Dissertations / Theses on the topic 'Neuroplasticity Of The Brain'

As opposed to earlier beliefs, the brain is altering itself throughout an individual’s life. The process of functional or structural alterations is referred to as plasticity, and can be induced by several factors such as experience or physical exercise. In this thesis, the research area of experience-dependent plasticity, with focus on exercise-induced plasticity is examined critically. Evidence from a vast array of studies are reviewed and compared in order to find whether physical exercise can induce neural plasticity in the human brain, how it may be beneficial, and what some of the plausible mediators of exercise-induced plasticity are. The findings demonstrated in this thesis suggest that although there are knowledge gaps and limitations in the literature, physical exercise can indeed result in exhibited plasticity as well as being beneficial for the human brain in several ways.

Neuroplasticity refers to the brain’s ability to change with experience. Continuous theta burst stimulation (cTBS) is a non-invasive brain stimulation technique capable of temporarily inducing neuroplasticity in the primary motor cortex (M1), as indicated by changes in the excitability of the stimulated brain region. However, cTBS-induced neuroplasticity shows large inter-individual variability, which limits its potential in research and clinical settings. The present study investigated whether down-regulating motor cortical inhibition, with cTBS applied using a lower than conventional intensity (cTBSlow), is capable of making the brain more amenable to the neuroplasticity-inducing effects of cTBS applied using the conventional intensity. Thirty-two, right-handed, healthy adults participated in two experimental sessions: 1) cTBS primed by cTBSlow; 2) cTBS primed by sham stimulation. Due to unforeseen technical issues, there were two groups: group 1 received cTBSlow with conventional bursts; group 2 received cTBSlow with reduced pulses per burst. Motor cortical excitability and inhibition were measured from an intrinsic hand muscle at baseline, between the two cTBS applications, and following cTBS. In group 1, cTBSlow reduced inhibition in M1, however, there was no systematic change in motor cortical excitability following cTBS primed by cTBSlow or primed by sham. This lack of effect may be due to unreliable neuroplasticity induction in M1 following cTBS alone. In group 2, long-lasting and less variable changes in motor cortical excitability were found following an unconventional cTBS pattern. These findings confirm the variability of cTBS-induced neuroplasticity and highlight the importance of developing novel protocols to induce less variable neuroplasticity responses.

Brain tumors are a rare disease, however the cost in term of unfavorable prognosis and impact on quality of life is very high. The complex treatment requested by a brain tumor (surgery and pharmacological therapy) may determine neurological and cognitive consequences, that need an immediate and precise intervention. For this reason, novel diagnostic methods that combine behavioral and imaging data are requested. This research work was aimed at investigating cognitive and imaging correlates of brain tumors and is built on different aims. The first goal was the definition of the neuropsychological profile of brain tumors. We specifically focused on cognitive deficits associated with the pathophysiology of the tumor. In other words, we investigated if brain tumors may cause a specific type of cognitive damage, based on the specific pathophysiological behavior in affecting the brain. To this end, an observational study was designed and the assessment of a cohort of brain tumor patients in the pre-operative stage was performed. By means of an extensive neuropsychological protocol, patients were evaluated in different cognitive domains. This study allows us to describe the cognitive features of the tumors, by taking into account some physiological variables: type of tumor (e.g. glioma vs meningioma), site of the lesion, extension of the lesion. To the best of our knowledge, no study so far has defined the cognitive profile of brain tumors taking in account the specific neurological nature of this pathology, in order to define a suitable neuropsychological battery for the cognitive characterization of brain tumors. The second aim concerned precisely the effort to define the specificity of the neuropsychological battery in detecting the particular cognitive disease consequent to brain tumors. To achieve this goal, we compared the neuropsychological performance of the group of patients with brain tumor with a group of patients with focal stroke, a neurological disorder involving a very different pathophysiological process. This implies the identification of the neuropsychological tests that are sensitive in detecting the specific as well as subtle cognitive deficits consequent to brain tumors. 7 The third aim had a longitudinal perspective and concerned the study of the effects of tumor resection on cognitive functions in the long term. To achieve this goal, we analyzed the behavioral data of the group of patients at three different time points: pre-surgical, post-surgical and one month follow-up. We expected a global worsening of the cognitive scores in the immediate post-operative stage, with a subsequent recovery at one month follow-up. A preliminary study was also conducted in order to define the effect of the treatment (radiotherapy and chemotherapy) on cognitive functions, with the aim to clarify the interaction of surgery and treatment in affecting the brain. Hence a further follow-up was also conducted four months from the neurosurgery and after the therapy. Importantly, this study clarified the interaction between the cognitive effects of the treatment and surgical intervention. Furthermore, it shed light on the relevance of follow-up neuropsychological assessment in monitoring brain tumors. The present doctoral thesis aimed at clarifying the contribution of neuropsychological as well as neuroimaging measures in order to better characterize the specific pathophysiological processes beneath functional and cognitive symptoms. For this reason, a further effort consisted in exploring structural and functional neuroimaging biomarkers able to predict the patient’s quality of life after tumor surgical resection. We furthermore aimed to assess the added value of the use of local and global brain connectivity in the clinical decision process. To this end, together with the neuropsychological evaluation, metabolism and perfusion data were longitudinally acquired, using simultaneous dynamic PET and MRI techniques. These data were acquired before surgery, after one month, and after three months from surgery. This study is still ongoing. The overarching goal in the long term of the whole research is to take into account together neuroplasticity and neuropsychological aspects in neuro-oncology in order to create a new way of taking care of patients with brain tumor. Of note, the correlation between tumor variables, behavioral outcome and structural, functional, and metabolic metrics of brain organization allows individualized planning of surgery and treatment. This planning will therefore be tailored considering the characteristics of the single patient, leading to a better outcome and a reduced impact on functions and quality of life.

Cholinergic precursors have represented the first approach to counter cognitive impairment occurring in adultonset dementia disorders. In preclinical studies choline alphoscerate increases the release of acetylcholine in rat hippocampus, facilitates learning and memory in experimental animals, improves brain transduction mechanisms and decreases age-dependent structural changes occurring in rat brain areas involved in learning and memory. The compound exerts neuroprotective effects in models of altered cholinergic neurotransmission and of brain vascular injury. Some of our studies have also shown that combination of ChE-Is and the cholinergic precursor choline alphoscerate increases brain acetylcholine levels more effectively than single compounds alone. In clinical studies choline alphoscerate improved memory and attention impairment, as well as affective and somatic symptoms in dementia disorders. ASCOMALVA (Effect of association between a ChE-I and choline alphoscerate on cognitive deficits in AD associated with cerebrovascular injury) is a double-blind trial investigating if the ChE-I donepezil and choline alphoscerate in combination are more effective that donepezil alone. Over the 24-month observation period, patients of the reference group showed a moderate time-dependent worsening in all the parameters investigated. Treatment with donepezil plus choline alphoscerate significantly slowed changes of the in cognitive and functional items and an improvement in behavioural parameters, mainly apathy, superior to that induced by donepezil alone. It is suggested that this association may represent a therapeutic option to prolong beneficial effects of cholinergic therapies in Alzheimer's disease patients with concomitant ischemic cerebrovascular disorders. In summary, choline alphoscerate has significant effects on cognitive function with a good safety profile and tolerability. Although limited both in terms of size of the samples investigated and of the length of treatment, preclinical and clinical results presented suggest that cognitive enhancing capabilities of choline alphoscerate merit of being further investigated in appropriate trials.

Catecholaminergic neurotransmission is regionally altered following injury, and drugs aimed at these systems offer promising avenues for post-TBI pharmacotherapies. Atomoxetine is a selective norepinephrine transporter (NET) inhibitor currently indicated for treatment of attention-deficit hyperactivity disorder (ADHD). The studies in this dissertation were designed to test the efficacy of atomoxetine for treating cognitive deficits following experimental TBI and the potential mechanism for any beneficial effect. The first part of the study focused on behavioral recovery following atomoxetine treatment. Several important questions of dose, therapeutic window, and duration of treatment were addressed in these studies. Sprague-Dawley rats were subjected to lateral fluid-percussion injury (L-FPI) of moderate severity (2.08 atm +/- .05). Four experiments were performed. In the first study, atomoxetine (.3 mg/kg, 1mg/kg, 3 mg/kg, or 9 mg/kg) or vehicle was administered daily on post injury days (PID) 1-15. Cognitive assessment was performed using the Morris water maze on PID 11-15. L-FPI resulted in significant cognitive impairment when compared to Sham-Injury. Treatment with lower doses of atomoxetine (.3mg/kg, 1mg/kg, and 3mg/kg) significantly attenuated the cognitive deficits in injured animals. Treatment with the higher dosage (9mg/kg) of atomoxetine resulted in animals that were not significantly different than injured-vehicle treated animals. The optimal response was achieved using 1 mg/kg atomoxetine. In the second study, treatment with atomoxetine (1mg/kg) or vehicle was delayed for 11 days post-injury. Rats were administered atomoxetine daily for 15 days and cognitive assessment was performed on PID 25-29. In this study, treatment with atomoxetine (1 mg/kg) did not result in improved cognitive performance. In the next study atomoxetine was given daily on PID 1-7 and then treatment was terminated. The animals were tested in the MWM on PID 11-15. We found that atomoxetine treatment for 7 days post-injury provides an enhancement of cognitive deficits that is not significantly different from sham animals. We then investigated whether a single treatment of atomoxetine 24 h after brain injury could influence behavioral outcome on days 11-15. From this study, we found a single dose of atomoxetine is not as effective as chronic treatment. Finally, we investigated changes in the protein expression of brain-derived neurotrophic factor, growth-associated protein-43, and synaptophysin on day 7 PID to investigate what effect atomoxetine may have on brain plasticity and regeneration. We found that atomoxetine can enhance both GAP-43 and BDNF, but not synaptophysin at this time point. In conclusion, this is the first study to show that low doses of atomoxetine initiated early after experimental traumatic brain injury results in improved cognition. Furthermore, we show that enhancement of catecholamines via atomoxetine treatment during periods of postinjury-induced plasticity can provide long-term functional and structural benefits.

