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Wednesday, October 16, 2024

Deep brain stimulation

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Deep_brain_stimulation
 
Deep brain stimulation
DBS-probes shown in X-ray of the skull (white areas around maxilla and mandible represent metal dentures and are unrelated to DBS devices)

Deep brain stimulation (DBS) is a surgical procedure that implants a neurostimulator and electrodes which sends electrical impulses to specified targets in the brain responsible for movement control. The treatment is designed for a range of movement disorders such as Parkinson's disease, essential tremor, and dystonia, as well as for certain neuropsychiatric conditions like obsessive-compulsive disorder (OCD) and epilepsy. The exact mechanisms of DBS are complex and not entirely clear, but it is known to modify brain activity in a structured way.

DBS has been approved by the Food and Drug Administration as a treatment for essential and Parkinsonian tremor and since 1997, and for Parkinson's disease (PD) since 2002. DBS was approved as humanitarian device excemptions for dystonia in 2003, obsessive–compulsive disorder (OCD) in 2009, and approved for epilepsy in 2018. DBS has been studied in clinical trials as a potential treatment for chronic pain, for various affective disorders, including major depression, for Alzheimer's Disease and drug addiction, among other brain disorders. It is one of few neurosurgical procedures that allow blinded studies.

As a first approximation, DBS is thought to mimic the clinical effects of lesioning, likely by attenuating (pathologically elevated) information flow through affected brain networks. Thus, DBS is thought to create an 'informational lesion', which can be switched off by turning off the DBS device, i.e. is largely reversible. This is a strong advantage compared to permanent brain lesions that are also applied to similar targets in similar conditions in the field of ablative stereotactic surgery.

Medical use

An adult male undergoing pre-op preparation for deep brain stimulation
Insertion of electrode during surgery using a stereotactic frame

DBS is FDA approved or has FDA device exemptions for treatment of Parkinson's Disease, dystonia, Essential Tremor, obsessive-compulsive disorder and epilepsy. In Europe, beyond these indications, a CE mark exists for treatment of Alzheimer's Disease, and while there had been a device exemption for OCD, as well, this has not been renewed. All other indications are considered investigational, i.e. carried out within medical studies under IRB approval. The table below summarizes FDA approvals.


Indication Approval Date Details DBS Target Evidence Source
Essential Tremor (or Parkinsonian Tremor) July 31, 1997 The FDA approved DBS for the suppression of tremor in the upper extremity in patients with essential tremor. Ventral intermediate nucleus of the thalamus (VIM) The approval was based on clinical trials showing significant tremor reduction with thalamic DBS in patients with essential tremor, demonstrating long-term efficacy and safety. The key study is. FDA
Parkinson's Disease January 14, 2002 Approved for advanced Parkinson’s disease symptoms not adequately controlled by medications. Subthalamic nucleus (STN) or internal globus pallidus (GPi) The key trial that led to approval is. Further large-scale randomized controlled trials such as, demonstrated the superiority of DBS in the subthalamic nucleus compared to best medical therapy, improving motor function and quality of life. FDA
Dystonia April 15, 2003 Granted under a Humanitarian Device Exemption (HDE) for the treatment of chronic, intractable primary dystonia, including generalized and segmental dystonia, hemidystonia, and cervical dystonia in patients seven years of age or above. Internal globus pallidus (GPi) The key evidence came from smaller clinical trials under the Humanitarian Device Exemption, where DBS significantly improved motor function in patients with primary dystonia. Prominent trials include. FDA
Obsessive-Compulsive Disorder February 19, 2009 Approved under HDE for adjunctive treatment of severe, treatment-resistant OCD. Nucleus Accumbens (NAc) Initial approval came under HDE based on evidence from smaller, open-label trials, such as, showing reductions in OCD symptoms in severe cases. FDA
Epilepsy April 27, 2018 Approved for bilateral stimulation of the anterior nucleus of the thalamus (ANT) as an adjunctive therapy to reduce the frequency of seizures in adults with partial-onset seizures. Anterior nucleus of the thalamus (ANT) The key evidence came from the SANTE trial, demonstrating a significant reduction in seizure frequency in patients receiving DBS. FDA

Parkinson's disease

DBS is used to manage some of the symptoms of Parkinson's disease that cannot be adequately controlled with medications. PD is treated by applying high-frequency (> 100 Hz) stimulation to target structures in the depth of the brain. Frequently used targets include the subthalamic nucleus (STN), internal pallidum (GPi) and ventrointermediate nucleus of the thalamus (VIM). The pedunculopontine nucleus has been used as an investigational target to treat freezing of gait.

DBS is recommended for people who have PD with motor fluctuations and tremors inadequately controlled by medication, or to those who are intolerant to medication, as long as they do not have severe neuropsychiatric problems. Four areas of the brain have been treated with neural stimulators in PD. Most DBS surgeries in routine practice target either the GPi or the STN, which, in prospective trials have been equally efficient in reducing motor symptoms, likely due to a shared network being stimulated with either target. General differences between targets are not easy to summarize, but often include the following:

  • DBS of the GPi has been shown to reduce uncontrollable movements called dyskinesias. This may sometimes allow a patient to take adequate (additional) quantities of medications (especially levodopa), thus leading to better control of symptoms.
  • DBS of the subthalamic nucleus has a more sudden effect on tremor (while effect on tremor in GPi is sometimes delayed). Also, studies associated STN-DBS with reductions in dopaminergic medication.
  • DBS of the VIM is mainly used to reduce shaking movements (tremor), and hence is, if at all, used in tremor-dominant variants of PD (and also to treat Essential Tremor).
  • Some studies suggested efficacy for DBS of the PPN in reducing freezing of gait, but results have been mixed and the target is not routinely used.

Selection of the correct DBS target is a complicated process. Multiple clinical characteristics are used to select the target including – identifying the most troublesome symptoms, the dose of levodopa that the patient is currently taking, the effects and side-effects of current medications and concurrent problems. Decisions are often made in multidisciplinary teams at specialized institutions.

