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Expanding indications for deep brain stimulation
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.226450
Keywords: Deep brain stimulation, indications for deep brain stimulation, neuromodulation, Parkinson's disease, psychiatric disorder surgery
This year happens to be the 30th year since the seminal paper on deep brain stimulation (DBS) for tremors was published by Benabid et al.[1] In March 1994, at the 11th Parkinson's disease (PD) symposium held in Rome, Grenoble neurologist Pierre Pollak presented the results of DBS of the subthalamic nucleus (STN), including a video of the first patient. The late Professor David Marsden, who was present in the audience, publicly stated then that this was “the most important discovery since levodopa.”[2] This was soon followed by a publication in Lancet as a report of three cases by Benabid's group.[3] DBS was approved by United States Food and Drug Administration (FDA) for tremors in 1997 and for Parkinson's disease in 2002.[4] In 2009, FDA approved DBS for obsessive compulsive disorders and for dystonia, under humanitarian device exemption rules.[5] Recently, the data from EARLY-STIM [6] study, (Class I evidence), led the FDA to approve DBS in patients with at least 4 years of disease duration and 4 months of motor complications as an adjunctive therapy [Table 1].[7]
The appeal of the DBS was in its reversibility and titratability as compared to lesional surgeries. These qualities along with the fact that it can be performed bilaterally, with “perceived” less morbidity led to exponential growth of this therapy in movement disorders and subsequently for other indications. This review will study some of the recent developments on the understanding of DBS for movement disorders and provide an overview of the emerging applications of DBS in the treatment of pain, neuropsychiatric illness, epilepsy, and cognition. Some of these indications are FDA approved, but most are not. However, several of these have CE approval and are widely practiced. [Table 2] classifies the various indications as currently practiced.
STN and globus pallidus interna (GPi) are the two common targets for DBS for PD. The initial penchant for the STN as the preferred target has been questioned as more and more information about the impact of STN DBS on cognitive, behavioural and other side effects have come to light.[29],[30],[31],[32] Each target has its merits and demerits and we think that “one size does not fit all”. STN is a much smaller target as compared to the GPi and hence the charge density and stimulation parameters required are much lower.[33] This leads to a longer battery life for the STN DBS than for the GPi DBS. The smaller target size, however, also has a disadvantage, as the stimulation can spread to neighbouring structures, leading to an increased incidence of side effects. Veterans and Netherlands SubThalamic and Pallidal Stimulation (NSTAPS) are two large randomized controlled studies comparing the outcome in OFF medication, ON stimulation motor scores, and between the STN and GPi DBS on a long term (36 months) follow up. The Veterans study showed that there was no difference between the two targets; whereas, the NSTAPS study showed that the motor symptoms and functioning improved more in the STN group than in the GPi group.[34],[35] Individual symptoms of tremors, bradykinesia and rigidity respond equally well with both the target sites. There have been case reports where an additional lead in GPi has been used to counter the side effects (e.g., dystonia, behavioural changes) or enhance the effects (e.g., tremors) of STN stimulation.[36],[37] There has been a suggestion that GPi may be more effective in controlling dyskinesias, but this has not been proven in randomized trials. Cognitive impairment and dementia are considered contraindications for DBS. However, in patients with mild cognitive changes, the decision to undergo DBS is a risk-benefit analysis between improved motor function and possible cognitive worsening. This has been one of the reasons for the consideration of GPi as a target site. The Veterans study showed that there is an increased decline in executive functioning in patients undergoing STN DBS as compared to GPi.[35] A meta-analysis of studies has also found that GPi DBS is associated with lesser long-term cognitive deterioration as compared to STN DBS.[38] Behavioural side effects and mood changes have been seen in patients with DBS.[30] Acute changes like delirium, confusion, hypomania and apathetic mood have been noted after STN DBS, with no similar changes reported in patients undergoing GPi DBS.[39] Disease related (as opposed to drug related) hallucinations have been noted after several years of STN stimulation, and in one study, with a 10-year follow-up, it was shown that this symptom can occur in up to 60% of patients. Impulse control disorders (ICD) are shown to reduce or disappear following STN DBS commensurate with the reduction in dopaminergic drugs. Maier et al., conducted a study to analyse the patient-perceived benefit of STN DBS. It revealed a negative outcome despite motor improvement following STN DBS. It highlighted apathy as the single most important factor towards the occurrence of subjective negative outcome after DBS.