Stimulation Of Deep Brain Regions Research Articles

Spatially Selective Retinal Ganglion Cell Activation Using Low Invasive Extraocular Temporal Interference Stimulation.

Conventional retinal implants involve complex surgical procedures and require invasive implantation. Temporal Interference Stimulation (TIS) has achieved noninvasive and focused stimulation of deep brain regions by delivering high-frequency currents with small frequency differences on multiple electrodes. In this study, we conducted in silico investigations to evaluate extraocular TIS's potential as a novel visual restoration approach. Different from the previously published retinal TIS model, the new model of extraocular TIS incorporated a biophysically detailed retinal ganglion cell (RGC) population, enabling a more accurate simulation of retinal outputs under electrical stimulation. Using this improved model, we made the following major discoveries: (1) the maximum value of TIS envelope electric potential ([Formula: see text] showed a strong correlation with TIS-induced RGC activation; (2) the preferred stimulating/return electrode (SE/RE) locations to achieve focalized TIS were predicted; (3) the performance of extraocular TIS was better than same-frequency sinusoidal stimulation (SSS) in terms of lower RGC threshold and more focused RGC activation; (4) the optimal stimulation parameters to achieve lower threshold and focused activation were identified; and (5) spatial selectivity of TIS could be improved by integrating current steering strategy and reducing electrode size. This study provides insights into the feasibility and effectiveness of a low-invasive stimulation approach in enhancing vision restoration.

Magnetic temporal interference for noninvasive and focal brain stimulation

Objective. Noninvasive focal stimulation of deep brain regions has been a major goal for neuroscience and neuromodulation in the past three decades. Transcranial magnetic stimulation (TMS), for instance, cannot target deep regions in the brain without activating the overlying tissues and has poor spatial resolution. In this manuscript, we propose a new concept that relies on the temporal interference (TI) of two high-frequency magnetic fields generated by two electromagnetic solenoids. Approach. To illustrate the concept, custom solenoids were fabricated and optimized to generate temporal interfering electric fields for rodent brain stimulation. C-Fos expression was used to track neuronal activation. Main result. C-Fos expression was not present in regions impacted by only one high-frequency magnetic field indicating ineffective recruitment of neural activity in non-target regions. In contrast, regions impacted by two fields that interfere to create a low-frequency envelope display a strong increase in c-Fos expression. Significance. Therefore, this magnetic temporal interference solenoid-based system provides a framework to perform further stimulation studies that would investigate the advantages it could bring over conventional TMS systems.

Transcranial Electrical Neurostimulation as a Potential Addiction Treatment.

Addiction remains difficult to treat, but non-invasive transcranial electrical and magnetic neurostimulation methods may provide promising and cost-effective treatment approaches. We provide a narrative review of recent developments and evidence of effectiveness and consider newer technology that may yield improved treatment approaches. In particular, we review temporal interference electrical neurostimulation, which allows non-invasive and focal stimulation of deep brain regions. This provides a promising new potential approach to treat addiction, because many of the brain regions that seem most important for addiction are deeper in the brain, out of reach of existing technologies such as transcranial direct current stimulation.

Feasibility of epidural temporal interference stimulation for minimally invasive electrical deep brain stimulation: simulation and phantom experimental studies

Objective. Temporal interference stimulation (TIS) has shown the potential as a new method for selective stimulation of deep brain structures in small animal experiments. However, it is challenging to deliver a sufficient temporal interference (TI) current to directly induce an action potential in the deep area of the human brain when electrodes are attached to the scalp because the amount of injection current is generally limited due to safety issues. Thus, we propose a novel method called epidural TIS (eTIS) to address this issue; in this method, the electrodes are attached to the epidural surface under the skull. Approach. We employed finite element method (FEM)-based electric field simulations to demonstrate the feasibility of eTIS. We first optimized the electrode conditions to deliver maximum TI currents to each of the three different targets (anterior hippocampus, subthalamic nucleus, and ventral intermediate nucleus) based on FEM, and compared the stimulation focality between eTIS and transcranial TIS (tTIS). Moreover, we conducted realistic skull-phantom experiments for validating the accuracy of the computational simulation for eTIS. Main results. Our simulation results showed that eTIS has the advantage of avoiding the delivery of TI currents over unwanted neocortical regions compared with tTIS for all three targets. It was shown that the optimized eTIS could induce neural action potentials at each of the three targets when a sufficiently large current equivalent to that for epidural cortical stimulation is injected. Additionally, the simulated results and measured results via the phantom experiments were in good agreement. Significance. We demonstrated the feasibility of eTIS, facilitating more focalized and stronger electrical stimulation of deep brain regions than tTIS, with the relatively less invasive placement of electrodes than conventional deep brain stimulation via computational simulation and realistic skull phantom experiments.

