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

Table 1: Deep brain stimulation targets for depression

Table 2: Deep brain stimulation targets for Alzheimer disease and dementia

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.¹ It is predicted that the number of new cases of Alzheimer disease (AD) will reach 115 million in the next 40 years.² 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.³ 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.² 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.

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

What is deep brain stimulation?

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 powerful scientific tool. 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.⁴

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.⁵ In these conditions, such as Parkinson disease, dystonia, and essential tremor, DBS can provide significant symptom relief and improved quality of life.⁶

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.

Influencing neural circuitswith DBS

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.

Major depression. MDD is the most common mood disorder, with an estimated lifetime prevalence of 16%.⁷ 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.⁸ 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.^9,10 Moreover, findings indicate that with successful pharmacological treatment of depression, this overactivity is reversed.¹¹

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).

We used ¹⁵O 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.¹² At 3 to 6 years following surgery, the response and remission rates were 64.3% and 42.9%, respectively.¹³

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.¹⁴

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.¹⁵ 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 colleagues¹⁶ 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 (Table 1). 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.¹⁷ 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.¹⁸

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.

Alzheimer disease. AD is the most common neurodegenerative condition, with nearly 5 million new cases diagnosed every year.¹⁹ 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.²⁰ 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 (Table 2).²¹ We found 3 main results:

• 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.^22,23 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.

Future directions

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.

Disclosures:

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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