03 - 30.3 Neurosurgical Treatments and Deep Brain

30.3 Neurosurgical Treatments and Deep Brain Stimulation

Luber B, Kinnunen LH, Rakitin BC, Ellsasser R, Stern Y. Facilitation of performance in a working memory task with rTMS stimulation of the precuneus: Frequency- and time-dependent effects. Brain Res. 2007;1128:120. Luber B, Stanford AD, Malaspina D, Lisanby SH. Revisiting the backward masking deficit in schizophrenia: Individual differences in performance and modeling with transcranial magnetic stimulation. Biol Psychiatry. 2007;62(7):793. Mall V, Berweck S, Fietzek UM, Glocker FX, Oberhuber U. Low level of intracortical inhibition in children shown by transcranial magnetic stimulation. Neuropediatrics. 2004;35(2):120. Peterchev AV, Kirov G, Ebmeier K, Scott A, Husain M. Frontiers in TMS technology development: Controllable pulse shape TMS (cTMS) and magnetic seizure therapy (MST) at 100 Hz. Biol Psychiatry. 2007;61:107S. Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK. Vagus nerve stimulation for treatment-resistant depression: A randomized, controlled acute phase trial. Biol Psychiatry. 2005;58(5):347. Schestatsky P, Simis M, Freeman R, Pascual-Leone A, Fregni F. Non-invasive brain stimulation and the autonomic nervous system. Clin Neurophysiol. 2013; 124(9):1716–1728. Schlaepfer TE, Lancaster E, Heidbreder R, Strain EC, Kosel M. Decreased frontal white-matter volume in chronic substance abuse. Int J Neuropsychopharmacol. 2006;9(2):147. Tomlinson SP, Davis NJ, Bracewell R. Brain stimulation studies of non-motor cerebellar function: A systematic review. Neurosci Biobehav Rev. 2013;37(5):766–789. 30.3 Neurosurgical Treatments and Deep Brain Stimulation After a long and checkered history, neurosurgical treatments for psychiatric illness have reemerged as a focus of great interest. Many still associate psychiatric neurosurgery with the bygone era of crude freehand “psychosurgery,” when prefrontal lobotomy saw wide and indiscriminate use. Those primitive operations, which predated modern psychopharmacology, yielded modest reductions in symptoms but were accompanied by unacceptable adverse effects. Over nearly five decades, techniques, and importantly, procedures and practices have evolved tremendously. First, ablative lesions are now accurately, precisely, and reproducibly placed in specific brain targets stereotactically guided by magnetic resonance imaging (MRI) and specialized software. Alternative methods include radiosurgery, which allows stereotactic lesion placement without craniotomy. Deep brain stimulation (DBS), while requiring craniotomy to implant stimulating electrodes in specific brain targets, is intentionally nonablative and allows flexible and reversible modulation of brain function. Second, strict criteria for patient selection are observed, and the process of determining appropriate candidacy has been formalized. Currently, surgical intervention is predominantly reserved for patients with severe, incapacitating major depression or obsessive-compulsive disorder (OCD) who have failed an exhaustive array of standard treatments. Surgery is not approved unless a multidisciplinary committee reaches consensus regarding its appropriateness for a given candidate and the patient renders informed consent. Although a large body of clinical data has already been collected that indicates the effectiveness and safety of modern neurosurgical interventions, major centers providing these treatments continue to gather information prospectively, and controlled trials are under way or planned. With these advances in neurosurgical techniques and better-

