Continuing Education Activity

Clinicians are beginning to reconsider neuromodulation surgery as a last resort for the treatment of refractory psychiatric disorders. Neurosurgical interventions aimed at treating psychiatric disorders are grouped into two categories: destructive (ablative psychosurgery) or selective stimulation (neuromodulation psychosurgery). Neuromodulation surgery involves implanting a device in the brain that modulates the neural networks within the brain. This activity reviews the role of the interprofessional team in providing neuromodulation surgery for patients with psychiatric disorders.

Objectives:

• Summarize the indications and contraindications for neuromodulation for psychiatric disorders.
• Review neuromodulation surgery in patients with psychiatric disorders.
• Summarize the principle of deep brain stimulation for psychiatric disorders.
• Outline the importance of improving care coordination among interprofessional team members in providing neuromodulation treatment for patients with psychiatric disorders.

Introduction

Despite the advances in pharmacotherapy for treating some psychiatric disorders like anxiety disorders, obsessive-compulsive disorder, depression, and schizophrenia, many patients become refractory and will not respond to pharmacologic treatments.[1] Clinicians are beginning to reconsider neuromodulation surgery as a last resort for the treatment of these patients. Neurosurgical interventions aimed at treating psychiatric disorders are grouped into destructive (ablative psychosurgery) or selective stimulation (neuromodulation psychosurgery).[1] Neuromodulation surgery involves implanting a device in the brain that modulates the neural networks within the brain.

The use of surgery for the treatment of psychiatric diseases is not a new concept. Historically, the concept of psychosurgery always raised general skepticism and stigma because of the way that it was used in the past with a high rate of complications and mortalities, but usually with little improvement in patients’ functionality.[1][2][3] In 1881, Gottlieb Burckhardt, a Swiss psychiatrist, reported on six patients that he performed surgery to treat aggressive behavior and hallucinations with partial results.[4][5] Three decades later, Puusepp operated in 1910 on three manic-depressive patients by interrupting the frontal fibers to the parietal cortex. Fulton and Jacobsen's classical experiments on two chimpanzees that received frontal lobe surgical ablation to improve neurotic behaviors were an inspiration for subsequent human ablative procedures. In 1935, a Portuguese neurologist named Egas Moniz first introduced a surgical procedure called prefrontal leucotomy.[3][6][7] Moniz believed that abnormal connections to the frontal lobe caused some psychiatric problems and that surgically removing the white fibers connecting the frontal lobe with the rest of the brain will help mental health conditions.[8] Moniz technique was later widely utilized in Europe and the United States. Moniz was awarded the Nobel Prize in 1949 for his contributions. In the United States, prefrontal leucotomy was initially used, but modified by an American neurosurgeon named Walter Freeman, who developed a transorbital leucotomy procedure.[1][2][9][10] Unlike the original lobotomy that involved an open surgery, transorbital leucotomy was a minor surgery.[11][12][13] It lasted about 10 to 20 minutes and aimed at separating the frontal lobe from the thalamus by accessing the brain through the back of the orbits with a sharp instrument similar to an ice pick.[13][14] Clinicians often used this treatment even though, at the time, there was not much data to evaluate the effectiveness of this method, and because of the lack of alternative treatment for patients who had debilitating mental health problems. Later, retrospective studies showed that while Dr. Freeman's approach helped calmed some severely agitated patients, many ended up with numerous complications.[1]

In the late 1950s, pharmacotherapy was introduced and changed the approach in treating psychiatric conditions.[1][5] Chlorpromazine was the first U.S. Food and Drug Administration approved psychotropic drug. While pharmacotherapy led to psychosurgery quietus, physicians laid the groundwork for the development of stereotactical microsurgery techniques. Speigel and Wycis developed the concept of stereotactic surgery to perform precise ablative lesions in deep areas of the brain in 1947.[15] In 1962, Foltz and White used this technique for stereotactic anterior cingulotomy.[16] Furthermore, the rapid development of numerous modalities helped to understand the structure and function of the brain. These new advances, coupled with the frustrations of the significant percentage of patients not responding to pharmacotherapy and positive results in the use of neuromodulation surgery like deep brain stimulation (DBS) in the treatment of movement disorders like Parkinson's disease, leaded clinicians to revisit the use of neuromodulation surgery for the treatment of psychiatric disorders.[5] However, professionals debated whether these techniques will be used only as a last resort for the treatment of refractory psychiatric symptoms, or if they will be used for other purposes like to modify the cognition of healthy individuals.[1][17][18]  Ethical requirements and guidelines for the procedures began to appear in physician's societies.

