AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

History of the Procedure

The legacy of lobotomy

Emerging simultaneously with the development of these somatic treatments was the seminal work by Portuguese neurologist Egas Moniz on the development of frontal leucotomy, the severing of frontal white matter tracts to treat psychiatric disorders. Not long after, Walter Freeman, an American neurologist and psychiatrist, seized upon Moniz's discovery and brought the procedure to the United States in 1936. John Fulton, the prominent Yale neurophysiologist, was in solid support of the medical community proceeding with the operations but predicated this support on the concept of carefully designed clinical trials in elite academic institutions.² The era of frontal lobotomy had begun. 

With the publication of Freeman and Watts' Psychosurgery in 1942, the fervor for the "success" of the lobotomy spread from the professional to the lay communities as Fulton's advice was largely ignored. Psychosurgery's fragile connection to the laboratory and the scientific community began to grow weaker and weaker. Gone were the days of "surgery of last resort," as Freeman wished to operate on a "better grade" of patient that included the recently institutionalized as well as the nonhospitalized. This led to Freeman's development of the transorbital lobotomy, a ghastly procedure in which an ice pick is inserted through skin and bone to sever tracts in the frontal lobe. The awarding of the Nobel Prize in medicine to Moniz in 1949 echoed Freeman's accelerated efforts. 

Yet, even as these operations enjoyed their heyday, a backlash had begun; the luster on this "miracle" cure began to tarnish. The indiscriminate use of crude surgical interventions, coupled with a paucity of valid tools to assess psychiatric outcomes, often led to tragic consequences such as radical personality changes and cognitive decline. By the mid 1950s, over 20,000 frontal lobotomies had been performed in the United States alone.³ The damage associated with such indiscriminate use of this procedure was twofold.  Firstly, although some patients benefited, many patients suffered. Secondly, the effort to surgically treat psychiatric disorders was permanently sullied. Indeed, many countries throughout the world outlawed the practice altogether. 

Problem

The emergence of the patient with treatment-resistant disease

In the mid-20th century, the only effective medical treatment of movement disorders such as Parkinson disease and essential tremor was stereotactic surgical procedures that lesioned various areas of the thalamus, subthalamus, and basal ganglia. By the end of the 1950s, Arvid Carlsson introduced levodopa to the world, and the surgical intervention for Parkinson disease had radically declined by the 1970s. 

Nevertheless, within 10 years, a new class of Parkinson disease patient, the medically refractory patient, became evident. This group was deemed medically refractory because of the diminishing effects of levodopa and the emergence of side effects such as dyskinesias. Surgery once again became, and still remains, a pillar of treatment for these patients.

Psychiatric disease faces a similar situation. One of the chief causes of the demise of lobotomy was the introduction of chlorpromazine (Thorazine) in 1954. However, the emergence of the psychiatric patient with treatment-refractory disease evolved more quickly than the Parkinson disease counterpart, largely because of the heterogeneous nature of psychiatric disease and the limited types of pharmacotherapy available. Clinicians once again turned to surgical intervention. 

With the advent of stereotaxis, surgery for psychiatric disease evolved from the open lobotomy into minimally invasive lesioning such as cingulotomy (stereotactic ablation of the anterior cingulate cortex; see Image 1), capsulotomy (surgical ablation of the anterior limb of the internal capsule; see Image 2), subcaudate tractotomy (surgical ablation of the area known as the substantia innominate, a region ventral to head of the caudate; see Image 3), and  limbic leucotomy (essentially a combined subcaudate tractotomy and cingulotomy).⁴  Nevertheless, because of the legacy of lobotomy and the permanence of the procedure, these procedures never came into widespread use and were not subject to scientific rigor and strict experimental protocol.

The evolution of neuromodulation offers new promise for these patients with treatment-resistant psychiatric disease. Neuromodulation can be defined as the therapeutic alteration of activity in the central, peripheral, or autonomic nervous systems (electrically or pharmacologically), often by means of implanted devices. In the field of movement disorders, neuromodulation in the form of deep brain stimulation (DBS) has become the criterion-standard treatment of advanced Parkinson disease, tremor, and dystonia. 

