Karen A. Moxon

Rhythm-specific pharmacological modulation of subthalamic activity in Parkinson's disease

The subthalamic nucleus (STN) has a key role in the pathophysiology of Parkinsons disease and is the primary target for high-frequency deep brain stimulation (DBS). The STN rest electrical activity in Parkinsons disease, however, is still unclear. Here we tested the hypothesis that pharmacological modulation of STN activity has rhythm-specific effects in the classical range of EEG frequencies, below 50 Hz. We recorded local field potentials (LFPs) through electrodes implanted in the STN of patients with Parkinsons disease (20 nuclei from 13 patients). After overnight withdrawal of antiparkinsonian therapy, LFPs were recorded at rest both before (off) and after (on) acute administration of different antiparkinsonian drugs: levodopa, apomorphine, or orphenadrine. In the off-state, STN LFPs showed clearly defined peaks of oscillatory activity below 50 Hz: at low frequencies (2-7 Hz), in the alpha (7-13 Hz), low-beta (13-20 Hz), and high-beta range (20-30 Hz). In the on-state after levodopa and apomorphine administration, low-beta activity significantly decreased and low-frequency activity increased. In contrast, orphenadrine increased beta activity. Power changes elicited by levodopa and apomorphine at low frequencies and in the beta range were not correlated, whereas changes in the alpha band, which were globally not significant, correlated with the beta rhythm (namely, low beta: 13-20 Hz). In conclusion, in the human STN, there are at least two rhythms below 50 Hz that are separately modulated by antiparkinsonian medication: one at low frequencies and one in the beta range. Multiple rhythms are consistent with the hypothesis of multiple oscillating systems, each possibly correlating with specific aspects of human STN function and dysfunction.

Ceramic-based multisite electrode arrays for chronic single-neuron recording

A method is described for the manufacture of a microelectrode array for chronic, multichannel, single neuron recording. The ceramic-based, multisite electrode array has four recording sites patterned onto a ceramic shaft the size of a single typical microwire electrode. The sites and connecting wires are applied to the ceramic substrate using a reverse photolithographic procedure. Recording sites (22/spl times/80 /spl mu/m) are separated by 200 /spl mu/m along the shaft. A layer of alumina insulation is applied over the whole array (exclusive of recording sites) by ion-beam assisted deposition. These arrays were capable of recording single neuron activity from each of their recording sites for at least three weeks during chronic implantation in the somatosensory cortex of rats, and several sites had recordings that lasted for more than 8 weeks. The vertical arrangement of the recording sites on these electrodes is ideal for simultaneously recording across the different layers of brain areas such as the cerebral cortex and hippocampus in chronic preparations.

Nanostructured surface modification of ceramic-based microelectrodes to enhance biocompatibility for a direct brain-machine interface

Many different types of microelectrodes have been developed for use as a direct Brain-Machine Interface (BMI) to chronically recording single neuron action potentials from ensembles of neurons. Unfortunately, the recordings from these microelectrode devices are not consistent and often last for only a few weeks. For most microelectrode types, the loss of these recordings is not due to failure of the electrodes but most likely due to damage to surrounding tissue that results in the formation of nonconductive glial-scar. Since the extracellular matrix consists of nanostructured microtubules, we have postulated that neurons may prefer a more complex surface structure than the smooth surface typical of thin-film microelectrodes. We, therefore, investigated the suitability of a nano-porous silicon surface layer to increase the biocompatibility of our thin film ceramic-insulated multisite electrodes. In-vitro testing demonstrated, for the first time, decreased adhesion of astrocytes and increased extension of neurites from pheochromocytoma cells on porous silicon surfaces compared to smooth silicon surfaces. Moreover, nano-porous surfaces were more biocompatible than macroporous surfaces. Collectively, these results support our hypothesis that nano-porous silicon may be an ideal material to improve biocompatibility of chronically implanted microelectrodes. We next developed a method to apply nano-porous surfaces to ceramic insulated, thin-film, microelectrodes and tested them in vivo. Chronic testing demonstrated that the nano-porous surface modification did not alter the electrical properties of the recording sites and did not interfere with proper functioning of the microelectrodes in vivo.

Responses of trigeminal ganglion neurons during natural whisking behaviors in the awake rat.

