Targeting Of Brain Structures Research Articles

Evaluation of the PaCER Algorithm for Postoperative Subthalamic Nucleus Deep Brain Stimulation Electrode Localization.

Deep Brain Stimulation (DBS) is an established therapy for many movement disorders. DBS entails electrical stimulation of precise brain structures using permanently implanted electrodes. Following implantation, locating the electrodes relative to the target brain structure assists patient outcome optimization. Here we evaluated an open-source automatic algorithm (PaCER) to localize individual electrodes on Computed Tomography imaging (co-registered to Magnetic Resonance Imaging). In a dataset of 111 participants, we found a modified version of the algorithm matched manual-markups with median error less than 0.191 mm (interquartile range 0.698 mm). Given the error is less than the voxel resolution (1 mm3) of the images, we conclude that the automatic algorithm is suitable for DBS electrode localizations.Clinical Relevance- Automated DBS electrode localization identifies the closest electrode to the target brain structure; allowing the neurologist to direct electrical stimulation to maximize patient outcomes. Further, if none of the electrodes are deemed suitable, localization will guide re-implantation.

Stereotactic Delivery of Helper-dependent Adenoviral Viral Vectors at Distinct Developmental Time Points to Perform Age-dependent Molecular Manipulations of the Mouse Calyx of Held.

Synapses are specialized structures that enable neuronal communication, which is essential for brain function and development. Alterations in synaptic proteins have been linked to various neurological and neuropsychiatric disorders. Therefore, manipulating synaptic proteins in vivo can provide insight into the molecular mechanisms underlying these disorders and aid in developing new therapeutic strategies. Previous methods such as constitutive knock-out animals are limited by developmental compensation and off-target effects. The current approach outlines procedures for age-dependent molecular manipulations in mice using helper-dependent adenovirus viral vectors (HdAd) at distinct developmental time points. Using stereotactic injection of HdAds in both newborn and juvenile mice, we demonstrate the versatility of this method to express Cre recombinase in globular bushy cells of juvenile Rac1fl/fl mice to ablate presynaptic Rac1 and study its role in synaptic transmission. Separately, we overexpress CaV2 α1 subunits at two distinct developmental time points to elucidate the mechanisms that determine presynaptic CaV2 channel abundance and preference. This method presents a reliable, cost-effective, and minimally invasive approach for controlling gene expression in specific regions of the mouse brain and will be a powerful tool to decipher brain function in health and disease. Key features Virus-mediated genetic perturbation in neonatal and young adult mice. Stereotaxic injection allows targeting of brain structures at different developmental stages to study the impact of genetic perturbation throughout the development.

Diff-ATAC-STARR-Seq: A Method for Genome-Wide Functional Screening of Enhancer Activity in Vivo.

Transcriptional regulatory elements, including promoters and enhancers, play a key role in the cell-type specific regulation of the transcriptome. Application of rapidly evolving genetic tools, such as optogenetic/chemogenetic actuators and fluorescent reporters to elucidate the function of cell subtypes in vivo necessitates cell-type specific promoters or enhancers. In this context, methods for genome-wide functional screening of cis-regulatory elements, including enhancers, are of utmost importance. In this study, we describe a novel method for genome-wide functional screening of enhancer activity in vivo with minimal handling. Application of the method to cells from different brain structures and subsequent differential analysis allow identification of active enhancers in the target tissue or brain structures. To demonstrate proof of concept, we applied this method to samples from the dorsal raphe nucleus (DRN) and the medial prefrontal cortex of the mouse brain and successfully identified six enhancers with highly biased activity towards the dorsal raphe nucleus. Considering that these two structures consist of largely similar cell types whereas serotonin and dopamine neurons exist only in the DRN, our results confirm the validity of this method in identifying cell-type specific and brain-structure specific enhancers. Overall, this method will be helpful in identifying cis-regulatory elements suitable for cell-type specific manipulations.

