Deep Brain Stimulation
Tourette syndrome (TS) is a neuropsychiatric syndrome characterized by multiple chronic, brief, involuntary movements and sounds, often called tics. Notably, TS has a high comorbid incidence with OCD and attention-deficit hyperactivity disorder, reflecting possible mechanistic overlaps. Current models of pathophysiology in TS suggest a reduction in GABAergic and cholinergic striatal interneurons, as well as decreased changes in numbers of parvalbumin-positive GABAergic neurons in the GPi (increased) and GPe (decreased). Parvalbumin is a calcium binding protein that has recently been found to play a role in rhythm generation in fast spiking interneurons, as well as in preventing narrow frequency synaptic facilitation at striatal neuron synapses on outside targets. Other research has also suggested that striatal disinhibition and aberrant oscillations in basal ganglia structures lead to cortex disinhibition and tic production. Clinical symptoms have also been found to correlate with the temporal power γ-band activity in the centromedian sulcus of the thalamus. Moreover, modulation of γ-band activity with DBS was found to influence clinical symptoms. Motor tics have also been associated with changes in normal rhythms throughout cerebro-basal ganglia-cerebellar networks. Although evidence continues to accumulate, an overarching model for the pathophysiology of TS remains a work in progress.
Current investigational targets for DBS include the medial thalamus (nucleus ventrooralis internis, centromedian nucleus, and substantia periventricularis), anterior medial (limbic) GPi, STN, nucleus accumbens, and anterior limb of the internal capsule. A small, double-blind, randomized crossover trial of stimulation targeting the thalamic intersection of the centromedian sulcus, the substantia periventricularis, and nucleus ventrooralis internus showed a 37% improvement on the Yale Global Tic Severity Scale in patients on stimulation compared with off stimulation. An open-label study of centromedian/parafascicular complex stimulation in 3 patients with medically intractable TS resulted in a 60%–80% reduction in Yale Global Tic Severity Scale score for each patient at 1 year. Despite early promising trials, there are also reports of no benefit after stimulation. Further work is needed to clarify stimulation targets, define appropriate selection criteria, and determine how target stimulation may effect comorbid psychiatric disorders.
Obesity is a growing epidemic in the US and worldwide. Stimulation targets for obesity are based on two complementary mechanisms that lead to overfeeding: reward circuitry and satiety centers. Hypothalamic structures are also under investigation, including the ventromedial hypothalamus and lateral hypothalamus. An initial pilot study in 3 patients of lateral hypothalamic DBS for refractory obesity reported no overall weight loss when stimulation was programmed with settings derived from experience with movement disorders.
Foods with high caloric content reinforce eating behaviors through reward circuitry, including the nucleus accumbens, suggesting that this structure may serve as a target for stimulation. Other studies have accumulated evidence implicating the subgenual cingulate and ventral tegmental area in addition to the nucleus accumbens. As stimulation targets in the hypothalamus have had limited success, a current clinical trial is recruiting patients refractory to gastric bypass for evaluation of targets involved in dysregulated reward circuitry. While gastric bypass is currently the gold standard therapy for morbid obesity, a recent study used decision analysis to note that DBS for obesity would only need an 83% success rate to achieve equivalence to bypass surgery.
Anorexia nervosa is another psychiatric disorder involving limbic circuits. Up to 70% of patients suffering from anorexia have a chronic refractory course, and it is one of the deadliest psychiatric disorders, with a mortality rate of 10%. Initial trials of DBS showed promising clinical results, as well as changes in metabolic activity in cortical and limbic regions associated with the subcallosal cingulate. Regions of the brain believed to be abnormal in anorexia nervosa include the parietal cortex, anterior and subgenual cingulate, and superior frontal, dorsolateral prefrontal, and orbitofrontal cortex. Many of these regions overlap with other psychiatric indications, notably major depressive disorder and OCD.
