Deep brain stimulation, vagal nerve stimulation and transcranial stimulation: An overview of stimulation parameters and neurotransmitter release

Neurological disorders are among the most challenging medical problems faced by science today. To treat these disorders more effectively, new technologies are being developed by reviving old ideas such as brain stimulation. This review aims to compile stimulation techniques that are currently in use to explore or treat neurological disorders. Transcranial magnetic stimulation is a non-invasive method of modulating neuronal activity with induced electric currents. Other more invasive methods, such as deep brain stimulation and vagal nerve stimulation, use implanted probes to introduce brain activity alterations. Scientific and clinical applications have largely preceded the development of extensive animal models, presenting a challenge for researchers. This has left researchers with information on alleviating symptoms in humans but without solid research as to the mechanisms and neurobiological effects of the devices. This review combines stimulation parameters developed in animal models and stimulation techniques used in human treatment; thus, resulting in a greater understanding of the mechanisms and neurobiological effects of neuromodulation devices.     

Continuous dopaminergic stimulation,pulsatile dopaminergic stimulation

Levodopa is the gold standard treatment for Parkinson's disease. The therapeutic effect may however be compromised by the inevitable risk of motor complications, with fluctuating motor control and dyskinesia, particularly in the younger patient. The Multiple pathophysiological mechanisms are undoubtedly involved but pulsed dopaminergic stimulation appears to play a determining role. This underlines the importance of a treatment which achieves a most stable and physiological dopaminergic stimulation as possible. Dopaminergic agonists provide a promising alternative. Another possibility is to modulate the peripheral kinetics of levodopa as soon as it is introduced using catechol-O-methyl transferase inhibitors.     

Brain stimulation procedures. Transcranial magnetic stimulation, magnetic seizure therapy and deep brain stimulation

Brain stimulation methods are promising treatment options in severe treatment-resistant psychiatric disorders. A safe and noninvasive method is transcranial magnetic stimulation, but the clinical application is not clear. Magnetic seizure therapy is a further development of transcranial magnetic stimulation, by which generalized seizures are induced under anaesthesia. Previous results with regard to the antidepressant effects and the fewer cognitive side effects were significant. Deep brain stimulation is an invasive procedure in which electrodes are stereotactically implanted in special brain areas. The effects in severe therapy-resistant obsessive-compulsive disorders and depressions are promising. However, the evaluation of ethical issues remains an important task.     

Failure of long-term pallidal stimulation corrected by subthalamic stimulation in PD

Bilateral high-frequency continuous stimulation of the internal globus pallidus or subthalamic nucleus constitutes a new therapeutic approach for the treatment of patients with severe PD. The authors report two patients in whom stimulation of the globus pallidus failed to give long-term relief and was successfully replaced by bilateral subthalamic stimulation. The results emphasize the reversibility of deep brain stimulation therapy and suggest that the subthalamic target is preferable to the pallidal target.     

Magneto-electrical stimulation of central motor pathways compared with percutaneous electrical stimulation

The central motor conduction to the relaxed muscles was studied in 30 normal volunteers using magneto-electrical stimulation (MES) of the central motor pathways. The results were compared with those obtained by the percutaneous electrical stimulation technique (PES) described previously. None of the cortical and spinal latencies (Lcor and Lsp, respectively) and the central motor conduction time were different between MES and PES in the upper limb muscles. In some lower limb muscles, however, the Lsps of MES were significantly shorter than those of PES. This was probably because the magnetic stimulation over the lumbar spinal column activated the motor roots at their exit from the spinal canal rather than the level of conus medullaris, at which activation occurs in the electrical stimulation.     

The function relating the subjective magnitude of brain stimulation reward to stimulation strength varies with site of stimulation.

