Cortical reorganization after spinal cord injury: always for good?

Plasticity constitutes the basis of behavioral changes as a result of experience. It refers to neural network shaping and re-shaping at the global level and to synaptic contacts remodeling at the local level, either during learning or memory encoding, or as a result of acute or chronic pathological conditions. 'Plastic' brain reorganization after central nervous system lesions has a pivotal role in the recovery and rehabilitation of sensory and motor dysfunction, but can also be "maladaptive". Moreover, it is clear that brain reorganization is not a "static" phenomenon but rather a very dynamic process. Spinal cord injury immediately initiates a change in brain state and starts cortical reorganization. In the long term, the impact of injury - with or without accompanying therapy - on the brain is a complex balance between supraspinal reorganization and spinal recovery. The degree of cortical reorganization after spinal cord injury is highly variable, and can range from no reorganization (i.e. "silencing") to massive cortical remapping. This variability critically depends on the species, the age of the animal when the injury occurs, the time after the injury has occurred, and the behavioral activity and possible therapy regimes after the injury. We will briefly discuss these dependencies, trying to highlight their translational value. Overall, it is not only necessary to better understand how the brain can reorganize after injury with or without therapy, it is also necessary to clarify when and why brain reorganization can be either "good" or "bad" in terms of its clinical consequences. This information is critical in order to develop and optimize cost-effective therapies to maximize functional recovery while minimizing maladaptive states after spinal cord injury.

Methods for implantation of micro-wire bundles and optimization of single/multi-unit recordings from human mesial temporal lobe.

OBJECTIVE: The authors report methods developed for the implantation of micro-wire bundles into mesial temporal lobe structures and subsequent single neuron recording in epileptic patients undergoing in-patient diagnostic monitoring. This is done with the intention of lowering the perceived barriers to routine single neuron recording from deep brain structures in the clinical setting. APPROACH: Over a 15 month period, 11 patients were implanted with platinum micro-wire bundles into mesial temporal structures. Protocols were developed for (A) monitoring electrode integrity through impedance testing, (B) ensuring continuous 24-7 recording, (C) localizing micro-wire position and 'splay' pattern and (D) monitoring grounding and referencing to maintain the quality of recordings. MAIN RESULTS: Five common modes of failure were identified: (1) broken micro-wires from acute tensile force, (2) broken micro-wires from cyclic fatigue at stress points, (3) poor in vivo micro-electrode separation, (4) motion artifact and (5) deteriorating ground connection and subsequent drop in common mode noise rejection. Single neurons have been observed up to 14 days post-implantation and on 40% of micro-wires. SIGNIFICANCE: Long-term success requires detailed review of each implant by both the clinical and research teams to identify failure modes, and appropriate refinement of techniques while moving forward. This approach leads to reliable unit recordings without prolonging operative times, which will help increase the availability and clinical viability of human single neuron data.

Preventing neuronal damage and inflammation in vivo during cortical microelectrode implantation through the use of poloxamer P-188.

OBJECTIVE: The aim of this study was to test the efficacy of Poloxamer P188 to reduce cell death and immune response associated with mechanical trauma to cells during implantation of a chronic recording electrode. APPROACH: Ceramic multi-site recording electrodes were implanted bilaterally into 15 adult male Long-Evans rats. One of each pair was randomly assigned to receive a coating of Poloxamer while the other was treated with saline. The extent of neuron loss, and glial cell recruitment were characterized at 2, 4 and 6 weeks post-implantation by stereologic analysis. MAIN RESULTS: At 2 and 4 weeks post-implantation, Poloxamer-coated implants showed significantly fewer glial cells and more neurons in the peri-electrode space than controls; however, this significance was lost by 6 weeks. SIGNIFICANCE: These findings are the first to suggest that Poloxamer has neuroprotective effects in vivo; however, at a fixed loading dose, these effects are limited to approximately 1 month post-implantation.

Changes in network dynamics during status epilepticus.

Status epilepticus (SE) is an acute event, characterized by repeated or continuous seizures, which alters neuronal properties of the brain and can promote the epileptic disorder. Experimental observations indicate that SE becomes progressively less responsive to anti-epileptic drugs, suggesting changes in the underlying physiology. To assess the effect of SE on neuronal dynamics as it progresses, we measured changes in neuronal activity from CA3 hippocampus, ipsilateral and contralateral to a focal intrahippocampal injection of kainic acid during the full course of SE, 24 h post-SE, and one week post-SE. The progressively intensifying behavioral response during SE was accompanied by changes in intrinsic firing properties of single neurons, LFP oscillations and interaction between single neurons and the oscillations. These results show important changes in neuronal and network activity underlying the progression of SE.

