Cortical modulation of dorsal column nuclei: a computational study

[Abstract] We present a computational study aimed at exploring the sensorimotor cortex modulation of the behaviour of dorsal column nuclei, specifically the impact of synaptic parameters, during both sleep and waking conditions. On the basis of the circuit proposed by Canedo et al. (2000), we have developed realistic computational models that have been tested with simultaneous electrocorticographic as well as intracellular cuneate recordings performed in anaesthetized cats. The results show that, (1) under sleep conditions, the model can block the transmission of afferent sensory information and, (2) operations expected during wakefulness, such as filtering and facilitation, can be performed if synaptic parameters are appropriately tuned.Argentina. Consejo Interinstitucional de Ciencia y Tecnología; PB01-121212Xunta de Galicia; XU02–211

A realistic computational model of the local circuitry of the cuneate nucleus

Intracellular recordings obtained under cutaneous and lemniscal stimulation show that the afferent fibers can establish excitatory and inhibitory synaptic connections with cuneothalamic neurons [5]. In addition, distinct types of recurrent collaterals with the capability of either exciting or inhibiting both cuneothalamic neurons and interneurons were also discovered [6]. With these data we have generated hypothesis about which circuits are implicated and also developed realistic computational models to test the hypothesis and study the cuneate properties [17,18]. The results show that the cuneate could perform spatial and temporal filtering and therefore detect dynamic edges

A Computational Model of Cuneothalamic Projection Neurons

[Abstract] The dorsal column nuclei, cuneatus and gracilis, play a fundamental role in the processing and integration of somesthetic ascending information. Intracellular and patch-clamp recordings obtained in cat in vivo have shown that cuneothalamic projection neurons present two modes of activity: oscillatory and tonic (Canedo et al 1998 Neuroscience 84 603–17). The former is the basis of generating, in sleep and anaesthetized states, slow, delta and spindle rhythms under the control of the cerebral cortex (Mari˜no et al 2000 Neuroscience 95 657–73). The latter is needed, during wakefulness, to process somesthetic information in real time. To study this behaviour we have developed the first realistic computational model of the cuneothalamic projection neurons. The modelling was guided by experimental recordings, which suggest the existence of hyperpolarization-activated inward currents, transient low- and high-threshold calcium currents, and calcium-activated potassium currents. The neuronal responses were simulated during (1) sleep, (2) transition from sleep to wakefulness and (3) wakefulness under both excitatory and inhibitory synaptic input. In wakefulness the model predicts a set of synaptically driven firing modes that could be associated with information processing strategies in the middle cuneate nucleus

Principles of organisation within the pathways in the brainstem and thalamus

There are few detailed studies on the pathways through the human brainstem and even fewer on those through the pons. This thesis aims to address this lack of fine detail, and used ultra-high-field magnetic resonance imaging (MRI) of human and macaque brains to identify and characterise fibre tracts connecting cortical and spinal areas as they traverse through brainstem and thalamic structures. The material in this thesis is based on a unique dataset of ultra-high-field (7 Tesla – Duke and 11, 7 Tesla – Johns Hopkins) MRI scans on postmortem specimens, on which deterministic tractography has been applied based on high-angular-resolution diffusion imaging (HARDI) and subsequently higher order tensor glyph models. The first results section of the thesis (Chapter 3) maps the descending fibre bundles associated with movement. From the motor cortical areas, the fibres of the internal capsule are traced through the crus cerebri, basilar pons and pyramids in three dimensions to reveal their organisation into functional and topographic subdivisions. While human cortico-pontine, -bulbar and -spinal tracts were traditionally considered to be dispersed, or a “melange”, I show here a much more discrete and defined organisation of these descending fibre bundles. Nine descending fibre bundles are identified and their anatomical location and terminations are described. A hitherto unknown pathway at the midline of the pons has been discovered and named herein as the Stria Pontis which connects the neocortex to the pontine tegmentum. Ten transverse fibre bundles connecting the pontine nuclei to the cerebellum are also identified. The second results section (Chapter 4) analyses the sensory pathways; the dorsal column - medial lemniscus pathway, the spinothalamic tract, the spinal trigeminal tract and the trigeminothalamic tracts. The third results section (Chapter 5) analyses the dentato-rubro-thalamic tract. The mapping identifies the superior cerebellar peduncle, the patterning of the fibres within the superior cerebellar decussation, the patterning of the fibres within the red nucleus and finally the projection of the dentato-rubro-thalamic tract from the red nucleus to the ventral lateral nucleus of the thalamus. Finally, I characterised 117 already known anatomical parts, areas and structures of the brainstem and thalamus in 3D