Benchmarking the effects of transcranial temporal interference stimulation (tTIS) in humans

Deep brain stimulation (DBS) provides clinical benefits for several neurological and psychiatric conditions. By overcoming the limitations and risks of conventional DBS, transcranial temporal interference stimulation (tTIS) has the potential to offer non-invasive stimulation of deep brain regions. However, research that investigates the efficacy of tTIS is limited to animal studies or computer simulations and its capability to modulate neural oscillations in humans has not been demonstrated so far. The method of tTIS is hypothesized to elicit its effects via neural entrainment, corresponding to the supposed mechanism of action underlying transcranial alternating current stimulation (tACS), another, more established non-invasive brain stimulation technique. Physiological effects of tACS are well established for cortical brain oscillations, but not for deep brain structures. In particular, aftereffects on the power of parieto-occipital alpha oscillations have been shown repeatedly. In a first attempt to test the efficacy of tTIS in the human brain, the current study thus seeks to compare the effects of tTIS to the well-studied aftereffect of tACS in the cortex. To investigate this research question, the current study compared MEG-recorded brain activity during a simple visual change detection task in 34 healthy subjects pre- and post-tTIS. Additionally, the effects of tTIS were contrasted to conventional tACS and a control stimulation. We expected that the parieto-occipital α-power will increase after tTIS and tACS, in contrast to the control stimulation. Overall, no difference between the experimental groups (tTIS, tACS and control stimulation) were found regarding the source-projected increase in α-power. Based on the results of the study two hypothesis can be made: tTIS, tACS and the control stimulation condition don't have an effect on human brain oscillations in the α-band, or, any experimental conditions of the current study can modulate brain oscillations in the α-band. Both hypotheses emphasize the importance of further studies investigating different carrier frequencies, and the comparison to sham stimulation.

Deep Transcranial Magnetic Stimulation Using Figure-of-Eight and Halo Coils

Transcranial magnetic stimulation (TMS) is a technique for noninvasive stimulation of the human brain. Stimulation is produced by generating a brief, transient high intensity magnetic field by passing a brief, transient electric current through a magnetic coil placed upon the scalp. The induced electrical currents in the underlying cortical tissue produce a localized axonal depolarization [1-3]. TMS has become a major tool in brain research and, potentially, a promising treatment for various neurobehavioral disorders. Recently, interests in stimulating deeper cortical, subcortical and limbic areas have arisen and have become an active research topic in transcranial magnetic stimulation, because several studies show that activation of deeper prefrontal and limbic regions may increase the antidepressant effect [4-5]. Standard TMS is applied with an electromagnetic coil called a round, or figure-of-eight (Fo8) coil which induces stimulation in cortical regions mainly just superficially under the windings of the coil. These coils are not suitable for stimulating deep brain regions directly. As the fields induced by these coils decrease rapidly as a function of depth, only very high intensities would allow functional stimulation of deep brain regions and such intensities would lead to painful scalp stimulation. Furthermore, the risk of seizure is increased. These limitations have led to the development of novel coil designs suitable for deep transcranial magnetic stimulation (dTMS). The Halo-coil, a large circular coil being placed around the head was developed for dTMS. It was shown that the Halo-coil working with a typical round coil at the top of the head can increase the fields at depth in the brain [6]. The present study was to study the field characteristics of Fo8 coil which was placed at the left dorsolateral prefrontal cortex (DLPFC) working with a Halo-coil as shown in Fig. 1. The purpose of this study is to show the field penetration depth by Fo8 coil can be further increased under the help of the Halo coil.

