Experimental and Monte Carlo based dosimetric investigation of a novel 3 mm radiosurgery 3 MV beam using the microSilicon detector.

BACKGROUND: The ZAP-X system is a novel gyroscopic radiosurgical system based on a 3 MV linear accelerator and collimator cones with a diameter between 4 and 25 mm. Advances in imaging modalities to detect small and early-stage pathologies allow for an early and less invasive treatment, where a smaller collimator matching the anatomical target could provide better sparing of surrounding healthy tissue. PURPOSE: A novel 3 mm collimator cone for the ZAP-X was developed. This study aims to investigate the usability of a commercial diode detector (microSilicon) for the dosimetric characterization of this small collimator cone; and to investigate the underlying small field perturbation effects. METHODS: Profile measurements in five depths as well as PDD and output ratio measurements were performed with a microSilicon detector and radiochromic EBT3 films. In addition, comprehensive Monte Carlo simulations were performed to validate the measurement observations and to quantify the perturbation effects of the microSilicon detector in these extremely small field conditions. RESULTS: It is shown that the microSilicon detector enables an accurate dosimetric characterization of the 3 mm beam. The profile parameters, such as the FWHM and 20%-80% penumbra width, agree within 0.1 to 0.2 mm between film and detector measurements. The output ratios agree within the measurement uncertainty between microSilicon detector and films, whereas the comparisons of the PDD results show good agreement with the Monte Carlo simulations. The analysis of the perturbation factors of the microSilicon detector reveals a small field correction factor of approximately 3% for the 3 mm circular beam and a correction factor smaller than 1.5% for field diameters above 3 mm. CONCLUSIONS: It could be shown that the microSilicon detector is well-suitable for the characterization of the new 3 mm circular beam of the ZAP-X system.

Neurocognitive Effects of Repetitive Transcranial Magnetic Stimulation With a 2-Coil Device in Treatment-Resistant Major Depressive Disorder.

BACKGROUND: Neurocognitive dysfunction is an understudied and undertreated aspect of psychiatric research and treatment. There is emerging evidence to suggest that repetitive transcranial magnetic stimulation (rTMS) may possess neurocognition-enhancing capabilities. METHODS: This study examined the neurocognitive data from a randomized, double-blind, sham-controlled trial of an investigational 2-coil rTMS device in antidepressant treatment or treatment-intolerant major depressive disorder patients. This device has the potential to stimulate deeper areas of the brain than the Food and Drug Administration-approved TMS devices, which primarily stimulate cortical brain areas and may therefore have different neurocognitive adverse effects. Patients received 20 daily rTMS treatments (10-Hz stimulation; either active or sham) with coil centers positioned over the left dorsolateral prefrontal cortex and dorsomedial prefrontal cortex. Neurocognitive safety was evaluated at baseline and within 72 hours of final treatment session with a computerized battery assessing aspects of attention and memory in 84 participants. RESULTS: There were no observed negative neurocognitive effects of the 2-coil rTMS device. A significant effect of active rTMS was observed on the quality of episodic memory. There were no observed effects for attention or working memory. Baseline quality of episodic memory predicted depression treatment response and remission, in that lower baseline episodic memory was associated with greater likelihood of depression response/remission. This was observed in logistic regression analyses controlling for treatment and baseline depressive symptoms. CONCLUSIONS: The 2-coil rTMS device is a cognitively safe treatment for treatment-resistant depression that may possess episodic memory-enhancing capabilities. Furthermore, baseline episodic memory may reflect an important predictor of subsequent depression treatment response/remission to rTMS.

Dosimetric Comparison of Dedicated Radiosurgery Platforms for the Treatment of Essential Tremor: Technical Report.