Rats use their whiskers to locate and discriminate tactile features of their environment. Mechanoreceptors surrounding each whisker encode and transmit sensory information from the environment to the brain via afferents whose cell bodies lie in the trigeminal ganglion (Vg). These afferents are classified as rapidly (RA) or slowly (SA) adapting by their response to stimulation. The activity of these cells in the awake behaving rat is yet unknown. Therefore, we developed a method to chronically record Vg neurons during natural whisking behaviors and found that all cells exhibited (1) no neuronal activity when the whiskers were not in motion, (2) increased activity when the rat whisked, with activity correlated to whisk frequency, and (3) robust increases in activity when the whiskers contacted an object. Moreover, we observed distinct differences in the firing rates between RA and SA cells, suggesting that they encode distinct aspects of stimuli in the awake rat.

Neural Prostheses for Restoration of Sensory and Motor Function

Sensory and Motor Prostheses Auditory Prostheses, B.E. Pfingst Advances in Upper Extremity Functional Restoration Employing Neuroprostheses, P.H. Peckham, K.L. Kilgore, and M.W. Keith BION(TM) Implants for Therapeutic and Functional Electrical Stimulation, G.E. Loeb and J.R. Richmond Intraspinal Chord Microstimulation: Techniques, Perspectives, and Prospects for FES, S.F. Giszter, W. Grill, M. Lemay, V. Mushahwar, and A. Prochazka How to Use Nerve Cuffs to Stimulate, Record, or Modulate Neural Activity, J.-A. Hoffer and K. Klaus Brain Control of Neural Prostheses Engineering the Brain-Machine Interface for Neural Prosthetic Devices, K.A. Moxon, J. Morizio, J.K. Chapin, M.A.L. Nicolelis, and P.D. Wolf. Dynamic Interplay of Neural Signals During the Emergence of Cursor-Related Cortex in a Human Implanted with the Neurotrophic Electrode, P.R. Kennedy and B. King Brain Control of Sensorimotor Prosthesis, J.K. Chapin and M.A.L. Nicolelis Drug Deliveries into the Microenvironment of Electrophysiologically Monitored Neurons in the brain of Behaving Rats and Monkeys, N. Ludvig

Spinal Cord Injury Immediately Changes the State of the Brain

Spinal cord injury can produce extensive long-term reorganization of the cerebral cortex. Little is known, however, about the sequence of cortical events starting immediately after the lesion. Here we show that a complete thoracic transection of the spinal cord produces immediate functional reorganization in the primary somatosensory cortex of anesthetized rats. Besides the obvious loss of cortical responses to hindpaw stimuli (below the level of the lesion), cortical responses evoked by forepaw stimuli (above the level of the lesion) markedly increase. Importantly, these increased responses correlate with a slower and overall more silent cortical spontaneous activity, representing a switch to a network state of slow-wave activity similar to that observed during slow-wave sleep. The same immediate cortical changes are observed after reversible pharmacological block of spinal cord conduction, but not after sham. We conclude that the deafferentation due to spinal cord injury can immediately (within minutes) change the state of large cortical networks, and that this state change plays a critical role in the early cortical reorganization after spinal cord injury.

Role of Spike Timing in the Forelimb Somatosensory Cortex of the Rat

The aim of this study was to test the hypothesis that the significance of spike timing in somatosensory processing is not a specific feature of the whisker cortex but a more general characteristic of the primary somatosensory cortex. We recorded ensembles of neurons using microwire arrays implanted in the deep layers of the forelimb region of the rat primary somatosensory cortex in response to step stimuli delivered to the cutaneous surface of the contralateral body. We used a recently developed peristimulus time histogram (PSTH)-based classification method to investigate the temporal precision of the code by evaluating how changing the bin size (from 40 to 1 msec) would affect the ability of the ensemble responses to discriminate stimulus location on a single-trial basis. The information related to the discrimination was redundantly distributed within the ensembles, and the ability to discriminate stimulus location increased when decreasing the bin size, reaching a maximum at 4 msec. In our experiment, at 4 msec bin size the first spike per neuron after the stimulus conveyed almost as much information as the entire responses, so the temporal precision of the code was preserved in the first spikes. Subsequent spikes were less frequent but conveyed more information per spike. Finally, not only the trials correctly classified but also the trials incorrectly classified conveyed information about stimulus location with a similar temporal precision. We conclude that the role of spike timing in cortical somatosensory processing is not an exclusive feature of the highly specialized rat trigeminal system, but a more general property of the rat primary somatosensory cortex.

