Changes in functional connectivity and GABA levels with long-term motor learning

Learning novel motor skills alters local inhibitory circuits within primary motor cortex (M1) (Floyer-Lea et al., 2006) and changes long-range functional connectivity (Albert et al., 2009). Whether such effects occur with long-term training is less well established. In addition, the relationship between learning-related changes in functional connectivity and local inhibition, and their modulation by practice, has not previously been tested. Here, we used resting-state functional magnetic resonance imaging (rs-fMRI) to assess functional connectivity and MR spectroscopy to quantify GABA in primary motor cortex (M1) before and after a 6 week regime of juggling practice. Participants practiced for either 30 min (high intensity group) or 15 min (low intensity group) per day. We hypothesized that different training regimes would be reflected in distinct changes in brain connectivity and local inhibition, and that correlations would be found between learning-induced changes in GABA and functional connectivity. Performance improved significantly with practice in both groups and we found no evidence for differences in performance outcomes between the low intensity and high intensity groups. Despite the absence of behavioral differences, we found distinct patterns of brain change in the two groups: the low intensity group showed increases in functional connectivity in the motor network and decreases in GABA, whereas the high intensity group showed decreases in functional connectivity and no significant change in GABA. Changes in functional connectivity correlated with performance outcome. Learning-related changes in functional connectivity correlated with changes in GABA. The results suggest that different training regimes are associated with distinct patterns of brain change, even when performance outcomes are comparable between practice schedules. Our results further indicate that learning-related changes in resting-state network strength in part reflect GABAergic plastic processes

Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation

Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration

Toward the language oscillogenome

Language has been argued to arise, both ontogenetically and phylogenetically, from specific patterns of brain wiring. We argue that it can further be shown that core features of language processing emerge from particular phasal and cross-frequency coupling properties of neural oscillations; what has been referred to as the language 'oscillome.' It is expected that basic aspects of the language oscillome result from genetic guidance, what we will here call the language 'oscillogenome,' for which we will put forward a list of candidate genes. We have considered genes for altered brain rhythmicity in conditions involving language deficits: autism spectrum disorders, schizophrenia, specific language impairment and dyslexia. These selected genes map on to aspects of brain function, particularly on to neurotransmitter function. We stress that caution should be adopted in the construction of any oscillogenome, given the range of potential roles particular localized frequency bands have in cognition. Our aim is to propose a set of genome-to-language linking hypotheses that, given testing, would grant explanatory power to brain rhythms with respect to language processing and evolution.Economic and Social Research Council scholarship 1474910Ministerio de Economía y Competitividad (España) FFI2016-78034-C2-2-

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring

Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)–mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia

Modulation of human corticospinal excitability by paired associative stimulation

Paired Associative Stimulation (PAS) has come to prominence as a potential therapeutic intervention for the treatment of brain injury/disease, and as an experimental method with which to investigate Hebbian principles of neural plasticity in humans. Prototypically, a single electrical stimulus is directed to a peripheral nerve in advance of transcranial magnetic stimulation (TMS) delivered to the contralateral primary motor cortex (M1). Repeated pairing of the stimuli (i.e., association) over an extended period may increase or decrease the excitability of corticospinal projections from M1, in manner that depends on the interstimulus interval (ISI). It has been suggested that these effects represent a form of associative long-term potentiation (LTP) and depression (LTD) that bears resemblance to spike-timing dependent plasticity (STDP) as it has been elaborated in animal models. With a large body of empirical evidence having emerged since the cardinal features of PAS were first described, and in light of the variations from the original protocols that have been implemented, it is opportune to consider whether the phenomenology of PAS remains consistent with the characteristic features that were initially disclosed. This assessment necessarily has bearing upon interpretation of the effects of PAS in relation to the specific cellular pathways that are putatively engaged, including those that adhere to the rules of STDP. The balance of evidence suggests that the mechanisms that contribute to the LTP- and LTD-type responses to PAS differ depending on the precise nature of the induction protocol that is used. In addition to emphasizing the requirement for additional explanatory models, in the present analysis we highlight the key features of the PAS phenomenology that require interpretation