The chief hallmark of neuromodulation is the inherent adjustability and reversibility of the process, which is a clear advance beyond older techniques such as lobotomy and electroconvulsive therapy. Once implanted, these devices can be programmed to minimize side effects and maximize benefits and ultimately can be entirely removed without substantially altering the nervous system. This rapidly growing field, combined with new insights gained in the pathophysiology of psychiatric disease from functional imaging, has allowed clinicians to revisit this once-taboo medical practice. This article focuses on various new, more-focused, and reversible neuromodulation procedures being investigated for the treatment of treatment-refractory obsessive-compulsive disorder (OCD) and major depressive disorder (MDD), the 2 difficult-to-treat, dire psychiatric diseases.

Frequency

OCD is one of the most debilitating and refractory psychiatric disorders. OCD affects up to 2-3% of the US population (an estimated 2.2 million people) and almost 50 million people worldwide.⁵ Up to 40% of patients with OCD are partial responders or nonresponders.⁶ Few patients with OCD experience a complete remission of symptomatology. 

MDD is the leading cause of disability in the United States for patients aged 15-44 years.⁷ In any given 1-year period, 9.5%of the population, or about 20.9 million American adults, suffer from a depressive illness.⁸ Up to 30% of these patients are refractory to treatment.⁹

Pathophysiology

Prior to the advent of functional imaging techniques such as functional MRI (fMRI), PET, and magnetoencephalography (MEG), insight into the neural structures underlying psychiatric phenomena was based on the same processes that led to lobotomy and the stereotactic lesioning procedures: careful observation of patient behavior after discrete lesions in specific brain areas. Several classifications of psychiatric surgery have developed over the past century. In 1937, James Papez introduced a circuitry that included the hippocampus, the fornix, the mammillary bodies, the mammillothalamic tract, the anterior thalamic, the subgenual cingulate (Brodmann area 25 or Cg25), the parahippocampal gyrus, and the entorhinal cortex.⁴  

This circuit, known as the Papez circuit, has been an important heuristic model for psychiatric research and practice (see Image 4).

In 1954, Paul McLean described a neural circuit that included cortical and subcortical structures. Known as the limbic system, this has been perhaps the most influential neuroanatomic model of psychiatric phenomena in the 20th and 21st centuries. The limbic system consists of the regions involved in the Papez circuit and adds the amygdala, the hypothalamus, the nucleus accumbens, and the orbitofrontal cortex.⁴

In general, insight into the pathophysiology of psychiatric disease is much less defined than the pathophysiology of movement disorders. Chief among these reasons is the lack of animal models of depression and OCD, as compared with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson disease. Animal models of psychiatric disease are currently being developed but are not nearly as mature as their movement disorder counterparts. The result is that much of the insight into the anatomy of psychiatric disease is derived from the observation of behavior after brain lesions in humans. 

A boon to this effort, however, is the application of functional imaging techniques such as fMRI, PET, and MEG to the understanding of the neural circuitry underlying psychiatric disease. However, there are currently limitations to their interpretation and perhaps contradictory findings. This may be due to the heterogeneous nature of psychiatric illness itself (eg, MDD). According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), to have MDD, a patient must show at least 5 of 9 different symptoms within a 2-week period. At the very least, there are 15,120 permutations according to this scheme. It is likely that biologically distinct subtypes may have different patterns of activity on functional imaging. A similar situation exists for the clinical subtypes of OCD.¹⁰

