Clinical aspects

Indications

Neuromodulation techniques for direct stimulation of are used for neurologic disorders as well as some nonneurologic disorders to improve upon current management with the following objectives:

Table 2 shows indications for neuromodulation.

Table 2. Indications for Neuromodulation

Epilepsy. Several neuromodulation techniques have been used as adjuncts for the treatment of intractable seizures. These include anterior thalamic deep brain stimulation, vagus nerve stimulation, trigeminal nerve stimulation, ultrasound, and optical release of antiepileptic drugs.

Closing the loop in epilepsy. Closed loop systems may provide new options for treatment of patients with intractable seizures who are not surgical candidates. Responsive neurostimulation involves an implanted neurostimulator and intracranial leads that detect incipient seizures and respond with electrical counterstimulation by vagus nerve stimulation. Responsive neurostimulation was approved by the FDA in 2013 and over 1800 patients were treated with responsive neurostimulation during the 5 years following its approval (21). A retrospective study on patients with drug-resistant epilepsy from a neuromodulation clinic of an epilepsy center has reported a more than 60% decrease in seizure frequency in 44% to 69% of patients during the 19-month study period (16).

Early prediction or detection of seizures improves seizure control by limiting the therapy to times when the patient is in need. Closed loop seizure therapies may enable stronger therapy doses that cannot be delivered chronically. Target for stimulation may be an area with neuromodulatory effects, eg, the superior anterior nucleus of the thalamus. Potential alternatives to electrical stimulation include optogenetics, biofeedback, focal cooling, and optical release of antiepileptic drugs.

Ultrasound in epilepsy. Preliminary clinical experiences and research studies with magnetic resonance-guided focused ultrasound have shown promising results, and reversible opening of the blood-brain barrier enables targeted delivery of antiepileptic drugs leading to the use of terms such as “sononeuromodulation” and “targeted therapeutics” for epilepsy (28).

Auditory neuromodulation in epilepsy. Results of a randomized study have shown reduction in seizures through daily listening to Mozart K.448 in adult individuals with epilepsy (27). This an example of auditory neuromodulation and can be used as adjunct therapy in epilepsy. Exploring the potential mechanism behind the observed effect, in addition to designing studies that include a control stimulus containing rhythmicity, are some of the suggested topics to be investigated in future.

Essential tremor. Although there are numerous devices for tremor based on control of the movements of muscles and joints, there are fewer neuromodulation approaches used for the management of essential tremor. Essential tremor was the original indication for deep brain stimulation and several modifications are still the most used methods for control of medication-refractory tremor.

A study on a rat model of essential tremor has shown the feasibility of obtaining significant reduction or suppression of tremor by application of nonthermal, noninvasive, reversible focused ultrasound (31).

Alzheimer disease. Neuromodulation techniques for Alzheimer disease include the following:

Deep brain stimulation. Targeting of memory circuits via stereotaxic deep brain stimulation for Alzheimer disease has attracted the interest of many experts as there is an association between memory deficits and defects of the integrated neuronal cortical areas known collectively as the default mode network (25). Amyloid deposits or other molecular abnormalities seen in patients with Alzheimer disease may interfere with this network and disrupt neuronal circuits beyond the localized brain areas. The rationale and evidence to support the study of deep brain stimulation of the hippocampal fornix as a novel treatment to improve neuronal circuitry within these integrated networks has been provided by results of deep brain stimulation of the fornix in open studies where PET imaging was used to show that this therapy was effective in reversing impaired glucose utilization in the temporal and parietal lobes and thereby sustaining memory function in early Alzheimer disease. The ADvance Trial was a multicenter, 12-month, double-blind, randomized study to evaluate the safety, efficacy, and tolerability of deep brain stimulation of the fornix in patients with mild, probable Alzheimer disease. Results showed that targeting of deep brain stimulation to the fornix without direct injury is feasible, and at 90 days after surgery, the procedure was well tolerated (26). There was evidence of regeneration of hippocampus after deep brain stimulation therapy but the trial failed a futility analysis. A study restricted to patients over the age of 65, who seemed to perform better in the ADVANCE clinical trial, started in 2016 (20). It is titled “A Twelve Month Double-Blind Randomized Controlled Feasibility Study to Evaluate the Safety, Efficacy and Tolerability of Deep Brain Stimulation of the Fornix (DBS-f) in Patients With Mild Probable Alzheimer Disease” (NCT01608061). The memory flashbacks from brain stimulation observed in this trial may provide information regarding the neuroanatomical substrates and pathways of memory encoding and retrieval (08).

