Dr. Ward is associate professor of psychiatry in the Department of Psychiatry at the University of Florida in Gainesville.

Dr. Shapira is assistant professor of psychiatry in the Department of Psychiatry at the University of Florida.

Dr. Goodman is professor of psychiatry and chairman of the Department of Psychiatry at the University of Florida.

Acknowledgments: The authors would like to thank Mary Lessig for her editorial assistance in the preparation of this manuscript.


 

Abstract

What alternative nonpharmacologic somatic treatment methods are available for patients with anxiety disorders? This article will review four such methods: ablative neurosurgery, deep-brain stimulation (DBS), vagus-nerve stimulation (VNS), and repetitive transcranial magnetic stimulation (rTMS). Major advances have been made in pharmacologic and psychological treatment of the anxiety disorders over the past 15 years. However, many patients remain refractory to all current treatments even after years of medication trials and cognitive-behavior therapy. For this group of severely ill, often debilitated patients, efforts are being made to offer anatomically based treatment. Modern stereotaxic procedures guided by high-resolution imaging have made ablative surgery (cingulotomy, capsulotomy, subcaudate tractotomy, limbic leucotomy) more precise and safe. “Functional ablation” is now possible using DBS, offering a reversible means of interrupting neurotransmission within circuits known to mediate anxiety and cognitions. VNS utilizes afferent input to cortical, limbic, and brainstem structures without craniotomy. rTMS provides a means of focal electrical stimulation of the surface of the brain. Mounting evidence for efficacy of rTMS in depression will hopefully lead to further development of this intervention in anxiety disorders.

 

Introduction

Over the past 15 years, well-controlled clinical trials have documented the effectiveness of pharmacologic and psychological treatments for anxiety disorders such as panic disorder, generalized anxiety disorder, social phobia (social anxiety disorder), posttraumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). Across these disorders, the majority of patients (60% to 80%) report clinically significant improvement with medication, cognitive-behavior therapy, or a combination of these interventions.1 However, for the treatment-refractory patient with anxiety, residual symptoms can be debilitating. Advances in neuroimaging and application of basic science models to clinical medicine are yielding more anatomically based treatment options for this group of severely ill patients. The anxiety disorder that has received the most investigation has been OCD. Of the 4–7 million people in the United States who suffer from OCD, approximately 20% are refractory to current pharmacotherapy and psychotherapy.2 This article will review four nonpharmacologic somatic treatments for refractory anxiety disorders: ablative neurosurgery, deep-brain stimulation (DBS), vagus-nerve stimulation (VNS), and repetitive transcranial magnetic stimulation (rTMS).

 

Neurobiology of Anxiety Disorders: Obsessive-Compulsive Disorder

Evidence from brain-imaging studies demonstrates that specific neural circuits may be responsible for OCD symptoms.3 Positron Emission Tomography (PET) scanning has shown hyperactivity in the orbitofrontal cortex and head of the caudate nucleus.4 Dysfunction in prefrontal basal-ganglia thalamic prefrontal circuits may be associated with information-processing deficits and intrusive symptoms in OCD.3,5 Anatomically based treatments share the strategy of interrupting neurotransmission within this circuit.

 

Ablative Neurosurgery

Ablative neurosurgery for psychiatric illness is performed in a few centers and reserved for the most seriously ill, treatment-refractory patients. Ablative neurosurgical techniques for OCD include cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leucotomy. Cingulotomy is the most common procedure in the US. Using magnetic resonance imaging (MRI)-guided stereotactic techniques, electrodes are inserted into the anterior cingulate gyrus, and lesions are created using radiofrequency thermocoagulation.3 For capsulotomy, lesions are created in the anterior limb of the internal capsule either by radiofrequency thermocoagulation or radiosurgically (γ-knife capsulotomy).3 The radiosurgical method avoids the need for craniotomy. Crossfiring beams of 60-Cobalt γ radiation from a stereotactic γ unit create lesions. Individual beams are not destructive to tissue except at their point of convergence.3,6 With subcaudate tractotomy, a lesion is created in the region of the substantia innominata just below the head of the caudate nucleus. Using MRI-guided stereotaxic techniques, lesions are made using β radioactive yttrium rods that have a half-life of approximately 60 hours and remain in the brain indefinitely.3,4 Typically, patients experience confusion in the first few weeks after the operation.3 Limbic leucotomy is a combination of subcaudate tractotomy and anterior cingulotomy.3 Lesions are created in the substantia innominata and the cingulate gyrus using thermocoagulation.