Deep brain stimulation for Rett syndrome

Mutations in the gene MECP2 cause an intellectual-disability disorder called Rett syndrome. In a mouse model, electrical stimulation of deep brain regions is found to ameliorate some of the features of the syndrome. See Letter p.430 Rett syndrome is a genetic disorder that causes profound intellectual disability and other impairments. Huda Zoghbi and colleagues now show that in a mouse model of the disorder, a two-week course of daily deep-brain stimulation of the fimbria-fornix — part of the brain that provides input to the hippocampus — restored hippocampal-dependent memory when tested three weeks after the end of the treatment. It also restored hippocampal long-term potentiation and neurogenesis. These findings indicate that deep-brain stimulation, which is already used in the treatment of motor diseases such as Parkinson's disease and dystonia, could be a viable approach to mitigating cognitive impairment in Rett syndrome and other disorders of childhood intellectual disability.

Deep TMS on alcoholics: effects on cortisolemia and dopamine pathway modulation. A pilot study.

The hypothalamic pituitary adrenal axis and dopamine have a key role in transition from alcohol social use to addiction. The medial prefrontal cortex was shown to modulate dopaminergic activity and cortisol releasing factor (CRF) release in hypothalamic and extra-hypothalamic systems. The recent advancements in non-invasive neurostimulation technologies has enabled stimulation of deeper brain regions using H-coil transcranial magnetic stimulation (TMS) in humans. This randomized double-blind placebo-controlled pilot study aims to evaluate H-coil efficacy in stimulating the medial prefrontal cortex. Cortisolemia and prolactinemia were evaluated as effectiveness markers. Alcohol intake and craving were considered as secondary outcomes. Eighteen alcoholics were recruited and randomized into 2 homogeneous groups: 9 in the real stimulation group and 9 in the sham stimulation group. Repetitive TMS (rTMS) was administered through a magnetic stimulator over 10 sessions at 20 Hz, directed to the medial prefrontal cortex. rTMS significantly reduced blood cortisol levels and decreased prolactinemia, thus suggesting dopamine increase. Craving visual analogic scale (VAS) in treated patients decreased, as well as mean number of alcoholic drinks/day and drinks on days of maximum alcohol intake (DMAI). In the sham group there was no significant effect observed on cortisolemia, prolactinemia, mean number of alcoholic drinks/day, or drinks/DMAI. Thus, deep rTMS could be considered a potential new treatment for alcoholism.

Maintenance Deep Transcranial Magnetic Stimulation Sessions are Associated with Reduced Depressive Relapses in Patients with Unipolar or Bipolar Depression.

Introduction: Deep transcranial magnetic stimulation (dTMS) is a new form of TMS allowing safe stimulation of deep brain regions. The objective of this preliminary study was to assess the role of dTMS maintenance sessions in protecting patients with bipolar disorder (BD) or recurrent major depressive disorder (MDD) from developing depressive or manic relapses in a 12-month follow-up period.Methods: Twenty-four drug-resistant patients with a current depressive episode and a diagnosis of MDD or BD have been enrolled in the study. All the participants underwent daily dTMS sessions for 4 weeks. One group (maintenance – M group) received additional maintenance dTMS sessions weekly or twice a week.Results: After the first dTMS cycle, a significant reduction of Hamilton Depression Rating Scale (HDRS) scores was observed in all participants. Subsequently, the HDRS mean scores did not significantly change over time in the M group, while it significantly increased in the non-M-group after 6 and 12 months.Discussion: This study confirms previous evidence of a positive therapeutic effect of dTMS on depressive symptoms and suggests that, after recovery from acute episodes, maintenance dTMS sessions may be helpful in maintaining euthymia in a 12-month follow-up period.

