Evolution of Deep Brain Stimulation: Human Electrometer and Smart Devices Supporting the Next Generation of Therapy

doi:10.1111/j.1525-1403.2009.00199.x

Neuromodulation: Technology at the Neural Interface

Volume 12, Issue 2, April 2009, Pages 85-103

https://doi.org/10.1111/j.1525-1403.2009.00199.x Get rights and content

ABSTRACT

Deep brain stimulation (DBS) provides therapeutic benefit for several neuropathologies, including Parkinson disease (PD), epilepsy, chronic pain, and depression. Despite well-established clinical efficacy, the mechanism of DBS remains poorly understood. In this review, we begin by summarizing the current understanding of the DBS mechanism. Using this knowledge as a framework, we then explore a specific hypothesis regarding DBS of the subthalamic nucleus (STN) for the treatment of PD. This hypothesis states that therapeutic benefit is provided, at least in part, by activation of surviving nigrostriatal dopaminergic neurons, subsequent striatal dopamine release, and resumption of striatal target cell control by dopamine. While highly controversial, we present preliminary data that are consistent with specific predications testing this hypothesis. We additionally propose that developing new technologies (e.g., human electrometer and closed-loop smart devices) for monitoring dopaminergic neurotransmission during STN DBS will further advance this treatment approach.

Section snippets

Hypotheses of DBS Mechanisms for PD

Despite acceptance of STN DBS as a therapeutic tool in the treatment of PD, the precise mechanisms of action are currently unknown. Because the therapeutic effects of DBS are similar to those of a lesion (i.e., subthalamotomy), DBS has been traditionally thought to silence pathologically hyperactive neurons at the site of stimulation (depolarization block) (18., 19., 20., 21.). However, emerging evidence from a number of basic and clinical studies implicates additional mechanisms, besides a (i)

Predictions of the Dopamine Release Hypothesis

The strength of a scientific hypothesis is related to its ability to predict outcomes successfully. In this regard, the dopamine release hypothesis of STN DBS for the treatment of PD lends itself to several important predictions that can be tested experimentally and clinically. While all of these predications may not be definitive, in the sense that if proven false the hypothesis would be rejected, these predictions if proven true would lend support to the dopamine release hypothesis. As

Future Directions: The Next Generation of DBS Systems

Although studies using animal models have proven to be invaluable for characterizing DBS mechanism and will continue to play an important role in future studies assessing this mechanism further, for clinicians and patients the eventual focus must be the human application and ultimately, increased therapeutic benefit. In this section, we describe new technological innovations that will not only permit examination of the dopamine release hypothesis of STN DBS in humans, but will also advance the

Conclusion

As our understanding of the DBS mechanisms of action continues to expand, it is likely that such advances will enable advances in the DBS approach by supporting improvements in the surgical technique and the development of next-generation “smart” DBS devices. The hope of significant improvements will also result in broadening the range of neurological and psychiatric conditions that can be treated by DBS. Whether next-generation “smart” DBS devices will utilize continuous neurochemical sensing

Conflict of Interest

Kendall H. Lee, MD, PhD, and Charles D. Blaha, PhD, have a patent pending on a smart DBS system. No other conflict of interest was reported.

References (106)

BenabidAL
Deep brain stimulation for Parkinson’s disease
Curr Opin Neurobiol
(2003)
BittarRG et al.
Deep brain stimulation for pain relief: a meta-analysis
J Clin Neurosci
(2005)
MaybergHS et al.
Deep brain stimulation for treatment-resistant depression
Neuron
(2005)
HardestyDE et al.
Deep brain stimulation in movement and psychiatric disorders
Biol Psychiatry
(2007)
BenazzouzA et al.
Responses of substantia nigra pars reticulata and globus pallidus complex to high frequency stimulation of the subthalamic nucleus in rats: electrophysiological data
Neurosci Lett
(1995)
LozanoAM et al.
How does DBS work?
Suppl Clin Neurophysiol
(2004)
McIntyreCC et al.
Uncovering the mechanism(s) of action of deep brain stimulation: activation, inhibition, or both
Clin Neurophysiol
(2004)
Magarinos-AsconeC et al.
High-frequency stimulation of the subthalamic nucleus silences subthalamic neurons: a possible cellular mechanism in Parkinson’s disease
Neuroscience
(2002)
AgidY.
Parkinson’s disease: pathophysiology
Lancet
(1991)
MeissnerW et al.
Striatal dopaminergic metabolism is increased by deep brain stimulation of the subthalamic nucleus in 6-hydroxydopamine lesioned rats
Neurosci Lett
(2001)

MeissnerW et al.

