Neuromodulation Surgery for Psychiatric Disorders Treatment & Management

Deep brain stimulation

Deep brain stimulation (DBS) implantation for refractory obsessive-compulsive disorder (OCD) or major depressive disease (MDD) is nearly identical to that for movement disorders.^[24] The procedure is typically staged by first implanting the leads (see the first image below) and then implanting the neurostimulator or pulse generator (see the second image below).

Lead implantation starts with the acquisition of high-resolution images of the target anatomy. This is generally accomplished by MRI or a combination of CT and MRI with computer-aided fusion techniques. Use of frame-based stereotactic equipment or so-called frameless stereotactic equipment allows these images to be referenced to a standard coordinate system that allows the surgeon to plan trajectories to reach these target areas with minimal brain trauma.

Unlike the use of DBS in movement disorders, current efforts in using DBS for the treatment of refractory psychiatric disease generally target areas that are easily seen on high-resolution MRI scans and include the cingulate gyrus (Cg25; depression), anterior internal capsule (AIC; OCD, depression), nucleus accumbens (NA; OCD), and inferior thalamic peduncle (ITP; depression).

Typically, current efforts in investigating the use of DBS in psychiatric disease perform this surgery with the patient awake to allow the monitoring of changes in patient behavior in response to intraoperative stimulation. Adverse behavioral changes may prompt the operative team to adjust the position of the electrode.

Although microelectrode recording in this clinical context has been described, its use in terms of clinical efficacy remains to be validated, as opposed to the use of DBS for movement disorders. Once the optimal position of the electrode is determined, the lead is locked into place with the use of commercially available burr-hole mounting systems. The distal aspect of the lead is often tunneled to the region just posterior to the pinna in preparation for the next phase.

The next phase involves the placement of the implantable pulse generator (IPG). Because of the extent of tissue manipulation, this is done under general anesthesia. Typically, the IPG is implanted in the upper chest/subclavicular region while an extension lead is tunneled from the chest to the posterior auricular region. There, the distal aspect of the implanted DBS lead is connected to the IPG via the tunneled extension lead. If bilateral DBS leads are implanted, this phase is repeated for the second side.

Currently, programming DBS for refractory OCD or MDD has no standard approach. In general, high-frequency (>100 Hz) stimulation has been explored at various pulse widths (duration of each electrical pulse in milliseconds) and current settings. Although acute effects have been reported, settings are made and behavioral effects are observed over a period of weeks before another adjustment is made. DBS programming for refractory psychiatric disease is still in the early stages of investigation.

Vagus nerve stimulation

The implantation of the vagus nerve stimulation (VNS) system is done in one stage under general anesthesia. The surgical target is the left vagus nerve, and the procedure is identical to the one used for refractory epilepsy.^[25] The patient is placed in a supine position on the operating room (OR) table with the head slightly turned to the right side. Either a longitudinal incision based along the anterior border of the sternocleidomastoid muscle or a transverse incision based on the level of the laryngeal prominence can be used. A standard anterior, trans-cervical approach is performed to expose the left vagus nerve in the carotid sheath.

Once exposed, a 2-contact, 1-reference electrode is placed around the main trunk of the vagus nerve. The distal aspect of this lead is tunneled down to the subclavicular region while the lead itself is anchored to the deep and superficial cervical fascia to prevent dislodgment with neck movement. In the subclavicular region, the lead is attached to a neurostimulator unit in the same fashion as DBS.

Two weeks after implantation of the VNS IPG, the implant is programmed to be active. The IPG works automatically to deliver the programmed parameters. The most common settings used to commence therapy are an output current of 0.25 mA (1.0 mA median value at 12 mo in a pivotal study completed by Rush in 2005^[26] ), a pulse width of 250-500 microseconds (500 microseconds median value at 12 mo in a pivotal study completed by Rush in 2005^[26] ), a signal frequency of 20-30 Hz (20 Hz median value at 12 mo in a pivotal study completed by Rush in 2005^[26] ), and a duty cycle of 10% that activates for 30 seconds every 5 minutes.

The output current is then increased over the following visits by 0.25 mA increments up to a tolerable level or, in this author’s experience, the derived target level of 1.75 mA. Very little data is available to guide individualized target doses. Subsequent visits include interrogating the IPG and running diagnostic tests and adjusting the parameters as needed. By adjusting output currents by 0.25 mA at a time, once or twice during each early office visit, treating physicians can identify the settings that produce the desired balance of benefits to side effects. Once patients respond, increasing the output current any further is unnecessary. Lower output currents extend the battery life.