Functional role of exercise-induced cortical organization of sensorimotor cortex after spinal transection.

Spinal cord transection silences neuronal activity in the deafferented cortex to cutaneous stimulation of the body and untreated animals show no improvement in functional outcome (weight-supported stepping) with time after lesion. However, adult rats spinalized since neonates that receive exercise therapy exhibit greater functional recovery and exhibit more cortical reorganization. This suggests that the change in the somatotopic organization of the cortex may be functionally relevant. To address this issue, we chronically implanted arrays of microwire electrodes into the infragranular layers of the hindlimb somatosensory cortex of adult rats neonatally transected at T8/T9 that received exercise training (spinalized rats) and of normal adult rats. Multiple, single neuron activity was recorded during passive sensory stimulation, when the animals were anesthetized, and during active sensorimotor stimulation during treadmill-induced locomotion when the animal was awake and free to move. Our results demonstrate that cortical neurons recorded from the spinalized rats that received exercise 1) had higher spontaneous firing rates, 2) were more likely to respond to both sensory and sensorimotor stimulations of the forelimbs, and also 3) responded with more spikes per stimulus than those recorded from normal rats, suggesting expansion of the forelimb map into the hindlimb map. During treadmill locomotion the activity of neurons recorded from neonatally spinalized rats was greater during weight-supported steps on the treadmill compared with the neuronal activity during nonweight supported steps. We hypothesize that this increased activity is related to the ability of the animal to take weight supported steps and that, therefore, these changes in cortical organization after spinal cord injury are relevant for functional recovery.

Correcting the bias of spike field coherence estimators due to a finite number of spikes.

The coherence between oscillatory activity in local field potentials (LFPs) and single neuron action potentials, or spikes, has been suggested as a neural substrate for the representation of information. The power spectrum of a spike-triggered average (STA) is commonly used to estimate spike field coherence (SFC). However, when a finite number of spikes is used to construct the STA, the coherence estimator is biased. We introduce here a correction for the bias imposed by the limited number of spikes available in experimental conditions. In addition, we present an alternative method for estimating SFC from an STA by using a filter bank approach. This method is shown to be more appropriate in some analyses, such as comparing coherence across frequency bands. The proposed bias correction is a linear transformation derived from an idealized model of spike-field interaction but is shown to hold in more realistic settings. Uncorrected and corrected SFC estimates from both estimation methods are compared across multiple simulated spike-field models and experimentally collected data. The bias correction was shown to reduce the bias of the estimators, but add variance. However, the corrected estimates had a reduced or unchanged mean squared error in the majority of conditions evaluated. The bias correction provides an effective way to reduce bias in an SFC estimator without increasing the mean squared error.

General Poisson exact breakdown of the mutual information to study the role of correlations in populations of neurons.

We present an integrative formalism of mutual information expansion, the general Poisson exact breakdown, which explicitly evaluates the informational contribution of correlations in the spike counts both between and within neurons. The formalism was validated on simulated data and applied to real neurons recorded from the rat somatosensory cortex. From the general Poisson exact breakdown, a considerable number of mutual information measures introduced in the neural computation literature can be directly derived, including the exact breakdown (Pola, Thiele, Hoffmann, & Panzeri, 2003), the Poisson exact breakdown (Scaglione, Foffani, Scannella, Cerutti, & Moxon, 2008) the synergy and redundancy between neurons (Schneidman, Bialek, & Berry, 2003), and the information lost by an optimal decoder that assumes the absence of correlations between neurons (Nirenberg & Latham, 2003; Pola et al., 2003). The general Poisson exact breakdown thus offers a convenient set of building blocks for studying the role of correlations in population codes.

Responses of infragranular neurons in the rat primary somatosensory cortex to forepaw and hindpaw tactile stimuli.

