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Fundamentals of Neuromodulation and Pathophysiology of Neural Networks in Health and Disease
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.302463
Keywords: Deep brain stimulation, dystonia, epilepsy, essential tremor, neuromodulation, Parkinson's disease
International Neuromodulation Society described neuromodulation as “the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body”. Although modern imaging and biotechnology have enabled sophisticated approaches to neuromodulation, its use and study predates the modern era. Scribonius Largo, a physician of Roman emperor Claudius in 46 AD, performed early human studies of stimulation of brain by use of the electric ray on cranial surface. In 1952, Jose Delgado implanted the first intracranial leads, which was joined to receiver to monitor brain waves. In the 1960s human trials and stimulation of deeper cortical structures were conducted which paved the foundation for modern understanding of neurophysiology and neurotherapeutics. In the interest of this article, we will limit our discussion of neuromodulation to the field of neurosciences with particular attention to Deep Brain Stimulation (DBS) technology. This has been extensively used for the treatment and symptom modification in individuals with Parkinson's disease (PD), essential tremor (ET), dystonia, epilepsy, tic disorder, depression as well as an obsessive-compulsive disorder to name a few. A large portion of the success of neuromodulation can be attributed to rapidly developing field of neuroimaging methods, the manufacturing of sophisticated electrode designs and implantable pulse generators, optogenetics as well as transmagnetic stimulation. Such technologies have enabled us to understand neural circuitries, connections as well as cellular and molecular changes that occur with such therapies. Neural circuitry in basal ganglia Basal ganglia comprises striatum, globus pallidus internus (GPi), globus pallidus externus (GPe), subthalamic nucleus (STN), and substantia nigra (SN) with corresponding networks that connect it to the thalamus and cortex. This network comprises the motor circuitry responsible for the execution of movement. The detailed illustration of this circuitry including the direct and indirect pathway along with the role of either of the pathways was explained in the 80s[1] [Figure 1]. Activity of these circuits depends on the action of neurotransmitters including dopamine, glutamate as well as GABA.
Fibers arise from the precentral motor fields terminating in the putamen with some connections in the lateral and dorsal motor portion of STN. There is evidence of subthalamic cortical connections separate from the corticostriatal pathways. Direct pathway comprises of the striatal projections to the GPi and the substantia nigra pars reticulate (SNPr) while the indirect pathway involves neurons of the GPe and the STN.[2] Direct pathway enables a movement while the indirect pathways play a key role inhibiting the movement.[3] This traditional explanation did not explain several inconsistencies with known physiological occurrences such as slower conduction via the indirect pathway opposed to faster conduction through the direct pathway that would lead to unchecked excessive movement. This was explained by the direct connectivity between the cortex and the STN which was designated “hyperdirect” pathway and was responsible for the inhibition of the movement.[4] However, without much fortifying evidence for these mechanisms, the mechanism of the circuitry and basal ganglia remain to be highly researched areas at this time.[5] Ablative therapies Ablative therapies were widely used in the pre-DBS era for surgical treatment of neurological conditions. Wilder Pendfield used stimulation of various cortical regions to study the responses and in turn lesion potential epileptogenic areas.[6] Ablative therapies involve lesioning a region of interest in the brain using mechanical devices, chemical agents, radiation, cryogenics or heat.[7] Radiofrequency (RF) ablation involves creating a lesion through heat production by passing current through an insulated electrode. The tip of the electrode which is the active site is non-insulated and is the site of greatest heat production resulting in lesioning the surrounding tissue.[7] Laser which is an acronym for “Light amplification by stimulated emission of radiation”, is a process of producing a beam of electromagnetic radiation. Laser interstitial thermal therapy (LITT) uses laser, which is non-ionizing radiation through optical fibers to produce heat and subsequent lesion in the targeted structures.[8] Modifying laser probe position and trajectory can produce lesions of various volumes and shapes to attain the desired clinical effect.[9] Gamma knife radiosurgery ablation (GKS) takes advantage of gamma rays originating from cobalt as a source of radiation. A focal point is decided based on 3- dimensional CT or MRI imaging of the region of interest and multiple beams are projected that converge at the focal point.[10] Focused ultrasound is another non-invasive technique, which utilizes thermal energy for lesioning the target. It involves an array of transducers that provides the ultrasonic mechanical energy, which is absorbed by the tissue. These Ultrasound waves cause vibration and rotation of macromolecules or part of macromolecules in the tissue leading to frictional heat energy resulting in cavitation.