EXPERT REVIEW

Deep brain stimulation and the role of astrocytesV Vedam-Mai1,6, EY van Battum2,6, W Kamphuis2, MGP Feenstra3, D Denys3,4, BA Reynolds1,

MS Okun1,5 and EM Hol2

1Department of Neurosurgery, Center for Movement Disorders and Neurorestoration, McKnight Brain Institute, University ofFlorida, Gainesville, FL, USA; 2Department of Astrocyte Biology and Neurodegeneration, Netherlands Institute forNeuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences (NIN-KNAW), Amsterdam, TheNetherlands; 3Department of Neuromodulation and Behaviour, NIN-KNAW, Amsterdam, The Netherlands; 4Department ofPsychiatry, Academic Medical Center, Amsterdam, The Netherlands and 5Department of Neurology, Center for MovementDisorders and Neurorestoration, University of Florida, Gainesville, FL, USA

Deep brain stimulation (DBS) has emerged as a powerful surgical therapy for the managementof treatment-resistant movement disorders, epilepsy and neuropsychiatric disorders.Although DBS may be clinically effective in many cases, its mode of action is still elusive.It is unclear which neural cell types are involved in the mechanism of DBS, and howhigh-frequency stimulation of these cells may lead to alleviation of the clinical symptoms.Neurons have commonly been a main focus in the many theories explaining the workingmechanism of DBS. Recent data, however, demonstrates that astrocytes may be active playersin the DBS mechanism of action. In this review article, we will discuss the potential role ofreactive and neurogenic astrocytes (neural progenitors) in DBS.Molecular Psychiatry (2012) 17, 124–131; doi:10.1038/mp.2011.61; published online 31 May 2011

Keywords: deep brain stimulation; astrocytes; glia; neural progenitors; reactive gliosis

Introduction

The first medical use of deep brain stimulation (DBS)was by the Roman physician Scribonius Largus, whoutilized the electric torpedo fish to treat arthritis andgout (Largus S 1529). It was only later with the carefulexpertise of Horsely1 and a series of neurosurgeonsthat the clinical application of brain lesioning wasexplored.1,2 This technique was refined to includeelectrical stimulation, particularly of the thalamusand pallidum, in cases of movement disorders.3 In theearly 1960s, it became evident that high-frequencyelectrical stimulation (HFS), which was routinelyused to determine the precise area of the lesion, alsohad beneficial effects on disease symptoms.4 It wasnot until the 1970s when HFS was more routinelyused as a chronic therapy to treat movement dis-orders, particularly those stemming from the cere-bellum.5,6 Later in the 1990s, the technology ofchronic implanted pacemakers was combined withchronic implanted deep brain electrodes,7 and themarriage resulted in what is now known as DBS.Today, DBS has become increasingly accepted as aneuromodulatory technique in the treatment of avariety of neurological and neuropsychiatric disor-ders.8–10 DBS therapy has been successfully applied

for numerous medication-refractory basal gangliadisorders such as Parkinson’s disease9 and dystonia,for essential tremor,8 and recently for epilepsy,11

depression,12 pain,13 Tourette’s syndrome14 andobsessive compulsive disorder.15 To date, the under-lying mechanism of DBS in the treatment of thesedisorders is unknown.16 The majority of studiesare focused on the change in neuronal activity in theimmediate stimulated target area (inhibition) as wellas in excitation of targets and circuits. However, it isconceivable that DBS will not only affect neurons inthis network, but also glial cells, and that a change inboth cell types may contribute to its therapeutic effect.

