Deep brain stimulation for refractory neurological disorder management: History
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Jamir Pitton Rissardo
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Ana Letícia Fornari Caprara

Deep brain stimulation (DBS) has been extensively studied due to its reversibility and significantly fewer side effects. DBS is mainly a symptomatic therapy, but the stimulation of subcortical areas by DBS is believed to affect the cytoarchitecture of the brain, leading to adaptability and neurogenesis. The neurological disorders most commonly studied with DBS were Parkinson’s disease, essential tremor, obsessive-compulsive disorder, and major depressive disorder. 

  • DBS
  • movement disorder
  • brain stimulation
  • electrical stimulation
  • IPG
  • Parkinson’s disease
  • tremor
  • symptomatic
  • neurosurgery
  • neurology

1. Introduction

Deep brain stimulation (DBS), according to the National Institute of Neurological Disorders and Stroke (NINDS), is a surgical method used to manage various neurological conditions that do not effectively respond to conventional therapy. It comprises a neurostimulator surgically implanted battery-powered gadget, which resembles a cardiac pacemaker, that provides electrical stimulation to the appropriate location to block aberrant nerve signals [1]. The first studies with electrical stimulation of the cortex were designed at the end of the 19th century. Still, the main devices were only developed in the mid-20th century, following the scientific and technological achievements of the information age (Table 1).
Table 1. Timeline of the deep brain stimulation development.
Year Description
1874 Electrical stimulation of the human cortex was performed by American physician Robert Bartholow
1947 The stereotactic frame was developed for human neurosurgery. Ernest A. Spiegel developed a stereotactic frame, which was followed in 1949 by the arc-based Leksell frame
1948 J. Lawrence Pool performed the first chronic DBS implantation using an electrode connected to an induction coil
1952 The first stereotactic atlas with coronal photographs of the brain was published
1954 Acute thalamic DBS to target chronic pain. It is considered one of the first functional applications for DBS
Acute DBS used in pre-lesion targeting for psychiatric disorder
1958 The first definitive cardiac pacemaker was implanted. The first temporary transcutaneous cardiac pacing device was made in 1952
1960 Acute DBS is used to identify lesion targets in essential tremor
Frequency-dependent effects of DBS reported
1961 The first human intraoperative microelectrode recordings
1963 José Manuel Rodríguez Delgado used a “stimoceiver” to inhibit the aggressive behavior of a bull
1968 Medtronic implantable pulse generator. Also, the first spinal cord stimulator was commercially available
1970s Computed tomography is used for stereotactic targeting
Radiofrequency control on an “external” transmitter on DBS systems
1972 The first chronic DBS implant for PD
1973 Thalamic DBS for denervation pain
1977 Periventricular DBS for pain
1980s MRI is used for stereotactic targeting
The first fully intracranial DBS devices were available. Also, the long-lasting implantable lithium batteries greatly extend implant life and the maintenance of the device
1980 DBS for multiple sclerosis tremor
1987 DBS of the ventral intermediate nucleus of the thalamus was effective in the management of tremor in individuals with PD
DBS therapy for the management of tremors was successfully reported by Alim-Louis Benabid
1990 Refinement of battery-driven pacemakers
DBS reverses motor symptoms in MPTP-induced parkinsonism in monkeys
1994 DBS of the subthalamic nucleus is used in the management of tremors in patients with PD
1997 The FDA approves DBS of the ventral intermediate nucleus of the thalamus for the management of essential tremors
1999 DBS of the anterior limb of the internal capsule was first used to manage obsessive-compulsive disorder
Visser-Vanderwalle reported the effective use of DBS of the medial thalamus in three patients with Tourette’s syndrome
Globus pallidus internus DBS for the management of refractory dystonia
Implantable pulse generators with dual-channel technology, which was developed after the creation of dual chamber cardiac pacing in 1998
2000s DBS therapy is refined for treating essential tremors, PD, and dystonia
