Findings from various neuroimaging studies have roughly delineated a cortical-limbic-thalamic-striatal neural circuit that is considered relatively important for understanding brain regions and their connections that are involved in the pathophysiology of depression and obsessive-compulsive disorder (OCD) (Kopell, Greenberg, & Rezai, 2004). Because pharmacotherapy, psychotherapy, and electroconvulsive therapy (ECT) are not always effective treatments for these disorders, alternative treatment approaches are needed. Modern stereotactic neurosurgical methods (Binder & Iskandar, 2000) have permitted the investigation of neurosurgical interventions for severe chronic treatment-resistant depression (TRD) and treatment-resistant OCD (TR-OCD). These ablative procedures involve the creation of small selective lesions within particular brain regions, and they have been demonstrated to alleviate symptoms of severe chronic TRD (Steele, Christmas, Eljamel, & Matthews, 2008) and TR-OCD (Greenberg et al., 2003) without causing the types of complications that plagued earlier so-called “psychosurgery” procedures. Stereotactic methods can also be used to implant electrodes in the brain. In contrast to ablative procedures, electrical stimulation by implanted electrodes, using programmable pulse generator devices, can reversibly modulate brain function by stimulating or inhibiting the activity of specific brain regions targeted by the electrodes. Deep brain stimulation (DBS) is a non-ablative neuromodulation procedure, and I will review recent work using DBS for psychiatric disorders.
What Is Deep Brain Stimulation?
The most commonly used neurosurgical form of brain stimulation is DBS (Pereira, Green, Nandi, & Aziz, 2007). The use of DBS involves the placement of stimulation electrodes into the deeper subcortical regions of the brain. The particular electrode placement depends on the disorder that is being treated. The basal ganglia are deep brain nuclei that function as part of the involuntary motor system, and they are involved in the symptom patterns seen with Parkinson’s disease, Huntington’s chorea, and other classical neurological disorders. With electrode placement in various basal ganglia, DBS has been demonstrated to be an effective treatment for essential tremor, Parkinson’s disease, and primary dystonia. The U.S. Food and Drug Administration (FDA) approved the use of DBS devices for the treatment of essential tremor in 1997, Parkinson’s disease In 2002, and primary dystonia in 2003, and DBS is now a commonly used approach around the world for their treatment.
The use of DBS that targets the ventral capsule/ventral striatum (VC/VS) region of the brain was approved by the FDA in 2009 (under a Humanitarian Device Exemption [HDE]) for the treatment of severe chronic TR-OCD. An HDE allows a medical device to be marketed for treating relatively rare disorders without requiring absolute evidence of its effectiveness, although the FDA reviews safety and efficacy data from clinical studies to determine that the probable health benefits of the device outweigh expected risks. Uncontrolled clinical studies of DBS have suggested that it is safe and effective in TR-OCD (Greenberg et al., 2006). Investigational studies using DBS also have been conducted for refractory epilepsy, obesity, chronic pain, tardive dyskinesia, Tourette syndrome, and other movement disorders, but none of these studies have led to FDA approval for these indications.
Deep Brain Stimulation for Depression
At least five different brain regions have been identified as potential targets for DBS to treat depression (Hauptman, DeSalles, Espinoza, Sedrak, & Ishida, 2008). Uncontrolled, open-label (unblinded) investigational studies of DBS for severe chronic TRD have focused on three particular regions: (a) the subgenual anterior cingulate cortex (Brodmann Area 25; Cg25) (Holtzheimer et al., 2012; Kennedy et al., 2011; Lozano et al., 2012); (b) the VC/VS region (Malone et al., 2009); and (c) the nucleus accumbens region (Bewernick, Kayser, Sturm, & Schlaepfer, 2012). Individuals enrolled in these five pilot studies were severely ill, had significant degrees of functional impairment, had lengthy episodes of depression, and did not respond to multiple trials of various drug therapies (alone, in combination, and together with psychotherapy). Most individuals had received ECT previously. These patients typically had comorbid psychiatric and medical conditions that ordinarily would have excluded them from standard clinical trials. The number of participants in each study ranged from 11 to 21 (a total of 84 individuals across all studies). Nine of the 84 participants had bipolar depression. The participants in these studies were followed for 1 to 6 years. At last follow up across all studies, response rates ranged from 29% to 92%, and remission rates ranged from 33% to 58%. The DBS surgical procedure and stimulation were relatively well tolerated. Infections occurred in a small number of patients, and one seizure was reported. Transient adverse mood changes were noted in several patients. There were no adverse cognitive effects. The number of serious adverse effects was small, and no patient experienced permanent neurological or psychological deficits. Four individuals made suicide attempts and two participants completed suicide, which is not surprising for such a chronically and severely ill depressed patient population.
