Continuous neuronal ensemble control of simulated arm reaching by a human with tetraplegia.

Functional electrical stimulation (FES), the coordinated electrical activation of multiple muscles, has been used to restore arm and hand function in people with paralysis. User interfaces for such systems typically derive commands from mechanically unrelated parts of the body with retained volitional control, and are unnatural and unable to simultaneously command the various joints of the arm. Neural interface systems, based on spiking intracortical signals recorded from the arm area of motor cortex, have shown the ability to control computer cursors, robotic arms and individual muscles in intact non-human primates. Such neural interface systems may thus offer a more natural source of commands for restoring dexterous movements via FES. However, the ability to use decoded neural signals to control the complex mechanical dynamics of a reanimated human limb, rather than the kinematics of a computer mouse, has not been demonstrated. This study demonstrates the ability of an individual with long-standing tetraplegia to use cortical neuron recordings to command the real-time movements of a simulated dynamic arm. This virtual arm replicates the dynamics associated with arm mass and muscle contractile properties, as well as those of an FES feedback controller that converts user commands into the required muscle activation patterns. An individual with long-standing tetraplegia was thus able to control a virtual, two-joint, dynamic arm in real time using commands derived from an existing human intracortical interface technology. These results show the feasibility of combining such an intracortical interface with existing FES systems to provide a high-performance, natural system for restoring arm and hand function in individuals with extensive paralysis.

Different forms of synaptic plasticity in somatosensory and motor areas of the neocortex.

We have studied vertical synaptic pathways in two cytoarchitectonically distinct areas of rat neocortex--the granular primary somatosensory (SI) area and the agranular primary motor (MI) area--and tested their propensity to generate long-term potentiation (LTP), long-term depression (LTD), and related forms of synaptic plasticity. Extracellular and intracellular responses were recorded in layer II/III of slices in vitro while stimulating in middle cortical layers (in or around layer IV). Under control conditions, 5 Hz theta-burst stimulation produced LTP in the granular area, but not in the agranular area. Agranular cortex did generate short-term potentiation that decayed within 20 min. Varying the inter-burst frequency from 2 Hz to 10 Hz reliably yielded LTP of 21-34% above control levels in granular cortex, but no lasting changes were induced in agranular cortex. However, the agranular cortex was capable of generating LTP if a GABAA receptor antagonist was applied locally at the recording site during the induction phase. In contrast to LTP, an identical form of homosynaptic LTD could be induced in both granular and agranular areas by applying low frequency stimulation (1 Hz for 15 min) to the middle layers. Under control conditions, both LTP and LTD were synapse-specific; theta-burst or low-frequency stimulation in the vertical pathway did not induce changes in responses to stimulation of a layer II/III horizontal pathway. Application of the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid (AP5) blocked the induction of both LTP and LTD in granular and agranular cortex. In the presence of AP5, low-frequency conditioning stimuli yielded a short-term depression in both areas that decayed within 10-15 min. Nifedipine, which blocks L-type, voltage-sensitive calcium channels, slightly depressed the magnitudes of LTP and LTD but did not abolish them. Synaptic responses evoked during theta-burst stimulation were strikingly different in granular and agranular areas. Responses in granular cortex were progressively facilitated during each sequence of 10 theta-bursts, and from sequence-to-sequence; in contrast, responses in agranular cortex were stable during an entire theta-burst tetanus. The results suggest that vertical pathways in primary somatosensory cortex and primary motor cortex express several forms of synaptic plasticity. They were equally capable of generating LTD, but the pathways in somatosensory cortex much more reliably generated LTP, unless inhibition was reduced. LTP may be more easily produced in sensory cortex because of the pronounced synaptic facilitation that occurs there during repetitive stimulation of the induction phase.(ABSTRACT TRUNCATED AT 400 WORDS)

N-methyl-D-aspartate receptor mediated component of field potentials evoked in horizontal pathways of rat motor cortex.