So far deep brain stimulation has proven effective in regions where stimulation produces a predictable functional change. The hippocampus and entorhinal cortex have a diverse functional anatomy, including heterogeneous neurons with widespread projections that represent different types of behavioral information. In a study on Alzheimer disease patients receiving fornix deep brain stimulation for 1 year, MRI showed that mean hippocampal atrophy was significantly slower in the deep brain stimulation group than the matched Alzheimer disease group (29). A series of experiments were performed to more fully characterize the effects of deep brain stimulation in the medial temporal lobe on human memory (15). Neurosurgical patients with implanted electrodes performed spatial and verbal-episodic memory tasks. During the encoding periods of both tasks, subjects received electrical stimulation at 50 Hz. In contrast to earlier work, electrical stimulation impaired memory performance significantly in both spatial and verbal tasks. Stimulation in both the entorhinal region and hippocampus caused decreased memory performance. These findings indicate that the entorhinal region and hippocampus are causally involved in human memory and suggest that refined methods are needed to use deep brain stimulation in these regions to improve memory. It may be helpful to refine the types of stimulation parameters that are used, perhaps by measuring ongoing brain activity or by refining stimulation targets based on individualized interregion connectivity patterns.

Transcranial magnetic stimulation. Transcranial magnetic stimulation has been used to assess neuroplastic changes in Alzheimer disease, corroborating findings that cortical physiology is altered due to the underlying neurodegenerative process. Combination of transcranial magnetic stimulation with other neurophysiological techniques, such as high-density EEG, enables one to study local and network cortical plasticity directly. Furthermore, transcranial magnetic stimulation can influence brain function if delivered repetitively; repetitive transcranial magnetic stimulation (rTMS) can modulate cortical excitability and inducing long-lasting neuroplastic changes. Preliminary findings indicate that rTMS can enhance performances on several cognitive functions impaired in Alzheimer disease and mild cognitive impairment (24). However, further well-controlled studies with appropriate methodology in larger patient cohorts are needed to replicate and extend the initial findings. A novel coil design (H2) for rTMS of deep brain structures leads to increased secretion of BDNF that promotes nerve-cell survival and growth and is undergoing a phase 2 clinical trial in Alzheimer disease (NCT02204969).

Ultrasound. After demonstration of safety and dose-dependent neuromodulation by transcranial pulse stimulation in preclinical studies, in vivo modulation of somatosensory evoked potentials in healthy subjects, a pilot clinical study including neuropsychological scores and fMRI was conducted in patients with Alzheimer disease (03). Improvement of neuropsychological scores was significant after transcranial pulse stimulation, lasted up to 3 months, and correlated with an upregulation of the memory network. The results encourage randomized sham-controlled clinical studies with potential for translation of the method into clinical therapy.

Vagus nerve stimulation. Vagus nerve stimulation is an established treatment method for therapy-refractory epilepsy and, in Europe, for treatment-resistant depression as well. Its effect on memory was noted during treatment of epilepsy and investigated further. In a clinical trial in 2002, vagus nerve stimulation administered after learning significantly enhanced memory by verbal learning, confirming the hypothesis in humans that vagus nerve activation modulates memory formation similarly to arousal. Two current clinical trials are evaluating transcutaneous vagus nerve stimulation for Alzheimer disease, which can now be performed without surgery by transcutaneous stimulation of the auricular branch of the vagus nerve with electrodes on the external ear: (1) A pseudo-randomized, cross-over clinical trial is investigating effects of vagus nerve stimulation of locus coeruleus, the sole source of noradrenalin to the brain, a neurotransmitter involved in arousal, which is the likely site of the onset of Alzheimer disease (ClinicalTrials.gov); (2) A randomized, crossover trial of vagus nerve stimulation versus sham stimulation in patients with mild cognitive impairment to assess enhancement of cognitive performance (ClinicalTrials.gov).