Astrocytes are excellent candidates to be involvedin DBS. They are known to assemble into networksof cells that can propagate calcium waves uponstimulation17,18 and form a tripartite synapse togetherwith neuronal synapses and, as such, are activeplayers in neural signaling.18,19 Not only can astro-cytes be directly stimulated by HFS,20 they also reactto the implantation of the stimulation electrode,21

which might lead to a change in their function.22,23

The presence of these reactive astrocytes in thevicinity of the implanted electrode may lead to analtered modulation of neural signaling. Furthermore, asubset of astrocytes is believed to function as neuralstem cells in the adult brain24,25 and brain injury mayinduce stem cell properties in cortical astrocytes.26

Thus an appealing hypothesis is emerging that theeffect of DBS on brain function is, at least in part,directly induced by the effect of astrocytes on neuronalnetworks, or by astrocyte-like neural stem cells that are

Received 25 September 2010; revised 1 March 2011; accepted 21April 2011; published online 31 May 2011

Correspondence: Dr EM Hol, Netherlands Institute for Neuro-science, Meibergdreef 47, Amsterdam 1105 BA, The Netherlands.E-mail: e.hol@nin.knaw.nl6These two authors contributed equally to this work.

Molecular Psychiatry (2012) 17, 124–131& 2012 Macmillan Publishers Limited All rights reserved 1359-4184/12

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capable of division and genesis of more astrocytes,neurons and oligodendrocytes in response to HFS.27–29

Mechanism of action of DBS

The typical therapeutic frequency range of DBS isbetween 80 and 185 Hz, with a stimulation currentbetween 1 and 10 mA.30 To develop a better under-standing of how DBS changes brain function, it isessential to understand how neural networks andneural cells are affected by chronic HFS. Over the lastyears, many excellent reviews have discussed andsurveyed the biological and theoretical data that couldexplain the clinical effect of DBS.30–32 These reviewsfocus on neurons and describe the potential effectsof HFS on myelinated and unmyelinated axons,dendrites, neuronal cell bodies and neuronalnetworks. We will summarize the neuronal theoriesand refer to extensive reviews on this topic.

Myelinated axons, neuronal cell bodies anddendrites all have different electrical properties(chronaxies), and based on these, it is likely that thestandard stimulation parameters of DBS will predo-minantly affect axons, rather than the cell bodiesor dendrites.16 This leads to complex patterns ofactivity with the net result that DBS may have bothexcitatory31 and inhibitory33 effects on neuronalactivity. The net inhibitory effect could be the resultof indirect synaptic inhibition by retrograde activationof the incoming axons (jamming), or of neurotrans-mitter depletion in the outgoing axons (synapticfatigue) due to extensive high-frequency synapticfiring.34,8 Furthermore, the net effect of the stimulationis also dependent on whether the stimulated axonsextend from an excitatory or inhibitory neuron.34,8

Interestingly, the activity in the axon and the neuronalcell body can even be decoupled,32 resulting ina hyper-polarization of the neuronal cell body and adepolarization of the axon. The overall outcome willbe a silenced neuronal firing of the target structure,with an increased synaptic output of the stimulatedaxons near the electrodes.30,31

Besides the local effects of DBS on neuronalelements, it might also act on large neural networks.Behavioral changes such as anxiety reduction, ormood improvement, which are often experienced bypatients within seconds following stimulation supportthe notion that there is a rapid, and global alteration inneural networks activity and function. More regular, andprobably normalized firing rates and patterns of neuronsare observed after DBS35,36 and the associated therapeu-tic benefit of DBS on Parkinson’s disease34,37 may in factthus be a network change. It is thought that duringstimulation, the cortico-basal-ganglia–thalamo-corticalnetwork is not restored to the pre-pathological state,but rather that HFS disrupts the pathological networkactivity allowing an improvement in the affected brainfunction.34 Whether similar changes in network activityalso underlie the therapeutic effect of DBS in neurop-sychiatric diseases or epilepsy is not clear yet.

