History, Applications, and Mechanisms of Deep Brain Stimulation

NEUROLOGICAL REVIEW

SECTION EDITOR: DAVID E. PLEASURE, MD History, Applications, and Mechanisms of Deep Brain Stimulation

Svjetlana Miocinovic, MD, PhD; Suvarchala Somayajula, MD; Shilpa Chitnis, MD, PhD; Jerrold L. Vitek, MD, PhD

eep brain stimulation (DBS) is an effective surgical treatment for medication-refractory hypokinetic and hyperkinetic movement disorders, and it is being explored for a variety of other neurological and psychiatric diseases. Deep brain stimulation has been Food and Drug Administration–approved for essential tremor and Parkinson disease and has Da humanitarian device exemption for dystonia and obsessive-compulsive disorder. Neurostimulation is the fruit of decades of both technical and scientific advances in the field of basic neuroscience and functional neurosurgery. Despite the clinical success of DBS, the therapeutic mechanism of DBS remains under debate. Our objective is to provide a comprehensive review of DBS focusing on movement disorders, including the historical evolution of the technique, applications and outcomes with an overview of the most pertinent literature, current views on mechanisms of stimulation, and de- scription of hardware and programming techniques. We conclude with a discussion of future developments in neurostimulation. JAMA Neurol. 2013;70(2):163-171. Published online November 12, 2012. doi:10.1001/2013.jamaneurol.45

Deep brain stimulation (DBS) has evolved recovery.1-4 New applications continue to as an important therapy for the treat- emerge, encouraged by past successes and ment of essential tremor, Parkinson dis- the fact that DBS effects are reversible al- ease (PD), and dystonia, and it is also lowing exploration of new targets and ap- emerging for the treatment of medication- plications not previously possible with le- refractory psychiatric disease. Food and sion surgery. The history of DBS is a Drug Administration approval was granted fascinating example of the interplay be- in 1997 for thalamic DBS for essential tween basic and clinical research. It is the tremor and PD-related tremor, followed in coming together of these 2 arenas that has 2003 by approval for subthalamic nucleus led to the evolution of DBS for the treat- (STN) and globus pallidus internus (GPi) ment of disease as it is used today and will DBS for PD. A humanitarian device ex- be used tomorrow. Table 1 summarizes emption for STN DBS and GPi DBS for milestones in the evolution of surgical primary generalized and segmental dys- therapy for movement disorders. tonia was granted in 2003 and for obsessive-compulsive disorder, in 2009. Deep CURRENT APPLICATIONS brain stimulation has also been used suc- AND OUTCOMES cessfully in the treatment of Tourette syndrome, depression, and epilepsy, and there Tremor are case reports of using DBS for the treatment of headache, pain, vegetative state, Deep brain stimulation is an attractive al- addiction, obesity, dementia, and stroke ternative to surgery for the management of tremor. Surgical ablation of the ventral Author Affiliations: Department of Neurology and Neurotherapeutics, University intermediate nucleus of the thalamus has of Texas Southwestern Medical Center, Dallas (Drs Miocinovic and Chitnis); and been used as a therapy for tremor since the Department of Neurology, University of Minnesota, Minneapolis (Drs Somayajula 1950s.8 However, bilateral thalamotomy and Vitek). is not well tolerated because of the risk of

