Nir Lipsman, MD

[[{"type":"media","view_mode":"media_crop","fid":"23135","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_7260563962522","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1772","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"margin: 5px; float: right;","title":" ","typeof":"foaf:Image"}}]]Anorexia nervosa (AN) is a serious medical condition with a high rate of both mortality and chronicity. Affecting both men and women, the mortality rate for the condition is estimated at 10% to 15%, and an additional 10% to 15% will go on to develop a chronic form of the illness.

Current treatments are able to help many individuals who suffer from this disorder. While there have been promising advances over the last decade in the treatment of adolescent AN through the development of novel forms of family therapy, there have been few significant improvements in treatment for adults, especially those with chronic illness. Treatments focused on this group would have a significant effect on reducing both mortality and general suffering experienced by these individuals.

Deep Brain Stimulation (DBS) is a neurosurgical procedure initially developed for the management of treatment-refractory movement disorders, such as Parkinson disease and essential tremor. More recently, there has been interest in investigating the use of the procedure in other circuit-based disorders, including psychiatric conditions, such as depression, OCD, schizophrenia, and Alzheimer dementia. Since 1987, over 100,000 individuals have had the procedure for neurological or psychiatric conditions, and the number of trials for new indications continues to grow.

During a DBS procedure, electrodes are introduced bilaterally under stereotactic and fluoroscopic guidance to deep brain targets identified on a pre-operative MRI. These electrodes are tested in the operating room with the patient awake and under local anesthesia, and then in a separate procedure the electrodes are connected to a programmable stimulator implanted in the anterior chest wall. The device is then activated a short period of time later, with the parameters of the stimulation monitored externally. The battery life for the stimulator depends on the intensity of the stimulation, but is typically 2 to 4 years. Replacements are performed with local anesthesia and sedation.

The rationale for the use of DBS in AN derives from several sources.

 The insula has been implicated in interoception-that is, in the way in which the body is experienced internally, and appears to be involved in decisions about acceptability of food. The anterior cingulated (AC), and in particular the subcallosal cingulate (SCC), appear to be implicated both structurally and functionally in the symptoms of AN. The AC is also involved in both mood states and the regulation of affect, both directly and through its influence on higher cortical structures. Finally, the ventral striatum, or nucleus accumbens (NAC), may be involved in reward circuits, with some research suggesting that the NAC does not function normally in anorexia nervosa patients compared with healthy controls. It was thus thought that stimulation of either the AC or NAC would be potential targets for a trial of DBS in AN.

In our research, we decided to focus our attention on the AC, and specifically the subcallosal cingulate. The rationale for this decision related to our understanding that alterations in mood and the regulation of mood seem to have a very important role in the initiation and maintenance of AN. We also were able to assess the response to AC stimulation in depression, given the presence of a large series of cases in our setting. Our initial work has been a phase I clinical trial to establish safety and tolerability: we are presently in the midst of a phase II trial to start the process of evaluating efficacy. Entry criteria for the trial includes a history of either chronic, treatment- resistant AN, or malignant AN. Risk of a premature death in the reasonably near future was an important factor to consider in selecting subjects suitable for the trial, which does represent a last hope for many subjects.

Our study presently has 15 subjects enrolled who have had the procedure. Six further patients are awaiting surgery. We recruited our first 12 patients in approximately 14 months. By comparison, in the first trial of DBS for depression conducted in this setting, it took two years to recruit the first 6 subjects. This alone suggests that there is a meaningful population of individuals with chronic, severe AN who are willing to undergo experimental neurosurgery in the hope that they might derive some benefit from the procedure.

We set a threshold of a BMI of 13 to be able to perform the surgery. Several subjects required hospitalizations before surgery to make them suitable for the procedure.

Our operative experience has been positive, with few adverse events, none of which were unexpected. Patients tolerated the procedure well, and there were few post-operative complications. One patient, with severe comorbid OCD did find it impossible to resist picking at the incision line in her scalp and we eventually had to remove the device.

We initially reported on 6 patients and we now have 8 subjects, on whom we have 1- to 2-year follow-up data.

 Other subjects have shorter periods of follow-up available, and we will report on these separately. We presented data on our first 8 patients in the fall of 2013.

 From a psychometric perspective, there are significant improvements in mood, anxiety, and obsessionality by 6 months post-simulator activation. These improvements occur outside of any active treatment for the most part and are striking given the notable difficulty in generating such improvements in very underweight individuals. Weight showed an initial decline back to pre-surgery levels, but was slowly increasing by 6 months.

There were some improvements in other core eating disorder (ED) symptoms, including reduced levels of bingeing and purging, and exercise. We noted consistent improvements in comorbid OCD and PTSD in several subjects who suffered from these conditions. Anecdotally, patients reported much better affective regulation, and explained symptom reduction, when it occurred, as a function of having much better control over their responses to affective events.