Etiology

With new diagnostic techniques, physicians' knowledge of the brain and function has improved over the past decades, but understanding psychiatric disorders remains a challenge. Physicians believe that the cause of many mental health disorders has multifactorial etiology, with genetics and environmental factors having a significant role to play. For example, while the exact cause of schizophrenia is unknown, about 80% of the cases might be due to genetic influence.[3] Early childhood events like maternal infection, malnutrition, and environmental factors like urbanization have been cited for playing a role in the etiology of schizophrenia.[3] Similar reports have been used to explain the obsessive-compulsive disorder (OCD), anxiety disorder, and depressive disorders. Genetic heritability is a vital factor for anorexia nervosa (AN).

Epidemiology

Psychiatric disorders are a huge problem in the United States and internationally. According to the American Psychiatric Association, about 25% of United States adults are diagnosed with a mental health disorder each year. Disability caused by psychiatric disorders are overwhelming for patients, and the financial burden on the economy is immense. Based on a 2002 publication, the cost of schizophrenia treatment alone was about $63 billion.[19] It is estimated that between 15-20% of the adults will suffer an episode of major depression in their lifetime.[20] OCD affects approximately 2-3% of the population.[21] Approximately 10-25% of the psychiatric population are unresponsive to pharmacotherapy and behavior therapy.[22] About 20-30% of patients with schizophrenia are unresponsive to antipsychotic medical treatment and will not live a healthy life.[23] Similar inferences can be made about refractory patients with other mental health disorders. AN is a psychiatric disorder most commonly seen in females with a prevalence of 1% among young women; however, it has the highest mortality among all the psychiatric disorders. 

Before introducing pharmacotherapy for psychiatric disorders, approximately 10,000 leucotomies were done in the United States and the United Kingdom.[24] A few years later, this number had increased significantly, with over 60,000 procedures performed.[7][25] With the introduction of chlorpromazine in 1954, it was estimated that 2 million patients received the drug during its first year.[7] In recent years, fewer than 15 ablative procedures per year are performed in the United States.

Pathophysiology

The arrival of new diagnostic techniques and the ability to integrate information from different diagnostic modalities made it possible for clinicians to understand the brain structure and function and help localize brain pathologies. Some of these diagnostic techniques include functional magnetic resonance imaging (fMRI), positive emission tomography (PET), neurophysiologic data from an electroencephalogram, magnetoencephalography, and transcranial magnetic stimulation (TMS).[26][27][28][29] These diagnostic modalities provide more in-depth knowledge of brain activities and a stronger foundation for specific targets for neuromodulation surgery and some psychiatric disorders.

Researchers cite that the pathophysiology of OCD stems from abnormal function of the cortical-striatal-thalamic circuits. The genu of the corpus callosum has been strongly implicated in the pathophysiology of depression and schizophrenia. In contrast, the medial cingulate cortex has been involved in the pathophysiology of anxiety disorders.[1][29][30] The inferior thalamic peduncle connects the thalamus and the orbitofrontal cortex and is a proven target for neuromodulation in OCD and depression.

History and Physical

While the advent of new diagnostic techniques and the ability to integrate information from different diagnostic modalities has made it possible to understand the brain structure and function and help localize brain pathologies, there are no tests or objective biological markers indicated as criteria for diagnosing a psychiatric disorder according to the Diagnostic and Statistical Manual of Mental Disorders.[31] A reliable diagnosis is based on the identification of symptoms, behaviors, personality traits, among other features. While diagnostic tests can be used, in most cases, they are used to rule out other organic causes that may be presenting as a psychiatric problem.

