neuroprotection trek—the next generation : neuromodulation i. techniques—deep brain stimulation,...

Ann. N.Y. Acad. Sci.

993: 1–13 (2003). ©2003 New York Academy of Sciences.

Neuroprotection Trek—The Next Generation

Neuromodulation I. Techniques—Deep Brain Stimulation, Vagus Nerve Stimulation, and Transcranial Magnetic Stimulation

RUSSELL J. ANDREWS

NASA Ames Research Center, Moffett Field, California, USA

A

BSTRACT

:

Neuromodulation

denotes controlled electrical stimulation of thecentral or peripheral nervous system. The three forms of neuromodulationdescribed in this paper—deep brain stimulation, vagus nerve stimulation, andtranscranial magnetic stimulation—were chosen primarily for their demon-strated or potential clinical usefulness. Deep brain stimulation is a completelyimplanted technique for improving movement disorders, such as Parkinson’sdisease, by very focal electrical stimulation of the brain—a technique thatemploys well-established hardware (electrode and pulse generator/battery).Vagus nerve stimulation is similar to deep brain stimulation in being well-established (for the treatment of refractory epilepsy), completely implanted,and having hardware that can be considered

standard

at the present time.Vagus nerve stimulation differs from deep brain stimulation, however, in thatafferent stimulation of the vagus nerve results in diffuse effects on manyregions throughout the brain. Although use of deep brain stimulation forapplications beyond movement disorders will no doubt involve placing thestimulating electrode(s) in regions other than the thalamus, subthalamus, orglobus pallidus, the use of vagus nerve stimulation for applications beyond epi-lepsy—for example, depression and eating disorders—is unlikely to requirealtering the hardware significantly (although stimulation protocols may dif-fer). Transcranial magnetic stimulation is an example of an external or non-implanted, intermittent (at least given the current state of the hardware) stim-ulation technique, the clinical value of which for neuromodulation and neuro-protection remains to be determined.

K

EYWORDS

: deep brain stimulation; electrical stimulation; neuromodulation;neuroprotection; transcranial magnetic stimulation; vagus nerve stimulation

INTRODUCTION

Neuromodulation

is the term adopted to denote controlled electrical stimulationof the central or peripheral nervous system. Neuromodulation implies focused stim-ulation of a specific region or nerve, in contrast to the generalized high intensitystimulation of, for example, electroconvulsive therapy (used for refractory depres-sion). The techniques include completely implanted devices (electrodes and pulse

Address for correspondence: Russell J. Andrews, M.D., 555 Knowles Drive, Suite 112, LosGatos, CA 95032, USA. Voice: 408-374-0401; fax: 408-866-8842.

[email protected]

2 ANNALS NEW YORK ACADEMY OF SCIENCES

generator/battery) as well as external devices for intermittent treatment (transcranialmagnetic stimulation offering the best example).

We review here three techniques of neuromodulation, two of which are in wide-spread clinical use for specific disorders, and a third—like the first two—that isunder active investigation for additional applications (some of which are discussedin the next paper in this volume).

DEEP BRAIN STIMULATION

Deep brain stimulation (DBS), which has been employed since the 1960s, useselectrodes on the order of a millimeter in diameter implanted, for example, into theperiaqueductal grey for the treatment of chronic pain.

1

For more than 20 years onlya handful of neurosurgeons embraced the technique, due to both the questionablebenefit in many patients and the lack of reliable implantable devices. In the late1980s, the French neurosurgeon Benabid obtained long-term results from thalamicDBS that matched those of thalamotomy in the treatment of tremor (both essentialand Parkinsonian).

2

Implanted devices provided by Medtronic (a pioneer in cardiacpacemaker development) reached a level of reliability that permitted widespreadclinical trials to be completed. DBS of the thalamus for tremor received CE Markapproval in Europe in 1993 and Food and Drug Administration (FDA) approval inthe USA in 1997. DBS of the subthalamic nucleus (STN) and the globus pallidusinterna (GPi) for movement disorders other than (or in addition to) tremor receivedthe CE Mark in 1998 and FDA approval in 2002.