• Orbitofrontal cortex (Brodmann areas 10, 11, 12, 47; see Image 5)  
• • This area processes tasks related to reward and punishment and extinction behavior in response to aversive stimuli.
  • This area’s role in psychiatric disease is perseverative cognitions and emotional response.
  • The anatomic connections in this area include the following:   
  • • It receives projections from every sensory modality (unique among any neocortical region).
    • Its influence over the autonomic nervous system is second only to the Cg25.
    • This area has extensive reciprocal connections to the dorsolateral prefrontal cortex and cingulate.
  • Functional imaging data   
  • • Increased metabolic activity in depression¹¹
    • Increased metabolic activity in OCD that normalizes with successful treatment¹²
• Dorsolateral prefrontal cortex (Brodmann area 9, lateral 10, 46; see Image 6)   
• • This area processes tasks related to working memory, spatial memory and executive function, and mediation of external environment on limbic responses.
  • This area’s role in psychiatric disease involves the patient’s insight into symptoms, the ability to suppress negative feelings and painful stimuli, and the psychomotor retardation of severe depression.
  • Anatomic connections include extensive reciprocal connections to OFC and the cingulate.
  • Functional imaging data include decreased metabolism in negative mood states and untreated depressed patients and increased metabolism with successful treatment.^{11, 13}
• Cingulate (Brodmann areas 24, 32, and 25; see Image 7)   
• • This area processes tasks related to attention and influence over visceromotor and vegetative functions.
  • This area’s role in psychiatric disease is related to disruptions in hedonic tone and motivation.
  • This area’s anatomic features include the following:  
  • • Extensive connections to autonomic circuitry
    • Extensive reciprocal connections to the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC)
  • Functional imaging data include the following:  
  • • Increased metabolism in OCD¹²
    • Increased metabolism in Cg25 in MDD¹⁴
    • Decreased metabolism in Cg25 in the successfully treated state of MDD¹⁴
    • Increased metabolism that predicts response to cingulotomy¹⁵ 

Increasingly, psychiatric changes are believed to not be attributed to a "center" of mood or behavior but, rather, are secondary to an imbalance in communication of multiple neuronal loops. However, the efficacy of DBS is typically attributed to a small generated electrical field that encompasses a very limited amount of cerebral tissue. Perhaps the stimulation generated at a certain target propagates downstream into the rest of the circuitry, gaining an amplified effect. 

Alternatively, the limitations so far encountered with the proposed therapies are possibly due not only to difficulties in patient selection but also to the restricted effect generated by the focal electrical field on the overall circuitry. Future analysis may reveal that the best results come not from a single stereotactic target but, instead, from a combination of neuromodulatory strategies that affect discrete circuits.

Clinical

What is obsessive-compulsive disorder?

Obsessive-compulsive disorder (OCD) is defined by the National Institute of Mental Health as an anxiety disorder characterized by recurrent, unwanted thoughts (obsessions) and/or repetitive behaviors (compulsions).

Repetitive behaviors such as handwashing, counting, checking, or cleaning are often performed with the hope of preventing obsessive thoughts or making them go away.

Performing these so-called "rituals," however, provides only temporary relief, and not performing them markedly increases anxiety.

Major depressive disorder (MDD) is defined by the National Institute of Mental health as manifesting a combination of symptoms that interfere with the ability to work, study, sleep, eat, and enjoy once pleasurable activities. Such a disabling episode of depression may occur only once but more commonly occurs several times in a lifetime. Symptoms may include the following:

• Persistent sad, anxious, or "empty" mood
• Feelings of hopelessness or pessimism
• Feelings of guilt, worthlessness, or helplessness
• Loss of interest or pleasure in hobbies and activities that were once enjoyed, including sex
• Decreased energy, fatigue, or being "slowed down"
• Difficulty concentrating, remembering, or making decisions
• Insomnia, early-morning awakening, or oversleeping
• Appetite loss and/or weight loss or overeating and weight gain
• Thoughts of death or suicide; suicide attempts
• Restlessness or irritability
• Persistent physical symptoms that do not respond to treatment, such as headaches, digestive disorders, and chronic pain

What is treatment resistance?

“Treatment-resistant” OCD or depression has no universally agreed upon definition. “Treatment resistance” can mean many things other than a difficult-to-treat biological illness, such as incorrect diagnosis (including comorbid psychiatric disorders, personality disorders, and substance abuse disorders), inadequate or incomplete antidepressant trials, and medication nonadherence. 

True treatment resistance is usually defined, however, as the subset of these refractory patients in whom contributory factors to treatment failure have been ruled out. These truly refractory patients are the patients who should be considered for these procedures. The incidence of patients with truly treatment-refractory disease is a controversial topic but is felt to be about 10-15%. 