Neuroplasticity induced by peripheral nerve stimulation

PhD ThesisNon-invasive methods have been developed to induce plastic changes in the sensorimotor cortex. These rely on stimulating pairs of afferent nerves. By associative stimulation (AS) of two afferent nerves, excitability changes in the motor cortex occur as indicated by studies reporting changes in motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). Repetitive stimulation of those nerves has a potential in rehabilitation and treatment of neurological disorders like stroke or spinal cord injury. Despite promising results and applications in human subjects using these methods, little is understood about the underlying basis for the changes which are seen. In the present study, behavioural, electrophysiological and immunohistochemical assessments were performed before and after paired associative and non-associative (NAS) median and ulnar nerve stimulation. Two macaque monkeys were trained to perform a skilled finger abduction task using refined behavioural methods. Monkeys were not able to move their thumb and index finger as selectively after one hour of paired AS as indicated by an increased number of errors and decreased performance measures. NAS however decreased error numbers and led to increased performances. Additionally, I recorded from identified pyramidal tract neurons and unidentified cells in primary motor cortex (M1), in two macaque monkeys before and after one hour of AS (and NAS) of the median and ulnar nerve. Cell discharge was recorded in response to electrical stimulation of each nerve independently. Some cells in M1 showed changed firing rates in response to nerve stimulation after AS (and NAS). Subsequently, structural changes in response to one week of paired AS were investigated. The laminar-specific density of parvalbumin-positive interneurons, perineuronal nets and the colocalisation of these two entities changed on the stimulated (in comparison to the non-stimulated) sensorimotor cortex. These findings suggest that the sensorimotor cortex undergoes plastic changes in response to AS (and NAS).Wellcome Trus

Relative Contribution of Proprioceptive and Vestibular Sensory Systems to Locomotion: Opportunities for Discovery in the Age of Molecular Science

Locomotion is a fundamental animal behavior required for survival and has been the subject of neuroscience research for centuries. In terrestrial mammals, the rhythmic and coordinated leg movements during locomotion are controlled by a combination of interconnected neurons in the spinal cord, referred as to the central pattern generator, and sensory feedback from the segmental somatosensory system and supraspinal centers such as the vestibular system. How segmental somatosensory and the vestibular systems work in parallel to enable terrestrial mammals to locomote in a natural environment is still relatively obscure. In this review, we first briefly describe what is known about how the two sensory systems control locomotion and use this information to formulate a hypothesis that the weight of the role of segmental feedback is less important at slower speeds but increases at higher speeds, whereas the weight of the role of vestibular system has the opposite relation. The new avenues presented by the latest developments in molecular sciences using the mouse as the model system allow the direct testing of the hypothesis

Modeling the Cerebellar Microcircuit: New Strategies for a Long-Standing Issue

The cerebellar microcircuit has been the work bench for theoretical and computational modeling since the beginning of neuroscientific research. The regular neural architecture of the cerebellum inspired different solutions to the long-standing issue of how its circuitry could control motor learning and coordination. Originally, the cerebellar network was modeled using a statistical-topological approach that was later extended by considering the geometrical organization of local microcircuits. However, with the advancement in anatomical and physiological investigations, new discoveries have revealed an unexpected richness of connections, neuronal dynamics and plasticity, calling for a change in modeling strategies, so as to include the multitude of elementary aspects of the network into an integrated and easily updatable computational framework. Recently, biophysically accurate realistic models using a bottom-up strategy accounted for both detailed connectivity and neuronal non-linear membrane dynamics. In this perspective review, we will consider the state of the art and discuss how these initial efforts could be further improved. Moreover, we will consider how embodied neurorobotic models including spiking cerebellar networks could help explaining the role and interplay of distributed forms of plasticity. We envisage that realistic modeling, combined with closed-loop simulations, will help to capture the essence of cerebellar computations and could eventually be applied to neurological diseases and neurorobotic control systems

Suitability of the dorsal column nuclei for a neural prosthesis: functional considerations

The brainstem dorsal column nuclei (DCN) may be an ideal target for a future neural prosthesis to restore somatosensation in tetraplegic patients. We aimed to investigate the functional and structural characteristics of the DCN, with the overarching goal of determining their suitability as a somatosensory neural prosthetic target. First, we review the neuroanatomy of the DCN and surrounding nuclei, including the cuneate, gracile, external cuneate, X, and Z nuclei, which together comprise the DCN-complex. We reveal that the DCN are not organised to only process and relay tactile information, as is commonly thought, but instead are a complex sensorimotor integration and distribution hub, with diverse projection targets throughout the hindbrain and midbrain. Next, we sought to show that somatosensory signals arriving in the DCN are reproducible, and that they carry decodable information about the location and quality of somatosensory stimuli, which we propose are necessary conditions for a potential somatosensory neural prosthetic target. We record somatosensory-evoked signals from various locations across the surface of the DCN in 8-week-old anaesthetised male Wistar rats. We characterised somatosensory-evoked DCN surface signals and demonstrated that they have robust and reproducible high-frequency and low-frequency features within and across animals. Using a machine-learning approach, we developed a metric for evaluating the relevance of machine-learning inputs to target outputs, which we coined feature-learnability. Using feature-learnability allowed us to determine the DCN signal features that were most relevant to peripheral somatosensory events, which facilitated very high accuracy prediction of the location and quality of somatosensory events, from small numbers of features. This thesis supports the DCN as a potential somatosensory neural prosthetic target by: i) showing DCN connectivity with sensorimotor targets essential for movement modulation in conscious and non-conscious neural pathways; ii) determining DCN signal features that are most relevant to peripheral tactile and proprioceptive events. New knowledge about the most relevant DCN signal features may inform the development of biomimetic stimulus patterns designed to artificially activate the DCN in future neural prosthetic devices for restoring somatosensory feedback