A closed loop brain-machine interface for epilepsy control using dorsal column electrical stimulation

Although electrical neurostimulation has been proposed as an alternative treatment for drug-resistant cases of epilepsy, current procedures such as deep brain stimulation, vagus, and trigeminal nerve stimulation are effective only in a fraction of the patients. Here we demonstrate a closed loop brain-machine interface that delivers electrical stimulation to the dorsal column (DCS) of the spinal cord to suppress epileptic seizures. Rats were implanted with cortical recording microelectrodes and spinal cord stimulating electrodes, and then injected with pentylenetetrazole to induce seizures. Seizures were detected in real time from cortical local field potentials, after which DCS was applied. This method decreased seizure episode frequency by 44% and seizure duration by 38%. We argue that the therapeutic effect of DCS is related to modulation of cortical theta waves, and propose that this closed-loop interface has the potential to become an effective and semi-invasive treatment for refractory epilepsy and other neurological disorders.We are grateful for the assistance from Jim Meloy for the design and production of the multielectrode arrays as well as setup development and maintenance, Laura Oliveira, Terry Jones, and Susan Halkiotis for administrative assistance and preparation of the manuscript. This work was funded by a grant from The Hartwell Foundation.info:eu-repo/semantics/publishedVersio

Spike firing and IPSPs in layer V pyramidal neurons during beta oscillations in rat primary motor cortex (M1) in vitro

Beta frequency oscillations (10-35 Hz) in motor regions of cerebral cortex play an important role in stabilising and suppressing unwanted movements, and become intensified during the pathological akinesia of Parkinson's Disease. We have used a cortical slice preparation of rat brain, combined with concurrent intracellular and field recordings from the primary motor cortex (M1), to explore the cellular basis of the persistent beta frequency (27-30 Hz) oscillations manifest in local field potentials (LFP) in layers II and V of M1 produced by continuous perfusion of kainic acid (100 nM) and carbachol (5 µM). Spontaneous depolarizing GABA-ergic IPSPs in layer V cells, intracellularly dialyzed with KCl and IEM1460 (to block glutamatergic EPSCs), were recorded at -80 mV. IPSPs showed a highly significant (P< 0.01) beta frequency component, which was highly significantly coherent with both the Layer II and V LFP oscillation (which were in antiphase to each other). Both IPSPs and the LFP beta oscillations were abolished by the GABAA antagonist bicuculline. Layer V cells at rest fired spontaneous action potentials at sub-beta frequencies (mean of 7.1+1.2 Hz; n = 27) which were phase-locked to the layer V LFP beta oscillation, preceding the peak of the LFP beta oscillation by some 20 ms. We propose that M1 beta oscillations, in common with other oscillations in other brain regions, can arise from synchronous hyperpolarization of pyramidal cells driven by synaptic inputs from a GABA-ergic interneuronal network (or networks) entrained by recurrent excitation derived from pyramidal cells. This mechanism plays an important role in both the physiology and pathophysiology of control of voluntary movement generation

Stimulus Dependence of Barrel Cortex Directional Selectivity

Neurons throughout the rat vibrissa somatosensory pathway are sensitive to the angular direction of whisker movement. Could this sensitivity help rats discriminate stimuli? Here we use a simple computational model of cortical neurons to analyze the robustness of directional selectivity. In the model, directional preference emerges from tuning of synaptic conductance amplitude and latency, as in recent experimental findings. We find that directional selectivity during stimulation with random deflection sequences is strongly dependent on the mean deflection frequency: Selectivity is weakened at high frequencies even when each individual deflection evokes strong directional tuning. This variability of directional selectivity is due to generic properties of synaptic integration by the neuronal membrane, and is therefore likely to hold under very general physiological conditions. Our results suggest that directional selectivity depends on stimulus context. It may participate in tasks involving brief whisker contact, such as detection of object position, but is likely to be weakened in tasks involving sustained whisker exploration (e.g., texture discrimination)

Cortical Modulation of the Transient Visual Response at Thalamic Level: A TMS Study

The transient visual response of feline dorsal lateral geniculate nucleus (dLGN) cells was studied under control conditions and during the application of repetitive transcranial magnetic stimulation at 1 Hz (rTMS@1Hz) on the primary visual cortex (V1). The results show that rTMS@1Hz modulates the firing mode of Y cells, inducing an increase in burst spikes and a decrease in tonic firing. On the other hand, rTMS@1Hz modifies the spatiotemporal characteristics of receptive fields of X cells, inducing a delay and a decrease of the peak response, and a change of the surround/center amplitude ratio of RF profiles. These results indicate that V1 controls the activity of the visual thalamus in a different way in the X and Y pathways, and that this feedback control is consistent with functional roles associated with each cell type

Upregulation of Barrel GABAergic Neurons Is Associated with Cross-Modal Plasticity in Olfactory Deficit

Background: Loss of a sensory function is often followed by the hypersensitivity of other modalities in mammals, which secures them well-awareness to environmental changes. Cellular and molecular mechanisms underlying cross-modal sensory plasticity remain to be documented. Methodology/Principal Findings: Multidisciplinary approaches, such as electrophysiology, behavioral task and immunohistochemistry, were used to examine the involvement of specific types of neurons in cross-modal plasticity. We have established a mouse model that olfactory deficit leads to a whisking upregulation, and studied how GABAergic neurons are involved in this cross-modal plasticity. In the meantime of inducing whisker tactile hypersensitivity, the olfactory injury recruits more GABAergic neurons and their fine processes in the barrel cortex, as well as upregulates their capacity of encoding action potentials. The hyperpolarization driven by inhibitory inputs strengthens the encoding ability of their target cells. Conclusion/Significance: The upregulation of GABAergic neurons and the functional enhancement of neuronal networks may play an important role in cross-modal sensory plasticity. This finding provides the clues for developing therapeuti

