Showing papers in "Progress in Brain Research in 2007"

The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies).

Abstract: The dentate gyrus is a simple cortical region that is an integral portion of the larger functional brain system called the hippocampal formation In this review, the fundamental neuroanatomical organization of the dentate gyrus is described, including principal cell types and their connectivity, and a summary of the major extrinsic inputs of the dentate gyrus is provided Together, this information provides essential information that can serve as an introduction to the dentate gyrus — a “dentate gyrus for dummies”

The functional neuroanatomy of PTSD: a critical review

Abstract: Neuroimaging provides an opportunity to understand core processes that mediate the experience of emotions in healthy individuals as well as dysregulation of these processes in conditions such as posttraumatic stress disorder (PTSD). The first decade of neuroimaging research produced symptom provocation, cognitive activation, and functional connectivity studies that highlighted the role of the medial prefrontal cortex (mPFC), amygdala, sublenticular extended amygdala (SLEA), and hippocampus, in mediating symptom formation in PTSD. There is a growing realization that a number of other psychological processes are relevant to PTSD, and they are emerging as a new focus of neuroimaging research. These include fear conditioning, habituation, and extinction; cognitive-emotional interactions; and self-related and social emotional processing. Neuroimaging findings are reviewed that suggest that the mPFC is implicated in a number of these processes. It is proposed that the mPFC plays a role in the "contextualization" of stimuli, and dysregulation of contextualization processes might play a key role in the generation of PTSD symptoms.

The cellular, molecular and ionic basis of GABA(A) receptor signalling.

Abstract: GABA(A) receptors mediate fast synaptic inhibition in the CNS. Whilst this is undoubtedly true, it is a gross oversimplification of their actions. The receptors themselves are diverse, being formed from a variety of subunits, each with a different temporal and spatial pattern of expression. This diversity is reflected in differences in subcellular targetting and in the subtleties of their response to GABA. While activation of the receptors leads to an inevitable increase in membrane conductance, the voltage response is dictated by the distribution of the permeant Cl(-) and HCO(3)(-) ions, which is established by anion transporters. Similar to GABA(A) receptors, the expression of these transporters is not only developmentally regulated but shows cell-specific and subcellular variation. Untangling all these complexities allows us to appreciate the variety of GABA-mediated signalling, a diverse set of phenomena encompassing both synaptic and non-synaptic functions that can be overtly excitatory as well as inhibitory.

To recognize shapes, first learn to generate images.

Abstract: The uniformity of the cortical architecture and the ability of functions to move to different areas of cortex following early damage strongly suggest that there is a single basic learning algorithm for extracting underlying structure from richly structured, high-dimensional sensory data. There have been many attempts to design such an algorithm, but until recently they all suffered from serious computational weaknesses. This chapter describes several of the proposed algorithms and shows how they can be combined to produce hybrid methods that work efficiently in networks with many layers and millions of adaptive connections.

The perforant path: projections from the entorhinal cortex to the dentate gyrus

Abstract: This paper provides a comprehensive description of the organization of projections from the entorhinal cortex to the dentate gyrus, which together with projections to other subfields of the hippocampal formation form the so-called perforant pathway. To this end, data that are primarily from anatomical studies in the rat will be summarized, complimented with comparative data from other species. The analysis of the organization of any of the connections of the hippocampus, including that of the entorhinal cortex to the dentate gyrus, is severely hampered because of the complex three-dimensional shape of the hippocampus. In particular in rodents, but to a lesser extent also in primates, all traditional planes of sectioning will result in sections that at some point or another do not cut through the hippocampus at an angle that is perpendicular to its long axis. To amend this, we will describe own unpublished tracing data obtained in the rat with the use of the so-called extended preparation. A number of issues will be addressed. First, data will be summarized which will clarify the laminar origin of the perforant pathway within the entorhinal cortex. Second, we will discuss whether or not a radial organization, along the proximo-distal dendritic axis of granule cells, characterizes the entorhinal-dentate projection. Third, we will discuss whether this projection is governed by any transverse organization, and fourth, we will focus on the organization along the longitudinal axis. Finally, the synaptic organization and the contralateral entorhinal-dentate projection will be described briefly. Taken together, the available data suggest that the projection from the entorhinal cortex to the dentate gyrus is a fairly well conserved connection, present in all species studied, exhibiting a grossly similar organization.

Progressive damage after brain and spinal cord injury: pathomechanisms and treatment strategies.