2002 US FDA approves DBS in PD
Quadripolar electrodes are commercially available
2003 The US FDA approves DBS for dystonia
2004 Computer models of DBS
2005 DBS is used to treat depression
2007 DBS is used to treat minimally conscious states
2009 DBS of the bilateral anterior limb of the internal capsule for the management of obsessive-compulsive disorder received a humanitarian device exemption from the FDA
Rechargeable DBS batteries are available
2010 Sin Alzheimer’s pilot trial evaluates the DBS of the fornix
2011 Close-loop stimulation for epilepsy management
2013 DBS device capable of simultaneous stimulation and recording activities of the local field potential signal processing.
DBS of the subcallosal cingulate gyrus in an anorexia pilot trial
A closed-loop, responsive DBS system was introduced to treat epilepsy. These devices need to have neural activity sensitivity, leading to a decreased number of side effects and a longer battery life
2015 The emergence of directional DBS leads can lead to an adjustment of the electrical field along the lead axis
2018 The US FDA has approved DBS as an add-on treatment for drug-resistant epilepsy in adults
2020 The US FDA approves a DBS device capable of neurosensitivity and directional leads
Wireless devices with three Tesla MRI compatibility
Abbreviations: DBS, deep brain stimulation; MRI, magnetic resonance imaging; PD, Parkinson’s disease; US FDA, US Food and Drug Administration.
The first condition approved to be managed with DBS was essential tremor in 1997 by the US Food and Drug Administration (FDA). In the following years, clinical trials were published showing the efficacy of DBS therapy for managing other movement disorders. In this context, DBS for Parkinson’s disease (PD) was approved by the FDA in 2002, and dystonia in 2003 [2]. The current guidelines recommend DBS rather than ablative surgical methods for treating drug-resistant PD. Additionally, DBS has shown promise in managing other neuropsychiatric conditions, such as substance-related and addictive disorders, aggressive behavior, eating disorders, major depressive disorder, obsessive-compulsive disorder, and refractory Gilles de la Tourette syndrome [3].
DBS implantation was based on lesioning operations performed in the last century to improve neurological symptoms, which resulted in a high percentage of undesired side effects [4]. DBS was considered a safer alternative when compared to lesioning procedures due to fewer adverse events, leading to active research and further investigation of neuromodulation approaches for various neurological disorders [5].
Although DBS has been extensively used in managing tremor in individuals with PD, the exact mechanism of action for improving the symptoms in the neural circuitry is not fully understood. It is believed that stimulating the main nerve tracts while inhibiting the nearby neurons may facilitate the movement (Figure 1). The zones of uncertainty and cerebellar-thalamic pathways, which decrease tremor and increase dopamine, are also implicated [6]. Moreover, the nosological entity with adequate stimulation parameters and the cytoarchitecture of the brain structure (typically subcortical) are probably related to the efficacy of DBS therapy [7]. In this way, some authors proposed that the leads of DBS can inhibit the structures rich in cell bodies or disinhibit a specific collection of axons, leading to the synchronization of an abnormal pattern, which can facilitate movement or inhibit unusual neuronal activity [8]. Some individuals show a progressive improvement in motor symptoms, suggesting a possible change in the cytoarchitecture of the central nervous system and neuroplasticity [9].
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Figure 1. Cortico-basal-ganglia-thalamo-cortical circuitry. The direct, indirect, and hyperdirect pathways are indicated. Green lines denote inhibitory connections (GABAergic), red lines denote excitatory connections (glutamatergic), black lines denote dopaminergic pathways, and blue lines denote mixed cholinergic connections. Notably, the pedunculopontine nucleus (PPN) exhibits anatomic projections to the striatum and cortex. Abbreviations: D1, dopamine receptor D1; D2, dopamine receptor D2; GPe, external globus pallidus; GPi, internal globus pallidus; PPN, pedunculopontine nucleus; SNC, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus.