Laser‐Driven Wireless Deep Brain Stimulation using Temporal Interference and Organic Electrolytic Photocapacitors

AbstractDeep brain stimulation (DBS) is a technique commonly used both in clinical and fundamental neurosciences. Classically, brain stimulation requires an implanted and wired electrode system to deliver stimulation directly to the target area. Although techniques such as temporal interference (TI) can provide stimulation at depth without involving any implanted electrodes, these methods still rely on a wired apparatus which limits free movement. Herein organic photocapacitors as untethered light‐driven electrodes which convert deep‐red light into electric current are reported. Pairs of these ultrathin devices can be driven using lasers at two different frequencies to deliver stimulation at depth via temporally interfering fields. This concept of laser TI stimulation using numerical modeling, tests with phantom brain samples, and finally in vivo tests is validated. Wireless organic photocapacitors are placed on the cortex and elicit stimulation in the hippocampus, while not delivering off‐target stimulation in the cortex. This laser‐driven wireless TI evokes a neuronal response at depth that is comparable to control experiments induced with deep brain stimulation protocols using implanted electrodes. This work shows that a combination of these two techniques—temporal interference and organic electrolytic photocapacitors—provides a reliable way to target brain structures requiring neither deeply implanted electrodes nor tethered stimulator devices. The laser TI protocol demonstrated here addresses two of the most important drawbacks in the field of DBS and thus holds potential to solve many issues in freely moving animal experiments or for clinical chronic therapy application.

An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement.

SUMMARYAlthough midbrain dopamine (DA) circuits are central to motivated behaviors, our knowledge of how experience modifies these circuits to facilitate subsequent behavioral adaptations is limited. Here we demonstrate the selective role of a ventral tegmental area DA projection to the amygdala (VTADA→amygdala) for cocaine-induced anxiety but not cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach reveals a persistent elevation in spontaneous and task-related activity of inhibitory GABAergic cells from the bed nucleus of the stria terminalis (BNST) and downstream VTADA→amygdala cells that can be detected even after a single cocaine exposure. Activity in BNSTGABA→midbrain cells is related to cocaine-induced anxiety but not reward or sensitization, and silencing this projection prevents development of anxiety during protracted withdrawal after cocaine administration. Finally, we observe that VTADA→amygdala cells are strongly activated after a challenge exposure to cocaine and that activity in these cells is necessary and sufficient for reinstatement of cocaine place preference.

Nanoparticle designs for delivery of nucleic acid therapeutics as brain cancer therapies.

Glioblastoma (GBM) is an aggressive central nervous system cancer with a dismal prognosis. The standard of care involves surgical resection followed by radiotherapy and chemotherapy, but five-year survival is only 5.6% despite these measures. Novel therapeutic approaches, such as immunotherapies, targeted therapies, and gene therapies, have been explored to attempt to extend survival for patients. Nanoparticles have been receiving increasing attention as promising vehicles for non-viral nucleic acid delivery in the context of GBM, though delivery is often limited by low blood-brain barrier permeability, particle instability, and low trafficking to target brain structures and cells. In this review, nanoparticle design considerations and new advances to overcome nucleic acid delivery challenges to treat brain cancer are summarized and discussed.

A literature review of magnetic resonance imaging sequence advancements in visualizing functional neurosurgery targets.

Historically, preoperative planning for functional neurosurgery has depended on the indirect localization of target brain structures using visible anatomical landmarks. However, recent technological advances in neuroimaging have permitted marked improvements in MRI-based direct target visualization, allowing for refinement of "first-pass" targeting. The authors reviewed studies relating to direct MRI visualization of the most common functional neurosurgery targets (subthalamic nucleus, globus pallidus, and thalamus) and summarize sequence specifications for the various approaches described in this literature. The peer-reviewed literature on MRI visualization of the subthalamic nucleus, globus pallidus, and thalamus was obtained by searching MEDLINE. Publications examining direct MRI visualization of these deep brain stimulation targets were included for review. A variety of specialized sequences and postprocessing methods for enhanced MRI visualization are in current use. These include susceptibility-based techniques such as quantitative susceptibility mapping, which exploit the amount of tissue iron in target structures, and white matter attenuated inversion recovery, which suppresses the signal from white matter to improve the distinction between gray matter nuclei. However, evidence confirming the superiority of these sequences over indirect targeting with respect to clinical outcome is sparse. Future targeting may utilize information about functional and structural networks, necessitating the use of resting-state functional MRI and diffusion-weighted imaging. Specialized MRI sequences have enabled considerable improvement in the visualization of common deep brain stimulation targets. With further validation of their ability to improve clinical outcomes and advances in imaging techniques, direct visualization of targets may play an increasingly important role in preoperative planning.