Abstract: The pathophysiology of brain and spinal cord injury (SCI) is complex and involves multiple injury mechanisms that are spatially and temporally specific. It is now appreciated that many of these injury mechanisms remain active days to weeks after a primary insult. Long-term survival studies in clinically relevant experimental studies have documented the structural changes that continue at the level of the insult as well as in remote brain structures. After traumatic brain injury (TBI), progressive atrophy of both gray and white matter structures continues up to 1 year post-trauma. Progressive changes may therefore underlie some of the long-term functional deficits observed in this patient population. After SCI, similar features of progressive injury are observed including delayed cell death of neurons and oligodendrocytes, axonal demyelination of intact fiber tracts and retrograde tract degeneration. SCI also leads to supraspinal changes in cell survival and remote brain circuitry. The progressive changes in multiple structures after brain and SCI are important because of their potential consequences on chronic or developing neurological deficits associated with these insults. In addition, the better understanding of these injury cascades may one day allow new treatments to be developed that can inhibit these responses to injury and hopefully promote recovery. This chapter summarizes some of the recent data regarding progressive damage after CNS trauma and mechanisms underlying these changes.

Statistical models for neural encoding, decoding, and optimal stimulus design

Abstract: There are two basic problems in the statistical analysis of neural data. The "encoding" problem concerns how information is encoded in neural spike trains: can we predict the spike trains of a neuron (or population of neurons), given an arbitrary stimulus or observed motor response? Conversely, the "decoding" problem concerns how much information is in a spike train, in particular, how well can we estimate the stimulus that gave rise to the spike train? This chapter describes statistical model-based techniques that in some cases provide a unified solution to these two coding problems. These models can capture stimulus dependencies as well as spike history and interneuronal interaction effects in population spike trains, and are intimately related to biophysically based models of integrate-and-fire type. We describe flexible, powerful likelihood-based methods for fitting these encoding models and then for using the models to perform optimal decoding. Each of these (apparently quite difficult) tasks turn out to be highly computationally tractable, due to a key concavity property of the model likelihood. Finally, we return to the encoding problem to describe how to use these models to adaptively optimize the stimuli presented to the cell on a trial-by-trial basis, in order that we may infer the optimal model parameters as efficiently as possible.

Pathophysiology of tinnitus

Abstract: Guided by findings from neural imaging and population responses in humans, where tinnitus is well characterized, several morphological and physiological substrates of tinnitus in animal studies are reviewed. These include changes in ion channels, receptor systems, single unit firing rate, and population responses. Most findings in humans can be interpreted as resulting from increased neural synchrony.

Consensus for tinnitus patient assessment and treatment outcome measurement: Tinnitus Research Initiative meeting, Regensburg, July 2006.

Abstract: There is widespread recognition that consistency between research centres in the ways that patients with tinnitus are assessed and outcomes following interventions are measured would facilitate more effective co-operation and more meaningful evaluations and comparisons of outcomes. At the first Tinnitus Research Initiative meeting held in Regensburg in July 2006 an attempt was made through workshops to gain a consensus both for patient assessments and for outcome measurements. It is hoped that this will contribute towards better cooperation between research centres in finding and evaluating treatments for tinnitus by allowing better comparability between studies.

Epileptogenesis in the dentate gyrus: a critical perspective.

Abstract: The dentate gyrus has long been a focal point for studies on the molecular, cellular, and network mechanisms responsible for epileptogenesis in temporal lobe epilepsy (TLE). Although several hypothetical mechanisms are considered in this chapter, two that have garnered particular interest and experimental support are: (1) the selective loss of vulnerable interneurons in the region of the hilus and (2) the formation of new recurrent excitatory circuits after mossy fiber sprouting. Histopathological data show that specific GABAergic interneurons in the hilus are lost in animal models of TLE, and several lines of electrophysiological evidence, including intracellular analyses of postsynaptic currents, support this hypothesis. In particular, whole-cell recordings have demonstrated a reduction in the frequency of miniature inhibitory postsynaptic currents in the dentate gyrus and other areas (e.g., CA1 pyramidal cells), which provides relatively specific evidence for a reduction in GABAergic input to granule cells. These studies support the viewpoint that modest alterations in GABAergic inhibition can have significant functional impact in the dentate gyrus, and suggest that dynamic activity-dependent mechanisms of GABAergic regulation add complexity to this local synaptic circuitry and to analyses of epileptogenesis. In regard to mossy fiber sprouting, a wide variety of experiments involving intracellular or whole-cell recordings during electrical stimulation of the hilus, glutamate microstimulation, and dual recordings from granule cells support the hypothesis that mossy fiber sprouting forms new recurrent excitatory circuits in the dentate gyrus in animal models of TLE. Similar to previous studies on recurrent excitation in the CA3 area, GABA-mediated inhibition and the intrinsic high threshold of granule cells in the dentate gyrus tends to mask the presence of the new recurrent excitatory circuits and reduce the likelihood that reorganized circuits will generate seizure-like activity. How cellular alterations such as neuron loss in the hilus and mossy fiber sprouting influence functional properties is potentially important for understanding fundamental aspects of epileptogenesis, such as the consequences of primary initial injuries, mechanisms underlying network synchronization, and progression of intractability. The continuous nature of the axonal sprouting and formation of recurrent excitation could account for aspects of the latent period and the progressive nature of the epileptogenesis. Future studies will need to identify precisely how these hypothetical mechanisms and others contribute to the process whereby epileptic seizures are initiated or propagated through an area such as the dentate gyrus. Finally, in addition to its unique features and potential importance in epileptogenesis, the dentate gyrus may also serve as a model for other cortical structures in acquired epilepsy.

