REVIEW

Current Directions in Deep Brain Stimulationfor Parkinson’s Disease—Directing Currentto Maximize Clinical Benefit

Aristide Merola . Alberto Romagnolo . Vibhor Krishna . Srivatsan Pallavaram .

Stephen Carcieri . Steven Goetz . George Mandybur . Andrew P. Duker . Brian Dalm .

John D. Rolston . Alfonso Fasano . Leo Verhagen

Received: January 6, 2020 / Published online: March 9, 2020� The Author(s) 2020

ABSTRACT

Several single-center studies and one largemulticenter clinical trial demonstrated thatdirectional deep brain stimulation (DBS) couldoptimize the volume of tissue activated (VTA)based on the individual placement of the leadin relation to the target. The ability to generateaxially asymmetric fields of stimulation trans-lates into a broader therapeutic window (TW)compared to conventional DBS. However,

changing the shape and surface of stimulatingelectrodes (directional segmented vs. conven-tional ring-shaped) also demands a revision ofthe programming strategies employed for DBSprogramming. Model-based approaches havebeen used to predict the shape of the VTA,which can be visualized on standardized neu-roimaging atlases or individual magnetic reso-nance imaging. While potentially useful foroptimizing clinical care, these systems remainlimited by factors such as patient-specificanatomical variability, postsurgical lead migra-tions, and inability to account for individualcontact impedances and orientation of the sys-tems of fibers surrounding the electrode. Alter-native programming tools based on thefunctional assessment of stimulation-inducedclinical benefits and side effects allow one tocollect and analyze data from each electrode ofthe DBS system and provide an action plan ofranked alternatives for therapeutic settingsbased on the selection of optimal directional

Aristide Merola and Alberto Romagnolo contributedequally to the manuscript and shared co-firstauthorship.

Enhanced digital features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.11864961.

Electronic supplementary material The onlineversion of this article (https://doi.org/10.1007/s40120-020-00181-9) contains supplementary material, which isavailable to authorized users.

A. Merola (&)Department of Neurology, Ohio State UniversityWexner Medical Center, Columbus, OH, USAe-mail: Aristide.Merola@osumc.edu

A. RomagnoloDepartment of Neuroscience ‘‘Rita Levi Montalcini’’,University of Turin, Turin, Italy

V. Krishna � B. DalmDepartment of Neurosurgery, Ohio State WexnerMedical Center, Columbus, OH, USA

S. PallavaramNeuromodulation Division, Abbott Laboratories,Austin, TX, USA

S. CarcieriBoston Scientific Neuromodulation, Valencia, CA,USA

S. GoetzMedtronic PLC Brain Modulation, Minneapolis,MN, USA

Neurol Ther (2020) 9:25–41

https://doi.org/10.1007/s40120-020-00181-9

contacts. Overall, an increasing amount of datasupports the use of directional DBS. It is con-ceivable that the use of directionality mayreduce the need for complex programmingparadigms such as bipolar configurations, fre-quency or pulse width modulation, or inter-leaving. At a minimum, stimulation throughdirectional electrodes can be considered asanother tool to improve the benefit/side effectratio. At a maximum, directionality maybecome the preferred way to program becauseof its larger TW and lower energy consumption.

Keywords: Contact; Deep brain stimulation;Directionality; Lead; Parkinson disease;Programming

Key Summary Points

Directional deep brain stimulation (DBS)has the potential to minimizestimulation-induced side effects andmaximize clinical benefits

To maximize the opportunity ofdirectionality, the surgical planningshould be based on the DBS lead levelcontaining segmented directionalelectrodes

Visualization software platforms can assistprogramming by estimating the volumeof tissue activated by conventional ordirectional DBS electrodes

Functional software platforms can supportdirectional programming by creating anaction plan of ranked alternatives thatmay be needed over time

Directional DBS may avoid the need forcomplex stimulation protocols, such asbipolar stimulation, frequency or pulsewidth modulation, or interleaving

INTRODUCTION

Over the last three decades, the long-term effi-cacy of deep brain stimulation (DBS) in themanagement of Parkinson disease (PD) has beenwell established, with 60% improvement oflevodopa-related motor complications [1, 2],40–60% amelioration in quality of life [3], and asignificant increase in quality-adjusted lifeexpectancy [4]. Despite these remarkableresults, not all patients experience maximalbenefit from DBS. Unintentional spread ofstimulation outside the target and into adjacentareas may result in dose-limiting motor or non-motor side effects, preventing an optimal out-come [5, 6].