2. Surgical Techniques

The surgical procedure for implanting DBS devices involves several key elements and can vary in approach and technique. A meticulous preoperative airway assessment is necessary since the patient’s head will be immobilized in a stereotactic headframe during the DBS procedure. Monitored anesthesia care with sedation is the most commonly used anesthesia technique during lead implantation for most patients. This leads to minimal effects of anesthetic agents on neuronal background and spike activity during microelectrode recording localization [10].
The primary components of a fully implanted DBS system include the precise implantation of an intracranial electrode, which involves surgically placing an intracranial electrode into the specific target area within the brain where stimulation is intended. The implant lead extension connects the intracranial electrode to the power-generating and programming sources. An internal pulse generator that generates electrical pulses for stimulation is implanted under the skin, typically in the chest or abdomen [11].
The surgical procedure for DBS can differ among medical facilities and centers. The most common approach for implanting the device is general anesthesia. On the other hand, local anesthetics are applied for device maintenance that does not involve lead manipulations such as battery changes [12]. A Leksell stereotactic frame is sometimes securely attached to the patient’s head under local anesthesia. This frame is used for precise targeting during the surgery. After securing the frame, stereotactic imaging is performed to aid in planning the electrode’s target and trajectory. Various software packages are available for this purpose, and they can employ coordinate frame-based, frameless, or robotic stereotaxic procedures [13].
Overall, the choice of approach and surgical technique may depend on the specific patient, the target area within the brain, and the preferences and expertise of the medical facility performing the procedure.
The surgical procedure for DBS involves the following steps: The patient is positioned semi-recumbent, and the scalp is prepared by clipping the hair and applying betadine solution to ensure sterility. Then, a coronally oriented incision is typically made, spanning Kocher’s point bilaterally on the scalp. However, alternative incision techniques can be used. The scalp is opened to expose the skull’s frontal bone. A hole, or trephination, is made approximately 1 cm anterior to the coronal suture and at least 2 cm lateral from the midline of the skull. The dura mater is coagulated and carefully incised. Special care is taken to minimize cerebrospinal fluid loss. A guide cannula is inserted into the brain, typically about 1.0 to 1.5 cm above the intended target area. Microelectrode recording is used to identify the electrophysiological characteristics of the target structure and determine its dorsal-ventral boundaries. This helps with the precise placement of the macrolectrodes. Once a suitable tract is identified, the microelectrodes are removed, and a permanent macroelectrode is inserted into the target structure [14].
Stimulation tests are conducted at each electrode contact point to evaluate for adverse effects and clinical efficacy. This ensures that the stimulation is effective and safe. The proper placement of the DBS electrode is verified through intra-operative fluoroscopy [15]. If placement is confirmed, the electrode is affixed to the skull. The incision is closed, completing the surgical procedure. These steps ensure the precise placement of the DBS electrode in the intended target area within the brain while minimizing complications. It is a delicate and highly specialized procedure performed by neurosurgeons with expertise in DBS. In some DBS centers, microelectrodes are advanced through the cannula for recording or stimulation. The microelectrode stimulation can define the anatomical location of the electrode, which can be further assessed with directional leads and changing the voltage and current. This is important for the evaluation of possible side effects related to the localization of the leads, such as paresthesia, muscle contractions, and flashes of light [16]. Also, during the insertion of the DBS lead, fluoroscopy can be used to confirm the location of the lead in a two-dimensional view (Table 2).
Table 2. Stimulus-induced side effects in DBS surgical procedures.
Adverse Event DBS Target Region Related to the Side Effect Correctional Reference
Dyskinesias GPe, GPi, STN Excessive modulation of the indirect pathway Decrease frequency. Removal of leads [17]
Dysphonia, dysarthria STN, GPi Internal capsule and associate circuits of basal ganglia If possible, change the hemisphere [18]
Muscle contractions STN, GPi, VOP Corticospinal tract of the internal capsule Move posterior [19]
Mood changes, risky behavior GPi, STN Associative and limbic circuits of the basal ganglia Move dorsal [20]
Oculomotor disturbances GPi, STN Internal capsule for conjugate eye deviation