Multiple system atrophy. Cerebellar modulation by low-frequency rTMS can resolve the abnormal cortical excitability in patients with multiple system atrophy-cerebellar subtype C. In results of a study on multiple system atrophy-cerebellar subtype C patients, the pathological disinhibition and reaction time showed an improvement because cerebellar rTMS impairs abnormal cerebellar-cortical inhibitory connections (36).

Pain management. Neuromodulation is being used for several painful conditions.

Chronic pain and neuropathic pain. Both noninvasive and invasive techniques are used for chronic pain relief as well as neuropathic pain. Noninvasive stimulation techniques include transcutaneous electrical nerve stimulation, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, remote electrical neuromodulation, and vagus nerve stimulation. Invasive stimulation techniques include occipital nerve stimulation, vagus nerve stimulation, epidural motor cortex stimulation, spinal cord stimulation, and deep brain stimulation. The clinical benefit of closed loop devices over open loop for relief of chronic pain is not proven yet may be of interest in the future (22).

A systematic review of publications on the neuromodulating effect of transcranial direct current stimulation on neuropathic pain showed significant effects when compared to the control group, except for 1 study on spinal cord injury and another related to radiculopathy (07). However, no definite conclusion on the efficacy neuromodulating effect was reached due to lack of good quality studies, variations in the number of sessions, and diversity of results.

New targets such as dorsal root ganglion, as well as high-frequency and patterned stimulation methods such as burst stimulation, are leading the way to better clinical outcomes. In the future, neural sensing, novel target-specific stimulation patterns, and approaches may be combined with neuromodulation therapies to significantly impact how neuromodulation is used (10).

Migraine. Approved neuromodulation methods for migraine include:

Chronic low backache. In 2020, the FDA approved ReActiv8, an implantable neuromodulation system, for the management of intractable chronic low back pain associated with multifidus muscle dysfunction, based on the results of a controlled clinical trial. Backache was assessed by imaging and physiological testing in adults who had failed physical therapy, did not respond to pain medications, and were not candidates for spine surgery.

Sleep disorders. Neurostimulation for sleep disorders is covered in a separate MedLink Neurology article. An important application is obstructive sleep apnea. The most common sleep disorder for which neuromodulation is under investigation is insomnia.

Obstructive sleep apnea. Hypoglossal nerve stimulation, a minimally invasive procedure, is well tolerated for the treatment of obstructive sleep apnea because it is a motor nerve and has shown a success rate of more than 80% (37). Patients generally prefer it over continuous positive airway pressure therapy.

Sleep enhancement by close loop neuromodulation. Auditory stimulation using precisely timed tones played during deep sleep, when neurons are most synchronized, is known to improve deep sleep. The noninvasive wearable device, based on SleepLoop technology (https://sleeploop.ch/), is in development at the University of Zurich. It enables safe brain activity recording and stimulation with temporal precision during selected sleep stages. Algorithms based on underlying brain activity are used to control and optimize stimulation to maximally enhance brain activity during deep sleep. This technology is in clinical trials in Switzerland prior to regulatory approval.

Vestibular nerve stimulation for sleep improvement. The stimulation is delivered through a headset that is worn for 30 minutes before going to bed with no need to wear it in bed. It works by sending a safe electrical pulse into the vestibular nerve that influences the areas of the hypothalamus (suprachiasmatic nucleus) and thalamus (intergeniculate leaflet) that control the user’s circadian rhythm and sleep-wake cycle. In an open study, stimulation of the vestibular nerve was shown to have a positive impact on Insomnia Severity Index scores when delivered on a regular basis prior to sleep onset (12). The device is in commercial development.