The influence of play behavior on the brain was investigated through plasticity and metaplasticity methodology. Regions in both cortical and sub-cortical areas were investigated. Animals in both studies either experienced play with juvenile partners or did not experience play by being paired with an adult. Play experience alone was shown to affect the plasticity in the prefrontal cortex, although it did not show structural changes to sub-cortical regions. If animals were given nicotine after play experiences, the affects of play in the prefrontal cortex were abolished. In addition, playful behaviors appear to prime some sub-cortical regions of the brain for expression of later plasticity. Thus, play appears to alter the structure of multiple brain areas, but do so in different ways.<br>ix, 67 leaves ; 29 cm

The physiological significance of noradrenergic sympathohabenular ingrowth following medial septal lesions was investigated. Following septal lesions, sympathetic fibers originating in the superior cervical ganglia are known to sprout into the medial habenular nuclei, and into the hippocampal formation. Previous work involving sympathohippocampal ingrowth showed that firing rates in septal animals with no ingrowth showed that firing rates in septal animals with no ingrowth were higher than rates of septal animals with ingrowth and controls. Those results suggested that sympathetic ingrowth in the hippocampus had some functional capability in a modulatory manner. The primary aim of the present study was to determine if the peripheral sympathetic ingrowth into the medial habenular nuclei following a septal lesion is functionally significant. The results showed that firing rates of neurons of the medial habenulae in animals receiving septal lesions were significantly higher than rates of control animals and septal lesioned + ganglionectomized animals.

The ability of two putative trophic agents, nerve growth factor (NGF) and the monosialoganglioside GM1, to induce neurochemical, morphological and behavioral recovery following injury to the adult rat basalo-cortical cholinergic pathway was studied. Treatment of unilaterally decorticated rats with these agents was shown to: attenuate deficits in holinergic markers of the nucleus basalis magnocellularis (NBM), prevent shrinkage of choline acetyltransferase (ChAT)- and p75$ sp{ rm NGFR}$-immunoreactive (IR) NBM neurons, and stimulate cortical ChAT activity and high affinity choline uptake, in a dose-dependent manner with equal efficacies but different potencies. Quantitative light and electron microscopic studies, assisted by image analysis, showed that GM1 or NGF treatment also similarly attenuated lesion-induced deficits in cortical ChAT-IR fiber length. By contrast, NGF, but not GM1, treatment caused significant synaptic remodelling in the remaining cortex of adult lesioned rats; this was reflected by increases in ChAT-IR varicosity number, presynaptic terminal size, and in the number of boutons with synaptic contacts. GM1 treatment only attenuated such lesion-induced deficits. Exogenous GM1 was also shown to potentiate NGF-reduced effects on basalo-cortical cholinergic markers and on cortical synaptic remodelling, but did not affect the affinity or number of NGF binding sites in brain membranes isolated from lesioned animals. This suggests that GM1 probably affects an alternative step of the NGF signal transduction cascade to potentiate NGF effects. Moreover, NGF or GM1 treatment were also shown to: distinctly regulate striatal cholinergic markers, differ with respect to the delay possible in treatment time onset for effective protection from retrograde regeneration, and diversely affect the behaviour of these animals in passive avoidance and Morris water maze tasks. In aged rats ($>$20 months), NGF and/or GM1 treatment were also shown to effectively prevent de<br>The work of this thesis has thus provided evidence that the injured adult rat basalo-cortical cholinergic pathway can exhibit substantial neurochemical and morphological plasticity in response to NGF and/or GM1 treatment. In particular, it has been shown that these agents cause significant alterations in cholinergic innervation.

Aside from preventing traumatic brain injuries (TBIs) altogether, treatment options for TBI typically focus on the secondary biochemical processes that occur in response to the primary mechanical insult. These secondary injuries can lead to apoptosis and necrosis in the days and weeks that follow a TBI. Therefore, finding a treatment that can prevent, reduce, and repair secondary damage is instrumental in the recovery of TBI patients. The flavonoid 7,8-dihydroxyflavone (7,8-DHF) has been identified as a TrkB agonist that mimics the effects of brain derived neurotrophin factor (BDNF). Upon binding to the TrkB receptor, signaling cascades are initiated that can promote neuronal survival and neural differentiation. The use of 7,8-DHF in the treatment of TBI is favorable due to its long half-life and ability to pass the blood-brain barrier (BBB). In this study, we evaluated the dosage time frame of 7,8-DHF that would allow for the greatest impact in recovery after a focal TBI. Adult Sprague-Dawley rats were subjected to a moderate cortical impact injury and administered a 5mg/kg dose of 7,8-DHF i.p. for five days starting on day 0, 2, 3, or 5 post injury. Sensorimotor function was evaluated with beam walk and rotarod test. Morris Water Maze (MWM) and fear conditioning test were used to analyze cognitive function. Biotinylated dextran amine (BDA) was injected into the contralateral cerebral cortex 14 days after injury and animals were sacrificed 28 dpi. Brain sections were processed for Giemsa histological staining to assess cortical lesion volume and the total number of surviving neurons. Parallel sections were processed for BDA staining to assess changes of axon sprouting in the injured cortex. VGlut-1 staining of the hippocampus was used to identify presynaptic plasticity. We found that the administration of 7,8- DHF starting at one hour after TBI could provide protection against motor and cognitive dysfunction. Histological examination showed a significant reduction of cortical lesion volume and higher number of survival neurons in the injured hippocampus when 7,8-DHF administration began one hour and two days after injury. BDA staining of intracortical axon sprouting and VGlut-1 staining of the hippocampus highlighted a trend that 7,8-DHF administration starting day five post brain injury may enhance neuronal plasticity. Collectively, the results indicate that 7,8-DHF can provide the better neuronal protection when administration begins one hour after TBI.

Prior research suggests aggressive cancer treatments contribute to cognitive impairments in children diagnosed with pediatric brain tumors. The literature also suggests that younger age at diagnosis (AAD) and treatment may result in disrupted cognitive trajectories due to limited brain plasticity. In line with this research, we hypothesized an interaction between radiation therapy (RT) and young AAD of brain tumors, where young AAD and RT results in lower standard scores on the WRAT-R Reading Comprehension Subtest. Analyses included archival data; the sample consists of 134 children diagnosed with pediatric brain tumors with multiple assessments resulting in 487 cases for analysis. Participants were diagnosed with mixed tumor types and locations. A two level multilevel model was used to analyze reading trajectories while taking into account AAD, time since diagnosis, socioeconomic status (SES), and RT. Results detected a positive interaction between AAD and RT (γ =2.08, p=.02). For participants with RT, younger AAD was associated with lower reading scores, whereas AAD had no effect for participants without RT. Results also detected a negative interaction between radiation and time (γ =-2.29, p=.00) indicating that children treated with RT have reading scores that decrease over time. These data suggested that children diagnosed with pediatric brain tumors treated with RT are at higher risk of reading impairment as reflected in their reading scores.

