Distributed Hypothesis Testing, Attention Shifts and Transmitter Dynatmics During the Self-Organization of Brain Recognition Codes

BP (89-A-1204); Defense Advanced Research Projects Agency (90-0083); National Science Foundation (IRI-90-00530); Air Force Office of Scientific Research (90-0175, 90-0128); Army Research Office (DAAL-03-88-K0088)

A Recurrent Cooperative/Competitive Field for Segmentation of Magnetic Resonance Brain Imagery

The Grey-White Decision Network is introduced as an application of an on-center, off-surround recurrent cooperative/competitive network for segmentation of magnetic resonance imaging (MRI) brain images. The three layer dynamical system relaxes into a solution where each pixel is labeled as either grey matter, white matter, or "other" matter by considering raw input intensity, edge information, and neighbor interactions. This network is presented as an example of applying a recurrent cooperative/competitive field (RCCF) to a problem with multiple conflicting constraints. Simulations of the network and its phase plane analysis are presented.

Living long-term with acquired brain injury in Ireland: towards a counter discourse

Irish literature on Acquired Brain Injury (ABI) is very scant and is mainly deficits and/or needs based. The focus is generally on how to manage the short term needs of the younger population with ABI. The starting position of my thesis is that people living long-term with ABI are important participants in developing knowledge about this social phenomenon, living with ABI while accepting that their brain injury does not determine them. Six mature adults with ABI and their six significant others participated in this longitudinal study. Using a narrative approach in interviews, over twenty months, five repeat individual interviews with each of the twelve participants was held. From this I gained an understanding of their lived experiences, their life-world and their experiences of our local public ABI/disability services, systems and discourse. Along with this new empirical data, theoretical developments from occupational therapy, occupational science, sociology, and disability studies were also used within a meta-narrative informed by critical theory and critical realism to develop a synthesis of this study. Social analysis of their narratives co-constructed with me, allowed me generate nuanced insights into tendencies and social processes that impacted and continues to impact on their everyday-everynight living. I discuss in some depth here, the relational attitudinal, structural, occupational and environmental supports, barriers or discrimination that they face(d) in their search for social participation and community inclusion. Personal recognition of the disabled participants by their family, friends and/or local community, was generally enhanced after much suffering, social supports, slow recovery, and with some form of meaningful occupational engagement. This engagement was generally linked with pre-injury interests or habits, while Time itself became both a major aid and a need. The present local ABI discourse seldom includes advocacy and inclusion in everyday/every night local events, yet most participants sought both peer-support or collective recognition, and social/community inclusion to help develop their own counter-discourse to the dominant ABI discourse. This thesis aims to give a broad social explanation on aspects of their social becoming, 'self-sameness' and social participation, and the status of the disabled participants wanting to live 'the slow life'. Tensions and dialectical issues involved in moving from the category of a person in coma, to person with a disability, to being a citizen should not demote the need for special services. While individualized short-term neuro-rehabilitation is necessary, it is not sufficient. Along with the participants, this researcher asks that community health and/or social care planners and service-providers rethink how ABI is understood and represented, and how people with ABI are included in their local communities

P-glycoprotein inhibition as a strategy to increase drug delivery across the blood-brain barrier: focus on antidepressants

Depression is among the leading causes of disability worldwide. Currently available antidepressant drugs have unsatisfactory efficacy, with up to 60% of depressed patients failing to respond adequately to treatment. Emerging evidence has highlighted a potential role for the efflux transporter P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), in the aetiology of treatment-resistant depression. In this thesis, the potential of P-gp inhibition as a strategy to enhance the brain distribution and pharmacodynamic effects of antidepressant drugs was investigated. Pharmacokinetic studies demonstrated that administration of the P-gp inhibitors verapamil or cyclosporin A (CsA) enhanced the BBB transport of the antidepressants imipramine and escitalopram in vivo. Furthermore, both imipramine and escitalopram were identified as transported substrates of human P-gp in vitro. Contrastingly, human P-gp exerted no effect on the transport of four other antidepressants (amitriptyline, duloxetine, fluoxetine and mirtazapine) in vitro. Pharmacodynamic studies revealed that pre-treatment with verapamil augmented the behavioural effects of escitalopram in the tail suspension test (TST) of antidepressant-like activity in mice. Moreover, pre-treatment with CsA exacerbated the behavioural manifestation of an escitalopram-induced mouse model of serotonin syndrome, a serious adverse reaction associated with serotonergic drugs. This finding highlights the potential for unwanted side-effects which may occur due to increasing brain levels of antidepressants by P-gp inhibition, although further studies are needed to fully elucidate the mechanism(s) at play. Taken together, the research outlined in this thesis indicates that P-gp may restrict brain concentrations of escitalopram and imipramine in patients. Moreover, we show that increasing the brain distribution of an antidepressant by P-gp inhibition can result in an augmentation of antidepressant-like activity in vivo. These findings raise the possibility that P-gp inhibition may represent a potentially beneficial strategy to augment antidepressant treatment in clinical practice. Further studies are now warranted to evaluate the safety and efficacy of this approach.