A two-lever choice paradigm with concurrent variable interval schedules of reward was used to measure the growth in the subjective magnitude of reward as a function of current, by finding the adjustment in the stimulating current required to offset a given difference in the rates at which two rewards were received. Increasing current by a factor of 2 increased subjective reward magnitude by a factor ranging from as little as 3 to as much as 4,000. This range was about as great between electrodes within one rat as between electrodes and rats. In the light of earlier findings regarding the equivalent effects of increments is current and pulse frequency, these large differences cannot readily be explained by differing fiber densities at the site of stimulation. It is suggested that the medial forebrain bundle terminates in more than one spatio-temporal integration mechanism. The magnitude of the spatio-temporally integrated effect of a barrage of action potentials in the reward-relevant axons depends on which subset of reward-relevant axons is excited by the stimulation.     

The safety of transcranial magnetic stimulation with deep brain stimulation instruments

ObjectivesTranscranial magnetic stimulation (TMS) has been employed in patients with an implanted deep brain stimulation (DBS) device. We investigated the safety of TMS using simulation models with an implanted DBS device.MethodsThe DBS lead was inserted into plastic phantoms filled with dilute gelatin showing impedance similar to that of human brain. TMS was performed with three different types of magnetic coil. During TMS (1) electrode movement, (2) temperature change around the lead, and (3) TMS-induced current in various situations were observed. The amplitude and area of each evoked current were measured to calculate charge density of the evoked current.ResultsThere was no movement or temperature increase during 0.2 Hz repetitive TMS with 100% stimulus intensity for 1 h. The size of evoked current linearly increased with TMS intensity. The maximum charge density exceeded the safety limit of 30 μC/cm²/phase during stimulation above the loops of the lead with intensity over 50% using a figure-eight coil.ConclusionsStrong TMS on the looped DBS leads should not be administered to avoid electrical tissue injury. Subcutaneous lead position should be paid enough attention for forthcoming situations during surgery.     

Brief bursts of pulse stimulation terminate afterdischarges caused by cortical stimulation

OBJECTIVE: To determine whether cortical electrical stimulation can terminate bursts of epileptiform activity in humans, we used afterdischarges (ADs) as a model of epileptiform activity. METHODS: Cortical stimulation was performed for clinical localization purposes using subdural electrodes implanted in patients undergoing preresection evaluations for treatment of medically intractable seizures. We used 0.3-millisecond pulses of alternating polarity, repeated at 50 pulses/second. When stimulation produced AD, we often applied short additional brief bursts of pulse stimulation (BPS). We examined the effectiveness of BPS in aborting ADs in 17 patients using survival analysis. RESULTS: With BPS, ADs stopped within 2 seconds in 115 cases, 2 to 5 seconds in 22 cases, and in more than 5 seconds in 89 cases. Without BPS, ADs stopped within 2 seconds in 21 cases, 2 to 5 seconds in 114 cases, and in more than 5 seconds in 340 cases. BPS was an effective method to abort ADs (Cox proportional hazards model: p<0.0001). At any time during the course of ADs, the instantaneous rate of stopping ADs within 2 seconds after BPS was applied was 4.6 times greater than when BPS was not applied (95% CI = 3.7, 5.7). In eight cases, ADs progressed to the occurrence of clinical seizures, always when BPS was not applied. CONCLUSIONS: Afterdischarges significantly decreased in duration after we applied brief bursts of pulse stimulation. Although afterdischarges are not identical to spontaneous epileptiform activity, these results support the idea that electrical stimulation, applied in an appropriate manner at seizure onset, could abort seizures in humans.     