Dynamics systems vs. optimal control--a unifying view.

Abstract: In the past, computational motor control has been approached from at least two major frameworks: the dynamic systems approach and the viewpoint of optimal control. The dynamic system approach emphasizes motor control as a process of self-organization between an animal and its environment. Nonlinear differential equations that can model entrainment and synchronization behavior are among the most favorable tools of dynamic systems modelers. In contrast, optimal control approaches view motor control as the evolutionary or development result of a nervous system that tries to optimize rather general organizational principles, e.g., energy consumption or accurate task achievement. Optimal control theory is usually employed to develop appropriate theories. Interestingly, there is rather little interaction between dynamic systems and optimal control modelers as the two approaches follow rather different philosophies and are often viewed as diametrically opposing. In this paper, we develop a computational approach to motor control that offers a unifying modeling framework for both dynamic systems and optimal control approaches. In discussions of several behavioral experiments and some theoretical and robotics studies, we demonstrate how our computational ideas allow both the representation of self-organizing processes and the optimization of movement based on reward criteria. Our modeling framework is rather simple and general, and opens opportunities to revisit many previous modeling results from this novel unifying view.

Transgenerational transmission of cortisol and PTSD risk.

Abstract: Parental posttraumatic stress disorder (PTSD) appears to be a relevant risk factor for the development of PTSD, as evidenced by a greater prevalence of PTSD, but not trauma exposure, in adult offspring of Holocaust survivors with PTSD, compared to children of Holocaust-exposed parents without PTSD. This paper summarizes recent neuroendocrine studies in offspring of parents with PTSD. Offspring of trauma survivors with PTSD show significantly lower 24-h mean urinary cortisol excretion and salivary cortisol levels as well as enhanced plasma cortisol suppression in response to low dose dexamethasone administration than offspring of survivors without PTSD. In all cases, neuroendocrine measures were negatively correlated with severity of parental PTSD symptoms, even after controlling for PTSD and even other symptoms in offspring. Though the majority of our work has focused on adult offspring of Holocaust survivors, recent observations in infants born to mothers who were pregnant on 9/11 demonstrate that low cortisol in relation to parental PTSD appears to be present early in the course of development and may be influenced by in utero factors such as glucocorticoid programming. Since low cortisol levels are particularly associated with the presence of maternal PTSD the findings suggest the involvement of epigenetic mechanisms.

The CA3 "backprojection" to the dentate gyrus.

Abstract: The hippocampus is typically described in the context of the trisynaptic circuit, a pathway that relays information from the perforant path to the dentate gyrus, dentate to area CA3, and CA3 to area CA1. Associated with this concept is the assumption that most hippocampal information processing occurs along the trisynaptic circuit. However, the entorhinal cortex may not be the only major extrinsic input to consider, and the trisynaptic circuit may not be the only way information is processed in hippocampus. Area CA3 receives input from a variety of sources, and may be as much of an "entry point" to hippocampus as the dentate gyrus. The axon of CA3 pyramidal cells targets diverse cell types, and has commissural projections, which together make it able to send information to much more of the hippocampus than granule cells. Therefore, CA3 pyramidal cells seem better designed to spread information through hippocampus than the granule cells. From this perspective, CA3 may be a point of entry that receives information which needs to be "broadcasted," whereas the dentate gyrus may be a point of entry that receives information with more selective needs for hippocampal processing. One aspect of the argument that CA3 pyramidal cells have a widespread projection is based on a part of its axonal arbor that has received relatively little attention, the collaterals that project in the opposite direction to the trisynaptic circuit, "back" to the dentate gyrus. The evidence for this "backprojection" to the dentate gyrus is strong, particularly in area CA3c, the region closest to the dentate gyrus, and in temporal hippocampus. The influence on granule cells is indirect, through hilar mossy cells and GABAergic neurons of the dentate gyrus, and appears to include direct projections in the case of CA3c pyramidal cells of ventral hippocampus. Physiological studies suggest that normally area CA3 does not have a robust excitatory influence on granule cells, but serves instead to inhibit it by activating dentate gyrus GABAergic neurons. Thus, GABAergic inhibition normally controls the backprojection to dentate granule cells, analogous to the way GABAergic inhibition appears to control the perforant path input to granule cells. From this perspective, the dentate gyrus has two robust glutamatergic inputs, entorhinal cortex and CA3, and two "gates," or inhibitory filters that reduce the efficacy of both inputs, keeping granule cells relatively quiescent. When GABAergic inhibition is reduced experimentally, or under pathological conditions, CA3 pyramidal cells activate granule cells reliably, and do so primarily by disynaptic excitation that is mediated by mossy cells. We suggest that the backprojection has important functions normally that are dynamically regulated by nonprincipal cells of the dentate gyrus. Slightly reduced GABAergic input would lead to increased polysynaptic associative processing between CA3 and the dentate gyrus. Under pathological conditions associated with loss of GABAergic interneurons, the backprojection may support reverberatory excitatory activity between CA3, mossy cells, and granule cells, possibly enhanced by mossy fiber sprouting. In this case, the backprojection could be important to seizure activity originating in hippocampus, and help explain the seizure susceptibility of ventral hippocampus.