The best for PhD thesis in the Faculties of Arts, Architecture, Business & Economics, Education, Law and Social Sciences (Universityof Hong Kong), Li Ka Shing prize, 2006-2007<br>published_or_final_version<br>abstract<br>Psychology<br>Doctoral<br>Doctor of Philosophy

Limited restoration of motor function occurs spontaneously during a plastic time window after stroke. A deeper understanding of post-stroke plasticity is critical to devise more effective pharmacological and rehabilitative treatments. Here, I have characterized the spontaneous evolution after a photothrombotic lesion in mice, both in terms of motor deficit and plasticity in the perilesional cortex. In generalized motor tasks such as the Gridwalk and Schallert Cylinder test, motor deficits were stable for at least 30 days after photothrombotic stroke in the Caudal Forelimb Area (CFA). The skilled reaching test, performed once a week, showed a trend for spontaneous improvement over time in the number of correct graspings. However, kinematic analysis, evaluated by means of an innovative semi-automated tool, revealed a persistent alterations in grasping movements, pointing to the development of compensatory strategies. The perilesional cortex has been proposed as the area mediating functional recovery. I found a reorganization of the motor maps in sensorimotor cortex around to the lesion. Particularly, I observed a significant shrinkage of the forelimb area, in favour of hindlimb representation using Intracortical Microstimulation (ICMS). Moreover, neuroanatomical markers, previously characterized in the literature as “neuroplasticity brakes” (i.e. Perineuronal nets, Parvalbumin- and Somatostatin-positive cells) spontaneously decrease after stroke, suggesting an enhancement of the potential for plastic rearrangements. Altogether these results, suggest a spontaneous attempt to reopen a critical period characterized by sprouting and plasticity phenomena, that needs to be amplified and properly guided for maximizing recovery. The GABAergic system is one of the key modulators of plasticity in the brain, and its role has been amply studied in relation to opening and closure of the “critical period” in sensory cortices during development. To test whether reductions in GABAergic signalling were causally involved in motor improvements, we treated animals during an early post-stroke period with a benzodiazepine inverse agonist, which impairs GABAA receptor function. We found that hampering GABAA signalling led to significant restoration of function in general motor tests such as the gridwalk and the pellet reaching tasks, with no significant impact on the kinematics of reaching movements. Improvements were persistent as they remained detectable about three weeks after treatment. Using electrophysiological recordings I found an electrical imbalance between the two hemispheres. In particular, contralesional motor cortex was found to exert an enhanced transcallosal inhibition over the spared, perilesional tissue. Silencing the healthy hemisphere using cortical infusion of Botulinum Neurotoxin E, partially improved motor recovery in the gridwalk test. We then established a rehabilitation protocol that combined intensive and highly repeatable exercise of the mouse forelimb with a robotic platform with reversible inactivation of the healthy, contralesional motor cortex. We found that such treatment promoted recovery in both Gridwalk and Schallert Cylinder tests and in end point measures during Skilled reaching test. Remarkably, the combined therapy also restores pre-lesion movement patterns during reaching movement, as evaluated by kinematic analysis. Furthermore, such rehabilitated animals showed a more plastic perilesional cortex, with an additional significant decrease in plasticity brakes.

Chronic musculoskeletal pain is a leading cause of disability worldwide yet the mechanisms of chronification and neural responses to effective treatment remain elusive. Non-invasive imaging techniques are useful for investigating brain alterations associated with health and disease. Thus the overall goal of this dissertation was to investigate the white (WM) and grey matter (GM) structural differences in patients with musculoskeletal pain before and after psychotherapeutic intervention: cognitive behavioral therapy (CBT). To aid in the interpretation of clinical findings, we used a novel porcine model of low back pain-like pathophysiology and developed a post-mortem, in situ, neuroimaging approach to facilitate translational investigation. The first objective of this dissertation (Chapter 2) was to identify structural brain alterations in chronic pain patients compared to healthy controls. To achieve this, we examined GM volume and diffusivity as well as WM metrics of complexity, density, and connectivity. Consistent with the literature, we observed robust differences in GM volume across a number of brain regions in chronic pain patients, however, findings of increased GM volume in several regions are in contrast to previous reports. We also identified WM changes, with pain patients exhibiting reduced WM density in tracts that project to descending pain modulatory regions as well as increased connectivity to default mode network structures, and bidirectional alterations in complexity. These findings may reflect network level dysfunction in patients with chronic pain. The second aim (Chapter 3) was to investigate reversibility or neuroplasticity of structural alterations in the chronic pain brain following CBT compared to an active control group. Longitudinal evaluation was carried out at baseline, following 11-week intervention, and a four-month follow-up. Similarly, we conducted structural brain assessments including GM morphometry and WM complexity and connectivity. We did not observe GM volumetric or WM connectivity changes, but we did discover differences in WM complexity after therapy and at follow-up visits. To facilitate mechanistic investigation of pain related brain changes, we used a novel porcine model of low back pain-like pathophysiology (Chapter 6). This model replicates hallmarks of chronic pain, such as soft tissue injury and movement alteration. We also developed a novel protocol to perform translational post-mortem, in situ, neuroimaging in our porcine model to reproduce WM and GM findings observed in humans, followed by a unique perfusion and immersion fixation protocol to enable histological assessment (Chapter 4). In conclusion, our clinical data suggest robust structural brain alterations in patients with chronic pain as compared to healthy individuals and in response to therapeutic intervention. However, the mechanism of these brain changes remains unknown. Therefore, we propose to use a porcine model of musculoskeletal pain with a novel neuroimaging protocol to promote mechanistic investigation and expand our interpretation of clinical findings.

Drug addiction is a chronic, relapsing brain disorder that relies on the substantial shift from a controlled drug use to compulsive drug seeking despite negative consequences. Among the growing and broad field of illicit drugs, so far cocaine still represents the most used psychostimulant. Although drug addiction can be considered an adult brain disorder, drug use peaks during adolescence. During this period the brain undergoes profound structural and molecular changes, making the adolescent brain more vulnerable to the pharmacological effects brought about by drugs of abuse and, perhaps, may set the stage to initiate drug use or relapse to drugs of abuse later in life. Accordingly, to understand the molecular mechanisms underlying drug use in adults is necessary to investigate the drug-induced molecular changes in the adolescent brain. We focused our molecular analyses on the medial prefrontal cortex (mPFC), a brain region that is still developing during adolescence and may result more sensitive to the pharmacologic effects of cocaine. We found that repeated exposure to cocaine during adolescence induces a maladaptive neuroplasticity after either short- and long-term withdrawal. In particular, we found that short-term withdrawal from developmental exposure to cocaine alters the physiological response of the glutamatergic system to a challenging situation, thus generating a hyper-reactive glutamatergic synapse. Moreover, three days of withdrawal are sufficient to induce a pro-depressive behavior that, perhaps, may reflect the cocaine-induced alteration of the stress-related system in the mPFC. One of the major clinical issues of drug addiction is the relapse even after long periods of abstinence. Accordingly, we investigated whether long-term withdrawal from developmental exposure to cocaine may have altered markers of neuroplasticity in the mPFC. Interestingly, we found an increase BDNF expression, its high-affinity receptor TrkB and the associated signaling pathway. On the other hand, we found reduced expression of GluA1 subunit of AMPA receptors, suggesting, perhaps, an indirect effect of BDNF on the glutamatergic system through the up-regulation of ARC expression. Further, we found that long-term withdrawal from developmental exposure to cocaine increases FGF-2 expression in the mPFC, as observed for BDNF. Taking into account that adolescence is a vulnerable period to initiate drug use, we investigated whether a single injection of cocaine is sufficient to produce a maladaptive molecular background that may contribute to develop maladaptive behaviors. Interestingly, we found that a single injection to cocaine is sufficient to up-regulate FGF-2 expression in the mPFC seven days later while its expression returns to baseline after the second challenge. However, a different modulation of the neurotrophin was observed in hippocampus. In particular, a single injection of cocaine reduces FGF-2 expression, as well as ARC, seven days later, suggesting, at least in part, a reduced neuronal activity. Altogether, these results further highlight the adolescence as a period of high vulnerability to the pharmacological effects brought about by cocaine in the mPFC after a single injection rather than repeated exposure to the psychostimulant. Further, these results add important preclinical evidence to the short- or long-term action of cocaine following exposure during adolescence.

C-type Natriuretic Peptide (CNP), a relatively new member of the natriuretic peptide family, is found throughout the central nervous system. Circumstantial evidence associates CNP with learning and memory, as its expression is highest in brain regions known to be involved in memory and associated with hippocampal physiology. Here, the first study housed rats in an enriched environment, regarded as providing an 'informal' learning experience, for either 14 or 28 days of housing in enrichment in six regions of interest, which was attributed to changes in the degradation of CNP. The second study examined a group of rats trained on object -recognition task – the bow-tie maze. A difference was found in CNP production in the limbic medial prefrontal cortex over repeated exposures to novel objects relative to controls that received 'yoked learning' an exposure only to the test room. CNP concentrations also tended to be lower in rats with better levels of discrimination between familiar objects. Together, these studies provide some initial evidence that CNP influences learning –induced plasticity in the intact brain.

Thesis (Ph. D.)--University of Oregon, 2007.<br>Typescript. Includes vita and abstract. Includes bibliographical references (leaves 146-163). Also available for download via the World Wide Web; free to University of Oregon users.