Neurobiology of DBS—the astrocyte contribution

Identifying the cell types involved in DBS is instru-mental in understanding its mechanism of action.It is becoming increasingly clear that astrocytes areactive players in neural communication,38 and thatan astrocytic network can modulate neuronal acti-vity.17,18 Rodent astrocytes possess small somata( < 10mm), and numerous highly branched processesthat can reach distances of up to 100mm.39 Theseprocesses connect to those of other astrocytes throughgap junctions,40 and enwrap neuronal synapses.41

This intimate interaction between the astrocytes andneuronal synapses is termed the ‘tripartite synapse,’42

see Figure 1. Moreover, astrocytes contact bloodvessels and can regulate local blood flow in thebrain.43 Human astrocytes are even more complex, asthey are threefold larger than rodent astrocytes, andhave more and longer processes. Importantly, it isestimated that one human astrocyte interacts with upto two million synapses, making them appropriatecandidates for playing an important role in modulat-ing DBS-induced neuronal function.44

Astrocyte signaling induced by HFSAstrocytes sense neural communication, as is evidentby the expression of numerous neurotransmitterreceptors on their membrane. The most predominantreceptors belong to the G protein-coupled receptorfamily.45,46 It also must be considered that astrocytescan release gliotransmitters, such as glutamate,D-serine and ATP, which interact with pre- and post-synaptic receptors.47 Furthermore, astrocytes can alsobe directly depolarized by HFS, leading to activatedastrocytes, which release calcium from intracellularstores that can modulate synaptic transmission.48

Astrocytes are also known to communicate with eachother by Ca2þ waves (through hemi-channels and gapjunctions), which are initiated after neuronal activa-tion via Gq G protein-coupled receptor signaling onastrocytic micro-domains (see Figure 1).45

A first indication that astrocytes respond to HFSis the observation that DBS modulates the regionalblood flow in the area stimulated with HFS.49–51 Thismight be an indirect effect caused by neuronalstimulation, as an increase or decrease in blood flowreflects an increase or decrease in neuronal activity.52

Nevertheless, a modulation in blood flow is a directmanifestation of a change in astrocytic activity eitherdirectly induced by DBS,43 or as a response tothe activation of a neuron or axon as a result ofDBS. Furthermore, astrocytes can exhibit a rapidCa2þ increase in response to electrical stimulationin vivo. Using two-photon imaging, Bekar et al.53

investigated 100 Hz stimulation (a frequency appliedfor DBS in the clinic) of the ventrolateral thalamicnucleus, and found increased Ca2þ levels in thecortex, demonstrating for the first time in a livinganimal that astrocytes can react to electrical stimula-tion, and can modulate neural networks in thismanner. Recently, Tawfik et al.20 showed that HFS

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abolished spontaneous spindle oscillations in ferretbrain slices and that simultaneously, the release ofglutamate and adenosine increased. Subsequent treat-ment with the Naþ channel inhibitor tetrodotoxin ledto an abolishment of spindles, but this treatment didnot block glutamate release. Tawfik et al. concludedthat the resultant effect is likely to be due to therelease of glutamate from astrocytes, since tetro-dotoxin inhibits axonal-dependent synaptic release,making a neuronal source unlikely. Furthermore, theyshowed that a direct HFS of primary astrocytesresulted in calcium waves and release of glutamate.This study corroborates the earlier study of Bekaret al.,53 in which they showed a Ca2þ -independentincrease in ATP, and subsequent accumulation ofadenosine in the extracellular space around theelectrode. Elimination of Ca2þ from the extracellularspace prevents a Ca2þ influx through voltage-gatedCa2þ channels upon depolarization of the membraneand, therefore, prevents neuronal synaptic release ofATP. Although astrocytes do express voltage-gatedCa2þ channels, it has been shown that the increase inintracellular [Ca2þ ] in astrocytes upon a depolariza-tion stimulus is a glutamate-mediated response,rather than a Ca2þ influx through the voltage-gatedCa2þ channels.54 Therefore, the finding of Bekar et al.strongly suggests that ATP is not synapticallyreleased, and, therefore, is likely to be released byastrocytes. The mechanism by which astrocytesrelease ATP is still poorly understood,47,55 but outsidethe cell, ATP is rapidly converted into adenosineby ecto-ATPase.56 Adenosine then can inhibit synap-tic transmission by acting on A1 receptors, which arehighly abundant in the brain.56 Activation of post-synaptic A1 receptors opens Kþ channels,57 while

pre-synaptic A1 receptors close Ca2þ channels.58

Both actions will lead to an inhibition of neuronalcommunication.