All of these surgical procedures have the common objective of severing interconnections between the frontal lobes and limbic and thalamic structures. Lesions in one region may affect the function of other brain areas. For example, lesions in the substantia innominata following subcaudate tractotomy cause neuronal degeneration of the internal capsule.7 Different surgical interventions with different targets for ablation may have similar effects on neurotransmission within the prefrontal basal-ganglia thalamic prefrontal circuits. Darin and colleagues8 recently reported on the long-term outcome of 44 patients who received cingulotomy for treatment-resistant OCD. Assessment measures, including the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised,9 the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Beck Depression Inventory, and the Sickness Impact Profile, were administered preoperatively and at follow-up. At 32 months postcingulotomy, 14 patients (32%) met criteria for treatment response and 6 others (14%) were partial responders.

Evaluation of efficacy for these different procedures for the treatment of OCD is inherently difficult.10 Severity of illness varies across studies and diagnostic criteria for OCD is inconsistent. In addition, some studies have been performed before effective pharmacologic intervention was available, and outcome measures vary across these studies. The optimal surgical procedure remains controversial, but response rates seem to vary from 35% to 65% for treatment-refractory OCD.11 The risk of neurosurgery for severe OCD is comparable to risk associated with stereotactic operations for nonpsychiatric illness.12 The risk of developing cognitive deficits after surgery has been evaluated in all four procedures described above, and no evidence of reduced intellectual function has been noted.13

 

Deep-Brain Stimulation

Bilateral DBS has been used successfully for essential tremor and Parkinson’s disease (PD) since about 1995, utilizing the Medtronic Activa Tremor Control System (Figure).14 Significant adverse events from the DBS procedure have included equipment failure or lead wire breakage, intracranial hemorrhage, infection, seizures, and paresis.

 

In 1999, a team of Swedish and Belgian physicians approached refractory OCD through DBS rather than bilateral capsulotomy.15 The selected stimulation targets for the chronic stimulation were identical to those aimed for in a capsulotomy. In four patients with severe treatment-resistant OCD, quadripolar electrodes were stereotactically bilaterally implanted in the anterior limbs of the internal capsule. Beneficial effects were seen in three patients. Of these, a 39-year-old woman suffering from severe OCD for more than 20 years reported feeling an almost instantaneous relief from anxiety and obsessive thinking when stimulation was activated. Her relief reportedly subsided with stimulation inactivation. She was continuously stimulated for 2 weeks during which her parents reporting that about 90% of her compulsive behavior and rituals had vanished. To further assess the effects of stimulation, the Profile of Mood States (POMS), was administered in a double-blind fashion by six independent raters. Ratings increased for social contact, communication, flow of ideas, assertiveness, and mobility during the stimulation period.15

These observations indicate that acute capsular stimulation can induce relevant beneficial effects in OCD and suggest that long-term stimulation may be useful in the management of treatment-resistant forms of OCD. The DBS-stimulating device operates at a level ≤100 Hz, which depolarizes the neurons, disrupting neurotransmission—essentially, functional ablation. It is hypothesized that bilateral electrical stimulation is effective because it targets the neuroanatomical substrate of OCD—ie, the limbs of the frontostriatal pallidal thalamic frontal loop—which passes through the anterior limb of the internal capsule.16

 

