Deep brain stimulation (DBS) is used to treat certain neuropsychiatric disorders by implanting stimulating electrodes into deep nuclei or other neural tissues of the brain through stereotactic surgery and performing electrical stimulation to alter the excitability of the corresponding nuclei or neural loops. Over the past 20 years, DBS technology has evolved rapidly and is now an important clinical treatment for movement disorders such as Parkinson’s disease, idiopathic tremor and dystonia, and has been extended to treat a variety of other disorders such as Tourette’s syndrome, obsessive-compulsive disorder, depression, anorexia nervosa, intractable pain, epilepsy, vegetative state and Alzheimer’s disease. Although the specific mechanism of action of the DBS technique is not well understood, clinical investigators continue to explore the application of this technique to treat a number of new surgical indications and to select new optimal stimulation locations.
1. Parkinson’s disease (PD)
PD is a common degenerative disease of the central nervous system, with lesions mainly in the substantia nigra, striatum, pallidum and other basal ganglia areas. The main clinical manifestations are resting tremor, slow movement, muscle rigidity and abnormal postural reflexes. Early Parkinson’s disease is more sensitive to drugs, but as the disease progresses, drug efficacy gradually decreases, and adverse drug reactions, such as on/off phenomenon, end-of-dose phenomenon and anomalies, can occur. Approximately 50% of patients eventually lose the effect of drugs, their quality of life decreases, and they even lose the ability to take care of themselves. The traditional approach to surgical treatment of Parkinson’s disease is to destroy certain nuclei in the pallidum and thalamus, but this procedure can only be done unilaterally to improve contralateral symptoms, and if done bilaterally it can easily result in temporary or permanent postoperative neurological deficits, even with staged surgery. Although thalamic DBS can improve tremor symptoms, it is less likely to improve other PD symptoms. Hyperactivity of the medial pallidum nucleus (GPi) and thalamic nucleus (STN) has been recognized as an important part of the pathophysiological mechanism of PD, and Benabid et al [1] and Siegfried et al [2] were the first to report successful treatment of PD with GPi DBS and STN DBS, respectively, in 1994, and tens of thousands of PD patients have been successfully treated with DBS worldwide to date.
Many series have demonstrated the long-term efficacy of DBS for PD. motor symptoms in PD patients can be significantly improved by both bilateral GPi DBS and STN DBS [3-4], and Weaver’s team [5] performed a large meta-analysis and found that PD patients treated with STN DBS had better motor symptoms than those treated with GPi DBS, but the two were not not statistically significant. For drug-induced dyskinesia, GPi DBS directly improves levodopa-induced dyskinesia, whereas STN DBS relies on a reduction in drug dose to achieve improvement [6]. Some evidence has shown that STN DBS is more likely to lead to neurocognitive complications and require more adjustment of stimulation parameters than GPi DBS, but many clinicians still prefer STN as a target for the treatment of PD [7]. Although, the mechanism of DBS for PD is not fully understood, DBS has become part of the standard of care for the treatment of progressive PD.
2 .Essential tremor (ET)
Idiopathic tremor is the most common form of pathological tremor, usually affecting mainly the upper extremities, but can also include the head, vocalization, tongue and lower extremities. the prevalence of ET increases with age, and many patients will have a family history of ET. Idiopathic tremor can be effectively treated with propranolol and paroxetine, and many patients can have a significant reduction in tremor. The thalamus is a cluster of nuclei containing many subnuclei, and stereotactic thalamic disruption can treat ET and has been reported to have good long-term outcomes. However, thalamic disruption can only be used for unilateral tremor. DBS treatment was first used for ET and can be implanted bilaterally, and its effectiveness and long-term efficacy in tremor control has been confirmed. The ventral intermediate nucleus of the thalamus (Vim) is the most widely recognized target, and most reports indicate that 70-90% of patients with tremor can be controlled by thalamic DBS [8-9]. Thalamotomy for head and voice tremor is poorly effective, but better results may be obtained with bilateral thalamic DBS. Some investigators have recently suggested that the thalamic floor nucleus (STN), undefined band, or anterior thalamic radiation may be more effective targets for some ET patients [10]. In conclusion, DBS for ET is an effective and safe treatment method.