Improving Stereotaxic Neurosurgery Techniques and Procedures Greatly Reduces the Number of Rats Used per Experimental Group—A Practice Report

Simple SummaryStereotaxic surgery techniques are commonly used today in research laboratories by a range of students, technicians, and researchers. Over the past twenty years, technical and scientific progress has been made in neurosurgery to meet the evolving requirements imposed by international legislation, and to promote the implementation of 3R rules. These improvements were motivated by a greater awareness of animal welfare and the necessary effort in the reduction of the number of animals used in experiments. The data presented in the present study show that technical and methodological improvements brought to our surgical procedures from 1992 resulted in reproducible stereotaxic neurosurgeries and in a significant reduction in experimental errors and animal morbidity. The effects of these improvements include a decrease in the final number of animals used in our experiments as well as better management of pain during and after surgery and the use of appropriate aseptic techniques. Correct stereotaxic surgical approaches are precisely described throughout the text.Techniques of stereotaxic surgery are commonly used in research laboratories by a range of students, technicians, and researchers. To meet the evolving requirements imposed by international legislation, and to promote the implementation of 3R rules (replacement, reduction, and refinement) by reducing experimental error, animal morbidity, and mortality, it is essential that standard operating procedures and proper conduct following such complex surgeries be precisely described and respected. The present report shows how refinements of our own neurosurgical techniques over decades, have significantly reduced the number of animals (rats) used in experiments and improved the animals’ well-being during the post-surgical recovery period. The current pre-, per-, and post-surgical procedures used in our laboratory are detailed. We describe the practical aspects of stereotaxic neurosurgery that have been refined in our laboratory since 1992 and that cover various areas including appropriate anesthesia and pain management during and after surgery, methods to determine the stereotaxic coordinates, and the best approach to the target brain structure. The application of these optimal surgical methods that combine reliable and reproducible results with an acute awareness of ethics and animal welfare leads to a significant reduction in the number of animals included in experimental research in accordance with ethical and regulatory rules as required by the European Directive on laboratory animal welfare.

Modulating effect of liposomal miR-101 on the processes of amyloidogenesis, smell, sleep and neuroinflammation in experimental Alzheimer's disease

The current therapy for Alzheimer's disease does not give patients a chance of recovery. Therefore, it is relevant to study the novel factors of influence, in particular microRNA, on the pathogenic mechanisms of amyloidosis. The aim of this work was to determine the effect of miR-101 on early predictors of amyloidosis in experimental Alzheimer's disease in animals. The study was carried out on 25 male rats of 14 months of age. A model of Alzheimer's disease was created by intrahippocampal administration of Aβ40 aggregates to animals. Ten days later, a 10-day course of nasal administration of miR-101 in liposomes was launched. The level of endogenous Aβ42 and cytokines (TNFα, IL-6 and IL-10) was determined in the supernatants of the nerve tissues of the target brain structures (hippocampus, olfactory bulbs, and olfactory tubercles). A neuroethological method of presenting smells of isovaleric acid and peanut butter was used to assess the olfactory system functional state in the experimental rats. In the course of polygraphic registration of the sleep-wakefulness cycle, the representation of wakefulness and individual sleep phases, as well as proportion of incomplete and complete sleep cycles were determined. It was shown that injection of Aβ40 aggregates into the hippocampus simulates an amyloidogenic state in the rat’s hippocampus and olfactory tubercles, but not in the olfactory bulbs. Moreover, a pro-inflammatory state was registered in the hippocampus of the animal brain (an increase in the concentration of pro-inflammatory cytokines TNFα and IL-6), while the cytokine level in the olfactory bulbs and tubercles did not change. When studying the functional state of olfactory analyzers in the rats with Alzheimer's disease, we revealed negative changes in behavioral response to the smell of isovaleric acid and peanut butter. In terms of somnograms, the Aβ40 toxicity caused reduction in the deep slow-wave sleep stage combined with deficiency of the paradoxical sleep phase, and predominance of incomplete sleep cycles. Nasal therapy with miR-101 in liposomes normalized the level of Aβ42 in the hippocampus and olfactory tubercles and decreased the level of proinflammatory cytokines in the hippocampus. MiR-101 prevented olfactory disfunctions in assessing smells of isovaleric acid and peanut butter, increased the ratio of deep slow-wave sleep and paradoxical sleep in the cycle structure and restored proportion of complete sleep cycles in animals. Thus, liposomal miR-101 has an anti-amyloidogenic and anti-inflammatory effect in rats with a model of Alzheimer's disease. It helps to restore the functional state of olfactory analyzer and optimize structural organization of the sleep-wakefulness cycle in sick animals.