Deep brain stimulation

The complications of deep brain stimulation (DBS) for refractory psychiatric disease can be broadly classified into 2 categories: general complications of the surgical implantation and side effects of stimulation.

• General: The complications of DBS implantation for refractory psychiatric disease are likely to be the same in character and frequency as the complications of DBS implantation for movement disorders, due to their similarities. These include intracranial hemorrhage, infection, and hardware complications (including lead breakage and erosions of hardware through the skin).^[27]
• Side effects: DBS for these conditions is still in the early phases of investigation. Side effects from the small numbered case series include the following: fear/panic response,^[28] hypomania,^[22] and disinhibition and subjective memory disturbance.^[29] Note that these effects are immediately reversible with cessation of stimulation or adjustment of stimulation settings. There have been no reported decrements in scores of neuropsychological tests following DBS implantation; indeed, improvements in scores have been reported.^[22]

Vagus nerve stimulation

• General: Possible surgical complications include a low risk of infection at the incision site and possible left vocal cord paresis, which is often transient. Asystole in the operating room has been rarely reported.
• Side effects

  • Common side effects
    • Side effects related to the use of VNS are only experienced during stimulation.
    • The most common adverse events noted are hoarseness, dyspnea, and cough, which are often related to the intensity of the output current.
    • Hoarseness is the most common adverse event and is generally mild in severity.
    • The adverse events tend to ameliorate with time, and only the hoarseness tends to persist.
    • VNS does not result in sexual dysfunction, dry mouth, urinary retention, weight gain, or other common side effects of psychotropics.^[20]
  • Uncommon side effects
    • Hypomanic symptoms may occur, as is true with any antidepressant treatment. In one pilot study, 3 patients (1.2%) developed mild hypomanic symptoms.^[30] Two of the three patients had a history of bipolar disorder, and symptoms resolved without intervention.
    • In the pivotal trial, 3 patients developed mania.^[26] Two cases were mild and developed within 3 months of patients having starting VNS, and they subsided spontaneously within 1-2 weeks. The third patient developed a manic episode that lasted for 2 months and required hospitalization and cessation of VNS. The VNS was ultimately safely restarted.
    • In the trials, no evidence has emerged that suggests a potential for VNS to worsen depression or induce suicidality.
    • VNS does not appear to have any negative cognitive effects and may improve cognition by improving depression.
    • Sackheim et al looked at 27 patients with depression as they were implanted with VNS and gave them a neurocognitive battery at baseline and at 12 weeks.^[31] They found no decrements in cognitive functioning, and 40% had improved depression.

Deep brain stimulation

Only a few published reports of deep brain stimulation (DBS) for the treatment of psychiatric disorders are currently available. These initial efforts have evolved from 2 stereotactic lesioning procedures: anterior capsulotomy and subcaudate tractotomy.^[4]

Developed first by Jean Talairach and then further refined by Lars Leksell, anterior capsulotomy has been in use for refractory psychiatric illness since 1949. The target area was between the anterior and middle third of the anterior limb of the internal capsule at the approximate level of the foramen of Monro. Presumably, such lesions modulate the flow of information between the orbitofrontal cortex (OFC), the dorsolateral prefrontal cortex (DLPFC), and the thalamic and basal ganglionic structures outlined above, in essence modulating the associative and limbic TC/CSTC circuits.

Subcaudate tractotomy (innominatomy) is another stereotactic procedure geared toward interrupting fibers from the orbitofrontal cortex to the thalamus. Developed by Knight in 1965 in London, the operation’s target site is a region of white matter localized beneath the head of the caudate, known as the substantia innominata.^[3] This procedure appears to selectively modulate information flow in the limbic TC/CSTC circuit as well as accessory pathways that involve the extended amygdala and cholinergic basal forebrain.

Anterior internal capsule

In 1999, a joint investigative group from Belgium and Sweden released an initial communication in The Lancet.^[32] In this report, the group implanted a model 3887 Pisces Quad Compact electrode (Medtronic, Inc), generally used for spinal cord stimulation, into the internal capsules of 4 patients with obsessive-compulsive disorder (OCD). The target coordinates, although not specified, were "identical to those aimed for capsulotomy." Also, the specific patient selection criteria were not explicitly revealed. In 3 of the 4 patients, "some beneficial effects" were observed. Although the authors assessed stimulation in a "double-blind" fashion, no scores were given with regard to standard measures of mood or OCD symptoms.