Infragranular layers constitute the main output of the primary somatosensory cortex and represent an important stage of cortico-cortical and cortico-subcortical integration. We have previously used chronic multiple single-unit recordings to study the spatiotemporal structure of tactile responses of infragranular neurons within the forepaw cortical representation in rats [Tutunculer B, Foffani G, Himes BT, Moxon KA (2006) Structure of the excitatory receptive fields of infragranular forelimb neurons in the rat primary somatosensory cortex responding to touch. Cereb Cortex 16:791-810]. Here we extend our understanding of this structure by studying the overlap between the forepaw and hindpaw cortical representations. We recorded 204 responsive neurons in chronic experiments from eight anesthetized rats. Overall, only 23% of neurons responded exclusively to one paw, 52% of neurons responded to two paws, 19% of neurons responded to three paws, and 5% of neurons responded to all four paws. Quantitative measures of response magnitudes and latencies revealed the following main results. (1) The responses of forepaw neurons overall displayed greater magnitudes and shorter latencies than the responses of hindpaw neurons. (2) The responses to ipsilateral stimuli displayed smaller magnitudes, and longer-and more variable-latencies than the responses to contralateral stimuli. (3) The responses of forepaw neurons to hindpaw stimuli displayed smaller magnitudes and longer latencies than the responses to forepaw stimuli, whereas the responses of hindpaw neurons to forepaw stimuli displayed smaller magnitudes but similar latencies compared with the responses to hindpaw stimuli. These results show that the spatiotemporal structure of tactile responses of infragranular neurons extends across all four paws, and provide the basic architecture for studying physiological integration and pathophysiological reorganization of tactile information in the infragranular layers of the rat primary somatosensory cortex.

Mutual information expansion for studying the role of correlations in population codes: how important are autocorrelations?

The role of correlations in the activity of neural populations responding to a set of stimuli can be studied within an information theory framework. Regardless of whether one approaches the problem from an encoding or decoding perspective, the main measures used to study the role of correlations can be derived from a common source: the expansion of the mutual information. Two main formalisms of mutual information expansion have been proposed: the series expansion and the exact breakdown. Here we clarify that these two formalisms have a different representation of autocorrelations, so that even when the total information estimated differs by less than 1%, individual terms can diverge. More precisely, the series expansion explicitly evaluates the informational contribution of autocorrelations in the count of spikes, that is, count autocorrelations, whereas the exact breakdown does not. We propose a new formalism of mutual information expansion, the Poisson exact breakdown, which introduces Poisson equivalents in order to explicitly evaluate the informational contribution of count autocorrelations with no approximation involved. Because several widely employed manipulations of spike trains, most notably binning and pooling, alter the structure of count autocorrelations, the new formalism can provide a useful general framework for studying the role of correlations in population codes.

Sensory gating in the human hippocampal and rhinal regions: regional differences.

To further explore the roles of medial temporal structures in mediating sensory gating of incoming irrelevant or redundant auditory input, twenty-seven patients with intractable epilepsy with depth electrodes implanted in the medial temporal lobe for presurgery evaluation underwent evoked response recording to auditory paired-stimuli (S1-S2). Seventeen subjects were diagnosed with left medial temporal lobe epilepsy (MTLE) and 10 with right MTLE. Only data from the nonlesion side were included. Twenty-three records from rhinal and anterior hippocampal regions, and 21 from posterior hippocampal regions were included in the analysis. The rhinal region had two prominent components (a negativity peaking around 200 ms followed by a positivity peaking around 400 ms). Both the anterior and posterior hippocampal regions exhibited a dominant negative potential peaking around 400 ms. These components were all composed predominantly of slower frequencies. In contrast, a negativity in the posterior hippocampus at around 100 ms was composed of slow and fast frequencies. All components but the early rhinal negativity were attenuated by stimulus repetition. This is the first report documenting that different regions of the medial temporal area are differentially involved in the processing of auditory input, most likely reflecting separate steps of processing. The data support the need for further exploration of the contribution of these regions to sensory gating. This information helps to increase our understanding of this basic but important and complex function.

Bioactive properties of nanostructured porous silicon for enhancing electrode to neuron interfaces.

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 on the order of months. 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 non-conductive glial scar. Since the extracellular matrix consists of nanostructured fibrous protein assemblies, we have postulated that neurons may prefer a more complex surface structure than the smooth surface typical of thin-film microelectrodes. This porous structure could then act as a drug-delivery reservoir to deliver bioactive agents to aid in the repair or survival of cells around the microelectrode, further reducing the glial scar. We, therefore, investigated the suitability of a nanoporous silicon surface layer to increase the biocompatibility of our thin film ceramic-insulated multisite electrodes. In vitro testing demonstrated increased extension of neurites from PC12 pheochromocytoma cells on porous silicon surfaces compared to smooth silicon surfaces. Moreover, the size of the pores and the pore coverage did not interfere with this bioactive surface property, suggesting that large highly porous nanostructured surfaces can be used for drug delivery. The most porous nanoporous surfaces were then tested in vivo and found to be more biocompatible than smooth surface, producing less glial activation and allowing more neurons to remain close to the device. Collectively, these results support our hypothesis that nanoporous silicon may be an ideal material to improve biocompatibility of chronically implanted microelectrodes. The next step in this work will be to apply these surfaces to active microelectrodes, use them to deliver bioactive agents, and test that they do improve neural recordings.