3, Dystonia
Dystonia is a clinical syndrome characterized by involuntary muscle contractions causing twisting, repetitive movements or postural abnormalities of the limbs or trunk, and the main pathophysiological basis is dysfunction of the basal ganglia in the brain. With the exception of dopamine-sensitive dystonia, most pharmacological treatments for dystonia are ineffective and often result in intolerable side effects. Surgical treatment initially improved the symptoms of dystonia by thalamus or GPi disruption [11]. In recent years many reported thalamic ventral intermediate nucleus (Vim) [12] and GPi DBS [13-14] for refractory primary dystonia, and it is generally believed that both target DBS treatments are effective for dystonia, but double-blind prospective studies suggest that GPi DBS may be a better choice for primary dystonia [15].Sun et al [16] were the first to report STN DBS for primary dystonia with very good efficacy and was soon validated by other centers. Several reports have shown that focal dystonia (e.g., Meige syndrome, spastic slant neck, etc.) can also be relieved by DBS [19-22].
DBS can also be used to treat some other types of dystonia, including post-traumatic, post-hypoxic, dystonia superimposed syndrome and tardive dystonia (TD) also with some efficacy, especially tardive dyskinesia can achieve perfect results [13-17].Kurtis et al [18] found that people with dystonia secondary to Kurtis et al [18] found significant clinical and neurophysiological improvement after treatment with bilateral GPi DBS in myoclonic dystonia secondary to epsilonsarcoglyan gene mutations. Brain iron accumulation neurodegeneration (NBIA) represents a rare group of neurodegenerative disorders characterized by iron accumulation in the brain, and generalized dystonia with severe speech and swallowing difficulties as well as pain, gait abnormalities and impaired respiratory coordination is a prominent symptom of NBIA.Timmermann et al [23] conducted a multicenter study of bilateral GPi DBS for the treatment of dystonia secondary to NBIA of dystonia in a multicenter study, with 2/3 of patients achieving more than 20% relief in dystonia severity scores and more than 30% achieving significant improvement in disability impairment. This cohort study suggests that GPi DBS may be an effective treatment for NBIA-induced dystonia.
4 .Neuropsychiatric disorders
4.1 Tourette’s syndrome (GTS)
GTS is a neuropsychiatric disorder that occurs most frequently in childhood and is characterized by buzzing sounds, vocal and motor tics, the pathophysiology of which is still poorly understood. the severity of symptoms and response to treatment vary widely among patients with GTS. Nearly 1% of the world’s children are reported to have GTS [24], and many of them have psychiatric comorbidities, including obsessive-compulsive disorder, anxiety disorder, depression, attention deficit disorder, and autism. The majority of patients with GTS have a self-limiting disease, which generally occurs after a peak in tic severity and is characterized by a marked decrease in symptoms after age 20. Since the mid-1950s, surgical disfigurement procedures have been used to treat drug-refractory GTS, with the thalamus, limbic system, prefrontal and cerebellum as targets, but with generally poor results and varying degrees of complications [25-26]. A recent series of studies found DBS to be effective in the treatment of GTS, with many authors reporting a significant reduction or even disappearance of twitching and psychiatric symptoms in patients after surgery [27-33].
Vandewalle et al [33] were the first to report DBS of the central median nucleus of the thalamus and the medial nucleus of the ventral mouth for GTS, and since then, the thalamus, GPi, nucleus ambiguus (NAc), and anterior limb of the internal capsule have been applied as targets [28,32,34]. Although DBS surgery is an effective treatment, the optimal therapeutic target is uncertain; therefore, systematic studies and the selection of the optimal target are the focus of future research.
4.2 Obsessive compulsive disorder (OCD)
OCD is a psychiatric disorder with obsessive thoughts and/or actions as the main symptoms. Treatment generally consists of cognitive interventions and medication, with up to 40% of patients experiencing poor outcomes and significant impact on quality of life with medication [35]. Surgical treatment is mainly internal capsule forelimb and cingulate gyrus nerve destruction therapy, which has been reported to achieve symptomatic relief in approximately 30-70% of patients [35-37]. Although the exact pathophysiological mechanisms are not clear, the abnormal function of the cortico-basal ganglia-thalamo-cortical loop plays an important role.
Over the past decade, small series of studies of DBS for OCD have been gradually reported [38-42], with symptom improvement mainly assessed by the Y-BOCS scale. The initial therapeutic target was the anterior limb of the internal capsule; Mallet et al [42] reported good efficacy of the STN as a target for OCD; the nucleus ambiguus as a therapeutic target was also reported in several studies [43]. Recently, the thalamic occipital, which links the orbitofrontal gyrus and the thalamus, has also been used as a therapeutic target for OCD [39-40], but this target has only been reported once, and although this study was not strictly controlled, the authors found a reduction of at least 35% in Y-BOCS scores in all patients. These preliminary studies suggest that DBS is a possible treatment option for severe refractory OCD. Clearly, the optimal therapeutic target has not been identified and further controlled studies are necessary. Potentially serious complications such as suicidal ideation and hypomania may arise in patients with DBS-treated OCD, and a combination of multiple therapeutic approaches is necessary for such patients.