Effects of Deep Repetitive Transcranial Magnetic Stimulation on Brain-Derived Neurotrophic Factor Serum Concentration in Healthy Volunteers

Objective: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive, safe and efficacious technique for treating various neuropsychiatric disorders, but its underlying mechanisms are poorly understood. A newly developed H-coil allows the stimulation of deeper brain regions. This study is the first to investigate the effects of deep high-frequency rTMS on brain-derived neurotrophic factor (BDNF) serum concentrations in healthy volunteers. We aimed to evaluate the short-term effect of deep rTMS on BDNF serum concentrations. Methods: This was a double-blind, randomized deep high-frequency rTMS study using an H-coil on a cohort of 13 healthy volunteers (NCT01106365). The following stimulation protocols were applied: 18-Hz stimulation of the left dorsolateral prefrontal cortex (PFC), 5-Hz stimulation of the primary motor cortex (MC) and sham stimulation in random order. Blood samples were obtained before, 30 min after and 60 min after each treatment. Results: The BDNF serum concentration decreased significantly after MC and PFC stimulation, but not after sham stimulation. Furthermore, BDNF serum level changes were associated with changes in individual alertness. Conclusion: Although BDNF serum concentrations do not necessarily correlate with BDNF levels in the cerebrospinal fluid or the brain, these results indicate an acute biological effect of deep rTMS on BDNF release, and demonstrate that this change correlates with alertness.

IS 44. Development and applications of deep rTMS in depression and addiction studies

Several psychiatric disorders involve impaired excitability and function of reward-related circuitries. Repeated stimulation of these circuitries can enhance neuroplasticity and induce long-lasting alterations in excitability and function, thereby becoming a novel therapeutic approach. Our animal studies revealed that multiple sessions of localized stimulation of the prefrontal cortex unilaterally or bilaterally can alter molecular and behavioral features of depression or addiction, respectively. In order to affect the relevant circuitries without a surgery, we have designed special transcranial magnetic stimulation (TMS) coils that enable stimulation of deeper and larger regions relative to those directly affected by standard TMS. These coils, termed H-coils, were tested for their safety and ability to reach deeper brain regions, and evaluation of their antidepressant potential when applied over the prefrontal cortex of medication-resistant depressive patients showed high rates of remission in a large multi-center study. The therapeutic potential of other versions of the H-coils are evaluated in several psychiatric disorders including addiction. We have recently completed a study in heavy smokers in which the effectiveness of several stimulation parameters were evaluated in combination with or without cue-induced craving. It was found that high-frequency stimulation of the prefrontal cortex and the insular cortex combined with craving induction causes significant lasting reductions in cigarette consumption, urine cotinine levels and cigarette craving. Such effect was not observed when stimulation did not follow psychological activation of craving or when stimulation was applied at low frequency. The choice of coil and target in TMS studies may be critical in both psychiatric and basic brain research. The ability to induce direct stimulation of deeper brain regions opens a wide range of therapeutic and research options. Optimization of stimulation parameters requires further investigation into mechanisms utilizing imaging and electrophysiological techniques.

Transcranial magnetic brain stimulation modulates blepharospasm

Benign essential blepharospasm (BEB) is a common form of focal dystonia. Besides pathology in the basal ganglia, accumulating evidence suggests pathologic changes in the anterior cingulate cortex (ACC). This is a randomized, sham-controlled, observer-blinded prospective study. In 12 patients with BEB, we evaluated the effects of a 15-minute session of low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS) over the ACC with stimulation intensities at 100% active motor threshold with 3 stimulation coils: a conventional circular coil (C-coil), a sham coil (S-coil), and a Hesed coil (H-coil, which allows stimulation of deeper brain regions. Primary outcome was the clinical effects on BEB (blink rate, number of spasms rated by a blinded physician and patient rating before, immediately after, and 1 hour after stimulation); secondary outcome was the blink reflex recovery curve. Subjective stimulation comfort was similar for each coil with no stimulation-associated adverse events. Stimulation with the H- and C-coils resulted in a significant improvement in all 3 outcome measures and was still detectable in physician rating and patient rating 1 hour after stimulation. S-coil stimulation had no effects. The active motor threshold was significantly lower for the H-coil compared to the other 2 coils. rTMS could be used as a therapeutic tool in BEB. Further studies will be necessary to show whether repeated stimulation applications result in lasting clinical effects. This study provides Class II evidence that for patients with BEB, H- and C-coil rTMS is safe and improves clinical symptoms of BEB immediately and 1 hour after stimulation.