A careful history and physical examination are fundamental tools for diagnosing and treating psychiatric disorders. Essential components of a patient's history include present illness, past medical history, psychiatric history, substance abuse, family and social information, and medication use. This history will provide insight into the patient’s current illness, predisposing factors like genetic vulnerabilities and low socioeconomic status, current life stressors, family dynamics, and support systems available to the patient. In some cases, medications that have worked for another family member may suggest that patient will benefit from it.

The physical examination starts by examining the patient's general appearance and begins as the physician sets an eye on the patient. The overall patient well-being and nutritional status may be assessed just through observation. A patient may appear messy or bizarre with clothing that may not be appropriate for the setting. Other important aspects that can be evaluated include the patient's psychomotor activity, the patient's mood and affect, and the patient's thought process and thought content. The clinician can observe whether the patient's movements are slow down or if the patient is fidgeting and agitated. The should evaluate patient speech patterns and determine if their thoughts are goal-directed or disorganized. Finally, assessing the patient's thoughts for any delusions, hallucinations, or suicidal and homicidal thoughts, among others, is essential.

A patient's history can help guide specific organ systems' physical examination to focus their attention first. For example, during an assessment of subconjunctival, a patient's pale and dry appearance may suggest self-neglect and inadequate dietary intake due to depression, schizophrenia, and AN. The skin examination is performed for evidence of cuttings marks associated with a borderline personality disorder, depression, and even eating disorders. Other systems-specific physical exams may be based on the patient's history that gives the physician a prompt for further assessment.

Evaluation

Different diagnostic methods that help evaluate brain function are among the most critical advances that have made it possible to target neuromodulatory psychiatric treatment. Several diagnostic techniques are good at giving information about the cortical structures and function.

• TMS provides a noninvasive means of probing the neurophysiology of different cortical structures function and dysfunction.[26][27][28]
• fMRI and PET help provide information about the subcortical structures.[26][27][28][29]

Laboratory workup is performed to exclude primary organic etiologies that may mimic psychiatric disorders. Neuroimaging studies include brain magnetic resonance imaging (MRI) and computed tomographic (CT) scans of specific body areas as needed.

Treatment / Management

The primary goal of treating psychiatric disorders is to improve the functionality of the patients in the society. While the stigma due to the origins of psychosurgery still looms, the utilization of neuromodulatory surgery to treat the psychiatric disorder is nowadays backed by not only a more profound understanding of brain structure and function, but also the development of new stereotactic microsurgical technique and results about successful management of other neurological disorders through neuromodulation. This fountain of knowledge has led to the development of treatment options that target a particular region of the brain and effects that can be reversible, unlike the earlier process like prefrontal leucotomy that involves the permanent removal of parts of the brain.

Only patients with severe, chronic, disabling, and treatment-refractory psychiatric illness should be considered for surgical intervention. Psychiatric disorders that might benefit from surgical intervention include OCD and major affective disorder (unipolar major depression or bipolar disorder). Schizophrenia diagnosis is not currently considered a clear indication for surgery. Ablative procedures, including cingulotomy, anterior capsulotomy, subcaudate tractotomy, and limbic leucotomy, are psychosurgical procedures still used today in some cases.

The concept of DBS in treating psychiatric disorders can be attributed to its success in treating movement disorders like Parkinson’s disease, essential tremor, and dystonia.[32] Current research and clinical experience have shown promising results in the use of DBS in treatment-resistant OCD, anxiety disorders, depression, and trials are underway for the utilization of this procedure in the treatment of schizophrenia.[33] DBS is a non-destructive treatment option that is reversible, less invasive, and can be modifiable based on the patients.[34] While cost-wise, DBS may be more expensive, recent studies show long-term benefits with cost leveling off.[35] DBS involves placing electrodes deep in the brain. Through these electrodes, a specific brain region is stimulated with frequencies as high as >100Hz.[36] This often results in the inhibition of the target area, producing some functional ablation which can be reversed if the stimulation is discontinued. The mechanism by which DBS exerts its effects is not entirely understood. It is believed that DBS modulates neural activity by stimulating or inhibiting neurons and fiber pathways that will subsequently allow neurochemical release.[36] Clinical trials are ongoing, and the DBS's acceptance is growing, albeit slowly in the psychiatric community.[37] The procedure is performed using a stereotactic frame fixed to the patient’s head with neuroimaging studies performed (brain MRI or head CT scan fused with a prior brain MRI). The target is determined based on the disorder's pathophysiological basis, and electrodes are introduced into these areas. The surgical trajectory must avoid intracranial vessels and ventricular walls during the navigation planning. After the procedure is finished, the electrode contacts' position must be verified postoperatively using a brain MRI before starting the stimulation. The stimulation parameters should be obtained and recorded for future adjustments. Psychiatric and neuropsychological assessments must be performed regularly to evaluate the effectiveness of the procedure.