A Phase 1 clinical trial of SCC DBS is currently recruiting patients with refractory anorexia nervosa for initial safety and efficacy estimation. This study is a continuation of a pilot study in which 6 patients underwent SCC stimulation for 9 months. Initial results after 9 months included 3 of 6 patients increasing and maintaining their body mass index, and improvement in mood, anxiety, obsessions, and compulsions in 4 of 6 patients. Another trial is currently recruiting similar patients for implantation and stimulation of the nucleus accumbens.
Another active area of investigation is whether DBS may be effective for treating disorders of learning and memory. Applications are being developed for memory impairment due to Alzheimer disease, traumatic brain injury, temporal lobe epilepsy, stroke, and encephalitis. Improvements in our understanding of the anatomy of the hippocampal entorhinal cortex circuit (reviewed in Squire et al., 2004), the role of phase-phase and phase-amplitude coupling in learning and memory (reviewed in Fell and Axmacher, 2011), and the role of DBS in augmenting learning and memory (reviewed in Suthana and Fried, 2013) are stimulating interest and research in the field.
The presence of phase-phase and phase-amplitude coupling has important implications in DBS for memory. Hippocampal stimulation, for example, has been found to both disrupt and enhance memory. The fact that memory enhancement requires the stimulation to be spatially and temporally matched to existing hippocampal input activity suggests that some sort of oscillatory coupling mechanism is involved and that DBS can augment this mechanism. In the medial temporal lobe, increases in the amplitude of θ band (3–8 Hz) LFP oscillations can predict whether an experience is encoded in memory, and reinforcing these θ oscillations with DBS has been shown to improve spatial working memory. Theta-phase γ-amplitude coupling has also been implicated in successful learning and is believed to play a role in communicating across large dispersed cortical brain networks. Oscillatory mechanisms are increasingly being used to tie together theories of brain function, as illustrated in a recent paper unifying the dual role of the hippocampus in memory and physical navigation.
Multiple stimulation targets are currently under exploration for memory improvement. A Phase I trial of fornix/hypothalamus stimulation in 6 patients with mild Alzheimer disease did not show significant improvement in clinical symptoms, but showed reversal of decreased glucose metabolism in parietal and temporal lobes after 12 months of stimulation. Stimulation of the entorhinal cortex has been shown to improve spatial learning, and stimulation of the medial septal nucleus has been shown to improve spatial working memory after traumatic brain injury. While studies performed to date provide promising evidence, randomized controlled trials are still needed. Fortunately, multiple clinical trials are currently underway to clarify the role of DBS in Alzheimer disease and other types of cognitive impairment.
Drug addiction is characterized by the compulsion to consume a substance, the loss of control in limiting its intake, and the development of a withdrawal state when the substance is withheld. This cycle becomes a chronic relapsing disease that affects approximately 2.9% of the adult US population (5.4 million) with illicit drugs and 7.7% (18 million) with alcohol. In addition, an estimated 28.6% (70.9 million) of Americans aged 12 or older are current tobacco users. Koob and Volkow, in their review of addiction and its neurocircuitry, describe 3 stages of addiction that they map to key regions of the brain: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. In the first stage, binge/intoxication, the nucleus accumbens and the ventral tegmentum are believed to play key roles, whereas in the withdrawal/negative affect stage, the amygdala is the central structure. Finally, the last stage, preoccupation/anticipation, appears to involve multiple structures including the prefrontal cortex, striatum, amygdala, hippocampus, insula, and cingulate gyrus. Given this network, DBS could potentially target any of these structures to interfere with addiction circuitry.
Several stimulation targets are under investigation, with the nucleus accumbens and STN receiving the most attention. In 2007, Kuhn and colleagues published a case report of a 54-year-old male with severe agoraphobia and panic attacks, with concomitant alcohol dependence, who received bilateral DBS of the nucleus accumbens for treatment of his anxiety disorder. He had no reduction in his anxiety, but he did experience a remarkable change in his alcohol dependency. Prior to DBS, he was consuming alcohol daily with an average of 10 drinks per day, with multiple hospitalizations for intoxications and withdrawal. After DBS, the patient claimed to have lost the desire to drink, and he only occasionally had 1–2 drinks in the year following his treatment. In 2009, the same group published a retrospective review of 20 patients who received nucleus accumbens DBS for OCD and TS. Of these patients, 10 were daily smokers and 4 had attempted smoking cessation unsuccessfully prior to DBS. Of the latter 4, 2 attempted and were successful at smoking cessation after DBS. Several preclinical studies in rats have investigated the effect of high-frequency DBS on ethanol consumption and cocaine/narcotic-seeking behavior. These studies showed a significant reduction in drug-seeking behaviors following DBS.