Evaluating The Relationship Between Short- and Long-Term Neural Adaptations to Motor Skill Acquisition and Retention

Attempting to understand the neurophysiological underpinnings of learned behaviors and the process of learning itself has yielded interesting findings relating to what happens in the brain and across the nervous system when learning a new skill. The nervous system displays several structural, functional and neurochemical adaptations to motor learning which have been highlighted through the use of neuroimaging techniques such as fMRI, EEG and TMS. This review attempts to outline the neural adaptations governing the acquisition and retention of motor skills, as well as build a timeline for these adaptations following Fitt’s model of motor learning (Fitts and Posner 1967). As one moves across the stages of learning (cognitive, associative, autonomous) the nervous system displays an initial increase in activity and plasticity in the frontal associative regions, motor cortical regions, parietal cortices, sensorimotor striatum, associative striatum, cerebral cortices and nuclei and hippocampus (Doyon et al., 2008), as well as the basal ganglia thalamocortical loops, medial cerebellum, anterior cingulate cortex, inferior frontal gyrus and the visual and parietal cortical areas (Seidler 2011). These neuro-plastic adaptations and activation patterns cement and refine themselves in later stages, indicating a more efficient circuitry and decreased cognitive load when performing the skill (Poldrack et al., 2005). In terms of practical applications of these findings, manipulation of the training principles involved in specific contexts of motor skill learning such as training specificity, duration and intensity, may yield improved neural adaptations and in turn performance on the skill in question

Il-15/il-15rα signalling and synaptic transmission: a crosstalk between the immune and the nervous system?

Immune and nervous system have been traditionally considered separately, but from ‘90s many studies had unraveled the deep interconnection and interdependence between these two systems, enough to coin the term “neuroimmune system” to define this relationship. While it was well known that central nervous system (CNS) actively communicates with the immune system to control immune responses both centrally and peripherally, the opposite action was just recently discovered. Related to the role of immune system in defending and react, the interactions between immune system and CNS have been classically studied in contexts of neuroinflammation such as trauma, injury and disease [1] [2]. Recent evidences about the neuroinflammatory process in non-pathological conditions and the discovery of the important involvement of adaptive immune system in healthy brain development and activity [3], have opened many questions about physiological neuroimmune cross-talk. In this view, the cytokine network, well known to operate in a bidirectional way affecting both immune and nervous system, has a pivotal role in neuroimmune cross-talk [4]. Traditionally seen as immunomodulators, in the last years has been evident that cytokines are also potent neuromodulators [5]. In the complex cytokine system, interleukin 15 (IL-15) is considered a bridge between adaptive and innate immune system and it is one of the first upregulated cytokines in neuroinflammation [6]. It has many bioregulatory roles which range from those of modulator of selected adaptive immune responses [7] [8] and central player in the development and homeostasis of several immunocyte populations [9] to those of a potent, general inhibitor of apoptosis in multiple systems [9]. Interestingly, has been shown that IL-15 and IL-15Rα deletions affect memory and neurotransmitters concentration suggesting a major role of this signalling in cerebral functions which cannot be compensated during the development [10] [11] [12]. IL-15Rα KO mice, in particular, show decreased retention of spatial memory and contextual fear, both related to hippocampus-dependent memory, and alteration in GABA concentration. Their hippocampal ultrastructure is, however, well preserved, suggesting that the modulatory changes may involve neural plasticity even if the exact role of IL15 in modulating neurotransmission has not been investigated so far. The understandings about the mechanism by which IL-15/IL-15Rα system affect the synaptic transmission may be useful to get insight into the mechanisms of cross talk between the immune and the nervous system and eventually to develop strategies to treat pathologies whose symptoms are memory impairments and neuroinflammation