The implanted components for DBS, illustrated in F

IGURE

1 and F

IGURE

2, consistof (1) an electrode that is approximately 1.25mm in diameter with four contacts;(2) a pulse generator/battery (similar to the device used for cardiac pacing, both inaction and in placement subcutaneously inferior to the clavicle); and (3) an extensionconnecting the two. The electrode is placed into the ventral intermediate nucleus ofthe thalamus (for tremor alone), the GPi (for dystonia and dyskinesias), and—mostfrequently in Parkinson’s disease patients with the cardinal findings of rigidity,bradykinesia, and/or tremor—the STN. CT- or MRI-based stereotactic image guid-ance is employed (usually requiring the application of a stereotactic head frameunder local anesthesia) for anatomic localization, and in some centers, ventriculog-raphy as well. Electrode placement is performed through a burr hole in the coronalregion with the patient awake (under light intravenous sedation) to allow testingof limb movements for relief of tremor, rigidity, and bradykinesia, as well as todetect adverse effects of stimulation on limb movements, paresthesias, eye move-ments, and speech. Microelectrode recording (with a microelectrode that is less than100microns in diameter) is carried out in many centers to aid in identifying the targetin relation to surrounding structures; for example, in the case of the STN, the fieldsof Forel dorsally and the substantia nigra ventrally.

3

With satisfactory electrophysi-ologic placement, the microelectrode is replaced with the permanent stimulatingelectrode (F

IG

. 2). Once accurate placement is confirmed, both for efficacy and forlack of adverse effects, by stimulation through the permanent electrode (with thepatient awake and responsive—similar to awake testing during resective surgery forepilepsy), the patient is placed under general anesthesia while implanting the pulse

3ANDREWS: NEUROMODULATION TECHNIQUES

FIGURE 1. The implanted components of deep brain stimulation: electrode, exten-sion, and pulse generator/battery (Soletra model). (Figure courtesy of Medtronic, Inc.)


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generator/battery and the extension connecting the two (running subcutaneouslyfrom the scalp to the infraclavicular area) (F

IG

. 1). Patients are typically dischargedwithin 24hours of surgery.

Bilateral DBS electrode placement is necessary in the vast majority of Parkin-son’s patients as well as essential tremor patients with bilateral symptoms. Thereduction in dosage of Parkinsonian medications seen in most patients with STNDBS (usually 50

%

or more) is only achieved with bilateral stimulation. The entireprocedure (from placement of the stereotactic frame through MRI scanning throughthe surgical procedure itself) may take 12hours or more, especially if ventriculogra-phy and extensive microelectrode recording (to map the STN region in detail) areundertaken. In centers that perform confirmatory microelectrode recording alone—or rely solely on macrostimulation for localization—the procedure may last six toeight hours (from placement of the stereotactic frame prior to MRI scanning toimplantation of the pulse generator/battery bilaterally). The two primary risks of theprocedure are (1) infection (increased over the risk for most intracranial proceduresdue to the extensive hardware implanted, and likely related to the length of the sur-gery as well), and (2) intracranial hemorrhage (subdural or intracerebral) due to theelectrode placement.

4

Intracranial hemorrhage can result in major neurological def-icit or death, and is related to the number of passes made with the microelectrode formapping—an argument for confirmatory microelectrode recording alone.

5

Success with DBS implantation depends significantly on the postimplantationprogramming of the pulse generator (F

IG

. 2 and see T

ABLE

1). The many parametersthat can be adjusted (T

ABLE

1) result in thousands of possible variations in stimula-tion. Although suggestions are being developed based on the experience of activeDBS implantation centers,

6

the huge variety of symptoms and medication schedulesof Parkinson’s patients, in particular, makes postoperative programming an essentialstep in optimizing DBS benefit for the patient.