In June 2003, this same group published the long-term follow-up of their initial data presented in 1999.^[33] The data were presented from 6 patients who were implanted with bilateral DBS electrodes in the internal capsule with follow-up that ranged from 3-31 months. Patient selection criteria were narrowly and specifically defined using Yale-Brown obsessive compulsive scale (Y-BOCS) and global assessment of functioning (GAF) scores. Targeting data were more explicitly given with the tip of the electrode from one of the patients (with the best clinical result) placed at 13 mm lateral to midline on the right, 14 mm lateral to midline on the left, 3.5 mm anterior to the anterior commissure, and at the level of the intercommissural plane. Of interest is that, while stimulating, contacts 1 and 2 were in the internal capsule, and the most distal electrode, 0, was in the region of the nucleus accumbens.

Under double-blinded conditions (both patient and evaluating psychiatrist did not know the stimulation state), 6 implanted patients were assessed in a crossover design that used Y-BOCS, clinical global severity (CGS) scale, clinical global improvement (CGI) scale, and the Beck depression inventory (BDI). One patient did not receive any benefit. Another patient required such high voltages for stimulation that the batteries were replaced every 5 months with only limited beneficial effects. The electrodes were electively removed. Both this patient and the first patient underwent standard RF capsulotomy. With chronic stimulation, 3 of the 6 patients were considered responders with improvements on Y-BOCS of at least 35%. Another patient who received chronic DBS had some improvement (less than 35%) and was considered a nonresponder. In the "off" state, the 3 responding patients had worsening mood and OCD symptoms that returned to baseline.

Another published report of anterior internal capsule (AIC) DBS is from a group at the Loyola University Medical Center. In 2003, they published a case report of DBS on the anterior internal capsule for OCD.^[34] Although full details of diagnosis were not given in this report, the patient, a 35-year-old female, had severe illness and functional impairment, reflected by a Y-BOCS score of 34 and a GAF score of 40.

Bilateral DBS electrodes (a standard model for DBS-3387) were placed in a target considerably more lateral and anterior to the Belgium/Sweden group, as follows: 18 mm lateral to midline, 13 mm anterior to anterior commissure, and at the level of the foramen of Monro. Stimulation parameters were kept constant: 2 V, 210 ms pulse width (PW), 100 Hz. Unipolar stimulation was used, but no mention was made of which contact served as the cathode. At 10 months of follow-up, the patient returned to work with all compulsions "abated." At 3 months, her Y-BOCS score fell to 7. No adverse effects were reported.

In 2005, Abelson et al performed capsular DBS in 4 OCD patients, using a more anterior target than that of Nuttin et al and a different stimulating electrode.^[35] Three of the 4 patients had significant benefit (>35% reduction in Y-BOCS scores). Disturbingly, one of the responders committed suicide despite a significant change in OCD symptoms.

Most recently, Greenberg and colleagues reported on a series of OCD patients who met stringent criteria for severity and treatment resistance and underwent DBS at a ventral internal capsule/ventral striatum target based on that described by Nuttin et al.^[19] Eight patients were followed for at least 36 months. Group Y-BOCS scores decreased from 34.6 (mean) at baseline (severe range) to 22.3 (moderate range) at 36 months (P < 0.001). Four of 8 patients had at least a 35% decrease in Y-BOCS severity at 36 months. In 2 other patients, scores declined 25-35%. Depression and anxiety also improved. GAF scores improved from 36.6 at baseline (indicating major functional impairment) to 53.8 (indicating moderate impairment) at 36 months (P < 0.001). This corresponded to improvements in self-care, independent living, and work, school, and social functioning.

This same group presented their findings of DBS in the AIC for treatment of refractory MDD in 2006. Six patients who were highly refractory to medication, psychotherapy, and bilateral electroconvulsive therapy (ECT) were enrolled in the study from 2003-2005. Stereotactic implantation of bilateral DBS leads in the ventral anterior internal capsule was performed. Four of the 6 patients met the response criterion of more than 50% reduction in depression severity on the Montgomery-Asberg depression rating scale at a minimum of 6 months follow-up. Quality-of-life measures also improved, and patients had progressive improvement in mood and functioning over time.