established selection criteria and long-term follow-up procedures, available data suggest that psychiatric neurosurgery yields substantial improvement in symptoms and functioning in approximately 40 to 70 percent of cases, with morbidity and mortality drastically lower than for earlier procedures. Although lesion procedures have been influenced by theories implicating corticolimbic systems in disordered behavior, they were initially developed largely empirically. Although psychiatric neurosurgery is sometimes criticized for this reason, as for any clinical therapy, the relevant issues are safety and efficacy, not correction of pathophysiological processes that are not yet fully understood. However, in addition to the promise of modern lesion procedures and DBS as clinical treatments, clinicians permit testing of hypotheses derived from the results of lesions or from systematic human neuroimaging. Thus, psychiatric neurosurgery is now developing in a scientific context where translation of data between clinical results to cross-species anatomical, neuroimaging, and physiological studies of neural networks involved a promise to illuminate mechanisms of therapeutic action. HISTORY Trephination performed by ancient civilizations probably represents the earliest form of surgical intervention for psychopathology. In 1891 the first formal report of neurosurgical treatment in psychiatry was published, describing bilateral cortical excisions in demented and depressed patients, which yielded mixed results. After four decades in which little progress was made, in 1935 John Fulton and Charles Jacobsen presented their research on primate behavior following frontal cortical ablation. They observed that lobectomized chimpanzees showed reduction in “experimental neurosis” and were less fearful, while retaining an ability to perform complex tasks. Egaz Moniz, a renowned Portuguese neurologist, pioneered prefrontal leukotomy in collaboration with his neurosurgical colleague Almeida Lima. First by using absolute alcohol injections and subsequently by mechanical means with a leukotome, Moniz and Lima performed “psychosurgery” on 20 severely ill institutionalized patients; 14 were said to have exhibited worthwhile improvement. In an era of overflowing asylums and few effective treatments for chronic debilitating psychiatric illness, this mode of therapy was initially enthusiastically embraced, and Moniz won the 1949 Nobel Prize in Medicine or Physiology for this contribution. From the mid-1930s until the emergence of the phenothiazines in the mid-1950s, these techniques proliferated globally. Walter Freeman, a neuropsychiatrist, was perhaps the most zealous promoter of psychosurgery in the United States. Pioneering a series of freehand procedures to achieve prefrontal lobotomy (i.e., severing the white matter connections between the prefrontal cortex and the rest of the brain), Freeman together with neurosurgeon James Watts reported on their first 200 cases by 1942. Although the benefits of the surgery were highlighted, others acknowledged a significant complication rate, including frontal lobe syndrome, seizures, and even deaths. At its peak, lobotomy was being performed on approximately 5,000 patients per year in the United States alone. A review of the results of 10,365 prefrontal lobotomies performed from 1942 to 1954 in Britain concluded that while 70 percent showed improvement, adverse effects included 6 percent mortality, seizures in 1 percent, and disinhibition syndromes in 1.5 percent. There were widespread reports of blunted personality and socially inappropriate behavior. In the late 1940s and early 1950s, recognition of these risks prompted attempts to develop modified stereotactic surgical procedures that might yield better results. For example, Ernest Spiegel and Henry Wycis, who began stereotactic neurosurgery in humans, reported in the 1940s that dorsomedial thalamotomies improved obsessive-compulsive symptoms. However, with the introduction of chlorpromazine

(Thorazine) in 1954, medical management of psychiatric illness became newly possible. Thus, despite the advent of stereotactic neurosurgical techniques and a continued high prevalence of severe, treatment-refractory psychiatric illness, psychiatric neurosurgery was all but abandoned in favor of nonsurgical therapies. PATIENT SELECTION: INDICATIONS AND CONTRAINDICATIONS Although limited reports have suggested efficacy across a broad range of psychiatric conditions and research is expanding rapidly, as of this writing the best established indications for psychiatric neurosurgery remain major depression and OCD. In evaluating candidates, several factors are considered:

