Key Points
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Deep brain stimulation (DBS) has shown remarkable therapeutic benefits for patients with otherwise treatment-resistant movement and affective disorders, such as chronic pain, Parkinson's disease, tremor and dystonia. Yet the precise mechanisms of action for DBS remain uncertain. Here we give an up-to-date overview of the principles of DBS, its neural mechanisms and its potential future applications.
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DBS directly changes brain activity in a controlled manner and, unlike those of lesioning techniques, its effects are reversible. Furthermore, DBS is the only neurosurgical technique that allows blinded studies. New targets for DBS have been discovered through the use of translational research, and in particular through highly successful rodent and primate models of movement disorders.
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DBS of both the normal and the diseased brain fundamentally depends on a number of parameters, including the physiological properties of the brain tissue, which may change with disease state, the stimulation parameters, including amplitude and temporal characteristics, and the geometric configuration of the electrode and the surrounding tissue.
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In vivo neurophysiological recordings of activity from a deep brain electrode in one brain region, made while stimulating another brain region, have shown that DBS modulates the pathological oscillatory activity between brain regions.
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Results from animal experiments have also shown that DBS appears to elicit neurotransmitter release in downstream brain structures, although there is conflicting evidence from human studies.
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Functional neuroimaging methods can be used to elucidate the whole-brain responses elicited by DBS, and on the whole they have confirmed the findings from recordings in other animals. However, methods such as functional MRI should be used with extreme caution, as they entail significant risks to the patient. Owing to its non-invasive nature and high spatial and temporal resolution, magnetoencepholography (MEG) is currently one of the most promising techniques for elucidating the neural mechanisms affected by DBS.
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On balance, the evidence so far suggests that the most likely mode of action for DBS is through stimulation-induced modulation of brain activity, where the modulation comes about through the local effects of the DBS electrode on the neural activity in the DBS target, which is passed on to mono- and poly-synaptic network connections.
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Future applications of DBS include finding more effective brain targets and delivering individualized closed-loop demand-driven stimulation. It will also be important to develop robust translational models of affective disorders. Overall, combining DBS with whole-brain neuroimaging methods like MEG has the makings of a powerful and sophisticated tool for unravelling the fundamental mechanisms of normal and abnormal human brain function.
Abstract
Deep brain stimulation (DBS) has shown remarkable therapeutic benefits for patients with otherwise treatment-resistant movement and affective disorders. This technique is not only clinically useful, but it can also provide new insights into fundamental brain functions through direct manipulation of both local and distributed brain networks in many different species. In particular, DBS can be used in conjunction with non-invasive neuroimaging methods such as magnetoencephalography to map the fundamental mechanisms of normal and abnormal oscillatory synchronization that underlie human brain function. The precise mechanisms of action for DBS remain uncertain, but here we give an up-to-date overview of the principles of DBS, its neural mechanisms and its potential future applications.
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Acknowledgements
The authors were funded by the Medical Research Council, the Norman Collisson Foundation, TrygFonden Charitable Foundation and the Charles Wolfson Charitable Trust.
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Supplementary information
Supplementary information S1 (movie)
This clip shows the effects of deep brain stimulation of the pedunculopontine nucleus in a patient with Parkinson's disease. (Clip courtesy of P. Silburn, T. Coyne and R. Wilcox). (WMV 2064 kb)
Supplementary information S2 (movie)
This clip shows the effects of deep brain stimulation of the internal globus pallidus in a patient with dystonia. (WMV 561 kb)
Supplementary information S3 (movie)
This clip shows the effects of deep brain stimulation in the periventricular/periaqueductal grey in a patient with chronic pain in a phantom limb. (WMV 897 kb)
Supplementary information S4 (movie)
This clip shows the effects of deep brain stimulation of the subthalamic nucleus on tremor in a patient with Parkinson's disease. (WMV 2070 kb)
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DATABASES
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FURTHER INFORMATION
Glossary
- Dystonia
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A movement disorder that leads to involuntary sustained muscle contractions, causing distorted posturing of the foot, leg or arm.