A quantitative theory of immediate visual recognition.

Abstract: Human and non-human primates excel at visual recognition tasks The primate visual system exhibits a strong degree of selectivity while at the same time being robust to changes in the input image We have developed a quantitative theory to account for the computations performed by the feedforward path in the ventral stream of the primate visual cortex Here we review recent predictions by a model instantiating the theory about physiological observations in higher visual areas We also show that the model can perform recognition tasks on datasets of complex natural images at a level comparable to psychophysical measurements on human observers during rapid categorization tasks In sum, the evidence suggests that the theory may provide a framework to explain the first 100-150 ms of visual object recognition The model also constitutes a vivid example of how computational models can interact with experimental observations in order to advance our understanding of a complex phenomenon We conclude by suggesting a number of open questions, predictions, and specific experiments for visual physiology and psychophysics

GABAergic control of substantia nigra dopaminergic neurons

Abstract: At least 70% of the afferents to substantia nigra dopaminergic neurons are GABAergic. The vast majority of these arise from the neostriatum, the external globus pallidus and the substantia nigra pars reticulata. Nigral dopaminergic neurons express both GABA(A) and GABA(B) receptors, and are inhibited by local application of GABA(A) or GABA(B) agonists in vivo and in vitro. However, in vivo, synaptic responses elicited by stimulation of neostriatal or pallidal afferents, or antidromic activation of nigral pars reticulata GABAergic projection neurons are mediated predominantly or exclusively by GABA(A) receptors. The clearest and most consistent role for the nigral GABA(B) receptor in vivo is as an inhibitory autoreceptor that presynaptically modulates GABA(A) synaptic responses that originate from all three principal GABAergic inputs. The firing pattern of dopaminergic neurons is also effectively modulated by GABAergic inputs in vivo. Local blockade of nigral GABA(A) receptors causes dopaminergic neurons to shift to a burst firing pattern regardless of the original firing pattern. This is accompanied by a modest increase in spontaneous firing rate. The GABAergic inputs from the axon collaterals of the pars reticulata projection neurons seem to be a particularly important source of a GABA(A) tone to the dopaminergic neurons, inhibition of which leads to burst firing. The globus pallidus exerts powerful control over the pars reticulata input, and through the latter, disynaptically over the dopaminergic neurons. Inhibition of pallidal output leads to a slight decrease in firing of the dopaminergic neurons due to disinhibition of the pars reticulata neurons whereas increased firing of pallidal neurons leads to burst firing in dopaminergic neurons that is associated with a modest increase in spontaneous firing rate and a significant increase in extracellular levels of dopamine in the neostriatum. The pallidal disynaptic disinhibitory control of the dopaminergic neurons dominates the monosynaptic inhibitory influence because of a differential sensitivity to GABA of the two nigral neuron types. Nigral GABAergic neurons are more sensitive to GABA(A)-mediated inhibition than dopaminergic neurons, in part due to a more hyperpolarized GABA(A) reversal potential. The more depolarized GABA(A) reversal potential in the dopaminergic neurons is due to the absence of KCC2, the chloride transporter responsible for setting up a hyperpolarizing Cl(-) gradient in most mature CNS neurons. The data reviewed in this chapter have made it increasingly clear that in addition to the effects that nigral GABAergic output neurons have on their target nuclei outside of the basal ganglia, local interactions between GABAergic projection neurons and dopaminergic neurons are crucially important to the functioning of the nigral dopaminergic neurons.

Globus pallidus external segment.

Abstract: The external segment of the pallidum (GP(e)) is a relatively large nucleus located caudomedial to the neostriatum (Str) The GP(e) receives major inputs from two major basal ganglia input nuclei, the Str and the subthalamic nucleus (STN), and sends its output to many basal ganglia nuclei including the STN, the Str, the internal pallidal segment (GP(i)), and the substantia nigra (SN) Thus, the GPe can be placed at the center of the basal ganglia connection diagram (Fig 1(A)) From the viewpoint that emphasizes the direct and indirect pathways of the basal ganglia, the GP(e) is a component of the indirect pathway that relays Str inputs to the STN The indirect pathway can be traced in Fig 1(A), although it comprises only a part of multiple indirect pathways This chapter begins with a brief description of the anatomical organization of the GP(e) followed by physiological and pharmacological characterizations of GABAergic responses in the GP(e)

Traumatic brain injury and Alzheimer's disease: a review.