1. Primary diagnosis: The patient must meet clinical criteria for the diagnostic indication, and this disorder should be a primary cause of the patient’s debility and suffering.
2. Severity: The patient must have chronic, severe, and debilitating illness; duration of the primary illness must exceed 1 year and typically exceeds 5 years. Severity is gauged on standardized instruments (e.g., patients with OCD typically have YaleBrown Obsessive-Compulsive Scale scores of 25 to 30; patients with major depression typically have Beck Depression Inventory scores of 30 or higher), while debility should be indicated by a low level of functioning (e.g., a Global Assessment of Functioning score of 50 or less) and a poor quality of life.
3. Adequacy of previous treatment: Patients must have already undergone an exhaustive array of other available established treatments, which are documented in detail.
4. Psychiatric comorbidity: Appropriate treatment must have been rendered for any comorbid psychiatric disorder; the presence of psychoactive substance use or severe personality disorders are considered strong relative contraindications.
5. Medical comorbidity and surgical fitness: Structural brain lesions or significant central nervous system injuries are strong contraindications. Medical conditions that increase neurosurgical risks (e.g., cardiopulmonary disease) and age 65 years are relative contraindications for lesion procedures, while for DBS the relative age restriction might be older. A history of past seizures is a risk factor for perioperative seizures after lesion procedures and must be weighed in the overall risk–benefit assessment (again, data are currently less clear in this regard for psychiatric DBS).
6. Access to postoperative care: The psychiatric neurosurgery procedures themselves represent the beginning of a new episode of care. It is crucial that patients have access to adequate postoperative treatment, including a psychiatrist (typically the referring physician) who will accept responsibility for managing the case after discharge. Arrangements for postoperative care (e.g., intensive behavior therapy) should be confirmed ahead of time. Importantly, after lesion procedures, care can generally be delivered in standard treatment settings without the need for highly specialized psychiatric neurosurgery teams. For deep brain stimulation, access to such teams is essential over the long term. Once implanted, patients require clinical monitoring and device adjustment, which can be intensive and time-consuming, especially early in treatment. Device monitoring and replacements may need to occur

on a relatively urgent basis. The continuing costs incurred can be substantial, and adequacy of third-party reimbursement needs to be ensured in advance to the extent possible. After either lesion procedures or DBS, family or significant others may be needed to support and accompany patients to follow-up care, similar to the level of support that is usually necessary during the intensive evaluation process. 7. Informed consent: Under no circumstances should psychiatric neurosurgery be performed on patients against their will. The patient must be able and willing to render an informed consent. Formal consent monitoring may be used to ensure that the consent process is adequate. In rare instances, these procedures are performed with assent of the patient and formal consent from a legal guardian. In this context, age less than 18 years also represents a relative contraindication. POSTOPERATIVE CARE Immediate postoperative care includes the standard medical and surgical considerations following any stereotactic neurosurgical procedure. Special attention is paid to signs or symptoms of potential surgical complications, including infection, hemorrhage, seizures, or altered mental status. A postoperative MRI should be obtained to document the placement and extent of lesions. Intensive postoperative psychiatric treatment is recommended since the efficacy of the surgery may rely on some synergy between the neurosurgical intervention itself and enhanced response to pharmacological or behavioral therapies. Although dosages of psychotropic medications may be reduced during the immediate perioperative period, the medication regimen should be readjusted as tolerated postoperatively. Moreover, in the case of OCD, intensive behavior therapy should be initiated as soon as possible, preferably within the first month postoperatively. For DBS, electrode implantation is usually followed by a several-week delay to enable resolution of local edema and stabilization of other factors that might influence the response to stimulation. Then, systematic outpatient adjustment of stimulation parameters is performed before initial settings are determined. This is often a timeconsuming process, lasting hours over 1 or more days. Ongoing protocols for DBS entail frequent follow-up, especially during the approximate 6 months after implantation, to enable optimization of stimulation parameters, monitoring of the patient, and coordination of other pharmacological and behavioral therapies. LESION PROCEDURES Although numerous approaches have been tried, four lesion procedures have evolved as the safest and most effective for treating psychiatric disorders. All four entail bilateral lesions and are performed using modern stereotactic methods. Subcaudate Tractotomy Subcaudate tractotomy was introduced by Geoffrey Knight in Great Britain in 1964 as one of the first attempts to limit