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

The subthalamic nucleus (STN) has a key role in the pathophysiology of Parkinson's disease and is the primary target for high-frequency deep brain stimulation (DBS). The STN rest electrical activity in Parkinson's 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 Parkinson's 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.

Distinct temporal activity patterns in the rat M1 and red nucleus during skilled versus unskilled limb movement.

The mammalian motor system contains multiple interconnected supraspinal networks, but little is known about their relative roles in producing different movements and behaviors, particularly given their apparently fused activity in primates. We tested whether the task context, as well as using a phylogenetically older mammal, rats, could distinguish the separate contributions of these networks. We obtained simultaneous multi-single neuron recordings from the forelimb motor cortex and magnocellular red nucleus as rats performed two contextually different, but kinematically similar, forelimb reach-like tasks: highly learned, skilled reaching for food through a narrow slot, a task requiring extensive training, versus the swing phases of treadmill locomotion. In both the M1 and the mRN, large subpopulations of neurons peaked in their spike firing rates near the onset and the end of the swing phase during treadmill locomotion. In contrast, neural subgroups in the two areas displayed different temporal sequences of activity during the skilled reaching task. In the mRN, the majority of task-modulated neurons peaked in their firing rate in the middle of the reach when the rat was preparing to project the arm through the slot, whereas large subgroups of M1 neurons displayed elevated firing rates during the initial and terminal phases of the reach. These results suggest that motor-behavioral context can alter the degree of overlapping activity in different supraspinal sensorimotor networks. Moreover, results for the skilled reaching task in rats may have highlighted a distinct processing role of the rubral complex: adapting natural muscle synergies across joints and limbs to novel task demands, in concert with cortically based learning.

300-Hz subthalamic oscillations in Parkinson's disease.

Despite several studies and models, much remains unclear about how the human basal ganglia operate. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for complicated Parkinson's disease, but how DBS acts also remains unknown. The clinical benefit of DBS at frequencies >100 Hz suggests the possible importance of neural rhythms operating at frequencies higher than the range normally considered for basal ganglia processing (<100 Hz). The electrodes implanted for DBS also offer the opportunity to record neural activity from the human basal ganglia. This study aimed to assess whether oscillations at frequencies >100 Hz operate in the human STN. While recording local field potentials from the STN of nine patients with Parkinson's disease through DBS electrodes, we found a dopamine- and movement-dependent 300-Hz rhythm. At rest, and in the absence of dopaminergic medication, in most cases (eight out of 11 nuclei) the 100-1000 Hz band showed no consistent rhythm. Levodopa administration elicited (or markedly increased) a 300-Hz rhythm at rest [(mean +/- SD) central frequency: 319 +/- 33 Hz; bandwidth: 72 +/- 21 Hz; power increase (after medication - before medication)/before medication: 1.30 +/- 1.25; n = 11, P = 0.00098]. The 300-Hz rhythm was also increased by apomorphine, but not by orphenadrine. The 300-Hz rhythm was modulated by voluntary movement. Before levodopa administration, movement-related power increase in the 300-Hz rhythm was variably present in different subjects, whereas after levodopa it became a robust phenomenon [before 0.014 +/- 0.014 arbitrary units (AU), after 0.178 +/- 0.339 AU; n = 8, P = 0.0078]. The dopamine-dependent 300-Hz rhythm probably reflects a bistable compound nuclear activity and supports high-resolution information processing in the basal ganglia circuit. An absent 300-Hz subthalamic rhythm could be a pathophysiological clue in Parkinson's disease. The 300-Hz rhythm also provides the rationale for an excitatory--and not only inhibitory--interpretation of DBS mechanism of action in humans.

Real-time control of a robot arm using simultaneously recorded neurons in the motor cortex.

To determine whether simultaneously recorded motor cortex neurons can be used for real-time device control, rats were trained to position a robot arm to obtain water by pressing a lever. Mathematical transformations, including neural networks, converted multineuron signals into 'neuronal population functions' that accurately predicted lever trajectory. Next, these functions were electronically converted into real-time signals for robot arm control. After switching to this 'neurorobotic' mode, 4 of 6 animals (those with > 25 task-related neurons) routinely used these brain-derived signals to position the robot arm and obtain water. With continued training in neurorobotic mode, the animals' lever movement diminished or stopped. These results suggest a possible means for movement restoration in paralysis patients.

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.