Additionally, astrocytic Ca2þ waves were found tooccur after stimulation, and these waves propagatedaway from the electrode site. Further experiments inmouse models for tremor indicate that adenosinesignaling is essential to the anti-tremor effect ofHFS. When the adenosine A1R antagonist DPCPX orthe ecto-ATPase inhibitor ARL-67156 was used,the HFS-induced suppression of thalamic neuronalactivity was abolished. This occurred in both homo-and heterosynaptic pathways. Furthermore, it wassuggested that adenosine reduced the distance of theDBS spread in the brain, thereby preventing anynegative outcome of the procedure.53

The effect of adenosine and glutamate (which couldboth be potentially released by astrocytes) on thetherapeutic effect of DBS has been investigated in twoother studies,59,60 which both suggest another levelof interference for these gliotransmitters in DBS. Theactual surgical procedure of inserting the DBSelectrode into the brain itself triggers the release ofadenosine and glutamate,60 which corresponds to themechanical stimulation, and induces activation ofcalcium signaling and ATP release in cultured astro-cytes.61,62 The astrocytic activation by DBS electrodesis thought to contribute to the microthalamotomyeffect of electrode insertion. The induction of sucha micro-lesion is, in some cases, enough to improveclinical symptoms. We have recently shown animprovement in postural and intention tremors uponmicroelectrode recording and macro-stimulation,which was used to refine the DBS lead placement inthe ventral intermediate nucleus of the thalamus.63

Figure 1 Astrocyte-neuron communication through Ca2þ and gliotransmitter signaling in tripartite synapse. Astrocytes(green) can directly communicate with neurons at the synapse (blue). Neurotransmitters, released by depolarized neurons,are sensed by the astrocytic Gq protein-coupled receptors (Gq-GPCRs), resulting in an increase in intracelluar Ca2þ , whichactivates gliotransmitter release. The mechanisms controlling the subsequent release of the gliotransmitters glutamate,D-serine and ATP and the direct effect of these transmitters on neurons are still not completely resolved. The Gq GPCRsactivate via a phospholipase C/inositol 1,4,5-triphosphate (PLC/IP3)-mediated pathway the release Ca2þ from intracellularcalcium stores, such as the endoplasmatic reticulum (ER). Astrocytes can also be activated by direct depolarization, whichleads to a release of intracellular Ca2þ . Calcium is a main player in neuron-astrocyte, intra-astrocyte and inter-astrocytecommunication. The gliotransmitters can modulate both pre- and post-synaptic neuronal signaling.

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Similarly, significant clinical improvements in motorfunction were observed as a result from a DBS leadplacement in the subthalamic nucleus (STN) andglobus pallidus pars interna of Parkinson patients.64

The possible involvement of astrocytes in DBS wassupported by another recent study in Parkinsonian’srats by Gradinaru et al.65 Using an optogeneticsapproach, this group aimed to dissect the Parkin-sonian’s disease circuitry and the mechanism of DBSin 6-hydroxydopamine-lesioned animals. Astrocyteswere specifically targeted with a lentiviral vectorthat contained an expression cassette of channelrho-dopsin-2 driven by the glial fibrillary acidic proteinpromoter. Stimulation using light resulted in theinhibition of neuronal firing in the STN, whichwas likely due to astrocytic Ca2þ waves that weretriggered by the activation of channelrhodopsin. It isimportant to note that this direct activation of theSTN astrocytes was able to inhibit STN neurons, butwas not sufficient to reduce the Parkinsonian’ssymptoms in the rats. These results provide evidencethat activation of astrocytes can lead to inhibition ofthe STN, but it also shows that astrocyte-inducedneuronal inhibition by itself is likely not sufficient forthe therapeutic effect of DBS in Parkinson’s disease.