Müller and colleagues reported a pilot study of 5 patients who received bilateral nucleus accumbens DBS for chronic alcoholism. Two of the 5 patients were abstinent for at least 5 years following DBS and the remaining 3 had marked decreases in their alcohol consumption. One patient had a 2-week hypomanic episode that resolved after changes in stimulation settings. Of note, they also reported that 1 patient agreed to additional studies; when the DBS was turned off, the patient experienced increased risky behavior during gambling paradigms administered when compared with the same tests with the DBS on. These studies suggest that nucleus accumbens DBS appeared to normalize reward processing, which may be dysregulated in patients with addictive disorders.
Subthalamic nucleus stimulation has not had as promising results as nucleus accumbens stimulation. Rouaud and colleagues investigated high-frequency STN stimulation on cocaine and food-seeking behavior in rats. Stimulation made the animals less willing to work for drugs but did not affect consumption of readily available cocaine. Human case reports looked at patients with PD and found that STN DBS could either reduce or induce addictive behavior. Several studies have also linked STN stimulation with increased impulsiveness. Given these mixed results, the overall consensus is that STN stimulation is not as effective and safe as nucleus accumbens stimulation in addiction.
Additional target areas have included the dorsal striatum, lateral habenula, medial prefrontal cortex, and lateral hypothalamus. Animal studies showed no effect on drug-related behaviors after stimulation of the dorsal striatum and lateral hypothalamus. Lateral habenula stimulation was effective in controlling drug consumption but also decreased food consumption, which was considered an undesirable side effect. Medial prefrontal cortex stimulation also appeared effective in animal studies, but no human cases have been reported.
Neuromodulation of the nucleus accumbens has been shown to be effective and safe in the treatment of refractory addiction in small cohorts of patients. Given the societal burden imposed by addictive disorders, additional work in this area is warranted.
Epilepsy has been extensively studied as an indication for DBS (reviewed in Lega et al., 2010 and Kahane and Depaulis, 2010). Initial results of the Stimulation of the Anterior Nucleus of Thalamus for Epilepsy (SANTE) trial, testing stimulation against placebo in patients with severely refractory epilepsy, were promising. Five-year follow-up data were recently presented showing a median 69% reduction in seizure frequency, increased from a 56% reduction at 2 years. The 5-year response rate (patients with > 50% seizure frequency reduction) was 69%, and patients also had improvement in quality of life measures (Long Term Efficacy of the SANTE Trial. Presented at American Epilepsy Society 66th Annual Meeting. Abstract 1.272, Platform A.04. December 2, 2012). Other targets under active investigation include the hippocampus, caudate, and centromedian nucleus.
Another psychiatric indication under early investigation is treatment-refractory aggression. Based on early lesioning studies, as well as lesion/stimulation work, the mediobasal hypothalamus ("hypothalamic aggression area") has emerged as a target for stimulation. A recently published retrospective chart review on long-term results of posteromedial hypothalamic DBS for refractory aggression showed a significant decrease in the number of violent outbursts in 5 of the 6 patients reviewed. Although significant care was taken in patient selection and consent (each patient was evaluated by 2 psychiatrists, a local ethics committee, and consent was obtained from patients' parents or legal guardians), DBS for aggression continues to have severe ethical implications that must be carefully considered before this indication is more widely studied.
Preclinical work is also ongoing for the treatment of posttraumatic stress disorder (PTSD), as well as improving the understanding of the brain circuitry involved in PTSD. Currently, the amygdala and ventral striatum/ventral capsule are preliminary targets.
