Optimal deep brain stimulation sites and networks for cervical vs. generalized dystonia.

Dystonia is a debilitating disease with few treatment options. One effective option is deep brain stimulation (DBS) to the internal pallidum. While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations regarding optimal stimulation sites and potential network effects have not been carried out. Here, we retrospectively studied clinical results following DBS for cervical and generalized dystonia in a multicenter cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce an approach to map optimal stimulation sites to anatomical space. Second, we investigate which tracts account for optimal clinical improvements, when modulated. Third, we investigate distributed stimulation effects on a whole-brain functional connectome level. Our results show marked differences of optimal stimulation sites that map to the somatotopic structure of the internal pallidum. While modulation of the striatopallidofugal axis of the basal ganglia accounted for optimal treatment of cervical dystonia, modulation of pallidothalamic bundles did so in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in the form of connectivity to the cerebellum and somatomotor cortex. Our results suggest a brief divergence of optimal stimulation networks for cervical vs. generalized dystonia within the pallidothalamic loop that merge again on a thalamo-cortical level and share a common whole-brain network.

Deep brain stimulation: is it time to change gears by closing the loop?

Objective.Adaptive deep brain stimulation (aDBS) is a form of invasive stimulation that was conceived to overcome the technical limitations of traditional DBS, which delivers continuous stimulation of the target structure without considering patients' symptoms or status in real-time. Instead, aDBS delivers on-demand, contingency-based stimulation. So far, aDBS has been tested in several neurological conditions, and will be soon extensively studied to translate it into clinical practice. However, an exhaustive description of technical aspects is still missing.Approach.in this topical review, we summarize the knowledge about the current (and future) aDBS approach and control algorithms to deliver the stimulation, as reference for a deeper undestending of aDBS model.Main results.We discuss the conceptual and functional model of aDBS, which is based on the sensing module (that assesses the feedback variable), the control module (which interpretes the variable and elaborates the new stimulation parameters), and the stimulation module (that controls the delivery of stimulation), considering both the historical perspective and the state-of-the-art of available biomarkers.Significance.aDBS modulates neuronal circuits based on clinically relevant biofeedback signals in real-time. First developed in the mid-2000s, many groups have worked on improving closed-loop DBS technology. The field is now at a point in conducting large-scale randomized clinical trials to translate aDBS into clinical practice. As we move towards implanting brain-computer interfaces in patients, it will be important to understand the technical aspects of aDBS.

Electrical Stimulation of the Mesencephalic Locomotor Region Has No Impact on Blood-Brain Barrier Alterations after Cerebral Photothrombosis in Rats.

Blood-brain barrier (BBB) disruption is a critical event after ischemic stroke, which results in edema formation and hemorrhagic transformation of infarcted tissue. BBB dysfunction following stroke is partly mediated by proinflammatory agents. We recently have shown that high frequency stimulation of the mesencephalic locomotor region (MLR-HFS) exerts an antiapoptotic and anti-inflammatory effect in the border zone of cerebral photothrombotic stroke in rats. Whether MLR-HFS also has an impact on BBB dysfunction in the early stage of stroke is unknown. In this study, rats were subjected to photothrombotic stroke of the sensorimotor cortex and implantation of a stimulating microelectrode into the ipsilesional MLR. Thereafter, either HFS or sham stimulation of the MLR was applied for 24 h. After scarifying the rats, BBB disruption was assessed by determining albumin extravasation and tight junction integrity (claudin 3, claudin 5, and occludin) using Western blot analyses and immunohistochemistry. In addition, by applying zymography, expression of pro-metalloproteinase-9 (pro-MMP-9) was analyzed. No differences were found regarding infarct size and BBB dysfunction between stimulated and unstimulated animals 24 h after induction of stroke. Our results indicate that MLR-HFS neither improves nor worsens the damaged BBB after stroke. Attenuating cytokines/chemokines in the perilesional area, as mediated by MLR-HFS, tend to play a less significant role in preventing the BBB integrity.

Phase matters: A role for the subthalamic network during gait.

