The evolutionary forces that led to the unprecedented expansion of the human brain and the extreme cognitive prowess possessed by humans have always attracted a great deal of attention from the scientific community. Presented here is a novel theoretical perspective, where the driving force on human brain evolution was the need for enhanced ability to infer social values of conspecifics in the face of degradation and loss of chemosensory signalling mechanisms necessary for social communication present in most mammals. The lack of chemosensory communication of biologically relevant information between humans in the face of the need to make adaptive and accurate social evaluations, led to an exaption of mammalian chemosensory brain regions for the more complex task of inferring social values from behavioural cues that are variable, ambiguous, or otherwise difficult to detect and interpret. This change in social processing from perceptual evaluation to inferential computation placed a premium on cognitive capacity, thus selecting for larger more powerful brains. These selective processes would have left an indelible mark on the human brain, where the human homologues of regions involved in mammalian conspecific chemical communication, in particular the target regions of this study the amygdala and ventromedial prefrontal cortex (VMPC), should be involved in the processing of biologically relevant information and social inference. Several experiments were conducted to examine the role of these brain regions in social inferential processing using the lesion deficit method. First, given that conspecific chemical communication is particularly relevant for biologically imperative evaluation for the purposes of reproduction, VMPC and amygdala damage may result in abnormal mate-related decisions. Second, normal social attributions exhibit the correspondence bias, however damage to the target regions may result in an abnormal lack correspondence bias. Third, the current hypothesis is contrasted with another leading hypothesis, the Social Brain Hypothesis whose proponents predict a relationship between group-size and social cognition. Finally, if the target brain regions are truly integral in inferring social information, then damage to these regions will interfere with the ability to utilize transitive inference in social situations, and potentially in using transitive inference in general. Damage to the target areas produces limited effects on mate-related decisions and preferences. However, the current hypothesis may suggest that the target brain regions are only involved when the problem is inferential in nature rather than simpler perception of social information. In support of this notion, damage to the target regions results in a lack of the correspondence bias when making economic decisions. This alteration in social attributions actually leads to more `rational' decision-making in this context. In contrast to the predictions of the Social Brain Hypothesis, damage to the target regions produces no observed reduction in social group size, nor is there any observed relationship between perspective-taking ability and group size. Finally, damage to the VMPC produces deficits in using transitive inference in a non-social context perhaps hinting at the underlying computations of this region in inferring social information. In conclusion, it appears that the notion that the human brain regions that have been exapted from their duties in chemosensation and communication in mammalian brains has at least some validity. Moreover, these brain regions have been shifted by evolution to a more computationally complex process of social inference possibly providing the push toward larger and more powerful human brains.

Neonatal hydrocephalus is a common neurological disorder leading to expansion of the cerebral ventricles. This disease is associated with significant morbidity and mortality and is often fatal if left untreated. Hydrocephalus was first described over 2500 years ago by Hippocrates, the father of medicine, and remains poorly understood today. Current therapies still rely on invasive procedures developed over 60 years ago that are associated with high failure and complication rates. Thus, the identification of molecular mechanisms and the development of non-invasive medical treatments for neonatal hydrocephalus are high priorities for the medical and scientific communities. The prevailing doctrine in the field is that hydrocephalus is strictly a "plumbing problem" caused by impaired cerebrospinal fluid (CSF) flow. Recently, animal models with impaired cilia have provided insight into the mechanisms involved in communicating (non-obstructive) hydrocephalus. However, as a result of a poor understanding of hydrocephalus, no animal studies to date have identified an effective non-invasive treatment. The goal of this thesis project is to investigate the molecular mechanisms underlying this disease and to identify a non-invasive, highly effective treatment strategy. In Chapter 2, we utilize a novel animal model with idiopathic hydrocephalus, mimicking the human ciliopathy Bardet-Biedl Syndrome (BBS), to examine the role of cilia in hydrocephalus. We find that these mice develop communicating hydrocephalus prior to the development of ependymal "motile" cilia, suggesting that this phenotype develops as a result of dysfunctional "primary" cilia. Primary cilia are non-motile and play a role in cellular signaling. These results challenge the current dogma that dysfunctional motile cilia underlies neonatal hydrocephalus and implicate a novel role for primary cilia and cellular signaling in this disease. Chapter 3 focuses on identifying the link between primary cilia and neonatal hydrocephalus. In this chapter, we report that disrupting the molecular machinery within primary cilia leads to faulty PDGFRα signaling and the loss of a particular class of neural progenitor cells called oligodendrocyte precursor cells (OPCs). We find that the loss of OPCs leads to neonatal hydrocephalus. Importantly, we identify the molecular mechanism underlying both the loss of OPCs and the pathogenesis of neonatal hydrocephalus. Chapter 4 explores the therapeutic potential of targeting the defective cellular signaling pathways to treat neonatal hydrocephalus. By targeting the faulty signaling, we restore normal development of oligodendrocyte precursor cells, and curtail the development of hydrocephalus. This work challenges the predominant view of hydrocephalus being strictly a "plumbing problem" treatable solely by surgical diversion of CSF. Here, we propose that hydrocephalus is a neurodevelopmental disorder that can be ameliorated by non-invasive means. Importantly, we introduce novel molecular targets and a non-invasive treatment strategy for this devastating disorder. To our knowledge, we are the first to successfully treat neonatal hydrocephalus in any model organism by targeting neural progenitor cells.