Biomimetic Brain Machine Interfaces for the Control of Movement

Quite recently, it has become possible to use signals recorded simultaneously from large numbers of cortical neurons for real-time control. Such brain machine interfaces (BMIs) have allowed animal subjects and human patients to control the position of a computer cursor or robotic limb under the guidance of visual feedback. Although impressive, such approaches essentially ignore the dynamics of the musculoskeletal system, and they lack potentially critical somatosensory feedback. In this mini-symposium, we will initiate a discussion of systems that more nearly mimic the control of natural limb movement. The work that we will describe is based on fundamental observations of sensorimotor physiology that have inspired novel BMI approaches. We will focus on what we consider to be three of the most important new directions for BMI development related to the control of movement. (1) We will present alternative methods for building decoders, including structured, nonlinear models, the explicit incorporation of limb state information, and novel approaches to the development of decoders for paralyzed subjects unable to generate an output signal. (2) We will describe the real-time prediction of dynamical signals, including joint torque, force, and EMG, and the real-time control of physical plants with dynamics like that of the real limb. (3) We will discuss critical factors that must be considered to incorporate somatosensory feedback to the BMI user, including its potential benefits, the differing representations of sensation and perception across cortical areas, and the changes in the cortical representation of tactile events after spinal injury.

Multiple single units and population responses during inhibitory gating of hippocampal auditory response in freely-moving rats

Paired clicks were presented to awake, freely-moving rats to examine neuronal activity associated with inhibitory gating of responses to repeated auditory stimuli. The rats had bundles of eight microwires implanted into each of four different brain areas: CA3 region of the hippocampus, medial septal nucleus, brainstem reticular nucleus, and the auditory cortex. Single-unit recordings from each wire were made while the local auditory-evoked potential was also recorded. The response to a conditioning stimulus was compared to the response to a test stimulus delivered 500 ms later: the ratio of the test response to the conditioning response provided a measure of inhibitory gating. Auditory-evoked potentials were recorded at all sites. Overall, brainstem reticular nucleus neurons showed the greatest gating of local auditory-evoked potentials, while the auditory cortex showed the least. However, except for the auditory cortex, both gating and non-gating of the evoked response were recorded at various times in all brain regions. Gating of the hippocampal response was significantly correlated with gating in the medial septal nucleus and brainstem reticular nucleus, but not the auditory cortex. Single-unit neuron firing in response to the clicks was most pronounced in the brainstem reticular nucleus and the medial septal nucleus, while relatively few neurons responded in the CA3 region of the hippocampus and the auditory cortex. Taken together, these data support the hypothesis that inhibitory gating of the auditory-evoked response originates in the non-lemniscal pathway and not in cortical areas of the rat brain.

Neuronal synchrony and the transition to spontaneous seizures

The role of inhibitory neuronal activity in the transition to seizure is unclear. On the one hand, seizures are associated with excessive neuronal activity that can spread across the brain, suggesting run-away excitation. On the other hand, recent in vitro studies suggest substantial activity of inhibitory interneurons prior to the onset of evoked seizure-like activity. Yet, little is known about the behavior of interneurons before and during spontaneous seizures in chronic temporal lobe epilepsy. Here, we examined the relationship between the on-going local field potential (LFP) and the activity of populations of hippocampal neurons during the transition to spontaneous seizures in the pilocarpine rat model of epilepsy. Pilocarpine treated rats that exhibited spontaneous seizures were implanted with drivable tetrodes including an LFP electrode and recordings were obtained from the CA3 region. For each recorded seizure, identified single units were classified into putative interneurons or pyramidal cells based on average firing rate, autocorrelation activity and waveform morphology. The onset of sustained ictal spiking, a consistent seizure event that occurred within seconds after the clinically defined seizure onset time, was used to align data from each seizure to a common reference point. Ictal spiking, in this paper, refers to spiking activity in the low-pass filtered LFP during seizures and not the neuronal action potentials. Results show that beginning minutes before the onset of sustained ictal spiking in the local field, subpopulations of putative interneurons displayed a sequence of synchronous behaviors. This includes progressive synchrony with local field oscillations at theta, gamma, and finally ictal spiking frequencies, and an increased firing rate seconds before the onset of ictal spiking. Conversely, putative pyramidal cells did not exhibit increased synchrony or firing rate until after ictal spiking had begun. Our data suggest that the transition to spontaneous seizure in this network is not mediated by increasing excitatory activity, but by distinct changes in the dynamical state of putative interneurons. While these states are not unique for seizure onset, they suggest a series of state transitions that continuously increase the likelihood of a seizure. These data help to interpret the link between in vitro studies demonstrating interneuron activation at the transition to seizure, and human studies demonstrating heterogeneous neuronal firing at this time.