An organism’s spatial ecology allows for access to essential resources such as food, mates, and escape from predators. Home range size, or the total area an organism inhabits, varies in relation to numerous factors including seasonality. During the breeding season, home range size increases in males across taxa. In addition, males usually also have larger home range sizes than females. This implicates testosterone (T) as a possible mediator of this relationship. Indeed, T causes an increase in home range size of males in numerous species of lizards. In addition to T causing an increase in home range size, it also causes an increase in coloration, which is used as a signal to deter or elicit aggressive behaviors in lizards. Potentially, contests are less common in natural settings than in the lab due to this signaling despite increased frequency overlap of home ranges in males. The larger the home range size of males, mediated through an increase in T, the more overlap with conspecifics. With this increase in spatial demand, or home range size, there is often a corresponding increase in spatially related brain regions. In reptiles, these brain regions are the medial and dorsal cortices (MC and DC respectively). The increase in cortical brain region size due to an increase in spatial demand may be mediated by an increase in neurogenesis. Proliferation of neurons occurs along the ventricles and radiate to numerous regions in the brain including the MC. With respect to the MC, immature neurons, which express the protein doublecortin (DCX), migrate from the ventricles, through the inner plexiform layer and are integrated into the cell layer. Because DCX is only expressed in recently born, migrating neurons, it can be used to measure neurogenesis. In mammals and birds, neurogenesis and growth of certain brain regions is affected by steroid hormones, including T. Here we tested two hypotheses: (1) T affects the home range size of Sceloporus occidentalis and (2) cortical brain region volumes are related to home range size and/or T which is mediated through changes in rates of neurogenesis. We surgically castrated individuals and implanted subjects with either a T-filled implant or blank implant and then released them at their initial capture sites. In addition to these castrated individuals, subjects not subjected to castration served as unmanipulated controls. Home range size of individuals in the field was quantified using a global positioning system (GPS) unit and later delineating those GPS points using minimum convex polygons (MCPs). We predicted that (1) castrated, T-treated lizards and unmanipulated control lizards would have larger home range sizes than castrated, control lizards c and (2) MC and DC cortices would be larger in volume and contain more DCX-immunoreactive cells in the lizards with the highest circulating T levels and with the largest home range sizes. We found that increased T caused an increase in the number of blue abdominal scales. We found no differences in home range size relating to T. Likewise, T did not affect MC volumes. However, we did observe a decrease in DC volume with increasing plasma levels of T. Because T did not affect home range size, it follows that we did not find an effect of T on MC volume. However, the significant result of T causing a decrease in DC volume implies a possible trade off with regards to energetics and the maintenance of brain region volumes as prior research indicates that T in increases energy expenditure and decreases foraging efforts.

Learning and memory formation are invaluable processes in human life; however, the cellular mechanisms that control these phenomena are largely unknown. Synaptic plasticity, which is the ability of the synapse between two neurons to change in strength based on activity, is believed to be a key process in the formation of memories and learning. Endocannabinoids (eCB) have recently emerged as important modulators of synaptic plasticity but their precise roles and mechanisms are not well understood and many contradictions exist in the current literature. We have investigated the roles of eCBs and their primary receptor, the CB1 receptor, in the central nervous system using electrophysiological recordings in rodent hippocampus. We find that a moderate frequency 10 Hz stimulation protocol produces long-term potentiation (LTP) that is modulated by eCBs in both mice and rats; but surprisingly, the roles played by eCBs differ greatly between species. In rats, 10 Hz LTP requires CB1 receptor activation, as it is completely abolished by the CB1 antagonists AM251 and SR141716. Unlike theta burst stimulation (TBS) induced LTP, 10 Hz LTP does not require NMDA receptor activation. However, it is prevented when both NMDA and group1 mGluR receptors are blocked. The 10 Hz LTP is also independent of GABAergic synaptic inhibition, suggesting it is a novel form of excitatory synaptic plasticity mediated by the eCB system in hippocampus. In mice, we find that CB1 has an inhibitory effect on 10 Hz induced LTP. When the receptor is genetically removed in CB1 (-/-) mice or pharmacologically blocked wild type mice, 10 Hz LTP is greatly facilitated. Similar to TBS LTP, 10 Hz LTP in mice is NMDA receptor mediated. Also, the ability to achieve successful long-term depression (LTD) is decreased in CB1 (-/-) mice; yet, the magnitude of successful LTD is not changed. Together, this data supports a role for the CB1 receptor in inhibiting the induction of LTP with moderate stimulation protocols in mice, while in rats CB1 activation is required for 10 Hz LTP. Overall, our data supports that eCBs are crucial modulators of synaptic plasticity, although the roles they play may differ among species.

Associative plasticity, which involves modification of synaptic strength by coactivation of two synaptic inputs, has been demonstrated in many species. Here I explore whether it is possible to induce associative plasticity within a corticocortical pathway in the human brain using a novel protocol that activates two brain areas repeatedly with double-site transcranial magnetic stimulation (TMS). The pathway between ventral premotor cortex (PMv) and primary motor cortex (M1) which computes hand movements for precision grasp was manipulated. First, I selectively potentiated physiological connectivity between the stimulated brain areas. The effects as assessed with paired-pulse TMS were in accordance with principles of spike timing-dependent plasticity (STDP), pathwayspecific and showed a different pattern of expression during rest and during performance of a naturalistic prehension task. Furthermore, I demonstrated that effects evolved rapidly, lasted for up to three hours and were reversible. In a follow-up study, the protocol‘s effects on network interactions were investigated using functional magnetic resonance imaging (fMRI), specifically focussing on functional connectivity of network nodes within the wider parietofrontal circuit controlling reaching-and-grasping. The study demonstrated that functional connectivity was causally modified between stimulated nodes and that those changes in coupling also affected parallel, functionally-related pathways. Comparison of neurophysiological (paired-pulse TMS) and functional (fMRI) connectivity between individuals revealed a linear relationship of these connectivity indices; the first can assess the physiological nature of the interaction, whereas the latter can elucidate global network effects, making the techniques complementary. Neurophysiological interactions of ipsilesional and contralesional PMv-M1 were tested in chronic subcortical stroke patients during grasping. Patients showed a diminished facilitatory influence of ipsilesional PMv on M1 compared to healthy controls which might contribute to their motor disability. Application of paired-associative TMS “normalised“ the reduced effective influence of ipsilesional PMv on M1 and this effect correlated with the patient‘s potential to improve their dexterity.

In the behavioral sciences, the concept of phenotypic plasticity can be roughly categorized into two classes: developmental and activational plasticity. Developmental plasticity denotes the capacity of an individual carrying a specific genetic background to adopt different developmental trajectories under distinct settings. Complementarily, activational plasticity refers to the differential activation of adaptation mechanisms: an individual with high activational plasticity would be able to detect a wide range of environments, and to respond to it using a psychobiological phenotype from a relatively large catalogue. In this context, it is feasible postulating that several etiopathogenic mechanisms of depression-related phenotypes can be clarified by expanding on processes of biobehavioral plasticity in response to the experience. This expansion can be elaborated on the basis of both neurodevelopmental phenomena (developmental plasticity) and novel biological mechanisms detectable through neuroimaging and epigenetics approaches (activational plasticity). The present work expands on two specific hypotheses. First, depression-related psychopathological phenotypes are induced by factors altering the early neurodevelopment, and these long-lasting changes can be assessed in adulthood (depression and developmental plasticity). Secondly, the clinical manifestation of depression-related psychopathological phenotypes can be understood as activational plasticity deficits; these deficits can be assessed as neurobiological disease traits using novel epigenetic and neuroimaging techniques (depression and activational plasticity). The results of this work provide support to the neuroplasticity hypothesis of depression, from both developmental and activational perspectives. Developmentally, they suggest putative etiopathogenic pathways leading from an altered early neurodevelopment to an increased risk for depression-related phenotypes. By exploring and combining genetic, environmental and psychopathologic concepts, the feasibility of these results has been explained by combining the popular genetic pleiotropy hypothesis in psychiatry with a notion of disease-specificity liability driven by the environment. With regards to activational plasticity, this work has proposed novel genetic and epigenetic signatures potentially underlying the clinical manifestation of neuropsychiatric and neurocognitive features of depression (i.e., the genetics of DNMT3B and the epigenetics of DEPDC7); additionally, it has proposed new putative neurobiological mechanisms to explain depressive traits (i.e., a combination of differential and variable methylation, a genetically-mediated hippocampal communication deficit, and a new amygdalar synchrony failure driven by the genes).