One of the primary benefits of DBS for Parkinson’s disease is a marked reductionin “off” time; patients who have a poor response to dopaminergic medications do notbenefit greatly from DBS as a rule. There can be synergy between DBS and thepatient’s Parkinson’s medications in that the best results on standard tests, such as

T

ABLE

1. Deep brain stimulation programming parameters

Parameter Range Typical Value

Amplitude 0–10.5 V less than 3.5 V

Pulse width 60–450

µ

sec 60–90

µ

sec

Rate 2–185 Hz 130–185 Hz

Polarity monopolar

bipolar any

multipolar

Electrode (each of four) positive

negative any

off


the unified Parkinson’s disease rating scale (UPDRS), may be modestly improvedfollowing DBS implantation. A benefit of the reduction in dosage of the Parkinson’smedications is a parallel reduction of the drug-induced dyskinesias that are charac-teristic of many Parkinson’s patients after five to eight years of pharmacologic treat-ment. Another finding in DBS is the gradual improvement in efficacy during a yearor longer in most patients—as evidenced by improvement in percent of time spent“on”, improvement in UPDRS scores, and decreased dosages of Parkinson’s medi-cations at one year in comparison with three or six months following STN DBSimplantation.

7

The mechanism of action of DBS in Parkinson’s disease (and other applications)is uncertain. Experimental evidence suggests that rather than jamming or function-ally (but reversibly) ablating neurons, DBS at therapeutic levels may affect axonsprimarily rather than cell bodies.

8

Recent clinical findings also support this: the stim-ulating electrode in Parkinson’s DBS patients has been found to lie at the dorsal bor-der of the STN or still further dorsal in the fiber tracts of the fields of Forel, ratherthan within the STN itself as originally intended.

9,10

The trend on follow-up is tohave the optimal stimulating contact lie slightly dorsal to the contact demonstrated(by microelectrode recording) to be within the STN. Another recent finding isthe presence of synchronous firing patterns (15–30Hz) between pairs of STN neu-rons in patients whose Parkinsonian symptoms are more responsive to dopaminergicmedications.

11

It is hypothesized that the beneficial effect of STN DBS, like that ofdopaminergic medications, is the result of a desynchronizing action on these firingpatterns. It is safe to say that our understanding of the efficacy of DBS for Parkin-son’s disease is rudimentary at present—and that we have just begun to explore thepotential of DBS for nervous system conditions beyond movement disorders (pleasesee the next paper in this volume).

VAGUS NERVE STIMULATION

For Parkinson’s patients, the discovery of the clinical efficacy of

L

-dopa in the1960s was a major therapeutic advance—unmatched by any of the newer medica-tions of the past 30 or more years. For patients with epilepsy, the advances in phar-macologic therapy have been even less robust during the past 30 or more years—atleast one-third of new-onset epilepsy patients remain uncontrolled with medicationsalone.

12

Again, like Parkinson’s disease, the side effects of the antiepileptic medica-tions (AEDs), for example, sedation and allergic reactions, are a significant draw-back (and frequently occur early in treatment, unlike dopamine-induced dyskinesias,which typically do not appear for five years or more). Thus, the hypothesis and dem-onstration that stimulation of the vagus nerve in the cervical region can have a ben-eficial effect on medication-refractory epilepsy have been a major advance for thosepatients who are not candidates for more definitive surgical resection (e.g., temporallobectomy).

13

Vagus nerve stimulation (VNS) has a briefer history than DBS, but since itspotential for application to refractory epilepsy in humans was hypothesized in the1980s the timeline of clinical development has been quite similar: CE Mark approvalwas obtained in Europe in 1994, and FDA approval in the USA in 1997. Its benefit


for patients with refractory epilepsy has increased substantially; more than 16,000patients have been implanted with vagus nerve stimulators, and a recent journal sup-plement is dedicated to a status report of VNS five years after FDA approval wasgranted in the USA [