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©2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Parkinson Disease Table 1. Evolution of Surgical Therapy for Movement Disorders One of the primary clinical uses of DBS is for the treatment of PD. A robust motor response to levodopa is gen- 1890 Horsley5 performed extirpation of the motor cortex for treatment of athetosis. erally considered a prerequisite for successful DBS out- 1947 Spiegel et al6 described a stereotactic frame. come in PD (except for tremor-predominant PD), and 1950 Spiegel et al7 made lesions in patients with PD to stimulation may be considered once patients develop dis- interrupt pallidofugal fibers causing improvement in abling motor fluctuations and dyskinesias while receiv- bradykinesia, rigidity, and tremor. ing medical therapy. Although thalamic stimulation has 8 9 1950s Hassler and Riechert and Talairach et al treated been effective in controlling parkinsonian tremor, the lack parkinsonism with lesions in the VL thalamic nucleus. Cooper10 attempted to section the cerebral peduncle of a reliable effect on other motor symptoms has limited but inadvertently interrupted the anterior choroidal thalamic DBS for the treatment of PD.45,46 Today, the STN artery and was forced to ligate it, leading to and GPi are the most commonly used targets in PD.20,21 disappearance of rigidity and tremor with preserved Electrode placement in the STN was initially favored be- motor and sensory function. 1963 Albe Fessard et al11 reported that stimulation in the area cause of reports that it yielded greater improvement in of the ventrointermediate nucleus of the thalamus at motor scores and a greater reduction in antiparkinso- frequencies of 100-200 Hz improved tremor in nian mediations compared with placement in the GPi.27,47 patients with parkinsonism. Additional studies have shown that GPi DBS also signifi- 1969 Levodopa was introduced, parkinsonian symptoms were 12 cantly improved the cardinal motor symptoms, drug- improved, and stereotactic surgery fell out of favor. 23,24,32,39 1987 Benabid and colleagues13 heralded the modern era of induced dyskinesia, and motor fluctuations. Al- DBS through their publication of thalamic DBS though STN remains the preferred target, GPi can be contralateral to thalamotomy in patients with tremor. considered in patients who have speech, cognitive, and 1989-1990 Albin et al14 and DeLong15 introduced a model of basal mood disturbances, as STN DBS can sometimes worsen ganglia function based on the hypothesis that there these symptoms.32,39 were segregated circuits within the basal ganglia thalamocortical network, each serving a different Studies of DBS for PD have reported significant im- function. provement in cardinal motor signs, including tremor, bra- 1992 Laitinen and colleagues16 reintroduced the Leksell dykinesia, and rigidity, with variable response in medi- pallidotomy technique for patients with advanced PD cation-refractory gait freezing, postural instability, and along with severe adverse effects from levodopa gait mechanics (Table 2). Marked benefits in improve- therapy. 1998 Documentation of safety and efficacy of bilateral STN ment of levodopa-related complications such as drug- DBS by Limousin et al,17 including its potential for induced dyskinesia, motor fluctuations, and off-period reducing the dose of dopaminergic medications in dystonia have also been demonstrated.29 Adverse effects patients with advanced PD. are typically transient and reversible.17,39 Additional limi- 18 2000 Coubes et al presented data for GPi DBS in treatment tations of DBS therapy that need to be considered prior of dystonia. to surgery include risk of hemorrhage or infection, risk Abbreviations: DBS, deep brain stimulation; GPi, globus pallidus internus; of mechanical failure (now much less common as both PD, Parkinson disease; STN, subthalamic nucleus; VL, ventrolateral. physicians and manufacturers develop more familiarity with the device), frequent follow-up visits, and cost of speech and swallowing deficits. Thalamic DBS has been the device and battery replacements. shown to be efficacious in the treatment of essential and parkinsonian tremor, with excellent long-term out- Dystonia comes and an acceptable adverse effect profile (Table 2). The main adverse effects of the stimulation Deep brain stimulation has also been useful for treat- are paresthesias, headache, dysarthria, paresis, gait dis- ment of primary dystonia. Renewed interest in pal- turbance, and ataxia.40 Adverse effects are usually mild lidotomy for PD in the early 1990s and the observation and effectively managed by stimulation parameter ad- that it improved dystonic symptoms in PD led to the pro- justment. Deep brain stimulation and thalamotomy posal of using pallidotomy for patients with primary gen- have also been used with less success in the treatment of eralized dystonia.48,49 Given concerns about bilateral GPi action tremor. This type of tremor typically occurs in lesions causing speech and cognitive deficits as seen in patients with multiple sclerosis, trauma, or stroke that PD, it was not long before GPi DBS was being explored leads to interruption of cerebellar outflow pathways for the treatment of primary generalized dystonia, some- and has a more complex pathophysiology.41 Clinical times with remarkable outcomes.18,25,50,51 Unlike tremor improvement in these patients is often short lived and, and PD, there is typically a gradually increasing clinical in the case of multiple sclerosis, complicated by disease response to stimulation over weeks to months of therapy. progression.42,43 Although treatment for tremor targets Efficacy of DBS in primary generalized and segmental dys- the ventral intermediate nucleus, several studies have tonia has been well documented35 (Table 2). There has suggested that the posterior subthalamic area is a better been no difference in outcomes based on DYT1 gene sta- location and that patients may be incidentally benefit- tus,31 but shorter disease duration has been reported to ing from electrode contacts located outside of the thala- lead to better results.52,53 Intractable cervical dystonia has mus.44 Overall, DBS for essential and parkinsonian also shown improvement in several smaller case se- tremor has been successful, while treatment of other ries.37 Secondary dystonia is a set of heterogeneous dis- causes of tremor has been more limited. orders, and their response to stimulation is more vari-

