Tracking the mechanisms of deep brain stimulation for neuropsychiatric disorders

Abstract

Deep brain stimulation (DBS) has recently emerged as a potential treatment for medically intractable neuropsychiatric disorders. Pilot clinical studies with encouraging results have been performed with DBS of the ventral anterior internal capsule (VAIC) and subgenual cingulate white matter (Cg25WM) for the treatment of obsessive-compulsive disorder and depression. However, little is known about the underlying response of individual neurons, or the networks they are connected to, when DBS is applied to the VAIC or Cg25WM. This review summarizes current understanding of the response of axons to DBS, and discusses the general brain network architectures thought to underlie neuropsychiatric disorders. We also employ diffusion tensor imaging tractography to better understand the axonal trajectories surrounding DBS electrodes implanted in the VAIC or Cg25WM. Finally, we attempt to reconcile various data sets by presenting generalized hypotheses on potential therapeutic mechanisms of DBS for neuropsychiatric disease. KeywordsDeep Brain Stimulation; Psychiatric Disorders; Depression; Obsessive Compulsive Disorder; Tractography; Neurostimulation; Neuromodulation; Review INTRODUCTIONNeuropsychiatric disorders such as major depression and obsessive compulsive disorder (OCD) are severely disabling conditions that interfere with the ability to work, interact socially, or live independently (1,2). Depression is associated with disturbances in attention, motivation, sleep, motor and mental speed, as well as recurrent thoughts of death (3,4). OCD is characterized by repetitive behaviors (compulsions) performed to neutralize the anxiety induced by undesired thoughts (obsessions) (5). Depression and OCD are among the most common neuropsychiatric conditions, affecting 5% and 2% respectively, of adult Americans each year (4,(6)(7)(8).Although most patients suffering from depression and OCD are treated effectively with a combination of medications (e.g., serotonin reuptake inhibitors) and/or cognitive behavioral therapy, 20 to 30% of patients fail to respond to treatment (4,9) and, consequently, remain severely disabled. Despite the effectiveness of ablative surgical procedures (e.g., anterior capsulotomy, anterior cingulotomy, limbic leucotomy, and subcaudate tractotomy) for treating intractable depression and OCD, their destructive and irreversible natures prevent them from being used as a conventional form of treatment (10,11).Send correspondence to: Cameron C. McIntyre, Department of Biomedical Engineering, Cleveland Clinic Foundation, 9500 Euclid Avenue ND20, Cleveland, Ohio. 44195, mcintyc@ccf Benabid and colleagues pioneered the concept of using high frequency cathodic electrical stimulation delivered directly into the surgical target to mimic the effect of a surgical lesion (12,13). Their work led to the development of the commercial clinical technology known as deep brain stimulation (DBS), a reversible stimulation paradigm for treating intractable neurologic disorders (14-16). DBS delivers electrical currents to th...

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