Stimulation Of Specific Brain Regions Research Articles

General Algorithm Applicability in Determining DBS Lead Orientation: Adapting 2D and 3D X-Ray Techniques for SenSightTM Leads

Introduction: With recent advancements in deep brain stimulation (DBS), directional leads featuring segmented contacts have been introduced, allowing for targeted stimulation of specific brain regions. Given that manufacturers employ diverse markers for lead orientation, our investigation focuses on the adaptability of the 2017 techniques proposed by the Cologne research group for lead orientation determination. Methods: We tailored the two separate 2D and 3D X-ray-based techniques published in 2017 and originally developed for C-shaped markers, to the dual-marker of the Medtronic SenSight™ lead. In a retrospective patient study, we evaluated their feasibility and consistency by comparing the degree of agreement between the two methods. Results: The Bland-Altman plot showed favorable concordance without any noticeable systematic errors. The mean difference was 0.79°, with limits of agreement spanning from 21.4° to −19.8°. The algorithms demonstrated high reliability, evidenced by an intraclass correlation coefficient of 0.99 (p < 0.001). Conclusion: The 2D and 3D algorithms, initially formulated for discerning the circular orientation of a C-shaped marker, were adapted to the marker of the Medtronic SenSight™ lead. Statistical analyses revealed a significant level of agreement between the two methods. Our findings highlight the adaptability of these algorithms to different markers, achievable through both low-dose intraoperative 2D X-ray imaging and standard CT imaging.

In-vivo verified anatomically aware deep learning for real-time electric field simulation

Objective. Transcranial magnetic stimulation (TMS) has emerged as a prominent non-invasive technique for modulating brain function and treating mental disorders. By generating a high-precision magnetically evoked electric field (E-field) using a TMS coil, it enables targeted stimulation of specific brain regions. However, current computational methods employed for E-field simulations necessitate extensive preprocessing and simulation time, limiting their fast applications in the determining the optimal coil placement. Approach. We present an attentional deep learning network to simulate E-fields. This network takes individual magnetic resonance images and coil configurations as inputs, firstly transforming the images into explicit brain tissues and subsequently generating the local E-field distribution near the target brain region. Main results. Relative to the previous deep-learning simulation method, the presented method reduced the mean relative error in simulated E-field strength of gray matter by 21.1%, and increased the correlation between regional E-field strengths and corresponding electrophysiological responses by 35.0% when applied into another dataset. In-vivo TMS experiments further revealed that the optimal coil placements derived from presented method exhibit comparable stimulation performance on motor evoked potentials to those obtained using computational methods. The simplified preprocessing and increased simulation efficiency result in a significant reduction in the overall time cost of traditional TMS coil placement optimization, from several hours to mere minutes. Significance. The precision and efficiency of presented simulation method hold promise for its application in determining individualized coil placements in clinical practice, paving the way for personalized TMS treatments.

Optogenetic Stimulation of the Central Amygdala Using Channelrhodopsin.

Optogenetics allows for the targeted temporary inhibition or stimulation of specific brain regions in vivo with precisetemporal resolution. Here, we describe the steps to perform intracranial optogenetic surgery in rodents as well as instructions to build an optogenetic headcap and set up an optogenetic testing environment to conduct experiments. Behavioral studies have implemented these methods to stimulate the central amygdala (CeA) to create an addictive-like preference for reward.

Accessibility of cortical regions to focal TES: Dependence on spatial position, safety, and practical constraints

Transcranial electric stimulation (TES) can modulate intrinsic neural activity in the brain by injecting weak currents through electrodes attached to the scalp. TES has been widely used as a neuroscience tool to investigate how behavioural and physiological variables of brain function are modulated by electric stimulation of specific brain regions. For an unambiguous interpretation of TES experiments, it is important that the electric fields can be steered towards one or several brain regions-of-interest. However, the conductive proprieties of the human head impose inherent physical limitations on how focal the electric fields in the brain produced by multi-electrode TES can be. As a rule of thumb, it is not feasible to selectively target deep brain areas with TES, although focusing the field in some specific deeper locations might be possible due to favourable conductive properties in the surrounding tissue. In the present study, we first propose a computationally efficient method for the automatic determination of electrode placements and stimulation intensities to optimally affect a given target position. We provide a robust implementation of the optimization procedure that is able to adhere to safety constraints, while explicitly controlling both the number of active electrodes and the angular deviation of the field in the target area relative to the desired field direction. Leveraging the high computational efficiency of our method, we systematically assess the achievable focality of multi-electrode TES for all cortex positions, thereby investigating the dependence on the chosen constraints. Our results provide comprehensive insight into the limitations regarding the achievable TES dose and focality that are imposed by the biophysical constraints and the safety considerations of TES.