Abstract: In an effort to identify the factors that are involved in the pathogenesis of Alzheimer's disease (AD), epidemiological studies have featured prominently in contemporary research. Of those epidemiological factors, accumulating evidence implicates traumatic brain injury (TBI) as a possible predisposing factor in AD development. Exactly how TBI triggers the neurodegenerative cascade of events in AD remains controversial. There has been extensive research directed towards understanding the potential relationship between TBI and AD and the putative influence that apolipoprotein E (APOE) genotype has on this relationship. The aim of the current paper is to provide a critical summary of the experimental and human studies regarding the association between TBI, AD and APOE genotype. It will be shown that despite significant discrepancies in the literature, there still appears to be an increasing trend to support the hypothesis that TBI is a potential risk factor for AD. Furthermore, although it is known that APOE genotype plays an important role in AD, its link to a deleterious outcome following TBI remains inconclusive and ambiguous.

Cellular and subcellular change evoked by diffuse traumatic brain injury: a complex web of change extending far beyond focal damage.

Abstract: Until recently, our understanding of the cellular and subcellular changes evoked by diffuse traumatic brain injury has been framed in the context of primary focal injury. In this regard, the ensuing cell death cascades were linked to contusional-mediated changes associated with frank hemorrhage and ischemia, and these were assumed to contribute to the observed apoptotic and necrotic neuronal death. Little consideration was given to the potential that other non-contusional cell death cascades could have been triggered by the diffuse mechanical forces of injury. While the importance of these classical, contusion-related apoptotic and necrotic cell death cascades cannot be discounted with diffuse injury, more recent information suggests that the mechanical force of injury itself can diffusely porate the neuronal plasmalemma and its axolemmal membranes, evoking other forms of cellular response that can contribute to cell injury or death. In this regard, the duration of the membrane alteration appears to be a dependent factor, with enduring membrane change, potentially leading to irreversible damage, whereas more transient membrane perturbation can be followed by cell membrane resealing associated with recovery and/or adaptive change. With more enduring mechanical membrane perturbation, it appears that some of the traditional death cascades involving the activation of cysteine proteases are at work. Equally important, non-traditional pathways involving the lysosomal dependent release of hydrolytic enzymes may also be players in the ensuing neuronal death. These mechanically related factors that directly impact upon the neuronal somata may also be influenced by concomitant and/or secondary axotomy-mediated responses. This axonal injury, although once thought to involve a singular intraaxonal response to injury, is now known to be more complex, reflecting differential responses to injuries of varying severity. Moreover, it now appears that fiber size and type may also influence the axon's reaction to injury. In sum, this review explicates the complexity of the cellular and subcellular responses evoked by diffuse traumatic brain injury in both the neuronal somata and its axonal appendages. This review further illustrates that our once simplistic views framed by evidence based upon contusional and/or ischemic change do not fully explain the complex repertoire of change evoked by diffuse traumatic brain injury.

A behavioral analysis of dentate gyrus function.

Abstract: Computational models of the dentate gyrus (DG) have suggested based on anatomical, electrophysiological, and computer simulation data that the DG plays an important role in learning and memory by processing and representing spatial information on the basis of conjunctive encoding, pattern separation, and encoding of spatial information in conjunction with the CA3. Behavioral evidence supports a role for the DG in mnemonic processing of spatial information based on the operation of conjunctive encoding of multiple sensory inputs, pattern separation of spatial (especially metric) information, and subsequent encoding in cooperation with CA3. A potential role of the DG in mediating processes, such as recall of sequential information and short-term memory as well as temporal order for remote memory, are also discussed.

Early care experiences and HPA axis regulation in children: a mechanism for later trauma vulnerability.

Abstract: Post-traumatic stress disorder (PTSD) is associated with functional abnormalities of the hypothalamic-pituitary-adrenocortical (HPA) axis. Emerging evidence suggests that failures in social regulation of the HPA axis in young children manifested as neglectful or abusive care may play a role in shaping cortico-limbic circuits involved in processing experiences threatening experiences encountered later in life. Low cortisol levels, particularly near the peak of the diurnal rhythm, have been reported in abused, neglected and deprived children. Thus early imprinting effects of parenting quality on the HPA system regulation may be one of the mechanisms causing heightened risk of PTSD in responses to later trauma. However there is also evidence that the altered patterns of cortisol production seen in the context of early adverse care are not permanent, and remit once the care children receive improves. What awaits study is whether periods of atypical cortisol levels and altered HPA function early in life, even if transient, impact brain development in ways that heighten vulnerability to PTSD in response to traumas experienced later.

Nanoparticles aggravate heat stress induced cognitive deficits, blood-brain barrier disruption, edema formation and brain pathology.