[40] There is not enough data for other important symptoms like gait and speech disturbances, effects on the autonomic symptoms and sleep to support GPi or STN DBS. Several studies have shown that there is a greater reduction of medications following STN DBS than GPi DBS.[34] In our practice, we offer GPi DBS to elderly patients who have increased cognitive deficits and early dementia. Our experience is in line with the above observations, that GPi DBS is effective for all symptoms of PD and does not offer greater medication reduction. However, the postoperative course and long term follow up of patients who have undergone GPi DBS has not shown any decline in their cognitive, behavioural and mood as compared to the baseline. In 2013, the results of EARLY-STIM (Early stimulus) study, a multicentre study to evaluate DBS in PD with early motor fluctuations was published.[6] Parkinson's disease questionnaire (PDQ-39), a quality of life measure, was chosen as the primary endpoint. Two years follow-up showed that the PDQ-39 score following the DBS procedure improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points. Neurostimulation was superior to medical therapy with respect to motor disability, activities of daily living, levodopa-induced motor complications, and time with good mobility and no dyskinesias. The medication dose was reduced 39% in the neurostimulation group but increased 21% in the medical treatment group. UPDRS-III scores improved by 53% in the neurostimulation group versus 4% in the medical group. No significant cognitive changes were found between the groups. Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Another study from Vanderbilt University showed that patients with DBS and best medical treatment had a 50-80% reduced risk of worsening after two years. Total UPDRS, complications of therapy and PDQ-39 significantly worsened in the medically treated group.[41] However, people have raised concerns and advice caution in interpreting this data. One of the concerns is the perceived placebo effect, which can last in some patients for up to 3 years, while the follow-up duration in the present study was only 2 years. Ethical issues that arise while addressing the short term and long term effects of DBS, including the accompanying behavioural and cognitive changes, will need to be clarified to the patient. Even so, the patient may not be able to make a very informed decision as he would be focused on getting relief from his present and perceived future symptoms. Another concern raised was related to the age group; the study was confined to patients below the age of 60 years and this data may not apply to elderly patients who have other issues.[42],[43] We have operated upon a few cases with a short medical history and early motor fluctuations. All patients were young and gainfully employed. Three of them were doctors and were actively practicing. Postoperatively, they had significantly improved quality of life and professional career. Studies have suggested that different oscillatory patterns within the brain networks may reflect states of normal function,[44] or conversely reflect pathological states associated with symptoms of PD.[45] This neuronal activity also varies dynamically at different time points in patients of PD, making the chronic fixed stimulation parameter stimulations offered by the present DBS systems less optimal.[46] One possible solution to these issues is to record the local field potential (LFP) directly from the stimulating electrode and to use this as a feedback signal to control the timing of the stimulation to be delivered. Increasing evidence suggests that beta frequency band (13–30Hz) oscillations in the LFP can be consistently picked up in the STN of patients with PD and that their level correlates with motor impairment, with and without treatment.[47] A multicentre study from Britain used adaptive DBS, which involved recording LFPs and delivering stimulation based on this, to control the symptoms of PD. Eight patient underwent implantation of Medtronic PC + S device. The outcome was compared between no stimulation, continuous stimulation (cDBS) and adaptive stimulation (aDBS). Motor scores improved by 66% (unblinded) and 50% (blinded) during aDBS, which were 29% (p 5 0.03) and 27% (p 5 0.005) better scores than that obtained using cDBS, respectively. These improvements were achieved with a 56% reduction in the stimulation time compared to cDBS, and a corresponding reduction in the energy requirements (P< 0.001). aDBS was also more effective than no stimulation and random intermittent stimulation.[47] These findings open up the field for further research. There are some other groups applying the same technology for studying Tourette syndrome and epilepsy.[46]