Essential Tremor

ET is a neurological condition characterized by involuntary and rhythmic shaking and the most common movement disorder. ET was the first indication to be approved for DBS (alongside Parkinsonian tremor) and before DBS had a long history of being treated with ablative brain lesioning. Already in the first publication on the matter by the team of Alim Louis Benabid, it could be shown that frequencies above 100 Hz are most effective for cessation of tremor, while lower frequencies have less effect. In clinical practice, frequencies between 80 and 180 Hz are typically applied. DBS electrodes commonly target the ventrointermediate nucleus of the thalamus (VIM) or ventrally adjacent areas that have been referred to as parts of the zona incerta, or posterior thalamic area. Recent metaanalytical evidence suggests that multiple targets along the circuitry of the cerebellothalamic pathway (also referred to as the dentatorubrothalamic or dentatothalamic tract) are similarly effective, i.e. modulating the cerebellar inflows into the thalamus may be key for therapeutic efficacy, for a review see. Despite its success, DBS for ET is not without side effects, which can include speech difficulties and paresthesia. Similar if not the same surgical targets have been applied to treat ET using surgical lesioning in both historical but also modern context, for instance using MR-guided Focused Ultrasound, Gamma-Knife Radiosurgery or conventional radiofrequency lesioning. For instance, the annual volume of MRgFUS thalamotomies has recently overtaken the volume of DBS cases to treat ET.

Dystonia

DBS is also an established therapeutic option for individuals with dystonia, a movement disorder characterized by sustained or repetitive muscle contractions, resulting in abnormal postures and involuntary movements. DBS is effective in treating primary generalized dystonia, and also used for focal dystonias such as cervical dystonia and task-specific dystonias (e.g., writer’s cramp). In dystonia, marked effects can be reached by targeting the GPi using high frequency DBS, with large randomized trials demonstrating improvements of ~45% and significant improvements in quality of life within the first six months of treatment. Similar effects have been reported in open label trials that targeted the STN (but this target is investigational for dystonia). In contrast to some symptoms in Parkinson's Disease or Essential Tremor, improvements in dystonia are often described to appear over weeks to months. This delayed response is thought to reflect the complexity of motor circuits involved in dystonia and the long-term plastic changes required for symptom relief. Despite the slower onset, many patients experience lasting and meaningful reductions in dystonia-related disability. DBS for dystonia is generally considered safe, but like all neuromodulation therapies, it comes with potential risks, including infection, hardware complications, or stimulation-related side effects such as speech difficulties. Ongoing research aims to optimize DBS targeting and stimulation settings to enhance outcomes for individuals with different types of dystonia. Recent large-scale mapping efforts have suggested slightly different optimal target sites for various forms of dystonia, such as generalized vs. cervical or appendicular vs. axial phenotypes of the disorder, potentially due to differing parts of the motor system being involved in different forms. In an attempt to develop physiomarkers that could guide adaptive forms of deep brain stimulation, researchers have identified elevated synchrony in the theta band to be associated with symptom severity, which was found maximally expressed at optimal stimulation sites within the GPi.

Obsessive-Compulsive-Disorder

DBS for OCD was first attempted by the team of Bart Nuttin in 1999. Curiously, the year 1999 marked three innovations all published in the Lancet: The first attempt to treat Tourette's Syndrome by the team of Veerle Visser-Vandewalle, the aforementioned trial by Nuttin and a trial reporting on bilateral stimulation of dystonia by Joachim Krauss and colleagues. Of these, the study by Visser-Vandewalle is considered the first modern-day indication of DBS in neuropsychiatric indication (Tourette's Syndrome), making the trial by Nuttin for OCD the second. DBS for OCD received a humanitarian device exemption from the FDA in 2009. In Europe, the CE Mark for Deep Brain Stimulation (DBS) for Obsessive-Compulsive Disorder (OCD) was active from 2009 to 2022 but not renewed thereafter, which was likely not motivated by a lack of evidence but by a lack of monetary interests, which has led to expert letters calling for a 'crisis of access' above and beyond Europe.

Beyond the original target in the anterior limb of the internal capsule (ALIC), multiple target sites have been probed, such as the nucleus accumbens (sometimes subsumized with the ALIC as the ventral capsule/ventral striatum or VC/VS target), the bed nucleus of stria terminalis, the inferior thalamic peduncle and the anteromedial portion of the STN. Within the ALIC region, large probabilistic mapping trials have identified two distinct sites of maximum efficacy, one likely corresponding to 'hyperdirect' pathway inputs to the subthalamic nucleus and other midbrain regions, the other potentially corresponding to 'indirect' pathway projections within the same basal ganglia thalamocortical loop. A potential circuit structure that seems to combine most effective targets in both the ALIC and STN region has been identified and termed the OCD response tract by the group of Andreas Horn. Modulating this fiber tract system, which has been described as projections from dorsal anterior cingulate and ventrolateral prefrontal cortices to the subthalamic nucleus (and potentially other midbrain structures), as well as reciprocal thalamic projections to the same sites, has been robustly associated with optimal treatment response across multiple studies from various groups. In an attempt to develop physiomarkers that could guide adaptive forms of deep brain stimulation, researchers have thus far identified mixed evidence, such as elevated delta activity to negatively correlate with OCD symptoms or elevated alpha activity to positively correlate with OCD symptoms. In 2024, Provenza et al. analyzed a larger cohort of 12 individuals implanted to the same target and confirmed and extended this latter finding: Elevated theta/alpha power (9 Hz) correlated with most symptomatic states. Curiously, they were expressed in a strong circadian pattern that allowed a high degree of predictability.