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Year Tremor PD Dystonia 1987 Vim DBS decreased tremor almost as well as thalamotomy. Optimal stimulation frequency was about 200 Hz but stimulator capabilities were limited to 130 Hz at the time.13 1991 Bilateral Vim stimulation was well tolerated and resulted in complete or almost complete tremor suppression in PD and ET.19 1993 First report of STN DBS in a patient with PD.20 1994 First use of GPi DBS in PD.21 1998 First open-label trial of bilateral STN DBS showing about 60% improvements in motor scores and dyskinesias.17 First blinded evaluation of STN DBS yielded similar results.22 Retrospective review showing greater motor improvement with STN DBS compared with GPi DBS.23 1999 Randomized comparison of STN and GPi DBS First case report of GPi DBS for dystonia showed similar improvement in both groups.24 resulting in a dramatic improvement.25 2000 GPi DBS was effective in treating DYT1 primary generalized dystonia.18 2001 Vim DBS provided long-term efficacy in In a large prospective, double-blind study, STN DBS ET, but device-related complications was associated with greater benefit compared were common.26 with GPi DBS (49% vs 37% motor score reduction); however, target sites were not randomized.27 2003 Multicenter trial showing persistent First long-term follow-up study of STN DBS showing In a small study, GPi DBS effectively treated suppression (approximately 50%) at about 50% improvement in motor and activities of generalized non-DYT1 dystonia.30 6 y in patients with essential tremor daily living scores at 5 y.29 with Vim DBS.28 2004 Efficacy of GPi DBS was equal in DYT1-positive and DYT1-negative patients, but improvement was greater in children than adults.31 2005 Randomized, blinded study showed both STN and Double-blinded evaluation of GPi DBS GPi DBS provided similar motor improvement, resulted in about 50% improvement in but cognitive and behavioral complications were dystonia score.33 seen only in STN DBS.32 2006 First randomized comparison demonstrating First randomized, double-blind, superiority of STN DBS over medical management sham-controlled trial of GPi DBS in in patients with advanced PD and primary segmental or generalized levodopa-related motor complications.34 dystonia.35 2007 Long-term Vim DBS showed persistent Single-blind study of GPi DBS in cervical efficacy in ET, although action dystonia resulted in about 40% component of tremor could improvement.37 reemerge.36 2009 Randomized trial showing no major differences in GPi DBS had variable effect on mood and cognition between STN and GPi DBS.23 dystonia-choreoathetosis in cerebral palsy.38 2010 Large randomized study of STN vs GPi DBS showed both targets provided similar improvement in motor function (25% and 28%, respectively), but smaller than seen in other studies.39

Abbreviations: DBS, deep brain stimulation; ET, essential tremor; GPi, globus pallidus internus; PD, Parkinson disease; STN, subthalamic nucleus; Vim, ventral intermediate nucleus.

able. For example, tardive dyskinesias typically respond orders, the mechanism of action underlying the thera- well,53,54 whereas dystonias due to encephalitis and birth peutic effectiveness of DBS continues to be debated. injury fare worse.55 The earliest hypotheses on DBS mechanisms attempted to reconcile the similarity in clinical outcome MECHANISMS OF DBS after a lesion and during DBS by proposing that high- frequency stimulation inhibited neurons and decreased Although an effective surgical therapy for medication- output from the stimulated site. Inhibition of activity was refractory hypokinetic and hyperkinetic movement dis- initially observed in rat STN DBS,56 and similar findings