Decision-making in the context of leadership, has received scant attention in the management literature, which has traditionally centered on general mental ability and personality as predictors of effectiveness. This research effort bridges the neuroscientific and management literatures to offer an alternative, neuropsychological profile of effective leadership by proposing prefrontal brain processes (executive function) as a key component and predictor of complex decision-making and leadership effectiveness. While the management literature has largely viewed decision-making as a cognitive ability, neuroscience informs us that this complex function emerges from the integration of affective and cognitive signals in the prefrontal cortex. In an attempt to identify the neural predictors of effective leadership decision-making, 105 corporate leaders were assessed on a robust array of neuropsychological indices of prefrontal brain function. These were in turn correlated with their leadership and decision-making abilities after controlling for general mental ability and personality, utilizing structural equation modeling. Executive function incrementally predicts complex decision-making and transformational leadership effectiveness, above and beyond general mental ability. Complex decision-making does not appear to be central to leadership effectiveness, while extraversion emerges as the strongest predictor of transformational leadership followed by executive function. Executive function, extraversion and general mental ability do not predict transactional leadership. These results would need replication in a larger dataset to establish their validity, especially in the case of executive function. While the heritability of leadership ability has emerged as fairly significant, this opens the field to unearthing the biological variables and predictors of leadership ability. Neuroscience thus has the potential to offer biomarkers and metrics of leadership that can further not only our foundational knowledge of organizational behavior, but can also find useful applications in recruitment, training and development practice, though this cross-disciplinary initiative is in its infancy. Based on the preliminary results from this study, executive function (which has so far remained in the domain of neurology) has the potential to inform and measure leadership effectiveness.

Empathy plays a crucial role in our relationships with others and enhances personal well-being. The brain areas that are critical for the experience of on-line empathy and empathic behavior are not known. The current study investigated the neural substrates of empathy through the examination of whether the ventromedial prefrontal cortex (VMPC) is critical for empathy. For the first time, on-line empathic experience and behavior were measured in patients with brain damage to the VMPC. Six patients with bilateral damage to the VMPC were case-matched on specific demographic and neuropsychological criteria to two comparison groups: a brain damage group and a healthy adult group. On-line empathy was induced in an ecologically-valid manner in which the participant experienced live the sorrow of another person. The participant thought they would be playing an economic game against two opponents. However, during the study the participant overheard their game opponent experience deep sadness, revealing that it was the anniversary of their son's death (empathic induction.) A comparison neutral induction involved the participant overhearing their opponent converse with the research assistant about a neutral topic. On-line empathic experience was measured by a questionnaire completed before and after the inductions. Empathic behavior was measured implicitly through an economic game. It was defined as the degree of behavioral change on the game as a result of the empathic induction (after accounting for baseline behavior.) The economic game used to measure empathic behavior was the Repeated Fixed Opponent variant of the well-validated Ultimatum Game. This particular variant had not been studied in participants of a similar age range to the patient sample (younger and older adults). Furthermore, there is evidence for some aging-related differences in behavior on economic games, providing additional rationale to examine the behavior of healthy younger and older adults on the game. Consequently, game behavior of younger and older adults was measured and then used to implement a model of healthy game behavior in the experiment that investigated empathy in patients with damage to the VMPC. Patients with damage to the VMPC experienced poor on-line empathy and showed poor empathic behavior. Patients with brain damage to the VMPC reported significantly less on-line empathy than patients with brain damage to other regions. Empathic behavior was not shown by patients with damage to the VMPC as a result of the empathic induction and their behavior was significantly different from both the healthy and the brain damage comparison groups which showed increased empathic behavior due to the empathic induction. A specific role for the VMPC region in empathy was demonstrated by the finding that patients with damage to this region had less on-line empathy and empathic behavior than patients with brain damage to other regions. This study showed that the VMPC region of the brain is critical for empathy. Further research is needed to elucidate whether patients with brain damage to the VMPC show decreased empathic behavior in all domains or whether it is specific to monetary decision-making.

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Abstract not available

<p>In the demyelinating autoimmune disease multiple sclerosis (MS) there is a great need for validated prognostic biomarkers that can give information about both prognosis and disease course. So far only clinical parameters have been shown to predict future outcome. CXCL13 is a potent B cell chemoattractant that has been suggested to be a potential biomarker candidate. The aim of this study was to investigate the usefulness of CXCL13 as a prognostic biomarker for MS.</p><p>Clinical, paraclinical, laboratory and MRI data about a large group of MS patients and controls were collected. CXCL13 levels in cerebrospinal fluid (CSF) samples from these patients were determined by standard enzymelinked immunosorbent assay (ELISA).</p><p>In general CXCL13 were increased in CSF in MS, especially in relapsing-remitting MS during relapses, i.e. with ongoing inflammations in the central nervous system. CXCL13 is a good candidate prognostic marker for MS, since newly diagnosed MS with high CXCL13 levels showed worsened disease course within five years. Most importantly, MS conversion occurred in higher rate in possible MS patients with high concentrations of CXCL13 in CSF, and in a shorter time point. This observation may support an early treatment decision in these patients.</p><p>In conclusion, this study provides support for an association between CXCL13 levels in the CSF and later development of disease severity in MS.</p>