Epilepsy

As many as 36.3% of epilepsy patients are drug-resistant, i.e. may not be sufficiently treated with medication alone. These patients are at risk for significant morbidity and mortality including sudden unexpected death in epilepsy (SUDEP). If a seizure focus (i.e. seizure onset zone) can be determined (using MRI and/or invasive stereo-EEG recordings) resective brain surgery that involves removing brain tissue with the ictal focus is generally preferred, since this may potentially lead to a curative outcome (i.e. a state where no seizures happen anymore). In cases where resective surgery is not an option, other neurosurgical options such as responsive neurostimulation (RNS), DBS, or vagus nerve stimulation may be considered. While RNS is a method that includes brain sensing and brain stimulation, i.e. represents a form of adaptive deep brain stimulation, classical forms of DBS are also applied, typically at the standard 130 Hz frequency. The anterior nucleus of the thalamus (ANT) is the most commonly targeted area in DBS for epilepsy and the only FDA approved target site (see above). This multicenter, randomized, controlled SANTE trial (Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy) demonstrated that DBS targeting the ANT significantly reduced seizure frequency in patients with medically refractory epilepsy. Over time, patients experienced sustained seizure reductions, with some achieving more than a 50% decrease in seizures. The SANTE trial has been a pivotal study, leading to the approval of ANT-DBS for epilepsy in many countries. This region plays a key role in the network of structures that propagate seizure activity.

Beyond the ANT, several other brain regions have been explored as potential DBS targets for epilepsy. These include:

  • Centromedian nucleus (CM): Located in the thalamus, CM-DBS has been used in some cases of generalized epilepsy, including Lennox-Gastaut syndrome. It targets the thalamocortical networks involved in seizure propagation and has been reported to help reduce seizure severity and frequency.
  • Hippocampus: Particularly in patients with temporal lobe epilepsy, hippocampal DBS has been investigated as an option due to its role in seizure propagation and memory function. Studies have generally shown promising results, particularly for temporal lobe seizures.
  • Subthalamic nucleus (STN): Commonly used in Parkinson’s disease, the STN has also been explored as a target for epilepsy due to its involvement in motor control and seizure modulation. Initial studies have shown seizure reduction, especially in patients with focal epilepsy.
  • Cerebellum: DBS of the cerebellum has been studied as a way to influence the modulation of neural circuits involved in epilepsy, although its use remains experimental.

Tourette syndrome

As mentioned above, the first DBS application for Tourette's Syndrome has been carried out by the team of Veerle Visser-Vandewalle in 1999. Building upon the ablative lesion cases carried out by Rolf Hassler and colleagues, Visser-Vandewalle chose the intersection between the centromedian, parafascicular and ventrooralis internus nuclei of the thalamus as her DBS target. Authors reported that, after surgery, tics disappeared and "a change in the patient’s character occurred in that he had become much more kind-hearted." DBS has been used experimentally in treating adults with severe Tourette syndrome who do not respond to conventional treatment. Despite widely publicized early successes, DBS remains a highly experimental procedure for treating Tourette's, and more study is needed to determine whether long-term benefits outweigh the risks. The procedure is well tolerated, but complications include "short battery life, abrupt symptom worsening upon cessation of stimulation, hypomanic or manic conversion, and the significant time and effort involved in optimizing stimulation parameters".

The procedure is invasive and expensive and requires long-term expert care. Benefits for severe Tourette's are inconclusive, considering the less robust effects of this surgery seen in the Netherlands. Tourette's is more common in pediatric populations, tending to remit in adulthood, so, in general, this would not be a recommended procedure for use on children. It may not always be obvious how to utilize DBS for a particular person because the diagnosis of Tourette's is based on a history of symptoms rather than an examination of neurological activity. Due to concern over the use of DBS in Tourette syndrome treatment, the Tourette Association of America convened a group of experts to develop recommendations guiding the use and potential clinical trials of DBS for TS.

Robertson reported that DBS had been used on 55 adults by 2011, remained an experimental treatment at that time, and recommended that the procedure "should only be conducted by experienced functional neurosurgeons operating in centres which also have a dedicated Tourette syndrome clinic". According to Malone et al. (2006), "Only patients with severe, debilitating, and treatment-refractory illness should be considered; while those with severe personality disorders and substance-abuse problems should be excluded." Du et al. (2010) say, "As an invasive therapy, DBS is currently only advisable for severely affected, treatment-refractory TS adults". Singer (2011) says, "pending determination of patient selection criteria and the outcome of carefully controlled clinical trials, a cautious approach is recommended". Viswanathan et al. (2012) say DBS should be used for people with "severe functional impairment that cannot be managed medically".

Major Depression

DBS has also been under investigational use for patients with treatment-resistant major depressive disorder (TRD), a condition in which individuals do not adequately respond to conventional therapies such as medication or psychotherapy. Following early endeavors of electrical brain stimulation starting in the 1950ies, the era of modern DBS for TRD started with the seminal study by Helen Mayberg and Andres Lozano which applied DBS to the subcallosal cingulate region (SCC, also referred to as Brodman Area 25). BA 25 is involved in the regulation of mood and implicated in the pathophysiology of depression. Initial and recent open-label studies showed promising results, with significant improvements in depressive symptoms for many patients.

Randomized controlled trials, such as those targeting the SCC and the ventral capsule/ventral striatum (VC/VS), have shown mixed outcomes, highlighting the complexity of DBS as a treatment for depression. Use of advanced imaging modalities such as diffusion-weighted imaging based tractography has led to the discovery of the so-called 'depression switch', the intersection of four bundles that allowed more deliberate targeting of DBS in the SCC area and improved results in additional open-label studies. More recently, it became possible to sense brain signals from the SCC region that allowed inferring states of depression which could potentially lead to adaptive deep brain stimulation for depression.

Despite these successes, mixed results in randomized trials has led to the exploration of alternative routes on how to personalize DBS therapy through better understanding of the brain networks involved in individual cases of depression. Based on personalization strategies established in surgical treatment of epilepsy (see above), research has begun to incorporate sEEG and intracranial recordings to map depression-relevant brain circuits and optimize stimulation parameters. Most notably, the studies by Scangos et al. (2020) and Sheth et al. (2022) explored personalized approaches to deep brain stimulation for TRD by utilizing intracranial recordings to tailor stimulation parameters. Scangos et al. demonstrated the effectiveness of mapping emotional and clinical responses to multi-site brain stimulation, revealing state-dependent and reproducible effects that offer proof of concept for circuit-specific neuromodulation. Sheth et al. also applied sEEG to map brain networks and optimize DBS settings in a 37-year-old patient, targeting the subcallosal cingulate and VC/VS area. This individualized approach led to the remission of depressive symptoms, showcasing the potential of sEEG-informed DBS as a platform for precise neuromodulation in psychiatric disorders.