Essential tremor (ET) is one of the most common adult movement disorders. As the worldwide population ages, the incidence and prevalence of ET is increasing. Although most cases can be managed conservatively, there is a subset of ET that is refractory to medical management. By virtue of being "reversible", deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of the thalamus is one commonly accepted intervention. As an alternative to invasive and expensive DBS, there has been a renaissance in treating ET with lesion-based approaches, spearheaded most recently by high-intensity focused ultrasound (HIFU), the hallmark of which is that it is non-invasive. Meanwhile, stereotactic radiosurgical (SRS) lesioning of VIM represents another time-honored lesion-based non-invasive treatment of ET, which is especially well suited for those patients that cannot tolerate open neurosurgery and is now also getting a "second look". While multiple SRS platforms have been and continue to be used to treat ET, there is little in the way of dosimetric comparison between different technologies. In this brief technical report we compare the dosimetric profiles of three major radiosurgical platforms (Gamma Knife, CyberKnife Robotic Radiosurgery, and Zap-X Gyroscopic Radiosurgery (GRS)) for the treatment of ET. In general, the GRS and Gamma Knife were shown to have the best theoretical dosimetric profiles for VIM lesioning. Nevertheless the relevance of such superiority to clinical outcomes requires future patient studies.

Shaped magnetic field pulses by multi-coil repetitive transcranial magnetic stimulation (rTMS) differentially modulate anterior cingulate cortex responses and pain in volunteers and fibromyalgia patients.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has shown promise in the alleviation of acute and chronic pain by altering the activity of cortical areas involved in pain sensation. However, current single-coil rTMS technology only allows for effects in surface cortical structures. The ability to affect activity in certain deep brain structures may however, allow for a better efficacy, safety, and tolerability. This study used PET imaging to determine whether a novel multi-coil rTMS would allow for preferential targeting of the dorsal anterior cingulate cortex (dACC), an area always activated with pain, and to provide preliminary evidence as to whether this targeted approach would allow for efficacious, safe, and tolerable analgesia both in a volunteer/acute pain model as well as in fibromyalgia chronic pain patients. METHODS: Part 1: Different coil configurations were tested in a placebo-controlled crossover design in volunteers (N = 16). Tonic pain was induced using a capsaicin/thermal pain model and functional brain imaging was performed by means of H2(15)O positron emission tomography - computed tomography (PET/CT) scans. Differences in NRS pain ratings between TMS and sham treatment (NRS(TMS)-NRS(placebo)) which were recorded each minute during the 10 minute PET scans. Part 2: 16 fibromyalgia patients were subjected to 20 multi-coil rTMS treatments over 4 weeks and effects on standard pain scales (Brief Pain Inventory, item 5, i.e. average pain NRS over the last 24 hours) were recorded. RESULTS: A single 30 minute session using one of 3 tested rTMS coil configurations operated at 1 Hz consistently produced robust reduction (mean 70% on NRS scale) in evoked pain in volunteers. In fibromyalgia patients, the 20 rTMS sessions also produced a significant pain inhibition (43% reduction in NRS pain over last 24 hours), but only when operated at 10 Hz. This degree of pain control was maintained for at least 4 weeks after the final session. CONCLUSION: Multi-coil rTMS may be a safe and effective treatment option for acute as well as for chronic pain, such as that accompanying fibromyalgia. Further studies are necessary to optimize configurations and settings as well as to elucidate the mechanisms that lead to the long-lasting pain control produced by these treatments.

Tracking stem cell differentiation in the setting of automated optogenetic stimulation.

Membrane depolarization has been shown to play an important role in the neural differentiation of stem cells and in the survival and function of mature neurons. Here, we introduce a microbial opsin into ESCs and develop optogenetic technology for stem cell engineering applications, with an automated system for noninvasive modulation of ESC differentiation employing fast optogenetic control of ion flux. Mouse ESCs were stably transduced with channelrhodopsin-2 (ChR2)-yellow fluorescent protein and purified by fluorescence activated cell sorting (FACS). Illumination of resulting ChR2-ESCs with pulses of blue light triggered inward currents. These labeled ESCs retained the capability to differentiate into functional mature neurons, assessed by the presence of voltage-gated sodium currents, action potentials, fast excitatory synaptic transmission, and expression of mature neuronal proteins and neuronal morphology. We designed and tested an apparatus for optically stimulating ChR2-ESCs during chronic neuronal differentiation, with high-speed optical switching on a custom robotic stage with environmental chamber for automated stimulation and imaging over days, with tracking for increased expression of neural and neuronal markers. These data point to potential uses of ChR2 technology for chronic and temporally precise noninvasive optical control of ESCs both in vitro and in vivo, ranging from noninvasive control of stem cell differentiation to causal assessment of the specific contribution of transplanted cells to tissue and network function.