[11] Using low energy focused ultrasound may lead to “temporary lesion” and produce neuromodulatory effects by blocking neural activity. This has been used to study physiological responses including inducing muscular contractions and has also has potential to modulate epileptic spread.[12] In addition to neurological conditions, ablative procedures have additionally had utility in several psychiatric conditions including depression, obsessive-compulsive disorders, eating disorders. Additionally, chronic pain has been treated with thalamotomy, cmesencephalotomy and cingulotomy.[7] Transcranial direct current stimulation Transcranial direct current (tDCS) entails using electrodes placed over the scalp (positive end i.e., anode for increasing cortical activity and negative end i.e., cathode for decreasing cortical excitability) to deliver currently directly which passes to the brain to complete the circuit.[13] The effects of this stimulation are seen during as well as after the procedure that can be further changed by altering the current intensity and duration. The current stimulates the resting membrane potential with the anodal stimulation depolarizing the neurons and cathodal stimulations hyperpolarizing the neurons.[14] Certain adverse effects associated with these therapies include skin lesions and burns at the site of electrode placement, local pain, headaches, mood changes including hypomania.[15],[16] Sites of stimulation include M1 region of motor cortex, left dorsolateral prefrontal cortex (DLPFC) or even primary visual cortex for migraine. So far, there is not much evidence of benefit from tDCS in PD with either motor or non-motor symptoms.[17],[18] There are fewer studies for efficacy in ET and most involved smaller samples of participants Additional review of tDCS did not reveal significant evidence of therapy in ET, stroke, epilepsy, or Alzheimer's disease.[18],[19],[20],[21] Cerebellar stimulation for movement disorders has also been reviewed and have shown modest improvement of symptoms in patients with tremor, ataxia, dystonia and Parkinson motor symptoms. However, due to lack of large-scale randomized controlled trials (RCT) their efficacies cannot be well established.[20],[22],[23],[24],[25] Transcranial magnetic stimulation Transcranial magnetic stimulation (TMS) uses a magnetic field to cause electric current in an area of the brain. This can involve single-pulse TMS that can help identify brain function through cortical stimulation or repetitive TMS, which can lead to change in the brain functioning over a longer time. TMS over the motor cortex leads to activation of the target muscle which is recorded as a motor evoked potential (MEP) on electromyography (EMG).[26] It utilizes monophasic or biphasic pulses that result in rapidly changing magnetic fields, which in turn induce circular currents in a perpendicular plane to the direction of magnetic field. Surrounding extra-cerebral structures such as scalp, bone and meninges, can hamper the force produced by magnetic field and the resultant electrical field. Most of TMS data are derived from stimulation of the M1 area which activates the pyramidal tract indirectly through the recruitment of cortical interneurons.[27] Although the initial principle of TMS was based on low frequency or “inhibitory: and high frequency or “excitatory” stimulation, more recent studies have shown that this dichotomy may not always be true. Theta burst pattern and the pattern of delivery of stimulation, i.e., continuous vs intermittent also influenced the outcome with the former producing inhibitory effect (after the initial facilitation and faster saturation of effect) and latter producing facilitation.[28] There have been studies to demonstrate possible indirect mechanism of the “excitatory” and “inhibitory” stimulations that could be a result of decreased GABA mediated intracortical inhibition leading to motor excitability.[29],[30] There is Level C evidence of utility of high-frequency repetitive TMS of bilateral M1 in ameliorating some of the parkinsonian motor symptoms.[31],[32],[33] However, there are not enough RCTs to support utilization of this technology for PD. Vagal nerve stimulation Vagus nerve, which is tenth cranial nerve, has a major role in the regulation of autonomic function in the body. Vagus nerve stimulation (VNS) was the first neuromodulation technique approved by FDA in 1997 to treat partial-onset seizures. This process involves implanting of a generator subcutaneously in the left side of the upper chest or left axillary border. A wire connects this generator to the left vagus nerve at the mid-cervical level. Right vagus nerve is usually not used for stimulation due to innervation of sinoatrial node and the need for cardiac monitoring; however, it may be used per case reports in case left vagus nerve is not approachable or advisable.[34],[35] Once implanted, a patient programmer is used to change parameters including current (measured in milliamperes), pulse width (measured in microseconds), frequency (measured in Hertz) and on-off duty cycle (duration of stimulus being on or off in seconds or minutes). The settings are optimized depending on the clinical seizure control, and tolerability. The implanted generator may be switched on or off using the programmer, or by the patient by placing a wand over the generator. Surgical side effects may include complete or partial vocal cord paralysis. Stimulation side effects of the left vagal nerve may include local pain, paresthesia, cough, dyspnea, voice changes and dysphagia.