Bilateral GPi DBS has been shown to have a sustained benefit at a follow up of three years in patients with dystonia.[9],[48] Long-term follow up has been reported in a small number of reports.[49],[50] Recently, Benabid reported the long-term (follow-up 7.9 ± 5.9 years; range 1-20.7) outcome of sixty-one patients. The primary dystonia score in patients (n = 37) improved at the first (20.4 ± 24.5; P < 0.00001) and last (22.2 ± 18.2; P < 0.001) follow-up visits, compared with the preoperatively assessed score (50.5 ± 28.0). In patients with secondary dystonia (n = 19), the Burke-Fahn-Marsden Dystonia Rating Scale-Motor (BFMDRS-M) score improved at 1-year (40.8 ± 26.5; P < 0.02) and late follow-up visits (44.3 ± 24.3; P < 0.04) compared with the preoperatively assessed scores (52.8 ± 24.2).[51] With the exception of the positive results reported for panthotenate kinase-associated neurodegeneration (PKAN) and tardive dystonia,[52] improvement in secondary dystonias after pallidal DBS, however, appear to be less significant and sustained when compared with primary dystonias. A multicentre, randomised, sham-controlled trial, of patients with cervical dystonia, from centres in Germany, Norway, and Austria was conducted. The patients received GPi DBS. 62 patients were recruited; the outcome data were recorded in 60 (97%) patients at 3 months.[10] At 3 months, the reduction in dystonia severity was significantly greater with neurostimulation (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] -5·1 points [standard deviation 5·1], 95% confidence interval (CI 7·0 to -3·5) than with the sham stimulation (-1·3 [2·4], -2·2 to -0·4, P = 0·0024; mean between-group difference 3·8 points, range 1·8 to 5·8) in the intention-to-treat population. In a study from Australia, TWSTRS scores of cervical dystonia improved by 74.25% and the disability improved by 80% at a one-year follow up period.[53] We have a similar experience in two cases, one suffering from cervical dystonia and the other from tardive dystonia, having a 54% improvement at a 2-year follow-up period. Pantothenate kinase associated neurodegeneration (PKAN) has been used to describe patients with PANK2 gene mutation whose function is presumed to be correlated with iron metabolism. In addition to the classical “eye of the tiger sign” formed by hypointensity in GP, there is PANK2 mutation in at least one allele in these patients.[54] Severe dystonia present in these patients is least amenable to medical treatment. GPi DBS has been performed in such patients with significant relief.[21] In our patient, the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) improved from 120 (the total maximum score being 120) to 42.5. The BFMDRS disability score improved from 28/29 to 25/29 at a 15-month follow-up period.[21] Since then, we have operated upon two more patients with a similar short-term benefit. Over a longer term follow up period (mean duration: 31 months), there was a progressive deterioration in the symptoms, the BFMDRS disability score approached the baseline, and there was 14% reduction in the BFMDRS dystonia scores. Though the disease disability progresses on long-term follow up, the patients continue to benefit from the DBS. A multicentre study from Germany followed up 23 patients undergoing surgery and found that there was an improvement of 26% in the BFMDRS and 16% in the disability score at 9-15 month follow up period.[55] The French group also had similar results in six patients.[56] Karlsborg et al., conducted a double-blind randomized controlled cross-over study of GPi and STN stimulation for dystonia. They found that there was not much difference in the outcome for the generalised dystonia patients, but the patients with cervical dystonia responded in a significantly better way to STN DBS. They concluded that STN seems to be a safe and promising target to be considered in the treatment of dystonia.[57]
Tremor was the first indication which received FDA approval for DBS. All kinds of tremors have been treated by DBS, the most common target being the Vim nucleus of the thalamus. The best results have been seen in Parknsonian and essential tremors. However, there have been reports about the development of tolerance to stimulation over a period of time, especially for essential tremors.[12] Of the other tremors, tremors due to multiple sclerosis respond less favourably. There is data to show that the interruption of the pathological oscillations within the cerebellothalamic projections may be responsible for tremor control. The posterior subthalamic area (PSA) is situated immediately inferior to the VIM and posteromedial to the subthalamic nucleus (STN). Cerebellothalamic axons are particularly dense within the PSA area. Caudal zona incerta (cZi) forms one of the components of PSA, the other being cerebellothalamic fasciculus.[58] Blomstedt et al., published the results of 18 patients, with a mean follow up of 48 months. They found that on the treated side, tremor of the upper extremity (item 5 or 6 of Essential Tremor Rating Scale (ETRS) improved from 6.1 to 0.5 (91.8%), and hand function (items 11-14) improved from 9.3 to 2.0 (78.0%). Activities of daily living improved by 65.8%. There was no increase in the stimulation strength over time.[13] We have performed one bilateral cZi DBS for SCA12 tremor patient. Though we had improvement in the ETRS, there was worsening of the gait at the parameters required to control the tremor and hence the patient could not benefit from the therapy.