The role of the subthalamic nucleus in human locomotion is unclear although relevant, given the troublesome management of gait disturbances with subthalamic deep brain stimulation in patients with Parkinson's disease. We investigated the subthalamic activity and inter-hemispheric connectivity during walking in eight freely-moving subjects with Parkinson's disease and bilateral deep brain stimulation. In particular, we compared the subthalamic power spectral densities and coherence, amplitude cross-correlation and phase locking value between resting state, upright standing, and steady forward walking. We observed a phase locking value drop in the ß-frequency band (≈13-35Hz) during walking with respect to resting and standing. This modulation was not accompanied by specific changes in subthalamic power spectral densities, which was not related to gait phases or to striatal dopamine loss measured with [123I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane and single-photon computed tomography. We speculate that the subthalamic inter-hemispheric desynchronization in the ß-frequency band reflects the information processing of each body side separately, which may support linear walking. This study also suggests that in some cases (i.e. gait) the brain signal, which could allow feedback-controlled stimulation, might derive from network activity.

Progressive gait ataxia following deep brain stimulation for essential tremor: adverse effect or lack of efficacy?

Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar syndrome caused by a maladaptive response to neurostimulation of the (sub)thalamic area. The metabolic signature of progressive gait ataxia is an activation of the cerebellar nodule, which may be caused by inadvertent current spread and antidromic stimulation of a cerebellar outflow pathway originating in the vermis. An anatomical candidate could be the ascending limb of the uncinate tract in the subthalamic area. Adjustments in programming and precise placement of the electrode may prevent this adverse effect and help fine-tuning deep brain stimulation to ameliorate tremor without negative cerebellar signs.

Differential effect of dopa and subthalamic stimulation on vestibular activity in Parkinson's disease.

Postural disturbances in advanced Parkinson's disease are less responsive to therapy than other cardinal motor signs. The vestibulocollic reflex represents one brain-stem neuronal circuit involved in postural adjustments. The objective of this study was to investigate the vestibulocollic reflex in parkinsonian patients and the effects of subthalamic stimulation and dopa by recording vestibular-evoked myogenic potentials. After overnight withdrawal of medication, 20 patients with Parkinson's disease with (6 men, 4 women; mean age, 64.4 ± 2.2 years) or without (8 men, 2 women; mean age, 62.7 ± 3.9 years) implanted subthalamic electrodes in different treatment conditions were compared with 10 age-matched controls (5 men, 5 women; mean age, 59.6 ± 2.4 years). Vestibular-evoked myogenic potentials were recorded by electromyographic surface electrodes applied to both sternocleidomastoid muscles (band-pass filter, 8-1600 Hz; sampling rate, 5 kHz) and averaged in response to bilateral auditory tone bursts (120 dB SPL; sine waves, 7 ms; 1000 Hz) applied through earphones. Adjusted vestibular-evoked myogenic potential amplitudes were significantly smaller in parkinsonian patients than in controls, in particular in patients without surgery. Administration of dopa, but not subthalamic stimulation, significantly increased amplitudes. Onset latencies were similar for all groups and treatment conditions. Decreased vestibular-evoked myogenic potential amplitudes in parkinsonian patients suggest reduced vestibular nuclei excitability within the brain stem, which is modulated by dopa but not by subthalamic stimulation. This suggests different pathways for the action of both treatment modalities in Parkinson's disease and may explain clinical differences in terms of postural disturbances. © 2012 Movement Disorder Society.

Lower limb joints kinematics in essential tremor and the effect of thalamic stimulation.

Following the hypothesis that thalamic deep brain stimulation improves ataxia in patients with essential tremor by modulating the cerebello-thalamo-cortical pathway, we examined the joint kinematics of lower limbs during uninterrupted gait in eleven patients who have been treated with bilateral thalamic stimulation for 24.7±20.3 months. Patients were assessed under routine chronic stimulation, supra-therapeutic amplitude, and off stimulation by means of an infrared movement analysis system while walking on a treadmill. Chronic thalamic DBS normalized the highly variable excursion throughout the gait cycle that characterized the subgroup of patients with longest disease duration. Supratherapeutic thalamic DBS amplitude did not reproduce such improvements while, more importantly, it induced ataxic changes of joint excursion. The normalization of kinematic abnormalities argues against the hypothesis of a cerebellar neurodegeneration in ET. Moreover, these results suggest that the beneficial effect of thalamic DBS on ataxic symptoms is limited to a narrow therapeutic window.

Gait ataxia in essential tremor is differentially modulated by thalamic stimulation.