Nucleus accumbens

In 2003, a group from Cologne, Germany, published their results using DBS for OCD symptoms.^[36] Their target, the nucleus accumbens (NA) shell, is in a similar anatomic area as that in the groups that use DBS in the ventral anterior internal capsule. Noting the relatively higher voltages used in capsular DBS for OCD, the group chose the NA because of its proximity to the ventral internal capsule and its relationship to the amygdala, the prefrontal/orbitofrontal cortex, and the dorsomedial thalamus, all areas implicated in the pathogenesis of OCD.

NA shell DBS was performed on the right side in 4 patients. Three of the 4 patients had a "nearly total recovery" of their OCD, although explicit Y-BOCS scores were not given. The fourth patient was noted to have had the DBS electrode not in the target area, although no information was given regarding reimplantation.

Ventral striatum

In 2004, a group from France presented a case report in which they implanted DBS electrodes into the ventromedial caudate in order to address refractory OCD and depression. They addressed this target specifically because of its anatomic relationships and because they observed that the high currents needed for capsular DBS "raised the essential issue of the exact area to be targeted."^[37] They placed the DBS electrode through the head of the caudate nucleus in such a way that the 2 lower contacts were located within the nucleus accumbens and the 2 upper contacts were within the ventromedial portion of the caudate nucleus. Depression symptoms resolved first, at 6 months, with OCD symptoms resolving at 15 months.

Cingulate gyrus

In 2005, Mayberg et al published their results that used a method of DBS for major depression.^[38] DBS electrodes were bilaterally implanted into the subcortical white matter in the region of area 25 in 6 patients. Patients were selected for notable but not extreme levels of treatment resistance and for a relative lack of psychiatric comorbidity. Four of the 6 implanted patients, at 6-month follow-up, were determined to have had their depression go into remission, which is defined by a 50% reduction in their Hamilton rating scale for depression scores.

Inferior thalamic peduncle

In 2005, Jimenez presented a case report at the 2005 annual meeting of the World Stereotactic and Functional Neurosurgery Society Meeting in Rome, Italy.^[39] DBS electrodes were placed bilaterally in the inferior thalamic peduncle (ITP) in a woman with refractory depression. This stimulation, via effects propagated by way of ITP fibers that continue rostrally in the ventral portion of the anterior limb of the internal capsule, is expected to modulate the projections of the dorsolateral prefrontal cortex (DLPFC), the orbitofrontal cortex (OFC), and the ventromedial striatum to the dorsomedial and intralaminar thalamus. After a substantial "microlesion" period (a benefit gained by the mass effect of the peri-electrode edema by the mere implantation of the electrodes), the patient was reported to have had continuing benefit from stimulation in this region. Further exploration and follow-up is necessary to establish whether this approach is both safe and beneficial.^[39]

Vagus nerve stimulation for major depressive disorder

Vagus nerve stimulation (VNS) was FDA approved for use in treatment-resistant depression in May 2005, based on both short-term and long-term data. The short-term data come from a 10-week pilot study in which 60 patients with severe, refractory depression were implanted with VNS for depression.^[30] The long-term data come from a larger, double-masked, sham-controlled, 10-week trial with 235 participants, also with severe, refractory depression.^[26] In all of these studies, VNS was used adjunctively (in addition to their regular medication regiment, which has, by definition, not brought much relief from the depression).

In the pilot study, 18 (30.5%) of the patients had a response (≥50% reduction from baseline HAMD28 score) and 9 (15.3%) remitted (HAMD28 score of 10 or less). The mean time to response was not acute at 48.1 days. The treatment was well tolerated.

In the larger study, VNS was compared with sham treatment (ie, the implant was not activated) for 12 weeks in patients with unipolar or bipolar depression that was refractory with a mean duration of current depressive episode of over 4 years. This 12-week study did not have 12 weeks of stimulation. VNS was activated after a 22-week postimplant recovery period, and the dose was titrated for another 2 weeks and was then held constant for the remaining 8 weeks. In this study, VNS did not separate from sham. The response rate (HDRS-24) for the study group was 15.2% and the sham group was 10.0% (P =0.251, last occurrence carried forward [LOCF]).

