Essential tremor (ET) is a multi‐faceted condition best known for postural and action tremor but also may include disordered gait and postural instability. Deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of the thalamus provides substantial tremor reduction yet some patients with bilateral VIM DBS have gait and balance impairment. This study examines gait and balance performance in 13 participants with ET who have bilateral VIM DBS compared with a matched control group. Participants with ET were tested with their stimulators off (DBS OFF) and on (DBS ON). For both standard and tandem walking, participants with ET walked significantly more slowly than controls, with significantly lower cadence, spending a lower percentage of the gait cycle in single limb support and a higher percentage in double support compared with controls. Participants with ET also had significantly lower tandem and one leg stance times, Berg balance scores, balance confidence, and required significantly greater time to perform the Timed Up‐and‐Go relative to controls. There were no significant differences in any gait or balance measures in the DBS OFF versus DBS ON conditions, but the effects of DBS on gait and balance were highly variable among individuals. Future studies are needed to determine why some individuals experience gait and balance difficulties after bilateral thalamic DBS and others do not. A better understanding of the mechanisms underlying gait and balance impairments in those with bilateral DBS is critical to reduce falls and fractures in this group. © 2008 Movement Disorder Society     

Mood and motor effects of thalamic deep brain stimulation surgery for essential tremor

Purpose: The aim of this study was to evaluate the effects of unilateral and bilateral ventralis intermedius (Vim) deep brain stimulation (DBS) on mood and motor function. Methods: Thirty‐one consecutive medication refractory patients with essential tremor who underwent unilateral or bilateral Vim DBS at University of Florida and returned for at least 6 ‐month follow‐up completed the Visual Analog Mood (VAMS), the Beck Depression Inventory (BDI), and the Tremor Rating Scale (TRS) before and after surgery. We excluded all patients who were implanted at other institutions. Results: The tense subscale of the VAMS improved significantly in both the unilateral and bilateral DBS groups (P < 0.001). On the VAMS afraid subscale, only the bilateral group trended toward improvement (P = 0.075). There were no significant changes for either group for the happy, confused, sad, angry, energetic or tired VAMS scores. TRS subscale scores all improved after unilateral and bilateral Vim DBS surgery (P < 0.001). Conclusions: Feelings of tenseness, tremor severity and ADLs improved following unilateral or bilateral Vim DBS for ET.     

Long-term efficacy of thalamic deep brain stimulation for tremor: double-blind assessments.

Thalamic deep brain stimulation (DBS) is proven to suppress tremor in Parkinson's disease (PD) and essential tremor (ET). However, there are few reports on its long-term efficacy. We studied the efficacy of DBS at 2 years and 6-7 years after electrode implantations in the ventrointermediate nucleus of the thalamus in 39 patients (20 PD, 19 ET) with severe tremor. Twenty-five of the patients completed the study. Evaluations were done in a double-blind manner with the Unified Parkinson's Disease Rating Scale (UPDRS) and Essential Tremor Rating Scale (ETRS). DBS decreased tremor sum scores in PD (P < 0.025) compared to the preoperative baseline (median, 7; Q25-75, 6-9) both at 2 years (median, 2; Q25-75, 2-3.5; n = 16) and at 6 to 7 years (median, 2.5; Q25-75, 0.5-3; n = 12). Stimulation on improved tremor sum as well as sub scores (P < 0.025) compared to stimulation off conditions. In ET, thalamic stimulation improved (P < 0.025) kinetic and positional tremor at both follow-up periods (n = 18 and n = 13, respectively) with significant improvements (P < 0.025) in hand-function tests. PD but not ET patients showed a general disease progression. Stimulation parameters were remarkably stable over time. We conclude that high-frequency electric thalamic stimulation can efficiently suppress severe tremor in PD and ET more than 6 years after permanent implantation of brain electrodes.     

Neuropsychological outcomes after thalamic deep brain stimulation for essential tremor

IntroductionNon-motor DBS outcomes have received little attention in ET relative to PD. This study examines neuropsychological outcomes in ET following thalamic VIM DBS.MethodsFifty patients completed neuropsychological evaluations preoperatively and approximately seven months postoperatively. Cognition and mood changes were analyzed at the group level and individual level. Additional associations with treatment, disease, and demographic characteristics were assessed.ResultsSignificant cognitive decline was not observed at the group level. At the individual level, 46% of patients demonstrated at least subtle overall cognitive decline (≥1SD on at least one test within at least two domains). Mild decline (≥1SD) was seen in 10%–29.17% of patients on individual tests across all cognitive domains, with highest rates in verbal memory. Substantial cognitive decline (≥2SD) occurred in less than 9% of the sample across all tests. Factors related to cognitive decline included higher DBS parameter settings, older age of ET onset, intracranial complications, and inability to reduce ET medications postoperatively. Depression and anxiety did not change when accounting for questionnaire items that could be falsely elevated by tremor.ConclusionSubstantial cognitive decline after VIM DBS is rare in patients with ET. However, subtle decrements can occur across cognitive domains and particularly in verbal memory. DBS parameter settings may relate to cognitive decline. Further research is needed to better understand possible associations with electrode lateralization and other variables that could also relate to disease progression and test-retest effects. Symptoms of depression and anxiety remain stable.     

