A study published online on Friday, October 4, in the American Journal of Psychiatry found that deep brain stimulation (DBS) of an area in the brain called the subcallosal cingulate (SCC) provides a robust antidepressant effect that is sustained over a long period of time in patients with treatment-resistant depression – the most severely depressed patients who have not responded to other treatments.
The long-term data presented in this study, conducted at Emory University and led by Helen S. Mayberg, MD, now Professor of Neurology, Neurosurgery, Psychiatry, and Neuroscience, and Founding Director of the Nash Family Center for Advanced Circuit Therapeutics at the Icahn School of Medicine at Mount Sinai, validates earlier work conducted by the research team and lays the foundation for additional studies to refine and optimize DBS for these patients.
Deep brain stimulation, currently approved by the U.S. Food and Drug Administration to treat essential tremor, Parkinson’s disease, epilepsy, and obsessive-compulsive disorder, is a neurosurgical procedure involving the placement of a neurostimulator (sometimes referred to as a “brain pacemaker”), which sends high-frequency electrical impulses through implanted electrodes deep in the brain to specific brain areas responsible for the symptoms of each disorder.
Dr. Mayberg led the first trial of DBS of the subcallosal cingulate white matter, known as Brodmann Area 25, for treatment-resistant depression patients in 2005, demonstrating that it could have clinical benefit.
Subsequent small open-label trials produced similarly favorable results, yet despite these encouraging open-label results, a multi-center, randomized trial was halted early due to a lack of statistically significant antidepressant response at the designated, six-month a priori time point.
“Despite the fact that larger trials were halted early, what my colleagues and I were seeing as we continued to follow patients from our initial trials was that over time, they were getting better and not only that, they were staying better.
So we stayed the course,” says Dr. Mayberg. “Over eight years of observation, most of our study participants experienced an antidepressant response to the deep brain stimulation of Area 25 that was robust and sustained.
Given that patients with treatment-resistant depression are highly susceptible to recurrent depressive episodes, the ability of DBS to support long-term maintenance of an antidepressant response and prevention of relapse is a treatment advance that can mean the difference between getting on with your life or always looking over your shoulder for your next debilitating depressive episode.”
Specifically, the study documents the long-term outcome data (4-8 years) for 28 patients who were enrolled in an open-label clinical trial of SCC DBS for treatment-resistant depression. Response and remission rates were maintained at or above 50 percent and 30 percent, respectively, through years 2-8 of the follow-up period.
Three-quarters of all participants met the treatment response criterion for more than half of their participation in the study, with 21 percent of all participants demonstrating continuous response to treatment from the first year forward.
Of 28 participants, 14 completed at least eight years of follow-up, 11 others completed at least four years, and three dropped out prior to eight years of participation.
Data presented through this study support the long-term safety and sustained efficacy of SCC DBS for treatment-resistant depression.
“While clinical trials generally are structured to compare active and placebo treatments over the short term, our research results suggest that the most important strength of DBS in this hard-to-treat clinical population lies in its sustained effects over the long term,” says Andrea Crowell, MD, Assistant Professor of Psychiatry and Behavioral Health Sciences at Emory University School of Medicine. “For people suffering from inescapable depression, the possibility that DBS can lead to significant and sustained improvement in depressive symptoms over several years will be welcome news.”
All study participants met criteria for either major depressive disorder or bipolar disorder type 2 and were in a current depressive episode of at least 12 months duration with non-response to at least four antidepressant treatments, psychotherapy, and electroconvulsive therapy.
All study participants underwent SCC DBS surgery at Emory University School of Medicine with the same surgeon and received the same device.
The first 17 participants were implanted between 2007-2009 in an open-label trial with a one-month, single-blind, stimulation-off, lead-in period. An additional 11 participants with major depressive disorder were implanted using tractography-guided anatomical targeting between 2011 and 2013.
A total of 178 patient-years of data were collected and combined for analysis in this long-term follow-up study. Participants were seen by a study psychiatrist weekly for 32 weeks, starting at least four weeks prior to surgery. Visits were then tapered to every six months for years 2-8 of the study. Currently, 23 patients continue in long-term follow-up.
“At the Center for Advanced Circuit Therapeutics at Mount Sinai, we are currently gearing up for the next phase of this research, now funded by the National Institutes of Health Brain Initiative.
Our new study will recruit treatment-resistant depression patients, as before, but they will be implanted with a new research prototype DBS system (Summit RC+S) that allows simultaneous recordings of brain activity directly from the site of stimulation during active DBS therapy.