In summary, these recent data suggest that (1) DBScan activate glia and increase the release of glia-derived transmitters; (2) glial activation may result inacute alterations in local neuronal activity; and (3)glial activation by DBS may have profound effects onnetwork activity patterns.

Reactive astrocytes near stimulation electrodeSeveral histological studies have shown the occur-rence of reactive astrocytes around the implantedelectrode. Reactive gliosis is defined by hypertrophyof astrocytes, and an increase in the production of theintermediate filament protein glial fibrillary acidicprotein, as well as vimentin, nestin and synemin.22 In1979, Stock et al.66 described that mild reactive gliosisoccurred around the track of stimulation electrodes incats, which were implanted in the rostral hippocam-pus and amygdala. They report a slight loss of neuronsaround the tip, and some remnants of micro-bleeding.The leptomeninges at the surface penetration site andthe choroid plexus showed a scarred connective tissuereaction, and some giant cells were reported. We haveobserved similar findings in a majority of brainsdeposited in the DBS brain tissue network.67

The first post-mortem study on neuropathologicalchanges induced by electrode implantations inthe human STN and thalamic ventral intermediatenucleus was published in 2000.68 In general, mildreactive astrogliosis was observed near the stimula-tion electrode. Activated microglia were absent in allcases, but these cells were not carefully examined.Single macrophages, mononuclear leukocytes andmultinucleated giant cells were observed in some ofthe cases. Another study in which the electrode wasimplanted in the anterior nucleus of the thalamusconfirmed these data.69 In a patient with Parkinson’s

disease who had 71 months of DBS, Rosenthal fibers(accumulation of aggregated glial fibrillary acidicprotein in astrocytes) were observed.70 A review ofthe literature up to 2006 reported gliosis in theimmediate vicinity of the electrode track in most ofthe studies.71 In 2010, a case report was published, inwhich a post-mortem analysis was performed 12 yearsafter implantation of the electrode in the thalamicventral intermediate nucleus. As in the other cases,the authors described a small rim of fibrous sheath,and reactive gliosis with some lymphocytic infiltra-tion near the electrodes.21 In all of these cases, theelectrodes had to be removed before the brain wasprocessed for histological analysis. Cells, includingreactive astrocytes around the electrode, are likely toadhere to the electrodes during the removal proce-dure, resulting in an underestimation of the glioticreaction in the brain.72

In a study using two Rhesus macaques, chronicallyimplanted electrodes have been reported to cause anincrease in reactive astrocytes and microglia. Themicroglial response in these cases was transient,and was only observed in the brain of the macaquethat had an electrode implanted for 3 months.Reactive astrocytes were observed in both macaquesat 3 months and 3 years after implantation.73 A recentstudy74 in rats in which electrodes were implantedin the STN revealed a region-dependent effect onneuroinflammation, as measured by in vitro auto-radiography with [3H]PK11195, a marker for microgliaactivity. It is likely that astrocytes are also activated inthis study, but this was not addressed. The corticalregions showed more pronounced neuroinflammationthan the STN. The implanted rats also showedmemory impairment as measured by the novelobject recognition task. In a separate study, electrodeswere implanted in the hippocampus of rats for akindling protocol. These experiments revealed thatthe insertion of electrodes itself induced reactivegliosis.75

Taken together, mild gliosis around the elec-trodes in patients, even after chronic implantation(12 years), indicates that DBS induces minor patho-logy in the brain tissue, and this may support itsoutstanding safety record. The study in macaques,however, shows that a more extensive reactive gliosisis possible. Furthermore, the recent study in rats74

suggests that neuroinflammation and memory impair-ment might occur post-DBS. Therefore, the inductionof reactive astrogliosis may modulate local or evenmore widespread neuronal activity. In an elegantstudy by Ortinki et al.,76 it was shown that reactiveastrocytes had a direct effect on neighboring neurons,which displayed reduced inhibitory synaptic cur-rents. The reactive astrocytes down-regulated gluta-mine synthetase, leading to a depletion in neuronalgamma-aminobutyric acid and thus a hyper-excit-ability in the hippocampal circuit. This effect may bedependent on HFS, but in some cases, it is merelyinduced by the physical presence of the electrode inthe brain.