DBS modulation can use several different targets, but current literature does not demonstrate clear superiority among these targets.[18] The most commonly used targets include the internal capsule/ventral striatum, nucleus accumbens, subthalamic nucleus, inferior thalamic peduncle,  cingulate cortex, and globus pallidus. For depression and other major affective disorders, ablative lesions in anterior cingulotomy, anterior capsulotomy, subcaudate tractotomy, and limbic leucotomy had been performed in the past. DBS to the subcallosal cingulate, nucleus accumbens, ventral striatum, or inferior thalamic peduncle has provided good results in 50-70% of the patients.

For OCD, traditional ablative lesions include anterior cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leucotomy. DBS to anterior limb internal capsule, ventral capsule, dorsal striatum, nucleus accumbens, subthalamic nucleus, inferior thalamic peduncle, or globus pallidus internus produces a positive response in 40-90% of the patients.[36]

Tourette’s syndrome (TS) is a recognized idiopathic neuropsychiatric disorder affecting approximately 1% of the population. Dysfunction in the cortico–basal ganglia–thalamocortical network is thought to be the pathophysiologic basis of impairment. DBS of the thalamus, globus pallidus internus, globus pallidus externus, internal capsule, or nucleus accumbens has been used to treat refractory TS.[38]

Case reports for neuromodulation of the nucleus accumbens, and the anterior limb of the internal capsule has successfully been used for preventing heroin use relapse.[39] A strategy used to increase the device's battery life is to use DBS only to the nucleus accumbens combined with an ablative anterior capsulotomy.[39]

DBS to the subcallosal cingulate or the nucleus accumbens for AN had been used with promising results in mood with a significant increase in body-mass index.[40][41][42] Sometimes, the stimulation to the nucleus accumbens is done bilaterally. Ablative procedures used include prefrontal leucotomy, anterior cingulotomy, anterior capsulotomy.

Vagal nerve stimulation (VNS) was initially developed to treat medical treatment-resistant epilepsy.[43] It was noted that many patients improved their depressive symptoms even if their seizures were not controlled. This procedure involves implanting a device by the neurosurgeon or vascular surgeon that stimulates the left vagal afferent nerve fibers in the neck to modulate seizure activity. It is now used to treat chronic and treatment-resistant depression and anxiety disorders. The right vagus nerve is not stimulated because of its direct involvement in the heart.[43] The surgical and psychiatric side effects reported are rare and involve hypomania, mania, and in some cases, worsening of depression and increase suicide risk.[43] Initial trials did not support the use of VNS as an effective treatment for these diseases. However, a 5-year, prospective nonrandomized study conducted at many centers in 795 patients with a major depressive episode showed effective outcomes in treatment-resistant depression using VNS.[44] Similar results in quality-of-life and response had been obtained in other recent studies.[45][46] It has also been studied in OCD patients with some case reports showing some improvement but not as promising as affective disorders.[47][48]

Other neuromodulation techniques that have been used for the treatment of psychiatric disorders that do not involve the application of a surgical device are TMS and electroconvulsive therapy (ECT). ECT has been widely reported in the literature as one of the most effective treatments for chronic major depression and pharmacotherapy-resistant major depression.[5][49] On the other hand, TMS is often used for diagnostic purposes to assess brain function and has been used to treat psychiatric disorders like major depressive disorder.[50] TMS had been used for neuromodulation of depression after traumatic brain injury targeted at the dorsolateral prefrontal cortex.[51][52][53] However, other studies have not found an effect.[54][55] While these methods are far less invasive than the neuromodulatory surgery and have been proven to be very useful, they are highly underutilized due to their stigma. Recently, magnetic-guided focused ultrasound bilateral capsulotomy has been performed, avoiding radiofrequency or stereotactic radiosurgery ablation for severe refractory depression and OCD.[56]