G. MandyburMayfield Brain and Spine, Cincinnati, OH, USA

A. P. DukerDepartment of Neurology, Gardner Family Centerfor Parkinson’s Disease and Movement Disorders,University of Cincinnati, Cincinnati, OH, USA

J. D. RolstonDepartment of Neurosurgery, University of Utah,Salt Lake City, UT, USA

J. D. RolstonDepartment of Biomedical Engineering, Universityof Utah, Salt Lake City, UT, USA

A. FasanoEdmond J. Safra Program in Parkinson’s Disease,Morton and Gloria Shulman Movement DisordersClinic, Toronto Western Hospital, UHN, Toronto,ON, Canada

A. FasanoDivision of Neurology, University of Toronto,Toronto, ON, Canada

A. FasanoKrembil Brain Institute, Toronto, ON, Canada

A. FasanoCenteR for Advancing NeurotechnologicalInnovation to Application (CRANIA), Toronto, ON,Canada

L. VerhagenDepartment of Neurological Sciences, MovementDisorder Section, Rush University, Chicago, IL, USA

26 Neurol Ther (2020) 9:25–41

Directional leads represent an innovativetechnology designed to address this issue. Theconcept of steering current away from sideeffects and towards benefits after the lead islocked into place is appealing when consideringthe need to further improve the accuracy of DBStargeting [7]. Here, we discuss opportunities andchallenges for directional DBS and review datain support of the integration of directional leadsinto clinical practice with regards to the func-tional anatomy of DBS target structures, plan-ning strategies for optimal lead placement, anduse of software platforms to assist the selectionof the most promising stimulation settings. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

CLINICAL DATA SUPPORTINGDIRECTIONALITY

In 2014, two groups reported the results ofintraoperative studies of directional DBS leads(not permanently implanted) (Table 1). In onestudy [8], the therapeutic window (TW), definedas the range between the minimal intensity ofstimulation required to obtain meaningfulclinical benefits, or therapeutic current strength(TCS), and the intensity of stimulation at whichthe first persistent side effect occurred, or sideeffect threshold (SET), was evaluated for singledirectional and omnidirectional configurationsin 13 patients with PD or essential tremor (ET).The electrode used had two segmented contactsat the distal end, with three segments each, andtwo solid ring electrodes proximally. When teststimulation was performed, the TW was foundto be 41.3% wider using the best directionalelectrode, compared to omnidirectional stimu-lation at that same level. The TCS was 43%lower for the best directional electrode com-pared to that required for omnidirectionalstimulation, indicating a higher degree of effi-ciency with directional DBS. In the secondstudy [9], eight patients with PD were assessedintraoperatively using an experimental leadwith 32 oval disc-shaped thin-film electrodecontacts arranged on eight rows of four

contacts. The patient, the evaluating neurolo-gist, and the neurosurgeon were blind to thedirection of the steering modes. When com-pared to omnidirectional stimulation, direc-tional DBS increased the TW in all patients,with a gain ranging from 0.5 to 1.5 mA. In sevenout of eight cases, SETs could be increased by atleast 1 mA when using directional DBS.

Three single-center studies investigated USFood and Drug Administration (FDA)-approveddirectional implants (Table 1) employing a ‘‘1-3-3-1’’ lead design with the two central rows seg-mented into three individually controlled elec-trodes; each segment spaced 120� apart in theplane orthogonal to the long axis of the lead.These studies found that best directional DBShas a significantly larger median TW and higherSET [10, 11], as well as slightly lower totalelectrical energy delivered (TEED) [12]. Morerecently, a large international, multicenter,prospective, crossover study of 234 patientswith PD undergoing subthalamic nucleus (STN)DBS from 37 centers across seven countries (thePROGRESS Study, Abbott St. Jude Medical,Plano, TX, USA) confirmed the superiority ofdirectional vs. omnidirectional programming[13]. In this study, patients were conventionally(i.e., non-directionally) stimulated for 3 monthsat the optimal ring. At the 3-month primaryendpoint, the optimal ring settings were con-firmed and in the same session the best direc-tional settings were identified between the threeindividual segments and the three pairwisecombinations of segments at the best seg-mented level. The best ring and best directionalmontages were then evaluated in a randomized(based on a coin toss) and double-blinded (pa-tient and the clinician) fashion and their TWswere recorded. Study details and results of theprimary endpoint are included in Table 2. Allpatients had 12 months of follow-up and sev-eral measures were tracked in this period at 3, 6,and 12 months including Unified PD RatingScale (UPDRS)-III (motor section), UPDRS-II(activities of daily living section), clinicianpreference, patient preference, 39-item PDQuestionnaire (PDQ-39), adverse events, andothers.

Neurol Ther (2020) 9:25–41 27

Table 1 Data from single-center studies on directional DBS

Author andyear

Samplesize

Leadconfiguration

Clinicalsetting

Efficacy measures FUP Main results

Pollo et al.

2014 [8]

11 PD

(STN)

2 ET

(Vim)

2 distal

segmented

contacts (3

segments

each)

2 proximal

ring

contacts

Intraoperative

double-

blinded

evaluation

Full effect on rigidity

or good effect on

tremor

NA TW 41.3% wider and

TCS 43% lower with

directional vs.

omnidirectional

stimulation

Contarino

et al.

