Deep brain stimulation (DBS) is a surgical neuromodulation therapy with several neuropsychiatric applications. The US Food and Drug Administration approved its use in the United States for the treatment of refractory essential tremor (approved in 1997), idiopathic Parkinson’s disease (thalamic stimulation approved in 1997 and subthalamic nucleus and globus pallidus pars interna stimulation in 2002), dystonia (2003), and obsessive-compulsive disorder (OCD; 2009).1,2 The last two disorders were approved under a humanitarian device exception.
DBS requires the surgical implantation of stimulating electrodes in a predetermined brain region using image-guided stereotaxic neurosurgery. The electrodes are connected through a wire to a programmable internal pulse generator (ie, a battery with a microprocessor that controls the stimulation), which is surgically implanted under the pectoral muscle. The connecting wires travel under the skin from the scalp and through the neck into the pectoral region.
The clinician has control over five DBS parameters. There are three primary electrical variables: voltage, pulse frequency, and pulse width. In addition, the stimulation location is determined before implantation and confirmed intraoperatively. Once the system is placed, the size of the electric field can also be modulated, allowing a finer degree of topographic control.
DBS was developed in the second half of the 20th century, integrating the fields of electrical neurostimulation and ablative neurosurgery. Today, it is one among a variety of available brain stimulation modalities, including transcranial magnetic stimulation, transcranial direct current stimulation, electroconvulsive therapy, and vagus nerve stimulation. DBS offers several advantages in comparison with ablative surgery, including its reversible and modulatory nature, which allows placebo-controlled examination of its effects. Nevertheless, it requires the implantation of hardware, which has its own risks and limitations, and it involves more complex follow-up. Compared with other device-based brain stimulation treatments, DBS offers the unique possibility to target deep neural structures directly with proven safety and efficacious outcomes.
In the last few years, the field of DBS has witnessed major progress with direct impact on patient care. Still, many questions remain unanswered, temporarily holding the development of new clinical applications. In this article, we review current research efforts and future directions of DBS with an emphasis on new psychiatric disorders and novel technologies.
Acknowledgment of a ‘Circuit Revolution’
A major paradigm shift has changed the clinical neurosciences in the last 10 to 15 years. A wealth of basic research has dramatically advanced our understanding of the anatomy and physiology of brain networks and the mechanisms by which they process cognition, behavior, and emotion.3 This “circuit revolution” has had a major impact by transforming our understanding of psychiatric pathophysiology but also by practically setting the stage for new treatment modalities (ie, brain stimulation) that use device-based strategies to therapeutically modulate disease-relevant circuits.
Any disorder that results from maladaptive physiological changes in brain circuits leading to pathological processing of affective, behavioral, and cognitive information is a potential candidate for brain stimulation. This definition encompasses most, if not all, psychiatric disorders. Currently, DBS is FDA-approved for treatment-resistant OCD, and extensive research is being conducted for major depressive disorder (MDD). Our understanding of the basic circuitry and mechanistic pathophysiology of other psychiatric disorders has allowed the exploration of new indications for other equally refractory and impairing disorders in which a neuromodulatory approach can be of therapeutic benefit.
Efficacy in Psychiatric Disorders
The reward circuitry processes information of extreme ecologic and clinical relevance. This network includes several bilateral cortical and subcortical regions, with the ventral tegmental area (VTA) and the nucleus accumbens (NAcc) at its core (see Figure 1).4 Reward is a central component for driving incentive-based learning and the development of goal-directed behaviors such as emotion, motivation, and cognition3 and is therefore pathologically altered in a number of neuropsychiatric disorders including, but not limited to, substance use disorders.
Figure 1. A schematic showing the key structures and pathways of the reward circuit of the prefrontal cortex. AMYG = amygdala; DA = dopamine (blue arrows); GABA = gamma aminobutyric acid (red arrows); GLU = glutamate (green arrows); GP = globus pallidus; NAcc = nucleus accumbens; VTA = ventral tegmental area. Image courtesy of Joan A. Camprodon, MD, MPH, PhD.