The long-term data come from following the responders in the previously discussed studies. The patients that responded in the pilot study^[20] at 3 months (early responders) or 1 year (late responders) were followed for 2 years.^[40] The 3-month response rate of 30.5% increased to 44.1% at 1 year and remained at that level (42.4%) at the 2-year time point. At 2 years, 55.6% of early responders and 78.6% of late responders continued to be responders.^[41]

All of the eligible patients (N=205) from the pivotal trial had their implants activated and were followed naturalistically after the trial.^{[26, 42]} Patients in the active group in the 3-month trial continued on VNS for an additional 9 months, totaling 12 months. Patients from the sham group in the 3-month trial were activated and followed for 12 months of active VNS.^{[26, 42]} In addition to receiving VNS therapy, all patients continued to receive treatment as usual (TAU). At LOCF end point, the response rate was 27.2%; 15.8% of patients remitted. Rates of response and remission doubled between 3 and 12 months of treatment (P < 0.005), indicating progressive clinical improvement after the initial 3 months of VNS therapy.

Finally, a comparison of VNS with a matched group of TAU patients was undertaken. Data from the 205 patients who completed the 12-month naturalistic study were compared with a matched control group of 124 patients with refractory depression who received only TAU.^{[42, 43]} At the end point, VNS therapy plus TAU was associated with a mean improvement on the IDS-SR30 score of 9.3 points, which represented a significantly greater improvement than TAU (4.2-point improvement; P < 0.001).

The VNS for MDD efficacy database that was used to make VNS approvable has been controversial. Some reviewers are unimpressed with the data set and point out that in the only sham-controlled trial that exists for VNS, the treatment’s primary measure did not separate from placebo.^[26] Others point out that this short trial was of insufficient length to show the superiority of VNS and that the secondary measure did actually separate from placebo.

It is often misunderstood and is important to note that the FDA approval standards for devices (eg, pacemakers, defibrillators, VNS, DBS) are different from those for drugs. Instead of requiring evidence of efficacy and safety from 2 positive, randomized, placebo-controlled trials, the FDA requires a different standard of efficacy and safety evidence for medical devices in accordance with their guidelines. For example, over 50% of newly approved device applications have evidence that consist of only nonrandomized clinical trials. Difficulties maintaining the blind (with the clear ability to "feel" the implant activate in active conditions) and the ethical concerns of giving placebo to patients with this severe level of illness loom large in attempting to conduct an adequately placebo-controlled and blinded study of VNS or other devices. These studies are commonly conducted in a retrospective manner, with historical controls or with a within-subject design.

With the exception of vagus nerve stimulation (VNS), there is no FDA-approved treatment, surgical or otherwise, for refractory OCD or major depression. The postapproval road for VNS has been a rocky one, fraught with controversy and refusal of private payers to reimburse VNS as a "covered benefit." Furthermore, the Centers for Medicare and Medicaid Services (CMS) denied a coverage policy in 2007, citing that the data submitted to the FDA do not meet criteria to be deemed as "necessary and reasonable" for use in depression. VNS trials currently underway hope to address treatment selection and optimum treatment parameters.

Other efforts to apply focused neuromodulation techniques to treatment-refractory psychiatric disease, while promising, are firmly within the realm of investigation. Two pivotal DBS trials for refractory depression supported by Advanced Neuromodulation Systems (ANS) and Medtronic are expected to begin late 2007 or early 2008.

Ironically, as psychiatric surgery started by targeting the frontal lobe, some of the newest efforts at neuromodulation for psychiatric disease have once again turned to the frontal lobe as a target. As discussed earlier, neuroimaging has not only identified Cg25 as a node in the mood circuit but also identified the DLPFC. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive means to focally stimulate brain areas, has been shown to have antidepressive effects in multiple small, uncontrolled trials.

In early 2007, an rTMS manufacturer sought FDA approval after a larger, multicenter, sham-controlled trial was completed. The initial recommendation by the FDA advisory panel was to reject approval because of issues of study design and modest efficacy (IEEE Spectrum Online Jan 2007), although the manufacturer plans to resubmit data upon further study. The frontal lobe is also being investigated as a target for an implantabledevice, a feasibility trial that is expected to have concluded in 2007.

Several promising options are on the horizon. The researchers must now be sure that these new options are safe and effective and past mistakes are not repeated.