Non-invasive chemogenetics.

A technique combining focused ultrasound for opening the blood–brain barrier and virally encoded engineered G-protein-coupled receptors for promoting the expression of a gene targeting excitatory neurons enables the non-invasive stimulation of specific brain regions and cell types in mice.

Causal mapping of emotion networks in the human brain: Framework and initial findings

Emotions involve many cortical and subcortical regions, prominently including the amygdala. It remains unknown how these multiple network components interact, and it remains unknown how they cause the behavioral, autonomic, and experiential effects of emotions. Here we describe a framework for combining a novel technique, concurrent electrical stimulation with fMRI (es-fMRI), together with a novel analysis, inferring causal structure from fMRI data (causal discovery). We outline a research program for investigating human emotion with these new tools, and provide initial findings from two large resting-state datasets as well as case studies in neurosurgical patients with electrical stimulation of the amygdala. The overarching goal is to use causal discovery methods on fMRI data to infer causal graphical models of how brain regions interact, and then to further constrain these models with direct stimulation of specific brain regions and concurrent fMRI. We conclude by discussing limitations and future extensions. The approach could yield anatomical hypotheses about brain connectivity, motivate rational strategies for treating mood disorders with deep brain stimulation, and could be extended to animal studies that use combined optogenetic fMRI.

Enhanced Working Memory Binding by Direct Electrical Stimulation of the Parietal Cortex.

Recent works evince the critical role of visual short-term memory (STM) binding deficits as a clinical and preclinical marker of Alzheimer’s disease (AD). These studies suggest a potential role of posterior brain regions in both the neurocognitive deficits of Alzheimer’s patients and STM binding in general. Thereupon, we surmised that stimulation of the posterior parietal cortex (PPC) might be a successful approach to tackle working memory deficits in this condition, especially at early stages. To date, no causal evidence exists of the role of the parietal cortex in STM binding. A unique approach to assess this issue is afforded by single-subject direct intracranial electrical stimulation of specific brain regions during a relevant cognitive task. Electrical stimulation has been used both for clinical purposes and to causally probe brain mechanisms. Previous evidence of electrical currents spreading through white matter along well defined functional circuits indicates that visual working memory mechanisms are subserved by a specific widely distributed network. Here, we stimulated the parietal cortex of a subject with intracranial electrodes as he performed the visual STM task. We compared the ensuing results to those from a non-stimulated condition and to the performance of a matched control group. In brief, direct stimulation of the parietal cortex induced a selective improvement in STM. These results, together with previous studies, provide very preliminary but promising ground to examine behavioral changes upon parietal stimulation in AD. We discuss our results regarding: (a) the usefulness of the task to target prodromal stages of AD; (b) the role of a posterior network in STM binding and in AD; and (c) the potential opportunity to improve STM binding through brain stimulation.

Connectomics and other novel methods for examining neural systems

Novel approaches for studying the brain and relating its activities to mental phenomena have come into use during the past decade (Bargmann, 2015). These include both new laboratory methods – involving, among others, generation of isolated cells which retain neuronal characteristics in vivo; the selective stimulation of neurons by light in vivo; and direct electrical stimulation of specific brain regions to restore a system's balance of excitation and inhibition – and a new organizing principle, “connectomics”, which recognizes that networks, and not simply a key nucleus or region, underlie most brain functions and malfunctions. Its application has already improved our comprehension of how the brain normally functions and our ability to help patients with such poorly treated neurologic and psychiatric diseases as Alzheimer's disease.

EP 18. Deep Brain Stimulation improves behavior and modulates neural circuits in a rodent model of schizophrenia

Background A growing body of evidence suggests that schizophrenia (scz) is a neurodevelopmental disorder in which some brain alterations already occur during early brain development and others progress along the developmental course. This progressive nature of scz raises interest in the development of preventive avenues, i.e. therapeutic interventions prior to the full symptoms manifestation. For that however, a profounder understanding of the exact nature of altered brain development in scz is needed. Given methodological and ethical limitations of human studies, the use of appropriate animal models of schizophrenia is an invaluable tool. Methods This study used a maternal immune stimulation (MIS) rodent model of schizophrenia together with a neuromodulation approach, namely deep brain stimulation (DBS), to investigate the neurobiological and behavioral alterations during the course of disease. In this model, the exposure of pregnant rodents on their gestational day 15 to the viral mimic polyriboinosinic-polyribocytidylic acid (poly I:C) results in schizophrenia-relevant behavioral abnormalities which first emerge in adulthood, complying with the postnatal delay of this disorder. We applied DBS-interventions to the medial prefrontal cortex (mPFC) or nucleus accumbens (Nacc) to either poly I:C progeny or controls, at two different time points of scz development: a continuous DBS during a pre-symptomatic adolescence period and an acute DBS at the full symptomatic period of adulthood. In adulthood, we tested the effects of both interventions on two behavioral processes known to be disrupted in scz and in this model: sensorimotor gating and attentional selectivity. In addition, we studied the effects of DBS on several neurobiological parameters at post mortem . Results When applied at adulthood, DBS to both regions was found to be successful in alleviating sensorimotor gating and attentional selectivity deficits in the MIS model. However, when applied in adolescence only mPFC stimulation prevented both behavioral deficits, whereas Nacc stimulation only normalized sensorimotor deficits. Moreover, stimulation in those two brain sites induced different brain metabolic effects and neurochemical alterations, even if the effect on behavior was identical. Conclusions This study adds to the growing literature suggesting that electrical stimulation of specific brain regions improves behavioral deficits in neuro-psychiatric disorders and also scz. Moreover, this study indicates that early neuro-modulation might halt the progression of scz in reliance on stimulation site.

