Deep Brain Stimulation for Emerging Psychiatric Indications

15 Deep Brain Stimulation for Emerging Psychiatric Indications

Brett E. Youngerman, Smit Shah, Sameer A. Sheth

Abstract

Deep brain stimulation (DBS) has become a mainstay treatment for some neurological conditions, including Parkinson’s disease, essential tremor, and dystonia. It has also demonstrated promise for a few psychiatric indications, including obsessive-compulsive disorder and depression. Previous chapters of this text book provide detailed, up-to-date accounts of the state of the science for these disorders. The success of DBS for these indications has led groups around the world to use this surgical platform to treat a variety of other neuropsychiatric disorders. The implicit assumption is that these disorders are manifestations of network-level dysfunction; if we can understand the underlying network and identify accessible nodes within it, we can perhaps treat disorders resulting from its dysfunction with targeted therapy such as DBS. In this chapter, we review the current state of DBS for these emerging indications, including anorexia nervosa, addiction and substance use disorders, aggressive and self-injurious behavior, post-traumatic stress disorder, and schizophrenia.

Keywords: anorexia nervosa, post-traumatic stress disorder, addiction, self-injurious behavior, schizophrenia

15.1 Introduction

Inspired by the success of deep brain stimulation (DBS) for the treatment of movement disorders and advances in the understanding of neural circuit dysfunction underlying brain disease, the last decade has seen a tremendous renewal of interest in neurosurgical interventions for the treatment of psychiatric disorders.1,2 DBS for movement disorders, including Parkinson’s disease, essential tremor, and dystonia, has demonstrated robust efficacy and it has become standard practice for appropriately selected patients. In 2009, the Food and Drug Administration (FDA) awarded DBS a Humanitarian Device Exemption (HDE) for obsessive-compulsive disorder (OCD) and evidence has continued to accumulate in favor of its efficacy.^2,3 As covered elsewhere in this book, DBS is under investigation for the treatment of refractory epilepsy, Tourette syndrome, and major depression.

In this chapter, we review the literature investigating the use of DBS for other emerging psychiatric applications, including anorexia nervosa (AN), addiction and substance use disorders, aggressive and self-injurious behavior (SIB), post-traumatic stress disorder (PTSD), and schizophrenia. For each indication, we briefly review the epidemiology and burden of refractory disease. We discuss advances in neuroanatomical and functional understanding of the diseases, including select human imaging and animal model findings, and the theoretical basis for proposed targets. Finally, we summarize the reported clinical experience with DBS for each indication.

15.2 Anorexia Nervosa

Anorexia nervosa (AN) is a chronic eating disorder characterized by abnormal patterns of eating behavior and distorted body image.4 Features include strict attitudes toward body weight and shape along with abnormal perception of body image. Individuals with AN demonstrate restricted food intake along with ritualized consumption of a low-calorie diet. AN is more common in women than men, with a lifetime prevalence as high as 2% in American women.⁵ Acute interventions include nutrition and treating the medical sequelae of prolonged starvation. Mainstays of longer-term therapy aimed at behavior modification include medications (i.e., selective serotonin reuptake inhibitors and antipsychotics) and cognitive behavioral therapy. However, approximately 30% of patients do not significantly improve, and mortality rates approach 15%, inclusive of medical complications and suicide.⁶ Family therapy has been relatively successful for the treatment of adolescents, who have the best prognosis,⁷ but there has been minimal improvement in treatments for adults, who are often highly refractory to intervention.⁴

Imaging studies in patients with AN have suggested certain reproducible patterns of neural dysfunction. Studies have demonstrated general sequelae likely related to poor nutrition including cerebral atrophy of both gray and white matter and a secondary relative increase in cerebrospinal fluid volume. More specifically, anorexic patients have different responses to distorted body image from controls including hyperactivity in the prefrontal cortex and inferior parietal lobule, suggesting dysfunction in perceptual pathways.⁸ They may also have different appetite regulation and dysfunction in the reward system, which is associated with comorbid mood disorders.⁹ Exposure to food is associated with abnormal activity in the insula, orbitofrontal cortex, and multiple regions of the cingulate cortex. These patients may also experience anxiety provocation and amygdala activation upon eating or exposure to food.¹⁰

AN has high comorbidity with mood disorders and OCD and shares many of the behavioral phenotypes. There has been significant overlap in neurosurgical targets for both OCD and depression. In the past, lesioning procedures including anterior capsulotomy, thalamotomy, and limbic leucotomy demonstrated success for highly refractory cases of AN, but adoption has been limited, largely due to the risk of permanent side effects.^11,12 Success of DBS for OCD has led to interest in its use for AN treatment.