Long-term potentiation (LTP) is an activity-dependent increase in the efficacy of synaptic transmission. In concert with long-term depression (LTD), this synaptic plasticity likely underlies some types of learning and memory. It has been suggested that for LTP/LTD to act as effective memory storage mechanisms, homeostatic regulation is required. This need for plasticity regulation is incorporated into the Bienenstock, Cooper and Munro (BCM) theory by a threshold determining LTD/LTP induction, which is altered by the previous history of activity (Bienenstock et al., 1982). The present work aimed to test key predictions of the BCM model. This was done using field and intracellular recordings in area CA1 of hippocampal slices from young, adult male Sprague-Dawley rats. The first prediction tested was that following a strong, high-frequency priming stimulation all synapses on primed cells will show inhibition of subsequent LTP and facilitation of LTD induction (heterosynaptic metaplasticity). This was confirmed using two independent Schaffer collateral pathways to the same CA1 pyramidal cells. Following priming stimulation to one pathway, LTP induction was heterosynaptically inhibited and LTD facilitated. To more fully investigate whether all synapses show metaplastic changes, the priming stimulation was given in a different dendritic compartment, in stratum oriens, prior to LTP induction in stratum radiatum. This experiment supported the conclusion that all synapses show inhibited LTP following priming. A second prediction of the BCM model is that metaplasticity induction is determined by the history of cell firing. To investigate this, cells were hyperpolarized during priming to completely prevent somatic action potentials. Under these conditions inhibitory priming of LTP was still observed, and thus somatic action potentials are not critical for the induction of the effect. The next aim was to determine the mechanism underlying heterosynaptic metaplasticity. One way in which plasticity induction can be altered is through changes in gamma-aminobutyric acid (GABA)-mediated inhibition of pyramidal cells. For this reason, it was tested whether blocking all GABAergic inhibition, for the duration of the experiment, would prevent priming of LTP. However, priming inhibited subsequent LTP and it was concluded that GABAergic changes do not underlie either the induction, or expression, of the metaplastic state. Proposed revisions to the BCM model predict that postsynaptic elevations in intracellular Ca�⁺ determine the induction of metaplasticity. There are many potential sources for postsynaptic Ca�⁺ elevations, including entry through N-methyl-D-asparate receptors (NMDARs) or voltage-dependent calcium channels (VDCCs), or release from intracellular stores. Results of the present work demonstrate that the inhibition of LTP is dependent on the release of Ca�⁺ from intracellular stores during priming; however this release is not triggered by Ca�⁺ entry through NMDARs or VDCCs, or via activation of metabotropic glutamate receptors. Overall, the present results show that, in accordance with the BCM model, a high level of prior activity induces a cell-wide metaplastic state, such that LTD is facilitated and LTP is inhibited. In contrast to predictions of the BCM model, this is not mediated by cell-firing during priming. Instead the release of Ca�⁺ from intracellular stores is critical for induction of the metaplastic state.

Bipolar disorder (BD) is a severe psychiatric illness with a consistent genetic influence, involving complex interactions between numerous genes and environmental factors. Immediate early genes (IEGs) are activated in the brain in response to environmental stimuli, such as stress. The potential to translate environmental stimuli into long-term changes in brain has led to increased interest in a potential role for these genes influencing risk for psychiatric disorders. Our recent finding using network-based approach has shown that the regulatory unit of early growth response gene 3 (EGR3) of IEGs family was robustly repressed in postmortem prefrontal cortex of BD patients. As a central transcription factor, EGR3 regulates an array of target genes that mediate critical neurobiological processes such as synaptic plasticity, memory and cognition. Considering that EGR3 expression is induced by brain-derived neurotrophic factor (BDNF) that has been consistently related to BD pathophysiology, we suggest a link between BDNF and EGR3 and their potential role in BD. A growing body of data from our group and others has shown that peripheral BDNF levels are reduced during mood episodes and also with illness progression. In this same vein, BDNF has been proposed as an important growth factor in the impaired cellular resilience related to BD. Taken together with the fact that EGR3 regulates the expression of the neurotrophin receptor p75NTR and may also indirectly induce BDNF expression, here we propose a feed-forward gene regulatory network involving EGR3 and BDNF and its potential role in BD.