Non-ablative doses of focal ionizing radiation alters function of central neural circuits.

BACKGROUND: Modulation of pathological neural circuit activity in the brain with a minimum of complications is an area of intense interest. OBJECTIVE: The goal of the study was to alter neurons' physiological states without apparent damage of cellular integrity using stereotactic radiosurgery (SRS). METHODS: We treated a 7.5 mm-diameter target on the visual cortex of Göttingen minipigs with doses of 40, 60, 80, and 100 Gy. Six months post-irradiation, the pigs were implanted with a 9 mm-wide, eight-shank multi-electrode probe, which spanned the radiation focus as well as the low-exposure neighboring areas. RESULTS: Doses of 40 Gy led to an increase of spontaneous firing rate, six months post-irradiation, while doses of 60 Gy and greater were associated with a decrease. Subjecting the animals to visual stimuli resulted in typical visual evoked potentials (VEP). At 40 Gy, a significant reduction of the P1 peak time, indicative of higher network excitability was observed. At 80 Gy, P1 peak time was not affected, while a minor reduction at 60 Gy was seen. No distance-dependent effects on spontaneous firing rate, or on VEP were observed. Post-mortem histology revealed no evidence of necrosis at doses below 60 Gy. In an in vitro assay comprising of iPS-derived human neuron-astrocyte co-cultures, we found a higher vulnerability of inhibitory neurons than excitatory neurons with respect to radiation, which might provide the cellular mechanism of the disinhibitory effect observed in vivo. CONCLUSION: We provide initial evidence for a rather circuit-wide, long-lasting disinhibitory effect of low sub-ablative doses of SRS.

Neuromodulation via Focal Radiation: Radiomodulation Update.

When radiation is focally delivered to brain tissue at sub-ablative doses, neural activity may be altered. When done at a specific brain circuit node or connection, this is referred to as "radiomodulation." Radiation-induced effects on brain tissue, basic science, and clinical research that supports the radiomodulation hypothesis are reviewed in this article. We review progress in defining the necessary parameters in terms of dose, volumes, and anatomical location. It may be possible to deliver therapeutic neuromodulation that is non-invasive, non-destructive, and durable.

Self-Shielding for the ZAP-X®: Revised Characterization and Evaluation.

The ZAP-X® is a newly designed, self-contained, and first-of-its-kind self-shielded therapeutic radiation therapy device dedicated to brain and head and neck stereotactic radiosurgery (SRS). By using an S-band linear accelerator (linac) and employing integrated minimal but sufficient shielding, the ZAP-X does not typically require a radiation bunker. At the same time, the self-shielded features of the ZAP-X are designed for more consistency of radiation protection, reducing the risk to radiation workers and others potentially exposed from a poorly designed or constructed radiotherapy vault. This study postulates that a radiosurgical system can be self-shielded, such that it produces radiation exposure levels deemed safe to the public while operating under a full clinical workload. The goal of self-shielding is achieved under all but the most exceptional clinical conditions. This work is intended to serve as guidance for the radiation safety evaluations of future ZAP-X treatment operations, following local or regional applicable regulatory requirements, and utilizing the unique provision of all or most of the required shielding material as an integral part of the device.

Effects of Focal Ionizing Radiation of the Squid Stellate Ganglion on Synaptic and Axonal Transmission in the Giant-Fiber Pathway.