New potential stimulation targets for noninvasive brain stimulation treatment of chronic insomnia

BackgroundNoninvasive brain stimulation (NIBS) was recently used as a therapeutic application in patients with insomnia. Most of the previous NIBS treatments for insomnia directly selected the dorsolateral prefrontal cortex (DLPFC) as the stimulation site. As the NIBS target is an important factor in the efficacy of NIBS, it is necessary to detect more potential cortical sites for NIBS in insomnia.MethodsA neuroimaging study-based meta-analysis was used to examine sleep-related brain regions. A sleep-associated brain region-based functional connectivity (FC) map was constructed in 50 patients with chronic insomnia disorder (CID) without any comorbidity. We also combined the meta-analysis and FC results to examine the potential surface targets for NIBS for CID.ResultsThe results identified the bilateral supplementary motor area (SMA), left superior temporal gyrus (STG), bilateral DLPFC, precentral lobule, supramarginal gyrus, angular gyrus, superior frontal gyrus, middle temporal gyrus and middle occipital gyrus as potential brain stimulation targets for insomnia treatment. Notably, the bilateral SMA, right DLPFC and left STG were identified in the FC and meta-analyses. In addition, the SMA and DLPFC were positively and STG was negatively connected with other sleep related brain regions, which indicated inhibitory and excitatory stimulation for NIBS treatment for CID, respectively.ConclusionOur study suggests the SMA, DLPFC and STG as preferentially selected brain targets of NIBS for CID treatment. We recommend an inhibitory stimulation over SMA and DLPFC, and an excitatory stimulation over STG for NIBS treatment. Future studies should test these new targets using NIBS treatment for insomnia.     

Multi-locus transcranial magnetic stimulation system for electronically targeted brain stimulation

BackgroundTranscranial magnetic stimulation (TMS) allows non-invasive stimulation of the cortex. In multi-locus TMS (mTMS), the stimulating electric field (E-field) is controlled electronically without coil movement by adjusting currents in the coils of a transducer.ObjectiveTo develop an mTMS system that allows adjusting the location and orientation of the E-field maximum within a cortical region.MethodsWe designed and manufactured a planar 5-coil mTMS transducer to allow controlling the maximum of the induced E-field within a cortical region approximately 30 mm in diameter. We developed electronics with a design consisting of independently controlled H-bridge circuits to drive up to six TMS coils. To control the hardware, we programmed software that runs on a field-programmable gate array and a computer. To induce the desired E-field in the cortex, we developed an optimization method to calculate the currents needed in the coils. We characterized the mTMS system and conducted a proof-of-concept motor-mapping experiment on a healthy volunteer. In the motor mapping, we kept the transducer placement fixed while electronically shifting the E-field maximum on the precentral gyrus and measuring electromyography from the contralateral hand.ResultsThe transducer consists of an oval coil, two figure-of-eight coils, and two four-leaf-clover coils stacked on top of each other. The technical characterization indicated that the mTMS system performs as designed. The measured motor evoked potential amplitudes varied consistently as a function of the location of the E-field maximum.ConclusionThe developed mTMS system enables electronically targeted brain stimulation within a cortical region.     

Electrocorticography and stimulation

Although acute electrocorticography (ECoG) is routinely used during epilepsy surgery there is little agreement as to its value nor criteria for its interpretation. Specific issues are reviewed on the basis of the literature and personal studies: does failure to resect the entire irritative zone prejudice seizure control, and are residual discharges predictive of failure; does activation of the ECoG by intravenous barbiturates provide information of clinical value; does intraoperative electrical stimulation help to improve localisation or avoid postoperative deficits; is the ECoG of value for monitoring functional procedures; can the value of ECoG be increased by new interpretive approaches? It is suggested that resection of the entire area of interictal discharge is not essential for satisfactory surgical outcome, but a distinction may need to be made between those discharging regions that function as pacemakers and those in which ECoG spikes appear secondarily. There is also evidence that, apart from any consideration of determining the area resected, the topography of epileptiform discharge may be predictive of pathology and surgical outcome. It is concluded that more detailed topographic and quantitative analysis of the ECoG is required before its value in planning surgery can be determined or objective interpretive criteria established.     