Beyond the SCC and VC/VS, a third target includes the so-called 'superolateral branch' of the medial forebrain bundle (MFB). It is critical to mention that, as acknowledged by the original authors, the anatomical description of this bundle rather matches the one of the anterior limb of the internal capsule (see above) and takes a course within the capsule, rather than following a trans-hypothalamic route as known for the MFB proper. This target site was discovered serendipitously when a patient with Parkinson's Disease developed hypomania under subthalamic nucleus DBS. While this is not an uncommon side-effect of STN-DBS and alternative pathomechanisms have been suggested, the original investigators attributed the occurrence of hypomania to stimulation of a hitherto undescribed 'superolateral' branch of the MFB, which supposedly only exists in humans. While anatomical descriptions as well as supposed mechanisms for this target site have been debated, clinical effects of this DBS target in patients with TRD have been very promising and at times with sudden onset of symptom improvements in open-label studies.

Chronic pain

Stimulation of the periaqueductal gray and periventricular gray for nociceptive pain, and the internal capsule, ventral posterolateral nucleus, and ventral posteromedial nucleus for neuropathic pain has produced impressive results with some people, but results vary. One study of 17 people with intractable cancer pain found that 13 were virtually pain-free and only four required opioid analgesics on release from hospital after the intervention. Most ultimately did resort to opioids, usually in the last few weeks of life. DBS has also been applied for phantom limb pain.

Other clinical applications

Results of DBS in people with dystonia, where positive effects often appear gradually over a period of weeks to months, indicate a role of functional reorganization in at least some cases. The procedure has been tested for effectiveness in people with epilepsy that is resistant to medication. DBS may reduce or eliminate epileptic seizures with programmed or responsive stimulation.

DBS of the septal areas of persons with schizophrenia has resulted in enhanced alertness, cooperation, and euphoria. Persons with narcolepsy and complex-partial seizures also reported euphoria and sexual thoughts from self-elicited DBS of the septal nuclei.

Orgasmic ecstasy was reported with the electrical stimulation of the brain with depth electrodes in the left hippocampus at 3mA, and the right hippocampus at 1 mA.

In 2015, a group of Brazilian researchers led by neurosurgeon Erich Fonoff [pt] described a new technique that allows for simultaneous implants of electrodes called bilateral stereotactic procedure for DBS. The main benefits are less time spent on the procedure and greater accuracy.

In 2016, DBS was found to improve learning and memory in a mouse model of Rett syndrome. More recent (2018) work showed, that forniceal DBS upregulates genes involved in synaptic function, cell survival, and neurogenesis, making some first steps at explaining the restoration of hippocampal circuit function.

Adaptive Deep Brain Stimulation

Adaptive of Closed Loop Deep Brain Stimulation is a technique in which a steering signal influences when, with which amplitude or at which electrode contacts the DBS system is activated. This steering signal can be a physiological sensing signal, which is typically either recorded from the same implanted electrode or a cortical electrode/ECoG strip/grid. Alternatively, signals from wearables, that e.g. detect symptoms such as tremor, may be used to guide stimulation across time. The concept of adaptive deep brain stimulation is as old as the concept of electrical stimulation of the brain, itself, i.e. originates in the 1950ies-1960ies and was implemented by early pioneers such as Carl-Wilhelm Sem-Jacobsen, Natalia Bechtereva, José Delgado or Robert Heath. The reason these scientists came up with the concept so early was out of necessity: At the time, chronic stimulation as carried out in open-loop (conventional) DBS applications was not technically possible using fully implanted devices, since the battery technology at the time was not ready to do so. With the advent of 'modern' DBS as implemented by the team of Alim Louis Benabid, for decades, chronic, open-loop DBS became the dominant application. Here, pulses are emitted to the brain tissue in a fixed frequency (often 130 Hz) without sensing brain signals or other forms of a steering signal.It took until the 2010s, after a demonstration of efficacy of aDBS in the macaque by the team of Hagai Bergman in 2011, the first in-human application of aDBS was carried out by the team of Peter Brown in 2013, followed by the team of Alberto Priori in the same year. Since then, several companies, including Medtronic and Newronika have begun developing commercial applications of closed-loop DBS.

Adverse effects

Arteriogram of the arterial supply that can hemorrhage during DBS implantation

DBS carries the risks of major surgery, with a complication rate related to the experience of the surgical team. The major complications include hemorrhage (1–2%) and infection (3–5%).

The potential exists for neuropsychiatric side effects after DBS, including apathy, hallucinations, hypersexuality, cognitive dysfunction, depression, and euphoria. However, these effects may be temporary and related to (1) incorrect placement of electrodes, (2) open-loop VS closed-loop stimulation, meaning a constant stimulation or an A.I. monitoring delivery system and (3) calibration of the stimulator, so these side effects are potentially reversible.

Because the brain can shift slightly during surgery, the electrodes can become displaced or dislodged from the specific location. This may cause more profound complications such as personality changes, but electrode misplacement is relatively easy to identify using CT scan. Also, surgery complications may occur, such as bleeding within the brain. After surgery, swelling of the brain tissue, mild disorientation, and sleepiness are normal. After 2–4 weeks, a follow-up visit is used to remove sutures, turn on the neurostimulator, and program it.

Impaired swimming skills surfaced as an unexpected risk of the procedure; several Parkinson's disease patients lost their ability to swim after receiving deep brain stimulation.

Mechanisms

The exact mechanism of action of DBS is not known. A variety of hypotheses try to explain the mechanisms of DBS:

  1. Depolarization blockade: Electrical currents block the neuronal output at or near the electrode site.
  2. Synaptic inhibition: This causes an indirect regulation of the neuronal output by activating axon terminals with synaptic connections to neurons near the stimulating electrode.
  3. Desynchronization of abnormal oscillatory activity of neurons
  4. Antidromic activation either activating/blockading distant neurons or blockading slow axons

DBS represents an advance on previous treatments which involved pallidotomy (i.e., surgical ablation of the globus pallidus) or thalamotomy (i.e., surgical ablation of the thalamus). Instead, a thin lead with multiple electrodes is implanted in the globus pallidus, nucleus ventralis intermedius thalami, or subthalamic nucleus, and electric pulses are used therapeutically. The lead from the implant is extended to the neurostimulator under the skin in the chest area.