Pedunculopontine nucleus (PPN), comprising of 80% cholinergic neurons, is a part of the mesencephalon locomotor system stimulation area and is also known to process sensory and behavioural information in humans.[59] PPN stimulation has been performed in patients manifesting with a freezing of gait (FOG) and in PD patients with gait disturbances.[60],[61] We reported four cases of PSP who underwent PPN DBS. These patients were selected based upon whether they were able to walk with or without support. They were typically stimulated at a low frequency (20-45Hz). The preoperative and postoperative PSP rating scores (PSPRS) and their subscores were compared at a 6- and 18- month follow up by a blinded reviewer. At the 6- and 18-month follow-up visits, the median change in PSPRS was from 33 (baseline) to 37.5 and 47, respectively. Similarly, the PSP staging changed from 3 to 2.5 and 3.5, item 25 from 1.5 to 2 and 3.5, item 26 from 2.5 to 2 and 3.5, item 27 from 3.5 to 3 and 3.5, and item 28 from 1.5 to 1.5 and 3. On subgroup analysis, we had found that patients with PSP of the Parkinsonian type (PSP-P, this is typically a slowly progressive PSP) responded favourably to DBS, with their improvements sustained at the last follow up, whereas the classical PSP patients continued to deteriorate despite the presence of DBS.[19] We have now operated upon 10 cases of PSP, of which 4 were of the PSP Richardson type and the rest were of the PSP-P type. The PSP-P subgroup showed comparable results to those published earlier in our report.
Vagal nerve stimulation was approved by FDA for intractable epilepsy in 1997. It has been used to treat complex partial seizures. The success rate varies across centres based upon the indications for which it is performed, with an average reduction of > 50% in the seizure frequency, and a small number of patients becoming seizure free.[62] Following the publication of the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial, there has been an increased interest in performing DBS of anterior nucleus (AN) of the thalamus. One hundred and ten patients were randomized to receive stimulation and no-stimulation for a period of three months. In the last month of follow up, the stimulated group had 29% more seizure reduction. At the end of 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months.[8] Direct stimulation of the mesiotemporal structures has been done in patients with temporal lobe epilepsy, especially if the patient had bilateral temporal lobe epileptogenesis. There was a significant amount of seizure reduction, irrespective of the presence of hippocampal sclerosis. McLachlan, found that the reduction in seizure continued even after stopping the stimulation and suggested that this could be due to neural plasticity.[63] Other targets that have been explored, include the STN and substantia nigra. The responsive neurostimulation system (RNS) is currently the only FDA approved direct brain stimulation therapy for epilepsy. This is used as an adjunctive therapy for medically resistant partial-onset seizures. The RNS system consists of a stimulator, implanted leads, a recording and stimulating device and a wireless wand. The electrodes can be implanted as depth electrodes, or placed on the surface of the brain to record and stimulate the seizure onset zone. More than one such system can be implanted in the case of bitemporal epilepsy or multifocal epilepsy. The system works by recording the seizures and learning from their pattern. A counter stimulus is programmed to deliver the stimulation to abort the seizure.[64] Long term studies have reported a seizure reduction of up to 44% at 1 year and 53% at 2 years.[65]
Neurosurgery for psychiatric disorders has evolved significantly from its chequered past. Better understanding about the subsets of psychiatric disorders, their underlying pathophysiology, and improved surgical techniques have improved the safety of these procedures.[66] Careful patient selection, adherence to ethical principles and adaptation of the guidelines has improved confidence of the physicians and the society, regarding the therapy.[67]
Obsessive-compulsive disorder (OCD) is characterized by the presence of upsetting, persistent thoughts, images, or impulses, which are experienced as intrusive and senseless (obsessions) and/or excessive repetitive behaviours or mental acts (compulsions) intended to neutralize the anxiety induced by the obsessions. OCD has a lifetime prevalence of 2.3%.[68] Despite the exhaustive use of optimal behavioural and pharmacological treatments, an estimated 10% of OCD patients remain resistant to all therapies and suffer from severe symptoms leading to a marked functional impairment. DBS or lesional surgery is offered as a treatment option for this group of patients.[69] Nuttin et al., reported that four patients who underwent DBS of the anterior limb of internal capsule (ALIC), had a good outcome.[70] They went on to report a long-term follow-up on 6 patients. They found that the Yale-Brown Obsessive- Compulsive Scale (Y-BOCS) score improved by more than 35% in three patients, classifying them as responders.