The reward circuitry is already a target for OCD and MDD in humans, but neurocircuitry underlying drug addiction makes DBS a viable treatment option for patients with this condition. Several groups have shown the success of DBS in attenuating drug-seeking and other addiction behaviors in animal models. Vassoler et al5 examined the influence of DBS of the NAcc shell on cocaine priming-induced reinstatement of drug-seeking behavior, an animal model of relapse. Higher doses of cocaine were found to produce the most reliable reinstatement of cocaine-seeking behavior; however, the administration of bilateral DBS significantly attenuated this reinstatement of drug-seeking behavior. DBS of the NAcc has also been shown to have an effect on alcohol consumption. Bilateral stimulation of the NAcc was shown to significantly reduce ethanol consumption and preference in alcohol-preferring rats.6,7 Similarly, chronic DBS of the NAcc in rats has been shown to attenuate morphine relapse in morphine-dependent rat models.8 Additionally, stimulation of the subthalamic nucleus has been shown to inhibit motivational processes selectively associated with drug addiction. DBS of the subthalamic nucleus reduces the craving for cocaine in addicted rats, without hindering the desire for food or other naturally rewarding activities.9
A number of case reports have described the success of DBS in treating addiction outcomes in human patients. The first such study described the efficacy of DBS of the NAcc in reducing alcohol consumption in a 54-year-old alcohol-dependent patient.10 This patient was diagnosed with severe anxiety disorder and secondary depressive disorder and was treated for these conditions with bilateral DBS of the NAcc. Despite the lack of improvement in his mood and anxiety disorder, a remarkable (although not primarily intended) alleviation of the patient’s comorbid alcohol dependency was observed.
Another case study reported the impact of DBS of the NAcc on reward processing during a behavioral task. DBS of the NAcc in a 38-year-old man treated for severe alcohol addiction significantly reduced the patient’s pattern of risk-taking behaviors, making him safer and more conservative during a gambling task.11
The animal studies and human case reports suggest that DBS has the potential to normalize reward processing; reduce impulsivity; and attenuate addictive behavior, drug cravings, and substance use. Several clinical trials are currently recruiting patients with severe and chronic substance use disorders to assess the efficacy of DBS therapy in a prospective and controlled manner with larger cohorts.12 Two clinical trials are presently recruiting patients with severe alcohol dependence at Tangdu Hospital, Xi’an, China (targeting the NAcc and the ventral anterior internal capsule) and the National Institute of Neurological Disorders and Stroke12 and will be targeting the ventral capsule/ventral striatum to see whether DBS can be used to treat chronic alcoholism. Additionally, there are another two trials studying the use of DBS to the NAcc for opiate dependence at Tang-Du Hospital and at the University of Cologne, Germany.12
The development of clinical trials in human patients points to the maturity of these hypotheses and the potential for DBS to become a safe and effective intervention for the treatment of severe treatment-resistant patients with substance use disorders in the near future.
Obesity is a growing public health problem with significant morbidity and mortality that is frequently treatment refractory. Current research is exploring the role of both specific feeding behavior networks and general reward-processing circuits.13 Modulation of either or both of these pathways may provide therapeutic benefit to patients suffering from severe obesity. The lateral hypothalamus and ventromedial hypothalamus are the appetite and satiety centers in the brain, respectively.13 These areas have been proposed as neuromodulation targets for DBS for appetite suppression and weight loss in appropriate severe and treatment-refractory patients. Sani et al14 stereotactically implanted electrodes bilaterally into the rat lateral hypothalamus. Half of the implanted animals underwent high-frequency stimulation, whereas the other half did not receive any stimulation. All rats were maintained on a high-fat diet. On postoperative day 24, rats receiving active stimulation had a mean body weight loss of 2.3%, whereas the unstimulated group had a mean weight gain of 13.8%. Interestingly, the difference in weight outcomes was not related to changes in food intake, leading to the conclusion that it was caused by metabolic changes driven by DBS (although no measurements of individual animals’ metabolic profiles were made).14 Stimulation of the ventromedial hypothalamus yielded similar results of reduced weight gain in a rat obesity model, although this appears to be a direct result of inhibited feeding in addition to an increase in metabolism.15 These data suggest that modulation of these specific feeding centers can be used as a therapeutic strategy for the treatment of obesity.
The application of DBS in the treatment of disorders characterized by impaired processing of reward and motivation has led researchers to begin investigating the effect of DBS on food-directed behavior. Reward sensation associated with high caloric food has been implicated in overconsumption and obesity; thus, regions of the brain’s reward circuitry, such as the NAcc, are also promising alternatives for DBS in obesity control.