Major depressive disorder (MDD). Deep brain stimulation is a promising treatment for severe major depressive disorder, but lack of efficacy in randomized trials raises questions regarding anatomical targeting. In a case study, effects of mild stimulation of several mood-related brain sites were mapped in a patient with severe treatment-resistant depression (30). Results showed that stimulation at different sites could alleviate distinct symptoms, such as reducing anxiety, boosting energy levels, or restoring pleasure in everyday activities; the benefits of different stimulation sites depended on the patient's mental state at the time. Results provide proof of concept for a personalized, circuit-specific method of treatment in psychiatry.

Non-implantable neuromodulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation are being increasingly considered for treatment of major depressive disorder in patients that do not respond to multiple medication trials and psychotherapy. NeuroStar Advanced Therapy System, a transcranial magnetic stimulation device for major depressive disorder, has received FDA’s Breakthrough Device Designation for the treatment of bipolar depression in patients who do not respond to medications and is intended to help patients as well as healthcare providers to receive more timely access to breakthrough technologies that have the potential to provide more effective treatment of irreversibly debilitating diseases. This designation creates an expedited pathway for prioritized FDA review.

Use of convulsive modalities is limited by their cognitive side effects. The efficacy of nonconvulsive techniques is still modest. Effects of nonimplantable neuromodulation can be enhanced by being combined with individualized cognitive interventions and closed-loop approaches and by identifying biomarkers, using computer electric field modeling to guide targeting, and using machine learning algorithms to integrate data collected at multiple biological levels to identify clinical responders (05).

Obsessive-compulsive behavior. Obsessive-compulsive behavior is characterized as maladaptive habit learning, which may be associated with abnormal beta-gamma rhythm of the orbitofrontal-striatal circuitry during reward processing. Based on this concept, a study modulated the orbitofrontal cortex with an alternating current, personalized to the intrinsic beta-gamma frequency of the reward network, and it demonstrated rapid, reversible, frequency-specific modulation of reward, but not punishment-guided choice behavior and learning (13). Furthermore, chronic application of the procedure over 5 days improved obsessive-compulsive behavior for 3 months, with the largest benefits for individuals with more severe symptoms. Mechanism underlying this effect provides the basis for the development of personalized circuit-based therapeutics for obsessive-compulsive disorders.

Implanted neuromodulation device survival and duration of relief. A retrospective analysis has evaluated the long-term (up to 15 years) rate of failure of implanted devices and duration of therapeutic benefit for several neuromodulation therapies in a large series of patients (32). Their results show higher device survival rates for deep brain stimulation and vagus nerve stimulation than for spinal cord stimulation. With all neuromodulation procedures, there was continued therapeutic benefit beyond initial device failures. This is an important point to emphasize when counseling patients.

Ethical aspects of neuromodulation. There are no official ethical guidelines for neuromodulation. Ethical issues pertaining to cranial nerve modulation implants cover informed consent, particularly for investigative studies, risk-benefit assessments, and security against unauthorized reprogramming of the devices (14).

There is a concern for nontherapeutic applications of some of the technologies, eg, enhancement to improve human traits and skills beyond a “normal” level of education, improve cognitive skills related to memory and learning, and to further problem-solving capacities. Nonmedical uses may be recreational or for enhancement of fighting capabilities of soldiers.

Contraindications

Not relevant as the article deals with multiple procedures on multiple indications and contraindication, if any, would be described with each technique.

Outcomes

Not relevant as the article deals with multiple procedures on multiple indications and results are described with each technique.

Adverse effects

Not relevant as the article deals with multiple procedures on multiple indications and adverse effects, if any, are described with each technique.

Scientific basis

Not relevant as the article deals with multiple procedures on multiple indications and scientific basis is described with each technique.

Future of neuromodulation. There is increased adoption of remote monitoring of brain function as a result of the current surge in teleneurology. In the next few years several devices for neuromodulation will be commercially available. Many of these will use wearable neurotechnology to manage chronic neurodegenerative and psychiatric conditions. Monitoring of brain signals at-home will only grow in importance as we improve our understanding of the links between brain signals and neuropsychiatric disorders. Closed loop systems will be used for noninvasive neuromodulation.