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Neurogenic astrocytes—stimulation of neuralprecursor proliferation by DBS?

A study by Jeong et al.77 in a co-culture of neuronsand astrocytes on microelectrode arrays demonstratedthat electrical stimulation led to migration of neuro-nal cell bodies, and was enhanced by the presence ofastrocytes near stimulating electrodes. This reportalso provided evidence that electrical stimulationcould induce an increase in spontaneous proliferativeactivity. The authors concluded that increased celldensity around the electrode was a result of focalstimulation, and this could be a product of rapidproliferation of progenitor cells that are derived froma sub-population of astrocytes with progenitor cellproperties.25,26,78,79 In a report by Toda et al.,80 it hasbeen shown that HFS of the anterior thalamic nucleusof adult rats produced a two- to threefold increase inthe number of neural progenitor cells in the hippo-campus, when compared with animals that under-went sham surgeries. Recently, Becker et al. reportedthat functional electrical stimulation in their rodentmodel was able to promote the formation of newborncells in the damaged spinal cord of animals. Theseauthors demonstrated that most new cells expressedmarkers of neural progenitor and glial cells.81 In 2010,Encinas et al.82 reported a twofold increase in thenumber of BrdU-positive cells in the dentate gyrus ofthe hippocampus upon HFS of the anterior thalamicnucleus in mice, these data confirm the earlier resultsin rats.80 They showed that HFS specifically stimulatethe proliferation of the transient amplifying neuralprogenitors, and that this leads to an increase in newneurons in the granular layer of the dentate gyrus ofthe hippocampus.82 HFS has similar effects on thesecells as physical exercise83 or the antidepressant

fluoxetine.84 In a rat 6-hydroxydopamine model forParkinson’s disease, Khaindrava et al.85 showed thata prolonged HFS of the STN resulted in a significantincrease in the survival of newborn neurons in thesubventricular zone-rostral migratory stream-olfac-tory bulb continuum, in the striatum and in thedentate gyrus of the hippocampus. Thus, if prolifera-tion of neural progenitors or neurogenic astrocytesand survival of newborn neurons can be driven byelectrical stimulation, DBS could prove to be a noveltherapeutic method to treat a broad spectrum ofsymptoms and diseases.

Conclusion and future directions

In this review, our primary focus was on the role ofastrocytes in the working mechanism of DBS. Sinceastrocytic signaling modulates neuronal networks andDBS is thought to interfere with a pathologicalactivity pattern in a neural network, astrocytes arean important cell type to be investigated. Severalpapers support the potential role of astrocytes in themechanism of action of DBS.43,65,86

In summary, we list three possible ways in whichglia in general and astrocytes in particular may beinvolved in the effects of DBS (see Figure 2).Astrocytes can be triggered by electrical stimulation,change the cerebral blood flow and release ATP andglutamate, both important neuromodulators andregulators of neuronal synaptic networks. Therefore,it is possible that the DBS-induced modulation ofnetwork activity is partially due to astrocytic glio-transmission. Another change in gliotransmissionmay be the observed increase in reactive astrocytesthought to result from the implantation of stimulation

Figure 2 Involvement of astrocytes in DBS. Astrocytes can potentially modulate the effect of DBS in several ways andmodulate neuronal network activity. The stimulating electrode itself can lead to hypermorphic reactive astrocytes (A), whichare likely to affect neuronal signaling. The HFS can act directly on astrocytes resulting in a change in the cerebral blood flow(B) and in the release of gliotransmitters glutamate (Glut) and ATP. Glutamate will stimulate neuronal synaptic release (þ inright synapse) and ATP is converted by ecto-ATPase into adenosine (ADO) and will silence neuronal communication (� inleft synapse) through pre-synaptic inhibition of A1-coupled Ca2þchannels and post-synaptic activation of A1-coupled Kþ

channels. Furthermore, HFS might also induce proliferation of neural precursors, which are an astrocyte subtype (C).

