Emerging technologies for improved deep brain stimulation

Abstract

Deep brain stimulation (DBS) is an effective treatment for common movement disorders and has been used to modulate neural activity through delivery of electrical stimulation to key brain structures. The long-term efficacy of stimulation in treating disorders, such as Parkinson's disease and essential tremor, has encouraged its application to a wide range of neurological and psychiatric conditions. Nevertheless, adoption of DBS remains limited, even in Parkinson's disease. Recent failed clinical trials of DBS in major depression, and modest treatment outcomes in dementia and epilepsy, are spurring further development. These improvements focus on interaction with disease circuits through complementary, spatially and temporally specific approaches. Spatial specificity is promoted by the use of segmented electrodes and field steering, and temporal specificity involves the delivery of patterned stimulation, mostly controlled through disease-related feedback. Underpinning these developments are new insights into brain structure-function relationships and aberrant circuit dynamics, including new methods with which to assess and refine the clinical effects of stimulation.

Fig. 1. Deep brain stimulation.

a, The electrodes and pulse generators are permanently implanted, self-contained systems. Electrodes can be implanted in one or both hemispheres of the brain, depending on the laterality of the symptoms. The electrode(s) implanted in the brain are connected to the pulse generator implanted in the chest. b, Traditional DBS electrodes consisted of four contacts (black cylinders), where typically a single contact was used to deliver stimulation. The most common surgical target for the treatment of Parkinson's disease is the subthalamic nucleus, which contains ~250,000 neurons, depicted in blue, and is much denser in reality than shown here. (Adapted with permission from ref. .) c, DBS enables wide-scale network modulation of the basal ganglia and cortex. This is because these structures are coupled into loops. There are many such overlapping loops, but here, for schematic purposes, a loop controlling the arm is illustrated. GPe, globus pallidus externa; GPi, globus pallidus interna. (Reprinted from ref. , Neurobiol. Dis. 38, C. C. McIntyre & P. J. Hahn, Network perspectives on the mechanisms of deep brain stimulation, 329–337, copyright 2010, with permission from Elsevier.).

Fig. 2. Field steering.

a, Schematic DBS electrode shown on magnetic resonance imaging scans targeting the subthalamic nucleus. Perioperative imaging is essential and intraoperative imaging desirable in the accurate placement of electrodes. b, Prototype research electrodes have been developed with higher densities of smaller contacts. c, These are designed with the intention of providing finer control of the electric field (blue volume). The top panel illustrates the spherical field predominating when a complete ring of contacts is activated to mimic the field derived with conventional DBS. On the right, the electrode and electric field are superimposed on a brain atlas. The electrode is in the target, the subthalamic nucleus, but the electric field extends outside of this, risking side effects. The lower panel illustrates the shaping of the electrical field that is possible when a subset of contacts is simultaneously activated. Now the field is limited to the subthalamic nucleus. (Adapted from ref. ; atlas image adapted with permission from G. Schaltenbrand & W. Wahren, Atlas for Stereotaxy of the Human Brain 2nd edn, Thieme, 1977.).

Fig. 3. A comparison of different stimulation strategies.

a comparison of different stimulation strategies. a, Stimulation timing and parameters are not automatically adjusted according to a disease biomarker, although the clinician will fine-tune stimulation during follow-up visits (usually twice a year). b, Local field potentials sensed using depth electrodes are continuously used to automatically determine stimulation timing or intensity. Stimulation is delivered via the same depth electrodes. c, Cortical signals sensed using an electrocorticography array are continuously used to automatically determine stimulation timing or intensity. Stimulation is delivered across the depth electrodes, creating a spatial separation between sensing and stimulation sites. d, Peripheral signals obtained from noninvasive measurement devices, such accelerometers and/or electromyography, are used to automatically determine stimulation timing or intensity. As in c, this allows a separation between sensing and stimulation sites and therefore minimizes the impact of stimulation artifacts. The gray box represents a computing device and could be an implantable pulse generator, a computer or cloud-based computing. The computing device is used to process signals and extract features such as the intensity of neural activity in a certain frequency band or phase–amplitude coupling to control stimulation timing and parameters.