Neoadjuvant Chemotherapy and Whole Ventricular Irradiation for Pure Intracranial Germinoma: A Comparison of Three Brain-Sparing Techniques.

ObjectiveTo quantitate and compare the dosimetric properties of three brain-sparing radiation therapy techniques for pure intracranial germinomas with dose-volume analysis of target and normal brain structures.MethodsWe identified 18 patients with central nervous system (CNS) germinoma who had achieved local control and had excellent neurocognitive outcomes. Four patients who were treated with a simultaneous integrated boost (SIB) plan of 22.5Gy to whole ventricle (WV) and 30Gy to primary were re-planned with 24Gy to WV-only and the Children’s Oncology Group (COG) protocol of 18Gy to WV with a sequential boost to 30Gy. Organ-at-risk (OAR) doses for hippocampi, temporal lobes, whole brain, whole brain minus whole ventricles planning target volume (WB-WVPTV), WVPTV, and boost volume were comparatively studied.ResultsFor patients treated with the SIB plan, an excellent neurocognitive function has previously been shown to be well preserved. Three-year event-free survival (EFS) and overall survival (OS) for this group have also previously been demonstrated (89.5% and 100%, respectively). Mean and integral OAR doses were comparable between SIB and WV-only plans but were lower for COG plans. Whole brain, whole brain minus WVPTV, and temporal lobe V20, V18, and V12, as well as hippocampi V20, V25, and V30, were comparable between SIB and WV-only plans but were lower for the COG plans.ConclusionCompared to the WV-only method, the SIB plan permits more dose to the primary site by 6 Gy without compromising neurocognitive control. While maintaining the 30Gy boost, the COG protocol reduces the WVPTV dose to 18Gy. It remains to be seen whether WV dose reduction risks reducing local control.

Causal Inferences in Repetitive Transcranial Magnetic Stimulation Research: Challenges and Perspectives.

Transcranial magnetic stimulation (TMS) is used to make inferences about relationships between brain areas and their functions because, in contrast to neuroimaging tools, it modulates neuronal activity. The central aim of this article is to critically evaluate to what extent it is possible to draw causal inferences from repetitive TMS (rTMS) data. To that end, we describe the logical limitations of inferences based on rTMS experiments. The presented analysis suggests that rTMS alone does not provide the sort of premises that are sufficient to warrant strong inferences about the direct causal properties of targeted brain structures. Overcoming these limitations demands a close look at the designs of rTMS studies, especially the methodological and theoretical conditions which are necessary for the functional decomposition of the relations between brain areas and cognitive functions. The main points of this article are that TMS-based inferences are limited in that stimulation-related causal effects are not equivalent to structure-related causal effects due to TMS side effects, the electric field distribution, and the sensitivity of neuroimaging and behavioral methods in detecting structure-related effects and disentangling them from confounds. Moreover, the postulated causal effects can be based on indirect (network) effects. A few suggestions on how to manage some of these limitations are presented. We discuss the benefits of combining rTMS with neuroimaging in experimental reasoning and we address the restrictions and requirements of rTMS control conditions. The use of neuroimaging and control conditions allows stronger inferences to be gained, but the strength of the inferences that can be drawn depends on the individual experiment’s designs. Moreover, in some cases, TMS might not be an appropriate method of answering causality-related questions or the hypotheses have to account for the limitations of this technique. We hope this summary and formalization of the reasoning behind rTMS research can be of use not only for scientists and clinicians who intend to interpret rTMS results causally but also for philosophers interested in causal inferences based on brain stimulation research.