Ongoing research in the pathophysiologic understanding of these circuits and targets is critical for the potential neurosurgical treatments of schizophrenia. The possibility of targeting the associative striatum, anterior hippocampus, and ventral striatum for therapeutic neuromodulation with DBS is being considered for schizophrenia.[29]

Differential Diagnosis

It is crucial to make a correct and definite diagnosis of a psychiatric disorder that can be amenable to neuromodulation. Improper diagnosis can expose patients to incorrect treatment modalities. Differential diagnoses for psychiatric disorders include the following disorders, which can present with some psychiatric traits but can be corrected after treating the primary disease.

• Attention-deficit/hyperactivity disorder
• Autoimmune disorders (rheumatoid arthritis and lupus)
• Chronic fatigue syndrome
• Hypercortisolism (Cushing disease, Cushing syndrome)
• Diabetes
• Fibromyalgia
• Hypothyroidism
• Lyme disease
• Sleep disorders

Prognosis

Despite the initial lousy reputation of ablative psychosurgery, modern cingulotomy offers positive outcomes in nearly 70% of patients with OCD and about 75% of patients with major depression on the five-year long-term follow-up. Anterior capsulotomy with radiosurgery in patients with intractable OCD offers more than 70% of response at a 5-year follow-up. For alcohol dependence and intractable AN, bilateral stereotactic radiofrequency ablation of the nucleus accumbens offers remission rates of 64-82%. Bilateral cingulotomy for heroin addiction offers a remission rate of 45%.

For DBS, the response rate varies depending on the psychiatric disorder and the target.

• For OCS, the internal capsule  provides a response in 55% of the patients, the anterior capsule/striatum a response in 62% with remission in 6%, the inferior thalamic peduncle a response in 100%, the nucleus accumbens a response in 38%, and the subthalamic nucleus a response in 50%[1]
• For mayor affective disorder, the anterior capsule/striatum provides a response in 40% with remission in 25% of the patients, the cingulate a response in 58% and remission in 28%, and the nucleus accumbens a response in 48% and remission in 5%[1]
• Only case reports and case series have been published for TS, documenting a wide range of improvements (46% to nearly 100%).

Complications

Seizures

Intracranial hemorrhage

Hypomania

Mania

Worsening of depression

Increase suicide risk

Battery changes requiring reoperations

Hardware malfunction

Infections

Electrode misplacement

Skin erosion

Hemiparesis

Consultations

Psychiatrist

Neurologist

Neurosurgeon

Social worker

Ethical committee

Deterrence and Patient Education

Despite pharmacotherapy advances for treating psychiatric disorders like schizophrenia, anxiety disorders, OCD, and depression, many patients become refractory. Neuromodulation provides an alternative, and many times, an effective treatment in these patients.

The medical and patient community needs to evaluate the new modulatory treatments for these unresponsive psychiatric disorders. Each procedure must be given credit bases on evidence-based information, and not on their tainted history. The use of all these neuromodulatory treatments should be evaluated in blind trials and systematic randomized trials. Still, the optimal patient selection and surgical targeting areas need to be explored.

In many patients, DBS indications are limited to intractable OCD, major affective disorders GTS, TS, and AN. Still, sometimes, it is used to treat drug addiction and certain forms of severe aggression or auto aggression.

Enhancing Healthcare Team Outcomes

An interprofessional team of nurses and physicians should be familiar with and educate patients and their families on the option of neuromodulation surgery as a last resort for the treatment of these patients. In the last 50 years, there has been a progressive replacement of ablative psychosurgery by using DBS in unresponsive psychiatric disorders. There is a significant amount of level II evidence for neuromodulation's safety and efficacy in treating refractory major affective disorders and OCD.[1] DBS provides a reversible and adjustable treatment in pharmacotherapy-resistant psychiatric disorders; however, its use is still on an investigational stage for many of the diagnoses, and ethical requirements and guidelines have been proposed. Through a multidisciplinary and integrated approach, the best outcomes can be obtained.