Robust penetrating microelectrodes for neural interfaces realized by titanium micromachining

Neural prosthetic interfaces based upon penetrating microelectrode devices have broadened our understanding of the brain and have shown promise for restoring neurological functions lost to disease, stroke, or injury. However, the eventual viability of such devices for use in the treatment of neurological dysfunction may be ultimately constrained by the intrinsic brittleness of silicon, the material most commonly used for manufacture of penetrating microelectrodes. This brittleness creates predisposition for catastrophic fracture, which may adversely affect the reliability and safety of such devices, due to potential for fragmentation within the brain. Herein, we report the development of titanium-based penetrating microelectrodes that seek to address this potential future limitation. Titanium provides advantage relative to silicon due to its superior fracture toughness, which affords potential for creation of robust devices that are resistant to catastrophic failure. Realization of these devices is enabled by recently developed techniques which provide opportunity for fabrication of high-aspect-ratio micromechanical structures in bulk titanium substrates. Details are presented regarding the design, fabrication, mechanical testing, in vitro functional characterization, and preliminary in vivo testing of devices intended for acute recording in rat auditory cortex and thalamus, both independently and simultaneously

Causal Measures of Structure and Plasticity in Simulated and Living Neural Networks

A major goal of neuroscience is to understand the relationship between neural structures and their function. Recording of neural activity with arrays of electrodes is a primary tool employed toward this goal. However, the relationships among the neural activity recorded by these arrays are often highly complex making it problematic to accurately quantify a network's structural information and then relate that structure to its function. Current statistical methods including cross correlation and coherence have achieved only modest success in characterizing the structural connectivity. Over the last decade an alternative technique known as Granger causality is emerging within neuroscience. This technique, borrowed from the field of economics, provides a strong mathematical foundation based on linear auto-regression to detect and quantify “causal” relationships among different time series. This paper presents a combination of three Granger based analytical methods that can quickly provide a relatively complete representation of the causal structure within a neural network. These are a simple pairwise Granger causality metric, a conditional metric, and a little known computationally inexpensive subtractive conditional method. Each causal metric is first described and evaluated in a series of biologically plausible neural simulations. We then demonstrate how Granger causality can detect and quantify changes in the strength of those relationships during plasticity using 60 channel spike train data from an in vitro cortical network measured on a microelectrode array. We show that these metrics can not only detect the presence of causal relationships, they also provide crucial information about the strength and direction of that relationship, particularly when that relationship maybe changing during plasticity. Although we focus on the analysis of multichannel spike train data the metrics we describe are applicable to any stationary time series in which causal relationships among multiple measures is desired. These techniques can be especially useful when the interactions among those measures are highly complex, difficult to untangle, and maybe changing over time

Interactive Responses of a Thalamic Neuron to Formalin Induced Lasting Pain in Behaving Mice

Thalamocortical (TC) neurons are known to relay incoming sensory information to the cortex via firing in tonic or burst mode. However, it is still unclear how respective firing modes of a single thalamic relay neuron contribute to pain perception under consciousness. Some studies report that bursting could increase pain in hyperalgesic conditions while others suggest the contrary. However, since previous studies were done under either neuropathic pain conditions or often under anesthesia, the mechanism of thalamic pain modulation under awake conditions is not well understood. We therefore characterized the thalamic firing patterns of behaving mice in response to nociceptive pain induced by inflammation. Our results demonstrated that nociceptive pain responses were positively correlated with tonic firing and negatively correlated with burst firing of individual TC neurons. Furthermore, burst properties such as intra-burst-interval (IntraBI) also turned out to be reliably correlated with the changes of nociceptive pain responses. In addition, brain stimulation experiments revealed that only bursts with specific bursting patterns could significantly abolish behavioral nociceptive responses. The results indicate that specific patterns of bursting activity in thalamocortical relay neurons play a critical role in controlling long-lasting inflammatory pain in awake and behaving mice

Rebound Discharge in Deep Cerebellar Nuclear Neurons In Vitro

Neurons of the deep cerebellar nuclei (DCN) play a critical role in defining the output of cerebellum in the course of encoding Purkinje cell inhibitory inputs. The earliest work performed with in vitro preparations established that DCN cells have the capacity to translate membrane hyperpolarizations into a rebound increase in firing frequency. The primary means of distinguishing between DCN neurons has been according to cell size and transmitter phenotype, but in some cases, differences in the firing properties of DCN cells maintained in vitro have been reported. In particular, it was shown that large diameter cells in the rat DCN exhibit two phenotypes of rebound discharge in vitro that may eventually help define their functional roles in cerebellar output. A transient burst and weak burst phenotype can be distinguished based on the frequency and pattern of rebound discharge immediately following a hyperpolarizing stimulus. Work to date indicates that the difference in excitability arises from at least the degree of activation of T-type Ca2+ current during the immediate phase of rebound firing and Ca2+-dependent K+ channels that underlie afterhyperpolarizations. Both phenotypes can be detected following stimulation of Purkinje cell inhibitory inputs under conditions that preserve resting membrane potential and natural ionic gradients. In this paper, we review the evidence supporting the existence of different rebound phenotypes in DCN cells and the ion channel expression patterns that underlie their generation

Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease

Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinson's disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinson's disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goal-directed action. © 2010 Macmillan Publishers Limited. All rights reserved