Neurology

59

(Suppl. 4): S1–S61, 2002].The implanted device in VNS, like DBS, consists of an electrode, a pulse gener-

ator/battery, and a connecting extension or lead (see F

IGURE

3). The electrode is com-posed of three helical coils that encircle the vagus nerve in the neck—the positiveelectrode cephalad, the negative electrode immediately caudad, and an anchoringcoil further caudad (F

IG

. 3). The left vagus nerve is used because it has more afferentfibers (and less cardiac effect on stimulation) than the right vagus nerve. Implanta-tion of the pulse generator/battery (in the infraclavicular region) is identical to that

FIGURE 3. The implanted components of vagus nerve stimulation: helical electrodeand pulse generator/battery. Inset: magnified view of three-section helical electrode encir-cling the vagus nerve—negative electrode superior, positive electrode middle, tetheringelectrode inferior. (Figure courtesy of Cyberonics, Inc.)


T

ABLE

2. Vagus nerve stimulation programming parameters

Parameter Range Typical Value

Current 0–3.5 milliamp 1.25 milliamp

Pulse width 130–1,000

µ

sec 500

µ

sec

Rate 1–30 Hz 30 Hz

Signal on time 7–60 sec 30 sec

Signal off time 12 sec–180 min 5min

FIGURE 4. Projections of the vagus nerve to diencephalic and cerebral structures, pri-marily via the nucleus of the tractus solitarius. Major projections include the thalamus,hypothalamus, amygdala, and other limbic structures. (Reprinted from Ref. 21 with permis-sion from Martin Dunitz.)


for DBS. The implantation surgery can be performed in one to two hours as an out-patient procedure under either local/regional or general anesthesia. In addition to theelectrical stimulation programmed by the physician (see T

ABLE

2)—which is inter-mittent (e.g., 30sec stimulation every five min) but continues 24 hours a day—thepatient can give him/herself an extra stimulation with a magnet placed briefly (for asecond) over the region of the pulse generator/battery. This is of particular benefitfor patients having an aura prior to a seizure: frequently the seizure can be complete-ly aborted, or at least reduced in duration and/or severity (both the ictal and the post-ictal periods). The same magnet, when taped or otherwise held over the pulsegenerator/battery, can turn off the VNS for temporary or extended periods. This is ofbenefit for those patients who experience voice changes during VNS and who areinvolved in singing or public speaking. The discomfort and voice changes the major-ity of VNS patients experience immediately following implantation rapidly amelio-rate in the vast majority of patients, and are very rarely a problem after the firstcouple of months.

The clinical benefit of VNS, again like DBS, improves with time followingimplantation; it is frequently 12 to 18 months before maximum benefit is achieved.The benefit is multifactorial:

1. reduction in seizure incidence and/or severity (reduction in seizure fre-quency is typically in the 40

%

to 70

%

range); up to 15

%

of VNS patientsachieve complete seizure control—especially if VNS is instituted early(within five years of epilepsy onset);

14,15

2. reduction in AED requirements (many patients can reduce the dosage ornumber of AEDs required with maintenance or improvement in seizurecontrol); possibly 10

%

of VNS patients are able to discontinue AEDsentirely;

16,17

3. improvement in mood and affect.

18

The mechanism of action of VNS is even less well understood than that ofDBS.

19,20

The connections of the afferent fibers of the vagus nerve—primarily viathe nucleus of the tractus solitarius in the medulla—extend to various regions of thebrainstem (e.g., the medullary reticular formation), the thalamic and hypothalamicregions, and limbic structures such as the amygdala (see F

IGURE

4).

20,21

This diffuseinnervation makes a precise understanding of the mechanism of action of VNSimprobable in the near future; it is likely multifactorial given the rich connections ofthe nucleus of the tractus solitarius. The effects of VNS on (1) electrophysiology(EEG and evoked potentials) and (2) cerebral blood flow (CBF) in the thalamus andother regions are being extensively studied.

19,20

Because of the widespread neurobiologic effects of VNS, the application of VNSto a variety of disorders has been hypothesized. Conditions other than refractory epi-lepsy for which clinical studies of VNS are ongoing include depression, anxiety,obesity, migraine, and Alzheimer’s disease.