Abstract: Our knowledge regarding the influence of nanoparticles on brain function in vivo during normal or hyperthermic conditions is still lacking Few reports indicate that when nanoparticles enter into the central nervous system (CNS) they may induce neurotoxicity On the other hand, nanoparticle-induced drug delivery to the brain enhances neurorepair processes Thus, it is likely that the inclusion of nanoparticles in body fluid compartments alters the normal brain function and/or its response to additional stress, eg, hyperthermia New data from our laboratory show that nanoparticles derived from metals (eg, Cu, Ag or Al, approximately 50-60nm) are capable of inducing brain dysfunction in normal animals and aggravating the brain pathology caused by whole-body hyperthermia (WBH) Thus, normal animals treated with nanoparticles (for 1 week) exhibited mild cognitive impairment and cellular alterations in the brain Subjection of these nanoparticle-treated rats to WBH resulted in profound cognitive and motor deficits, exacerbation of blood-brain barrier (BBB) disruption, edema formation and brain pathology compared with naive animals These novel observations suggest that nanoparticles enhance brain pathology and cognitive dysfunction in hyperthermia The possible mechanisms of nanoparticle-induced exacerbation of brain damage in WBH and its functional significance in relation to our current knowledge are discussed in this review

Tinnitus and insomnia.

Abstract: Sleep problems are common in individuals with tinnitus but it is not known if they can be seen as a reaction to the acoustic percept of tinnitus disturbing normal sleep, or if there are common causes. Sleep problems further impair the quality of life of individuals with tinnitus and the impairment correlates with the severity of the tinnitus. However the nature of the relationship between tinnitus and disturbed sleep in individuals with tinnitus is not clearly understood. Preliminary studies suggest that chronically disturbed sleep (insomnia) in individuals with tinnitus that is not caused by organic disorders exists unrelated to the tinnitus. We studied the relationship between tinnitus and insomnia in a retrospective sleep study of 13 hospitalized patients with insomnia and tinnitus. Patients with sleep apnea, periodic leg movements, or a severe psychiatric disorder were excluded. We collected physiologic sleep measures (EEG, EOG, EMG, and respiration) and subjective sleep information from a morning protocol during two nights. We also obtained information about performance in sustained attention tasks and the scores of self-rated depression scale and self-rated daytime-tiredness scale. Thirteen age- and sex-matched inpatients with primary insomnia who did not have tinnitus served as controls. There were no significant differences between the physiologic data obtained in patients with tinnitus and in the controls. Both groups had low sleep efficiency but the patients with both insomnia and tinnitus had longer subjective sleep latencies than insomnia patients without tinnitus (controls). No differences were found in sustained attention tasks, subjective daytime tiredness, and depression rating scores between the two groups. Similarities between the results from these two groups suggest that sleep specific psychotherapeutic methods, which are established for treating insomnia, should be further developed for the use in patients with insomnia and tinnitus.

Children-robot interaction: a pilot study in autism therapy.

Abstract: We present here a pilot study of child-robot interactions, in which we discuss developmental origins of human interpersonal communication. For the past few years, we have been observing 2- to 4-year-old children with autism interacting with Keepon, a creature-like robot that is only capable of expressing its attention (directing its gaze) and emotions (pleasure and excitement). While controlled by a remote experimenter, Keepon interacted with the children with its simple appearance and actions. With a sense of curiosity and security, the children spontaneously approached Keepon and engaged in dyadic interaction with it, which then extended to triadic interactions where they exchanged with adult caregivers pleasure and surprise they found in Keepon. Qualitative and quantitative analysis of these unfolding interactions suggests that autistic children possess the motivation to share mental states with others, which is contrary to the commonly held position that this motivation is impaired in autism. We assume Keepon's minimal expressiveness helped the children understand socially meaningful information, which then activated their intact motivation to share interests and feelings with others. We conclude that simple robots like Keepon would facilitate social interaction and its development in autistic children.

Unmasking recurrent excitation generated by mossy fiber sprouting in the epileptic dentate gyrus: an emergent property of a complex system