Of these 8 subjects, 6 decided to re-enter specialized treatment for their AN in the 4- to 9-month period post-surgery. None of these patients had previously been able to become fully weight restored, and between them they had over 50 intensive treatments. Strikingly, all 6 were able to complete treatment, and with much less difficulty than expected. Improved mood, decreased anxiety, and better regulation of affect seemed to allow these patients to tolerate the treatment more easily-and most reported having been able to do therapeutic work in treatment that they had not previously felt comfortable with.

Brain imaging, via positron emission tomography (PET), has shown significant changes in cerebral glucose metabolism in key AN-relevant brain structures, including the subcallosal cingulate, insula, and parietal lobe. These results are consistent with our initial hypotheses relating to brain circuit functioning in AN.

We have had 3 long-term good outcomes from this cohort, two of whom are weight restored at 10 to 12 months, after 17, 20, and 35 years’ duration of illness. Several of these subjects have required a battery replacement. Interestingly, several subjects who have not had any meaningful response in terms of their ED have also decided to have their battery replaced, as well.

These findings are extremely preliminary and need to be considered with some care. The possibility of a placebo response cannot be ruled out, and this will require a sham-controlled trial. The apparent responses in terms of mood, anxiety, affective regulation, and ED symptom change, while appearing to be fairly robust in the face of significant dietary restraint, can attenuate if the patient’s nutritional state deteriorates sufficiently-and then return with even a small improvement in eating.

The availability of functional brain imaging as a routine part of therapeutic trials in psychiatry-via PET and functional magnetic resonance imaging-do open up an exciting new door to our understanding, not only of brain functioning in AN, but also to the direct effect of our treatments of brain function.

Finally, the long-term acceptability of surgical treatments for psychiatric illness such as AN remains an open question. With the advent of new surgical techniques that improve the side-effect profile of the procedures, it is certainly possible that we may see a continuing interest in techniques such as DBT.

Dr  Woodside is Medical Director, Program for Eating Disorders, Toronto General Hospital, and Professor, Department of  Psychiatry, University of Toronto, Toronto, Ontario, Canada. Dr Lipsman is a  resident in the Department of Neurosurgery, Toronto Western Hospital, Toronto,  Ontario, Canada. Dr Lozano is Chair, Division of Neurosurgery, Toronto Western  Hospital, and Professor, Department of Surgery, University of Toronto, Toronto,  Ontario, Canada.

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4. Lipsman N, Woodside DB, Lozano A. Deep Brain Stimulation in Anorexia Nervosa. Eating Disorders Research Society Annual Meeting [Poster presentation]. Bethesda, MD. September 2013.
5. Lipsman N, Woodside DB, Giacobbe P, et al. Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial. 

Articles

Deep Brain Stimulation is a neurosurgical procedure initially developed for the management of treatment-refractory movement disorders. More recently, the rationale for the use of DBS in anorexia nervosa derives from several sources.

Deep Brain Stimulation in Chronic and Severe Anorexia Nervosa

The global burden of neuropsychiatric disease is significant, and it is predicted to rise exponentially in the coming decades. The World Health Organization estimates that nearly 350 million people are affected by major depression.

 It is predicted that the number of new cases of Alzheimer disease (AD) will reach 115 million in the next 40 years.

 It is clear that demographic shifts and rising life expectancies will lead to an epidemic of chronic neuropsychiatric disease, and the societal and public health costs will be enormous.

The problem is compounded by the limitations of current treatments. More than a third of patients with MDD experience resistance to current medical and psychotherapeutic treatment.

 In AD, clinical advances have been slow. The use of anti-amyloid immunotherapies and attempts to boost synaptic acetylcholine levels have shown limited benefit in clinical studies.

 Given the advances in genetics, physiology, and imaging, there is hope that the development of novel therapies for MDD and AD will accelerate in the coming years.

 (DBS)-a procedure that interfaces directly with the neural elements driving pathological behavior-could be useful.

DBS is achieved through neurosurgical implantation of electrodes into brain structures involved in the generation of neurological and psychiatric symptoms. The procedure is performed in 2 stages. In the first, with the patient awake and under local or general anesthesia, electrodes are inserted into the brain and are activated to check for acute effects of stimulation as well as for the presence of any stimulation-related adverse events. The second stage, performed with the patient under general anesthesia, involves the internalization of electrodes and implantation of a programmable pulse generator, similar to a cardiac pacemaker. With the system in place, stimulation settings such as voltage, frequency, and pulse width, can be programmed wirelessly.

In addition to its clinical utility, DBS has emerged as a 

. Microelectrode recording during the implantation stage allows researchers to identify neural signatures of individual target neurons or their response to intraoperative experimental stimuli and to precisely map different regions of the brain. After surgery, the device can be turned on or off in a blinded fashion, which may facilitate sham-controlled trials.