Vagus-Nerve Stimulation

The vagus nerve (10th cranial nerve) is best known for its efferent function with parasympathetic inervation to organs such as the heart and gut. However, approximately 80% of vagal-nerve fibers are afferent sensory fibers that relay information from the body to the brain.17 These afferent fibers project via the nucleus tractus solitarii to the locus ceruleus and parabracial nucleus. The locus ceruleus and parabracial nucleus project to all levels of the forebrain including the hypothalamus, orbital frontal cortex, amygdala, and bed nucleus of the stria terminalis.18 In theory, direct stimulation of the vagus afferent fibers could affect sensory input to limbic, brain stem, and cortical areas known to be involved in mood and anxiety disorders.

The US Food and Drug Administration approved VNS in 1997 for treatment-resistant partial-onset seizures in epilepsy. The device, VNS™ NeuroCybernetic Prosthesis (NCP) System, is manufactured by Cyberonics, Inc., in Houston, Tex, and has been implanted in over 12,000 patients worldwide. Implantation of VNS™ is similar to implantation of a pacemaker. The pulse generator is about the size of a pocket watch and is implanted subcutaneously in the left chest wall. The vagus nerve is exposed through a separate incision near the carotid artery. A tunnel is made under the skin up to the neck for connection of bipolar leads to the vagus nerve. Generator settings are checked and adjusted telemetrically by holding a wand connected to a laptop computer, over the pulse generator. Patients are given a magnet that when held over the generator, turns it off. Stimulation cycles are typically 30 seconds of stimulation every 5 minutes. Current output, pulse width, and frequency can also be adjusted using the telemetric wand and laptop.

VNS has had an excellent safety record in seizure patients.19 The most common adverse event related to implantation is mild pain at the incision site that typically resolves over the 2 weeks following surgery. Stimulation-related side effects include hoarseness, throat/neck pain, and shortness of breath while the stimulator is on. These are typically mild and can be minimized by adjustments in stimulator settings.

Among psychiatric disorders, VNS has been best studied in depression. Rush and colleagues20 conducted a multicenter open trial of VNS in 30 adult outpatients with nonpsychotic, treatment-resistant major depression, bipolar I or II (depressed phase). Positive findings have led to a pivotal trial of VNS in major depression that has been completed and is awaiting analysis of the data.

A multicenter pilot study of VNS in treatment-resistant anxiety disorders is now under way. There are currently seven patients with OCD, two patients with PTSD, and one panic disorder patient implanted with the device. Acute and long-term data is not yet available on these patients.

 

Repetitive Transcranial Magnetic Stimulation

Transcranial magnetic stimulation was introduced by Barker and colleagues21 in 1985 as a noninvasive means of stimulating the cerebral cortex. It involves placing an electromagnetic coil on the scalp and passing a rapidly-alternating high-intensity current through the coil. This sets up a magnetic field, which passes through the cranium and induces local electrical changes on the surface of the cortex.22 Initially, TMS was used to study nerve conduction by stimulating an area of the motor cortex and measuring contralateral muscular-evoked potentials.23 Therapeutically, rTMS has received the most attention with treatment-resistant depression.24-28

Studies of patients with anxiety disorder has been much more limited. For example, Greenberg and colleagues29 treated 12 patients with OCD and found that a single session of right prefrontal rTMS decreased compulsive urges for 8 hours, but there was no effect on obsessions. In addition, Alonso and colleagues30 randomly assigned 18 patients with OCD to real or sham rTMS. Five patients were unmedicated and eight were receiving therapeutic doses of fluoxetine or a combination of clomipramine and fluvoxamine. All patients received 18 20-minute sessions of stimulation at 1 Hz. Intensity was 110% of motor threshold for real rTMS and 20% of motor threshold for sham condition. The Y-BOCS and the Hamilton Rating Scale for Depression were used for assessment. No significant changes in OCD symptoms were detected in either group after treatment. In another study, McCann and colleagues31 treated two PTSD patients openly with right frontal 1-Hz rTMS at 80% of motor threshold. Each session was 20 minutes. One patient received 17 sessions and the other patient received 30 sessions. Both patients reported symptom improvement. However, in both cases, symptoms returned to pretreatment levels by 1 month after rTMS discontinuation. Finally, Grisaru and colleagues32 treated 10 PTSD patients openly using a single session of TMS at slow frequency over the motor cortex. Improvement in core symptoms of avoidance, anxiety, and somatization were noted, but the effect was short lived with return to baseline symptoms by day.28
 