Neurological degenerative diseases like stroke, Alzheimer, Amyothrophic Lateral Sclerosis (ALS), Parkinson and many others are constantly increasing their incidence in the world health statistics as far as the mean age of the global population is getting higher and higher. This leads to a general need for effective, at-home and low-cost rehabilitative and health-daily-care tools. The latter should consist either of technological devices implemented for operating in a remote way, i.e. tele-medicine is quickly spreading around the world, or very-advanced computer-based and robotic systems to realize intense and repetitive trainings. This is the challenge in which Information and Communications Technology (ICT) is asked to play a major role in order to bring medicine to reach further advancements. Indeed, no way to cope with these issues is possible outside a strong and vivid cooperation among multi-disciplinary teams of clinicians, physicians, biologists, neuro-psychologists and engineers and without a resolute pushing towards a widespread inter-operability between Institutes, Hospitals and Universities all over the world, as recently highlighted during the main International conferences on ICT in healthcare. The establishment of well-defined standards for gathering and sharing data will then represent a key element to enhance the efficacy of the aforementioned collaborations. Among the others, stroke is one of the most common neurological pathologies being the second or third cause of mortality in the world; moreover, it causes more than sixty percent survivors remain with severe cognitive and motor impairments that impede them in living normal lives and require a twenty-four-hours daily care. As a consequence, on one side stroke survivors experience a frustrating condition of being completely dependent on other people even to perform simple daily actions like reach and grasp an object, hold a glass of water to drink it and so on. States, by their side, have to take into account additional costs to provide stroke patients and their families with appropriate cares and supports to cope with their needs. For this reason, more and more fundings are recently made available by means of grants, European and International projects, programs to exchange different expertise among various countries with the aim to study how to accelerate and make more effective the recovery process of chronic stroke patients. The global research about this topic is conducted on several parallel aspects: as regard as the basic knowledge of brain processes, neurophysiologists, biologists and engineers are particularly interested in an in-depth understanding of the so-called neuroplastic changes that brain daily operates in order to adapt individuals to life changes, experiences and to realize more extensively their own potentialities. Neuroplasticity is indeed the corner stone for most of the trainings nowadays adopted by the standard as well as the more innovative methods in the rehabilitative programs for post-stroke recovery. Specifically speaking, motor rehabilitation usually includes long term, repetitive and intense goal-directed exercises that promote neuroplastic mechanisms such as neural sprouting, synapto-genesis and dendritic branching. These processes are strictly related with motor improvements and their study could - one day - serve as prognostic measures of the recovery. Another aspect of this eld of neuroscience research is the number of applications that it makes feasible. One of the most exciting is to connect an injured brain to a computer or a robotic device in a Brain-Computer or Brain-Machine Interface (BCI or BMI) scheme aiming at bypassing the impairments of the patient and make him/her autonomously move again or train his/her motor abilities in a more effective way. This kind of research can already count an amount of literature that provides several proofs of concept that these heterogeneous systems constituted by humans and robots can work at the purpose. A particular application of BCI for restoring or enhancing, at least, the reaching abilities of chronic stroke survivors was implemented and is still currently being improved at I.R.C.C.S. San Camillo Hospital Foundation, an Institute for the rehabilitation from neurological diseases located in Lido of Venice and partially technically supported by the Department of Information Engineering of Padua in range of an agreement signed in 2009. This specific BCI platform allows patients to train and improve their reaching movements by means of a robotic arm that provides a force that helps patients in completing the training exercise, i.e. to hit a predetermined target. This force feedback is however subject to a strict condition: during the movement, the person has to produce the expected pattern of cerebral activity. Whenever this is accomplished, a force is delivered proportionally to the entity of the latter activity, otherwise the patient is obliged to operate without any help. In this way, this platform implements the so-called operant-learning, that is one of the most effective conditioning techniques to make a subject learn or re-learn a task. If, on one hand, the primary and explicit task is to improve a movement, on the other side the secondary but most important task is to deploy the perilesional part of the brain - still healthy - in becoming responsible for the control of the movement. It is a popular and widely-accepted opinion within the neuroscience community, indeed, that a healthy region of the sensorimotor area nearby the damaged one - which was previously in charge of performing the (reaching) movement - can optimally accomplish the impaired motor function substituting the original control area. Technically speaking, the main crucial feature that can ensure the effectiveness of the whole system is the precise and in real-time identification and quantification of the cerebral pattern associated with the movement, the worldwide named movement-related desynchronization (MRD). Starting from its original definition, passing through the most used techniques for its recognition, the thesis work presents a series of criticisms of the current signal processing method to detect the MRD and a complete analysis of the possible features that can better represent the movement condition and that can be more easily extracted during the on-line operations. Brain - it is well-known - learns by trials and errors and it needs a slightly-delayed (in the range of fraction of seconds) feedback of its performance to learn a task in the best way. This BCI application was born with the purpose to provide the above-mentioned feedback: however, this is only feasible if a computationally easy and contingent signal processing technique is available. This thesis work would like to cope with the lack of a well-planned real-time signal analysis in the current experimental protocol.<br>L'identificazione e la quantificazione in tempo reale dei correlati cerebrali del movimento e' uno degli aspetti piu' critici nell'ambito delle cosiddette Brain-Computer Interface (BCI), ovvero quelle applicazioni in cui un individuo, dopo uno specifico percorso di apprendimento, impara a controllare un computer (o un altro dispositivo) tramite la modulazione volontaria della sua attivita' cerebrale, con lo scopo finale di trarre vantaggio dall'utilizzo dell'apparecchiatura cosi' controllata. La BCI e' solo uno delle molteplici tecniche di riabilitazione motoria oggigiorno disponibili. Indipendentemente dalla specifica tecnica scelta, il metodo riabilitativo mira a recuperare le funzionalita' del cosiddetto sistema sensorimotorio, quel complesso di aree corticali e strutture sotto-corticali che permette ad un individuo di ricevere impulsi somatosensoriali dal mondo esterno, di elaborare la risposta motoria piu' opportuna e realizzarla grazie agli attuatori finali del movimento rappresentati dai muscoli. Per perseguire questo obbiettivo, la maggior parte delle tecniche riabilitative, ivi compresa la BCI, pongono grande attenzione alla promozione e sfruttamento di quei processi spontanei che il cervello costantemente impiega per svolgere le sue attivita', adattarsi a nuove condizioni ambientali e anche cercare di recuperare le abilita' perse a seguito di un evento dannoso quale un ictus. Questi fenomeni vengono generalmente riassunti nel termine neuroplasticita' e sono stati paradossalmente sfruttati per anni nella pratica clinica, ma solo recentemente sono diventati materia di rigorosi e approfonditi studi scientici portati avanti da neuroscienziati provenienti da ogni tipo di formazione (neurologi, neurofisiologi, biologi, ingegneri, neuropsicologi, ...). Nel particolare contesto della riabilitazione motoria che ambisce essenzialmente a promuovere fenomeni di (ri-)apprendimento motorio da parte del paziente colpito da ictus, la letteratura ha fermamente indicato il condizionamento operante come la strategia piu' efficace per favorire i processi di plasticita' corticale e, di conseguenza, il recupero, seppur parziale, della motricita'. Il condizionamento operante si applica tramite la ripetitiva associazione di un comportamento corretto (scorretto) effettuato dal soggetto e uno stimolo gratificante (penalizzante) dato contestualmente o in un tempo appena successivo all'esecuzione del comportamento. Sfruttando il fondamentale meccanismo di apprendimento del cervello per prove ed errori, esso impara a utilizzare il comportamento corretto per svolgere il compito richiesto. Tale comportamento corretto e', in questo caso, lo sfruttamento di risorse ridondanti prima dell'ictus ma ancora sane dopo l'evento per controllare le funzioni motorie rimaste indebolite o completamente perse a seguito del danno cerebrale. Data la fondamentale importanza della contingenza tra l'attivita' cerebrale del paziente coinvolto nell'esperimento e lo stimolo di feedback, un robusto algoritmo di elaborazione del segnale cerebrale si rende fortemente necessario. In questo lavoro di tesi e' stata analizzata una particolare applicazione BCI per la riabilitazione motoria di pazienti lievemente o moderatamente aetti da emiparesi dovuta a ictus e sono stati proposti degli algoritmi con la relativa soluzione software per la realizzazione ottimale della strategia di apprendimento operante durante il recupero di un movimento di raggiungimento. Il vincolo principale da considerare per ottenere questo tipo di risultato e' la possibilita' di identificare e quanticare il correlato neurofisiologico legato al movimento, la cosiddetta desincronizzazione movimento correlata, in tempo reale durante l'esecuzione del movimento da parte del soggetto. Nell'ottica del condizionamento operante, un dispositivo haptico inserito nel sistema funge da feedback positivo che aiuta il paziente a completare il movimento nel solo caso in cui venga riconosciuta la desincronizzazione. In caso contrario, il soggetto non riceve alcun feedback o il suo movimento viene reso piu' difficile. Dopo un primo capitolo introduttivo sul sistema sensorimotorio arricchito con alcune informazioni riguardanti la particolare patologia in questione, il secondo capitolo introduce gli elementi fondamentali della piattaforma sperimentale utilizzata, ovvero l'elettroencefalogramma (EEG) e la BCI nella sua accezione generale, accennando anche ai maggiori successi in questo ambito delle ICT applicate alla medicina riabilitativa. Nel capitolo 3 viene descritta la particolare piattaforma BCI basata su EEG menzionata sopra e nei capitoli 4 e 5 vengono presentate ampiamente le analisi, le procedure e i risultati sviluppati ed ottenuti in questi anni di studio. In particolare, nella prima parte del capitolo 4 viene illustrato l'algoritmo con cui e' possibile identificare e rimuovere in tempo reale un particolare evento di disturbo che puo' verificarsi durante la registrazione EEG, il cosiddetto artefatto electrode pop dovuto al temporaneo sollevamento di un elettrodo che causa abnormi valori negativi nelle tracce EEG. Una volta rimosso questo tipo di eventp, il segnale viene filtrato e nella seconda parte del capitolo 4 viene presentata un'esaustiva analisi dell'energia delle tracce EEG acquisite durante la registrazione dell'esperimento di cui sopra in soggetti sani di controllo e in alcuni pazienti reduci da ictus. Inoltre, viene suggerita una versione modificata del piu' noto metodo di quantificazione della desincronizzazione fornito da Pfurtscheller e colleghi a partire dagli anni '70 i cui risultati promettenti sono forniti e discussi nel capitolo finale della tesi. La tesi si conclude con una breve sezione dedicata alle prospettive future di applicazione della piattaforma con l'integrazione delle soluzioni software apportate da questa tesi e alle questioni ancora aperte da risolvere al fine di ottimizzare il sistema BCI in tutti i suoi aspetti in modo da realizzare nel modo piu efficace il condizionamento operante e promuovere quei processi spontanei che sottostanno al recupero funzionale della motricita'.

Impaired motor function following neurological injury may be overcome through therapies that induce neuroplastic changes in the brain. Therapeutic methods include repetitive exercises that promote use-dependent plasticity (UDP), the benefit of which may be increased by first administering peripheral nerve stimulation (PNS) to activate afferent fibers, resulting in increased cortical excitability. We speculate that PNS delivered only in response to attempted movement would induce timing-dependent plasticity (TDP), a mechanism essential to normal motor learning. Here we develop a brain-machine interface (BMI) to detect movement intent and effort in healthy volunteers (n=5) from their electroencephalogram (EEG). This could be used in the future to promote TDP by triggering PNS in response to a patient’s level of effort in a motor task. Linear classifiers were used to predict state (rest, sham, right, left) based on EEG variables in a handgrip task and to determine between three levels of force applied. Mean classification accuracy with out-of-sample data was 54% (23-73%) for tasks and 44% (21-65%) for force. There was a slight but significant correlation (p<0.001) between sample entropy and force exerted. The results indicate the feasibility of applying PNS in response to motor intent detected from the brain.

Long-term adrenalectomy (ADX) results in a specific loss of dentate gyrus granule cells in the hippocampus of adult rats, occurring over a period of weeks to months. This loss of granule cells results in cognitive deficits in a number of tasks that depend on intact hippocampal function. The gradual nature of ADX-induced cell death and the ensuing deficits in cognition are similar to those experienced by patient populations suffering from a variety of pathological conditions. Here we present an animal model by which we use ADX to produce a loss of granule cells within the hippocampus of rats. We also provide experimental evidence for a treatment strategy by which the lost granule cells may be replaced, with the goal of functional recovery in mind.<br>xii, 191 leaves : ill. (chiefly col.) ; 28 cm