Deep brain stimulation of subthalamic neurons increases striatal dopamine metabolism and induces contralateral circling in freely moving 6-hydroxydopamine-lesioned rats

Neurosci Lett

(2002)

LaruelleM et al.

Positron emission tomography: imaging and quantification of neurotransporter availability

Methods

(2002)

AlbinRL et al.

The functional anatomy of basal ganglia disorders

Trends Neurosci

(1989)

GraybielAM

Neurotransmitters and neuromodulators in the basal ganglia

Trends Neurosci

(1990)

OvertonPG et al.

Burst firing in midbrain dopaminergic neurons

Brain Res Rev

(1997)

KitaiST et al.

Afferent modulation of dopamine neuron firing patterns

Curr Opin Neurobiol

(1999)

WoolfNJ

Cholinergic systems in mammalian brain and spinal cord

Prog Neurobiol

(1991)

GrillnerP et al.

Intrinsic membrane properties and synaptic inputs regulating the firing activity of the dopamine neurons

Behav Brain Res

(2002)

McGintyJF

Co-localization of GABA with other neuroactive substances in the basal ganglia

Prog Brain Res

(2007)

MeltzerLT et al.

Modulation of dopamine neuronal activity by glutamate receptor subtypes

Neurosci Biobehav Rev

(1997)

PaladiniCA et al.

Striatal, pallidal, and pars reticulata evoked inhibition of nigrostriatal dopaminergic neurons is mediated by GABA_A receptors in vivo

Neuroscience

(1999)

CeladaP et al.

GABAergic control of nigra dopamine neurons: role of globus pallidus and nigra reticulata

Neuroscience

(1999)

LeeKH et al.

High frequency stimulation of the subthalamic nucleus increases glutamate in the subthalamic nucleus of rats as demonstrated by in vivo enzyme-linked glutamate sensor

Brain Res

(2007)

VernadakisA et al.

Role of astrocytes in aging. late passage primary mouse brain astrocytes and C-6 glial cells as models

Prog Brain Res

(1992)

HammondC et al.

Electrophysiological demonstration of an excitatory subthalamonigral pathway in the rat

Brain Res

(1978)

BergstromBP et al.

Utility of a tripolar stimulating electrode for eliciting dopamine release in the rat striatum

J Neurosci Methods

(1999)

Clapp-LillyKL et al.

An ultrastructural analysis of tissue surrounding a microdialysis probe

J Neurosci Methods

(1999)

TangA et al.

Characterization of probe and tissue factors that influence interpretation of quantitative microdialysis experiments for dopamine

J Neurosci Methods

(2003)

BorlandLM et al.

Voltammetric study of extracellular dopamine near microdialysis probes acutely implanted in the striatum of the anesthetized rat

J Neurosci Methods

(2005)

Di ChiaraG et al.

Stimulation of dopamine transmission in the dorsal caudate nucleus by pargyline as demonstrated by dopamine and acetylcholine microdialysis and Fos immunohistochemistry

Neuroscience

(1993)

BlahaCD et al.

Does monoamine oxidase inhibition by pargyline increase extracellular dopamine concentrations in the striatum?

Neuroscience

(1996)

PetersJL et al.

Ultrastructure at carbon fiber microelectrode implantation sites after acute voltammetric measurements in the striatum of anesthetized rats

J Neurosci Methods

(2004)

ZigmondMJ et al.

Compensations after lesions of central dopaminergic neurons: some clinical and basic implications

Trends Neurosci

(1990)

ChangJ-Y et al.

Studies of the neural mechanisms of deep brain stimulation in rodent models of Parkinson’s disease

Neurosci Biobehav Rev

(2007)

BlahaCD et al.

Application of in vivo electrochemistry to the measurement of changes in dopamine release during intracranial self-stimulation

J Neurosci Methods

(1990)

KilpatrickMR et al.

Extracellular dopamine dynamics in rat caudate-putamen during experimenter-delivered and intracranial self-stimulation

Neuroscience

(2000)

YavichL et al.

In vivo voltammetry with removable carbon fibre electrodes in freely-moving mice: dopamine release during intracranial self-stimulation

J Neurosci Methods

(2000)

CarelliRM et al.

Functional microcircuitry in the accumbens underlying drug addiction: insights from real-time signaling during behavior

Curr Opin Neurobiol

(2004)

DeuschlG et al.