Abstract: Seizure-induced sprouting of the mossy fiber pathway in the dentate gyrus has been observed nearly universally in experimental models of limbic epilepsy and in the epileptic human hippocampus. The observation of progressive mossy fiber sprouting induced by kindling demonstrated that even a few repeated seizures are sufficient to alter synaptic connectivity and circuit organization. As it is now recognized that seizures induce synaptic reorganization in hippocampal and cortical pathways, the implications of seizure-induced synaptic reorganization for circuit properties and function have been subjects of intense interest. Detailed anatomical characterization of the sprouted mossy fiber pathway has revealed that the overwhelming majority of sprouted synapses in the inner molecular layer of the dentate gyrus form recurrent excitatory connections, and are thus likely to contribute to recurrent excitation and potentially to enhanced susceptibility to seizures. Nevertheless, difficulties in detecting functional abnormalities in circuits reorganized by mossy fiber sprouting and the fact that some sprouted axons appear to form synapses with inhibitory interneurons have been cited as evidence that sprouting may not contribute to seizure susceptibility, but could form recurrent inhibitory circuits and be a compensatory response to prevent seizures. Quantitative analysis of the synaptic connections of the sprouted mossy fiber pathway, assessment of the functional features of sprouted circuitry using reliable physiological measures, and the perspective of complex systems analysis of neural circuits strongly support the view that the functional effects of the recurrent excitatory circuits formed by mossy fiber sprouting after seizures or injury emerge only conditionally and intermittently, as observed with spontaneous seizures in human epilepsy. The recognition that mossy fiber sprouting is induced after hippocampal injury and seizures and contributes conditionally to emergence of recurrent excitation has provided a conceptual framework for understanding how injury and seizure-induced circuit reorganization may contribute to paroxysmal network synchronization, epileptogenesis, and the consequences of repeated seizures, and thus has had a major influence on understanding of fundamental aspects of the epilepsies.

Pro-inflammatory cytokines and their effects in the dentate gyrus.

Abstract: The older notion of a central nervous system existing in essential isolation from the immune system has changed dramatically in recent years as the body of evidence relating to the interactions between these two systems has grown. Here we address the role of a particular subset of immune modulatory molecules, the pro-inflammatory cytokines, in regulating neuronal function and viability in the dentate gyrus of the hippocampus. These inflammatory mediators are known to be elevated in many neuropathological conditions, such as Alzheimer's disease, Parkinson's disease and ischaemic injury that follows stroke. Pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1beta) and interleukin 18 (IL-18), have been shown to regulate neurotoxicity; although, due to the complexity of the cytokine action in neurons and glia, the effect may be either facilitatory or protective, depending on the circumstances. As well as their role in neurotoxicity and neuroprotection, the pro-inflammatory cytokines have also been shown to be potent regulators of synaptic function. In particular, TNF-alpha, IL-1beta and IL-18 have all been shown to inhibit long-term potentiation, a form of neuronal plasticity widely believed to underlie learning and memory, both in the early p38 mitogen activated protein kinase-dependant phase and the later protein synthesis-dependant phase. In this article we address the mechanisms underlying these cytokine effects in the dentate gyrus of the hippocampus.

Dimensional reduction in sensorimotor systems: A framework for understanding muscle coordination of posture

Abstract: The simple act of standing up is an important and essential motor behavior that most humans and animals achieve with ease. Yet, maintaining standing balance involves complex sensorimotor transformations that must continually integrate a large array of sensory inputs and coordinate multiple motor outputs to muscles throughout the body. Multiple, redundant local sensory signals are integrated to form an estimate of a few global, task-level variables important to postural control, such as body center of mass (CoM) position and body orientation with respect to Earth-vertical. Evidence suggests that a limited set of muscle synergies, reflecting preferential sets of muscle activation patterns, are used to move task-variables such as CoM position in a predictable direction following postural perturbations. We propose a hierarchical feedback control system that allows the nervous system the simplicity of performing goal-directed computations in task-variable space, while maintaining the robustness afforded by redundant sensory and motor systems. We predict that modulation of postural actions occurs in task-variable space, and in the associated transformations between the low-dimensional task-space and high-dimensional sensor and muscle spaces. Development of neuromechanical models that reflect these neural transformations between low- and high-dimensional representations will reveal the organizational principles and constraints underlying sensorimotor transformations for balance control, and perhaps motor tasks in general. This framework and accompanying computational models could be used to formulate specific hypotheses about how specific sensory inputs and motor outputs are generated and altered following neural injury, sensory loss, or rehabilitation.

CNS injury biomechanics and experimental models.

Abstract: Traumatic brain injury (TBI) and traumatic spinal cord injury (SCI) are acquired when an external physical insult causes damage to the central nervous system (CNS). Functional disabilities resulting from CNS trauma are dependent upon the mode, severity, and anatomical location of the mechanical impact as well as the mechanical properties of the tissue. Although the biomechanical insult is the initiating factor in the pathophysiology of CNS trauma, the anatomical loading distribution and the resulting cellular responses are currently not well understood. For example, the primary response phase includes events such as increased membrane permeability to ions and other molecules, which may initiate complex signaling cascades that account for the prolonged damage and dysfunction. Correlation of insult parameters with cellular changes and subsequent deficits may lead to refined tolerance criteria and facilitate the development of improved protective gear. In addition, advancements in the understanding of injury biomechanics are essential for the development and interpretation of experimental studies at both the in vitro and in vivo levels and may lead to the development of new treatment approaches by determining injury mechanisms across the temporal spectrum of the injury response. Here we discuss basic concepts relevant to the biomechanics of CNS trauma, injury models used to experimentally simulate TBI and SCI, and novel multilevel approaches for improving the current understanding of primary damage mechanisms.