Response to deep TMS in depressive patients with previous electroconvulsive treatment

The efficacy of transcranial magnetic stimulation (TMS) in the treatment of major depression has already been shown. Novel TMS coils allowing stimulation of deeper brain regions have recently been developed and studied. Our study is aimed at exploring the possible efficacy of deep TMS in patients with resistant depression, who previously underwent electroconvalsive therapy (ECT). Using Brainsway's deep TMS H1 coil, six patients who previously underwent ECT, were treated with 120% power of the motor threshold at a frequency of 20 Hz. Patients underwent five sessions per week, up to 4 weeks. Before the study, patients were evaluated using the Hamilton depression rating scale (HDRS, 24 items), the Hamilton anxiety scale, and the Beck depression inventory and were again evaluated after 5, 10, 15, and 20 daily treatments. Response to treatment was considered a reduction in the HDRS of at least 50%, and remission was considered a reduction of the HDRS-24 below 10 points. Two of six patients responded to the treatment with deep TMS, including one who achieved full remission. Our results suggest the possibility of a subpopulation of depressed patients who may benefit from deep TMS treatment, including patients who did not respond to ECT previously. However, the power of the study is small and similar larger samples are needed.

Deep transcranial magnetic stimulation over the prefrontal cortex: Evaluation of antidepressant and cognitive effects in depressive patients

Electroconvulsive therapy (ECT) is an effective alternative for pharmacotherapy in treatment-resistant depressive patients, but the side effects limit its use. Transcranial magnetic stimulation (TMS) has been proposed as a refined alternative, but most studies do not indicate that TMS is as effective as ECT for severe depression. We propose that the limited effectiveness of standard TMS resides in its superficial effect on the cortex, although much of the pathophysiology of depression is associated with deeper and larger brain regions implicated in the reward system. Herein, we tested the effectiveness and safety of a novel TMS coil, the "H-coil," which enables direct stimulation of deeper brain regions, at the expense of focality. We have studied the antidepressant and cognitive effects induced by 4 weeks of high-frequency (20 Hz) repeated deep TMS (DTMS) over the prefrontal cortex (PFC) of 65 medication-free depressive patients, who have failed to benefit from prior medications. Patients were randomly assigned to various treatment configurations, differing in stimulation intensity and laterality. Effects were assessed by the 24-item Hamilton depression rating scale (HDRS-24) and several secondary outcome measures. A significant improvement in HDRS scores was found when high, but not low, stimulation intensity was used. Several cognitive improvements were evident, and no treatment-related serious adverse events were observed. DTMS over the PFC was found safe and effective in alleviating depression. The results accentuate the significance of deep, high-intensity stimulation over low, and serve as the first study to indicate the potential of DTMS in psychiatric and neurologic disorders.

High permeability cores to optimize the stimulation of deeply located brain regions using transcranial magnetic stimulation

Efficient stimulation of deeply located brain regions with transcranial magnetic stimulation (TMS) poses many challenges, arising from the fact that the induced field decays rapidly and becomes less focal with depth. We propose a new method to improve the efficiency of TMS of deep brain regions that combines high permeability cores, to increase focality and field intensity, with a coil specifically designed to induce a field that decays slowly with increasing depth. The performance of the proposed design was investigated using the finite element method to determine the total electric field induced by this coil/core arrangement on a realistically shaped homogeneous head model. The calculations show that the inclusion of the cores increases the field's magnitude by as much as 25% while also decreasing the field's decay with depth along specific directions. The focality, as measured by the area where the field's norm is greater than of its maximum value, is also improved by as much as 15% with some core arrangements. The coil's inductance is not significantly increased by the cores. These results show that the presence of the cores might make this specially designed coil even more suited for the effective stimulation of deep brain regions.