DBS for Other Emerging Indications
Tourette Syndrome
Tourette syndrome (TS) is a neuropsychiatric syndrome characterized by multiple chronic, brief, involuntary movements and sounds, often called tics. Notably, TS has a high comorbid incidence with OCD and attention-deficit hyperactivity disorder, reflecting possible mechanistic overlaps. Current models of pathophysiology in TS suggest a reduction in GABAergic and cholinergic striatal interneurons, as well as decreased changes in numbers of parvalbumin-positive GABAergic neurons in the GPi (increased) and GPe (decreased). Parvalbumin is a calcium binding protein that has recently been found to play a role in rhythm generation in fast spiking interneurons, as well as in preventing narrow frequency synaptic facilitation at striatal neuron synapses on outside targets. Other research has also suggested that striatal disinhibition and aberrant oscillations in basal ganglia structures lead to cortex disinhibition and tic production. Clinical symptoms have also been found to correlate with the temporal power γ-band activity in the centromedian sulcus of the thalamus. Moreover, modulation of γ-band activity with DBS was found to influence clinical symptoms. Motor tics have also been associated with changes in normal rhythms throughout cerebro-basal ganglia-cerebellar networks. Although evidence continues to accumulate, an overarching model for the pathophysiology of TS remains a work in progress.
Current investigational targets for DBS include the medial thalamus (nucleus ventrooralis internis, centromedian nucleus, and substantia periventricularis), anterior medial (limbic) GPi, STN, nucleus accumbens, and anterior limb of the internal capsule. A small, double-blind, randomized crossover trial of stimulation targeting the thalamic intersection of the centromedian sulcus, the substantia periventricularis, and nucleus ventrooralis internus showed a 37% improvement on the Yale Global Tic Severity Scale in patients on stimulation compared with off stimulation. An open-label study of centromedian/parafascicular complex stimulation in 3 patients with medically intractable TS resulted in a 60%–80% reduction in Yale Global Tic Severity Scale score for each patient at 1 year. Despite early promising trials, there are also reports of no benefit after stimulation. Further work is needed to clarify stimulation targets, define appropriate selection criteria, and determine how target stimulation may effect comorbid psychiatric disorders.
Obesity and Anorexia
Obesity is a growing epidemic in the US and worldwide. Stimulation targets for obesity are based on two complementary mechanisms that lead to overfeeding: reward circuitry and satiety centers. Hypothalamic structures are also under investigation, including the ventromedial hypothalamus and lateral hypothalamus. An initial pilot study in 3 patients of lateral hypothalamic DBS for refractory obesity reported no overall weight loss when stimulation was programmed with settings derived from experience with movement disorders.
Foods with high caloric content reinforce eating behaviors through reward circuitry, including the nucleus accumbens, suggesting that this structure may serve as a target for stimulation. Other studies have accumulated evidence implicating the subgenual cingulate and ventral tegmental area in addition to the nucleus accumbens. As stimulation targets in the hypothalamus have had limited success, a current clinical trial is recruiting patients refractory to gastric bypass for evaluation of targets involved in dysregulated reward circuitry. While gastric bypass is currently the gold standard therapy for morbid obesity, a recent study used decision analysis to note that DBS for obesity would only need an 83% success rate to achieve equivalence to bypass surgery.
Anorexia nervosa is another psychiatric disorder involving limbic circuits. Up to 70% of patients suffering from anorexia have a chronic refractory course, and it is one of the deadliest psychiatric disorders, with a mortality rate of 10%. Initial trials of DBS showed promising clinical results, as well as changes in metabolic activity in cortical and limbic regions associated with the subcallosal cingulate. Regions of the brain believed to be abnormal in anorexia nervosa include the parietal cortex, anterior and subgenual cingulate, and superior frontal, dorsolateral prefrontal, and orbitofrontal cortex. Many of these regions overlap with other psychiatric indications, notably major depressive disorder and OCD.