Its direct effect on the physiology of brain cells and neurotransmitters is currently debated, but by sending high-frequency electrical impulses into specific areas of the brain, it can mitigate symptoms and directly diminish the side effects induced by PD medications, allowing a decrease in medications, or making a medication regimen more tolerable.

Components and placement

The DBS system consists of three components: the implanted pulse generator (IPG), the lead, and an extension. The IPG is a battery-powered neurostimulator encased in a titanium housing, which sends electrical pulses to the brain that interfere with neural activity at the target site. The lead is a coiled wire insulated in polyurethane with four platinum-iridium electrodes and is placed in one or two different nuclei of the brain. The lead is connected to the IPG by an extension, an insulated wire that runs below the skin, from the head, down the side of the neck, behind the ear, to the IPG, which is placed subcutaneously below the clavicle, or in some cases, the abdomen.[19] The IPG can be calibrated by a neurologist, nurse, or trained technician to optimize symptom suppression and control side effects.

DBS leads are placed in the brain according to the type of symptoms to be addressed. For non-Parkinsonian essential tremor, the lead is placed in either the ventrointermediate nucleus of the thalamus or the zona incerta; for dystonia and symptoms associated with PD (rigidity, bradykinesia/akinesia, and tremor), the lead may be placed in either the globus pallidus internus or the subthalamic nucleus; for OCD and depression to the nucleus accumbens; for incessant pain to the posterior thalamic region or periaqueductal gray; and for epilepsy treatment to the anterior thalamic nucleus.

All three components are surgically implanted inside the body. Lead implantation may take place under local anesthesia or under general anesthesia ("asleep DBS"), such as for dystonia. A hole about 14 mm in diameter is drilled in the skull and the probe electrode is inserted stereotactically, using either frame-based or frameless stereotaxis. During the awake procedure with local anesthesia, feedback from the person is used to determine the optimal placement of the permanent electrode. During the asleep procedure, intraoperative MRI guidance is used for direct visualization of brain tissue and device. The installation of the IPG and extension leads occurs under general anesthesia. The right side of the brain is stimulated to address symptoms on the left side of the body and vice versa.

Neural engineering

From Wikipedia, the free encyclopedia

Neural engineering (also known as neuroengineering) is a discipline within biomedical engineering that uses engineering techniques to understand, repair, replace, or enhance neural systems. Neural engineers are uniquely qualified to solve design problems at the interface of living neural tissue and non-living constructs.

Overview

The field of neural engineering draws on the fields of computational neuroscience, experimental neuroscience, neurology, electrical engineering and signal processing of living neural tissue, and encompasses elements from robotics, cybernetics, computer engineering, neural tissue engineering, materials science, and nanotechnology.

Prominent goals in the field include restoration and augmentation of human function via direct interactions between the nervous system and artificial devices.

Much current research is focused on understanding the coding and processing of information in the sensory and motor systems, quantifying how this processing is altered in the pathological state, and how it can be manipulated through interactions with artificial devices including brain–computer interfaces and neuroprosthetics.

Other research concentrates more on investigation by experimentation, including the use of neural implants connected with external technology.

Neurohydrodynamics is a division of neural engineering that focuses on hydrodynamics of the neurological system.

History

The origins of neural engineering begins with Italian physicist and biologist Luigi Galvani. Galvani along with pioneers like Emil du Bois-Reymond discovered that electrical signals in nerves and muscles control movement, which marks the first understanding of the brain's electrical nature. As neural engineering is a relatively new field, information and research relating to it is comparatively limited, although this is changing rapidly. The first journals specifically devoted to neural engineering, The Journal of Neural Engineering and The Journal of NeuroEngineering and Rehabilitation both emerged in 2004. International conferences on neural engineering have been held by the IEEE since 2003, from 29 April until 2 May 2009 in Antalya, Turkey 4th Conference on Neural Engineering, the 5th International IEEE EMBS Conference on Neural Engineering in April/May 2011 in Cancún, Mexico, and the 6th conference in San Diego, California in November 2013. The 7th conference was held in April 2015 in Montpellier. The 8th conference was held in May 2017 in Shanghai.

Fundamentals

The fundamentals behind neuroengineering involve the relationship of neurons, neural networks, and nervous system functions to quantifiable models to aid the development of devices that could interpret and control signals and produce purposeful responses.

Neuroscience

Messages that the body uses to influence thoughts, senses, movements, and survival are directed by nerve impulses transmitted across brain tissue and to the rest of the body. Neurons are the basic functional unit of the nervous system and are highly specialized cells that are capable of sending these signals that operate high and low level functions needed for survival and quality of life. Neurons have special electro-chemical properties that allow them to process information and then transmit that information to other cells. Neuronal activity is dependent upon neural membrane potential and the changes that occur along and across it. A constant voltage, known as the membrane potential, is normally maintained by certain concentrations of specific ions across neuronal membranes. Disruptions or variations in this voltage create an imbalance, or polarization, across the membrane. Depolarization of the membrane past its threshold potential generates an action potential, which is the main source of signal transmission, known as neurotransmission of the nervous system. An action potential results in a cascade of ion flux down and across an axonal membrane, creating an effective voltage spike train or "electrical signal" which can transmit further electrical changes in other cells. Signals can be generated by electrical, chemical, magnetic, optical, and other forms of stimuli that influence the flow of charges, and thus voltage levels across neural membranes.

Engineering

Engineers employ quantitative tools that can be used for understanding and interacting with complex neural systems. Methods of studying and generating chemical, electrical, magnetic, and optical signals responsible for extracellular field potentials and synaptic transmission in neural tissue aid researchers in the modulation of neural system activity. To understand properties of neural system activity, engineers use signal processing techniques and computational modeling. To process these signals, neural engineers must translate the voltages across neural membranes into corresponding code, a process known as neural coding. Neural coding studies on how the brain encodes simple commands in the form of central pattern generators (CPGs), movement vectors, the cerebellar internal model, and somatotopic maps to understand movement and sensory phenomena. Decoding of these signals in the realm of neuroscience is the process by which neurons understand the voltages that have been transmitted to them. Transformations involve the mechanisms that signals of a certain form get interpreted and then translated into another form. Engineers look to mathematically model these transformations. There are a variety of methods being used to record these voltage signals. These can be intracellular or extracellular. Extracellular methods involve single-unit recordings, extracellular field potentials, and amperometry; more recently, multielectrode arrays have been used to record and mimic signals.