2014 [9]

8 PD

(STN)

32 oval disc-

shaped

contacts

Intraoperative

double-

blinded

evaluation

Full effect on rigidity NA TW wider

(0.5–1.5 mA) with

directional vs.

omnidirectional

stimulation

Steigerwald

et al.

2016 [10]

7 PD

(STN)

2 central

segmented

contacts (3

segments

each)

1 proximal

and 1 distal

ring

contacts

Retrospective

unblinded

analysis of

permanently

implanted

patients

Full effect on rigidity 3–6 months TW variations from

- 100% to ? 440%

with directional vs.

omnidirectional

stimulation

Best TW improvement

with the best

directional contact at

the less effective level

At 3–6 months, all

patients remained in

directional

stimulation

28 Neurol Ther (2020) 9:25–41

Table 1 continued

Author andyear

Samplesize

Leadconfiguration

Clinicalsetting

Efficacy measures FUP Main results

Dembek

et al.

2017 [11]

10 PD

(STN)

2 central

segmented

contacts (3

segments

each)

1 proximal

and 1 distal

ring

contacts

Prospective

double-

blinded

Improvement of at

least 1.5 points in

the UPDRS-III

composite scores of

upper limb rigidity,

finger tapping, and

hand rotation

3–6 months TW wider with

directional vs.

omnidirectional

stimulation (median

2 mA vs 1 mA)

SET higher with

directional vs.

omnidirectional

stimulation (median

4 mA vs 3 mA)

At 3–6 months, 14

leads remained in

directional

stimulation

Rebelo et al.

2018 [12]

3 PD

(Vim)

3 DT

(Vim)

2 ET

(Vim)

2 central

segmented

contacts (3

segments

each)

1 proximal

and 1 distal

ring

contacts

Retrospective

unblinded

analysis of

permanently

implanted

patients

Full effect on tremor 6 months TW wider (1.86 mA

vs. 0.97 mA) and

TCS lower (1.51 mA

vs. 2.19 mA) with

directional vs.

omnidirectional

stimulation

TEED 6–18% lower

with directional vs.

omnidirectional

stimulation

At 6 months, 9 leads

remained in

directional

stimulation

DT dystonic tremor, ET essential tremor, FUP follow-up, PD Parkinson disease, NA not applicable, SET side effectsthreshold, STN subthalamic nucleus, TCS therapeutic current strength, TEED total electrical energy delivered, TWtherapeutic window, UPDRS Unified PD Rating Scale, Vim ventral intermediate nucleus

Neurol Ther (2020) 9:25–41 29

CHALLENGES ASSOCIATEDWITH DIRECTIONALPROGRAMMING

While directional DBS systems allow fine con-trol over the parameters by which they deliverstimulation, including location, size, shape, andnature of neural activation, this increased abil-ity to provide accurate and personalized stimu-lation demands a revision of paradigmscurrently used for the placement and program-ming of DBS electrodes. In particular, theanatomical and functional connections of the

DBS targets, as well as the bioelectrical proper-ties of directional vs. conventional leads, rep-resent critical aspects to be considered for thedevelopment of innovative DBS protocols.

DBS Target Structures: Anatomicaland Functional Connections

The STN is a small lens-shaped structure locatedin the anterior-lateral portion of the midbrain atthe junction of the cerebral peduncle to thetegmentum (Fig. 1). Leads are generallyimplanted following an oblique trajectory from

Table 2 Data from the PROGRESS study

Device Abbott St. Jude InfinityTM IPG system

Enrollment 234 patients with PD (157 male; 77 female)

Demographics Age 61.7 ± 8.4 years

PD duration since onset 11.7 ± 7.6 years

PD duration since diagnosis 10.2 ± 7.4 years

Number of centers 37 centers, from 7 countries

Lead configuration 2 central segmented contacts (3 segments each), 1 proximal and 1 distal ring contacts; 1-3-3-1

Clinical setting Prospective, blinded subject, blinded observer, crossover study of directional versus non-directional

stimulation

Study endpoints Primary endpoint

Superiority benchmark: at least 60% of patients at 3 months have wider TW with directional

stimulation when compared to non-directional stimulation in a randomized evaluation

Secondary endpoints

Non-inferiority benchmark: 40–60% of patients at 3 months have wider TW with directional

stimulation when compared to non-directional stimulation in a randomized evaluation

Comparison of UPDRS III at 3 months on non-directional stimulation versus at 6 months after

switching to directional stimulation

Descriptive endpoints

Patient and clinician preference at 6 months between directional and non-directional stimulation

Comparison of TW and TCS amplitudes between directional and non-directional stimulation

Device-related adverse events

Primary endpoint

results

In 90.6% of patients (183/202), TW was wider with directional stimulation as compared to non-

directional stimulation; primary endpoint superiority exceeded (p\ 0.001)

DBS deep brain stimulation, PD Parkinson disease, TCS therapeutic current strength, TW therapeutic window

30 Neurol Ther (2020) 9:25–41

a dorsal lateral entry point to a more ventralmedial endpoint in the STN. Given the highnumber of important surrounding structures,stimulation-induced side effects are importantto recognize and, if seen, can guide inferencesabout the location of the lead in relation to theplanned STN target (Table 3). Functionally, theSTN has a complex microanatomy, with largedendritic trees that are synaptically convergentbetween afferents from different functionalareas [14–16] (Table 4).