[36] Per a metanalysis, patients that had undergone VNS placement had reduced seizure frequency by an average of 45% with 36% reduction in seizures at 3-12 months after surgery and 51% reduction after > 1 year of therapy. Posttraumatic epilepsy and tuberous sclerosis were positive predictors for a favorable outcome per this study.[37] Deep brain stimulation Deep brain stimulation (DBS) is a novel and a widely used technique to deliver constant current via electrodes in a specified region of interest in the brain usually involving deeper subcortical structures.[38] This affects the target and the corresponding neural network leading to myriad of physiological effects which can help relieve disease symptoms. It was officially approved by the US FDA for treatment of ET in 1997 (target at the ventero intermedius nucleus (Vim) in the thalamus), for PD (targets STN and GPi) in 2002, for dystonia under Humantiarian Device Exemption rule (target GPI) in 2003, obsessive-compulsive disorder (target anterior limb of internal capsule) in 2009 and for medication refractory epilepsy (target at the anterior nucleus of thalamus) in 2018. This technique has been clinically used for several other indications including but not limited to depression, addiction, Alzheimer disease, etc. Physiological effects of DBS To explain the effects of DBS various mechanism of actions have been proposed over the decades. The effects of DBS can be further categorized as being local on the cell body, dendrites and axons or distant from its influence on the basal ganglia–thalamo–cortical circuitry. One such mechanism included inhibitory action.[39],[40],[41] It was believed that this action was through depolarization block, which involved keeping the neuronal membrane depolarized below the threshold required to generate an action potential. However further studies demonstrated that the depolarization block did not explain all effects observed with DBS.[42] Some studies reported that DBS had excitatory effect especially on the afferent axons that projected to the target region.[43],[44],[45] This was also reported with increased flow of blood to the targeted region indicating activation rather than inhibition at the site.[46],[47] Additional studies showed the presence of body cell body inhibition from presynaptic axons and GABA release while efferent axon was activated.[48] Activation thresholds further vary depending on the structures with the lowest threshold in myelinated axons and higher threshold in the unmyelinated axons, dendrites and cell bodies.[49] DBS has also shown possible neurogenesis and neuroplasticity through inducing growth factors and gene expression[50],[51] [Figure 2]. Recently the more popular theory encompasses disruption of the pathological circuits and synchronized oscillations, which can lead to improvement of the clinical symptoms.[52],[53],[54],[55]
Parkinson disease and DBS Parkinson's disease which is characterized by resting tremor, cogwheel rigidity, bradykinesia as well as postural and gait abnormalities is a result of reduced dopaminergic neurons at the level of SN. Dopamine depletion is seen to unbalance the spiny projection neuron (SPN) activity rates and disrupt the movement-encoding – SPN clusters involved in the indirect pathway.[56] Electrophysiological studies have shown local field potentials (LFP) in these patients to be in the beta band (12-30 Hz). Spontaneous fluctuations of the beta activity have correlated with clinical symptoms including bradykinesia[57] while changes to the gamma (60-80 Hz) and high frequency (300 Hz) oscillations was seen with dopaminergic therapy. In the pathological off state the high-frequency oscillations amplitude was coupled with beta activity while in the on state this coupling is greatly reduced.[54],[55] Stimulation with high frequencies is believed to assist in the decoupling and alleviating parkinsonian symptoms. Both GPi and STN have proven to alleviate PD symptoms including tremor, bradykinesia and rigidity equally.[58] Further, there were no differences in efficacy at the three years follow up between either targets.[59] However one may consider GPi as a target for antidyskinetic effects in cases with dopamine-induced dyskinesia.[60] A meta-analysis done has shown that overall higher frequency stimulation (130-150 Hz) of the STN helps with tremor control, while lower frequency stimulations (60–80 Hz) have been seen to help other symptoms of PD including bradykinesia.[61],[62] Further higher voltage and narrower pulse width (30 microseconds) at the STN tend to produce better symptom control compared to low voltage or wide pulse width.[63] Dystonia and DBS Dystonia is characterized by sustained muscle contraction of a group of muscles that leads to abnormal posturing. This can arise from genetic causes such as TOR1A gene mutation as seen in DYT1 or from injury to the basal ganglia circuitry such as a vascular insult. It is commonly found to coexist with other heredodegenerative disorders including Huntington's disease, neuroacanthocytosis, Wilson's disease as well as PD to name a few. Physiological studies in dystonia have shown decreased activity in both Vim and ventralis oralis posterior (Vop) nuclei in the thalamus. There is some evidence to show that sensory input drives the activity of cells in Vim to produce dystonia in the setting of altered somatic sensory maps to multiple muscles. Further thalamic representation of individual joints was seen to be greater in dystonia. Pallidal activity has also been seen to be decreased in dystonia.[64] Another mechanism proposed to explain the phenomena has been that dystonia is a result of disruption of the inhibitory cortical pathways which leads to unchecked activation of muscle groups.