Scope

Neuromechanics

Neuromechanics is the coupling of neurobiology, biomechanics, sensation and perception, and robotics. Researchers are using advanced techniques and models to study the mechanical properties of neural tissues and their effects on the tissues' ability to withstand and generate force and movements as well as their vulnerability to traumatic loading. This area of research focuses on translating the transformations of information among the neuromuscular and skeletal systems to develop functions and governing rules relating to operation and organization of these systems. Neuromechanics can be simulated by connecting computational models of neural circuits to models of animal bodies situated in virtual physical worlds. Experimental analysis of biomechanics including the kinematics and dynamics of movements, the process and patterns of motor and sensory feedback during movement processes, and the circuit and synaptic organization of the brain responsible for motor control are all currently being researched to understand the complexity of animal movement. Dr. Michelle LaPlaca's lab at Georgia Institute of Technology is involved in the study of mechanical stretch of cell cultures, shear deformation of planar cell cultures, and shear deformation of 3D cell containing matrices. Understanding of these processes is followed by development of functioning models capable of characterizing these systems under closed loop conditions with specially defined parameters. The study of neuromechanics is aimed at improving treatments for physiological health problems which includes optimization of prostheses design, restoration of movement post injury, and design and control of mobile robots. By studying structures in 3D hydrogels, researchers can identify new models of nerve cell mechanoproperties. For example, LaPlaca et al. developed a new model showing that strain may play a role in cell culture.

Neuromodulation

Neuromodulation aims to treat disease or injury by employing medical device technologies that would enhance or suppress activity of the nervous system with the delivery of pharmaceutical agents, electrical signals, or other forms of energy stimulus to re-establish balance in impaired regions of the brain. Researchers in this field face the challenge of linking advances in understanding neural signals to advancements in technologies delivering and analyzing these signals with increased sensitivity, biocompatibility, and viability in closed loops schemes in the brain such that new treatments and clinical applications can be created to treat those with neural damage of various kinds. Neuromodulator devices can correct nervous system dysfunction related to Parkinson's disease, dystonia, tremor, Tourette's, chronic pain, OCD, severe depression, and eventually epilepsy. Neuromodulation is appealing as treatment for varying defects because it focuses in on treating highly specific regions of the brain only, contrasting that of systemic treatments that can have side effects on the body. Neuromodulator stimulators such as microelectrode arrays can stimulate and record brain function and with further improvements are meant to become adjustable and responsive delivery devices for drugs and other stimuli.

Neural regrowth and repair

Neural engineering and rehabilitation applies neuroscience and engineering to investigating peripheral and central nervous system function and to finding clinical solutions to problems created by brain damage or malfunction. Engineering applied to neuroregeneration focuses on engineering devices and materials that facilitate the growth of neurons for specific applications such as the regeneration of peripheral nerve injury, the regeneration of the spinal cord tissue for spinal cord injury, and the regeneration of retinal tissue. Genetic engineering and tissue engineering are areas developing scaffolds for spinal cord to regrow across thus helping neurological problems.

Research and applications

Research focused on neural engineering utilizes devices to study how the nervous system functions and malfunctions.

Neural imaging

Neuroimaging techniques are used to investigate the activity of neural networks, as well as the structure and function of the brain. Neuroimaging technologies include functional magnetic resonance imaging (fMRI), magnetic resonance imaging (MRI), positron emission tomography (PET) and computed axial tomography (CAT) scans. Functional neuroimaging studies are interested in which areas of the brain perform specific tasks. fMRI measures hemodynamic activity that is closely linked to neural activity. It is used to map metabolic responses in specific regions of the brain to a given task or stimulus. PET, CT scanners, and electroencephalography (EEG) are currently being improved and used for similar purposes.

Neural networks

Scientists can use experimental observations of neuronal systems and theoretical and computational models of these systems to create Neural networks with the hopes of modeling neural systems in as realistic a manner as possible. Neural networks can be used for analyses to help design further neurotechnological devices. Specifically, researchers handle analytical or finite element modeling to determine nervous system control of movements and apply these techniques to help patients with brain injuries or disorders. Artificial neural networks can be built from theoretical and computational models and implemented on computers from theoretically devices equations or experimental results of observed behavior of neuronal systems. Models might represent ion concentration dynamics, channel kinetics, synaptic transmission, single neuron computation, oxygen metabolism, or application of dynamic system theory. Liquid-based template assembly was used to engineer 3D neural networks from neuron-seeded microcarrier beads.

Neural interfaces

Neural interfaces are a major element used for studying neural systems and enhancing or replacing neuronal function with engineered devices. Engineers are challenged with developing electrodes that can selectively record from associated electronic circuits to collect information about the nervous system activity and to stimulate specified regions of neural tissue to restore function or sensation of that tissue (Cullen et al. 2011). The materials used for these devices must match the mechanical properties of neural tissue in which they are placed and the damage must be assessed. Neural interfacing involves temporary regeneration of biomaterial scaffolds or chronic electrodes and must manage the body's response to foreign materials. Microelectrode arrays are recent advances that can be used to study neural networks (Cullen & Pfister 2011). Optical neural interfaces involve optical recordings and optogenetics, making certain brain cells sensitive to light in order to modulate their activity. Fiber optics can be implanted in the brain to stimulate or silence targeted neurons using light, as well as record photon activity—a proxy of neural activity— instead of using electrodes. Two-photon excitation microscopy can study living neuronal networks and the communicatory events among neurons.

