A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression.

Target identification and contact selection are known contributors to variability in efficacy across different clinical indications of deep brain stimulation surgery. A retrospective analysis of responders to subcallosal cingulate deep brain stimulation (SCC DBS) for depression demonstrated the common impact of the electrical stimulation on a stereotypic connectome of converging white matter bundles (forceps minor, uncinate fasciculus, cingulum and fronto-striatal fibers). To test the utility of a prospective connectomic approach for SCC DBS surgery, this pilot study used the four-bundle tractography 'connectome blueprint' to plan surgical targeting in 11 participants with treatment-resistant depression. Before surgery, targets were selected individually using deterministic tractography. Selection of contacts for chronic stimulation was made by matching the post-operative probabilistic tractography map to the pre-surgical deterministic tractography map for each subject. Intraoperative behavioral responses were used as a secondary verification of location. A probabilistic tract map of all participants demonstrated inclusion of the four bundles as intended, matching the connectome blueprint previously defined. Eight of 11 patients (72.7%) were responders and 5 were remitters after 6 months of open-label stimulation. At one year, 9 of 11 patients (81.8%) were responders, with 6 of them in remission. These results support the utility of a group probabilistic tractography map as a connectome blueprint for individualized, patient-specific, deterministic tractography targeting, confirming retrospective findings previously published. This new method represents a connectomic approach to guide future SCC DBS studies.

Theoretical principles underlying optical stimulation of myelinated axons expressing channelrhodopsin-2.

Numerous clinical conditions can be treated by neuromodulation of the peripheral nervous system (PNS). Typical electrical PNS therapies activate large diameter axons at lower electrical stimulus thresholds than small diameter axons. However, recent animal experiments with peripheral optogenetic neural stimulation (PONS) of myelinated axons expressing channelrhodopsin-2 (ChR2) have shown that this technique activates small diameter axons at lower irradiances than large diameter axons. We hypothesized that the small-to-large diameter recruitment order primarily arises from the internodal spacing relationship of myelinated axons. Small diameter axons have shorter distances between their nodes of Ranvier, which increases the number of nodes of Ranvier directly illuminated relative to larger diameter axons. We constructed "light-axon" PONS models that included multi-compartment, double cable, myelinated axon models embedded with ChR2 membrane dynamics, coupled with a model of blue light dynamics in the tissue medium from a range of different light sources. The light-axon models enabled direct calculation of threshold irradiance for different diameter axons. Our simulations demonstrate that illumination of multiple nodal sections reduces the threshold irradiance and enhances the small-to-large diameter recruitment order. In addition to addressing biophysical questions, our light-axon model system could also be useful in guiding the engineering design of optical stimulation technology that could maximize the efficiency and selectivity of PONS.

Patient-specific analysis of the relationship between the volume of tissue activated during DBS and verbal fluency.

Deep brain stimulation (DBS) for the treatment of advanced Parkinson's disease involves implantation of a lead with four small contacts usually within the subthalamic nucleus (STN) or globus pallidus internus (GPi). While generally safe from a cognitive standpoint, STN DBS has been commonly associated with a decrease in the speeded production of words, a skill referred to as verbal fluency. Virtually all studies comparing presurgical to postsurgical verbal fluency performance have detected a decrease with DBS. The decline may be attributable in part to the surgical procedures, yet the relative contributions of stimulation effects are not known. In the present study, we used patient-specific DBS computer models to investigate the effects of stimulation on verbal fluency performance. Specifically, we investigated relationships of the volume and locus of activated STN tissue to verbal fluency outcome. Stimulation of different electrode contacts within the STN did not affect total verbal fluency scores. However, models of activation revealed subtle relationships between the locus and volume of activated tissue and verbal fluency performance. At ventral contacts, more tissue activation inside the STN was associated with decreased letter fluency performance. At optimal contacts, more tissue activation within the STN was associated with improved letter fluency performance. These findings suggest subtle effects of stimulation on verbal fluency performance, consistent with the functional nonmotor subregions/somatotopy of the STN.

Deep brain stimulation activation volumes and their association with neurophysiological mapping and therapeutic outcomes.

OBJECTIVE: Despite the clinical success of deep brain stimulation (DBS) for the treatment of Parkinson's disease (PD), little is known about the electrical spread of the stimulation. The primary goal of this study was to integrate neuroimaging, neurophysiology and neurostimulation data sets from 10 patients with PD, unilaterally implanted with subthalamic nucleus (STN) DBS electrodes, to identify the theoretical volume of tissue activated (VTA) by clinically defined therapeutic stimulation parameters. METHODS: Each patient specific model was created with a series of five steps: (1) definition of the neurosurgical stereotactic coordinate system within the context of preoperative imaging data; (2) entry of intraoperative microelectrode recording locations from neurophysiologically defined thalamic, subthalamic and substantia nigra neurons into the context of the imaging data; (3) fitting a three dimensional brain atlas to the neuroanatomy and neurophysiology of the patient; (4) positioning the DBS electrode in the documented stereotactic location, verified by postoperative imaging data; and (5) calculation of the VTA using a diffusion tensor based finite element neurostimulation model. RESULTS: The patient specific models show that therapeutic benefit was achieved with direct stimulation of a wide range of anatomical structures in the subthalamic region. Interestingly, of the five patients exhibiting a greater than 40% improvement in their Unified PD Rating Scale (UPDRS), all but one had the majority of their VTA outside the atlas defined borders of the STN. Furthermore, of the five patients with less than 40% UPDRS improvement, all but one had the majority of their VTA inside the STN. CONCLUSIONS: Our results are consistent with previous studies suggesting that therapeutic benefit is associated with electrode contacts near the dorsal border of the STN, and provide quantitative estimates of the electrical spread of the stimulation in a clinically relevant context.