DBS for AN has been reported in the subcallosal cingulate sulcus (SCC), the nucleus accumbens (NAcc), and ventral capsule/ventral striatum (VC/VS), all of which have been targets for depression, OCD, or both. However, investigation of these targets in AN is at an earlier stage, with evidence limited to open-label case series and reports ( Table 15.1).

Lipsman et al initially demonstrated promising results of DBS of the SCC in six patients with AN at 9-months follow-up.¹³ As of their most recent publication, 16 patients aged 20 to 60 years with chronic (average duration 18 years), treatment-resistant AN (restricting or binge-purging subtype) have undergone DBS of the SCC and open-label continuous stimulation.¹⁴ At 1 year, mean body mass index (BMI; normal range 18.5–25) increased from 13.83 (SD = 1.49) to 17.34 (SD = 3.40) kg/m² (p = 0.0009). Patients also experienced significant improvements in depression, anxiety, and affective regulation. Given the precarious health of patients with chronic anorexia, the primary endpoint of the trial was safety. Serious adverse events were largely attributable to the underlying disorder with few major procedure-related complications.

Positron-emission tomography (PET) imaging at 6 and 12 months showed significant changes in glucose metabolism in multiple brain structures implicated in AN, suggesting that DBS can alter relevant brain circuitry. Activity in the SCC and the immediately adjacent anterior cingulate was reduced with chronic stimulation, and parietal areas including the supramarginal gryus and cuneus developed significant hyperactivity over time. The cingulate plays an important role in selective processing and the assignment of reward value to external stimuli, both of which are abnormal in patients with AN.15 There are direct projections from the SCC to the affected parietal areas. Prior studies had shown hyperactivity in the anterior cingulate and hypometabolism in the parietal regions in both acutely ill and recovered AN patients.¹⁶ The PET findings suggest a reversal of the functional imaging abnormalities seen in AN and thus a potential therapeutic mechanism for the intervention.

The primary limitation of the study was its open label nature, making it susceptible to placebo effect and other biases. However, the sustained clinical improvement at 1-year follow-up and objective imaging changes are promising. The authors plan continued long-term follow-up and favor a sham-controlled, randomized trial. They also favor inclusion of hormonal markers in future trials, as there are often significant hormonal disturbances in patients with AN, and such biomarkers offer an objective outcome metric not always available in studies of psychiatric disease.

Evidence for the NAcc and VC/VS is more limited. Wu et al reported on two patients who underwent DBS of the NAcc and experienced increases in BMI from 13.3 and 12.9 at baseline to 18.0 and 20.8, respectively, at 1-year follow-up.¹⁷ They also had improvement in anxiety and depressive symptoms, and in attitudes toward food. Notably, they had normalization of core temperature and heart rate. In another report, four patients who underwent NAcc DBS experienced an increase in average BMI from 11.9 to 19.6 over varying multi-year time periods with persistent benefit after removal.¹⁸ However, these patients were all adolescents with relatively short histories (less than 2.5 years) of AN. Given that this cohort is more likely to have resolution of symptoms with medication and therapy,⁷ these findings may be influenced by natural history. Finally, in a single case report of VC/VS DBS primarily for OCD, the patient had improvement in comorbid AN including eating habits and BMI.¹⁹

15.3 Addiction and Substance Use Disorders

Addiction is a broad category of disorders characterized by compulsive, repetitive engagement in behaviors with negative physical, psychological, or social consequences.20 Addiction includes substance use disorders, as well as other potentially compulsive behaviors such as gambling. The annual prevalence is over 30% for smoking, 7% for alcohol abuse, and 5% for other illicit drug use.²¹ While there is often a component of increased tolerance and physical withdrawal in substance use disorders, preoccupation with the addictive behavior and relapse often occur in the absence of these effects or after they have subsided.²² These clinical observations, along with numerous imaging and animal model studies, suggest that addiction involves underlying or longer-term brain dysfunction, most likely in the reward system.

Neural mechanisms of addiction are well studied and have led to a focus on the NAcc as a potential target for stimulation. Psychoactive substances lead to activation of the reward system. Dopaminergic neurons project from the ventral tegmental area (VTA) to the VS (including the NAcc), the amygdala and septal nuclei, and the prefrontal and cingulate cortices.22,23,24 The connections between the VTA and NAcc modulate reward learning and repetitive behavior, making them particularly relevant in addiction.