Evolution in practice: how has British neurosurgery changed in the last 10 years?

Neurosurgery is a fast-evolving surgical subspecialty driven by technological advances, socio-economic factors and patient expectations. In this study, we have compared the work-load volume in a single institution in the years of 1994 and 2004 and commented on the possible reasons for the changes and the impacts they may have for the future. A retrospective, log-book review of all operations performed in the years 1994 and 2004 in a single, tertiary, neurosurgical centre was performed. Neurosurgical practice has evolved over this period. Current practice has moved away from clipping of aneurysms and towards coil embolisation performed by interventional radiologists. Electrode stimulation of deep brain regions for movement disorders is the current practice, whereas 10 years ago the same disorders were dealt with by lesioning of the relevant regions. In spinal neurosurgery, instrumentation is increasingly favoured currently. In the field of neuro-oncology, current practice favours minimal access to the target area by the use of stereotactic localisation. Changes were most pronounced in the subspecialties of vascular, functional and spinal neurosurgery within this 10-year period. Knowledge of such dynamics is valuable in health resource management as well as planning for neurosurgical training programmes.

GABA outflow is modulated by electrical high frequency pulses during N-methyl-D-aspartate receptor activation in the rat caudate nucleus

GABAergic neurons have been demonstrated to play an essential role in the mechanism of high frequency stimulation of deep brain regions, which is an effective treatment in Parkinson's disease. In this study, the effects of electrical high frequency (hf)-pulses and N-methyl-D-aspartate (NMDA) receptor activation on GABA and glutamate outflow were examined in slices of the rat caudate nucleus. Therefore, superfusion experiments were performed and GABA and glutamate outflow were measured by means of HPLC with electrochemical detection after pre-column derivatisation with o-phthaldialdehyde sulphite.

Transcranial magnetic stimulation of deep brain regions: evidence for efficacy of the H-Coil

Standard coils used in research and the clinic for noninvasive magnetic stimulation of the human brain are not capable of stimulating deep brain regions directly. As the fields induced by these coils decrease rapidly as a function of depth, only very high intensities would allow functional stimulation of deep brain regions and such intensities would lead to undesirable side effects. We have designed a coil based on numerical simulations and phantom brain measurements that allows stimulation of deeper brain regions, termed the Hesed coil (H-coil). In the present study we tested the efficacy and some safety aspects of the H-coil on healthy volunteers. The H-coil was compared to a regular figure-8 coil in 6 healthy volunteers by measuring thresholds for activation of the abductor pollicis brevis (APB) representation in the motor cortex as a function of distance from each of the coils. The rate of decrease in the coil intensity as a function of distance is markedly slower for the H-coil. The motor cortex could be activated by the H-coil at a distance of 5.5 cm compared to 2 cm with the figure-8 coil. The present study indicate that the H-coil is likely to have the ability of deep brain stimulation and without the need of increasing the intensity to extreme levels that would cause a much greater stimulation in cortical regions. The ability of non-invasive deep brain stimulation potentially opens a wide range of both research and therapeutic applications.

EVOKED RESPONSES AND CHANGES DURING ATTENTIVE FACTORS IN MAN.

Dawson,⁶in 1947, was the first investigator to describe the recording of evoked potentials over the scalp in man. A summation technique was employed permitting extraction of small signals from a noisy background with stimulation of the ulnar nerve. Derbyshire and associates,⁷Marshall and co-workers,²³and Adrian¹have described the variety of evoked potentials recorded from the cortical surface of animals during tactual or sensory neural stimulation. The study of potentials evoked at cortical sites in response to stimulation of deep brain regions has contributed to the understanding of cortical-subcortical relations.^2,14,24In detailed investigations with animals under barbiturate anesthesia, responses are divided into "primary," "secondary," and "repetitive" responses. Primary and secondary components of the evoked responses in man recorded from the scalp have been described by Cigánek.^4,5Jasper and associates¹⁹trported a technique for rapid recording and localization of evoked potentials from the