At typical settings (eg, 130 Hz, 90 microseconds, 3 to 5 volts), the DBS battery lasts about 3 to 5 years, at which point it needs to be replaced. Although largely safe and associated with few serious adverse events, DBS remains a neurosurgical procedure with the attendant risks of brain surgery. The risk of serious complications, such as major stroke and hemorrhage, is less than 1% to 2%; device malfunction, wire breakage, and infection occur in 5% to 8% of patients.

The exact mechanism of DBS and its effects on mood is not yet fully understood. Circuit models of motor function helped establish that intervening in critical nodes of a circuit can lead to symptom relief in some movement disorders.

 In these conditions, such as Parkinson disease, dystonia, and essential tremor, DBS can provide significant symptom relief and improved quality of life.

At some targets, such as the globus pallidus, both stimulation and ablation appear to have the same effects on symptoms such as tremor. At other targets, such as the fornix, stimulation and ablation have significantly different effects, with lesions producing memory deficits and stimulation providing possible memory enhancement. The advantages of DBS over lesions include its reversibility and the ability to titrate the stimulation parameters to clinical effect. It further appears that both the microenvironment and macroenvironment surrounding the DBS electrodes influence the overall effect of stimulation. The neuronal element stimulated, whether it is axons or cell bodies, and which structures are upstream and downstream from the target are factors that contribute to an observed clinical effect.

Human behavior is governed by the actions of neural circuits, and neuropsychiatric conditions arise from circuit pathology. The nature of circuit dysfunction varies between disorders, and characterizing this disturbance is an area of active investigation. For example, in Parkinson disease, neurons in key motor structures fire in characteristic “bursting” or oscillatory patterns, whereas in essential tremor, neurons become entrained to the rhythm of a tremor. DBS disrupts these firing patterns and leads to symptom relief. In other conditions (eg, MDD, AD), abnormal metabolic activity within key structures has been linked to clinical symptoms. Understanding the circuits’ functional abnormalities underlying these conditions could guide the use of DBS to restore their integrity.

 MDD is the most common mood disorder, with an estimated lifetime prevalence of 16%.

 Despite current treatments for MDD, a substantial proportion of patients fail to respond. For such patients, neuromodulation approaches, including DBS, have been examined.

In 2005, our group published the first series on DBS that targeted the subcallosal cingulate in 6 patients with treatment-refractory MDD.

 We chose this as our target for several reasons. Imaging studies have linked subcallosal cingulate overactivity to sadness in both healthy control subjects and unmedicated depressed patients.

 Moreover, findings indicate that with successful pharmacological treatment of depression, this overactivity is reversed.

The subcallosal cingulate has also been linked with key structures involved in mood pathways, including the nucleus accumbens and the dorsolateral prefrontal cortex. As a result, we hypothesized that intervening locally in the subcallosal cingulate with DBS could alter its pathological activity and influence activity of its upstream and downstream projections. We found that at 6 months following surgery, 4 of 6 patients achieved clinical response as evidenced by a greater than 50% reduction on the Hamilton Depression Rating Scale (HAMD), and 2 patients had clinical remission of symptoms (HAMD score < 8).

O positron emission tomography scans to monitor perfusion with DBS. Following 6 months of stimulation, we found significant reductions in activity in the subcallosal cingulate, as would be predicted with an antidepressant response, as well as significant increases in activity in lateral prefrontal regions. DBS was able to reverse known baseline metabolic abnormalities in the depressed brain. We further reported on 20 patients who underwent DBS, and at 1-year follow-up found that 55% were treatment responders and 35% either had symptom remission or were within 1 point of remission.

 At 3 to 6 years following surgery, the response and remission rates were 64.3% and 42.9%, respectively.

A multicenter Canadian study examined subcallosal cingulate DBS in 21 patients. Response rates of 29% were seen at 12 months, and a majority of patients-62%-had a reduction of at least 40% in HAMD scores.

Other groups have also explored the subcallosal cingulate target for depression. The Emory group published their experience with 17 patients: 10 with MDD and 7 with bipolar depression.

 At the 2-year follow-up, 92% of patients had treatment response, defined by a greater than 50% reduction in HAMD scores, with 58% in remission, defined by HAMD scores less than 8. Findings from Puigdemont and colleagues

 indicate response and remission rates of 62.5% and 50%, respectively, at 1-year follow-up in 8 patients with treatment-resistant depression.

Several other DBS targets for depression have been explored, including the ventral caudate/ventral striatum, nucleus accumbens, lateral habenula, inferior thalamic peduncle, and most recently, the medial forebrain bundle (

). Results from these open-label studies, which investigated highly refractory unipolar depression, are generally positive. One study examined DBS that targeted the nucleus accumbens in 10 patients and reported a 50% treatment response at 1 year.