The globus pallidus pars interna (GPi) is atriangular-shaped structure forming the innerpart of the lentiform nucleus of the basal gan-glia (Fig. 1). DBS leads are generally implantedfollowing a parasagittal trajectory that traversesputamen, globus pallidus pars externa (GPe),and GPi. The target is in the posterolateral partof GPi, just medial to the medullary lamina thatseparates GPe and GPi and the tip of the elec-trode will be just dorsolateral to the optic tract.Stimulation-induced side effects, when present,can guide inferences about the location of thelead in relation to the planned target (Table 3).Functionally, the GPi is a site of convergence ofstriatal–pallidal efferents [17–28]. Together withthe substantia nigra pars reticulata (SNr), GPirepresents the main basal ganglia output to theventroanterior and ventrolateral thalamicnuclei and, eventually, to the cortex [29](Table 4).

Surgical Approach and ConsiderationsRelated to Type of DBS Lead

In currently used planning strategies, the STNmay be targeted at the anterior border of the rednucleus, 2 mm lateral to its medial border, andat 4 mm inferior to the anterior commis-sure–posterior commissure (AC–PC) plane [30].GPi may be targeted 3 mm lateral to its medialborder and one-third of its length anterior fromits posterior margin, all at the AC–PC plane [30].However, these heuristics are not absolute, andother effective targeting strategies may also beapplied. In addition, the precise targets withinthese areas are still contested by experts [31, 32].In particular, the optimal spot for stimulationwithin the STN remains debated [33].

For directional leads, targeting currentlyremains the same as for legacy quadripolarleads. However, more attention must be paid tothe depth of the electrodes. Most manufacturers(Boston Scientific and Abbott) have directionalcapabilities only in their second and thirdcontact rows, not in the first or fourth. TheAleva directSTN Acute lead, on the other hand,has directional first and second rows only,which better suit GPi because of the proximityto the internal capsule at the bottom of the lead

Fig. 1 DBS target structures. Anatomical DBS structuresof the left hemisphere in the anterior (left) and posterior(right) views. Courtesy of Abbott’s anatomical visualiza-tion educational software (StimDirect), available on the St.Jude InfinityTM clinician programmer. Subthalamicnucleus (STN): ventrally, the STN is bordered by thesubstantia nigra (SN), anterolaterally by the internalcapsule (IC), posteriorly by the medial lemniscus (ML),dorsally by the zona incerta and the fields of Forel, andmedially by the red nucleus (RN), the medial forebrainbundle, and the midbrain course of the oculomotor nerve.Globus pallidus pars interna (GPi): ventrally, the GPi isbordered by the ansa lenticularis, which separates it fromthe nucleus basalis and the amygdala, ventromedially by theoptic tract, dorsally and medially by the posterior limb ofthe internal capsule, and laterally by the internal medullarylamina of the globus pallidus which separates it from theglobus pallidus pars externa (GPe). Additionally, the GPi isdivided into an internal and external component by theincomplete medullary lamina of the globus pallidus. Ththalamus

Neurol Ther (2020) 9:25–41 31

[34]. With currently available electrodes, thedepth of the electrode should be targeted withthe intention of using a directional row (typi-cally the second or third) as the active contact.Depending on the surgeon’s practice, this mightrequire inserting the electrode deeper than witha standard quadripolar lead.

To help ensure consistent orientation of thesegments of the directional lead, manufacturershave placed a fiducial on the lead proximal tothe four electrode levels. When the fiducialpoints in the anterior direction, the three seg-ments face anteriorly, posteromedially, andposterolaterally, respectively. Nevertheless,

during implantation, the lead is subject to tor-sional movements, making it difficult to predictthe exact position of the fiducial marker and,therefore, the exact orientation of each seg-ment. If there is uncertainty regarding thedirectionality, high-resolution X-rays, fluo-roscopy, or CT scan can be used to verify therotational orientation [35].