Conclusion

Currently, only patients with chronic, severe, disabling illness refractory to all reasonable conventional therapies, are considered for ablative surgery. For OCD, this usually means a 5-year treatment period with therapeutic trials (at least 10 weeks) of clomipramine, all selective serotonin reuptake inhibitors, and a monoamine oxidase inhibitor. Augmentation strategies must be attempted. Additionally, an extended trial of cognitive-behavior therapy (exposure with response prevention) must be documented. The same criteria must be met for DBS in treatment-refractory OCD. However, it should be noted that disruption in neural transmission with DBS is reversible. VNS avoids craniotomy and stimulates brainstem, limbic, and cortical pathways via vagal stimulation in the neck. In anxiety disorders, VNS is just in the pilot stage of investigation. Least invasive, rTMS delivers localized electrical stimulation on the surface of the cortex. It has shown considerable promise in depression, but findings have been mixed in anxiety disorders. It should be noted that DBS, VNS, and rTMS remain investigational at this point and are only available through research protocols.    PP
 

 

References

1.    Ballenger JC. Current treatments of the anxiety disorders in adults. Biol Psychiatry. 1999;46:1579-1594.
2.    Rasmussen SA, Eisen JL. The epidemiology and clinical features of OCD. Psychiatr Clin North Am. 1992;15:743-758.
3.    Binder DK, Iskander BJ. Modern neurosurgery for psychiatric disorders. Neurosurgery. 2000;47:9-23.
4.    Baxter LR, Ackermann RF, Swerdlow NR, et al. Specific brain system mediation of obsessive-compulsive disorder responsive to either medication or behavior therapy. In: Obsessive Compulsive Disorder: Contemporary Issues in Treatment. Goodman Wk, Rudorfer MV, Maser JD, eds. Mahwah, NJ: Lawrence Earlbaum Associates; 2000:573-609.
5.    Mindus P, Rasmussen SA, Lindquist C. Neurosurgical treatment for refractory obsessive compulsive disorder: implications for understanding frontal lobe function.
J Neuropsychiatry. 1994;6:467-477.
6.    Mindus P, Bergstrom K, Levander SE, et al. Magnetic resonance images related to clinical outcome after psychosurgical intervention in severe anxiety disorder. J Neurol, Neurosurg, Psychiatry. 1987;50:1288.
7.    Corsellis J, Jack, AB. Neuropathological observations on yttrium implants and on undercutting in the orbito-frontal areas of the brain. In: Laitinen LV, Livingston KE, eds. Surgical Approaches in Psychiatry. Baltimore, MD: University Park Press; 1973:60.
8.    Darin DD, Baer L, Cosgrove GR, et al. Prospective long-term follow-up of 44 patients who received cingulotomy for treatment-refractory obsessive-compulsive disorder. Am J Psychiatry. 2002;159:269-275.
9.    Diagnostic and Statistical Manual of Mental Disorders. 3rd ed rev. Washington DC: American Psychiatric Association; 1987.
10.    Jenike MA. Neurosurgical treatment of obsessive-compulsive disorder. In: Goodman WK, Rudorfer MV, Maser JD, eds. Obsessive-Compulsive Disorder, Contemporary Issues in Treatment. London, England: Lawrence Erlbaum Associates; 2000:457-482.
11.    Cosgrove GR. Surgery for psychiatric disorders. CNS Spectrums. 2000;5:43-52.
12.    Blaauw C, Braakman R. Pitfalls in diagnostic stereotactic brain surgery. Acta Neurosurgery. 1988;42(suppl):161.