Ionizing radiation is clinically used to treat neurological problems and reduce pathological levels of neural activity in the brain, but its cellular-level mechanisms are not well understood. Although spontaneous and stimulated synaptic activity has been produced in rodents by clinically and environmentally relevant doses of radiation, the effects on basic excitability properties of neurons have seldom been reported. This study examined the effects of focused ionizing radiation on synaptic transmission and action potential generation in the squid giant-fiber system, which includes the giant synapse between a secondary interneuron and the tertiary giant motor axons. Radiation of 140-300 Gy was delivered to a stellate ganglion of a living squid over several minutes, with the contralateral stellate ganglion serving as an internal control. No qualitative changes in the efficacy of synaptic transmission were noted in conjunction with stimulation of the input to the giant synapse, although in one irradiated ganglion, the refractory period increased from about 5 ms to more than 45 seconds. Small but significant changes in the action potential recorded from the giant motor axon in response to electrical stimulation were associated with an increased maximum rate of fall and a shortened action potential duration. Other action-potential parameters, including resting potential, overshoot, the maximum rate of the rise, and the refractory period were not significantly changed. Attempts to account for the observed changes in the action potential were carried through a Hodgkin-Huxley model of the action potential. This approach suggests that an increase in the maximum voltage-gated potassium conductance of about 50% mimics the action potential shortening and increased rate of fall that was experimentally observed. We propose that such an effect could result from phosphorylation of squid potassium channels.

An Intracortical Implantable Brain-Computer Interface for Telemetric Real-Time Recording and Manipulation of Neuronal Circuits for Closed-Loop Intervention.

Recording and manipulating neuronal ensemble activity is a key requirement in advanced neuromodulatory and behavior studies. Devices capable of both recording and manipulating neuronal activity brain-computer interfaces (BCIs) should ideally operate un-tethered and allow chronic longitudinal manipulations in the freely moving animal. In this study, we designed a new intracortical BCI feasible of telemetric recording and stimulating local gray and white matter of visual neural circuit after irradiation exposure. To increase the translational reliance, we put forward a Göttingen minipig model. The animal was stereotactically irradiated at the level of the visual cortex upon defining the target by a fused cerebral MRI and CT scan. A fully implantable neural telemetry system consisting of a 64 channel intracortical multielectrode array, a telemetry capsule, and an inductive rechargeable battery was then implanted into the visual cortex to record and manipulate local field potentials, and multi-unit activity. We achieved a 3-month stability of the functionality of the un-tethered BCI in terms of telemetric radio-communication, inductive battery charging, and device biocompatibility for 3 months. Finally, we could reliably record the local signature of sub- and suprathreshold neuronal activity in the visual cortex with high bandwidth without complications. The ability to wireless induction charging combined with the entirely implantable design, the rather high recording bandwidth, and the ability to record and stimulate simultaneously put forward a wireless BCI capable of long-term un-tethered real-time communication for causal preclinical circuit-based closed-loop interventions.

A Perspective of International Collaboration Through Web-Based Telecommunication-Inspired by COVID-19 Crisis.

The tsunami effect of the COVID-19 pandemic is affecting many aspects of scientific activities. Multidisciplinary experimental studies with international collaborators are hindered by the closing of the national borders, logistic issues due to lockdown, quarantine restrictions, and social distancing requirements. The full impact of this crisis on science is not clear yet, but the above-mentioned issues have most certainly restrained academic research activities. Sharing innovative solutions between researchers is in high demand in this situation. The aim of this paper is to share our successful practice of using web-based communication and remote control software for real-time long-distance control of brain stimulation. This solution may guide and encourage researchers to cope with restrictions and has the potential to help expanding international collaborations by lowering travel time and costs.

Correction: Characterization of a Novel Revolving Radiation Collimator.

[This corrects the article DOI: 10.7759/cureus.2146.].

Correction: Self-Shielding Analysis of the Zap-X System.

[This corrects the article DOI: 10.7759/cureus.1917.].

Characterization of a Novel Revolving Radiation Collimator.