La correcta migració, la polarització neuronal i el manteniment de l'estructura neuronal són claus per l'òptim funcionament del cervell. Existeix un reconeixement molecular que permet la formació de les connexions neuronals. El manteniment d'aquestes connexions són claus en cervell adult. A més a més, la pèrdua progressiva d'aquestes donen lloc a processos neurodegeneratius. Les molècules d'adhesió cel·lulars realitzen diferents funcions essencials durant el desenvolupament i en la plasticitat neuronal. Estan involucrades en la migració creixement neurític, sinaptogènesi i plasticitat. Aquesta tesi es focalitza en l'estudi de les funcions que realitza una d'aquestes molècules d'adhesió, la molècula d'adhesió cel·lular neuronal 2 (neural cell adhesion molecule 2, Ncam2). Ncam2 és una glicoproteïna de la família de les Ncam. En concret, el gen Ncam2 és paràleg amb Ncam1 i presenta el mateix domini extracel·lular que Ncam1. Ncam2 presenta dues isoformes degut a un empalmament alternatiu que genera la isoforma Ncam2.1 i la isoforma Ncam2.2. En mamífers, Ncam2 s'expressa en diferents teixits del cos i el teixit on és més abundant és el cervell. Ncam2 s'expressa en diferents regions del cervell però la seva funció ha estat extensament estudiada en el bulb olfactori, on s'ha vist que participa en la formació i el manteniments de les connexions en el glomèrul. En concret, participa en la fasciculació dels axons i el creixement neurític. A més a més, en cultius de neurones corticals Ncam2 participa en la formació de fil·lopodis i la ramificació de les neurites. Tot i l'expressió en hipocamp i còrtex, la funció de Ncam2 no és coneixia en aquests teixits. En aquest sentit, al llarg de la tesi hem modulat l'expressió en diferents experiments in vitro i in vivo per determinar la funció de Ncam2 en el desenvolupament, morfogènesi neuronal i plasticitat adulta. En desenvolupament hem observat que Ncam2 s'expressa en les neurones que migren radialment i la seva expressió és necessària pel correcte posicionament en el còrtex. A més a més, l'expressió de Ncam2 en hipocamp és necessària per la morfogènesi neuronal degut a que participa en els processos de polarització, creixement dendrític i ramificació axonal. En hipocamp adult, Ncam2 controla la plasticitat neuronal i la neurogènesi adulta. En concret, Ncam2 controla la densitat d'espines de les neurones piramidals de CA1 i les neurones granulars del gir dentat. A més a més, també modula la densitat de contactes que formen les fibres molsoses a la CA3. A nivell de neurogènesi adulta, els nostres resultats indiquen que Ncam2 controla la diferenciació neuronal de les neurones generades en el gir dentat. A nivell de senyalització, els nostres resultats indiquen que Ncam2 interacciona amb diferents molècules que controlen les dinàmiques del citoesquelet d'actina i microtúbuls, la senyalització de calci, la transcripció genètica i el tràfic cel·lular. Aquestes dades obren la via d'estudi dels mecanismes que vehiculen les funcions de Ncam2. Les nostres dades posen de manifest diferents funcions que realitza Ncam2 en el cervell. En cap sentit, les interaccions i funcions descrites semblen exclusives de Ncam2 sinó que són processos en que hi ha un solapament funcional de moltes proteïnes d'adhesió, fet que confereix robustesa als processos de formació, manteniment i remodelació de les estructures neuronals. En concret, Ncam2 formaria part del conjunt de molècules que permeten la identitat molecular de les neurones. Una identitat clau perquè permet la formació i el manteniment de circuits neuronals específics.<br>The proper migration, neuronal polarity and long-term maintenance of neurons are crucial for correct brain functioning, with special relevance for the connectivity orchestration during development and learning processes. Furthermore, changes in these processes are one of the keys features in neurodegenerative diseases. Cell Adhesion Molecules (CAMs) play an important role during brain development and brain plasticity processes, being involved in neurite outgrowth, synaptogenesis and synaptic plasticity. Neural cell adhesion molecule 2 (Ncam2) is a CAM family member homologous to Ncam1 with a similar ectodomain. Ncam2 has two different isoforms generated by alternative splicing known as Ncam2.1 (transmembrane isoform) and Ncam2.2 (glycosylphosphatidylinositol (GPI) anchored isoform). In mammals, NCAM2 is expressed predominantly in brain, and its expression pattern demonstrates a putative important role of this protein in both embryonic and adult brain function. NCAM2 role has been extensively investigated in the olfactory system where it plays an important role in axonal fasciculation and neurite outgrowth. Recently, different studies have revealed that Ncam2 also participates in the formation of filopodia and in neurite branching of cortical mouse neurons. Nevertheless its function in hippocampal development and adult plasticity remains largely unknown. We used different cell biology and molecular approaches, including loos-of- and gain-of-function models, to determine the role of Ncam2 in the development of the brain and adult plasticity. Our data show that Ncam2 is expressed in migrating neurons and that it is necessary for their correct position in the cortex. Moreover, Ncam2 is also expressed in the hippocampus and it is essential for the appropriate neuronal polarity. Ncam2 plays a role in neurite outgrowth, axonal branching and dendrite formation by modulating cytoskeletal dynamics. In adult hippocampus, our data show that Ncam2 contributes in synaptic plasticity and adult neurogenesis. Ncam2 modulates the spine density of pyramidal neurons in CA1 and granule cells in dentate gyrus. Furthermore, Ncam2 controls the mossy fibber contacts in CA3. Regarding to the adult neurogenesis, gain-of function of Ncam2 changes the neuronal differentiation of the new neurons. Our experiments indicate that Ncam2 interacts with a diversity of proteins including cytoskeletal components associated to the microtubule and actin networks, thus pointing to hypothetical mechanistic insights to be explored. Taken together, our results indicate that Ncam2 is an important molecule for the development, specification and connectivity of brain formation and adult plasticity.

The ability of the brain to change and form new neuropathways after brain injury is remarkable. The current study investigates the brains ability to form new pathways for language processing following traumatic brain injury (TBI), specifically a left temporal lobectomy. Two subjects participated in this study; one participant with TBI and one age-matched control. Sentence stimuli consisted of four types: semantically correct, semantically incorrect, syntactically correct, and syntactically incorrect. Participants underwent a fMRI scan while the auditory stimuli were presented in four blocks. Participants were asked to record if the sentence was correct or incorrect by pressing the corresponding button. It was found that reaction times for both the participant with TBI and the control were longer for the incorrect conditions. The participant with TBI generally had longer reaction times compared to the control participant and had more errors. During the fMRI scans, patient movement occurred. The block design was not set up to account for movement. Due to this factor, imaging results are questionable. While there were differences between the participant with TBI and the control participant, these differences are expected to be much larger in someone with this degree of brain injury. It is recommended for further studies to be conducted in this area with a revised block design to account for patient movement.

L'analyse et l'intégration de données multimodales pour élucider les processus et réseaux cérébraux qui sous-tendent la cognition et le comportement est l'un des principaux défis de ce 21ème siècle en neurosciences cognitives. Cette thèse vise à identifier les profils neurocognitifs (c'est-à-dire les signatures intégrant cognition et biomarqueurs) typiques mais aussi atypiques présentés notamment par les patients souffrant d'épilepsie temporale pharmaco-résistante. Plus précisément et à travers plusieurs études, nous avons cherché à estimer la topologie, l'intensité et la nature des changements macroscopiques cérébraux pouvant être observés chez les patients, en utilisant différentes méthodes d'imagerie par résonance magnétique (IRM) qui impliquent respectivement la structure (IRM de diffusion) et le fonctionnement cérébral (IRM de tâche et de repos). Nous adoptons une approche basée sur la connectivité, ce qui nous permet de modéliser les informations extraites de ces diverses modalités sous forme de réseaux d'information. Nous nous efforçons ensuite de relier ces informations aux scores neuropsychologiques et aux données cliniques afin notamment d’identifier l'efficience des réorganisations mises en place. Pour aborder les modifications neurocognitives chez les patients, nous nous sommes concentrés tout au long de nos études sur le fonctionnement du langage et de la mémoire (Language-and-Memory Network ; LMN) particulièrement vulnérable dans l’épilepsie du lobe temporal. Dans cette perspective, nous proposons un modèle neurocognitif compréhensif des réorganisations observées chez ces patients. En complément de l'identification des patterns de neuroplasticité typiquement observés dans l'épilepsie temporale, nous proposons également une méthode d'investigation pour appréhender la variabilité inter- et intra-individuelle. Enfin, nous proposons des perspectives d'intégration statistique des données multimodales pour tendre vers des modèles toujours plus détaillés et intégratifs. Dans l'ensemble, nous cherchons à répondre aux questions fondamentales, conceptuelles et cliniques contemporaines afin d'enrichir la littérature actuelle et de fournir de nouveaux outils pour la médecine de demain<br>The analysis and integration of multimodal data to elucidate the neural processes and networks underlying cognition and behavior are one of the main challenges of this 21st century in cognitive neuroscience. This thesis aims at identifying the typical but also atypical neurocognitive profiles (i.e. signatures embedding cognition and biomarkers) presented by patients suffering from pharmaco-resistant temporal epilepsy (TLE) in particular. More precisely and across several studies, we sought to estimate the macroscopic topology, intensity, and nature of the brain changes in patients by using different magnetic resonance imaging (MRI) methods, involving respectively structure (diffusion MRI) and function (task and resting-state fMRI). We adopt a connectivity-based approach, enabling us to model the different information extracted from these modalities as informative networks. We link this information with neuropsychological scores and clinical data to assess neuroplasticity efficiency. To tackle neurocognitive modifications in patients we focused all through our studies on the language-and-memory functioning (Language-and-Memory Network; LMN), particularly vulnerable in the temporal lobe epilepsy affection. From that perspective, we propose a comprehensive model of the reorganization observed in these patients. Next to the identification of patterns typically observed in TLE, we also propose an investigative method to apprehend inter- and intra-individual variability. And finally, we suggest perspectives for the statistical integration of multimodal data to develop ever more detailed and integrative models. Overall, we endeavor to respond to both fundamental and clinical contemporary questions to enrich the current literature and provide new tools for tomorrow's medicine

In order to assess flexibility in acquiring and using conflicting response rules, rats with selective lesions of the NBM or sham-lesion controls were subjected to serial reversal training in a simple operant discrimination paradigm. The NBM lesion group did not differ from the control group in acquisition of the original rules; the NBM lesion group required more time to master the changes in rules in the first reversal, but not in subsequent reversals.