Vagus nerve stimulation in neuropsychiatry: Targeting anatomy-based stimulation sites

The vagus nerve (VN) is the longest cranial nerve, extending from the brain to the abdominal cavity. The VN consists of both afferent and efferent fibers (respectively 80% and 20%). Vagus nerve stimulation (VNS) is a neuromodulation strategy first developed in the 1980s for epilepsy. More recently, growing efforts in clinical research have been underscoring possible clinical benefits of VNS for different medical conditions such as epilepsy, major depression, anxiety disorders, and Tourette syndrome. Following the rational of VN anatomy and cranial innervation presented above, we hereby hypothesize that transcutaneously placing electrodes over the mastoid process could be a useful study protocol for future tVNS trials.     

Determining the site of stimulation during magnetic stimulation of a peripheral nerve.

Magnetic stimulation has not been routinely used for studies of peripheral nerve conduction primarily because of uncertainty about the location of the stimulation site. We performed several experiments to locate the site of nerve stimulation. Uniform latency shifts, similar to those that can be obtained during electrical stimulation, were observed when a magnetic coil was moved along the median nerve in the region of the elbow, thereby ensuring that the properties of the nerve and surrounding volume conductor were uniform. By evoking muscle responses both electrically and magnetically and matching their latencies, amplitudes and shapes, the site of stimulation was determined to be 3.0 +/- 0.5 cm from the center of an 8-shaped coil toward the coil handle. When the polarity of the current was reversed by rotating the coil, the latency of the evoked response shifted by 0.65 +/- 0.05 msec, which implies that the site of stimulation was displaced 4.1 +/- 0.5 cm. Additional evidence of cathode- and anode-like behavior during magnetic stimulation comes from observations of preferential activation of motor responses over H-reflexes with stimulation of a distal site, and of preferential activation of H-reflexes over motor responses with stimulation of a proximal site. Analogous behavior is observed with electrical stimulation. These experiments were motivated by, and are qualitatively consistent with, a mathematical model of magnetic stimulation of an axon.     

The application of vagus nerve stimulation and deep brain stimulation in depression

Despite the progress in the pharmacotherapy of depression, there is a substantial proportion of treatment-resistant patients. Recently, reversible invasive stimulation methods, i.e. vagus nerve stimulation (VNS) and deep brain stimulation (DBS), have been introduced into the management of treatment-resistant depression (TRD). VNS has already received regulatory approval for TRD. This paper reviews the available clinical evidence and neurobiology of VNS and DBS in TRD. The principle of VNS is a stimulation of the left cervical vagus nerve with a programmable neurostimulator. VNS was examined in 4 clinical trials with 355 patients. VNS demonstrated steadily increasing improvement with full benefit after 6-12 months, sustained up to 2 years. Patients who responded best had a low-to-moderate antidepressant resistance. However, the primary results of the only controlled trial were negative. DBS involves stereotactical implantation of electrodes powered by a pulse generator into the specific brain regions. For depression, the targeted areas are the subthalamic nucleus, internal globus pallidus, ventral internal capsule/ventral striatum, the subgenual cingulated region, and the nucleus accumbens. Antidepressant effects of DBS were examined in case series with a total number of 50 TRD patients. Stimulation of different brain regions resulted in a reduction of depressive symptoms. The clinical data on the use of VNS and DBS in TRD are encouraging. The major contribution of the methods is a novel approach that allows for precise targeting of the specific brain areas, nuclei and circuits implicated in the etiopathogenesis of neuropsychiatric disorders. For clinical practice, it is necessary to identify patients who may best benefit from VNS or DBS.     

Vagus nerve stimulation for epilepsy: randomized comparison of three stimulation paradigms

Vagus nerve stimulation (VNS) is an effective adjunctive treatment for intractable epilepsy. However, the optimal range of device duty-cycles [on/(on + off times)] is poorly understood. The authors performed a multicenter, randomized trial of three unique modes of VNS, which varied primarily by duty-cycle. The results indicate that the three duty-cycles were equally effective. The data support the use of standard duty-cycles as initial therapy.