Animal Models of Tinnitus Treatment: Cochlear and Brain Stimulation.

Neuromodulation, via stimulation of a variety of peripheral and central structures, is used to suppress tinnitus. However, investigative limitations in humans due to ethical reasons have made it difficult to decipher the mechanisms underlying treatment-induced tinnitus relief, so a number of animal models have arisen to address these unknowns. This chapter reviews animal models of cochlear and brain stimulation and assesses their modulatory effects on behavioral evidence of tinnitus and its related neural correlates. When a structure is stimulated, localized modulation, often presenting as downregulation of spontaneous neuronal spike firing rate, bursting and neurosynchrony, occurs within the brain area. Through anatomical projections and transmitter pathways, the interventions activate both auditory- and non-auditory structures by taking bottom-up ascending and top-down descending modes to influence their target brain structures. Furthermore, it is the brain oscillations that cochlear or brain stimulation evoke and connect the prefrontal cortex, striatal systems, and other limbic structures to refresh neural networks and relieve auditory, attentive, conscious, as well as emotional reactive aspects of tinnitus. This oscillatory neural network connectivity is achieved via the thalamocorticothalamic circuitry including the lemniscal and non-lemniscal auditory brain structures. Beyond existing technologies, the review also reveals opportunities for developing advanced animal models using new modalities to achieve precision neuromodulation and tinnitus abatement, such as optogenetic cochlear and/or brain stimulation.

Novel method of combined photon beam radiotherapy and brachytherapy for treatment of extensive advanced scalp squamous cell carcinoma

Radiotherapy of extensive malignant scalp lesions has always been a challenge for radiation oncologists considering the proximity of critical structures.We treated a 39-year-old patient with extensive scalp squamous cell carcinoma with application of adjuvant concurrent chemoradiation and external beam radiation therapy (EBRT), followed by high-dose-rate (HDR) surface brachytherapy boost using an exclusively designed mould, and assessed the radiation dose reaching planning target volume, brain, and optic structures.Comparison between conventional planning with sole EBRT and combined treatment planning with EBRT and brachytherapy, assured the use of the latter treatment to avoid high radiation doses from reaching critical organs at risk without compromising the required dose for planning target volume.

Focused Ultrasound Induced Blood-Brain Barrier Opening for Targeting Brain Structures and Evaluating Chemogenetic Neuromodulation

Focused Ultrasound Induced Blood-Brain Barrier Opening for Targeting Brain Structures and Evaluating Chemogenetic Neuromodulation

Focused Ultrasound Induced Blood-Brain Barrier Opening for Targeting Brain Structures and Evaluating Chemogenetic Neuromodulation.

Acoustically Targeted Chemogenetics (ATAC) allows for the noninvasive control of specific neural circuits. ATAC achieves such control through a combination of focused ultrasound (FUS) induced blood-brain barrier opening (FUS-BBBO), gene delivery with adeno-associated viral (AAV) vectors, and activation of cellular signaling with engineered, chemogenetic, protein receptors and their cognate ligands. With ATAC, it is possible to transduce both large and small brain regions with millimeter precision using a single noninvasive ultrasound application. This transduction can later allow for a long-term, noninvasive, device-free neuromodulation in freely moving animals using a drug. Since FUS-BBBO, AAVs, and chemogenetics have been used in multiple animals, ATAC should also be scalable for the use in other animal species. This paper expands upon a previously published protocol and outlines how to optimize the gene delivery with FUS-BBBO to small brain regions with MRI-guidance but without a need for a complicated MRI-compatible FUS device. The protocol, also, describes the design of mouse targeting and restraint components that can be 3D-printed by any lab and can be easily modified for different species or custom equipment. To aid reproducibility, the protocol describes in detail how the microbubbles, AAVs, and venipuncture were used in ATAC development. Finally, an example data is shown to guide the preliminary investigations of studies utilizing ATAC.