Pazienti con lesioni cerebrali o spinali possono essere affetti da gravi deficit nelle funzioni sensoriali, motorie e comunicative; sono perciò sempre più necessarie tecniche di riabilitazione avanzate, personalizzate e adattative, per limitare i deficit insorti e restituire al paziente una vita il più normale possibile. Negli ultimi decenni, numerosi gruppi di ricerca hanno sviluppato Brain-Computer Interface (BCI) basate sul segnale elettroencefalografico (EEG) con l’obbiettivo di fornire mezzi di comunicazione o riabilitazione motoria funzionale. Tuttavia, le tecnologie BCI hanno un ampio potenziale al di là della sola riabilitazione motoria. Applicazioni dei sistemi BCI in protocolli di riabilitazione cognitiva, ad esempio, hanno conseguito risultati promettenti nella prospettiva di migliorare funzioni quali l’attenzione, l'apprendimento e la memoria in pazienti con disturbi delle funzioni cognitive. In questo lavoro di Tesi si analizzano i principi di funzionamento dei sistemi BCI, a partire dall’acquisizione del segnale elettroencefalografico fino all’estrazione e alla classificazione delle feature del segnale per decodificare intenzioni motorie e processi cognitivi (memoria, attenzione) dell’utente. Viene poi presentata un’analisi della letteratura per quando riguarda gli approcci BCI in riabilitazione sia motoria che cognitiva, prestando particolare attenzione ai metodi utilizzati per l’elaborazione e traduzione del segnale EEG. Sono stati considerati con particolare attenzione studi che valutano gli effetti dell’applicazione di BCI non solo attraverso performance motorie e cognitive ma anche utilizzando tecniche di neuro-imaging avanzate, per indagare possibili cambiamenti nell’organizzazione funzionale della corteccia cerebrale sottostanti i risultati positivi ottenuti. Infine, vengono commentati i vantaggi e le limitazioni di queste tecnologie riabilitative e i problemi ancora aperti.

Adrenalectomy (ADX) has been shown to cause selective degeneration of granule cells in the dentate gyrus (DG). This occurs due to the reduction of corticosterone (CORT) and behavioural deficits are associated with the loss of these neurons. Dentate lesions and cell loss associated with ADX have been shown to effect behaviour in a number of spatial tasks. In contras, it has been shown granule cell loss does not affect the specificity of place cells in CA3 and CA1. We used the ADX model to examine the role of DG granule cells plays in representing space using immediate early gene (IEG) activation in the principal hippocampal subfields after exploration of novel environments. Rats were allowed to free explore multiple novel environments and then the mRNA for the IEG Homer 1a (H1a) was used as a marker of neural activity. After degeneration of approximately half of the DG granule cells we found a significant increase in number of active cells in the DG, CA3 and CA1 in ADX animals. The results indicate a reduction in granule cells causes a dramatic increase in the proportion of remaining DG granule cells in response to exploration. The change in DG activation disrupts the representations in CA3 and CA1 and thereby affects behaviour.<br>vii, 60 leaves : ill. (some col.) ; 29 cm

A new mathematical model of short-term synaptic plasticity (STP) at the Schaffer collateral is introduced. Like other models of STP, the new model relates short-term synaptic plasticity to an interaction between facilitative and depressive dynamic influences. Unlike previous models, the new model successfully simulates facilitative and depressive dynamics within the framework of the synaptic vesicle cycle. The novelty of the model lies in the description of a competitive interaction between calcium-sensitive proteins for binding sites on the vesicle release machinery. By attributing specific molecular causes to observable presynaptic effects, the new model of STP can predict the effects of specific alterations to the presynaptic neurotransmitter release mechanism. This understanding will guide further experiments into presynaptic functionality, and may contribute insights into the development of pharmaceuticals that target illnesses manifesting aberrant synaptic dynamics, such as Fragile-X syndrome and schizophrenia. The new model of STP will also add realism to brain circuit models that simulate cognitive processes such as attention and memory. The hippocampal processing loop is an example of a brain circuit involved in memory formation. The hippocampus filters and organizes large amounts of spatio-temporal data in real time according to contextual significance. The role of synaptic dynamics in the hippocampal system is speculated to help keep the system close to a region of instability that increases encoding capacity and discriminating capability. In particular, synaptic dynamics at the Schaffer collateral are proposed to coordinate the output of the highly dynamic CA3 region of the hippocampus with the phase-code in the CA1 that modulates communication between the hippocampus and the neocortex.

Une altération du métabolisme de l'homocystéine constitue un facteur de risque pour la survenue des maladies neurodégénératives. Par ailleurs, alors que les effets délétères d'une hypoxie néonatale sévère sont bien connus, il a été récemment montré qu'un épisode hypoxique modéré exerçait une neuroprotection via une stimulation de la neurogenèse. Notre objectif fut l'étude des conséquences cérébrales d'une carence précoce en donneurs de méthyles (folates, vitamine B12) combinée ou non à une stimulation hypoxie modérée. Un modèle in vivo de rats nés de mères carencées en donneurs de méthyles fut utilisé. Il a été étudié les mécanismes impliqués dans un modèle de progéniteurs neuronaux carencés. Les résultats ont montré des atteintes de l'intégrité tissulaire et fonctionnelle de l'hippocampe et du cervelet associée à des déficits comportementaux, à différents stades de la vie chez les animaux carencés malgré le retour à une alimentation standard au sevrage. Ces perturbations sont liées aux processus épigénétiques et à l'homocystéinylation de protéines neuronales. De plus, un dimorphisme sexuel est apparu en lien avec le récepteur nucléaire ER alpha. La neurogenèse issue de l'hypoxie a engendré des conséquences bénéfiques à long terme sur le vieillissement cérébral des rats mâles, avec un maintien de l'intégrité hippocampique. Enfin, la combinaison de la carence et de l'hypoxie, a montré que le conditionnement hypoxique améliorait le devenir tissulaire et fonctionnel du cerveau des animaux carencés. Les mécanismes clés surviendraient au cours de périodes critiques de maturation des différentes structures cérébrales, soulignant l'importance des processus de la programmation foetale<br>The alteration of homocysteine metabolism has been shown to constitute a risk factor for neurodegenerative diseases. Furthermore, whereas deleterious effects of severe neonatal hypoxia have been well documented, it was shown that a moderate episode of hypoxia can exert a neuroprotection with neurogenesis stimulation. Our main goal was to study the consequences on the brain of an early deficiency of methyl donors (folate, vitamin B12) with or without a hypoxia-related stimulation of neurogenesis. The effects of deficiency were investigated in rats born from dams fed a deficient diet until weaning. In vitro neuroprogenitors were additionally used for the study of cell mechanisms involved. Data showed alterations of tissue integrity in the hippocampus and the cerebellum, with associated behavioural deficits at various ages, despite a return to normal diet at weaning. Brain alterations were shown to be mainly related to epigenetic mechanisms and to homocysteinylation of specific neuronal proteins. Moreover, a sexual dimorphism was depicted, with the participation of ER alpha receptor. Neurogenesis induced in germinative zones by a brief neonatal hypoxia led to long term beneficial effects on brain aging in male rats, with preserved hippocampus integrity, in terms of cell density, synaptic plasticity, and related cognitive functions. Finally, the combination of deficiency and hypoxia revealed that brain conditioning by brief neonatal hypoxia was able to improve tissular and functional brain outcome in deficient rats. The key mechanisms involved would occur at critical periods during the maturation of the various brain structures, thus highlighting the role of fetal programming

The present thesis examines the effects of transcranial direct current stimulation and forelimb rehabilitation on motor recovery after stroke in rats. Post-stroke motor outcomes were quantified using an innovative battery of behavioural tests and high resolution, in vivo electrophysiology was employed to examine coherence of neural activity between hemispheres. It was shown that rats that received brain stimulation concurrently with forelimb rehabilitation displayed functional recovery, whereas rats that received rehabilitation alone partially regained motor function, but the improvements were not due to restitution of original movement patterns. Results from electrophysiological recordings showed that rats that received brain stimulation and rehabilitation regained pre-stroke levels of interhemispheric coherence, but rats that received rehabilitation alone did not. The present thesis suggests that transcranial direct current stimulation may be a viable adjunct therapy to increase the efficacy of physical rehabilitation with regard to post-stroke motor outcomes. Interhemishperic coherence between homotopic neuronal populations may represent a biomarker of genuine motor recovery after stroke.<br>ix, 75 leaves : col. ill. ; 29 cm