[71] Another multicentre study reported on 26 patients. This open study showed 62% patients responding with a 13-point decrease in the Y-BOCS scores at a 3-36 month follow-up.[16] Two other randomized controlled studies showed a similar improvement after ventral capsule/ventral striatum (Vc/Vs) DBS.[72],[73] Along with the improvement in the Y-BOCS scores, these studies found significant improvements in depression and anxiety. Over a period of time, the surgical target in the vicinity of the ALIC has been further explored. Several structures in the neighbouring area have been found to be effective in controlling the symptoms of OCD. These include nucleus accumbens (NAc) and bed nucleus of striae terminalis (BST). The traditional target used to be much more anterior from the anterior border of anterior commissure (AC), with the actual distance ranging from 7-15 mm. However, based on the observations of DBS, the current requirements and the success rates shown by Ali Rezai's and Bart Nuttin's group, the target has been moved more posteriorly and is now only a couple of mm anterior to the AC.[16] We have performed one DBS procedure targeting the BST for intractable OCD. The patient had a dramatic response in the immediate postoperative period. His OCD symptoms almost disappeared. He was a businessman and he started conducting business transactions whilst still being in the hospital. His anxiety scores also reduced. However, during the following few days, he started demonstrating increased “energy,” which later on manifested as a full blown mania.[74] We were able to control this with further programming and drug adjustments. At the last follow up, his YBOCS has reduced from a score 38 to 8 and his anxiety scores are at present 80% better. In a recently conducted review of literature, 18 studies with a total 112 patients had undergone DBS for OCD. The VC/VS was targeted in 30, NAc in 36 and STN in 25 cases. A French multicentre double-blind crossover study of 16 patients revealed that the mean Y-BOCS in the stimulated group was 19.7, in comparison to 28.7 in the sham stimulated group.[75] Though the common side effects are related to the hardware, there are specific therapy related side effects that one needs to be aware about. These included acute worsening on cessation of therapy or battery failures, with associated depression and anxiety. In some patients, mania and hypomania have also been reported.[74] However, most of these side effects can be controlled by careful programming.
Major depressive disorders (MDDs) pose a significant health burden and 30% of these patients are resistant to treatment.[76] Amongst various alternative treatments, there has been a growing interest in offering DBS and lesional surgeries to these patients. Various targets have been used for depression in lesional and DBS surgeries. The sub-callosal cingulate gyrus (SCCG), NAc and VC/VS are the commonly used target that have shown efficacy.[18],[77],[78] Lozano et al., presented a long term follow-up of an open ended study of 20 patients undergoing SCCG DBS for treatment refractory MDD. The mean duration of follow-up was 42.1 months. In the first year, 62.5% patients responded to treatment; this figure dropped to 46.% in the second year and again improved to 75% in the third year. The majority of the responders at the last follow-up visit (8 out of 11) had also been responders at year 1. The remission rate was 19%, 15%, 50% and 43% at 1, 2, 3 years and at the last follow-up after surgery.[79] The effectiveness of SCCG DBS was also evaluated for bipolar disorders, where a 92% response rate was obtained with 58% patients achieving remission at a 2-year follow up duration.[80] Bewernick et al., performed NAc DBS on 10 patients; 5 of them were classified as responders at a 1-year follow-up and the effect was maintained at 4 years.[81] Coenen et al., proposed that these three targets actually modulate the medial forebrain bundle (MFB). The MFB is close to the ventral tegmental area and projects to the forebrain regions such as the NAc and the prefrontal cortex. Among the seven patients who underwent MFB DBS, they noted a >50% improvement in six patients.[82] Nuttin et al., recently performed the anterior limb of the internal capsule (ALIC) and bed nucleus of the stria terminalis (BST) stimulation for treatment-resistant major depressive disorder (TRD). In a double-blind crossover design, the effects of electrical stimulation at both the targets were compared in TRD patients. The 17-item Hamilton Depression Rating scale (HAM-D) was the primary outcome measure. During the first crossover, patients received ALIC/BST stimulation versus no stimulation in a random order (2 × 1 weeks). During the second crossover (3 × 2 months), the patients received ALIC/BST versus ITP versus no stimulation. The patients and the evaluators were blinded for the stimulation conditions. All patients (n = 7) were followed up for at least 3 years. During the first crossover, the mean (and standard deviation) HAM-D scores were 21.5 (2.7) for no stimulation and 11.5 (8.8) for ALIC/BST stimulation. During the second crossover, HAM-D scores were 15.4 (7.5) for no stimulation, 7.6 (3.8) for ALIC/BST stimulation and 11.2 (7.5) for ITP stimulation. They concluded that on a long term basis, both ITP and ALIC/BST stimulation may alleviate depressive symptoms in patients suffering from TRD. Although the open label studies and limited number of randomized studies proved the efficacy of DBS for various targets, two large multicentric trials failed to establish the efficacy of DBS in TRD. The first one was for the VC/VS targets. Thirty patients were randomized to receive stimulation and sham stimulation for a duration of 16 weeks. 