adverse effects by restricting lesion size. By targeting the substantia innominata (just inferior to the head of the caudate nucleus), the goal was to interrupt white matter tracts connecting orbitofrontal cortex and subcortical structures. The surgery involved placement of radioactive yttrium-90 seeds at the desired centroid, yielding lesion volumes of approximately 2 cc on each side. Indications for subcaudate tractotomy are major depression, OCD, and other severe anxiety disorders. ANTERIOR CINGULOTOMY Anterior cingulotomy remains the most commonly employed neurosurgical treatment for psychiatric disease in North America. The surgery is conducted under local anesthesia and two or three approximately 1-cc lesions are made on each side by thermocoagulation through bilateral burr holes. The target is within the anterior cingulate cortex (Brodmann areas 24 and 32), at the margin of the white matter bundle known as the cingulum. Originally, the placement of lesions was determined by ventriculography; however, since 1991, anterior cingulotomy has been conducted via MRI guidance. Approximately 40 percent of patients return several months following the first operation for a second procedure to extend the first set of lesions. The indications for anterior cingulotomy include major depression and OCD. Limbic Leukotomy Limbic leukotomy was introduced by Desmond Kelly and colleagues in England in 1973. The procedure combines the targets of subcaudate tractotomy and anterior cingulotomy. The lesions have typically been made via thermocoagulation or with a cryoprobe. Historically, the precise placement of the lesions was guided by intraoperative stimulation; pronounced autonomic responses were believed to designate the optimal lesion site. The indications for limbic leukotomy include major depression, OCD, and other severe anxiety disorders. More recently, there is also some evidence that this procedure might be beneficial for repetitive self-injurious behaviors or in the context of severe tic disorders. ANTERIOR CAPSULOTOMY Anterior capsulotomy or its newer variant, Gamma Knife (Elekta, Stockholm) capsulotomy, are used in Scandinavia, the United States, Belgium, Brazil, and elsewhere. The procedure places lesions within the anterior limb of the internal capsule, which impinges on the adjacent ventral striatum, thereby interrupting fibers of passage between prefrontal cortex and subcortical nuclei including the dorsomedial thalamus. Although the original anterior capsulotomy procedure is performed using thermocoagulation via burr holes in the skull, over the past 15 years capsulotomy has also been performed using the Gamma Knife as an alternative. This radiosurgical instrument makes craniotomy unnecessary. Typically, gamma capsulotomy lesions are smaller than those induced by thermocapsulotomy, remaining within the ventral portion of the anterior capsule. Hence, the term gamma ventral capsulotomy is coming into use to describe this procedure. In contrast to thermocapsulotomy, gamma ventral capsulotomy may be performed as an outpatient procedure, with an overnight hospital stay usually the most that is required. The relative advantages and disadvantages of this radiosurgical approach are the focus of ongoing research, including a current controlled study of gamma ventral capsulotomy for OCD, the first of its kind for a lesion procedure in psychiatry. Some data suggest, unsurprisingly, that the rates of neuropsychiatric adverse effects may be considerably lower for gamma ventral capsulotomy than for earlier procedures in which much larger tissue volumes were lesioned. Indications for anterior capsulotomy include major depression, OCD, and other severe anxiety disorders.

Deep Brain Stimulation DBS for psychiatric illness is not a new idea, although the devices, surgical techniques, and theoretical models of relevant neurocircuitry have all advanced. The procedure involves placement of small-diameter brain “leads” (e.g., approximately 1.3 mm) with multiple electrode contacts into subcortical nuclei or specific white matter tracts. The surgeon drills burr holes in skull bone under local anesthesia and then places the leads, guided by multimodal imaging and precise stereotactic landmarking. Usually this is done bilaterally. The patient is typically sedated but awake during surgery. Later, the “pacemaker” (also known as an implantable neurostimulator or pulse generator) is implanted subdermally (e.g., in the upper chest wall) and connects it, via extension wires tunneled under the skin, to the brain leads. The goals of DBS are to achieve improved efficacy and more favorable adverse effect profiles in comparison with ablation. Because various combinations of electrodes can be activated, at adjustable polarity, intensity, and frequency, DBS allows more flexible modulation of brain function, referred to as neuromodulation. Thus, parameters can be optimized for individual patients, but the process, typically performed by a specially trained psychiatrist in the outpatient setting, can be quite time-consuming and requires attentive, long-term follow-up. In cases where no beneficial settings can be identified despite extensive efforts, the electrodes can be inactivated, and devices may be removed. In that event, devices are usually only partly explanted, with the brain electrodes left in place given the small risk of hemorrhage upon removal. The relative advantages and disadvantages of DBS are the focus of very active research. TREATMENT OUTCOME For all four contemporary ablative procedures, outcome cannot be fairly assessed for a considerable period postoperatively, which could extend from 6 months to 2 years. In the first two or three decades of this work, clinical reports usually employed measures of global improvement, such as the Pippard Postoperative Rating Scale, which rates outcomes as follows: (1) symptom free, (2) much improved, (3) slightly improved, (4) unchanged, and (5) worse. Most studies have operationalized significant improvement as categories 1 and 2. In addition, many of the reports employ a measure of symptom severity that is specific to the indication for the procedure (e.g., the Yale-Brown Obsessive-Compulsive Scale for OCD and the Beck Depression Inventory for major depression). The majority of studies focus on one or another of the procedures and are best reviewed according to surgical approach. Outcome with Subcaudate Tractotomy Significant improvement was seen in 68 percent of patients with major depression, 50 percent of patients with OCD, and 62.5 percent of patients with other anxiety disorders. Patients with schizophrenia, substance abuse, or personality disorders did poorly. Shortterm side effects include transient headache and confusion or somnolence, which