Treatment-resistance obsessive-compulsive disorder  

No definitive agreement exists on what constitutes treatment-resistant OCD. The definition most commonly used is an unsatisfactory response to 2 adequate trials of serotonin reuptake inhibitors,¹⁸ although most would suggest a trial of cognitive behavioral therapy (CBT) prior to defining someone as treatment resistant. Determination of "failure" or an “unsatisfactory response” is made when the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score is reduced by less than 25% or when improvement is greater than 25% but the patient still experiences significant OCD-caused impairment (meaning that the obsessions or compulsions continue to cause impairment in functioning, even in their improved state). Approximately 10% of the OCD population may be candidates for neuromodulation surgery based on these criteria of treatment resistance.¹⁹
 
Treatment-resistant depression

Treatment-resistant depression also has no agreed upon definition. Attempts have been made to define degrees of treatment refractoriness.²⁰ Thase and O’Reardon defined treatment refractory depression as treatment nonresponse (ie, persistence of significant depressive symptoms) despite at least 2 treatment trials with drugs from different pharmacologic classes, each used in an adequate dose for an adequate time period.^{20, 21}

The FDA went beyond this most commonly used definition when its approved vagus nerve stimulation (VNS) for treatment-resistant depression raised the number of failed adequate trials to 4 but did not define the types or quality of trials needed. These trials may include medications, therapies, and other treatments such as electroconvulsive therapy (ECT). Approximately 10-15% of the major depressive disease (MDD) population may be candidates for neuromodulation surgery based on these criteria of treatment resistance.²²

INDICATIONS

Section 3 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Patient selection is perhaps the most crucial issue facing the renewed interest in neuromodulation for psychiatric disease. Careful patient selection is the key to not recapitulating the mistakes of the lobotomy era. An emphasis is placed on a multidisciplinary approach in which a team led by psychiatrists who are expert in the treatment of refractory obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) carefully reviews all patients prior to surgical intervention.

Recent publications have given the following guidelines for forming such a team: an ethics committee, a patient assessment committee, strict adherence to accepted criteria for treatment-refractory MDD/OCD, limitation of such efforts to tertiary-care academic centers, limitation of patient selection to those patients with decision-making capacity, and the avoidance of procedures whose purpose involves law enforcement, political, or social ends.²³

RELEVANT ANATOMY

Section 4 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

See Pathophysiology

CONTRAINDICATIONS

Section 5 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

The primary contraindications for deep brain stimulation (DBS) or VNS implantation for psychiatric disease are similar to those for movement disorders or refractory epilepsy: current antiplatelet or anticoagulation therapy or unstable medical comorbidity. At this time, age per se is not an absolute contraindication, but pediatric patients are excluded.

Also, because DBS relies heavily on MRI images for electrode targeting, the presence of an implanted cardiac pacemaker also presumably contraindicates this surgery. Specific psychiatric contraindications for DBS or VNS implantations may include the following general disorders:

• Psychotic disorders  
• • The efficacy and safety of DBS or VNS in psychotic disorders, including major depressive disorder (MDD) with psychotic features, has not been established.
  • This may be problematic for several reasons, including the difficulty of obtaining informed consent for surgery in a psychotic patient as well as the obvious concerns about implanting a permanent indwelling device in a psychotic patient.
• Substance use disorders  
• • Severe and active substance use disorders can obscure the diagnostic certainty needed in these disorders. Further, in the face of active substance use, establishing the adequacy of failed medical trials is impossible.
  • Like most interventions, neither DBS nor VNS has been systematically studied in patients with severe and active substance use.
• Personality disorders  
• • Neither of these interventions has been studied systematically in populations with severe and active personality disorders.
  • Some patients with cluster B personality disorders (borderline, histrionic) have been excluded from recent neuromodulation trials.
  • This can be a particular diagnostic challenge, as patients with severe depression can manifest personality traits that resolve with treatment of the depression.
  • As with most treatments, the presence of a personality disorder lowers the expected benefit and may shift the risk-benefit analysis in surgical treatments, such as those treatments with relatively high risk compared with standard treatments.
• Axis I comorbidity  
• • DBS and VNS have not been systematically studied in patients who have comorbid mood and anxiety disorders.
  • Attempts have been made in some of the trials to exclude patients with axis I comorbidity.
• VNS-specific disorders  
• • Although bipolar depression is generally believed to be within the indications for VNS, as several patients with bipolar disorder were included in the VNS pivotal trial, no large trials of VNS for bipolar disorder have been published.
  • VNS may be more likely to cause mood instability in those with bipolar disorder and with inadequate levels of mood stabilization medication.
  • VNS has not been systematically studied for use in anxiety disorders, including OCD.
• DBS-specific disorders: DBS has not been studied in patients with bipolar disorder, and there is a concern about DBS causing an unbalanced switch to mania.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Surgical therapy

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 Image 24) and then implanting the neurostimulator or pulse generator (see Image 25).