Advanced imaging, behavioral, and physiological assessments will also be performed at regular intervals in the lab.
These studies will provide an unprecedented opportunity to monitor the trajectory of recovery over days, weeks, and months at the neural level,” says Dr. Mayberg. “Building on preliminary findings from Emory, we anticipate that these brain signatures will provide important new insights into DBS mechanisms and, importantly, will help guide future decisions about DBS management that can further optimize clinical outcomes in our patients.”
Journal information: American Journal of Psychiatry
Provided by The Mount Sinai Hospital
The use of deep brain stimulation (DBS) to intervene directly in pathological neural circuits has changed the way that brain disorders are treated and understood. DBS is a neurosurgical procedure that involves the implantation of electrodes into specific targets within the brain and the delivery of constant or intermittent electricity from an implanted battery source.
Over 160,000 patients worldwide have undergone DBS for a variety of neurological and non-neurological conditions, with numbers increasing each year1. As a clinical tool, DBS offers several advantages over other surgical approaches for neuromodulation. These advantages include the non-lesional nature of DBS, the capacity to titrate stimulation parameters to maximize benefit and reduce adverse effects and the opportunity to directly interface with the circuit pathology that drives overt symptoms.
As a scientific tool, DBS can be used to investigate the physiological underpinnings of brain dysfunction, which enables identification and correction of pathological neuronal signatures and helps to drive technological innovation and enhance safety and clinical outcomes2. Furthermore, as a highly focal intervention with anatomic targets typically on the order of millimetres, DBS has contributed to circuit theories of brain dysfunction by demonstrating that localized dysfunction and intervention can have profound influences on brain-wide networks3–5.
This duality of DBS as probe and modulator of brain circuitry has led to the investigation of the therapeutic potential of DBS in a broad range of disorders, including those affecting motor, limbic, memory and cognitive functions1.
Notwithstanding its advantages, DBS remains an invasive surgical intervention with low but potentially serious attendant risks, including haemorrhage and infection. Although DBS has become standard of care in patients with movement disorders, its use in other disorders is limited to highly refractory patients and conditions, typically in the context of expert multidisciplinary care and clinical research6.
To date, few indications have been approved for DBS, with the vast majority of procedures performed for movement disorders, most commonly Parkinson disease (PD). Indeed, several randomized controlled trials have found that few treatments are as effective as DBS for controlling the troubling motor symptoms of PD7,8.
However, despite the success of DBS, PD is paradigmatic of both the promise and challenges of the technique. For example, although DBS is highly effective in properly selected patients with PD, stimulation at the most commonly used targets — the subthalamic nucleus (STN) or globus pallidus internus (GPi) — is ineffective for the treatment of gait and other axial symptoms and does little to improve (or can even exacerbate) speech and affective and cognitive symptoms9,10.
Therefore, intervention at a highly focal point is insufficient as a means of addressing dysfunction of multiple circuits. This concept represents an important limitation and challenge for the field. Additional technical and clinical challenges also exist. Technical innovation will focus on the improvement of practicability, including extension of battery life, design of smaller devices and development of more tailored and adaptive stimulation in addition to the integration of wireless technology.
Clinically, the main challenge will be to meet the needs of an ageing population worldwide and expand indications for DBS to circuitopathies other than PD, including depression and Alzheimer disease (AD)1. Even within established indications such as PD, key questions remain unanswered. Biomarkers that predict clinical response and aid in patient selection and stimulation parameter settings are still largely lacking.
Furthermore, the timing of intervention is controversial, with some strong evidence that early surgery might be more beneficial than late7. Answers to these questions will shape not only which patients are offered surgery but also the direction of the field for years to come.
The scope of DBS is rapidly expanding and parallels our increasing understanding of the nature of brain circuit dysfunction (Table 1). In order to take stock of the field, this Review addresses the status of DBS by highlighting its current challenges and future.
We begin by reviewing the putative mechanisms of DBS and its effects on neural tissue and networks, followed by an overview of how preclinical models have informed translational applications. We then provide an overview of the spectrum of clinical applications, from motor to non-motor, including the challenges for both widely used and emerging indications. Finally, we conclude by examining the clinical, technical and ethical challenges that will help to inform future directions of the field.