Introduction The ZAP-X is a novel self-contained and first-of-its-kind self-shielded therapeutic radiation device dedicated to brain and head and neck radiosurgery. By utilizing a 2.7-MV linear accelerator and incorporating a design in which a beam stop and major mechanical elements serve a radiation shielding function, the Zap-X does not typically require a radiation bunker. The unique collimator design of the Zap-X is especially critical to the performance of the overall system. The collimator consists of a shielded tungsten wheel oriented with its rotational axis perpendicular to the beam's central axis; the goal of this design is to minimize radiation leakage. Beam selection is accomplished by rotating the wheel within its tungsten-shielded housing. We investigated radiation leakage from the Zap-X collimator to determine its compliance with internationally accepted standards using direct radiation measurements. Materials and methods To measure collimator leakage in the plane of the patient, equidistant measurement stations were defined in a plane perpendicular to the central beam axis (cax) 1 m from this axis (1 m from the radiation focal spot). To measure leakage alongside and adjacent to the accelerator, equidistant measurement stations were located 1 m from the cax along a line parallel to the cax in the plane of the collimator wheel and along a line parallel to the cax 90 degrees offset from the first line of stations. Results Radiation leakage emanating from the collimating head of the linear accelerator in the patient plane ranged between 4.0 and 10.4 mR. Radiation along the linear accelerator (1000 R delivered in the primary beam) varied between 1.7 and 6.8 mR and constituted between 0.00017% to 0.00068% of the primary beam. The former radiation originated from X-ray target leakage, while the latter is produced directly by the linear accelerator and both contributed to the overall leakage radiation that would reach a patient. Discussion Due to the large diameter of the Zap-X tungsten collimator wheel and the massive Zap-X tungsten cylindrical collimator shield, the overall patient leakage is 0.00104% of the primary beam at a 1-m distance from the beam central axis in the patient plane. Leakage radiation in the patient plane is limited by the International Electrotechnical Commission (IEC) to 0.1% of the total primary radiation. Radiation leakage along the linear accelerator and the collimator housing was determined to be 0.00068% of primary radiation intensity. This leakage value is lower than the 0.1% leakage limit stipulated by IEC by more than a factor of 100. Conclusions Typically, an MV radiation therapy system minimizes exposure by utilizing a combination of device and structural shielding. However, the Zap-X has been uniquely designed to minimize the need for structural shielding. Our results indicate radiation leakage from the collimator meets internationally accepted standards as defined by the IEC.

An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology.

Neural interface technology has made enormous strides in recent years but stimulating electrodes remain incapable of reliably targeting specific cell types (e.g. excitatory or inhibitory neurons) within neural tissue. This obstacle has major scientific and clinical implications. For example, there is intense debate among physicians, neuroengineers and neuroscientists regarding the relevant cell types recruited during deep brain stimulation (DBS); moreover, many debilitating side effects of DBS likely result from lack of cell-type specificity. We describe here a novel optical neural interface technology that will allow neuroengineers to optically address specific cell types in vivo with millisecond temporal precision. Channelrhodopsin-2 (ChR2), an algal light-activated ion channel we developed for use in mammals, can give rise to safe, light-driven stimulation of CNS neurons on a timescale of milliseconds. Because ChR2 is genetically targetable, specific populations of neurons even sparsely embedded within intact circuitry can be stimulated with high temporal precision. Here we report the first in vivo behavioral demonstration of a functional optical neural interface (ONI) in intact animals, involving integrated fiberoptic and optogenetic technology. We developed a solid-state laser diode system that can be pulsed with millisecond precision, outputs 20 mW of power at 473 nm, and is coupled to a lightweight, flexible multimode optical fiber, approximately 200 microm in diameter. To capitalize on the unique advantages of this system, we specifically targeted ChR2 to excitatory cells in vivo with the CaMKIIalpha promoter. Under these conditions, the intensity of light exiting the fiber ( approximately 380 mW mm(-2)) was sufficient to drive excitatory neurons in vivo and control motor cortex function with behavioral output in intact rodents. No exogenous chemical cofactor was needed at any point, a crucial finding for in vivo work in large mammals. Achieving modulation of behavior with optical control of neuronal subtypes may give rise to fundamental network-level insights complementary to what electrode methodologies have taught us, and the emerging optogenetic toolkit may find application across a broad range of neuroscience, neuroengineering and clinical questions.

Self-Shielding Analysis of the Zap-X System.