 Interesting results have also been seen with the medial forebrain bundle as a target of DBS: the antidepressant response occurred within days and was seen in almost all patients.

Preliminary results over the past decade suggest that DBS can be beneficial for some patients with severe, long-standing MDD. The next step is to conduct phase 3 randomized placebo-controlled trials to establish whether DBS has a role in the management of patients with depression. Such trials are currently under way in both Canada and the United States.

 AD is the most common neurodegenerative condition, with nearly 5 million new cases diagnosed every year.

 Despite advances in our understanding of its genetics, pathology, and imaging features, there are no effective and enduring therapies.

AD affects the entire brain, but the clinical signs and symptoms suggest specific circuit dysfunction. In the healthy brain, structures within the memory circuit, including the hippocampus, fornix, and anterior thalamus, interact with those that make up the brain’s default mode network. Structures contained in this network are most active in the resting state and deactivate during the performance of cognitive tasks. In AD, these structures fail to show this deactivation, and plaques and neurofibrillary tangles, which are the pathological hallmarks of AD, accumulate preferentially in these and other memory circuit structures. With time and disease progression, these structures undergo both structural and functional changes, such as atrophy and decreased glucose utilization.

The impetus for DBS in AD arose from findings in a single patient who underwent hypothalamic DBS for appetite modulation in severe obesity.

 The patient had no history of memory impairment. During intraoperative stimulation, the patient reported spontaneous recall of autobiographical memories that were reliably and vividly reproduced with blinded stimulation. Postoperatively, the patient demonstrated significant improvements in neuropsychological testing compared with baseline, which in the absence of a preoperative deficit, represented an enhancement of normal memory.

This finding motivated our subsequent trial of hypothalamic/fornix DBS in 6 patients with AD (

• Some patients with mild AD appeared to show a stabilization of memory decline at 12 months after surgery

• Impulses generated by DBS electrodes in the fornix propagated to, and activated, key components of the memory circuit

• There were significant increases in glucose utilization compared with baseline in critical memory-related structures

DBS in our small cohort thus appeared to reverse known baseline hypometabolic deficits in AD and activated structures that were previously “offline.” We are now conducting a phase 2, multicenter, randomized, blinded, controlled trial to further study the clinical and neuroimaging effects of DBS in early AD.

Other targets for memory enhancement with DBS have been explored, including the nucleus basalis of Meynert and entorhinal cortex, in patients without AD. Although the global experience is small and results from larger trials remain to be seen, findings suggest that there could be several potential targets for therapeutic DBS along the memory circuit.

The mechanisms of DBS in AD are still under investigation but are informed by both human imaging and preclinical work. We have shown, for example, that DBS of the entorhinal cortex in mice and the anterior thalamus in rats can lead to the generation of new hippocampal neurons that are integrated into functional memory networks.

 Early imaging work by our group further suggests that fornix DBS in humans leads to hippocampal volume increases in AD patients and that key preoperative anatomic features, such as fornix volumes, might predict postoperative outcomes.

DBS remains an investigational treatment for MDD and AD, and although results from open-label studies are promising, data from larger controlled trials are needed. It is clear, however, that focused, brain-based therapeutics will be an important part of the future treatment options available to patients with neuropsychiatric conditions.

DBS will continue to evolve as devices become more efficient, allowing optimization of stimulation parameters, and as additional indications are added. Furthermore, technical advances, such as those in the fields of optogenetics and nanotechnology, will allow us to intervene with greater spatial and temporal accuracy in neural circuits. Conceptual advances will continue to add to our understanding of these illnesses, and there is hope that the future will see safe and effective strategies to treat these conditions.

Dr Lipsman is a PGY4 Resident in the division of neurosurgery at Toronto Western Hospital, University Health Network of the University of Toronto. Dr Lozano is Senior Scientist in the Division of Brain Imaging & Behaviour–Systems Neuroscience, Toronto Western Research Institute; RR Tasker Chair in Functional Neurosurgery, University Health Network; Canada Research Chair in Neuroscience (Tier 1); and Dan Family Chair in Neurosurgery at the University of Toronto. Dr Lipsman has no conflicts of interest concerning the subject matter of this article. Dr Lozano is a consultant for St Jude Medical, Medtronic, and Boston Scientific.

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Demographic shifts and rising life expectancies will lead to an epidemic of chronic neuropsychiatric disease, and societal and public health costs will be enormous. Deep brain stimulation--a procedure that interfaces directly with the neural elements that drive pathological behavior--could be useful.

Nir Lipsman, MD

Articles

Deep Brain Stimulation in Chronic and Severe Anorexia Nervosa

Deep Brain Stimulation for Depression and Alzheimer Disease: An Emerging Therapy