Van der Plasse et al16 implanted rats with bilateral electrodes in the various anatomic subdivisions of the NAcc including the core, the lateral shell, and the medial shell. These structures are known to process different reward-related information. They then measured the effects of stimulation of each subarea on food consumption and the motivational and appetitive properties of food. Their findings revealed a functional dissociation between the lateral and medial shell. DBS of the lateral shell reduced motivation to respond to sucrose, whereas DBS of the medial shell profoundly and selectively increased the intake of generic rat food. DBS to the NAcc core was not found to alter any form of food-directed behavior that was studied. Thus, the intake of generic rat food and the motivation to work for special palatable food were shown to be independently modulated by DBS to subdivisions of the NAcc shell.16 It is important to note that none of these studies have included overweight or obese animals. This study used DBS to modulate the reward system, as opposed to the feeding centers, as a potential treatment for obesity.
Clinical trials are now testing this hypothesis and interventional approach with human clinical populations. Researchers at Ohio State University, are currently enrolling patients for a study to investigate the safety and efficacy of DBS in the management of severe, treatment-refractory morbid obesity.12
Anorexia nervosa (AN) is a debilitating and potentially life-threatening disorder characterized by severe dietary restriction, compulsive exercise, and binging and/or purging.17 Aside from failure to maintain normal body mass, patients with AN have intense fears of weight gain, distorted perceptions about their bodies, and often minimize the severity of their illness even in the face of serious physical and psychological consequences. Treatments for AN have shown very limited efficacy, and the disorder frequently presents as relatively intractable.
A case report of a 56-year-old woman has provided promising data suggesting DBS as a prospective treatment option for eating disorders (EDs).17 The patient had recurrent bouts of restrictive AN and underwent bilateral DBS electrode implantation in the subgenual cingulate for the treatment of comorbid major depressive disorder. Despite two severe depressive relapses, the patient’s depression improved and remained relatively stable since the implantation surgery. Interestingly, her AN showed a long-standing remission for the first time since she was 17 years old. The patient required no further interventions for her EDs and maintained an average body mass index of 19.1 for 2 years, showing considerable improvement from her lowest body mass index of 14.4. At 3 years postoperatively, the Eating Disorders Examination questionnaire and interview were administered and revealed low scores in restraint and weight and shape concerns, comparable with the normal population. Although it is difficult to determine whether the amelioration of AN symptoms was a primary consequence of DBS or a secondary effect linked to the improvement of her depressive disorder, this case highlights a potential new strategy for the treatment of EDs.
Two clinical trials are currently investigating the therapeutic role of DBS for patients with refractory AN in a prospective manner at the University Health Network, Toronto, and Ruijin Hospital, Shanghai.12 The emergence of these trials proves promising and will hopefully serve as the impetus to conduct additional studies.
Tourette’s syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics and is often associated with affective and behavioral disturbances. Current knowledge of the aberrant corticobasal ganglia-thalamocortical circuits provides an explanation for the beneficial effects of DBS on tics. Since the introduction in 1999 of thalamic DBS as a potential treatment for patients with refractory TS, several other targets have been identified. Five targets have now been used for DBS in TS in a small number of cases, including the medial thalamus, the centromedian parafascicular of the medial thalamus, the ventroposterolateral globus pallidus pars interna (GPi), the anteromedial GPi, and the NAcc.18
Case reports have published the beneficial effects of DBS in TS using various targets for stimulation. These case studies reported a significant reduction in tics, with some resulting in up to 100% tic reduction.19–23 Unfortunately, these reports are limited by the small number of patients who have been treated. Furthermore, the most optimal target has not yet been defined, highlighting the need for continued study.