To identify potential sites of synaptic modification of intrinsic cortical circuits, the contribution of the N-methyl-D-aspartate type of glutamate receptors to field potentials evoked in horizontal and oblique intracortical pathways was examined in rat motor cortex slice preparations. Presumably monosynaptic, short latency responses with a prominent negativity (-0.4 to -2.0 mV) were recorded in both superficial (across layer III) and deep (across layer V) horizontal pathways at a distance of approximately equal to 500 microns lateral to electrical stimulation sites and in oblique V-III pathway (-0.3 to -1.6 mV). Bath application of the N-methyl-D-aspartate receptor antagonist D,L-2-amino-5-phosphonovaleric acid (100 microM) reversibly decreased field potentials. Although decreases were observed in all components of the waveform, the most pronounced effect was on the late phase of the response. D,L-2-Amino-5-phosphonovaleric acid produced on average a 22% decrease in area, 12% in initial slope and 11% in peak amplitude of responses. Combined application of 100 microM D,L-2-amino-5-phosphonovaleric acid and a non-N-methyl-D-aspartate glutamate receptor antagonist, 6-cyano-7-nitro- or 6,7-dinitro-quinoxaline-2,3- dione (10-20 microM), eliminated all but a small, early and presumably non-synaptic response. In 18 of 23 cases, the relative contribution of the D,L-2-amino-5-phosphonovaleric acid-sensitive component was unrelated to field potential magnitude, suggesting that this component is present in all fiber classes. It is concluded that glutamate is the major transmitter of horizontal connections of layers II/III and layer V, as well as in the oblique V-III pathway. While most glutamatergic transmission is relayed by other glutamate receptor subtypes, N-methyl-D-aspartate receptor activation contributes a small but consistent part of ordinary transmission in each of these pathways in vitro. The results further suggest that a potential for N-methyl-D-aspartate receptor-mediated synaptic modification exists in intrinsic horizontal pathways of both superficial and deep layers of rat motor cortex.

Location of nicotinic and muscarinic cholinergic and mu-opiate receptors in rat cerebral neocortex: evidence from thalamic and cortical lesions.

In vitro receptor binding techniques were used to identify the cellular location of nicotinic and muscarinic cholinergic and mu-opiate receptors in the fronto-parietal region of rat cerebral neocortex. Changes in the normal pattern of receptor binding of ligands for these 3 receptors were examined in a series of adjacent sections after unilateral thalamic fiber or cortical cell lesions. Thalamocortical fibers were destroyed by making either electrolytic lesions or kainic acid injections centered in the region of the thalamic ventrobasal complex. These lesions reduced cortical labeling of nicotinic ([3H]nicotine) and mu-opiate ([3H]DAGO) receptors while they did not affect cortical muscarinic ([3H]quinuclidinyl benzilate ([3H]QNB)) labeling. Intracortical injections of quinolinic acid (QA) were used to destroy cortical neurons and spare extrinsic fibers. Cortical QA lesions markedly reduced muscarinic and mu-opiate labeling, but had no significant effect on nicotinic binding at short survivals. Our results suggest that a subset of nicotinic receptors is located presynaptically on the specific thalamo-cortical fibers, while muscarinic receptors are located primarily on cortical neurons. Receptors of the mu-opiate type appear to be located both presynaptically on thalamo-cortical terminals and on intrinsic cortical neurons. The differences in the location of these receptor types suggest that each one modulates discrete aspects of cortical processing.

Localization of glutaminase-like and aspartate aminotransferase-like immunoreactivity in neurons of cerebral neocortex.

The distribution of glutaminase (GLNase)- and aspartate aminotransferase (AATase)-immunoreactive cells was examined in the cerebral neocortex of rat and guinea pig and in the somatic sensorimotor and primary visual cortex of the Macaca fascicularis monkey. These enzymes are involved in the metabolism of glutamate and aspartate, two amino acids thought to be excitatory amino acid transmitters for cortical neurons. In each of the species examined a large percentage of layer V and VI pyramidal neurons have pronounced glutaminase-like immunoreactivity (GLNase IR). In contrast, neurons in layers I, II, and IV show little GLNase IR. Layer III in the rat and guinea pig contains only a few, densely labeled GLNase-like-immunoreactive (GLNase-Ir) pyramidal neurons, whereas in the monkey the number of GLNase-Ir cells in layer III varies between cytoarchitectonic fields. Area 3b of the primary somatic sensory cortex and area 17 (primary visual cortex) contain few GLNase-Ir cells in layer III. However, layer III contains moderate numbers of GLNase IR in cells in areas 3a, 1, 2, 5, and in the primary motor cortex. Within the motor cortex the largest pyramidal ("Betz") cells are not labeled. In marked contrast to the results with antibody to GLNase, antibody to AATase labels cells that appear nonpyramidal in form, and these cells are in all cortical layers in each of the species examined. This distribution is roughly similar throughout all areas of rodent neocortex, but in monkey visual cortex AATase-immunoreactive neurons are more numerous in layers II-III, IVc, and VI. When combined with the findings of other studies, our results suggest that GLNase IR marks pyramidal neurons that use an excitatory amino acid transmitter. Antibody to AATase appears to mark intrinsic cortical neurons. The AATase immunoreactivity of these cells could indicate that they use an excitatory amino acid transmitter. However, their form and distribution in cortex suggest that this antibody labels GABAergic neurons.