3/15 patients in the active stimulation arm and 2/15 patients in the sham stimulation arm showed a response. This was not statistically significant. During the open label continuation phase, 20-27% patients responded at some point in time. However, there have been several questions raised regarding the selection of the patients as well as the duration of the trial.[83] In an accompanying commentary, Dr. Schlaepfer noted that “these are examples of failed trials and not treatment.” In another study performed to evaluate SCCG as a target in 90 randomized patients, there was no significant improvement in the sham stimulation and the actual stimulation group. The authors concluded that a better patient selection and electrode localization may improve the outcome.[84] We have performed 3 DBS of SCCG, with a follow-up of 1-4 years. The HAM-D scores improved from 27 to 4 and the Hamilton anxiety scores improved from 26 to 4 at the last follow up.
Tourette's syndrome (TS) is an overlap of psychiatric and movement disorders. It is characterised by motor and vocal tics, associated with obsessive compulsive behaviour.[85] Between 1999-2015, 48 studies reported on 120 cases, from 23 centres and 13 countries. The most common targets for TS have been the centromedian/parafascicular complex (CM/Pf) nucleus of the thalamus and the anteromedial GPi. Savica et al., reported three cases of TS, undergoing CM/Pf stimulation. They had a mean reduction of 70% (range, 60%-80%) in the total Yale Global Tic Severity Scale Score (YGTSS) at a 1-year follow-up period. Servello et al., reported a study of 18 patients who underwent CM/Pf DBS. The 2-year outcome in 15 of these 18 patients showed a 52% reduction of the YGTSS score.[17] Two double-blind trials including 5 to 6 patients each, found an improvement in the score ranging from 43% to 49%.[86] Sachdev et al., reported a series of 17 patients undergoing anteromedial GPi DBS for TS.[87] The antero-medial pallidal target was approximately 6 mm anterior to the AC/PC midpoint and 14–17 mm lateral to the midline at the same depth as the pallidotomy target, 3–5 mm below the AC/PC plane. 12 out of 17 patients had >70% improvement in the YGTSS scores and three others had a meaningful improvement, as evidenced by changes in the quality of life scores. There were usual hardware related complications like lead fracture and infection. The treatment related complications were transient and could be corrected by programming. We have had an experience of managing two patients who underwent GPi DBS. They both had >80% reduction in their YGTSS scores. One patient developed infection at the implanted site and had to have his hardware, including the electrodes, explanted seven months after surgery. His TS symptoms were still controlled six months after stopping the stimulation and he is awaiting reimplantation.
The pathogenesis involving the development of obesity is complex. The reward circuitry that includes the lateral hypothalamus, ventromedial hypothalamus and NAc has been implicated, and thus, these areas form potential targets. Bilateral stimulation of the lateral hypothalamus (LH) has been shown to cause weight loss in a rat model.[88] Whiting et al., reported the efficacy and safety of the procedure in 3 patients undergoing LH DBS. At a 35-month follow-up, 1%, 12% and 16% increase in the metabolic rate was reported in these three patients.[22] In a study directed at anorexia nervosa (AN), Lipsman et al., performed DBS of the subcallosal cingulate gyrus (SCCG) in six patients. At a 6- and 9- month follow-up duration, 2 and 3 patients, respectively, reached above their preoperative body mass index (BMI). There was associated improvement in mood, anxiety and quality of life.[89] Sun et al., reported a weight gain in 65% of the patients after an average follow-up of 38 months following the NAc stimulation.[90]
Addiction or substance dependence is a chronic relapsing disease characterized by a strong psychological and physical dependence, resulting in a withdrawal syndrome when the use of the drug is stopped.[91] Various targets have been tried in the past and also recently, for treating addiction. These include hypothalamotomy, cingulotomy, resection of substantia innominata, etc.[92] DBS of the NAc and STN has been tried. Muller et al., reported successful abstinence in two patients and improvement in one patient following NAc DBS in three patients.[23] No adverse events were reported. DBS of the STN in patients of PD with dopamine dysregulation syndrome (DDS) have shown a variable response. Some series have reported significant improvement,[93] while others have shown no change or even worsening.[94] Overall, DBS for addiction still has an investigational status and NAc proves to be a promising target.