Three clinical studies are currently evaluating the effects of DBS in TS.12 One study at University Hospitals of Cleveland, targeting the thalamus was recently completed, although the results have not yet been published.12 Another study measuring the impact of DBS on the GPi in TS at University College London, is recruiting participants.12 The third study investigating the impact of thalamic DBS for the treatment of TS was recently started at Johns Hopkins University.12
Alzheimer’s disease (AD) is a neurodegenerative dementia that is a growing public health concern. The hypothesized pathophysiological mechanism for this devastating disease includes misprocessing of fibrillar amyloid leading to oligomerization, the deposition of amyloid plaques causing a disruption of neural network activity, a loss of synaptic function, and eventual neuronal death.24
A novel circuit-based strategy to treat AD is the use of DBS to the hippocampal fornix (a key component of the memory circuit). This approach is supported by rodent studies in which DBS to this neural structure in memory-impaired rodents led to improved memory on the Morris water maze task and increased hippocampal neurogenesis based on histopathological studies.24
DBS of the fornix for the treatment of patients with early AD is also supported by promising (but preliminary) results from a small, open-label phase 1 trial conducted in Toronto by Laxton and colleagues.25 Six AD patients underwent DBS of the fornix and were treated for 12 months. Clinical evaluation using the conventional Alzheimer Disease Assessment Scale-Cognitive subscale and the Mini-Mental State Examination suggested possible slowing in the rate of progressive cognitive decline in these patients.26 It is important to note that this was a small open-label study without a placebo control group, and, thus, the results must be interpreted with caution. Furthermore, these patients all presented with very mild AD at the time of DBS implantation. Nevertheless, these findings suggest that the underlying DBS mechanism of action may involve the upregulation of processing, capacity, and/or sustained integrity of these neuronal circuits. Consequently, a circuitry-based treatment like DBS may be helpful for patients with early AD, and continued investigation is warranted.
Currently, there are six distinct clinical trials evaluating the role of DBS in memory disorders being conducted in Europe and the United States.12 The majority of these trials is targeting the fornix, but one is targeting the nucleus basalis of Meynert to treat cognitive deficits associated with AD.
Schizophrenia is a complex and challenging psychiatric condition. Although the traditional clinical and research focus had been centered on the positive symptoms of the disease, recent years have brought attention to its negative symptoms, which are associated with significant social and occupational dysfunction, clinical morbidity, and mortality.
Currently, there is one clinical trial at the Centre for Addiction and Mental Health, Toronto, investigating the efficacy of DBS on the negative symptoms of schizophrenia. Both the NAcc and VTA have been found to be hypoactive in patients with primarily negative symptoms, suggesting that they are warranted targets for stimulation. Based on this evidence, the Centre for Addiction and Mental Health will administer NAcc DBS to half the participants and VTA DBS to the other half to examine its effects (see Table).12
Table. Published Case Reports/Series of Deep Brain Stimulation for New Conditions
Comprehension of New Methods
The mechanisms of action of DBS are not fully understood, despite its use for various decades.27 Important biological and engineering questions remain unanswered, which have major clinical consequences. The progress of this therapeutic intervention will require a more refined understanding of the pathophysiology of neuropsychiatric disorders to expand its use to novel indications, as described above. Nevertheless, our understanding of the effects of the current technology on neurons, synapses, circuits, and symptoms is very limited and remains the greatest obstacle in the development of safer, more effective, and possibly individualized approaches to DBS.
DBS Parameter Selection
As discussed previously, there are five parameters that can be controlled by the DBS clinician. Other than location, little is known about how specific variables affect neurons; how these neurons then impact circuits; and how these circuits influence behaviors, cognitive or affective states, and symptoms. Currently, parameters are changed in a relatively empirical manner within known safety limits, and clinicians have a very limited understanding of how parameter changes affect neurobiological and clinical variables.
What is known is that the effects are determined by multiple factors and, like all matters in the brain, are not static but rather dynamic. Different neural structures have different conductivities, and conductivity itself may vary as a consequence of pathological changes specific to each disorder. Also, the introduction of a foreign body (ie, the electrodes) in the brain parenchyma induces changes and scarring in the tissue surrounding the electrode, which will affect the distribution and flow of current.28
The duration and waveform of the electric stimuli can have a profound impact on the efficacy and safety of DBS. Also, different stimulation frequencies, pulse width, voltages, and field sizes are likely to induce variable response duration, robustness, and quality (eg, inhibition vs. activation). Nevertheless, the same parameters may induce different effects in different regions, and the effects may be disorder or patient specific. Although the field is moving forward in an attempt to establish population-based guidelines and parameters, a closer look at the problems clinicians face highlights the need to develop individualized treatment strategies based on each patient and not each disorder. This will require new knowledge and tools.
A Focus on Target Selection
The implantation of DBS electrodes in patients is a complex neurosurgical procedure. The technique varies across centers, but it generally involves stereotactic targeting of the brain structure to be stimulated based on one or more imaging modalities such as computed tomography and/or magnetic resonance imaging (MRI).