Visual and visuocognitive development in children born very prematurely

Abstract: Visual development provides a set of milestones and sensitive methods for assessing brain development in infancy. In particular the first months of post-term life see the emergence of visual cortical function. Measures of subcortical and cortical function have led us to a detailed neurobiological model of normal visual development which gives a basis for assessing visual development in very premature infants. This chapter reviews the ocular and cerebral factors associated with preterm birth (at 32 weeks gestation or earlier) which may impair development and presents the behavioural and electrophysiological methods now available (including ‘fixation shifts’ for gauging visual attention and specific visual event-related potentials (VERP)) which allow assessment of the impact of these factors on development and the prediction of likely later neurocognitive deficits. Studies are reviewed which show that in the first year of post-term life, visual cortical development in healthy preterm-born infants is generally similar to term-born infants matched for post-term age, although there is some small relative delay in the development of motion processing in the first few months of life. However, infants in whom neonatal MRI reveals cerebral damage, in particular white matter abnormality, show deficits in visual and visuocognitive development that are graded according to the severity of the damage. These deficits are also predictive of later neurocognitive status. In the preschool years, visuocognitive functions show the impact of preterm birth. By age 6, the preterm group as a whole show selective deficits in visuomotor functions, attention, including executive control, and other aspects of spatial cognition. These deficits are primarily associated with the dorsal stream of visual, spatial, and visuomotor processing controlling actions. These dorsal stream networks are linked to and overlap with those underpinning different components of attention. However, this ‘vulnerability’ of the dorsal system is not unique to children born very preterm; it is also a feature of many neurodevelopmental disorders, e.g. autism, Williams syndrome, Fragile X, and children with congenital cataract. The main challenge for the future is to use these new measures and technologies, developed as child-friendly methods for successful assessment of developmental progress in early life, in early trials of intervention. Such early measures should, in the long term, help preterm infants develop cognitive abilities that allow them to reach their true intellectual and social potential.

Interneurons of the dentate gyrus: an overview of cell types, terminal fields and neurochemical identity.

Abstract: Interneurons of the dentate gyrus are a diverse group of neurons that use GABA as their primary neurotransmitter. Morphological studies of these neurons have been challenging since no single neuroanatomical method provides a complete view of these interneurons. However, through the integration of findings obtained from multiple methods, an interesting picture of this complex group of neurons is emerging, and this review focuses on studies in rats and mice. In situ hybridization of mRNAs for the two isoforms of the GABA synthesizing enzyme, glutamate decarboxylase (GAD65 and GAD67), demonstrates the abundance of GABA neurons in the dentate gyrus and their high concentration in the hilus and along the base of the granule cell layer. Likewise, immunohistochemical studies, particularly of GAD65, demonstrate the rich fields of GABA terminals not only around the somata of granule cells but also in the dendritic regions of the molecular layer. This broad group of GABA neurons and their terminals can be subdivided according to their morphological characteristics, including the distribution of their axonal plexus, and their neurochemical identity. Intracellular labeling of single interneurons has been instrumental in demonstrating the extensiveness of their axonal plexus and the relatively specific spatial distribution of their axonal fields. These findings have led to the broad classification of interneurons into those that terminate primarily at perisomatic regions and those that innervate the dendrites of granule cells. The interneurons also can be classified according to their neuropeptide and calcium-binding protein content. These and other molecules contribute to the rich diversity of dentate interneurons and may provide opportunities for selectively regulating specific groups of GABA neurons in the dentate gyrus in order to enhance their function or protect vulnerable neurons from damage.

Update on the treatment of spinal cord injury

Abstract: Acute spinal cord injury (SCI) is a devastating neurological disorder that can affect any individual at a given instance. Current treatment options for SCI include the use of high dose methylprednisolone sodium succinate, a corticosteroid, surgical interventions to stabilize and decompress the spinal cord, intensive multisystem medical management, and rehabilitative care. While utility of these therapeutic options provides modest benefits, there is a critical need to identify novel approaches to treat or repair the injured spinal cord in hope to, at the very least, improve upon the patient's quality of life. Thankfully, several discoveries at the preclinical level are now transitioning into the clinical arena. These include the Surgical Treatment for Acute Spinal Cord Injury Study (STASCIS) Trial to evaluate the role and timing of surgical decompression for acute SCI, neuroprotection with the semisynthetic second generation tetracycline derivative, minocycline; aiding axonal conduction with the potassium channel blockers, neuroregenerative/neuroprotective approaches with the Rho antagonist, Cethrin ® ; the use of anti-NOGO monoclonal antibodies to augment plasticity and regeneration; as well as cell-mediated repair with stem cells, bone marrow stromal cells, and olfactory ensheathing cells. This review overviews the pathobiology of SCI and current treatment choices before focusing the rest of the discussion on the variety of promising neuroprotective and cell-based approaches that have recently moved, or are very close, to clinical testing.