Role of external stimulation in shaping evoked activity in a macroscopic model of cortex

The activity of the brain exhibits stereotypical patterns at various temporal and spatial scales. Novel techniques such as functional magnetic resonance imaging (fMRI) allow the simultaneous recording of the macroscopic activity from all brain regions while subjects perform various tasks, such as passive hearing and active visual recognition. How neural activity is related to cognitive tasks is a long-standing question for the neuroscience community. This study examines an interesting aspect of this broad question, namely the comparison between the resting state (when the subjects is idle) and evoked activity during a task. Neural activity patterns consist of the correlations of firing activity between cortical regions - or functional connectivity - at a slow time scale (hundreds of ms), which can be related to data obtained from fMRI. The cortex has an intricate architecture of connections, both local and long-range. The latter have been mapped for the whole human cortex using diffusion techniques [1]. A recent model has demonstrated that this broad-scale structural connectivity is crucial to reproduce resting-state patterns of cortical activity [2]. Here we consider the same model and simulate tasks by exciting specific brain regions. We rely on mathematical and numerical analysis in order to uncover the respective roles of the long-range projections and external inputs in shaping the evoked activity. Our primary aim is to understand how the stimulation of specific brain regions can dramatically modify the functional connectivity, as compared to the resting state. We also examine the influence of long-range excitatory projections onto inhibitory populations, a novel dynamical ingredient compared to the previous model, in decorrelating brain regions.

Non-invasive Transcranial Magnetic Stimulation (TMS) of the Motor Cortex for Neuropathic Pain—At the Tipping Point?

The term “neuropathic pain” (NP) refers to chronic pain caused by illnesses or injuries that damage peripheral or central pain-sensing neural pathways to cause them to fire inappropriately and signal pain without cause. Neuropathic pain is common, complicating diabetes, shingles, HIV, and cancer. Medications are often ineffective or cause various adverse effects, so better approaches are needed. Half a century ago, electrical stimulation of specific brain regions (neuromodulation) was demonstrated to relieve refractory NP without distant effects, but the need for surgical electrode implantation limited use of deep brain stimulation. Next, electrodes applied to the dura outside the brain’s surface to stimulate the motor cortex were shown to relieve NP less invasively. Now, electromagnetic induction permits cortical neurons to be stimulated entirely non-invasively using transcranial magnetic stimulation (TMS). Repeated sessions of many TMS pulses (rTMS) can trigger neuronal plasticity to produce long-lasting therapeutic benefit. Repeated TMS already has US and European regulatory approval for treating refractory depression, and multiple small studies report efficacy for neuropathic pain. Recent improvements include “frameless stereotactic” neuronavigation systems, in which patients’ head MRIs allow TMS to be applied to precise underlying cortical targets, minimizing variability between sessions and patients, which may enhance efficacy. Transcranial magnetic stimulation appears poised for the larger trials necessary for regulatory approval of a NP indication. Since few clinicians are familiar with TMS, we review its theoretical basis and historical development, summarize the neuropathic pain trial results, and identify issues to resolve before large-scale clinical trials.

Brain stimulation in the study and treatment of addiction

Addiction is a devastating and chronically relapsing disorder. Repeated drug administration induces neuroadaptations associated with abnormal dopaminergic activity in the mesocorticolimbic circuitry, resulting in altered cortical neurotransmission and excitability. Electrical stimulation of specific brain regions can be used in animal models and humans to induce local activation or disruption of specific circuitries or alter neuronal excitability and cause neuroadaptations. Non-surgical stimulation of specific brain regions in human addicts can be achieved by transcranial magnetic stimulation (TMS). TMS is used for transient stimulation or disruption of neural activity in specific cortical regions, which can be used to assess cortical excitability, and to induce changes in cortical excitability. Moreover, it is suggested that repeated stimulation can cause long-lasting neuroadaptations. Therefore, TMS paradigms were used in some studies to assess the presence of altered cortical excitability associated with chronic drug consumption, while other studies have begun to assess the therapeutic potential of repetitive TMS. Similarly, transcranial direct current stimulation (tDCS) is used to modulate neuronal resting membrane potential in humans and alter cortical excitability. The current review describes how these brain stimulation techniques have recently been used for the study and treatment of addiction in animal models and humans.