Patients with advanced stages of essential tremor frequently exhibit tandem gait ataxia with impaired balance control and imprecise foot placement, resembling patients with a cerebellar deficit. Thalamic deep brain stimulation, a surgical therapy for otherwise intractable cases, has been shown to improve tremor, but its impact on cerebellar-like gait difficulties remains to be elucidated. Eleven patients affected by essential tremor (five females; age 69.8 ± 3.9 years; disease duration 24.4 ± 11.2 years; follow-up after surgery 24.7 ± 20.3 months) were evaluated during the following conditions: stimulation off, stimulation on and supra-therapeutic stimulation. Ten age-matched healthy controls served as the comparison group. Locomotion by patients and controls was assessed with (i) overground gait and tandem gait; (ii) balance-assisted treadmill tandem gait and (iii) unassisted treadmill gait. The two treadmill paradigms were kinematically analysed using a 3D opto-electronic motion analysis system. Established clinical and kinesiological measures of ataxia were computed. During stimulation off, the patients exhibited ataxia in all assessment paradigms, which improved during stimulation on and worsened again during supra-therapeutic stimulation. During over ground tandem gait, patients had more missteps and slower gait velocities during stimulation off and supra-therapeutic stimulation than during stimulation on. During balance-assisted tandem gait, stimulation on reduced the temporospatial variability in foot trajectories to nearly normal values, while highly variable (ataxic) foot trajectories were observed during stimulation off and supra-therapeutic stimulation. During unassisted treadmill gait, stimulation on improved gait stability compared with stimulation off and supra-therapeutic stimulation, as demonstrated by increased gait velocity and ankle rotation. These improvements in ataxia were not a function of reduced tremor in the lower limbs or torso. In conclusion, we demonstrate the impact of thalamic stimulation on gait ataxia in patients with essential tremor with improvement by stimulation on and deterioration by supra-therapeutic stimulation, despite continued control of tremor. Thus, cerebellar dysfunction in these patients can be differentially modulated with optimal versus supra-therapeutic stimulation. The cerebellar movement disorder of essential tremor is due to a typical cerebellar deficit, not to trembling extremities. We hypothesize that deep brain stimulation affects two major regulating circuits: the cortico-thalamo-cortical loop for tremor reduction and the cerebello-thalamo-cortical pathway for ataxia reduction (stimulation on) and ataxia induction (supra-therapeutic stimulation).

Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor.

Deep brain stimulation of the thalamus (thalamic DBS) is an established therapy for medically intractable essential tremor and tremor caused by multiple sclerosis. In both disorders, motor disability results from complex interaction between kinetic tremor and accompanying ataxia with voluntary movements. In clinical studies, the efficacy of thalamic DBS has been thoroughly assessed. However, the optimal anatomical target structure for neurostimulation is still debated and has never been analysed in conjunction with objective measurements of the different aspects of motor impairment. In 10 essential tremor and 11 multiple sclerosis patients, we analysed the effect of thalamic DBS through each contact of the quadripolar electrode on the contralateral tremor rating scale, accelerometry and kinematic measures of reach-to-grasp-movements. These measures were correlated with the anatomical position of the stimulating electrode in stereotactic space and in relation to nuclear boundaries derived from intraoperative microrecording. We found a significant impact of the stereotactic z-coordinate of stimulation contacts on the TRS, accelerometry total power and spatial deviation in the deceleration and target period of reach-to-grasp-movements. Most effective contacts clustered within the subthalamic area (STA) covering the posterior Zona incerta and prelemniscal radiation. Stimulation within this region led to a mean reduction of the lateralized tremor rating scale by 15.8 points which was significantly superior to stimulation within the thalamus (P < 0.05, student's t-test). STA stimulation resulted in reduction of the accelerometry total power by 99%, whereas stimulation at the ventral thalamic border (68%) or within the thalamus proper (2.5%) was significantly less effective (P < 0.01). Concomitantly, STA stimulation led to a significantly higher increase of tremor frequency and decrease in EMG synchronization compared to stimulation within the thalamus proper (P < 0.001). In reach-to-grasp movements, STA stimulation reduced the spatial variability of the movement path in the deceleration period by 28.9% and in the target period by 58.4%, whereas stimulation within the thalamus was again significantly less effective (P < 0.05), with a reduction in the deceleration period between 6.5 and 21.8% and in the target period between 1.2 and 11.3%. An analysis of the nuclear boundaries from intraoperative microrecording confirmed the anatomical impression that most effective electrodes were located within the STA. Our data demonstrate a profound effect of deep brain stimulation of the thalamic region on tremor and ataxia in essential tremor and tremor caused by multiple sclerosis. The better efficacy of stimulation within the STA compared to thalamus proper favours the concept of a modulation of cerebello-thalamic projections underlying the improvement of these symptoms.