The Zap-X is a self-contained and first-of-its-kind self-shielded therapeutic radiation device dedicated to brain as well as head and neck stereotactic radiosurgery (SRS). By utilizing an S-band linear accelerator (linac) with a 2.7 megavolt (MV) accelerating potential and incorporating radiation-shielded mechanical structures, the Zap-X does not typically require a radiation bunker, thereby saving SRS facilities considerable cost. At the same time, the self-shielded features of the Zap-X are designed for more consistency of radiation protection, reducing the risk to radiation workers and others potentially exposed from a poorly designed or constructed radiotherapy vault. The hypothesis of the present study is that a radiosurgical system can be self-shielded such that it produces radiation exposure levels deemed safe to the public while operating under a full clinical workload. This study summarizes the Zap-X system shielding and found that the overall system radiation leakage values are reduced by a factor of 50 compared to the occupational radiation limit stipulated by the Nuclear Regulatory Commission (NRC) or agreement states. The goal of self-shielding is achieved under all but the most exceptional conditions for which additional room shielding or a larger restricted area in the vicinity of the Zap-X system would be required.

rTMS with a two-coil array: Safety and efficacy for treatment resistant major depressive disorder.

BACKGROUND: Therapeutic repetitive Transcranial Magnetic Stimulation (rTMS) has emerged as a standard of care for individuals with major depressive disorder (MDD) who do not benefit from, or are unable to tolerate, antidepressant pharmacotherapy. Depth of stimulation is limited with currently approved figure-eight coils and larger coils capable of deeper penetration may be associated with loss of stimulation focality and undesired recruitment of motor cortex. A second generation 2-coil array rTMS system was designed to target converging brain pathways for potentially deeper prefrontal cortex stimulation. METHODS: A randomized, double-blind, sham-controlled trial examined the safety and efficacy of an investigational 2-coil rTMS device. Antidepressant treatment-resistant or treatment-intolerant MDD patients (n = 92) received 20 daily rTMS treatments with coil centers positioned over left dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC). 10 Hz stimulation (maximum summated power for both coils ≤ 120% motor threshold) was delivered. Primary efficacy endpoint was change in HAMD-24 score from baseline to the conclusion of treatments. RESULTS: Data from n = 75 (per-protocol sample) showed significantly greater improvement (mean HAMD-24 change) over time for the active (n = 38) versus sham (n = 37) group after 20 sessions (F = 7.174; p = 0.008) and also at the one-month follow-up (F = 6.748; p = 0.010). Response rates were 55.3% (active) versus 32.4% (sham) (p = 0.063); remission rates were 26.3% versus 18.9% (p > 0.05). Other secondary outcomes were generally supportive. CONCLUSIONS: The results confirmed safety and acute efficacy of the 2-coil rTMS device. Despite modest sample size, primary outcome was clinically and statistically significant, and the effect size was comparable with those reported for regulatory trials with FDA-cleared devices.

Reducing pain and unpleasantness during repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is associated with significant scalp discomfort under the coil for a high percentage of participants, especially with high stimulation intensities (100% of motor threshold or higher) or frequencies (1 Hz or greater). Some patients in rTMS clinical trials have been unable to tolerate the pain and have dropped out. There seem to be no published studies of strategies to reduce the localized pain and discomfort associated with rTMS. Thus, the authors conducted preliminary pilot trials of 4 different strategies for managing discomfort associated with left prefrontal rTMS. Healthy adults rated the painfulness and unpleasantness of left prefrontal rTMS (10 Hz; 5 seconds, on; 30 seconds, off; at 100% and 120% of resting motor threshold) before and after (1) topical application of a eutectic mixture of local anesthetics cream, (2) scalp injection of lidocaine, (3) scalp injection of lidocaine and epinephrine, and (4) with or without 3 x 3-in thin foam sheets between the coil and scalp. The discomfort produced by rTMS under these experimental conditions was compared with the discomfort produced by stimulation with the same parameters without the interventions. Localized anesthetic injections were associated with a significant decrease in pain intensity and unpleasantness, whereas the eutectic mixture of local anesthetics cream had no effect on rTMS-related discomfort. The use of foam sheets was associated with a slight but noticeable decrease in pain intensity and unpleasantness. More systematic research is needed on the effectiveness of different strategies for reducing rTMS-related pain and discomfort.