Amygdala has been targeted for various psychiatric disorders. It has been associated with emotions, especially of fear and anger. The basolateral nucleus of amygdala (BLn) contains “fear cells” that are active during fear acquisition and consolidation, and “extinction cells” that are active during fear extinction. Post-traumatic stress disorder (PTSD) may alter the modulation in these cells and prevent the amygdala cells from getting conditioned to ignore fear, by altering the neuroplasticity of the extinction cells.[24] Langevin et al., described a single case of BLn DBS in an American war veteran who suffered from PTSD. He suffered from vivid nightmares during which charred corpses would surround him. Upon being given reminders and exposure to the traumatic situations he had faced, he would enter into an unresponsive, hyper -aroused, and a dissociated state. He often missed workdays after a triggered flashback and lost several jobs due to absenteeism. Postoperatively, he showed considerable improvement.[24] A pilot randomized blinded controlled study has been initiated to study the efficacy of BLn DBS in 6 war veterans.[95] This therapy is still investigational and should be only performed by an experienced multidisciplinary team.
Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders characterized by a lack of social interaction as well as verbal and nonverbal communication in the first 3 years of life. The distinctive social behaviours include an avoidance of eye contact, problems with emotional control or understanding the emotions of others, and a markedly restricted range of activities and interests. The prevalence of autism is around 1%.[96] Genetic mutations interfere with the typical neurodevelopment, both in utero and throughout the childhood of the patient. These complexes of genes have been involved in synaptogenesis and axon motility. Also, the resultant microstructural, macrostructural, and functional abnormalities that emerge during the brain development, create a pattern of dysfunctional neural networks involved in socioemotional processing. Macrostructurally, MRI studies assessing brain volume in individuals with ASD have consistently shown cortical and subcortical gray matter overgrowth in early brain development. Functionally, resting-state fMRI studies show a narrative of widespread global underconnectivity in socioemotional networks, and task-based fMRI studies show a decreased activation of networks involved in socioemotional processing.[97] The amygdala has been implicated in the manifestations of social and aggressive behaviour in patients of ASD.[98] Post-mortem studies have shown a small neuronal size and increased cell density in the cortical, medial, and central nuclei of the amygdala in ASD patients.[99] Besides amygdala, nucleus accumbens (NAc) is also considered as the key structure which is related with the social reward response in ASD. The rationale for NAc to be considered as the potential target of DBS for ASD is because of its predominant role in modulating the processing of reward and pleasure.[100] Anticipation of pleasurable stimuli recruits the NAc. NAc is also activated by incentive motivation to reach salient goals.[101] NAc is also implicated in the other behavioural symptoms of obsessive compulsive behaviour (OCB) and aggression seen in ASD patients. This makes it a potential target for neuromodulation. Park and colleagues reported the first case of NAc DBS for autism with a two year follow-up.[25] The Clinical Global Impression-Severity (CGI-S) score gradually decreased from an initial score of 6 to a post-procedural score of 4; Irritability scores also decreased in the immediate postoperative period. The Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) total score decreased 68.2% from its initial value, and in the ADHD Rating Scale (ARS), only hyperactivity decreased by 40.7%. Followed by this encouraging report, we recently performed NAc DBS in an adult ASD patient who had suddenly become more aggressive and violent. We found that immediate postoperatively, there was remarkable improvement in her OCB and aggression. She also started developing an increased interest in the surroundings and even did “Namaste”, a gesture to say thank-you to the waiter who brought her food. This promising results will encourage us and others to explore this treatment option.