Basic algorithms for the programming of deep brain stimulation in Parkinson's disease.

The clinical success of deep brain stimulation (DBS) for treating Parkinson's disease (PD) critically depends on the quality of postoperative neurological management. Movement disorder specialists becoming involved with this therapy need to acquire new skills to adapt optimally stimulation parameters and medication after implantation of a DBS system. At first glance, the infinite number of theoretically possible parameter combinations seems to make programming a complex and time-consuming art. This article outlines a stepwise and standardized approach, reducing the possible parameter settings in DBS to a few relevant combinations. The basic programming algorithms for thalamic, subthalamic, and pallidal stimulation in PD are explained and summarized in flowcharts.

Most effective stimulation site in subthalamic deep brain stimulation for Parkinson's disease.

The optimal stimulation site in subthalamic deep brain stimulation (STN-DBS) was evaluated by correlation of the stereotactic position of the stimulation electrode with the electrophysiologically specified dorsal STN border. In a series of 25 electrodes, best clinical results with least energy consumption were found in contacts located in the dorsolateral border zone, whereas contacts within the subthalamic white matter, e.g., zona incerta, were significantly less effective. We suggest that the dorsolateral STN border should be covered by STN-DBS.

Long-term results of bilateral pallidal stimulation in Parkinson's disease.

We followed up 11 patients for up to 5 years after bilateral pallidal deep brain stimulation for advanced Parkinson's disease. Dyskinesias remained significantly reduced until the last assessment. The initial improvement of off-period motor symptoms and fluctuations, however, was not sustained and gradually declined. Beneficial effects of pallidal deep brain stimulation on activities of daily living in the on- and off-period were lost after the first year. Replacement of pallidal electrodes into the subthalamic nucleus in four patients could restore the initial benefit of deep brain stimulation and allowed a significant reduction of dopaminergic drug therapy.

Deep brain stimulation for the treatment of Parkinson's disease.

Deep brain stimulation (DBS) is increasingly accepted as an adjunct therapy for Parkinson's disease (PD). It is considered a surgical treatment alternative for patients with intractable tremor or for those patients who are affected by long-term complications of levodopa therapy such as motor fluctuations and severe dyskinesias. Thalamic stimulation in the ventral intermediate nucleus (Vim) leads to a marked reduction of contralateral tremor but has no beneficial effect on other symptoms of Parkinson's disease. The subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) are targeted for the treatment of advanced Parkinson's disease. Several studies have proven the efficacy of STN-DBS and GPi-DBS in alleviating off motor symptoms and dyskinesias. Sub-thalamic nucleus deep brain stimulation is currently considered superior to GPi-DBS because the antiakinetic effect seems to be more pronounced, allows a more marked reduction of antiparkinsonian medication, and requires less stimulation energy. More recently, however, a number of reports on possible psychiatric and behavioral side effects of STN-DBS have been a matter of concern. Given the chronic nature of PD and the noncurative approach of DBS, both targets will need to be reevaluated on the basis of their long-term efficacy and their impact on quality of life. Despite the rapidly increasing numbers of DBS procedures, surprisingly few controlled clinical trials are available that address important clinical issues such as: When should DBS be applied during the course of disease? Which patients should be selected? Which target should be considered? Which guidelines should be followed during postoperative care? Here is summarized the available evidence on DBS as a therapeutic tool for the treatment of Parkinson's disease and the current state of debate on open issues.

Effect of subthalamic deep brain stimulation on the function of the urinary bladder.

Detrusor hyperreflexia is a relevant clinical symptom for patients suffering from Parkinson's disease. In a series of 16 patients, we demonstrated that subthalamic deep brain stimulation has a significant and urodynamically recordable effect leading to a normalization of pathologically increased bladder sensibility.

Deep brain stimulation of the subthalamic nucleus enhances emotional processing in Parkinson disease.