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©2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 cell bodies through activation of the inhibitory synaptic Normal Parkinson disease terminals, and this effect was dependent on the distance 68 Cortex Cortex from the electrode. When a neuron is exposed to extracellular stimulation, the stimulation-induced action Putamen Putamen potential initiates in the axon rather than the cell body, D2 D1 D2 D1 in which case inhibition of the cell body can occur co-

Indirect Direct Indirect Direct incident with axonal activation. Experimental and pathway SNc pathway pathway SNc pathway modeling studies noted that axonal response was time- locked to the stimulus leading to a regularization of GPe GPe neuronal activity.61,68 These data led to the hypothesis that DBS exerts its Thal Thal therapeutic effects by overriding the irregular, pathological activity from the stimulation target and replac- STN STN ing it with a stimulus-induced regular pattern. This effect spreads downstream through the entire basal ganglia 61 GPi/SNr GPi/SNr thalamocortical network. For example, STN DBS af- Brainstem Brainstem fects not only pallidal activity but also causes neurons and spinal cord and spinal cord in the pallidal- and cerebellar-receiving areas in the thalamus to become more periodic and regular.69 In the same Excitatory Inhibitory way, GPi DBS induces changes in the firing pattern of the motor cortex.70 Parkinson disease is also character- Figure 1. Basal ganglia-thalamo-cortical circuit schematic in the normal and ized by the development of rhythmic, oscillatory activ- parkinsonian states. Thickness of the arrows indicates strength of the ity within the basal ganglia predominantly in the 15- to connections. Loss of substantia nigra neurons leads to increased thalamic 30-Hz (beta) range.71 Treatment with levodopa attenu- inhibition. The diagram does not account for firing pattern and oscillatory 72 activity, both of which are important factors in understanding the effects of ates these low-frequency oscillations. Similarly, STN DBS

deep brain stimulation on the network. D1 and D2 indicate postsynaptic shifts pallidal and thalamic oscillatory activity from low dopamine receptor type; GPe, globus pallidus externus; GPi, globus pallidus to high frequencies.69,73 internus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; and Thal, thalamus. The stimulus-induced tonic high-frequency firing pattern was hypothesized to be devoid of informational content and results in an “informational lesion,” pre- were replicated in humans and monkeys with either STN venting the pathological activity from being transmitted or GPi stimulation.57-59 Activation of presynaptic inhibi- within the basal ganglia.74 More recent studies, how- tory afferents to the stimulated site was hypothesized to ever, suggest that information processing is enhanced be the underlying mechanism for the observed inhibi- and DBS is associated with improved information con- tion. One study on thalamic DBS has shown that tha- tent in the network.75,76 Modeling studies have shown lamic neurons that receive predominantly excitatory af- that DBS-induced regularization of basal ganglia input ferents can be excited by stimulation.60 into the thalamus restores the responsiveness of thala- At the same time, studies that recorded neuronal ac- mocortical cells to the incoming sensorimotor informa- tivity in the downstream nuclei showed an increase in tion, resulting in improved motor function.76,77 While overall firing, suggesting that output from the stimu- this theory provides a framework to begin understand- lated nucleus was, in fact, increased. Hashimoto et al61 ing the mechanisms of DBS, PD symptoms respond to applied STN DBS in parkinsonian monkeys and re- stimulation at different latencies so more than 1 mecha- corded increased activity in the GPi and external globus nism is likely responsible for the overall therapeutic pallidus, both of which receive excitatory glutamatergic benefit. afferents from the STN (Figure 1). Similar findings were Although the initial focus had been on the direct seen with inhibitory efferents; GPi stimulation inhib- effects on the stimulated target, more recent work has ited thalamic neurons in normal monkeys62 and pa- suggested that activation of adjacent fiber tracts sur- tients with dystonia,63 and external globus pallidus stimu- rounding or running through the stimulated site may lation inhibited STN neurons.64 In addition, human also contribute to the observed clinical effects. Stimula- positron emission tomography studies showed an in- tion of the STN can activate nigrostriatal (increasing crease in blood flow in the region of the GPi during STN release of dopamine), pallidothalamic, cerebellotha- DBS65 and an increase in cortical blood flow during thalamic, and pallidonigral fiber tracts, all of which could lamic DBS, both consistent with activation of output from contribute to the therapeutic effects of DBS.75 One the stimulated site.66 Similarly, a functional magnetic reso- example is the reported beneficial effect of STN DBS on nance imaging study found an increase in blood oxygen essential tremor as a result of activation of cerebellotha- level–dependent signal in the GPi of patients undergo- lamic fiber pathways that pass just posterior and ventral ing STN DBS.67 to the STN.78,79 This also explains why cerebellar- Inhibition of firing in the stimulated nucleus with a receiving areas of the thalamus can be modulated by simultaneous increase in activity in the downstream STN stimulation.69 structures presented an apparent paradox. Modeling In summary, DBS increases output from the stimu- studies suggested that extracellular electrical stimula- lated nucleus and activates surrounding fiber path- tion directly activated the axons while suppressing the ways resulting in a complex pattern of excitatory and

