© 2008, Northstar Neuroscience, Inc.
Neuroanatomical and brain imaging studies have been used to identify distinct brain regions and the pathways that connect them, which may underlie various mental disorders. Delineating such brain circuits is relevant because these disorders are highly unlikely to be explained solely by focusing on simple neurotransmitter, genetic, or specific brain region abnormalities (Nestler et al., 2002; Ressler & Mayberg, 2007). A cortical-limbic-thalamic-striatal neural circuit that is important for understanding depression and obsessive-compulsive disorder (OCD) has been roughly outlined (Kopell, Greenberg, & Rezai, 2004; Surguladze, Keedwell, & Phillips, 2003). Within this circuit, certain brain regions are relatively overactive, whereas other regions are underactive. Effective treatments may ultimately work by modulating the function of this circuit. Treatment with drug therapies (Chen et al., in press; Mayberg, 2003), psychotherapies (Brody et al., 2001; Goldapple et al., 2004), and even placebo (Benedetti, Mayberg, Wager, Stohler, & Zubieta, 2005; Mayberg et al., 2002) are associated with changes in this circuit, although how and where the changes occur in the circuit differ depending on the treatment method.
During the 1940s and 1950s, under the influence of Egas Moniz and Walter Freeman, many patients with severe intractable psychotic disorders and OCD were treated by frontal lobotomy, so called because these surgical procedures resulted in destruction of the white matter tracts of the frontal lobes of the brain (Pressman, 1998; Valenstein, 1986). Although some patients improved, many others experienced irreversible personality deterioration, as well as surgical complications. With the advent of psychotropic drug treatments, the use of this controversial treatment declined.
Unfortunately, available therapies are not always effective for some patients. The development of modern stereotactic neurosurgical methods (Binder & Iskandar, 2000) has led to a renewed interest in neurosurgical interventions. These involve the selective ablation or lesioning of particular brain regions that can alleviate treatment-resistant depression (TRD) (Steele, Christmas, Eljamel, & Matthews, in press) and treatment-resistant OCD (TROCD) (Greenberg et al., 2003). Similar neurosurgical methods have also been used to implant electrodes in the brain. Electrical stimulation by these electrodes with pacemaker-like devices can be used to modulate brain function by stimulating or inhibiting the activity of specific brain regions, without causing permanent or destructive lesions that cannot be reversed.
Deep Brain Stimulation
The most widely used neurosurgical form of therapeutic brain stimulation is deep brain stimulation (DBS) (Pereira, Green, Nandi, & Aziz, 2007). This involves the placement of stimulation electrodes into deep subcortical regions of the brain. The particular electrode placement depends on the condition being treated. Currently, DBS (with electrode placement in various basal ganglia) is a treatment approved by the U.S. Food and Drug Administration (FDA) for essential tremor and Parkinson’s disease. It is also an investigational treatment for other movement disorders, epilepsy, chronic pain, obesity, TROCD, and TRD (Covalin, Feshali, & Judy, 2005; Kopell et al., 2004; Pereira et al., 2007).
Investigational studies of DBS for TROCD have been conducted with electrode placement in the anterior limb of the internal capsule (Van Laere et al., 2006). Several different research groups have shown this to be effective (Abelson et al., 2005; Greenberg et al., 2006; Nuttin et al., 2003). Investigational studies of DBS for TRD have focused on two different regions: the subgenual anterior cingulate (Brodmann area 25; Cg25) and the ventral capsule/ventral striatum (VC/VS).
In depression, Cg25 is relatively overactive (Agid et al., 2007). Six patients with TRD were enrolled in a pilot study using Cg25 DBS (Mayberg et al., 2005). On average, the patients had been in a current episode of depression for 6 years, and at least four different antidepressant treatments had failed. Five patients had previously received electroconvulsive therapy (ECT). By 6 months, 2 patients were in remission, 2 were responders, and 2 were nonresponders. Preliminary results of brain imaging studies showed that the baseline findings of increased Cg25 metabolism and decreased dorsolateral prefrontal cortex (DLPFC) metabolism tended to normalize over time with continued DBS. On the basis of these results, a larger pivotal study of Cg25 DBS for TRD has been initiated (ClinicalTrials.gov, n.d.).
Another research group has focused on VC/VS DBS in patients with TRD. This region is close to where DBS for TROCD has been performed. Studies of DBS for TROCD found that comorbid depression often improved. The VC/VS region is relatively underactive in depression (Surguladze et al., 2003). In an initial report of a pilot study using VC/VS DBS for TRD, electrodes were implanted in 5 patients (Greenberg et al., 2004). By 3 months, 3 patients were responders, and 2 were partial responders.
In a subsequent report of 15 patients from this study who were followed from 6 months to 4 years, the 6-month response rate was 47%, and the remission rate was 27% (Malone et al., in press). At the last follow-up visit (mean = 24 months), the response rate was 53%, and the remission rate was 33%. The patients in this study had been in a current episode of depression for at least 2 years, and approximately 12 different anti-depressant treatments had failed. All patients had previously received ECT and psychotherapy. On the basis of these results, a larger pivotal study of VC/VS DBS for TRD is being initiated (ClinicalTrials.gov, n.d.).