Comprehensive Investigation of Metabolic Changes Occurring in the Rat Brain Hippocampus after Fluoxetine Administration Using Two Complementary In Vivo Techniques: Solid Phase Microextraction and Microdialysis.

Fluoxetine is among the most prescribed antidepressant drugs worldwide. Nevertheless, limited information is known about its definitive mechanism. Although in vivo examinations performed directly in related brain structures can provide more realistic, and therefore more insightful, knowledge regarding the mechanisms and efficacy of this drug, only a few techniques are applicable for in vivo monitoring of metabolic alterations in the brain following an inducement. Among them, solid phase microextraction (SPME) and microdialysis (MD) have emerged as ideal in vivo tools for extraction of information from biosystems. In this investigation, we scrutinized the capabilities of SPME and MD to detect ongoing changes in the brain following acute fluoxetine administration. Sequential in vivo samples were collected simultaneously from male rats' hippocampi using SPME and MD before drug administration in order to establish a baseline; then samples were collected again following fluoxetine administration for an investigation of small molecule alterations. Our results indicate that MD provides more comprehensive information for polar compounds, while SPME provides superior information with respect to lipids and other medium level polar molecules. Interestingly, in the lipidomic investigation, all dysregulated features were found to be membrane lipids and associated compounds. Moreover, in the metabolomic investigations, dysregulation of hippocampal metabolite levels associated with fatty acid transportation and purine metabolisms were among the most notable findings. Overall, our evaluation of the obtained data corroborates that, when used in tandem, SPME and MD are capable of providing comprehensive information regarding the effect of fluoxetine in targeted brain structures and further elucidating this drug's mechanisms of action in the brain.

Deep Brain Stimulation for Treatment-Resistant Depression: Towards a More Personalized Treatment Approach.

Major depressive disorder (MDD) affects approximately 4.4% of the world’s population. One third of MDD patients do not respond to routine psychotherapeutic and pharmacotherapeutic treatment and are said to suffer from treatment-resistant depression (TRD). Deep brain stimulation (DBS) is increasingly being investigated as a treatment modality for TRD. Although early case studies showed promising results of DBS, open-label trials and placebo-controlled studies have reported inconsistent outcomes. This has raised discussion about the correct interpretation of trial results as well as the criteria for patient selection, the choice of stimulation target, and the optimal stimulation parameters. In this narrative review, we summarize recent studies of the effectiveness of DBS in TRD and address the relation between the targeted brain structures and clinical outcomes. Elaborating upon that, we hypothesize that the effectiveness of DBS in TRD can be increased by a more personalized and symptom-based approach. This may be achieved by using resting-state connectivity mapping for neurophysiological subtyping of TRD, by using individualized tractography to help decisions about stimulation target and electrode placement, and by using a more detailed registration of symptomatic improvements during DBS, for instance by using ‘experience sampling’ methods.

A pilot study of brain morphometry following donepezil treatment in mild cognitive impairment: volume changes of cortical/subcortical regions and hippocampal subfields