DIRECTIONAL PROGRAMMING

The main goal of the first programming visit isto determine the TW for each of the electrode

Table 3 Stimulation-induced side effects

Direction of current spread Side effect Structures involved

STN Lateral or anterolateral Contralateral muscle contractions

Facial or tongue pulling

Dysarthria

Eyelid opening apraxia

Contralateral gaze deviation

Internal capsule

Anteromedial Autonomic changes/vegetative side effects

(nausea, heat sensation, sweating)

Lateral hypothalamic area

Medioventral Disconjugate gaze

Diplopia

Oculomotor nerve

Posterior Paresthesias Medial lemniscus

Dorsal or ventral Bradykinesia worseninga

Levodopa effect reduction

Mood changes (mania, depression, or apathy)

Zona incerta/thalamus

Substantia nigra

Scarcely localizable Impulsivity

Hypophonia

–

GPi Medial Contralateral muscle contractions Internal capsule

Posterior Bradykinesia worseninga

Dorsal Dyskinesia Globus pallidus pars externa

Ventral Phosphenes Optic tract

Lateral

Anterior

No side effects Globus pallidus pars externa

GPi globus pallidus pars interna, STN subthalamic nucleusa In spite of rigidity improvement

32 Neurol Ther (2020) 9:25–41

contacts [36]. Directional leads are often firsttested in ring mode, followed by directionalstimulation on individual segments if efficacyin ring mode is limited by stimulation-relatedside effects, or to identify programming strate-gies that allow a larger TW with lower energyconsumption [37]. Supporting programming

software allows for visualizations of theanatomical context along with the predictedvolume of tissue activated (VTA) and for func-tional mapping of the thresholds for clinicalefficacy and side effects. Some of these tools alsoallow for an integrated analysis of power con-sumption adjusted to each contact impedance.

Table 4 STN and GPi functional connections

Input Output

Afferents Neurotransmitter STN areainvolved

Efferents Neurotransmitter

STN Globus pallidus pars externa GABA Dorsolateral

(motor area)

Ventromedial

(limbic area)

Globus pallidus

pars interna

Glutamate

Primary motor cortex

Supplementary motor area

Premotor cortex

Glutamate Dorsolateral

(motor area)

Substantia nigra

pars reticulata

Glutamate

Prefrontal cortex

Prelimbic-medial orbital areas

Glutamate Ventromedial

(limbic area)

– –

Thalamus (parafascicular and

centromedian nuclei)

Glutamate Dorsolateral

(motor area)

Ventromedial

(limbic area)

– –

Input Output

Afferent area Neurotransmitter Efferent area Neurotransmitter

GPi Striatum (putamen and caudate) GABA Thalamus (ventroanterior and

ventrolateral nuclei)

GABA

Globus pallidus pars externa GABA Substantia nigra pars compacta GABA

Thalamus (intralaminar nucleus) Glutamate Lateral habenular nucleus GABA

STN Glutamate Pedunculopontine nucleus GABA

Pedunculopontine nucleus Glutamate and

acetylcholine

– –

Dorsal raphe nucleus Serotonin – –

Substantia nigra Dopamine – –

GABA gamma-aminobutyric acid, GPi globus pallidus pars interna, STN subthalamic nucleus

Neurol Ther (2020) 9:25–41 33

Visualization of Volume of TissueActivated

The volume of neural activation can be esti-mated using finite element techniques, whereina computer system subdivides a volumetricregion of interest and solves for a scenario byapplying appropriate mathematical relation-ships, initial conditions, and boundary condi-tions and iterating until a stable solutionresults. In this domain, this is applied by posi-tioning an appropriate model of a stimulatingelectrode, configuring it with appropriate stim-ulation parameters (polarities, stimulus ampli-tude), and determining the resulting currentflows and voltage gradients in the surroundingtissue. These electromagnetic gradients canthen be applied, in a second step, to a popula-tion of simulated neurons positioned and ori-ented preferentially around the stimulatingelectrode so as to determine points at whichneurons may be activated by a given stimula-tion regime [38]. These neurons may be mod-eled such that they respond both to theintensity of the stimulation (current amplitude)and the time-dependent parameters such as thewidth of a stimulation pulse [38]. As an exam-ple, various neuron fiber diameters may beincluded, such that the response of smallerfibers to a given stimulus pulse is different thanthat of larger fibers. The resulting neuron pop-ulation that is predicted to be activated canthen be represented visually, as a volumeenclosing the points of activation.

Model-based approaches have been shown tohave some predictive value when used in visualprogramming systems [39]. However, validatingthese models can be challenging, as it is difficultto know with certainty which neural tissuevolumes are indeed activated by stimulation.One thing that has been established is that fullyfeatured models incorporating voltage drop andcapacitance of the electrode–electrolyte inter-face, tissue encapsulation of the electrode, anddiffusion tensor-based 3D tissue anisotropy andinhomogeneity produce more realistic predic-tions than simpler models that do not accountfor these factors [40].