Brain–computer interfaces

Brain–computer interfaces seek to directly communicate with human nervous system to monitor and stimulate neural circuits as well as diagnose and treat intrinsic neurological dysfunction. Deep brain stimulation is a significant advance in this field that is especially effective in treating movement disorders such as Parkinson's disease with high frequency stimulation of neural tissue to suppress tremors (Lega et al. 2011).

Microsystems

Neural microsystems can be developed to interpret and deliver electrical, chemical, magnetic, and optical signals to neural tissue. They can detect variations in membrane potential and measure electrical properties such as spike population, amplitude, or rate by using electrodes, or by assessment of chemical concentrations, fluorescence light intensity, or magnetic field potential. The goal of these systems is to deliver signals that would influence neuronal tissue potential and thus stimulate the brain tissue to evoke a desired response.

Microelectrode arrays

Microelectrode arrays are specific tools used to detect the sharp changes in voltage in the extracellular environments that occur from propagation of an action potential down an axon. Dr. Mark Allen and Dr. LaPlaca have microfabricated 3D electrodes out of cytocompatible materials such as SU-8 and SLA polymers which have led to the development of in vitro and in vivo microelectrode systems with the characteristics of high compliance and flexibility to minimize tissue disruption.

Neural prostheses

Neuroprosthetics are devices capable of supplementing or replacing missing functions of the nervous system by stimulating the nervous system and recording its activity. Electrodes that measure firing of nerves can integrate with prosthetic devices and signal them to perform the function intended by the transmitted signal. Sensory prostheses use artificial sensors to replace neural input that might be missing from biological sources. Engineers researching these devices are charged with providing a chronic, safe, artificial interface with neuronal tissue. Perhaps the most successful of these sensory prostheses is the cochlear implant which has restored hearing abilities to the deaf. Visual prosthesis for restoring visual capabilities of blind persons is still in more elementary stages of development. Motor prosthetics are devices involved with electrical stimulation of biological neural muscular system that can substitute for control mechanisms of the brain or spinal cord. Smart prostheses can be designed to replace missing limbs controlled by neural signals by transplanting nerves from the stump of an amputee to muscles. Sensory prosthetics provide sensory feedback by transforming mechanical stimuli from the periphery into encoded information accessible by the nervous system. Electrodes placed on the skin can interpret signals and then control the prosthetic limb. These prosthetics have been very successful. Functional electrical stimulation (FES) is a system aimed at restoring motor processes such as standing, walking, and hand grasp.

Neurorobotics

Neurorobotics is the study of how neural systems can be embodied and movements emulated in mechanical machines. Neurorobots are typically used to study motor control and locomotion, learning and memory selection, and value systems and action selection. By studying neurorobots in real-world environments, they are more easily observed and assessed to describe heuristics of robot function in terms of its embedded neural systems and the reactions of these systems to its environment. For instance, making use of a computational model of epilectic spike-wave dynamics, it has been already proven the effectiveness of a method to simulate seizure abatement through a pseudospectral protocol. The computational model emulates the brain connectivity by using a magnetic imaging resonance from a patient with idiopathic generalized epilepsy. The method was able to generate stimuli able to lessen the seizures.

Neural tissue regeneration

Neural tissue regeneration, or neuroregeneration looks to restore function to those neurons that have been damaged in small injuries and larger injuries like those caused by traumatic brain injury. Functional restoration of damaged nerves involves re-establishment of a continuous pathway for regenerating axons to the site of innervation. Researchers like Dr. LaPlaca at Georgia Institute of Technology are looking to help find treatment for repair and regeneration after traumatic brain injury and spinal cord injuries by applying tissue engineering strategies. Dr. LaPlaca is looking into methods combining neural stem cells with an extracellular matrix protein based scaffold for minimally invasive delivery into the irregular shaped lesions that form after a traumatic insult. By studying the neural stem cells in vitro and exploring alternative cell sources, engineering novel biopolymers that could be utilized in a scaffold, and investigating cell or tissue engineered construct transplants in vivo in models of traumatic brain and spinal cord injury, Dr. LaPlaca's lab aims to identify optimal strategies for nerve regeneration post injury.

Current approaches to clinical treatment

End to end surgical suture of damaged nerve ends can repair small gaps with autologous nerve grafts. For larger injuries, an autologous nerve graft that has been harvested from another site in the body might be used, though this process is time-consuming, costly and requires two surgeries. Clinical treatment for CNS is minimally available and focuses mostly on reducing collateral damage caused by bone fragments near the site of injury or inflammation. After swelling surrounding injury lessens, patients undergo rehabilitation so that remaining nerves can be trained to compensate for the lack of nerve function in injured nerves. No treatment currently exists to restore nerve function of CNS nerves that have been damaged.

Engineering strategies for repair

Engineering strategies for the repair of spinal cord injury are focused on creating a friendly environment for nerve regeneration. Only Peripheral PNS nerve damage has been clinically possible so far, but advances in research of genetic techniques and biomaterials demonstrate the potential for SC nerves to regenerate in permissible environments.

Grafts

Advantages of autologous tissue grafts are that they come from natural materials which have a high likelihood of biocompatibility while providing structural support to nerves that encourage cell adhesion and migration.[13] Nonautologous tissue, acellular grafts, and extracellular matrix based materials are all options that may also provide ideal scaffolding for nerve regeneration. Some come from allogenic or xenogenic tissues that must be combined with immunosuppressants. while others include small intestinal submucosa and amniotic tissue grafts.Synthetic materials are attractive options because their physical and chemical properties can typically be controlled. A challenge that remains with synthetic materials is biocompatibility. Methylcellulose-based constructs have been shown to be a biocompatible option serving this purpose. AxoGen uses a cell graft technology AVANCE to mimic a human nerve. It has been shown to achieve meaningful recovery in 87 percent of patients with peripheral nerve injuries.

Nerve guidance channels

Nerve guidance channels, Nerve guidance conduit are innovative strategies focusing on larger defects that provide a conduit for sprouting axons directing growth and reducing growth inhibition from scar tissue. Nerve guidance channels must be readily formed into a conduit with the desired dimensions, sterilizable, tear resistant, and easy to handle and suture. Ideally they would degrade over time with nerve regeneration, be pliable, semipermeable, maintain their shape, and have a smooth inner wall that mimics that of a real nerve.