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©2013 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 inhibitory effects that modulate the entire basal gan- tain precautions, or alternatively, preoperative mag- glia thalamocortical network. The stimulation-induced netic resonance imaging can be fused with postopera- regularization of neuronal patterns prevents transmis- tive computed tomography.82 Stimulation targets have sion of pathologic bursting and oscillatory activity been derived from prior clinical experience, which in- within the network, resulting in improved processing corporates evolving understanding of the DBS mecha- of sensorimotor information and reduction of disease nisms. For example, in the case of STN stimulation for symptoms. PD, the optimal stimulation target is thought to be the dorsal area of the STN that borders the lenticular fas- DBS HARDWARE ciculus carrying pallidothalamic and nigrostriatal effer- AND PROGRAMMING ent fibers.83,84 Detailed biophysical computational models can then be used to calculate the electric field induced Electrodes and Pulse Generators by the DBS electrode and predict its effect on the surrounding neurons. These predictions can subsequently A DBS system is composed of 1 or more electrode leads be used to derive stimulation parameters that will pro- implanted in the brain parenchyma and extension wires vide maximum activation of the target area while mini- tunneled underneath the skin to an implanted pulse mizing spread of stimulation to the surrounding areas.85 generator (IPG) positioned below the collar bone. The Even though computationally intensive, model-derived Medtronic Inc electrode is a flexible urethane 1.27-mm- parameters have shown to be superior to traditionally de- diameter cylinder with 4 platinum/iridium contacts at rived parameters and would presumably minimize the the distal end. The IPG is a battery-powered device, amount of patient time spent in programming ses- about the size of a half a deck of cards, that sends a con- sions86 (Figure 2). tinuous electric signal to the brain at a set amplitude, When therapeutic target sites are near areas causing pulse width, and frequency. Traditional IPGs were volt- adverse effects, it is necessary to sculpt the electric field age controlled, meaning the stimulation amplitude was or steer the flow of current in a desired direction to set in volts and the amount of current delivered to the achieve the optimal stimulation. At present, this goal is brain tissue would depend on electrode impedance, most commonly achieved by choosing either monopo- which can vary because of electrochemical changes oc- lar or bipolar stimulation and using various combina- curring at the electrode-brain interface.80 Since the tions of active contacts.87 In monopolar stimulation, the amount of current delivered determines the volume of active contact is set as the negative pole, or cathode, and brain tissue stimulated, the clinical effects of stimula- the IPG case is set as the positive pole, or anode. This tion could theoretically be variable when using voltage- creates a wide electric field with relatively equal spread controlled stimulation. The latest IPG from Medtronic of stimulation in all directions. In bipolar stimulation, (Activa PC) offers a current-controlled stimulation another electrode contact serves as the anode, minimiz- mode, and several other companies are in the process of ing the spread of current and yielding a narrower area of bringing current-controlled stimulation systems to the stimulation. Various combinations of active contacts US market. A recently completed clinical trial demon- can be used to direct current flow through desired tar- strated comparable outcomes with current-controlled get areas.88 Additionally, novel electrode designs can DBS.81 provide more freedom in sculpting the area of activation. Compared with circumferential cylindrical con- Programming Parameters tacts, segmented electrode arrays can be used to steer current and preferentially activate tissue along only 1 Selecting appropriate patients and implanting hardware side of the DBS lead89 (Figure 3). This feature would are only first steps toward successful DBS therapy. Pro- be especially useful in cases of suboptimal electrode gramming refers to the process of selecting the most ap- placement. Another stimulation technique that is al- propriate stimulation parameters to provide the patient ready available in clinically approved IPGs is pulse in- with maximum therapeutic benefit while minimizing ad- terleaving, which allows rapid switching between 2 sets verse effects. Finding the optimal electrode contact, stimu- of parameters and electrode contacts. This can be par- lus amplitude, pulse width, and frequency has tradition- ticularly useful in cases where stimulation at 1 contact ally been a process of trial and error. After withholding cannot alleviate all symptoms and simultaneous stimu- the patient’s medication, the medical provider goes lation with equal amplitudes at multiple contacts in- through the arduous process of trying out each elec- duces adverse effects.90,91 trode contact and various combinations of stimulation parameters while subjectively assessing the clinical ben- FUTURE DEVELOPMENTS efit and degree of adverse effects. Novel computational techniques can make program- Programming ming a more efficient process. Computer models have been used to determine optimal stimulation parameters Deep brain stimulation programming, whether done as based on the precise electrode location, the desired stimu- a trial-and-error procedure or computer model target- lation target, and the estimated spread of current through ing of predefined therapeutic volumes, relies on a sub- the brain tissue.70 The electrode location can be deter- jective evaluation of clinical benefit during program- mined with postoperative magnetic resonance imaging, ming sessions. A more objective approach to parameter which has shown to be safe when performed with cer- selection could be achieved through closed-loop pro-