Several groups are using diffusion tensor imaging as an alternative approach to target selection.29 Diffusion tensor imaging is a magnetic resonance imaging technique that measures the diffusion of water molecules in the brain to reveal the structural anatomy of white-matter tracts. This method has been used to establish the connectivity of subcortical and brainstem structures of relevance to neuropsychiatric disorders with indications for DBS.30 This approach implies a conceptual change because it shifts the focus from specific areas to networks, highlighting the role of connectivity on the processing of disease-relevant information.
Even with refined DBS leads, the electrical field generated with current approaches encompasses thousands of neurons and axons with limited topographic selectivity and null functional specificity. Optogenetics is a relatively new technique that allows the modulation of selective neuronal populations with light.30 Genes encoding for light-sensitive membrane channels can be introduced in neurons with the use of vectors that recognize very specific types of neurons (eg, dopaminergic projection neurons). When these membrane receptors are expressed in the neuronal membrane, its exposure to light will induce structural molecular changes that open the channel and allow the flow of charged particles leading to the controlled modulation of membrane potentials and, therefore, activity. Targeted illumination of brain regions will selectively regulate the neurons expressing these light-sensitive channels and can be used to modulate cells and circuits in living tissue, even in freely moving animals, with incredible temporal and spatial resolution.31 Light can be delivered to its desired location using small stereotactically placed optical fibers attached to a light source that can be implanted subcutaneously, similar to a DBS battery. The precise targeting abilities of optogenetics make it a valuable method for studying the function of the neuronal networks that underlie behavior. This approach has already been used to successfully control and study dopaminergic neurons in Parkinsonian mice models and cholinergic neurons in the NAcc of cocaine-addicted rodents.32 This approach reduces nonspecific stimulation to surrounding cells, while allowing superior spatial and temporal control over the frequency and amplitude of stimulation, making it key in advancing our understanding of behavior at the cellular and circuit level. Although human trials have not yet been attempted, optogenetics offers a revolutionary strategy to precisely dissect brain circuits in animal models to determine the best approach for therapeutic DBS modulation in humans. The use of optogenetics in humans offers an exciting alternative to DBS, but important methodologic and safety problems need to be solved.
Another advancement in neuromodulatory techniques includes closed-loop systems. Closed-loop devices use a feedback mechanism that modulates the stimulation based on a particular measured variable (eg, the activity of a specific region), rather than just providing constant stimulation. Such a device has been developed for the treatment of epilepsy; when a sensor detects a burst of epileptic activity, the systems generates an abortive stimulation output.33 A similar device could be used for psychiatric disorders in which a sensor would continuously measure neurotransmitter levels and trigger a specific output when those measured levels reach a defined threshold. Input signals could include dopamine levels in a particular structure, such as the striatum. The output could then take the form of electrical pulses for a DBS-style closed-loop device. Because these devices are composed of a feedback mechanism, they clear out errors between input and output signals and, hence, remain unaffected to external noise sources, allowing them to be more accurate predictors of the underlying mechanism of action of the studied condition.
PET Imaging, Plausability of fMRI
Neuroimaging has considerably broadened the horizons of neuroscience and psychiatric research, allowing researchers to essentially look inside the living brain. Within the subgroup of patients implanted with DBS systems, positron emission tomography (PET) imaging is generally used to measure changes in brain activity and to produce two- or three-dimensional images of the distribution of chemicals throughout the brain. It is particularly important in mapping different aspects of neurotransmitter activity. PET does not involve any magnetic field, making it a safe imaging technique for use in DBS patients. Functional MRI (fMRI) is an imaging modality used to image the functional properties of the brain with much greater spatial and temporal resolution than PET. Unfortunately, because current DBS electrodes are not magnetic resonance compatible, it is not safe for DBS patients to undergo fMRI scans. Limited protocols exist that allow low-field anatomic MRI scans to be conducted safely, but there are no available options for precise MRI-based functional imaging for individuals with implanted DBS systems. The use of fMRI in DBS patients would provide invaluable data about the mechanism of action of this intervention and could be used as a biomarker to monitor and adjust the parameters of stimulation. The prospective role of fMRI in uncovering the mechanism of DBS emphasizes the importance of developing MRI-compatible devices and electrodes.