Disorders currently under investigation with deep brain stimulation
|Disorder||Circuit||Postulated circuit dysfunction||Deep brain stimulation target(s) being studied or that could be considered||Stage of study|
|Parkinson disease, essential tremor or dystonia||Motor||Beta and theta oscillationsGPi overactivitySTN overactivityNeuronal bursting||STN, GPi, GPe, VL thalamus, PPN and spinal cord||Standard of care|
|Major depression||Limbic||Increased activity in OFC, SCC, amygdala and VSFailure to downregulate amygdalar activation||SCC, NAcc, habenula and medial forebrain bundle||Phase III|
|Obsessive–compulsive disorder||Motor and limbic||OFC hyperactivityFailure of VS-mediated thalamofrontal inhibition||NAcc, BNST, ITP, ALIC and STN||Phase II/III|
|Tinnitus||Auditory||Sensory deafferentationThalamocortical dysrhythmia||Auditory pathways and caudate nucleus||Phase I|
|Tourette syndrome||Motor and limbic||Overactive direct pathwayFailure of thalamocortical inhibition||GPi and CM-Pf||Phase I|
|Schizophrenia — positive symptoms||Executive function, cognition and reward||Thalamocortical dysrhythmiaFailure of saliency networks||Temporal cortex and NAcc||Preclinical|
|Schizophrenia — negative symptoms||Motivation, reward, cognition and mood||Mesolimbic and mesocortical dysfunctionFailure to engage anticipatory hedonic system||NAcc, VTA and SCC||Preclinical|
|Alzheimer disease||Cognitive and memory circuits||Amyloid-β plaques throughout the brainDefault mode network dysfunctionCholinergic degenerationEntorhinal cortex and hippocampal atrophy||Fornix, entorhinal cortex, hippocampus, cingulate, precuneus, frontal cortex and nucleus basalis||Phase II/III|
|Pain (phantom pain, deafferentation pain, central pain and nociceptive pain)||Sensory systems and interoceptive awareness||Sensory deafferentationAbnormal neuronal spontaneous bursting behaviour||Sensory pathways, periventricular and periaqueductal areas, cingulate and insula||Phase I/II|
|Addiction||Reward||NAcc sensitivity to reward||NAcc||Phase I/II|
|Anorexia nervosa||Reward and mood||Frontoparietal disconnectionParietal hypometabolismInsular abnormalitySCC overactivity||SCC and NAcc||Phase II|
|Epilepsy||Various||Abnormal excitability and synchrony||CM thalamus, anterior thalamic nucleus, thalamus and seizure focus||Phase II/III|
ALIC, anterior limb of the capsula interna; BNST, bed nucleus of stria terminalis; CM, centromedian; CM-Pf, CM–parafascicular; GPe, globus pallidus externus; GPi, globus pallidus internus; ITP, inferior thalamic peduncle; NAcc, nucleus accumbens; OFC, orbitofrontal cortex; PPN, pedunculopontine nucleus; SCC, subgenual cingulate cortex; STN, subthalamic nucleus; VL, ventral lateral; VS, ventral striatum; VTA, ventral tegmental area. Adapted with permission from REF.1, Elsevier.
Rationale and mechanisms of action
Many hypotheses have been proposed for the mechanisms by which DBS operates (Table 2). Prevailing theories have focused on stimulation-induced disruption of pathological brain circuit activity1,11. The stimulation effects responsible for this disruption occur at the ionic, protein, cellular and network levels to generate improvements in symptoms12 (Fig. 1). Although it is currently unclear which of the wide-ranging effects of DBS are necessary and sufficient to generate therapeutic outcomes, it is clear that high-frequency (~100 Hz) trains of pulses (~0.1 ms) produce network responses that are fundamentally different (for example, inhibitory effects) from low-frequency (~10 Hz) stimulation.
Proposed deep brain stimulation mechanisms
|Concept||Example evidence for||Example evidence against||Refs|
|Direct inhibition of neural activity||Somatic recordings from neurons close to the stimulating electrode||Antidromic and/or postsynaptic recordings from downstream or upstream nucleiComputational modelling of deep brain stimulation biophysics||133,134|
|Direct excitation of neural activity||Biophysics of axonal responses to electrical stimulationAntidromic and/or postsynaptic recordings||Stimulation-induced action potentials intermittently or inconsistently generate postsynaptic responses||135,136|
|Information lesion (jamming)||Extension of the ‘excitation mechanism’Disruption of low-frequency oscillatory patterns||Network interactions remain intact for high-frequency signals||20,21|
|Synaptic filtering||Extension of the ‘excitation mechanism’Biophysics of high-frequency synaptic transmission||Limited understanding of chronic high-frequency driving of synapses||137,17|
At the ionic level, the purpose of an electrode implanted into the brain and polarized to a negative potential (that is, a cathode) is to redistribute charged particles (such as Na+ and Cl− ions) throughout the extracellular space.