A Phase 1 clinical trial of SCC DBS is currently recruiting patients with refractory anorexia nervosa for initial safety and efficacy estimation. This study is a continuation of a pilot study in which 6 patients underwent SCC stimulation for 9 months. Initial results after 9 months included 3 of 6 patients increasing and maintaining their body mass index, and improvement in mood, anxiety, obsessions, and compulsions in 4 of 6 patients. Another trial is currently recruiting similar patients for implantation and stimulation of the nucleus accumbens.
Learning and Memory
Another active area of investigation is whether DBS may be effective for treating disorders of learning and memory. Applications are being developed for memory impairment due to Alzheimer disease, traumatic brain injury, temporal lobe epilepsy, stroke, and encephalitis. Improvements in our understanding of the anatomy of the hippocampal entorhinal cortex circuit (reviewed in Squire et al., 2004), the role of phase-phase and phase-amplitude coupling in learning and memory (reviewed in Fell and Axmacher, 2011), and the role of DBS in augmenting learning and memory (reviewed in Suthana and Fried, 2013) are stimulating interest and research in the field.
The presence of phase-phase and phase-amplitude coupling has important implications in DBS for memory. Hippocampal stimulation, for example, has been found to both disrupt and enhance memory. The fact that memory enhancement requires the stimulation to be spatially and temporally matched to existing hippocampal input activity suggests that some sort of oscillatory coupling mechanism is involved and that DBS can augment this mechanism. In the medial temporal lobe, increases in the amplitude of θ band (3–8 Hz) LFP oscillations can predict whether an experience is encoded in memory, and reinforcing these θ oscillations with DBS has been shown to improve spatial working memory. Theta-phase γ-amplitude coupling has also been implicated in successful learning and is believed to play a role in communicating across large dispersed cortical brain networks. Oscillatory mechanisms are increasingly being used to tie together theories of brain function, as illustrated in a recent paper unifying the dual role of the hippocampus in memory and physical navigation.
Multiple stimulation targets are currently under exploration for memory improvement. A Phase I trial of fornix/hypothalamus stimulation in 6 patients with mild Alzheimer disease did not show significant improvement in clinical symptoms, but showed reversal of decreased glucose metabolism in parietal and temporal lobes after 12 months of stimulation. Stimulation of the entorhinal cortex has been shown to improve spatial learning, and stimulation of the medial septal nucleus has been shown to improve spatial working memory after traumatic brain injury. While studies performed to date provide promising evidence, randomized controlled trials are still needed. Fortunately, multiple clinical trials are currently underway to clarify the role of DBS in Alzheimer disease and other types of cognitive impairment.
Addiction
Drug addiction is characterized by the compulsion to consume a substance, the loss of control in limiting its intake, and the development of a withdrawal state when the substance is withheld. This cycle becomes a chronic relapsing disease that affects approximately 2.9% of the adult US population (5.4 million) with illicit drugs and 7.7% (18 million) with alcohol. In addition, an estimated 28.6% (70.9 million) of Americans aged 12 or older are current tobacco users. Koob and Volkow, in their review of addiction and its neurocircuitry, describe 3 stages of addiction that they map to key regions of the brain: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. In the first stage, binge/intoxication, the nucleus accumbens and the ventral tegmentum are believed to play key roles, whereas in the withdrawal/negative affect stage, the amygdala is the central structure. Finally, the last stage, preoccupation/anticipation, appears to involve multiple structures including the prefrontal cortex, striatum, amygdala, hippocampus, insula, and cingulate gyrus. Given this network, DBS could potentially target any of these structures to interfere with addiction circuitry.
Several stimulation targets are under investigation, with the nucleus accumbens and STN receiving the most attention. In 2007, Kuhn and colleagues published a case report of a 54-year-old male with severe agoraphobia and panic attacks, with concomitant alcohol dependence, who received bilateral DBS of the nucleus accumbens for treatment of his anxiety disorder. He had no reduction in his anxiety, but he did experience a remarkable change in his alcohol dependency. Prior to DBS, he was consuming alcohol daily with an average of 10 drinks per day, with multiple hospitalizations for intoxications and withdrawal. After DBS, the patient claimed to have lost the desire to drink, and he only occasionally had 1–2 drinks in the year following his treatment. In 2009, the same group published a retrospective review of 20 patients who received nucleus accumbens DBS for OCD and TS. Of these patients, 10 were daily smokers and 4 had attempted smoking cessation unsuccessfully prior to DBS. Of the latter 4, 2 attempted and were successful at smoking cessation after DBS. Several preclinical studies in rats have investigated the effect of high-frequency DBS on ethanol consumption and cocaine/narcotic-seeking behavior. These studies showed a significant reduction in drug-seeking behaviors following DBS.