typically resolve in less than 1 week. Patients are usually ambulatory by the third postoperative day. Transient disinhibition syndromes were common. In 1994, a largescale review of 1,300 cases was conducted and concluded that the procedure enables 40 to 60 percent of patients to lead normal or near normal lives, with a reduction in suicide rate to 1 percent versus 15 percent in a similarly affected control group with major affective disorders. Outcome with Anterior Cingulotomy Significant improvement occurred in 62 percent of patients with affective disorders, 56 percent with OCD, and 79 percent with other anxiety disorders. Among patients with unipolar depression, 60 percent responded favorably; among patients with bipolar disorder, 40 percent responded favorably; and among patients with OCD, 27 percent were classified as responders with another 27 percent categorized as possible responders. Short-term side effects include headache, nausea, or difficulty with urination; however, these typically resolve within a few days. Patients are usually ambulatory within 12 hours following the operation and discharged on the third to fifth postoperative day. Over the past 10 years the practice of treating patients who experience perioperative seizures with chronic anticonvulsant therapy has been discontinued, and no cases of new onset recurrent seizures have been seen. Although patients have occasionally (5 percent or less) noted transient problems with memory, an independent analysis of 34 patients was performed and demonstrated no significant intellectual or behavioral impairments attributable to anterior cingulotomy; a subsequent study of 57 patients likewise found no evidence for lasting neurological or behavioral adverse effects. Outcome with Limbic Leukotomy Significant improvement occurred in 89 percent of patients with OCD, 78 percent with major depression, and 66 percent with other anxiety conditions. Short-term side effects include headache, lethargy or apathy, confusion, and lack of sphincter control, which may last from a few days to a few weeks. In particular, it is common for postoperative confusion to last at least several days, and patients are often not discharged in less than 1 week. There were no seizures and no deaths; however, one patient suffered severe memory loss due to improper lesion placement, and enduring lethargy was present in 12 percent of cases. Outcome with Anterior Capsulotomy Thermocapsulotomy. A favorable response occurred in 50 percent of those with OCD and 48 percent of those with major depression. Short-term side effects can include transient headache or incontinence. Postoperative confusion often lasts for up to 1 week. Recovery from gamma capsulotomy is swifter and characterized by less discomfort and virtually no confusion, but side effects from radiation exposure,