DBS is an available yet novel therapeutic option for several treatment-resistant neuropsychiatric disorders. Its development follows a paradigm shift in the clinical neurosciences, which moved the focus of pathophysiological models from neurotransmitter imbalances to brain circuit dynamics. In this article, we reviewed how a deeper understanding of the anatomy and physiology of disease-relevant circuits and the pathological mechanisms that change it are driving the exploration of novel clinical indications and guiding DBS clinical trials. We also discussed some of the current technical limitations DBS clinicians face and some of the potential solutions currently in development. Clinicians managing patients across the neuropsychiatric spectrum will benefit from becoming familiar with these concepts and literature as this research is quickly moving from the laboratory to the clinic. DBS is already available in the therapeutic tool-box for the practicing psychiatrist (in addition to psychotherapy, medications, and other brain stimulation treatments), and it offers options and hope for the most difficult and treatment-refractory patients.
- Yu H, Neimat JS. The treatment of movement disorders by deep brain stimulation. Neurotherapeutics. 2008;5(1):26–36.
- Mian MK, Campos M, Sheth S A, Eskandar EN.Deep brain stimulation for obsessive-compulsive disorder: past, present, and future. Neurosurg Focus. 2010;29(2): E10.
- Haber S, Knutson B. The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology. 2010;35(1):4–26.
- Hikosaka O, Bromberg-Martin E, Hong S, Matsumoto M. New insights on the subcortical representation of reward. Curr Opin Neurobiol. 2008;18(2):203–308.
- Vassoler FM, Schmidt HD, Gerard ME, Famous KR, et al. Deep brain stimulation of the nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug seeking in rats. J Neurosci. 2008;28(35):8735–8739.
- Knapp CM, Tozier L, Pak A, Ciraulo DA, Kornetsky C. Deep brain stimulation of the nucleus accumbens reduces ethanol consumption in rats. Pharmacol Biochem Behav. 2009;92(3):474–479.
- Henderson MB, Green AI, Bradford PS, Chau DT, Roberts DW, Leiter JC. Deep brain stimulation of the nucleus accumbens reduces alcohol intake in alcohol-preferring rats. Neurosurg Focus. 2010;29(2):E12.
- Liu HY, Jin J, Tang JS, et al. Chronic deep brain stimulation in the rat nucleus accumbens and its effect on morphine reinforcement. Addict Biol. 2008;13(1):40–6.
- Rouaud T, Lardeux S, Panayotis N, Paleressompoulle D, Cador M, Baunez C. Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation. Proc Natl Acad Sci USA. 2010;107(3):1196–1200.
- Kuhn J, Lenartz D, Huff W, et al. Remission of an alcohol dependency following deep brain stimulation (DBS) of the nucleus accumbens – valuable therapeutic implications?J Neurol Neurosurg Psychiatry. 2007;78(1):1152–1153.
- Heldmann M, Berding G, Voges J, et al. Deep brain stimulation of nucleus accumbens region in alcoholism affects reward processing. PLoS One. 2012;7(5):e36572.
- Deep Brain Stiumulation. ClinicalTrials.gov, US National Institutes of Health. Available at: clinicaltrials.gov/ct2/results?term=Deep+Brain+Stimulation&Search=Search. Accessed July 08, 2013.
- Halpern CH, Wolf JA, Bale TL, et al. Deep brain stimulation in the treatment of obesity. J Neurosurg. 2008;109(4):625–634.
- Sani S, Jobe K, Smith A, Kordower JH, Bakay RA. Deep brain stimulation for treatment of obesity in rats. J Neurosurg. 2007;107(4):809–813.
- Covalin A, Feshali A, Judy J. Deep brain stimulation for obesity control: analyzing stimulation parameters to modulate energy expenditure. Paper presented at: 2nd International IEEE EMBS Conference on Neural Engineering. ; March 16–19, 2005. ; Arlington, VA. .
- van der Plasse G, Schrama R, Seters SP, Vanderschuren LJ, Westenberg HG. Deep brain stimulation reveals a dissociation of consummatory and motivated behaviour in the medial and lateral nucleus accumbens shell of the rat. PLoS One. 2012;7(3):e33455.
- Israel M, Steiger H, Kolivakis T, McGregor L, Sadikot AF. Deep brain stimulation in the subgenual cingulate cortex for an intractable eating disorder. Biol Psychiatry. 2010;67(9):e53–e54.