Alzheimer's disease (AD) is one of the leading cause of dementia and cognitive dysfunction in the aging population. The pathogenesis of this neurodegenerative disorder includes accumulation of abnormal proteins such as tau and beta amyloid with abnormal responses to oxidative stresses and initiation of inflammatory cascades.[102] Animal studies targeting the anterior/midline thalamic region for a high frequency stimulation have shown an increased hippocampal neurogenesis with improved neuroplasticity and short-term memory functions.[103] Various nodes such hypothalamus/fornix, nucleus basalis of Meyernet (NBM), entorhinal cortex/hippocampus, pedunculopontine nucleus, anterior limb of the internal capsule, nucleus accumbens have been shown to be potential DBS targets in patients with AD.[26] In a phase 1 study of bilateral hypothalamus and fornix DBS, it was seen that 2 out of 6 patients had a slower cognitive decline at one year with improved glucose metabolism in the temporal and parietal lobes.[104] In another study, bilateral forniceal stimulation improved glucose metabolism and increased hippocampal volume at three years in 2 out of 6 patients.[105] This are early results and further studies are underway to define the outcome and the targets.
Central thalamus and its connections with the reticular activating system play an important role in the arousal state. The cortical projections of the central thalamus and their subsequent dysfunction following traumatic brain injury results in altered consciousness levels.[106] DBS of these targets has been postulated to improve the persistent vegetative state (PVS) or minimally conscious state (MCS). The first DBS for PVS was done in 1968, by stimulating intralaminar thalamic nucleus. Cohadon et al.,[107] published results of 25 patients undergoing stimulation of the centromedian parafascicular (CMPf) complex nucleus. 13 of the 25 patients (52%) showed a significant improvement. Tsubokawa et al.,[27] reported a series of 21 patients undergoing DBS, 19 of whom had CMPf as the target. They reported that 8 patients recovered to the stage of following commands. The patients who recovered showed desynchronization on continuous electroencephalographic (EEG) frequency analysis. It was possible to record the Vth wave of the auditory brainstem response and N20 waveform of the somatosensory evoked potential in these patients preoperatively. The pain-related evoked response (P250) was recorded with an amplitude of > 7 μV. They predicted that these criteria could be used to predict outcome. Rezai et al.,[108] implanted bilateral DBS in the intralaminar and paralaminar thalamic nuclei in a patient with MCS. They noted persistent improvement in feeding and communication in this patient.
DBS has been offered for various painful conditions, ranging from thalamic pain to deafferentation pain, with a variable response.[109] The periventricular grey matter (PVG)/periaqueductal grey matter (PAG) and the ventroposterolateral or the ventroposteromedial (VPL/VPM) nuclei are the two most common targets. In one study, it was found that nociceptive pain responded better to stimulation than deafferentation pain.[14] A meta-analysis by Levy et al., found that PVG DBS (59% versus none) was superior to PVL DBS in nociceptive pain control, whereas, VPL DBS (56% vs 23%) was superior to PVG in neuropathic pain control.[110] Recently, the affective component (implying the emotional response) to pain is gaining interest as a potential strategy for pain modulation. Thalamic pain is one of the most difficult pain syndromes that is not uniformly responsive to DBS.[111] NAc, the target for various psychiatric disorder surgeries, has also been implicated in pain processing. Lee et al., performed a dual implant of PVG and NAc in a 72-year old patient with post-stroke pain. They found sustained pain relief at a 1-year follow up.[15] DBS of the posterior hypothalamic area was first introduced in 2000 to treat drug-refractory chronic cluster headache (CH). 79 patients suffering from various forms of intractable short-lasting unilateral headache, mainly the trigeminal autonomic cephalalgia, have undergone DBS. The majority (88.6%) were suffering from a chronic CH. At a mean follow up of 2.2 years, 69.6% of the 55 hypothalamic-stimulated patients showed a ≥50% improvement in their headache.[112]
The field of neuromodulation is rapidly expanding. Not only the indications of DBS are widening, the technology is also rapidly changing. Smaller implantable pulse generators, some of them tiny enough to be skull mounted, are being tested. The lead configurations are changing, and so are the programming algorithms. Apart from DBS, neuromodulation by several other techniques, like the peripheral nerve stimulation, spinal cord stimulation or intrathecal therapies, are pushing the horizons. Similarly, neuromodulation is now not only limited to the neurosurgeons or neurologists, but pain specialist, psychiatrists, rehabilitation specialists and several other interdisciplininary specialists are being involved in obtaining the optimum benefit of these treatment options. Acknowledgment I am thankful to the management, scientific and ethics committee of Jaslok Hospital and Research Centre for their continued support. All our surgical procedures mentioned in the above article have been performed at the Jaslok Hospital with proper informed consent and approval of the ethics committee. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Table 1], [Table 2]
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