principally cerebral edema, may be delayed for up to 8 to 12 months. For the open capsulotomy, patients are typically ambulatory in a matter of hours to days following the operation, although the length of hospital stay may be influenced by the duration of confusion. Weight gain has been noted to be a common enduring side effect with a mean increase in mass of 10 percent. Gamma Ventral Capsulotomy. Gamma capsulotomy was generally well tolerated and effective for patients with otherwise intractable OCD. Adverse events included cerebral edema and headache, small asymptomatic caudate infarctions, and possible exacerbation of preexisting bipolar mania. A therapeutic response, defined conservatively, was seen in 60 percent of over 50 patients receiving the most recent gamma capsulotomy procedure, in which pairs of lesions in the ventral capsule are made bilaterally, impinging on the ventral striatum. Therapeutic benefit was achieved over 1 to 2 years and was essentially stable by 3 years. Adverse effects of gamma ventral capsulotomy include significant radiation-induced edema, appearing months after the procedure, apparently due to a differential sensitivity to radiation that remains poorly understood. Long-term follow-up will be necessary to clarify risks and benefits of gamma ventral capsulotomy. The same applies to any neurosurgery, including lesion procedures and deep brain stimulation. Outcomes with DBS Obsessive-Compulsive Disorder. Over the past 10 years, four groups have collaborated closely on development of DBS at the ventral anterior limb of the internal capsule and adjacent ventral striatum (the VC/VS) for otherwise intractable OCD: Leuven/Antwerp, Butler Hospital/Brown University, the Cleveland Clinic, and the University of Florida. Long-term outcomes of open stimulation in 26 patients showed clinically significant symptom reductions and functional improvement in about two thirds of patients overall. Conservatively defined responses (35 percent or greater reductions on the Yale-Brown Obsessive-Compulsive Scale) were seen in one third of patients in the initial group, irrespective of study center, while the response rate was over 70 percent in the second and third patient cohorts treated. Development of psychiatric DBS is following the path of stimulation for movement disorders, where several targets have been pursued with therapeutic benefit. As in movement disorders, overlapping or converging effects of DBS at different anatomical sites on the neurocircuitry involved are likely and are a focus of active research. The same reasoning applies to DBS for depression. Major Depression. A body of functional neuroimaging research implicates the subgenual cingulate cortex as a node in circuits involved in the normal experience of sadness, symptoms of depressive illness, and responses to depression treatments. Chronic DBS for up to 6 months was associated with sustained remission of depression in four of the six patients studied. Another line of research on DBS for depression was

prompted by the OCD research discussed above and also by the reported antidepressant effects of anterior capsulotomy on which the VC/VC stimulation target was initially based. The OCD patients, who had very high rates of comorbid depression, characteristically responded to stimulation onset with mood enhancement and reductions in nonspecific as well as OCD-related anxiety. Such effects were accompanied, or even preceded, by improvements in social interaction and daily functioning. Worsening in these same clinical domains was noted in some patients with cessation of VC/VS stimulation. Moreover, DBS-induced changes in mood and nonspecific anxiety often seemed to precede reductions in core OCD symptoms. Outcome Across Contemporary Neurosurgical Procedures Although the field is developing rapidly, the conclusion reached is that 40 to 70 percent of carefully selected psychiatric patients should meaningfully benefit from contemporary neurosurgical treatment. Twenty-five percent or more might be expected to show outstanding improvement. Responses to ablative procedures have appeared marginally superior for major depression than for OCD generally. The adverse-effect profiles of this group of procedures are influenced by lesion size, the surgical approach, and whether radiosurgical methods (in which the tempo of lesion development is very slow versus thermocoagulation) are used. But adverse effects are greatly minimized in comparison with procedures of the past. Although minor short-term side effects may be common after some modern ablative procedures, severe or enduring adverse consequences are relatively rare. These can include seizures in about 1 to 5 percent of cases. Although frontal syndromes, confusion, or subtle cognitive deficits can still be seen, overall cognitive function, as indicated by the standard intelligence quotient, is generally enhanced, a finding that has been attributed to the overriding beneficial effects of symptomatic improvement. Psychiatric neurosurgery likely reduces mortality, as evidenced by data on comparative suicide rates. Nonetheless, patients who undergo and fail to benefit from these procedures are at particularly high risk for completed suicide. Therefore, as with any therapy, the potential risks and benefits of psychiatric neurosurgery must be weighed against the potential risks and benefits of undergoing this brand of treatment. The advent of DBS in psychiatry has created tremendous interest and considerable research activity. This therapy is intentionally nonablative, can be optimized for individual patients, is reversible, and is based on devices that are (to varying degrees) removable. DBS may therefore be accepted by patients who would not choose to undergo lesion procedures (although the reverse is also true). With all of its advantages, DBS requires that patients be treated by highly specialized teams willing and able to provide long-term care. The logistics and expenses involved can represent significant barriers. In contrast, psychiatric care can be delivered in standard treatment settings after lesion procedures. However, although the relative risks of enduring adverse effects after psychiatric DBS remain to be clearly established, at this stage ablative methods appear to carry a greater potential for them. Because rates of adverse outcomes are low

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