The efficacy of donepezil is well known for improving the cognitive performance in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Most of the recent neuroimaging studies focusing on the brain morphometry have dealt with the targeted brain structures, and thus it remains unknown how donepezil treatment influences the volume change over the whole brain areas including the cortical and subcortical regions and hippocampal subfields in particular. This study aimed to evaluate overall gray matter (GM) volume changes after donepezil treatment in MCI, which is a prodromal phase of AD, using voxel-based morphometry. Patients with MCI underwent the magnetic resonance imaging (MRI) before and after 6-month donepezil treatment. The cognitive function for MCI was evaluated using the questionnaires of the Korean version of the mini-mental state examination (K-MMSE) and Alzheimer’s disease assessment scale-cognitive subscale (ADAS-Cog). Compared with healthy controls, patients with MCI showed significantly lower GM volumes in the hippocampus and its subfields, specifically in the right subiculum and left cornu ammonis (CA3). The average scores of K-MMSE in patients with MCI improved by 8% after donepezil treatment. Treated patients showed significantly higher GM volumes in the putamen, globus pailldus, and inferior frontal gyrus after donepezil treatment (p < 0.001). However, whole hippocampal volume in the patients decreased by 0.6% after 6-month treatment, and the rate of volume change in the left hippocampus was negatively correlated with the period of treatment. These findings will be useful for screening and tracking MCI, as well as understanding of the pathogenesis of MCI in connection with brain morphometric change.

Adaptable Angled Stereotactic Approach for Versatile Neuroscience Techniques.

Stereotactic surgery is an essential tool in the modern neuroscience lab. However, the ability to precisely and accurately target difficult-to-reach brain regions still presents a challenge, particularly when targeting brain structures along the midline. These challenges include avoiding of the superior sagittal sinus and third ventricle and the ability to consistently target selective and discrete brain nuclei. In addition, more advanced neuroscience techniques (e.g., optogenetics, fiber photometry, and two-photon imaging) rely on targeted implantation of significant hardware to the brain, and spatial limitations are a common hindrance. Presented here is a modifiable protocol for stereotactic targeting of rodent brain structures using an angled coronal approach. It can be adapted to 1) mouse or rat models, 2) various neuroscience techniques, and 3) multiple brain regions. As a representative example, it includes the calculation of stereotactic coordinates for targeting of the mouse hypothalamic ventromedial nucleus (VMN) for an optogenetic inhibition experiment. This procedure begins with the bilateral microinjection of an adeno-associated virus (AAV) encoding a light-sensitive chloride channel (SwiChR++) to a Cre-dependent mouse model, followed by the angled bilateral implantation of fiberoptic cannulae. Using this approach, findings show that activation of a subset of VMN neurons is required for intact glucose counterregulatory responses to insulin-induced hypoglycemia.

High resolution transcranial acoustoelectric imaging of current densities from a directional deep brain stimulator

Objective. New innovations in deep brain stimulation (DBS) enable directional current steering—allowing more precise electrical stimulation of the targeted brain structures for Parkinson’s disease, essential tremor and other neurological disorders. While intra-operative navigation through MRI or CT approaches millimeter accuracy for placing the DBS leads, no existing modality provides feedback of the currents as they spread from the contacts through the brain tissue. In this study, we investigate transcranial acoustoelectric imaging (tAEI) as a new modality to non-invasively image and characterize current produced from a directional DBS lead. tAEI uses ultrasound (US) to modulate tissue resistivity to generate detectable voltage signals proportional to the local currents. Approach. An 8-channel directional DBS lead (Infinity 6172ANS, Abbott Inc) was inserted inside three adult human skulls submerged in 0.9% NaCl. A 2.5 MHz linear array delivered US pulses through the transtemporal window and focused near the contacts on the lead, while a custom amplifier and acquisition system recorded the acoustoelectric (AE) interaction used to generate images. Main results. tAEI detected monopolar current with stimulation pulses as short as 100 µs with an SNR ranging from 10–27 dB when using safe US pressure (mechanical indices <0.78) and injected current of ~2 mA peak amplitude. Adjacent contacts were discernable along the length and within each ring of the lead with a mean radial separation between contacts of 2.10 and 1.34 mm, respectively. Significance. These results demonstrate the feasibility of tAEI for high resolution mapping of directional DBS currents using clinically-relevant stimulation parameters. This new modality may improve the accuracy for placing the DBS leads, guide calibration and programming, and monitor long-term performance of DBS for treatment of Parkinson’s disease.