13.    Sweet WH, Meyerson BA. Neurosurgical aspects of primary affective disorders. In: Youmans JR, ed. Neurological Surgery. Philadelphia, PA: Saunders; 1990.
14.    Medtronic Inc. Submission of premarked approval application (PMA) P960009 Supplement 7 for the Medtronic Activa Parkinson’s Control System. Presented at: 13th Neurological Devices Advisory Panel Meeting of the Food and Drug Administration; March 31, 2000; Rockville, Md.
15.    Nuttin B, Cosyns P, Demeulemeester H, et al. Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder. Lancet. 1999;354:1526.
16.    Irle E, Exner C, Thielen K, et al. Obsessive-compulsive disorder and ventromedial frontal lesions: clinical and neuropsychological findings. Am J Psychiatry. 1998;155:255-263.
17.    Foley JO, DuBois F. Quantitative studies of the vagus nerve in the cat, I: the ratio of sensory and motor studies. J Comp Neurol. 1937;67:49-67.
18.    Van Bockstaele EJ, Peoples J, Valentino RJ. Anatomic basis for differential regulation of the rostrolateral peri-locus coeruleus region by limbic afferents. Biol Psychiatry. 1999;46:1352-1363.
19.    Fisher RS, Handforth A. Reassessment: Vagus nerve stimulation for epilepsy: A report of he Therapeutics and Technology Assessment Subcommittee for the American Academy of Neurology. Neurology. 1999;53:666-669.
20. Rush JA, George MS, Sackeim HA, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: A multicenter study. Biol Psychiatry. 2000;47:276-286.
21. Barker AT, Jalinous R, Freeston IL. Non-invasive stimulation of the human motor cortex. Lancet. 1985;1:1106-1107.
22.    Barker AT. An introduction to the basic principles of magnetic nerve stimulation. J Clin Physiol. 1991;8:26-37.
23. Hallet M, Cohen LG. Magnetism: A new method for stimulation of nerve and brain. JAMA 1989;262:538-541.
24.    George MS, Wasserman EM, Kibrell TA, et al. Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial. Am J Psychiatry. 1997;154:1752-1756.
25.    Klein E, Kreinin I, Chistyakov A, et al. Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression: a double-blind controlled study. Arch Gen Psychiatry. 1999;56:315-320.
26.    Triggs WSJ, McCoy KJ, Greer R, et al. Effects of left frontal transcranial magnetic stimulation on depressed mood, cognition, and corticomotor threshold. Biol Psychiatry. 1999;45:1440-1446.
27.    Berman, RM, Narasimhan M, Sanacora G, et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol Psychiatry. 2000;47:332-337.
28.    Grunhaus L, Dannon PN, Schreiber S, et al. Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of non-delusional major depressive disorder: an open study. Biol Psychiatry. 2000;47:314-324.
29.    Greenberg BD, George MS, Dearing J, et al. Effect of prefrontal repetitive transcranial magnetic stimulation (rTMS) in obsessive-compulsive disorder: a preliminary study. Am J Psychiatry. 1997;154:867-869.
30.    Alonso P, Pujol J, Cardoner N, et al. Right prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: A double-blind, placebo-controlled study. Am J Psychiatry. 2001;158:1143-1145.
31.    Mc Cann UD, Kimbrell TA, Morgan CM, et al. Repetitive transcranial magnetic stimulation for posttraumatic stress disorder. Arch Gen Psychiatry. 1998;55:276-278.
32.    Grisaru N, Amir M, Cohen H, Kaplan Z. Effect of transcranial magnetic stimulation in posttraumatic stress disorder: a preliminary study. Biol Psychiatry. 1998;44:52-55.