Third nerve medial to STN for ipsilateral eye movements		 Move medial; Move lateral [21]
Paresthesia Vim, STN, VOP, PPN Lemniscal fibers Move anterior [22]
Phosphenes GPi Optic tract Move medial [23]
Sadness, depression STN Ventromedial STN, substantia nigra pars reticularis Move dorsal [24]
Verbal fluency, working memory GPi, STN Associative circuits of the basal ganglia Move dorsal [25]
Weight gain STN, GPi Normalization of energy metabolism Increase physical activity [26]
Abbreviations: DBS, deep brain stimulation; GPe, globus pallidus externus; GPi, globus pallidus internus; PPN, pedunculopontine nucleus; STN, subthalamic nucleus; Vim, ventral intermediate nucleus of the thalamus; VOP, posterior ventral oral nucleus.
Following the initial procedure, the patient undergoes general anesthesia, and the intracranial electrodes are connected to extension wires. These wires are placed under the skin, behind the ear, and down to the chest through a tunnel. An additional incision is made below the clavicle to create a pocket for the internal pulse generator. Then, the extension wires are connected to the internal pulse generator, and the system’s impedances are checked to ensure proper function [27]. Patients are usually admitted for observation for one night after the procedure. After, an outpatient appointment is scheduled within eight weeks of the procedure for device activation and programming, ensuring the DBS system is optimized for their specific needs. When treating Parkinson’s disease, programmers often begin with a monopolar configuration to stimulate the brain. In this configuration, a contact electrode is the cathode with a negative voltage. In contrast, the outer casing of the implantable pulse generator serves as the anode with a positive voltage. If adverse effects arise at higher voltages, a bipolar stimulation configuration can be used. In this configuration, one contact serves as the cathode and another as the anode, limiting current spread into adjacent brain regions that cause side effects. This technique is useful in ensuring that therapy remains within the therapeutic range and does not induce any side effects (Figure 2) [28].
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Figure 2. Modes of stimulation. The monopolar (cathodic) stimulation has a spreading negative current in all directions. In the bipolar, the electrode has both anodic and cathodic contact points, with a narrower and more intense flow of current between them.
The implantable pulse generators contain a battery, power module, central processing unit, program memory, and a microprocessor. They are the DBS system’s active components and control the devices’ functions, including activation, deactivation, pulsing parameters, internal diagnostics, and communication with external devices. Features of implantable pulse generators for deep brain stimulation are described in Table 3 [29].
Table 3. Features of implantable pulse generators for deep brain stimulation.
Model No. of Chambers Weight (g) Size (mm) Rechargeable Cell Frequency Range (Hz) Pulse Width (μs) Temporal Fractionation Current Fractionation Directional Lead Magnetic Resonance Safety Local Field Potential
St. Jude (Abbott) Infinity 5 a 2 49 56 × 50 × 13 No 2–240 20–500 Multi-stim set Coactivation Yes Conditional: more than 1.5T requires specific conditions No
St. Jude (Abbott) Infinity 7 a 2 58 67 × 50 × 14 No 2–240 20–500 Multi-stim set Coactivation Yes Conditional: more than 1.5T requires specific conditions No
Boston Scientific Vercise PC b 2 55 71 × 50 × 11 No 2–255 10–450 Areas Multiple independent current controls Yes Unsafe failure of the equipment No
Boston Scientific Vercise Gevia b 2 26 51 × 46 × 11 Yes 2–255 20–450 Areas Multiple independent current controls Yes Conditional No
Boston Scientific Vercise Genus P8/P16 b 1 or 2 58 72 × 50 × 12 No 2–255 20–450 Areas Multiple independent current controls Yes Conditional No
Boston Scientific Vercise Genus R16 b 2 27 52 × 46 × 11 Yes 2–255 20–450 Areas Multiple independent current controls Yes Conditional No
Medtronic Activa PC c 2 67 65 × 49 × 15 No 2–250 60–450 Interleaving No No Conditional, certain requirements No
Medtronic Activa RC c 2 40 54 × 54 × 9 Yes 2–250 60–450 Interleaving No No Conditional, 1.5T MRI No
Medtronic Activa SC c 1 44 55 × 60 × 11 No 3–250 60–450 Interleaving No No Conditional, but not eligible for full-body MRI No
Medtronic Perpcept PC c 2 61 68 × 51 × 12 No 2–250 20–450 Interleaving No No Conditional, 3T, and 1.5T MRI Yes
a https://www.neuromodulation.abbott/us/en/parkinsons/infinity-for-deep-brain-stimulation.html, accessed on 15 October 2023. b https://www.bostonscientific.com/en-US/products/deep-brain-stimulation-systems.html, accessed on 15 October 2023. c https://www.medtronic.com/us-en/patients/treatments-therapies/deep-brain-stimulation-parkinsons-disease/about-dbs-therapy/dbs-products.html, accessed on 15 October 2023.

This entry is adapted from the peer-reviewed paper 10.3390/medicina59111991

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