Müller and colleagues reported a pilot study of 5 patients who received bilateral nucleus accumbens DBS for chronic alcoholism. Two of the 5 patients were abstinent for at least 5 years following DBS and the remaining 3 had marked decreases in their alcohol consumption. One patient had a 2-week hypomanic episode that resolved after changes in stimulation settings. Of note, they also reported that 1 patient agreed to additional studies; when the DBS was turned off, the patient experienced increased risky behavior during gambling paradigms administered when compared with the same tests with the DBS on. These studies suggest that nucleus accumbens DBS appeared to normalize reward processing, which may be dysregulated in patients with addictive disorders.
Subthalamic nucleus stimulation has not had as promising results as nucleus accumbens stimulation. Rouaud and colleagues investigated high-frequency STN stimulation on cocaine and food-seeking behavior in rats. Stimulation made the animals less willing to work for drugs but did not affect consumption of readily available cocaine. Human case reports looked at patients with PD and found that STN DBS could either reduce or induce addictive behavior. Several studies have also linked STN stimulation with increased impulsiveness. Given these mixed results, the overall consensus is that STN stimulation is not as effective and safe as nucleus accumbens stimulation in addiction.
Additional target areas have included the dorsal striatum, lateral habenula, medial prefrontal cortex, and lateral hypothalamus. Animal studies showed no effect on drug-related behaviors after stimulation of the dorsal striatum and lateral hypothalamus. Lateral habenula stimulation was effective in controlling drug consumption but also decreased food consumption, which was considered an undesirable side effect. Medial prefrontal cortex stimulation also appeared effective in animal studies, but no human cases have been reported.
Neuromodulation of the nucleus accumbens has been shown to be effective and safe in the treatment of refractory addiction in small cohorts of patients. Given the societal burden imposed by addictive disorders, additional work in this area is warranted.
Others Indications: Epilepsy, Aggression, and PTSD
Epilepsy has been extensively studied as an indication for DBS (reviewed in Lega et al., 2010 and Kahane and Depaulis, 2010). Initial results of the Stimulation of the Anterior Nucleus of Thalamus for Epilepsy (SANTE) trial, testing stimulation against placebo in patients with severely refractory epilepsy, were promising. Five-year follow-up data were recently presented showing a median 69% reduction in seizure frequency, increased from a 56% reduction at 2 years. The 5-year response rate (patients with > 50% seizure frequency reduction) was 69%, and patients also had improvement in quality of life measures (Long Term Efficacy of the SANTE Trial. Presented at American Epilepsy Society 66th Annual Meeting. Abstract 1.272, Platform A.04. December 2, 2012). Other targets under active investigation include the hippocampus, caudate, and centromedian nucleus.
Another psychiatric indication under early investigation is treatment-refractory aggression. Based on early lesioning studies, as well as lesion/stimulation work, the mediobasal hypothalamus ("hypothalamic aggression area") has emerged as a target for stimulation. A recently published retrospective chart review on long-term results of posteromedial hypothalamic DBS for refractory aggression showed a significant decrease in the number of violent outbursts in 5 of the 6 patients reviewed. Although significant care was taken in patient selection and consent (each patient was evaluated by 2 psychiatrists, a local ethics committee, and consent was obtained from patients' parents or legal guardians), DBS for aggression continues to have severe ethical implications that must be carefully considered before this indication is more widely studied.
Preclinical work is also ongoing for the treatment of posttraumatic stress disorder (PTSD), as well as improving the understanding of the brain circuitry involved in PTSD. Currently, the amygdala and ventral striatum/ventral capsule are preliminary targets.
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