4.3 Depression (Depression)
Depression is the most common psychiatric disorder, and despite antidepressants, electroconvulsive therapy, and neurodestructive surgery, 20% of patients still have poor outcomes with all therapeutic interventions.In 2005, Mayberg et al [44] reported the experience of six patients undergoing bilateral subcallosal knee DBS for depression, and four patients achieved sustained symptom relief at a 6-month follow-up.Schlaepfer et al [45] reported improvement in depressive symptoms in 3 patients treated with ventral striatum DBS. Several other targets have also been investigated. Although the best target for stimulation is inconclusive, DBS has emerged as a treatment option for refractory depression.
4.4 Impulsive behavior (Aggressive behavior)
Impulsive and aggressive behaviors that do not respond to most pharmacological treatments are very challenging. Hypothalamic disruption therapy has been shown to significantly improve symptoms. Recently, researchers have reported a few experiences with the application of posterior hypothalamic area stimulation to treat patients with severe aggressive and violent behavior disorders. kuhn et al [46] demonstrated the complete disappearance of self-harming behavior in a 22-year-old woman treated with bilateral hypothalamic DBS. Franzini et al [47] reported that six patients with severe violent and aggressive behaviors showed significant improvement in five patients after hypothalamic DBS treatment. DBS treatment of aggressive behavior disorders is only an initial experience and there is still a lot of work to be done.
4.5 Obesity, substance addiction, and anorexia nervosa
Obesity is an increasingly important health problem and DBS has been reported to be used in the treatment of obese patients [48-51]. The lateral hypothalamus and the ventral medial hypothalamus are the appetite and satiety centers of the brain, and recent attention has been directed toward the vomeronasal nucleus (NAc), the reward center of the brain [48]. Recent reports on chronic stimulation of the NAc suggest that modulation of the reward center may influence eating preferences. Systematic analyses have reported that DBS has achieved an 83% success rate for the treatment of obesity, comparable to current bariatric surgical procedures. Other substance addictions, including smoking and alcohol abuse, have reported symptomatic improvement after voxel nucleus DBS treatment [52-53].
Anorexia nervosa (AN) is a group of intractable psychiatric disorders characterized by fear of fat, blind weight loss, wasting, and amenorrhea. the prevalence of AN is 0.5-1% in young women in Europe, with a mortality rate of up to 10%, and the incidence of AN is also on the rise in China. AN can be divided into two clinical subtypes: restrictive and binge/elimination, and the etiology of AN is still unknown. Currently, the main treatment methods are psycho-behavioral therapy and medication, but more than 30% of patients are still resistant to treatment. The argument that anorexia nervosa is a form of the obsessive-compulsive spectrum was reported decades ago, and surgeons began to try to apply surgical procedures to treat it, the main treatment being cerebral white matter destruction, but psychosurgical destruction procedures may produce some irreversible personality changes and other side effects. To date, there are limited reports of DBS for AN [54-58], and the earliest experience with DBS for AN came from DBS for depressed and obsessive-compulsive patients with anorexia nervosa, who showed significant improvement in anorexia nervosa after surgery.Sun et al [57] were the first to report surgical treatment of AN, and the initial results showed four adolescent patients treated with NAc DBS with a 38-month follow-up and a flat weight gain of 65%. More recently, Lipsman et al [58] reported a prospective study of six adult patients with refractory anorexia nervosa treated with bilateral ACC DBS, in which four patients showed improvement in mood, anxiety, emotion regulation, and obsessive-compulsive symptoms associated with anorexia, in addition to an improvement in BMI in three patients at 9 months of follow-up. However, more research is needed to determine whether DBS can be a more effective treatment for AN and whether there is an optimal target for stimulation.
5. Chronic pain
The application of DBS for the treatment of various types of pain initially focused on the most commonly used targets such as the thalamic sensory nucleus, the posterior lateral thalamic nucleus and the posterior intermediate nucleus, which cause neuropathic pain [59]. Subsequent studies have shown that chronic stimulation of the periaqueductal gray matter (PAG) and periventricular gray matter (PVG) areas at the level of the three ventricles is also effective [60].The PAG and PVG areas have gradually become therapeutic targets for the treatment of sensory-injurious pain, with the posterior lateral thalamic nucleus and posterior intermediate ventral nucleus DBS being used primarily for the treatment of neuropathic pain [61]. Some recent international studies have reported that DBS can successfully treat a variety of different chronic pain symptoms, Hamani et al [62] applied DBS to the ventral caudate nucleus of the thalamus and the PAG/PVG region to treat 21 patients with chronic pain, 13 patients underwent permanent stimulator implantation and only 5 achieved long-term relief, and the target of implantation was the thalamic subnucleus.Vittar et al [63] reported that DBS in the PAG/PVG area was very effective in the treatment of phantom limb pain. In conclusion, DBS has become a treatment option for refractory pain, and the key to surgical efficacy lies in the choice of indication.