22,23

TRANSCRANIAL MAGNETIC STIMULATION

Although d’Arsonval reported phosphenes (flickering lights—likely due tostimulation of the retina) when, in 1896, he placed his head in a coil (110volts,


30amperes), it was not until 1985 that an electric coil placed on the scalp was dem-onstrated to stimulate a region of the underlying brain—in this instance motorcortex.

24

Stimulation of the brain transcranially by the application of electrical cur-rent has been tried (and is of continued research interest

25,26

) but its clinical appli-cation has been limited by side effects (e.g., scalp pain or burns) and by difficultywith conduction through the tissues of the scalp and skull. The initial clinical appli-cation of transcranial magnetic stimulation (TMS)—to demonstrate the integrity ofthe motor system from motor cortex to limb muscle (e.g., during spinal surgery)—has expanded to potential therapeutic efficacy in a wide variety of disorders, fromdepression to epilepsy.

27–29

None of these applications, however, has achieved thestatus of accepted therapy (e.g., FDA approval) but several are currently under inves-tigation in a number of centers worldwide.

TMS, as the name implies, is a noninvasive technique of stimulating a region ofthe cortex (to a depth of several centimeters) by means of a rapidly cycling magneticfield. A pulse generator creates a high current (5,000amperes or more) for a briefperiod (on the order of one msec) that is passed through a coil placed on the scalp.The rapidly changing current creates a strong magnetic field (one to two tesla, i.e.,comparable to that of clinical MRI scanners—although clearly a very focal magneticfield only), which—unlike transcranial electrical stimulation—is unimpeded andundistorted by the intervening scalp and skull (see F

IGURE

5). The rapidly alternatingmagnetic field induces electrical currents intracranially. By placing two TMS coilsin figure-of-eight fashion, a relatively focused electrical stimulation of the cortexunderlying the center of the figure-of-eight can be achieved. Greater clinical effectfrom TMS can be achieved by rapidly repeating the stimulations (up to 60Hz) forseveral seconds—repetitive transcranial magnetic stimulation (rTMS).

The major adverse effect of TMS—and likely more common with rTMS—is theinduction of seizures by the magnetic stimulation of the cortex.

30

The incidence isperhaps 1 to 2

%

of subjects undergoing TMS or rTMS, although many studies haveincluded subjects with epilepsy and/or depression. The expected postictal slowingon EEG has been noted, but in general long-term clinical sequellæ have not—andEEG changes have resolved within 48hours.

30

Other adverse effects include head-ache, facial muscle twitching, and tinnitus.

28

Guidelines for, and contraindicationsto, rTMS have been established; the latter include:

30

1. absolute contraindications—metal in cranium, intracardiac lines, increasedintracranial pressure; and

2. relative contraindications—pregnancy, childhood, heart disease, cardiacpacemaker, implanted medication pump, tricyclic antidepressants, neuro-leptics, family history of epilepsy.

Adherence to such safety guidelines has probably been the reason for a lack of sei-zures in recent studies employing TMS/rTMS.

28

The clinical benefit of TMS and rTMS is under investigation, with the majorityof studies to date involving neuropsychiatric applications: depression, obsessive–compulsive disorder, posttraumatic stress disorder, and schizophrenia.

27,28

For neu-ropsychiatric disorders, rTMS has customarily been applied over the dorsolateralprefrontal cortex. Repeated treatments of depressed patients with rTMS daily forone or two weeks, or longer, has been shown to have a degree of benefit approachingthat of electroconvulsive therapy (ECT).

28

One interesting effect of rTMS over the


dorsolateral prefrontal cortex—which may prove relevant to the treatment of Parkin-son’s disease—is a release of endogenous dopamine in the ipsilateral caudate nucle-us.

31

The preliminary work on rTMS for refractory epilepsy is addressed in thefollowing paper in this volume.

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