This redistribution creates an electric field that can manipulate the voltage sensor of sodium channel proteins imbedded in the membrane of neurons13. At the cellular level, the opening of sodium channels can generate an action potential, which typically initiates in the axon.
Stimulation-induced action potentials then propagate in both the orthodromic and antidromic directions to the axon terminals of the neuron. Under the typical conditions of DBS, many axons will be stimulated.
The stimulated axons are capable of following stimulation frequencies at ~100 Hz with very high fidelity, but synaptic transmission of these high-frequency signals is a far less robust and much more complicated process than that of axonal transmission14,15.
Even if these synapses remain functional during DBS, information processing theories dictate that they will become low-pass filters that suppress transmission of low-frequency signals18.
This general phenomenon, known as ‘synaptic filtering’, could have a key role in DBS, whereby the neurons and connections that are directly stimulated by DBS hinder the propagation of oscillatory activity patterns within their associated brain networks19.
The basic biophysical effects of DBS provide a context in which to begin to interpret the network activity patterns that are observed in patients.
As stimulation frequency remains constant during DBS, the information content of the stimulation signal is effectively zero, which could generate what is known as an ‘information lesion’ in stimulated neurons20. Under this hypothesis, DBS-induced action potentials effectively override any intrinsic activity in the directly stimulated neurons and thereby limit the propagation of oscillatory activity through the network. In addition, the basic concepts of information lesion and synaptic filtering might work in concert to generate robust suppression of low-frequency signals in stimulated brain circuits.
However, not all data support the hypothesis that high-frequency DBS introduces a simple information lesion. Studies in awake and behaving primates have provided some evidence that physiological sensorimotor-related discharge in the pallidum might be maintained at least partially during STN or pallidal DBS21,22.
These studies suggest that DBS might act as a filter that permits some sensorimotor-related modulation of the activity of neurons in the stimulated area while selectively blocking transmission of pathological low-frequency oscillations.
Likewise, other basal ganglia functions such as motor sequence learning or reward-based decision-making can be preserved during DBS of the STN or globus pallidus23. Nevertheless, the information lesion hypothesis might be reconciled with these observations if physiological coding in the basal ganglia is predominantly supported by mechanisms other than synchronization, which are thereby mostly spared by high-frequency DBS.
Indeed, the sparsity of correlations between neurons in the basal ganglia in health supports this model24.
Other network-level factors might also have important roles in the therapeutic mechanisms of DBS for PD. First, the thalamus might act as a low-pass filter by transmitting synchronized inputs from the basal ganglia at frequencies within and below the beta band (12–30 Hz) but not transmitting signals at the high frequencies driven by DBS (>100 Hz)25–28.
The net result of such factors is that high-frequency DBS might provide an effective local information lesion that blocks the transmission of low-frequency oscillations but, unlike synchronization at low frequency, might have little effect on the function of the wider network27,31.
One of the attractions of this schema is that high-frequency DBS then becomes a generic tool that is able to override different forms of pathological low-frequency oscillation, such as those underlying mobile dystonia, tremor and akinesia–rigidity32.
The hypothetical mechanism for DBS outlined above helps to explain only the acute effects of DBS in a subset of movement disorders. It does not explain the longlatency, chronic adaptive changes that occur after DBS in patients with dystonia and can characterize the response to DBS in psychiatric diseases such as depression. One relevant possibility is that low-frequency oscillations are actively reinforced through long-term potentiation, whereas high-frequency stimulation has a lesser effect on plasticity.
In this way, replacement of low-frequency patterning with high-frequency stimulation might undo some chronic disease-related phenomena33. Even so, little evidence currently supports an association between psychiatric diseases and pathologically synchronized low-frequency activity within basal ganglia–cortical circuits, which leaves open the possibility that DBS might also work through other mechanisms. One key area of current interest is the effects of DBS on astrocytes, given their role in integrating synaptic information and regulating synaptic plasticity12.
The effects of DBS are often delayed and progressive and sometimes take months to achieve maximal benefit in a variety of disorders, including dystonia, depression and epilepsy. Interest is growing in the neuroplastic changes induced by DBS that might be linked to the ability to upregulate the expression of trophic and synaptic proteins with stimulation34.