Several targets have been studied for surgical lesions in patients with addiction. Lesions of the anterior cingulate, hypothalamus, and subcallosal white matter have all been attempted in open-label series, with varying measures of efficacy and adverse effects.²³ In 2003, Gao et al reported 28 patients who underwent bilateral NAcc ablation for addiction.²⁵ The study suffered from poor follow-up, but complete remission was reported in 7 patients (mean follow-up 15 months), and an additional 10 patients relapsed within 6 months but experienced alleviation of withdrawal symptoms. There was a 19.2% rate of serious complications including temporary memory loss and personality changes, which further limited adoption. However, the advent of DBS has offered the opportunity for a less destructive, titratable intervention.

Animal studies have demonstrated that stimulation of the NAcc attenuates behaviors learned in association with substances of abuse.^26,27,28 It is not clear if stimulation acts by reducing the rewarding value of the substance or by decreasing the association between behavior and reward.²⁹

There are several small series and case reports describing DBS for primary or comorbid abuse of heroin, alcohol, or cigarette smoking ( Table 15.2). Two case reports describe patients treated with bilateral NAcc stimulation for heroin addiction. Zhou et al reported a patient who was explanted after 3 years but remained abstinent at last follow-up of 6 years.³⁰ The patient treated by Valencia-Alfonso et al remained abstinent at 6 months. Interestingly, in the latter report, different stimulation parameters reportedly correlated reliably with increases or decreases in drug use, cravings, and intracranial EEG responses to images of heroin.³¹

Kuhn and colleagues reported two successful cases of NAcc DBS for chronic alcoholism. In the first case, a patient treated for severe anxiety and depression did not see improvement in these symptoms but did have resolution of his comorbid alcoholism at 1 year.³² A second patient later underwent implantation primarily for chronic alcoholism and achieved abstinence at 1-year follow-up.³³ Notably, this patient also had improvement in error-related negativity, an electrophysiological marker linked to the anterior cingulate cortex. In a small initial series of three patients from another institution, two of the three patients who underwent NAcc DBS for alcoholism were abstinent at 1 year.³⁴ In an expanded series of five patients, however, only two remained abstinent at 4 years, though all patients had significant reductions in alcohol consumption and cravings.³⁵

Evidence for NAcc DBS for smoking comes exclusively from observed changes in patients treated for other primary indications. In a single case report, a patient who responded successfully to treatment of her OCD also experienced concurrent smoking cessation (and weight loss), which was sustained at 2-year follow-up.³⁶ In a series of 10 smokers who underwent DBS primarily for Tourette syndrome, OCD, or anxiety, only 3 patients had stopped smoking at 30 months.³⁷ The use of retrospective self-assessment of baseline nicotine dependence limits interpretation of results in this series, but smoking cessation was unaided and most patients exhibited decreases in smoking.

15.4 Aggressive and Self-Injurious Behavior

Neurosurgery has historically been employed to treat a range of disorders involving aggression and poor impulse control. Aggressive behavior is increasingly common in patients with a variety of brain insults in association with mental retardation and epilepsy.38 Similarly, SIB is observed in similar patients, as well as those with severe autism. These behaviors are notoriously refractory to behavioral interventions and neuroleptic medications, at least at doses that are not excessively sedating.

The amygdala is a potential target for DBS in aggressive behavior. The amygdala and its projections have a role in anger processing, fear response, and relevance detection.³⁹ It also has a role in social processing, which is believed to be dysfunctional in autism. Historically, bilateral amygdala ablation was used in the treatment of epilepsy with comorbid aggression, but aberrant behavior eventually became the primary indication in the 1960s and 1970s.^2,39 These ablations were associated with reduced autonomic response to stressful stimuli and hypersexuality (i.e., Klüver–Bucy syndrome) and fell out favor with the growing use of pharmacologic restraint.² However, the growing applications of DBS and its reversible nature have renewed interest in the amygdala as a target. In one case report,⁴⁰ a 13-year-old boy with SIB, mental retardation, and autism, who had failed multiple trials of behavioral and pharmacotherapy, underwent bilateral DBS to the basolateral amygdala (BLA) ( Table 15.3). The patient experienced improvement in SIB as well as emotional, social, and cognitive symptoms of the autism spectrum over 24 months.