As new stimulation modalities are intro-duced, including the new options afforded by

directional leads, these VTA models may beused to compare the different stimulationoptions available. As examples, in bipolarstimulation, they can be used to understand thedifferences in volume between anodal andcathodal activation regions. For interleavedstimulation, they can be used to understandareas of overlap in separate pulse trains, whereintissue receives stimulation at double theunderlying frequency [41]. In directional stim-ulation, the ability to push stimulation off axis,commonly referred to as displacement of theVTA centroid, can be explored in comparison totraditional ring mode stimulation. This may beof specific interest, as the thresholds to activa-tion in directional stimulation may be differentthan in traditional rings. For fixed stimulationamplitudes, the smaller surface area of a direc-tional segment creates relatively higher gradi-ents around the electrode which may increasethe probability of neural activation [38].

Visualization Strategies: Opportunities

Patient-Specific AnatomyA preoperative magnetic resonance imaging(MRI) may be used to establish the location andboundaries of anatomical structures, eitherthrough adaptation of an anatomical atlas ordirect segmentation of structure boundariesfrom intensity information in the imagesthemselves. Further, fiber tracts may addition-ally be represented if appropriate imagingsequences (diffusion tensor imaging) or atlasesare available.

Final Lead Location and OrientationA postoperative, or in some cases an intraoper-ative, image may be used to establish the finallead location and orientation. For this purpose,images that clearly delineate the electrodepositions and the orientation of fiducial mark-ers included in the lead body via a hyper- orhypo-intense image artifact can be used.

Visualization of Predicted Stimulation ExtentA VTA or similar model may be applied to therepresentation of the stimulating electrodes.Models may be created for one or more

34 Neurol Ther (2020) 9:25–41

potential sets of stimulating parameters (i.e.,different active contacts, different current orvoltage amplitudes, monopolar vs. bipolarstimulation, directional vs. conventional ringstimulation, etc.) such that the overlap of theresulting stimulation field to patient anatomycan be assessed.

Integration of Ancillary InformationIn addition to anatomy, lead location, andstimulation extent, visualization solutions mayadditionally allow for the addition of otherinformation of potential use in identifyingoptimal stimulation settings. For example,intra- or postoperative electrophysiologicalmeasures may be visualized in the patient-specific anatomical context. In addition, aggre-gated historical information about stimulationoutcome in the form of a statistical outcome orside effect map may be visualized in the patient-specific anatomical context to further informprogramming decisions.

Visualization Strategies: Challenges

Limitations of Anatomical ModelsCurrently used anatomical models on whichthe lead is visualized are usually not patient-specific, and even when patient-specific, theyare based on presurgical MRI images that do notaccount for procedural brain shift and postsur-gical anatomical changes reported at up to4 mm in the deep brain [42–46].

Deviation of DBS LeadDBS leads show large deviations from theirintended implanted orientation: more than 30�rotation in 42% of the leads and more than 60�rotation in 11% of the leads [47]. Thus, theorientation of the individual segmented con-tacts might be no longer valid relative to theunderlying anatomy in presurgical MRI pre-sented during programming. Furthermore, sig-nificant lead migration (greater than 3 mm)along the ventrodorsal axis or upward dis-placement from immediate to delayed CT hasbeen reported in over 12% of leads placed at anexpert center [48, 49].

Variability in Tissue Impedanceand AnisotropyValidating VTA models is challenging as it isdifficult to know with certainty which neuraltissue volumes are stimulated [50]. VTA modelsmade available for programming are based ongeneric homogeneous models that do notaccount for tissue inhomogeneities, for instancepermittivity and conductivity of brain struc-tures, which may alter VTA predictions from- 44% to 174% [51]. Also, VTA models availablein programming platforms do not account forpatient-specific tissue anisotropy that can atbest only be modeled using tractography fromhigh-resolution patient-specific diffusion tensorimaging (DTI) [52, 53]. Other real-world factors,not usually modeled, that influence the accu-racy, shape, and extent of the VTA includephysiology and pathophysiology [50], brainpulsation and patient hydration [54], glial scarformation around the electrode [55], and localfluid retention [56].

Software Platforms to Assist DBSProgramming

SureTuneTM (Supplementary Fig. S1) is a pro-gramming visualization tool available for clini-cal use in many regions and close to beingreleased also in the USA. It incorporates theBardinet–Yelnick anatomic atlas and registra-tion algorithm [57], and further allows a user tomanually adjust structure size, shape, andlocation to allow for valid representation of apatient’s specific anatomical variation. It alsosupports intensity-based segmentation of MRIvisible structures. Within the existing software,leads can be placed according to stereotacticcoordinates or aligned via postoperative images.Anatomic representations of structures can bevalidated by co-registration of microelectroderecordings to confirm anatomical boundaries ifadditional confidence is desired. Stimulationmodeling is available for common stimulationconfigurations, and stimulation plans can becreated for use in the clinical setting. Finally, viaa service offering, statistical maps of outcome orside effects can be created which can then beprospectively visualized to inform future

Neurol Ther (2020) 9:25–41 35

clinical decision-making or research applica-tions: a recent study [58] showed that suchstatistical maps correlated well with best clinicalprogramming, demonstrating predictive utilityin prospective cohorts for GPi stimulation indystonia.