[65],[66] Although basal ganglia has been implicated in its role in dystonia there is evidence of cerebellar control and modulation that further affects the faulty sensorimotor response in dystonia.[67] Connections between striatum and cerebellum have been established which further solidifies the role of aberrant efferent fibers in contributing to abnormal burst like activity in the basal ganglia.[68] High-frequency driving by DBS helps in disrupting the pathological activity in the cortico-basal ganglia-thalamic- cortical motor.[68],[69] Essential tremor and DBS ET comprises of rhythmic, involuntary movement of a part of the body including, limbs, trunk head or even voice. Pathological oscillations have been recorded in motor cortex as well as cotico-thalamic-circuitry which have been found to oscillate at tremor frequency.[70],[71],[72] Additionally, the cerebellothalamic bursting inputs seem to propagate thalamic tremor oscillations.[73] Although DBS provides significant improvement to tremor and quality of life for patients with ET there has been some evidence of treatment resistance and decreased responsiveness to the DBS.[74] However, whether this was a result of disease progression or effect of neural modulation from stimulation remains to be determined. Epilepsy and DBS DBS has recently been approved for treatment of drug-resistant epilepsy. Mechanisms that have been proposed for DBS therapy in epilepsy include potentiation or inhibition of the target which could help disrupt propagation of the seizure. High-frequency stimulation has been shown to disrupt synchronization and propagation of epileptiform activity.[75],[76] Anterior nucleus of thalamus, which is the target for DBS, is a part of the papez circuit and further helps in seizure occurrence and propagation. This is connected to other parts and deeper structures including cerebellum and STN. Further thalamo-cortical pathways also have shown to play a role in causing seizures and propagating them. Lesions in the pathway have been shown to suppress seizure activity.[77],[78] Hardware Implanted DBS lead is connected to the implantable pulse generator (IPG) through a connecting wire. Newer DBS systems are MRI compatible and patient has the option of choosing between rechargeable or non-rechargeable IPG. Each lead includes multiple contacts, which could serve as the anode or cathode for the circuit. Leads vary from encasing 4 to as many as 8 electrodes or contacts to provide good coverage of the intracranial target. The orientation and positioning of these contacts play a major role in the clinical programming. Medtronic system used lead models 3387 (40 cm long, 1.27 mm wide and 1.5 mm length and placed 1.5 mm apart) or lead model 3389 (same as above with the exception of spacing of 0.5 mm between each contact). Boston scientific Vercise system has directional electrode with 8 contacts (45 cm or 30 cm, diameter 1.3 mm, contact length 1.5 mm and contact spacing 2 mm). Abbott also provides directional leads (40 cm in length, contact length 1.5 mm and spacing 0.5 mm) which 3 segments in the middle two contacts. In the last decade, there has been a move to include the use of segmented directional leads in programming which would helping steering electric field. This could potentially reduce side effects while improving the therapeutic window for programming.[79] Further programming adjustments and local effect may be steered by altering configurations on the electrode and the subsequent local electric field that is generated. Closed loop Newer devices by Medtronic have capacity to record LFPs that are generated at the target locations. In this system, a sensor continuously records local field potentials which is correlated with symptomatology. These adaptive closed-loop DBS devices will be able to provide feedback and rapid response to real-time LFP changes.[80] This will lead to automated stimulation without the requirement of an external physician programmer. Side effects Stimulation of target location may lead to side effects depending on the fibers that get involved [Figure 3]. When the target location is STN the ideal location for target is in the dorsolateral aspect which is the motor territory in STN. Spread of current to neighboring structures may lead to capsular effects (laterally, anteriorly, superiorly), sensory changes (posteriorly), visual changes (capsular effect or cranial nerve III involvement), nausea, flushing (red nucleus), mood and personality changes (limbic area medially).[81]
Ideal location at the GPi is in the postero-ventral aspect of GPi. The side effects from stimulation may include capsular effects (medially and posteriorly) or phosphenes from stimulation of optic tract. Vim targeting and stimulation can lead to dysarthria, capsular effect (laterally), paresthesia (posteriorly) and ataxia (inferiorly).[81]
Neuromodulation has dramatically changed the disease outcome and quality of life in patients. There is ongoing research with use of different parameters and better programming techniques such as closed-loop system and remote programming. Newer target development may pave way to better disease management for neurodegenerative conditions. With the advancement and rapid adaptation of newer platforms, the role of neuromodulation such as DBS and programming is likely to transition to being easier and more feasible. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]
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