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 2005²⁶), a pulse width of 250-500 microseconds (500 microseconds median value at 12 mo in a pivotal study completed by Rush in 2005²⁶), a signal frequency of 20-30 Hz (20 Hz median value at 12 mo in a pivotal study completed by Rush in 2005²⁶), 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.

COMPLICATIONS

Section 7 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

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.

OUTCOME AND PROGNOSIS

Section 8 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

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. 

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 study²⁰ 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.

FUTURE AND CONTROVERSIES

Section 9 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

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.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Indications
• Relevant Anatomy
• Contraindications
• Treatment
• Complications
• Outcome and Prognosis
• Future and Controversies
• Multimedia
• References

Media file 1:  Cingulotomy. The position of the lesion is shown.
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Media file 2:  Anterior capsulotomy. The position of the lesion is shown.
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Media file 3:  Subcaudate tractotomy. The position of the lesion is shown.
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Media file 4:  The Papez circuit.
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Media file 5:  The orbitofrontal cortex. Adapted from an image from Professor Mark Dubin, University of Colorado.
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Media file 6:  The dorsolateral prefrontal cortex. Adapted from an image from Professor Mark Dubin, University of Colorado.
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Media file 7:  The cingulate gyrus (Cg25; in green). Adapted from an image from Professor Mark Dubin, University of Colorado.
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Media file 8:  The dorsal "compartment" of the frontal lobe. Adapted from an image from Professor Mark Dubin, University of Colorado.
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Media file 9:  The ventral "compartment" of the frontal lobe. Adapted from an image from Professor Mark Dubin, University of Colorado.
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Media file 10:  The limbic thalamocortical loop. MOFC = medial orbitofrontal cortex. DMmc = dorsomedial thalamic nucleus, magnocellular portion.
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Media file 11:  The cortico-striato-thalamocortical loop (CSTC loop) as it relates to neuromodulation for psychiatry. DLPFC = dorsolateral prefrontal cortex. LOFC = lateral orbitofrontal cortex. MOFC = medial orbitofrontal cortex. GPe = globus pallidus pars externa. GPi = globus pallidus pars interna. STN = subthalamic nucleus. SNc = substantia nigra pars compacta. SNr = substantia nigra pars reticularis. VTA = ventral tegmental area.
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Media file 12:  The associative thalamocortical loop. DLPFC = dorsolateral prefrontal cortex. LOFC = lateral orbitofrontal cortex. VApc = ventral anterior thalamic nucleus, parvocellular portion. VAmc = ventral anterior thalamic nucleus, magnocellular portion. DMpc = dorsomedial thalamic nucleus, parvocellular portion.
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Media file 13:  The hypothalamic-pituitary axis as it relates to the aforementioned circuitry. OFC = orbitofrontal cortex.
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Media file 14:  How neuromodulation at the cingulate gyrus (Cg25) interacts at the aforementioned circuitries. The highlighted area represents Cg25.
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Media file 15:  How neuromodulation at cingulate gyrus (Cg25) interacts at the aforementioned circuitries. The highlighted area represents Cg25.
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Media file 16:  How neuromodulation at the anterior internal capsule (AIC) interacts at the aforementioned circuitries. The highlighted area represents AIC.
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Media file 17:  How neuromodulation at the anterior internal capsule (AIC) interacts at the aforementioned circuitries. The highlighted area represents AIC.
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Media file 18:  How neuromodulation at the nucleus accumbens (NA) shell interacts at the aforementioned circuitries. The highlighted area represents the NA shell.
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Media file 19:  How neuromodulation at the nucleus accumbens (NA) shell interacts at the aforementioned circuitries. The highlighted area represents the NA shell.
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Media file 20:  How neuromodulation at the ventral striatum (VS) interacts at the aforementioned circuitries. The highlighted area represents VS.
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Media file 21:  How neuromodulation at the ventral striatum (VS) interacts at the aforementioned circuitries. The highlighted area represents VS.
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