Biomolecular therapies

Highly controlled delivery systems are needed to promote neural regeneration. Neurotrophic factors can influence development, survival, outgrowth, and branching. Neurotrophins include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5). Other factors are ciliary neurotrophic factor (CNTF), glial cell line-derived growth factor (GDNF) and acidic and basic fibroblast growth factor (aFGF, bFGF) that promote a range of neural responses. Fibronectin has also been shown to support nerve regeneration following TBI in rats. Other therapies are looking into regeneration of nerves by upregulating regeneration associated genes (RAGs), neuronal cytoskeletal components, and antiapoptosis factors. RAGs include GAP-43 and Cap-23, adhesion molecules such as L1 family, NCAM, and N-cadherin. There is also the potential for blocking inhibitory biomolecules in the CNS due to glial scarring. Some currently being studied are treatments with chondroitinase ABC and blocking NgR, ADP-ribose.

Delivery techniques

Delivery devices must be biocompatible and stable in vivo. Some examples include osmotic pumps, silicone reservoirs, polymer matrices, and microspheres. Gene therapy techniques have also been studied to provide long-term production of growth factors and could be delivered with viral or non-viral vectors such as lipoplexes. Cells are also effective delivery vehicles for ECM components, neurotrophic factors and cell adhesion molecules. Olfactory ensheathing cells (OECs) and stem cells as well as genetically modified cells have been used as transplants to support nerve regeneration.

Advanced therapies

Advanced therapies combine complex guidance channels and multiple stimuli that focus on internal structures that mimic the nerve architecture containing internal matrices of longitudinally aligned fibers or channels. Fabrication of these structures can use a number of technologies: magnetic polymer fiber alignment, injection molding, phase separation, solid free-form fabrication, and ink jet polymer printing.

Neural enhancement

Augmentation of human neural systems, or human enhancement using engineering techniques is another possible application of neuroengineering. Deep brain stimulation has already been shown to enhance memory recall as noted by patients currently using this treatment for neurological disorders. Brain stimulation techniques are postulated to be able to sculpt emotions and personalities as well as enhance motivation, reduce inhibitions, etc. as requested by the individual. Ethical issues with this sort of human augmentation are a new set of questions that neural engineers have to grapple with as these studies develop.

Tuesday, October 15, 2024

Neurophysics

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Neurophysics

Neurophysics (or neurobiophysics) is the branch of biophysics dealing with the development and use of physical methods to gain information about the nervous system. Neurophysics is an interdisciplinary science using physics and combining it with other neurosciences to better understand neural processes. The methods used include the techniques of experimental biophysics and other physical measurements such as EEG mostly to study electrical, mechanical or fluidic properties, as well as theoretical and computational approaches. The term "neurophysics" is a portmanteau of "neuron" and "physics".

Among other examples, the theorisation of ectopic action potentials in neurons using a Kramers-Moyal expansion and the description of physical phenomena measured during an EEG using a dipole approximation use neurophysics to better understand neural activity.

Another quite distinct theoretical approach considers neurons as having Ising model energies of interaction and explores the physical consequences of this for various Cayley tree topologies and large neural networks. In 1981, the exact solution for the closed Cayley tree (with loops) was derived by Peter Barth for an arbitrary branching ratio and found to exhibit an unusual phase transition behavior in its local-apex and long-range site-site correlations, suggesting that the emergence of structurally-determined and connectivity-influenced cooperative phenomena may play a significant role in large neural networks.

Recording techniques

Old techniques to record brain activity using physical phenomena are already widespread in research and medicine. Electroencephalography (EEG) uses electrophysiology to measure electrical activity within the brain. This technique, with which Hans Berger first recorded brain electrical activity on a human in 1924, is non-invasive and uses electrodes placed on the scalp of the patient to record brain activity. Based on the same principle, electrocorticography (ECoG) requires a craniotomy to record electrical activity directly on the cerebral cortex.

In the recent decades, physicists have come up with technologies and devices to image the brain and its activity. The Functional Magnetic Resonance Imaging (fMRI) technique, discovered by Seiji Ogawa in 1990, reveals blood flow changes inside the brain. Based on the existing medical imaging technique Magnetic Resonance Imaging (MRI) and on the link between the neural activity and the cerebral blood flow, this tool enables scientists to study brain activities when they are triggered by a controlled stimulation. Another technique, the Two Photons Microscopy (2P), invented by Winfried Denk (for which he has been awarded the Brain Prize in 2015), John H. Strickler and Watt W. Webb in 1990 at Cornell University, uses fluorescent proteins and dyes to image brain cells. This technique combines the two-photon absorption, first theorized by Maria Goeppert-Mayer in 1931, with lasers. Today, this technique is widely used in research and often coupled with genetic engineering to study the behavior of a specific type of neuron.

Theories of consciousness

Consciousness is still an unknown mechanism and theorists have yet to come up with physical hypotheses explaining its mechanisms. Some theories rely on the idea that consciousness could be explained by the disturbances in the cerebral electromagnetic field generated by the action potentials triggered during brain activity. These theories are called electromagnetic theories of consciousness. Another group of hypotheses suggest that consciousness cannot be explained by classical dynamics but with quantum mechanics and its phenomena. These hypotheses are grouped into the idea of quantum mind and were first introduced by Eugene Wigner.

Neurophysics institutes

Awards

Among the list of prizes that reward neurophysicists for their contribution to neurology and related fields, the most notable one is the Brain Prize, whose last laureates are Adrian Bird and Huda Zoghbi for "their groundbreaking work to map and understand epigenetic regulation of the brain and for identifying the gene that causes Rett syndrome". The other most relevant prizes that can be awarded to a neurophysicist are: the NAS Award in the Neurosciences, the Kavli Prize and to some extent the Nobel Prize in Physiology or Medicine. It can be noted that a Nobel Prize was awarded to scientists that developed techniques which contributed widely to a better understanding of the nervous system, such as Neher and Sakmann in 1991 for the patch clamp, and also to Lauterbur and Mansfield for their work on Magnetic resonance imaging (MRI) in 2003.

Operator (computer programming)

From Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Operator_(computer_programmin...