A randomized trial of deep-brain stimulation for Parkinson’s disease

N Engl J Med

(2006)

BenabidAL et al.

Chronic VIM thalamic stimulation in Parkinson’s disease, essential tremor and extra-pyramidal dyskinesias

Acta Neurochir Suppl (Wien)

(1993)

GreeneP.

Deep-brain stimulation for generalized dystonia

N Engl J Med

(2005)

HodaieM et al.

Chronic anterior thalamus stimulation for intractable epilepsy

Epilepsia

(2002)

BoonP et al.

Deep brain stimulation in patients with refractory temporal lobe epilepsy

Epilepsia

(2007)

VonckK et al.

Anatomical and physiological basis and mechanism of action of neurostimulation for epilepsy

Acta Neurochir Suppl

(2007)

RascheD et al.

Deep brain stimulation for the treatment of various chronic pain syndromes

Neurosurg Focus

(2006)

MaciunasRJ et al.

Prospective randomized double-blind trial of bilateral thalamic deep brain stimulation in adults with Tourette syndrome

J Neurosurg

(2007)

GreenbergBD et al.

Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder

Neuropsychopharmacology

(2006)

LipsmanN et al.

Deep brain stimulation for treatment-refractory obsessive-compulsive disorder: the search for a valid target

Neurosurgery

(2007)

SchlaepferTE et al.

Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression

Neuropsychopharmacology

(2008)

McIntyreCC et al.

Optimizing deep brain stimulation parameter selection with detailed models of the electrode–tissue interface

Conf Proc IEEE Eng Med Biol Soc

(2006)

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Deep brain stimulation (DBS) was first used to treat essential tremor and the movement disorders associated with Parkinson disease. Its success led to its consideration as treatment for a wide variety of applications, including other neurologic as well as psychiatric and cognitive impairments. Extensive research conducted over the past 20 years has attempted to explain the as-yet uncertain mechanisms of DBS, with a focus on its effects on neuronal and astrocytic activity at the cellular, regional, and network level within the basal ganglia thalamocortical circuitry. Based on experimental evidence and theoretical considerations, five potentially co-occurring mechanisms have been proposed. DBS may produce local changes in the stimulated brain nuclei, as well as distal changes in efferent outputs and target nuclei.
These theories of mechanism may not be exclusionary. Determining the degree to which some or all of these cellular and circuitry mechanisms account for the therapeutic efficacy as well as the potential adverse effects of DBS has been an important matter of debate. A review of the literature suggests that DBS mechanisms of action may be too complex to be supported by a single hypothesis, and they cannot be reduced to a simple question of inactivation or inhibition of neuronal activity and neurotransmission. This review summarizes each of these theories and advances in the understanding of the action of DBS, particularly as they relate to the modulation of neuronal spike generation, oscillatory network activity, and enhanced neurotransmission in the basal ganglia–thalamocortical circuit.
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Neuromodulation with electrical stimulation (ES) is an effective intervention. A limitation, however, is that present-day implanted systems provide only continuous stimulation and any change in the underlying neurophysiologic state requires that the patients manually adjust their stimulation parameters. Fortunately, the technology is rapidly advancing to develop integrated closed-loop systems that use sensors to detect neural activity and effectors to adjust ES based on the sensed data. Electrical sensors that detect evoked compound action potentials (ECAPs) are among the most powerful because these tools precisely and directly monitor the neural milieu. In deep brain stimulation, ECAPs can be used to detect motor symptoms and to optimize stimulation parameters accordingly. In spinal cord stimulation, ECAP data are used by effectors to automatically adjust the amplitude of stimulation during patient activities. Because sensed data is applied in real time to maximize therapeutic benefit and patient comfort, this has clear implications for improving clinical outcomes.
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Rapid advancements in neurostimulation technologies are providing relief to an unprecedented number of patients affected by debilitating neurologic and psychiatric disorders. Neurostimulation therapies include invasive and noninvasive approaches that involve the application of electrical stimulation to drive neural function within a circuit. This review focuses on established invasive electrical stimulation systems used clinically to induce therapeutic neuromodulation of dysfunctional neural circuitry. These implantable neurostimulation systems target specific deep subcortical, cortical, spinal, cranial, and peripheral nerve structures to modulate neuronal activity, providing therapeutic effects for a myriad of neuropsychiatric disorders. Recent advances in neurotechnologies and neuroimaging, along with an increased understanding of neurocircuitry, are factors contributing to the rapid rise in the use of neurostimulation therapies to treat an increasingly wide range of neurologic and psychiatric disorders. Electrical stimulation technologies are evolving after remaining fairly stagnant for the past 30 years, moving toward potential closed-loop therapeutic control systems with the ability to deliver stimulation with higher spatial resolution to provide continuous customized neuromodulation for optimal clinical outcomes. Even so, there is still much to be learned about disease pathogenesis of these neurodegenerative and psychiatric disorders and the latent mechanisms of neurostimulation that provide therapeutic relief. This review provides an overview of the increasingly common stimulation systems, their clinical indications, and enabling technologies.
Toward sophisticated basal ganglia neuromodulation: Review on basal ganglia deep brain stimulation
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Visual stimuli evoked increases in striatal DA release via a direct input to the superior colliculus from the retina that, in turn, activated midbrain dopaminergic cells at a short latency. Collectively, these studies have confirmed the utility of fast electrochemical recording procedures to measure DA transmission driven by polysynaptic pathways such as those we have proposed to mediate DBS-evoked DA neurotransmission (Lee et al., 2006, 2009; Shah et al., 2010). With respect to quantifying glutamate release using FPA, recent development of enzyme-coated platinum microelectrodes based on work by Hu et al. (1994) have shown a high degree of reliability as a selective, sensitive and rapidly responding glutamate sensor in vivo (Wilson and Gifford, 2005).
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They summarize what is known regarding the use of carbon nanofibers for both electrical and chemical recording and stimulation of nervous system tissue. They present, as others have (166), how, in large animal models, a wireless instantaneous neurotransmitter concentration sensing system (WINCS) monitors neurochemical release during experimental and clinical DBS surgical procedures. The WINCS device measures in vivo dopamine and adenosine release during DBS using carbon-fiber microelectrodes and glutamate release using an enzyme-linked biosensor.
The International Neuromodulation Society (INS) has determined that there is a need to provide an expert consensus that defines the appropriate use of neuromodulation technologies for appropriate patients. The Neuromodulation Appropriateness Consensus Committee (NACC) was formed to give guidance to current practice and insight into future developments.
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Evolution of Deep Brain Stimulation: Human Electrometer and Smart Devices Supporting the Next Generation of Therapy