BACKGROUND: High-frequency electrical stimulation of the subthalamic nucleus is a new and highly effective therapy for complications of long-term levodopa therapy and motor symptoms in advanced Parkinson disease (PD). Clinical observations indicate additional influence on emotional behavior. METHODS: Electrical stimulation of deep brain nuclei with pulse rates above 100 Hz provokes a reversible, lesioning-like effect. Here, the effect of deep brain stimulation of the subthalamic nucleus on emotional, cognitive, and motor performance in patients with PD (n = 12) was examined. The results were compared with the effects of a suprathreshold dose of levodopa intended to transiently restore striatal dopamine deficiency. Patients were tested during medication off/stimulation off (STIM OFF), medication off/stimulation on (STIM ON), and during the best motor state after taking levodopa without deep brain stimulation (MED). RESULTS: More positive self-reported mood and an enhanced mood induction effect as well as improvement in emotional memory during STIM ON were observed, while during STIM OFF, patients revealed reduced emotional performance. Comparable effects were revealed by STIM ON and MED. Cognitive performance was not affected by the different conditions and treatments. CONCLUSIONS: Deep brain stimulation of the subthalamic nucleus selectively enhanced affective processing and subjective well-being and seemed to be antidepressive. Levodopa and deep brain stimulation had similar effects on emotion. This finding may provide new clues about the neurobiologic bases of emotion and mood disorders, and it illustrates the important role of the basal ganglia and the dopaminergic system in emotional processing in addition to the well-known motor and cognitive functions.

Deep brain stimulation for dystonia: patient selection and evaluation.

Deep brain stimulation (DBS) for dystonia still needs to be considered investigational, because there are no controlled studies for this indication, the optimal target point is uncertain, and long-term effects are unknown. The striking improvement of levodopa-induced dyskinesias in Parkinson's disease by deep brain stimulation of the internal pallidum has encouraged the use of this therapy for generalized and severe segmental dystonia in children and adults. Single case and small cohort studies have reported impressive efficacy of pallidal DBS in patients with primary dystonia, especially DYT1 mutation carriers, but results in secondary dystonia are less conclusive. This article discusses the different factors influencing patient selection for surgical treatment and describes standardized methods and the caveats for clinical documentation of treatment results in dystonia.

Introduction to the programming of deep brain stimulators.

The clinical success of deep brain stimulation (DBS) for treating Parkinson's disease, tremor, or dystonia critically depends on the quality of postoperative neurologic management. Movement disorder specialists becoming involved with this therapy need to acquire new skills to optimally adapt stimulation parameters and medication after implantation of a DBS system. In clinical practice, the infinite number of possible parameter settings in DBS can be reduced to few relevant combinations. In this article, the authors describe a general scheme of selecting stimulation parameters in DBS and provide clinical and neurophysiological arguments for such a standardized algorithm. They also describe noninvasive technical trouble shooting by using programming features of the commercially available neurostimulation devices.

Bilateral high-frequency stimulation in the subthalamic nucleus for the treatment of Parkinson disease: correlation of therapeutic effect with anatomical electrode position.

OBJECT: The goal of this study was to relate the degree of clinical improvement and that of energy consumption to the anatomical position of electrode poles used for long-term stimulation. METHODS: The authors conducted a retrospective analysis of 15 consecutive patients in whom targeting of the subthalamic nucleus (STN) had been performed using ventriculography, three-dimensional (3D) magnetic resonance (MR) imaging, and 3D computerized tomography, together with macrostimulation and teleradiographic control of the electrode position. In these patients the follow-up period ranged from 6 to 12 months. Postoperative improvement in contralateral motor symptoms, which was assessed by assigning a lateralized motor subscore of the Unified Parkinson's Disease Rating Scale (UPDRS), and stimulus intensity required for optimal treatment results were correlated with the intracerebral position of the active electrode pole. Bilateral high-frequency stimulation of the STN improved the UPDRS motor score during the medication-off period by an average of 60.5% compared with that at baseline. Repeated transfer of stereotactic coordinates from postoperative teleradiography to treatment-planning MR images documented the proper localization of the most distal electrode pole (pole 0) in the targeted STN. Nevertheless, in most cases the best clinical improvement was achieved using electrode poles that were located several millimeters above the electrode tip. If the relative improvement in motor symptoms was correlated with the required electrical energy for chronic stimulation, the best coefficient was observed for active electrode poles projecting onto white matter dorsal to the STN. CONCLUSIONS: This observation makes blocking or activation of large fiber connections arising in the STN or running nearby more likely than electrical interference with cell bodies inside the STN. Anatomical correlates may be the pallidothalamic bundle (including Field H of Forel and the thalamic fascicle), the pallidosubthalamic tract, and/or the zona incerta.