Graduation date: 1994

Humans and animals interaction is showing promise as a way to provide complementary and alternative medicine for humans. Children have an affinity for animals that could be useful therapeutically. Emotional stress and trauma impacts the neurobiology of children, who are vulnerable given the developmental plasticity of the brain. Some research suggests that neuropeptides and neuromodulators in both humans and the animals are mutually altered through human animal interaction, resulting in the attenuation of stressful responses in both (Yorke, in press; McCabe & Albano, 2004; Uvnas-Moberg, 2009). Human or animal touch, proximity and mind body interaction has been found to contribute to trauma recovery (Brooks, 2006; Perry, 2006; Van der Kolk, 2003; Yorke, Adams & Coady, 2008). Trauma results in the release of the peptide glucocortisoid, or cortisol leading to an ongoing over-arousal of the anatomic nervous system (ANS). Kindling (sensitivity) of the brain, a result of stress, ironically makes the brain more receptive to attunement and enriched environments (Francis & Meaney, 1999; Kramer, 1993; Putnam, 2005). Attunement with others as well as enriched environments is prophylactic, contributing to resilience and normal brain development (Caldji, Diorio & Meaney, 2000; Carter, 1998; Lewis & Todd, 2007; Nelson, 2000; Shore, 2003). The empirical evidence indicates that companion animals impact humans in helpful ways (Friedmann, Katcher, Thomas, Lynch & Messent, 1983; Shiloh, S., Sorek, G., & Terkel, J., 2003; Virues-Ortega, & Bruela-Casal, 2006; Wilson, 1991; Uvnas-Moberg, 2009). Equine-human interaction in particular has demonstrated contradictory results (Bass, Duchowny & Llabre, 2009; Davis, 2009; Schultz, Remick-Barlow & Robbins, 2007). Equine-human interaction can be viewed as a kind of ‘mind body experience’ that incorporates the characteristics of affiliation and attunement into a child’s environment (Finger & Arnold, 2002). A pilot study, multiple base line, single case design of four traumatized children, eight to ten years old and four therapeutic riding horses explores the neurobiological interaction between the children and horses. It hypothesizes that there will be physiological resonance and symmetry in the responses. Some trends suggest the need for further research.

Chitosan is widely investigated for biomedical applications due to its excellent properties, such as biocompatibility, biodegradability, bioadhesivity, antibacterial, etc. In the field of neural engineering, it has been extensively studied in forms of film and hydrogel, and has been used as scaffolds for nerve regeneration in the peripheral nervous system and spinal cord. One of the main issues in neural engineering is the incapability of neuron to attach on biomaterials. The present study, from a new aspect, aims to take advantage of the bio-adhesive property of chitosan to develop chitosan-based materials for neural engineering, specifically in the fields of brain repair and neuroprosthetics. Neuronal responses to the developed biomaterials will also be investigated and discussed. In the first part of this study (Chapter II), chitosan was blended with a well-studied hydrogel material (agarose) to form a simply prepared hydrogel system. The stiffness of the agarose gel was maintained despite the inclusion of chitosan. The structure of the blended hydrogels was characterized by light microscopy and scanning electron microscopy. In vitro cell studies revealed the capability of chitosan to promote neuron adhesion. The concentration of chitosan in the hydrogel had great influence on neurite extension. An optimum range of chitosan concentration in agarose hydrogel, to enhance neuron attachment and neurite extension, was identified based on the results. A “steric hindrance” effect of chitosan was proposed, which explains the origin of the morphological differences of neurons in the blended gels as well as the influence of the physical environment on neuron adhesion and neurite outgrowth. This chitosan-agarose (C-A) hydrogel system and its multi-functionality allow for applications of simply prepared agarose-based hydrogels for brain tissue repair. In the second part of this study (Chapter III), chitosan was blended with graphene to form a series of graphene-chitosan (G-C) nanocomposites for potential neural interface applications. Both substrate-supported coatings and free standing films could be prepared by air evaporation of precursor solutions. The electrical conductivity of graphene was maintained after the addition of chitosan, which is non-conductive. The surface characteristic of the films was sensitively dependent on film composition, and in turn, influenced neuron adhesion and neurite extension. Biological studies showed good cytocompatibility of graphene for both fibroblast and neuron. Good cell-substrate interactions between neurons and G-C nanocomposites were found on samples with appropriate compositions. The results suggest this unique nanocomposite system may be a promising substrate material used for the fabrication of implantable neural electrodes. Overall, these studies confirmed the bio-adhesive property of chitosan. More importantly, the developed chitosan-based materials also have great potential in the fields of neural tissue engineering and neuroprosthetics.