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     

The effect of electrical stimulation of the subthalamic nucleus on seizures is frequency dependent

PURPOSE: Animal studies and anecdotal human case reports have indicated that the subthalamic nucleus (STN) may be a site of anticonvulsant action. METHODS: We tested the hypothesis that continuous electrical stimulation of the STN inhibits seizures acutely. We determined the effects of three stimulation frequencies, 130 Hz, 260 Hz, and 800 Hz, on generalized clonic and tonic-clonic flurothyl seizures. Adult male rats were implanted with concentric bipolar stimulating electrodes in the STN bilaterally. After recovery, rats underwent flurothyl seizures to compare the effects of each stimulation frequency on seizure threshold. Rats were tested 4 times, twice in the stimulated condition, and twice in the unstimulated condition. The order of trials was random, except that stimulation trials alternated with control trials. Flurothyl seizure thresholds under each stimulation condition were compared with control values from the same animal. RESULTS: Bilateral stimulation of the STN at 130 Hz produced a significant increase in the seizure threshold for clonic flurothyl seizures, whereas stimulation at 260 Hz did not appear to have any effect on seizures. STN stimulation at 800 Hz significantly lowered seizure threshold for tonic-clonic seizures. CONCLUSIONS: We conclude that electrical stimulation of the STN can be anticonvulsant, but the effects appear to depend on the stimulation frequency and the type of seizure.     

Deactivation of thalamocortical activity is responsible for suppression of parkinsonian tremor by thalamic stimulation: a Tc-ECD SPECT study

Four patients with Parkinson's disease (PD) achieved excellent improvement of their unilateral tremor by chronic deep brain stimulation (DBS) of the contralateral ventral intermediate (Vim) nucleus of the thalamus. Repeated measurements of cerebral blood flow were obtained 14 days apart off and on stimulation using ^99mTc-ECD SPECT. Subjects were scanned at rest and the data were compared with those of normal healthy volunteers. During stimulation, there were highly significant deactivations in the motor area and supplementary motor area on the electrode side and in the prefrontal area and the anterior cingulum bilaterally. No cerebellar deactivation was detected. We conclude that the mechanism responsible for suppression of parkinsonian tremor by thalamic stimulation is deactivation of thalamocortical activity.     

Deep brain stimulation for essential tremor: A systematic review

Deep brain stimulation (DBS) is a neurosurgical treatment, which has proven useful in treating Parkinson's disease. This systematic review assessed the safety and effectiveness of DBS for another movement disorder, essential tremor. All studies concerning the use of DBS in patients with essential tremor were identified through searching of electronic databases and hand searching of reference lists. Studies were categorized as before/after DBS or DBS stimulation on/off to allow the effect of the stimulation to be analyzed separately to that of the surgery itself. A total of 430 patients who had received DBS for essential tremor were identified. Most of the reported adverse events were mild and could be treated through changing the stimulation settings. Generally, in all studies, there was a significant improvement in outcomes after DBS compared with baseline scores. In addition, DBS was significantly better in testing when the stimulation was turned on, compared with stimulation turned off or baseline. Based on Level IV evidence, DBS is possibly a safe and effective therapy for essential tremor. © 2010 Movement Disorders Society     

Effects of chronic alcohol consumption on long-term outcomes of thalamic deep brain stimulation for essential tremor

The prevalence of essential tremor (ET) is about 4% above 40 years of age. Chronic alcohol consumption is present in around 20% of patients with ET. Our objective was to identify whether chronic alcohol consumption was associated with a negative effect on tremor outcome after thalamic deep brain stimulation (DBS) in ET patients. We conducted a retrospective chart review, from January 2005 to December 2012, from which 23 patients who had ventral intermediate nucleus (Vim)-DBS surgery for ET were identified. Seven patients had a positive history of chronic alcohol consumption. We defined as chronic alcohol users those patients with a habit of drinking alcohol every day in order to suppress tremor. In the overall group of 23 patients, there was a reduction in the median tremor score from 8 pre-operatively, to 1 post-operatively (p < 0.0001). The alcohol consumers group experienced a reduction in the median tremor score from 6 pre-operatively to 0 post-operatively (p = 0.03). The non-alcohol consumers group had a reduction in the median tremor score from 8 pre-operatively to 1.7 post-operatively (p < 0.0001). Both groups of patients experienced significant benefit from thalamic DBS. A larger study may reveal statistically significant differences between subgroups.     