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electrodes. Finally, we discuss how HFS increases theproliferation of neurogenic astrocytes, which differ-entiate into neurons.

DBS outcomes have been thus far mainly ascribed toa direct effect on neuronal elements. The growinginsight into the role of astrocytes in neuronal commu-nication, and the recent experimental data on apotential role of astrocytes in DBS, asks for anadjustment of the neuronal hypothesis. DBS can eitherinhibit or stimulate a target area.31,33 From an astrocyticpoint of view, the local inhibitory effect can beexplained by a direct stimulation of astrocytes torelease ATP,53,20 which subsequently leads to aninhibition of synaptic transmission through the actionof adenosine on post- and pre-synaptic A1 receptors.56

On the other hand, release of astrocytic glutamateupon HFS can lead to a local stimulation of synapticactivity.20 Also, reactive astrocytes, induced by theimplantation of the stimulation electrode, can con-tribute to a stimulation of synaptic activity, as in thesecells, the glutamate–glutamine cycle is impaired,leading to synaptic gamma-aminobutyric acid deple-tion.76 Due to the propagation of calcium waves inastrocytic networks,17 the astrocytic effects mightspread distant from the stimulation electrode. Aclinical effect that might be partly explained by astimulation of proliferation and neuronal differentia-tion of neurogenic astrocytes in the hippocampusupon application of HFS to the anterior thalamicnucleus80,82,85 are the changes in mood.87

We are only now beginning to understand thepotential role of astrocytes in the mechanism of actionof DBS. To fully grasp the outcome of HFS on themodulation of brain function, both neuronal andastrocytic effects need to be considered. Criticalexperiments are needed in animal models of DBS, inwhich HFS is combined with a specific and selectiveintervention in either astrocytic, or neuronal signal-ing, or both. A pharmacological approach, for in-stance, by interfering with receptor function lacksspecificity, since some receptors are expressed both inastrocytes and neurons. Therefore, a viral vectorapproach has to be applied to specifically targetastrocytes in a confined brain area with a transgeneunder control of a cell-type specific, or activity-dependent promoter.88 Another approach would beto develop novel, inducible mouse models, in whicheither astrocytic communication can be blocked, forinstance by targeting gliotransmitters,89 or intracellu-lar Ca2þ .90 Characterizing the potential role of astro-cytes in the working of DBS will provide a morein-depth comprehension of the way it functions torestore normal brain function. This will hope-fully enable us continue to enhance DBS techno-logies so that we can improve surgical outcomes inpatients.

Conflict of interest

MSO serves as a consultant for the National ParkinsonFoundation. He has in the past received honoraria for

DBS educational talks prior to 2010, but currentlyreceives no support (since July 2009). He also hasreceived royalties for publications with Demos, Man-son, and Cambridge (movement disorders books). Andhe has potential royalty interest in the COMPRESStool for DBS. MSO has participated in CME activitieson movement disorders sponsored by the USF CMEoffice. VV-M, EYB, WK, MGPF, DD, BAR and EMHdeclare no potential conflict of interest.

Acknowledgments

We acknowledge the financial support for ourresearch by the Netherlands Organisation of ScientificResearch—NWO (ALW-Vici 865.09.003 to EMH andZON-MW VENI 916.66.095 to DD), InternationalParkinson Foundation-IPF (to EMH), InternationalAlzheimer Foundation (ISAO 08504 to EMH andWK), Overstreet foundation and Brain and SpinalCord Injury Trust Fund of Florida (to BR) and NIH,NPF, the Michael J. Fox Foundation, the ParkinsonAlliance, Medtronic peer reviewed fellowship train-ing grants and the UF Foundation (to MSO). Informa-tion from the UF National Deep Brain StimulationBrain Tissue Network was utilized for the writing ofthis manuscript.

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