While potentially useful for optimizingclinical care, SureTuneTM has several limita-tions. Its atlas is a single brain histologicallybased example that may not account for subjectto subject variation in anatomy. While itsapproach of algorithmic fitting plus humanadjustment can be highly accurate, it is alsodependent on image quality and human judg-ment to achieve a good patient-specific fit.Finally, it uses homogeneous and isotropicassumptions in its VTA methodology, whichmay introduce errors in the visualization due tovariation of tissue properties within a specificpatient’s brain.

SureTuneTM is tightly integrated with otherMedtronic surgical tools, allowing import ofsurgical information from StealthTM navigationand planning software and the documentationof intraoperative electrophysiology which mayfurther validate a patient-specific visualization.Medtronic’s current programming offeringallows visualization of the VTA created by thedevice and the annotation of clinical observa-tions. Future updates to SureTuneTM will extendinteroperability, allowing anatomical and elec-trophysiological information to appear on theprogramming tablet along with the stimulationvolumes.

Boston Scientific GUIDETM XTThe Boston Scientific neuromodulation stimu-lators use a system that includes both VTAmodeling and functional testing. Visualizationof VTAs with the Boston Scientific system isavailable through a software tool (GUIDETM

XT). GUIDETM XT is compatible with theBrainLab Elements (Munich, Germany) surgicalplanning software, available for clinical use inmany countries. The software enables 3D mod-eling and visualization of the VTA relative tothe patient’s anatomical structures. To generatea model of lead location in the brain, a simu-lated DBS lead from a patient’s postoperative CTscan is registered to an anatomical atlas based

on segmentation of a patient’s preoperativeMRI. Clinical stimulation parameters can thenbe programmed onto the simulated lead togenerate the associated VTA. In cases of subop-timal electrode placement or clinical response,additional options may be needed, and currentsteering between directional segments may beuseful to expand the TW (SupplementaryFig. S2) [10]. Visualization tools may be usefulfor understanding these nuances of directionalDBS and adjusting stimulation appropriately.For example, the VTA created by coactivation oftwo segments has a different shape than theVTA created by activation of a single segment,with the former having a lesser radial extent ofactivation than the latter at the same ampli-tudes. The VerciseTM system also includes theNeural Navigator software, intended to aid infunctional testing of different stimulator set-tings by mapping the resulting clinical effects.Therapeutic effects and side effects associatedwith monopolar stimulation on both ring anddirectional electrodes are represented on a 2Dclinical effects map (Supplementary Figs. S3 andS4), and effects may be recorded on all leads forall stimulation configurations. VTAs for bothstandard DBS leads and directional DBS leadsare also visualized within the Neural Navigatorsoftware, which can import the anatomicalstructures from the BrainLab platform.

Abbott InformityTM

While the Abbott InfinityTM clinician program-mer does not have a VTA visualization tool, itincludes the InformityTM programming soft-ware designed primarily for simplifying func-tional programming. The software guides theuser through directional programming usingvisual representations of stimulation responses,occurrences of stimulation-induced symptomrelief and side effects, to create an action plan ofranked electrode montage alternatives that maybe needed over time during therapy. The layoutand workflow of the InformityTM programmingsoftware enable ‘‘event markers’’ to documentthe amplitudes that produce symptom reliefand side effects (Supplementary Figs. S5, S6, andS7). After monopolar survey of ring and seg-mented electrodes, the InformityTM softwareallows clinicians to rank the investigated

36 Neurol Ther (2020) 9:25–41

montages according to various clinically rele-vant criteria. With traditional omnidirectionalprogramming, amongst montages with compa-rable outcomes some clinicians prioritize max-imizing the TW while others prioritizeminimizing the TCS (power consumption). Tothat end, the decision support tool availablewithin the InformityTM software not onlyallows ranking the montages on the basis ofpower (microwatts) and TW (milliamps) butalso on the basis of a measure referred to as thetherapeutic window percentage (TW%). TW%,which is TW expressed as a percentage of TCS, isa means to balance the trade-off between max-imizing TW and minimizing TCS and givesclinicians a means to optimize gains in bothTCS and TW simultaneously. A final sortingoption, balanced threshold, gives clinicians anadditional level of optimization to balancegains in TW% while minimizing power con-sumption as per clinician preference (Supple-mentary Fig. S7). The software allows completecustomization of symptom relief and side effectlists and enables the export of the entire func-tional programming session in the form of aPDF report that can be exported to electronicmedical records for future review.