- Neural elements
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The cell body, myelinated axons, dendrites and supporting glial cells.
- Bradykinesia
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The slowing of, and difficulty in initiating, movement that is characteristic of Parkinson's disease.
- Frequency band
-
Neural oscillations have been classified into different frequency bands: delta (1–3 Hz), theta (4–7 Hz), alpha (8–13 Hz), beta (14–30 Hz), gamma (30–80 Hz), fast (80–200 Hz) and ultra fast (200–600 Hz).
- Open-loop stimulator
-
An open-loop stimulator is a simple type of non-feedback controller whereby the input into the brain region is determined using only the current behavioural state and a model of the system.
- 6-hydroxydopamine
-
(6-OHDA). The first agent used to model Parkinson's disease. Injection of 6-OHDA into the substantia nigra causes it to selectively accumulate in dopamine neurons, and then kill them as a result of toxicity that is thought to involve the generation of free radicals. 6-OHDA can produce non-specific damage to other neurons.
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
-
(MPTP). A neurotoxin that causes degeneration of dopaminergic neurons in the substantia nigra and hence is used to study the pathophysiology of Parkinson's disease.
- Local field potential
-
(LFP). The extracellular voltage fluctuations that reflect the sum of events in the dendrites of a local neuronal population.
- Positron emission tomography
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(PET). A medical imaging technique that uses injected radiolabelled tracer compounds, in conjunction with mathematical reconstruction methods, to produce a three-dimensional image, or map, of functional processes in the body (such as glucose metabolism, blood flow or receptor distributions).
- Magnetic resonance imaging
-
(MRI). A non-invasive method used to obtain images of living tissue. It uses radio-frequency pulses and magnetic field gradients; the principle of nuclear magnetic resonance is used to reconstruct images of tissue characteristics (for example, proton density or water diffusion parameters).
- Blood-oxygen-level-dependent signal
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(BOLD signal). Local changes in the proportion of oxygenated blood in the brain, as measured by functional MRI. This proportion changes in response to neural activity, therefore the BOLD signal, or haemodynamic response, indicates the location and magnitude of neural activity.
- Diffusion tensor imaging
-
(DTI). A technique based on MRI developed in the mid-1990s in which the diffusion constants of water molecules are measured along many (>six) orientations and diffusion anisotropy is characterized. It is used to visualize the location, orientation and anisotropy of the brain's white-matter tracts, and is sensitive to the directional parameters of water diffusion in the brain.
- Essential tremor
-
The most common neurological movement disorder. Symptoms include involuntary rhythmic movements of the limbs, head or neck.
- Magnetoencephalography
-
(MEG). A non-invasive neuroimaging technique that detects the changing magnetic fields associated with brain activity on the timescale of milliseconds.
- Beamforming method
-
A signal processing technique that uses receptor arrays to detect signals (for example, in MEG). These techniques can be used to determine the brain sources of signals measured from SQUIDS.
- Antidromic impulse
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Conduction opposite the normal, orthodromic direction, whereby an action potential moves from the starting point of the depolarization towards the axons of the neuron.
- Lenticular fasciculus
-
The output pathway of the basal ganglia that originates in the globus pallidus and terminates in the thalamus.
- (14C)2-deoxyglucose
-
A glucose analogue that is used in imaging techniques carried out on experimental animals in order to estimate the level of neural activity in specific brain regions. The (14C)2-deoxyglucose is administered to the animals and subsequently taken up and trapped by active neurons.
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Kringelbach, M., Jenkinson, N., Owen, S. et al. Translational principles of deep brain stimulation. Nat Rev Neurosci 8, 623–635 (2007). https://doi.org/10.1038/nrn2196
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DOI: https://doi.org/10.1038/nrn2196
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