The global burden of neuropsychiatric disease is significant, and it is predicted to rise exponentially in the coming decades. The World Health Organization estimates that nearly 350 million people are affected by major depression.1 It is predicted that the number of new cases of Alzheimer disease (AD) will reach 115 million in the next 40 years.2 It is clear that demographic shifts and rising life expectancies will lead to an epidemic of chronic neuropsychiatric disease, and the societal and public health costs will be enormous.
The problem is compounded by the limitations of current treatments. More than a third of patients with MDD experience resistance to current medical and psychotherapeutic treatment.3 In AD, clinical advances have been slow. The use of anti-amyloid immunotherapies and attempts to boost synaptic acetylcholine levels have shown limited benefit in clinical studies.2 Given the advances in genetics, physiology, and imaging, there is hope that the development of novel therapies for MDD and AD will accelerate in the coming years.
Deep brain stimulation (DBS)—a procedure that interfaces directly with the neural elements driving pathological behavior—could be useful.
What is deep brain stimulation?
DBS is achieved through neurosurgical implantation of electrodes into brain structures involved in the generation of neurological and psychiatric symptoms. The procedure is performed in 2 stages. In the first, with the patient awake and under local or general anesthesia, electrodes are inserted into the brain and are activated to check for acute effects of stimulation as well as for the presence of any stimulation-related adverse events. The second stage, performed with the patient under general anesthesia, involves the internalization of electrodes and implantation of a programmable pulse generator, similar to a cardiac pacemaker. With the system in place, stimulation settings such as voltage, frequency, and pulse width, can be programmed wirelessly.
In addition to its clinical utility, DBS has emerged as a powerful scientific tool. Microelectrode recording during the implantation stage allows researchers to identify neural signatures of individual target neurons or their response to intraoperative experimental stimuli and to precisely map different regions of the brain. After surgery, the device can be turned on or off in a blinded fashion, which may facilitate sham-controlled trials.
At typical settings (eg, 130 Hz, 90 microseconds, 3 to 5 volts), the DBS battery lasts about 3 to 5 years, at which point it needs to be replaced. Although largely safe and associated with few serious adverse events, DBS remains a neurosurgical procedure with the attendant risks of brain surgery. The risk of serious complications, such as major stroke and hemorrhage, is less than 1% to 2%; device malfunction, wire breakage, and infection occur in 5% to 8% of patients.4
The exact mechanism of DBS and its effects on mood is not yet fully understood. Circuit models of motor function helped establish that intervening in critical nodes of a circuit can lead to symptom relief in some movement disorders.5 In these conditions, such as Parkinson disease, dystonia, and essential tremor, DBS can provide significant symptom relief and improved quality of life.6
At some targets, such as the globus pallidus, both stimulation and ablation appear to have the same effects on symptoms such as tremor. At other targets, such as the fornix, stimulation and ablation have significantly different effects, with lesions producing memory deficits and stimulation providing possible memory enhancement. The advantages of DBS over lesions include its reversibility and the ability to titrate the stimulation parameters to clinical effect. It further appears that both the microenvironment and macroenvironment surrounding the DBS electrodes influence the overall effect of stimulation. The neuronal element stimulated, whether it is axons or cell bodies, and which structures are upstream and downstream from the target are factors that contribute to an observed clinical effect.
Dr Lipsman is a PGY4 Resident in the division of neurosurgery at Toronto Western Hospital, University Health Network of the University of Toronto. Dr Lozano is Senior Scientist in the Division of Brain Imaging & Behaviour–Systems Neuroscience, Toronto Western Research Institute; RR Tasker Chair in Functional Neurosurgery, University Health Network; Canada Research Chair in Neuroscience (Tier 1); and Dan Family Chair in Neurosurgery at the University of Toronto. Dr Lipsman has no conflicts of interest concerning the subject matter of this article. Dr Lozano is a consultant for St Jude Medical, Medtronic, and Boston Scientific.
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