Cortical Brain Stimulation (CBS)
A less well-studied neurosurgical form of therapeutic brain stimulation is CBS (Friedland, Gaggl, Runge-Samuelson, Ulmer, & Kopell, 2007; Harvey & Nudo, 2007; Kopell et al., 2007). This investigational procedure involves the placement of stimulation electrodes onto the cortical surface of the brain. The particular placement depends on the condition being treated. Investigational studies have been conducted with electrode placement on the temporoparietal cortex for severe tinnitus (Friedland et al., 2007), on the motor cortex for stroke (Harvey & Nudo, 2007), and on the left DLPFC for TRD (Kopell et al., 2007).
The rationale for using CBS in TRD is based on studies using high-frequency repetitive transcranial magnetic stimulation (rTMS) directed at the left DLPFC, an area that is underactive in depression. Treatment with rTMS requires multiple weekly sessions and may require continual application over a longer period of time because the acute antidepressant effects seem to be temporary. A pacemaker-driven surgically implanted electrode array located over the left DLPFC might therefore provide more practical long-term benefits.
In a feasibility study of left DLPFC CBS for TRD, 12 patients were randomized to single-blind active or sham stimulation for 8 weeks, then active stimulation thereafter (Kopell et al., 2007). The patients had been in a current episode of depression for 7 years, and approximately 10 different antidepressant treatments had failed. Ten patients had previously received ECT. After 8 weeks, patients receiving active stimulation improved to a greater degree than did patients receiving sham stimulation. By 16 weeks, 5 of 10 patients were considered clinical responders.
Electrical stimulation by these electrodes with pacemaker-like devices can be used to modulate brain function.
Preliminary results of brain imaging studies showed that the magnitude of decreased metabolism of the left DLPFC correlated with the magnitude of improvement with CBS. Therefore, greater degrees of abnormal DLPFC function predicted relatively better improvement with CBS. CBS was well tolerated, and there have not been any significant surgical-related or stimulation-related adverse events. On the basis of these results, a larger study of CBS for TRD is planned. In addition to stimulation of the left DLPFC, another research group is planning to study the effects of CBS directed over the medial pre-frontal cortex in patients with TRD (ClinicalTrials.gov, n.d.).
Clinical Procedures with DBS and CBS
Treatment with DBS and CBS involves the surgical implantation of pacemaker-like, programmable pulse generator devices similar to those used for vagus nerve stimulation (VNS) therapy for TRD or epilepsy. For DBS, two subcutaneous generators are implanted bilaterally into the left and right upper chest while the patient is under general anesthesia. While the patient is under local anesthesia, two bilateral craniotomies are performed near the crown of the skull. A stereotactic frame and magnetic resonance imaging scanning are used to guide placement of the electrodes deep into targeted subcortical areas of interest in each hemisphere. The precise placement depends on the condition being treated. For depression, intra-operative testing is conducted while the patient is awake to assess the acute mood effects and electrode placement.
For CBS, two incisions are made while the patient is under general anesthesia—in the left upper chest, where the generator is implanted subcutaneously; and a craniotomy over the left DLPFC, where the lead wire enters and is connected to the electrode grid sutured on the epidural surface of the DLP-FC. No intraoperative testing is conducted with CBS. For both DBS and CBS, the lead wire(s) is passed through a tunnel under the skin and attached to the generator(s).
Therapeutic stimulation typically begins approximately 1 week after implant surgery for CBS and approximately 4 weeks after implant surgery for DBS. Seizures, bleeding, and infection are possible complications (Grill, 2005), but these are more likely with DBS than with CBS. Possible stimulation-related adverse effects of DBS include paresthesias, muscle contraction, dysarthria, and diplopia, as well as possible adverse mood, memory, and cognitive effects. These do not seem to occur with CBS.
These...techniques are appealing because the stimulation is nonablative and can be modified or discontinued depending on the clinical response.
For DBS and CBS, stimulation parameters are adjusted using a handheld computer that programs the generator via a programming wand held on the skin over the device (a procedure similar to VNS therapy). The programmable parameters are the current charge (intensity of the electrical pulse or stimulus), the pulse width (the duration of each electrical pulse), the frequency of electrical pulses, and the on/off duty cycle (the stimulus on time and off time). During clinical follow up, the stimulation settings can each be adjusted to optimize efficacy and tolerability. In addition, different stimulation parameters can be used to cause excitation or inhibition of brain function in the region of interest. For example, the intent of DLPFC CBS is to increase activity of an area that is underactive in depression, whereas the intent of Cg25 DBS is to inhibit activity of an area that is overactive.
The generator operates continuously, according to the programmed parameters, 24 hours per day. Patients can turn off a generator temporarily by holding a magnet over the device; it will start working again by removing the magnet. Depending on the stimulation parameters, the expected battery life of CBS and DBS generators ranges from 1 to 3 years. This is considerably shorter than for VNS therapy, because CBS and DBS have higher energy demands than does VNS.
Generators can be replaced or permanently removed in a simple surgical procedure. If replaced, it is attached to the same lead wire, which never needs to be replaced unless it breaks. Because magnetic fields may cause heating of the electrical lead, magnetic resonance imaging scans cannot be performed unless special shielding techniques are used. Shortwave, microwave, or therapeutic ultrasound diathermy used for therapeutic tissue heating cannot be used, but diagnostic ultrasound is safe. Metal detectors, microwave ovens, cellular telephones, and other electrical or electronic equipment will not affect the generators.
DBS and CBS are potentially viable approaches for the treatment of TRD and TROCD. In contrast with classic psycho-surgery, these therapeutic brain stimulation techniques are appealing because the stimulation is nonablative and can be modified or discontinued depending on the clinical response. Nurses should be familiar with DBS and CBS because they may be in a position to participate in the programming and clinical monitoring of these devices.
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