CONCLUSIONS

Increasing clinical evidence supports the supe-riority of directional over omnidirectionalstimulation. It is conceivable that directionalleads, by providing asymmetric stimulation,may avoid the need for complex programmingparadigms such as bipolar stimulation, fre-quency or pulse width modulation, or inter-leaving. At a minimum, stimulation throughdirectional electrodes can be considered asanother tool to improve the benefit/side effectratio. At a maximum, directional stimulationmay become the preferred way to program, evenwhen omnidirectional stimulation causes noside effects, because of its larger TW and lowerenergy consumption.

However, as new DBS systems increase intheir capability to control the shape, size, andlocation of stimulated neural tissue, the com-plexity of optimizing the configuration of such

systems grows as well. The use of simple pro-gramming protocols, such as the activation of asingle directional segment, has proved to beeffective in the vast majority of cases [13].Directional multiple-electrode programmingconfigurations, whether using independentcurrent controllers or interleaving, may provideadditional nuances in programming strategies,but may also result in increased programmingcomplexity [59], changes to battery powerconsumption, and reduction in the laterality ofthe volume of activation [60]. To assist withDBS programming, DBS producers developedinnovative software platforms for functionalmapping, as well as tools for visualization of thevolume of neural activation. Still, these modelsare constrained by simplifying assumptions,such as using homogeneous and isotropic tissueenvironments and arbitrarily positioned popu-lations of generally linear axons. Also, no studyhas so far established if commercially availablesoftware platforms are superior to standardprogramming.

In conclusion, while directionality offers aunique opportunity to improve the functionaloutcomes of DBS, it also requires definition ofunified strategies for functional mapping andcommon standards for VTA visualization sincesuboptimal programming remains one of themajor causes for DBS failure [6, 61]. Here, weadvocate for intensive collaboration betweenDBS manufacturers and academic centers todevelop and test in large multicenter clinicaltrials innovative programming algorithms aim-ing at maximizing the benefits of directionalDBS.

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle.

Authorship. All named authors (Dr. Merola,Dr. Romagnolo, Dr. Krishna, Dr. Pallavaram, Dr.Carcieri, Dr. Goetz, Dr. Mandybur, Dr. Duker,Dr. Dalm, Dr. Rolston, Dr. Fasano, and Dr.Verhagen Metman) meet the International

Neurol Ther (2020) 9:25–41 37

Committee of Medical Journal Editors (ICMJE)criteria for authorship for this article, takeresponsibility for the integrity of the work as awhole, and have given their approval for thisversion to be published.

Disclosures. Aristide Merola is supported byNIH (KL2 TR001426) and has received speakerhonoraria from CSL Behring, Abbvie, andCynapsus Therapeutics. He has received Grantsupport from Lundbeck. Alberto Romagnolo hasreceived Grant support and speaker honorariafrom AbbVie, speaker honoraria from ChiesiFarmaceutici and travel Grants from Lusofar-maco, Chiesi Farmaceutici, Medtronic, and UCBPharma. Vibhor Krishna has received researchGrant from Medtronic, Boston Scientific, andAbbott. Srivatsan Pallavaram is a Medical Sci-ence Advisor (Medical Affairs) at Abbott Labsand receives salary for his services. StephenCarcieri is an employee at Boston Scientific andreceives salary for his services. Steven Goetz isan employee at Medtronic and receives salaryfor his services. George Mandybur has receivedconsulting agreement with Boston Scientificand Abbott, as well as research Grants fromBoston Scientific. Andrew P. Duker and BrianDalm have nothing to declare. John D. Rolstonhas consulting agreements with NeuroPace andMedtronic, and stock in Axion Biosystems. Hereceived funding from the NIH (NCATS KL2TR002539 and NINDS K23 NS114178). AlfonsoFasano sits in the advisory board of Evotion,Inbrain Neuroelectronics and Cortics, receivedhonoraria for consultancies from Apple, Abbvie,Abbott, BrainLab, Boston Scientific, Chiesi far-maceutici, Ipsen, Medtronic, Sunovion, andUCB; honoraria for participation in advisoryboards from Abbvie, Boston Scientific, andIpsen; research Grants from Abbvie, BostonScientific, Cummings Foundation, DystoniaMedical Research Foundation Canada, MichaelJ. Fox Foundation, Medtronic, and University ofToronto. Leo Verhagen sits in the advisoryboards of Abbott Neuromodulation, AbbVie Inc,Biogen Inc. He is in the editorial board of Neu-rology and Therapy and Brain Sciences. He hasreceived consultancies from Abbott, AbbVie Inc,and Boston Scientific, and research supportfrom Medtronic, Boston Scientific, Abbott,

AbbVie, Neuroderm, Biogen Inc, and Prileniatherapeutics. He has received NIH funding (R01NS40902) as a site-PI. Leo Verhagen is a memberof the journal’s Editorial Board.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Data availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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