Cicerone: stereotactic neurophysiological recording and deep brain stimulation electrode placement software system.

Stereotactic neurosurgery and neurophysiological microelectrode recordings in both humans and monkeys are typically done with conventional 2D atlases and paper records of the stereotactic coordinates. This approach is prone to error because the brain size, shape, and location of subcortical structures can vary between subjects. Furthermore, paper record keeping is inefficient and limits opportunities for data visualization. To address these limitations, we developed a software tool (Cicerone) that enables interactive 3D visualization of co-registered magnetic resonance images (MRI), computed tomography (CT) scans, 3D brain atlases, neurophysiological microelectrode recording (MER) data, and deep brain stimulation (DBS) electrode(s) with the volume of tissue activated (VTA) as a function of the stimulation parameters. The software can be used in pre-operative planning to help select the optimal position on the skull for burr hole (in humans) or chamber (in monkeys) placement to maximize the likelihood of complete microelectrode and DBS coverage of the intended anatomical target. Intra-operatively, Cicerone allows entry of the stereotactic microdrive coordinates and MER data, enabling real-time interactive visualization of the electrode location in 3D relative to the surrounding neuroanatomy and neurophysiology. In addition, the software enables prediction of the VTA generated by DBS for a range of electrode trajectories and tip locations. In turn, the neurosurgeon can use the combination of anatomical (MRI/CT/3D brain atlas), neurophysiological (MER), and electrical (DBS VTA) data to optimize the placement of the DBS electrode prior to permanent implantation.

StimExplorer: deep brain stimulation parameter selection software system.

StimExplorer is a Windows-based software package intended to aid the clinical implementation of deep brain stimulation (DBS) technology. StimExplorer uses detailed computer models to provide a quantitative description of the 3D volume of tissue activated (VTA) by DBS as a function of the stimulation parameters and electrode location within the brain. The stimulation models are tailored to the individual patient by importing their magnetic resonance imaging (MRI) data and interactively scaling 3D anatomical nuclei to fit the patient anatomy. The user also inputs the DBS electrode orientation, location, and impedance data. The software then provides theoretically optimal stimulation parameter suggestions, intended to represent the start point for clinical programming of the DBS device. The software system is packaged into a clinician-friendly graphical user interface that allows for simultaneous interactive 3D visualization of the MRI, anatomical nuclei, DBS electrode, and VTAs for a wide range of stimulation parameter settings (contact, impedance, voltage, pulse width, and frequency). The goals of the StimExplorer system are to educate clinicians on the impact of stimulation parameter manipulation, and improve therapeutic outcomes by providing quantitative anatomical and electrical information useful for customizing DBS to individual patients.

Synaptic plasticity: a molecular memory switch.

Recent work shows that two molecules with major roles in synaptic plasticity--CaMKII and the NMDA receptor--bind to each other. This binding activates CaMKII and triggers its autophosphorylation. In this state, it may act as a memory switch and strengthen synapses through enzymatic and structural processes.

Finite element analysis of the current-density and electric field generated by metal microelectrodes.

Electrical stimulation via implanted microelectrodes permits excitation of small, highly localized populations of neurons, and allows access to features of neuronal organization that are not accessible with larger electrodes implanted on the surface of the brain or spinal cord. As a result there are a wide range of potential applications for the use of microelectrodes in neural engineering. However, little is known about the current-density and electric field generated by microelectrodes. The objectives of this project were to answer three fundamental questions regarding electrical stimulation with metal microelectrodes using geometrically and electrically accurate finite elements models. First, what is the spatial distribution of the current density over the surface of the electrode? Second, how do alterations in the electrode geometry effect neural excitation? Third, under what conditions can an electrode of finite size be modeled as a point source? Analysis of the models showed that the current density was concentrated at the tip of the microelectrode and at the electrode-insulation interface. Changing the surface area of the electrode, radius of curvature of the electrode tip, or applying a resistive coating to the electrode surface altered the current-density distribution on the surface of the electrode. Changes in the electrode geometry had little effect on neural excitation patterns, and modeling the electric field generated by sharply tipped microelectrodes using a theoretical point source was valid for distances > approximately 50 microm from the electrode tip. The results of this study suggest that a nearly uniform current-density distribution along the surface of the electrode can be achieved using a relatively large surface area electrode (500-1000 microm2), with a relatively blunt tip (3-6 microm radius of curvature), in combination with a thin (approximately 1 microm) moderately resistive coating (approximately 50 omega m).