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Y X 3-C + 1.8 V 60 µS 130 Hz

C Clinical DBS D 25 ∗ ∗ ∗

Time Within Force Target, s Target, Within Force Time No DBS Clinical DBS Model DBS 2-C + 3.2 V 90 µS 10 130 Hz Force Tracking Force + 0-Back Force + 1-Back Force + 2-Back Condition

Figure 2. Patient-specific computational deep brain stimulation (DBS) model. A, Electrode location shown with respect to the subthalamic nucleus (green), thalamus (yellow), and desired stimulation target (gray). B and C, Computational estimate of volume of tissue activated (red) using model-defined (B) and clinically defined (C) stimulation parameters. D, The patient’s ability to maintain uniform finger motor force (y-axis) during an increasingly difficult cognitive task (x-axis) is optimal when using model-defined parameters.86 *P Ͻ .05. Image courtesy of Cameron McIntyre, PhD (Cleveland Clinic).

gramming, which is defined as a dynamic adjustment of levels have also been proposed as an input variable for stimulation parameters based on a patient’s current clini- the closed-loop system.95 cal status. This concept has been applied to neurostimu- This approach to treating PD is complicated by the lation in epilepsy treatment, where detection of abnor- fact that the disease has many different symptoms that mal cortical activity turns on the stimulator to abort an can have varying pathological signatures that may impending seizure.92 respond to different stimulation settings. Similarly, Various patient responses can be used to provide stimulation of distinct regions within the target feedback to the stimulator, such as kinematics of move- nucleus may preferentially affect various symptoms.75 ment, electrical neural activity, or neurotransmitter Stimulation using sequential high-frequency pulse concentration in a target nucleus. Kinematic data ac- trains at different contacts within the target region has quired using motion sensors to quantify the degree of been shown, theoretically and in animal studies, to impairment during patient test movements can be used prolong the therapeutic benefits beyond the period of to systematically find the optimal stimulation settings.93 active stimulation. This concept of coordinated reset Neural activity can be determined by local field poten- stimulation was developed using techniques from non- tials, which can be measured through the unused con- linear dynamics and was designed specifically to coun- tacts of the DBS electrode. Local field potential charac- teract pathological synchronization processes by pro- teristics, which define the disease state, such as viding an antikindling effect and retraining the neural excessive oscillations in the beta frequency range, could network.96 These approaches potentially increase the then trigger the appropriate stimulation response.94 complexity of upcoming closed-loop stimulation sys- Electrical discharge is not the only measure of neuronal tems but also represent a groundbreaking develop- activity, and micro measurements of neurotransmitter ment in DBS therapy.