Do muscle blood flow detectors link breathing to oxygen consumption in exercise?

One of the mysteries of physiology is how breathing is so closely linked to oxygen consumption in a wide variety of conditions such that arterial PO2 and PCO2 remain constant. This is especially true in mild to moderate aerobic muscular exercise where alveolar ventilation increases in direct proportion to oxygen consumption. How this occurs has been difficult to understand. There are two schools of thought. (1) ‘Central command’. The brain ‘decides’ to exercise and matches the motor activities of locomotion and breathing. This view arises from the observation that stimulation of specific brain regions increases both locomotor activity and breathing in a coordinated manner (Eldridge et al. 1985). The mystery here is how these neural events can be linked to metabolism in the distant tissue. (2) ‘Peripheral signals.’ Receptors in the periphery detect oxygen utilization (or its corollaries) and report to the brain, which then modifies breathing. Eligible receptors include the carotid body and the central chemoreceptors, which are quite sensitive to small changes in CO2, and an array of receptors in muscle that respond to mechanical and/or chemical signals including ATP (Kaufman & Hayes, 2002; Hanna & Kaufman, 2003). Haouzi and colleagues have been pursuing a particularly interesting subset of the ‘peripheral signals’ hypothesis, that sensory afferents detect the distension of small blood vessels (Haouzi et al. 2004). This distension could reflect muscle blood flow, which changes in proportion to tissue oxygen utilization. In this issue of The Journal of Physiology, Haouzi & Chenuel (2005) provide data that rule out any role for the carotid body and the central chemoreceptors in the exercise breathing response and indirectly support the vessel distension (blood flow) hypothesis. The experimental model is an anaesthetized sheep with exercise produced by electrically induced rhythmic muscle contractions (ERC). The induction of exercise by ERC eliminates ‘central command’ as a variable. By clever use of the vagaries of the cerebral circulation in this species, they perfuse vessels supplying both the carotid body and the central chemoreceptors with blood of constant arterial PO2 and PCO2 eliminating them as a source of the signal to breathe. During ERC under these conditions, ventilation still increases in direct proportion to muscle oxygen utilization. With block of venous return the appropriate match of ventilation to oxygen use remains unaltered suggesting that the signal for this match arises in the periphery. With block of arterial flow to the muscle, which decreases venous return without the vascular distension that occurs with venous block, ventilation is no longer linked to oxygen utilization. Thus in this model, the match of ventilation to muscle oxygen use involves distension of the small vessels (or accompanying tissue distortion), which the authors suggest represents a blood flow detector. Natural exercise differs remarkably from the experimental models used to examine the ‘central command’ and ‘peripheral signals’ hypotheses. With central stimulation (‘central command’) breathing does increase along with locomotion but the arterial PCO2 values decrease, and the match is imperfect. While the evidence from ERC experiments is intriguing, it seems unlikely that peripheral signals can be the single cause that links breathing to oxygen consumption in natural exercise given the powerful effects of central stimulation. In natural exercise perhaps ‘central command’ determines an initial match of locomotion and breathing that is modified by feedback from ‘peripheral signals’, an approach alluded to by most workers (Eldridge et al. 1985; Hanna & Kaufman, 2003; Haouzi & Chenuel, 2005). What is new here is the possibility that these ‘peripheral signals’ include a muscle blood flow detector, an intriguing suggestion that will doubtless promote discussion and experimentation.

Addictive drugs and brain stimulation reward.

Direct electrical or chemical stimulation of specific brain regions can establish response habits similar to those established by natural rewards such as food or sexual contact. Cocaine, mu and delta opiates, nicotine, phencyclidine, and cannabis each have actions that summate with rewarding electrical stimulation of the medial forebrain bundle (MFB). The reward-potentiating effects of amphetamine and opiates are associated with central sites of action where these drugs also have their direct rewarding effects, suggesting common mechanisms for drug reward per se and for drug potentiation of brain stimulation reward. The central sites at which these and perhaps other drugs of abuse potentiate brain stimulation reward and are rewarding in their own right are consistent with the hypothesis that the laboratory reward of brain stimulation and the pharmacological rewards of addictive drugs are habit forming because they act in the brain circuits that subserve more natural and biologically significant rewards.