Decoding voluntary movements and postural tremor based on thalamic LFPs as a basis for closed-loop stimulation for essential tremor

BackgroundHigh frequency Deep brain stimulation (DBS) targeting motor thalamus is an effective therapy for essential tremor (ET). However, conventional continuous stimulation may deliver unnecessary current to the brain since tremor mainly affects voluntary movements and sustained postures in ET.ObjectiveWe aim to decode both voluntary movements and the presence of postural tremor from the Local field potentials (LFPs) recorded from the electrode implanted in motor thalamus for stimulation, in order to close the loop for DBS so that stimulation could be delivered on demand, without the need for peripheral sensors or additional invasive electrodes.MethodsLFPs from the motor thalamus, surface electromyographic (EMG) signals and/or behavioural measurements were simultaneously recorded in seven ET patients during temporary lead externalisation 3–5 days after the first surgery for DBS when they performed different voluntary upper limb movements. Nine different patients were recorded during the surgery, when they were asked to lift their arms to trigger postural tremor. A machine learning based binary classifier was used to detect voluntary movements and postural tremor based on features extracted from thalamic LFPs.ResultsCross-validation demonstrated that both voluntary movements and postural tremor can be decoded with an average sensitivity of 0.8 and false detection rate of 0.2. Oscillatory activities in the beta frequency bands (13–23 Hz) and the theta frequency bands (4–7 Hz) contributed most to the decoding of movements and postural tremor, respectively, though incorporating features in different frequency bands using a machine learning approach increased the accuracy of decoding.     

Effects of ramped-frequency thalamic deep brain stimulation on tremor and activity of modeled neurons

ObjectiveWe conducted intraoperative measurements of tremor to quantify the effects of temporally patterned ramped-frequency DBS trains on tremor.MethodsSeven patterns of stimulation were tested in nine subjects with thalamic DBS for essential tremor: stimulation ‘off’, three ramped-frequency stimulation (RFS) trains from 130 → 50 Hz, 130 → 60 Hz, and 235 → 90 Hz, and three constant frequency stimulation (CFS) trains at 72, 82, and 130 Hz. The same patterns were applied to a computational model of the thalamic neural network.ResultsTemporally patterned 130 → 60 Hz ramped-frequency trains suppressed tremor relative to stimulation ‘off,’ but 130 → 50 Hz, 130 → 60 Hz, and 235 → 90 Hz ramped-frequency trains were no more effective than constant frequency stimulation with the same mean interpulse interval (IPI). Computational modeling revealed that rhythmic burst-driver inputs to thalamus were masked during DBS, but long IPIs, concurrent with pauses in afferent cerebellar and cortical firing, allowed propagation of bursting activity. The mean firing rate of bursting-type model neurons as well as the firing pattern entropy of model neurons were both strongly correlated with tremor power across stimulation conditions.ConclusionFrequency-ramped DBS produced equivalent tremor suppression as constant frequency thalamic DBS. Tremor-related thalamic burst activity may result from burst-driver input, rather than by an intrinsic rebound mechanism.SignificanceRamping stimulation frequency may exacerbate thalamic burst firing by introducing consecutive pauses of increasing duration to the stimulation pattern.     

Lower stimulation frequency can enhance tolerability and efficacy of pallidal deep brain stimulation for dystonia.

We report the case of a patient with medically refractory primary dystonia who was treated with bilateral pallidal deep brain stimulation. Stimulation at 130 Hz or higher, by means of the more ventral contacts generated capsular side effects, which made their use impractical. Consequently, the patient was treated for 9 months at 130 to 185 Hz, by means of the more dorsal contacts, achieving modest results. By reducing the stimulation frequency to 80 Hz, we were able to activate the ventral contacts without inducing side effects. Within days, the patient experienced a dramatic improvement in function that has persisted for 1 year. A further reduction in stimulation frequency to 60 Hz resulted in a worsening of his symptoms. We conclude that chronic stimulation at frequencies of <100 Hz may be efficacious in dystonia and may enhance the tolerability of stimulation by means of contacts that are positioned posteroventrally within the internal globus pallidus, nearer the internal capsule.     

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.     

Complete suppression of paroxysmal nonkinesigenic dyskinesia by globus pallidus internus pallidal stimulation.

Stereotactic functional surgery is being explored as potential therapies for medically intractable paroxysmal dyskinesias (PxD). We report on a 59-year-old man in whom stimulation of globus pallidus internus produced immediate and sustained relief of paroxysmal non-kinesigenic dyskinesia secondary to a rotator cuff tears on the left shoulder. Our finding strongly suggests that altered function of neuronal circuits of the basal ganglia underlies the manifestation of PxD.