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CI CI Lateral Lateral Medlal Medlal

STN STN

ZI ZI

Posterior Posterior

Figure 3. Current steering using novel deep brain stimulation (DBS) array electrode design. Estimate of volume of activated tissue is overlaid with an atlas section. A, Conventional DBS electrode (left) activates tissue contained within the blue circle, which is adequate for the electrode positioned in the center of the subthalamic nucleus (STN). B, Displacing the electrode by 1 mm laterally and anteriorly causes undesired activation of the internal capsule (CI) with the conventional electrode, but it can be avoided by using a novel DBS array electrode.89 Reprinted with permission. ZI indicates zona incerta.

Optogenetic Techniques netic applications, will make DBS a more versatile and successful treatment strategy. The electric field generated by DBS is applied indiscrimi- nately to all the neural elements surrounding the elec- Accepted for Publication: July 27, 2012. trode. This can sometimes result in stimulation of areas Published Online: November 12, 2012. doi:10.1001 that cause undesirable adverse effects (eg, corticospinal /2013.jamaneurol.45 axons in the internal capsule). Optogenetics is a power- Correspondence: Jerrold L. Vitek, MD, PhD, Depart- ful and promising technique that allows selective acti- ment of Neurology, University of Minnesota, MMC 295, vation of neurons using light, rather than electricity.97 A 420 Delaware St SE, Minneapolis, MN 55455 (vitek004 viral vector targeted to select neural populations can be @umn.edu). used to carry genes for light-sensitive excitatory or in- Author Contributions: Drs Miocinovic and Somayajula hibitory ion channels, which can then be triggered by light. had full access to all of the data in the study and take full Although clinical applications of this technology are still responsibility for the integrity of the data and accuracy remote, it has been used to further elucidate the mecha- of the data analysis. Study concept and design: Mioci- nisms of DBS in animal models.98 novic, Somayajula, Chitnis, and Vitek. Acquisition of data: Miocinovic and Vitek. Analysis and interpretation of data: CONCLUSIONS Miocinovic, Somayajula, and Vitek. Drafting of the manuscript: Miocinovic, Somayajula, and Chitnis. Critical re- Deep brain stimulation therapy has revolutionized vision of the manuscript for important intellectual content: treatment of movement disorders such as tremor, Par- Miocinovic and Vitek. Administrative, technical, and ma- kinson disease, and dystonia, and it has shown promise terial support: Miocinovic, Somayajula, Chitnis, and Vi- in other neuropsychiatric disorders, eg, depression, epi- tek. Study supervision: Chitnis and Vitek. lepsy, and obsessive-compulsive disorder. Additional Conflict of Interest Disclosures: None reported. applications continue to be explored including Tourette syndrome, headache, vegetative state, stroke recovery, dementia, and addiction. Mechanisms of DBS are being REFERENCES actively investigated. Current understanding is that DBS activates neurons and regularizes pathologic activity 1. Holtzheimer PE, Mayberg HS. Deep brain stimulation for psychiatric disorders. and oscillations within the basal ganglia thalamocortical Annu Rev Neurosci. 2011;34:289-307. network, which in turn improves sensorimotor process- 2. Fisher R, Salanova V, Witt T, et al; SANTE Study Group. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia. ing and alleviates disease symptoms. Better understand- 2010;51(5):899-908. ing of basic science concepts has encouraged develop- 3. Jenkins B, Tepper SJ. Neurostimulation for primary headache disorders: part 2, ment of new techniques that are permeating into the review of central neurostimulators for primary headache, overall therapeutic effi- clinical practice, such as current-controlled stimulators, cacy, safety, cost, patient selection, and future research in headache neuromodulation. Headache. 2011;51(9):1408-1418. novel electrode designs, and optimization of stimula- 4. Shah SA, Schiff ND. Central thalamic deep brain stimulation for cognitive neu- tion parameters. More exciting developments on the romodulation: a review of proposed mechanisms and investigational studies. Eur horizon, including closed-loop stimulators and optoge- J Neurosci. 2010;32(7):1135-1144.

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