6 Headache
Cluster headache is a severe headache with recurrent cyclic attacks, sometimes lasting weeks or months at a time, and approximately 20% of patients are resistant to medication.In 2001, Leone et al [64] were the first to report the efficacy of DBS in the posterior hypothalamus for medically refractory cluster headache, and since then, more than 50 patients have been treated with DBS in the posterior hypothalamus. A number of other targets including periaqueductal gray matter, anterior hypothalamus, and subunited areas are being investigated for the treatment of cluster headache.
Franzini [65] et al. reported the efficacy of DBS in the posterior hypothalamus for neuropathic trigeminal neuralgia and trigeminal neuralgia due to multiple sclerosis, in which DBS for neuropathic trigeminal neuralgia was ineffective, whereas trigeminal neuralgia due to multiple sclerosis showed significant improvement. of obtaining significant pain relief. Therefore, DBS may also be an effective treatment for some refractory headache disorders.
7 , Epilepsy
Epilepsy is one of the common neurological disorders characterized by abnormal brain neuronal discharges causing recurrent epileptic seizures, and nearly 1% of adults and 5% of children are diagnosed with or have suffered from epilepsy, and more than 30% of patients have refractory epilepsy. refractory epilepsy. The central thalamic nucleus (CM) and anterior thalamic nucleus (AN) have been proposed as targets for DBS for epilepsy, and Andrade et al [69] reported that eight patients underwent bilateral DBS for refractory epilepsy (six patients underwent AN DBS and two stimulated CM); however, two patients underwent CM DBS without significant benefit, and five of the six patients treated with AN DBS had The seizures were significantly reduced in five of the six patients treated with AN DBS. Based on these studies, AN DBS has been approved as a treatment for epilepsy in Europe, but not by the FDA in the United States. The hippocampal gyrus can also be used as a therapeutic target for DBS, mainly in patients with temporal lobe epilepsy with bilateral hippocampal foci of epilepsy. Velasco et al [70] initially reported that 85% of patients who underwent bilateral hippocampal gyrus DBS stimulation achieved sustained seizure remission; in a long-term follow-up study, Boon et al [71] reported no significant improvement in 10 patients who underwent unilateral hippocampal gyrus DBS. A randomized double-blind multicenter sham stimulation trial on neurostimulation response is under study in the United States, but additional randomized double-blind multicenter controlled trials are needed to establish the future role of DBS for epilepsy.
8 , Vegetative state
Persistent vegetative state (PVS) or minimal conscious state (MCS) due to trauma or other causes has become a research area for the treatment of DBS. Brain stimulation for PVC/MCS was reported as early as 1950, and in 2010, Yamamoto [72] et al. reported the effect of DBS treatment with thalamic CM-Pf complex in 21 patients with traumatic or non-traumatic brain injury resulting in PVC or MCS, with 8-19 months of follow-up and improvement in consciousness and cognitive function in 8 patients. Recently, Sen et al [73] and Lancioni et al [74] published a review suggesting that DBS may be an effective and feasible option for PVC/MCS treatment for future studies and clinical trials.
9 , Alzheimer disease (AD)
AD is a progressive neurodegenerative disease, and some recent data suggest that this disease may be caused by disturbances in the integrity of cortical and subcortical pathways.Laxton et al [75] reported the results of applying vault/hypothalamic DBS to six patients with mild AD, and cognitive function assessments performed at 6 and 12 months after DBS showed symptom improvement or slowed disease progression. However, the results of this clinical trial cannot be relied upon to conclude that DBS is effective in treating AD. However, if the natural course of the disease in AD can be interrupted or disrupted, any possible treatment option should be explored.
In conclusion
DBS has the advantage of being minimally invasive, reversible, and modifiable compared to conventional surgery, and therefore has a better future. It has been shown that many diseases can be treated with DBS to obtain clinical improvement, but there are still many areas of research to be explored. In the past 20 years, scientists have devoted themselves to research on DBS such as further elucidating its mechanism of action, exploring new indications for surgery, improving surgical techniques, and finding more effective stimulation targets, so that its excellent results and unique value will enable it to play a greater role in the future treatment of neuropsychiatric disorders.