A major limitation of these pilot studies was the lack of blinding and the lack of a sham-control (“placebo” comparison). In the study by Holtzheimer et al. (2012), using DBS targeting Cg25, single-blind discontinuation was planned after 24 weeks of active DBS. Participants in this study were told during their informed consent that they would be blindly randomized to receive either active or sham stimulation, but all patients actually received sham stimulation. In the three participants who entered this phase of the study, a depressive relapse occurred within the first 2 weeks of discontinuation and their depressive symptoms did not improve immediately after stimulation was restarted. Because of safety concerns (i.e., the rapid depressive relapse and the difficulty with restabilization by resuming DBS stimulation), this phase of the study was eliminated for the remaining participants.
In a completed pilot and feasibility study (whose findings have been presented at scientific meetings, but have not yet been published) using DBS targeting the VC/VS region, 30 patients with severe chronic TRD were randomized prospectively to receive active or sham stimulation during an initial 4-month double-blind phase, followed by a long-term open-label active stimulation phase for all participants (Dougherty et al., 2012). At the end of the blinded phase, the active stimulation response rate (20%) was numerically higher than the sham stimulation response rate (14.3%), but these rates were not statistically significantly different. After 1-year follow up with active stimulation, six (21%) of the 29 patients were considered treatment responders. DBS was safe and relatively well tolerated in this study, similar to the experience of DBS-treated patients in other studies for depression, OCD, and neurological disorders.
Deep Brain Stimulation and Aggression
Although DBS is an established neurosurgical treatment option for various movement disorders, the origins of DBS lie in the historically earlier use of electrical stimulation via implanted depth electrodes to study and treat emotional and behavioral disorders, which even included patients with aggressive behaviors (Hariz, Blomstedt, & Zrinzo, 2010).
Torres et al. (2013) published a report describing their experience using DBS targeting the posteromedial hypothalamus (PMH) region in six patients who had severe chronic medication-resistant aggressiveness. The patients all had permanent and significant intellectual and neurobehavioral disabilities requiring institutionalized care, had daily uncontrollable aggressiveness for more than 5 years, and had not responded to multiple medication trials. The use of DBS for aggression in these patients was approved after an extensive multidisciplinary evaluation, local ethics committee review, and informed consent with the patients’ parents or legal guardians. Outcomes compared to baseline were reported for the patients’ last follow up (range = 6 to 82 months post-surgery). One patient died following a stroke 6 months after DBS surgery, but this patient was noted to have had a progressive reduction in violent attacks during the 6 months of DBS. Another patient died approximately 3 years after DBS surgery, having shown no benefit from DBS. Neither death was judged to be related to DBS. Of the remaining four patients, three showed significant improvements on various measures of aggressiveness. Improvement was noted from the first month of stimulation in these three patients. Notable limitations of this study were the small sample, limited set of assessment measures, allowance of medication changes, a lack of sham control, and lack of blinded assessments. The PMH region is a particular region of interest as a target (using ablative procedures or DBS) for the treatment of pathological aggression (Howland, 2013). Neural circuits involving the mediobasal hypothalamus, amygdala, frontal cortex, and other brain regions have also been implicated in pathological forms of aggression. The future investigation and use of DBS for pathological aggression should be considered carefully in regard to its clinical and ethical appropriateness.
The tolerability and safety of implanted DBS systems have been clearly demonstrated based on worldwide experience in patients with various neuropsychiatric disorders. The efficacy of DBS for specific psychiatric disorders, however, has not yet been well established in randomized controlled trials. The use of DBS for TR-OCD was approved under an HDE from the FDA, but the studies supporting its safety and probable effectiveness were not blinded or controlled. Indeed, the only double-blind, sham-controlled study in psychiatry to date (for TRD) demonstrated minimal benefit for active DBS therapy (Dougherty et al., 2012). Nevertheless, these studies only represent the earliest efforts at systematically investigating the potential therapeutic use of DBS for severe chronic psychiatric disorders. Further studies are warranted. Psychiatric-mental health nurses should become familiar with developments in DBS therapy, as they will likely play a key role in the management of patients receiving DBS, including programming DBS devices and clinical monitoring.
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