Modelling the effects of electric fields on nerve fibres: influence of the myelin sheath.

The excitation and conduction properties of computer-based cable models of mammalian motor nerve fibres, incorporating three different myelin representations, are compared. The three myelin representations are a perfectly insulating single cable (model A), a finite impedance single cable (model B) and a finite impedance double cable (model C). Extracellular stimulation of the three models is used to study their strength-duration and current-distance (I-X) relationships, conduction velocity (CV) and action potential shape. All three models have a chronaxie time that is within the experimental range. Models B and C have increased threshold currents compared with model A, but each model has slope to the I-X relationship that matches experimental results. Model B has a CV that matches experimental data, whereas the CV of models A and C are above and below the experimental range, respectively. Model C is able to produce a depolarising afterpotential (DAP), whereas models A and B exhibit hyperpolarising afterpotentials. Models A and B are determined to be the preferred models when low-frequency stimulation (< approximately 25 Hz) is used, owing to their efficiency and accurate excitation and conduction properties. For high frequency stimulation (approximately 25 Hz and greater), model C, with its ability to produce a DAP, is necessary accurately to simulate excitation behaviour.

Selective microstimulation of central nervous system neurons.

The goal of this study was to identify stimulus parameters and electrode geometries that were effective in selectively stimulating targeted neuronal populations within the central nervous system (CNS). Cable models of neurons that included an axon, initial segment, soma, and branching dendritic tree, with geometries and membrane dynamics derived from mammalian motoneurons, were used to study excitation with extracellular electrodes. The models reproduced a wide range of experimentally documented excitation patterns including current-distance and strength-duration relationships. Evaluation of different stimulus paradigms was performed using populations of fifty cells and fifty fibers of passage randomly positioned about an extracellular electrode(s). Monophasic cathodic or anodic stimuli enabled selective stimulation of fibers over cells or cells over fibers, respectively. However, when a symmetrical charge-balancing stimulus phase was incorporated, selectivity was greatly diminished. An anodic first, cathodic second asymmetrical biphasic stimulus enabled selective stimulation of fibers, while a cathodic first, anodic second asymmetrical biphasic stimulus enabled selective stimulation of cells. These novel waveforms provided enhanced selectivity while preserving charge balancing as is required to minimize the risk of electrode corrosion and tissue injury. Furthermore, the models developed in this study can predict the effectiveness of electrode geometries and stimulus parameters for selective activation of specific neuronal populations, and in turn represent useful tools for the design of electrodes and stimulus waveforms for use in CNS neural prosthetic devices.

Excitation of central nervous system neurons by nonuniform electric fields.

The goal of this study was to determine which neural elements are excited by microstimulation of the central nervous system. A cable model of a neuron including an axon, initial segment, axon hillock, soma, and simplified dendritic tree was used to study excitation with an extracellular point source electrode. The model reproduced a wide range of experimentally documented extracellular excitation patterns. The site of action potential initiation (API) was a function of the electrode position, stimulus duration, and stimulus polarity. The axon or initial segment was always the site of API at threshold. When the electrode was positioned near the cell body, the site of excitation was dependent on the stimulus amplitude. With the electrode in close proximity to the neuron, short-duration cathodic pulses produced lower thresholds with the electrode positioned over the axon than over the cell body, and long-duration stimuli produced opposite relative thresholds. This result was robust to alterations in either the maximum conductances or the intracellular resistivities of the model. The site of maximum depolarization was not always an accurate predictor of the site of API, and the temporal evolution of the changes in membrane potential played a strong role in determining the site of excitation.

Sensitivity analysis of a model of mammalian neural membrane.

The sensitivity of the strength-duration (S-D) relationship to changes in the parameters describing the sodium channel of mammalian neuronal membrane was determined by computer simulation. A space-clamped patch of neuronal membrane was modeled by a parallel nonlinear sodium conductance, linear leakage conductance, and membrane capacitance. Each parameter that governs the activation (m) and inactivation (h) variables of the sodium channel was varied from -50% to +50% of its default value, and for each variation a S-D relationship was generated. Individual changes in six of the eleven parameters (alpha mA, alpha mD, alpha hA, beta mA, beta mB, and beta hB) generated substantial changes in the rheobase current and chronaxie time (Tch) of the model. Changing the parameter values individually did not correct for the model's failure to generate excitation after the release from a long duration hyperpolarization (anode break excitation). Scaling a combination of five parameters (alpha mA, alpha mB, alpha hA, beta mA, and beta hB) by an equal amount produced a model that generated anode break excitation and increased Tch, but also decreased the amplitude of the action potential. To reproduce the amplitude of the action potential, the maximum sodium conductance and sodium Nernst potential were increased. These modifications generated a model that had S-D properties closer to experimental results, could produce anode break excitation, and reproduced the action potential amplitude.