- Ackermans L, Temel Y, Visser-Vandewalle V. Deep brain stimulation in Tourette’s Syndrome. Neurotherapeutics. 2008;5(2):339–344.
- Vandewalle V, van der Linden C, Groenewegen HJ, Caemaert J. Sterotactic treatment of Gilles de la Tourette syndrome by high frequency stimulation of thalamus. Lancet. 1999;353(9154):724.
- Van der Linden C, Colle H, Vandewalle V, Alessi G, Rijckaert D, De Waele L. Successful treatment of tics with bilateral internal pallidum stimulation in a 27-year-old male patient with Gilles de la Tourette’s syndrome. Mov Disord. 2002;17:S341.
- Houeto JL, Karachi C, Mallet L, et al. Tourette’s syndrome and deep brain stimulation. J Neurol Neurosurg Psychiatry. 2005;76(7):992–995.
- Kuhn J, Lenartz D, Mai JK, et al. Deep brain stimulation of the nucleus accumbens and the internal capsule in therapeutically refractory Tourette-syndrome. J Neurol. 2007;254(7):963–965.
- Shahed J, Poysky J, Kenney C, Simpson K, Jankovic J. GPi deep brain stimulation for Tourette syndrome improves tics and psychiatric comorbidities. Neurology. 2007;68(2):159–160.
- Lyketsos CG, Targum SD, Pendergass JC, Lozano AM. Deep brain stimulation: a novel strategy for treating Alzheimer’s disease. Innov Clin Neurosci. 2012;9(11–12):10–17.
- Laxton AW, Tang-Wei DF, McAndrews MP, et al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s Disease. Ann Neurol. 2010;68(4):521–534.
- Ito K, Ahadieh S, Corrigan B, et al. Disease progression meta-analysis model in Alzheimer’s disease. Alzheimers Dement. 2010;6(1):39–53.
- Kuhn J, Gruendler T, Klosterkotter J, Bartsch C. Stimulating the addictive brain. Front Hum Neurosci. 2012;6:220.
- Gubellini P, Salin P, Kerkerian-Le G, Baunez C. Deep brain stimulation in neurological diseases and experimental models: from molecule to complex behavior. Prog Neurobiol. 2009;89(1):79–123.
- Gutman DA, Holtzheimer PE, Behrens TE, Johansen-Berg H, Mayberg HS. A tractography analysis of two deep brain stimulation white matter targets for depression. Biol Psychiatry. 2009;65(4):276–282.
- Tye KM, Deisseroth K. Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat Rev Neurosci. 2012;13(4):251–266.
- Chen B, Yau H, Hatch C, et al. Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature. 2013;496(7445):359–362.
- Witten IB, Lin SC, Brodsky M, et al. Cholinergic interneurons control local circuit activity and cocaine conditioning. Science. 2010;330(6011):1677–1681.
- Sun FT, Morrell MJ, Wharen RE Jr, . Responsive cortical stimulation for the treatment of epilepsy. Neurotherapeutics. 2008;5(1):68–74.
Published Case Reports/Series of Deep Brain Stimulation for New Conditions
||Number of Patients
||Pw: 90 mcs
F: 130 Hz
V: 4.5 V
||No change in anxiety symptoms but alleviation of alcohol dependency
||Kuhn et al, 200710
||Pw: 90 mcs
F: 130 Hz
V: 3.5 V
||Reduced consumption, reduced risky decision-making
||Heldman et al, 201211
||Pw: 91 mcs
F: 130 Hz
V: 5 V
||Israel et al, 201017
||Pw: 450 mcs
F: 130 Hz
V: 4 V
||90%–100% tic reduction
||Vandewalle et al, 199919
||95% tic reduction
||Van der Linden et al, 200220
||Pw: 60 mcs
F: 130 Hz
V: 1.5 V
||70% tic reduction
||Houeto et al, 200521
||Pw: 60 mcs
F: 130 Hz
V: 1.5 V
||70% tic reduction
||Houeto et al, 200521
||Pw: 90 mcs
F: 130 Hz
V: 7 V
||40%–50% tic reduction
||Kuhn et al, 200722
||Pw: 90 mcs
F: 160 Hz
V: 5 V
||84% tic reduction
||Shahed et al, 200723
||Pw: 90 mcs
F: 130 Hz
V: 3–3.5 V
||Average increase of 4.2 points on ADAS-Cog and slight decrease of MMSE score
||Laxton et al, 201025