ABSTRACT

Section snippets

Hypotheses of DBS Mechanisms for PD

Predictions of the Dopamine Release Hypothesis

Future Directions: The Next Generation of DBS Systems

Conclusion

Conflict of Interest

Curr Opin Neurobiol

J Clin Neurosci

Neuron

Biol Psychiatry

Neurosci Lett

Suppl Clin Neurophysiol

Clin Neurophysiol

Neuroscience

Lancet

Neurosci Lett

Neurosci Lett

Methods

Trends Neurosci

Trends Neurosci

Brain Res Rev

Curr Opin Neurobiol

Prog Neurobiol

Behav Brain Res

Prog Brain Res

Neurosci Biobehav Rev

Neuroscience

Neuroscience

Brain Res

Prog Brain Res

Brain Res

J Neurosci Methods

J Neurosci Methods

J Neurosci Methods

J Neurosci Methods

Neuroscience

Neuroscience

J Neurosci Methods

Trends Neurosci

Neurosci Biobehav Rev

J Neurosci Methods

Neuroscience

J Neurosci Methods

Curr Opin Neurobiol

A randomized trial of deep-brain stimulation for Parkinson’s disease

N Engl J Med

Chronic VIM thalamic stimulation in Parkinson’s disease, essential tremor and extra-pyramidal dyskinesias

Acta Neurochir Suppl (Wien)

Deep-brain stimulation for generalized dystonia

N Engl J Med

Chronic anterior thalamus stimulation for intractable epilepsy

Epilepsia

Deep brain stimulation in patients with refractory temporal lobe epilepsy

Epilepsia

Anatomical and physiological basis and mechanism of action of neurostimulation for epilepsy

Acta Neurochir Suppl

Deep brain stimulation for the treatment of various chronic pain syndromes

Neurosurg Focus

Prospective randomized double-blind trial of bilateral thalamic deep brain stimulation in adults with Tourette syndrome

J Neurosurg

Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder

Neuropsychopharmacology

Deep brain stimulation for treatment-refractory obsessive-compulsive disorder: the search for a valid target

Neurosurgery

Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression

Neuropsychopharmacology

Optimizing deep brain stimulation parameter selection with detailed models of the electrode–tissue interface

Conf Proc IEEE Eng Med Biol Soc