Towards a cognitive neurobiology of brain-gut axis disorders

The past two decades have seen substantial gains in our understanding of the complex processes underlying disturbed brain-gut communication in disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Despite a growing understanding of the neurobiology of brain-gut axis dysfunction, there is a relative paucity of investigations into how the various factors involved in dysregulating the brain-gut axis, including stress, immune activation and pain, could impact on fundamental brain processes such as cognitive performance. To this end, we proposed a cognitive neurobiology of brain-gut axis dysfunction and took a novel approach to examine how disturbed brain-gut interactions may manifest as altered cognitive performance in IBS and IBD, both cross-sectionally and prospectively. We have demonstrated that, disorders of the brain-gut axis are characterised by stable deficits in specific cognitive domains. Specifically, patients with IBS exhibit a consistent hippocampal mediated visuospatial memory impairment. In addition we have found evidence to suggest a similar visuospatial impairment in IBD. However, our most consistent finding within this population was that patients with Crohn’s disease exhibit impaired selective attention/ response inhibition on the classic Stroop interference test. These cognitive deficits may serve to perpetuate and sustain brain-gut axis dysfunction. Furthermore, this research has shed light on some of the underlying neurobiological mechanisms that may be mediating cognitive dysfunction in IBS. Our findings may have significant implications for the individual who suffers from a brain-gut axis disorder and may also inform future treatment strategies. Taken together, these findings can be incorporated into existing neurobiological models of brain-gut axis dysfunction, to develop a more comprehensive model accounting for the cognitive-neurobiology of brain-gut axis disorders. This has furthered our understanding of disease pathophysiology and may ultimately aid in both the diagnosis and treatment of these highly prevalent, but poorly understood disorders.

Living with acquired brain injury

This study found that natural community supports were comprised of two distinct groupings; firstly immediate families, friends and peer support groups; secondly neighbours and local community groups such as sporting and activity- based organisations and groups. The findings of this study indicate that living with acquired brain injury involves a process where the person moves from acute high intensity health services onto rehabilitative services and then onto re-establishing independent lives. It is evident that smooth transitions and interconnectivity of services are essential in facilitating this recovery process. Instrumental to the recovery is the support of immediate family and close friends, who form people’s immediate natural support network and go a long way towards facilitating individuals in rebuilding their lives. A key finding of this study is that broader natural community supports do not appear to play as central a role in supporting individuals to live independent lives when compared to the role of family and friends. The lack of involvement of broader community groups, in many ways, prompted individuals to contact formal support services. For the majority of participants, independence is facilitated through the combination of immediate natural community supports and formal services. The role of formal support services is key to developing broader community support networks. This study found a blurred division between formal services and broader community support networks. The authors recommended that the role of formal supports services in acting as a bridge between the needs of the individual and the development of meaningful community networks, be formally recognised and further developed. Additionally, they argued that the importance of the role of broader natural community, supports such as those provided by community and sporting groups must be enhanced. Greater awareness of the issues faced by people living with acquired brain injury and its often invisible nature is necessary in this endeavour. The authors stated it is important to recognise that there are multiple issues impacting on independent living and these issues intersect, for instance with age, gender, employment, qualifications and so on. A lack of public awareness of acquired brain injury was found to be a key barrier to independent living, along with issues relating to socialising, access to employment and finances. The findings of this study reflect the complexities of living with acquired brain injury and the need for holistic support that is cognisant of the factors which impact on integration. It is vital that flexible, personalised services are developed which are fit for purpose and meet the needs of not only people with acquired brain injury but also their immediate natural community support network. Recognition of the intersection between immediate/ broader natural community supports and formal services is also key to developing the comprehensive and practical supports required to achieve an independent life. This was a qualitative study and all participants were sourced through Headway, a community based service provider for people with ABI. Data collection was divided into two stages: firstly focus groups, followed by individual interviews. Four focus groups were convened in Cork (2), Dublin (1) and Limerick (1). Each focus group was facilitated by at least two members of the research team and a total of twenty-six individuals participated in the focus groups. Thematic analysis of the data was undertaken to guide and inform the second stage of the study; the individual interviews. Ten interviews were undertaken with individuals who presented with ABI in the Cork and Limerick regions.

Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens

Two clearly opposing views exist on the function of alpha-fetoprotein (AFP), a fetal plasma protein that binds estrogens with high affinity, in the sexual differentiation of the rodent brain. AFP has been proposed to either prevent the entry of estrogens or to actively transport estrogens into the developing female brain. The availability of Afp mutant mice (Afp-/-) now finally allows us to resolve this longstanding controversy concerning the role of AFP in brain sexual differentiation, and thus to determine whether prenatal estrogens contribute to the development of the female brain. Here we show that the brain and behavior of female Afp-/- mice were masculinized and defeminized. However, when estrogen production was blocked by embryonic treatment with the aromatase inhibitor 1,4,6-androstatriene-3,17- dione, the feminine phenotype of these mice was rescued. These results clearly demonstrate that prenatal estrogens masculinize and defeminize the brain and that AFP protects the female brain from these effects of estrogens. © 2006 Nature Publishing Group.

Traumatic brain injury exacerbates neurodegenerative pathology: improvement with an apolipoprotein E-based therapeutic.

Cognitive impairment is common following traumatic brain injury (TBI), and neuroinflammatory mechanisms may predispose to the development of neurodegenerative disease. Apolipoprotein E (apoE) polymorphisms modify neuroinflammatory responses, and influence both outcome from acute brain injury and the risk of developing neurodegenerative disease. We demonstrate that TBI accelerates neurodegenerative pathology in double-transgenic animals expressing the common human apoE alleles and mutated amyloid precursor protein, and that pathology is exacerbated in the presence of the apoE4 allele. The administration of an apoE-mimetic peptide markedly reduced the development of neurodegenerative pathology in mice homozygous for apoE3 as well as apoE3/E4 heterozygotes. These results demonstrate that TBI accelerates the cardinal neuropathological features of neurodegenerative disease, and establishes the potential for apoE mimetic therapies in reducing pathology associated with neurodegeneration.

High-field FMRI reveals brain activation patterns underlying saccade execution in the human superior colliculus.

BACKGROUND: The superior colliculus (SC) has been shown to play a crucial role in the initiation and coordination of eye- and head-movements. The knowledge about the function of this structure is mainly based on single-unit recordings in animals with relatively few neuroimaging studies investigating eye-movement related brain activity in humans. METHODOLOGY/PRINCIPAL FINDINGS: The present study employed high-field (7 Tesla) functional magnetic resonance imaging (fMRI) to investigate SC responses during endogenously cued saccades in humans. In response to centrally presented instructional cues, subjects either performed saccades away from (centrifugal) or towards (centripetal) the center of straight gaze or maintained fixation at the center position. Compared to central fixation, the execution of saccades elicited hemodynamic activity within a network of cortical and subcortical areas that included the SC, lateral geniculate nucleus (LGN), occipital cortex, striatum, and the pulvinar. CONCLUSIONS/SIGNIFICANCE: Activity in the SC was enhanced contralateral to the direction of the saccade (i.e., greater activity in the right as compared to left SC during leftward saccades and vice versa) during both centrifugal and centripetal saccades, thereby demonstrating that the contralateral predominance for saccade execution that has been shown to exist in animals is also present in the human SC. In addition, centrifugal saccades elicited greater activity in the SC than did centripetal saccades, while also being accompanied by an enhanced deactivation within the prefrontal default-mode network. This pattern of brain activity might reflect the reduced processing effort required to move the eyes toward as compared to away from the center of straight gaze, a position that might serve as a spatial baseline in which the retinotopic and craniotopic reference frames are aligned.

Variability in frontotemporal brain structure: the importance of recruitment of African Americans in neuroscience research.

BACKGROUND: Variation in brain structure is both genetically and environmentally influenced. The question about potential differences in brain anatomy across populations of differing race and ethnicity remains a controversial issue. There are few studies specifically examining racial or ethnic differences and also few studies that test for race-related differences in context of other neuropsychiatric research, possibly due to the underrepresentation of ethnic minorities in clinical research. It is within this context that we conducted a secondary data analysis examining volumetric MRI data from healthy participants and compared the volumes of the amygdala, hippocampus, lateral ventricles, caudate nucleus, orbitofrontal cortex (OFC) and total cerebral volume between Caucasian and African-American participants. We discuss the importance of this finding in context of neuroimaging methodology, but also the need for improved recruitment of African Americans in clinical research and its broader implications for a better understanding of the neural basis of neuropsychiatric disorders. METHODOLOGY/PRINCIPAL FINDINGS: This was a case control study in the setting of an academic medical center outpatient service. Participants consisted of 44 Caucasians and 33 ethnic minorities. The following volumetric data were obtained: amygdala, hippocampus, lateral ventricles, caudate nucleus, orbitofrontal cortex (OFC) and total cerebrum. Each participant completed a 1.5 T magnetic resonance imaging (MRI). Our primary finding in analyses of brain subregions was that when compared to Caucasians, African Americans exhibited larger left OFC volumes (F (1,68) = 7.50, p = 0.008). CONCLUSIONS: The biological implications of our findings are unclear as we do not know what factors may be contributing to these observed differences. However, this study raises several questions that have important implications for the future of neuropsychiatric research.

The impact of anxiety-inducing distraction on cognitive performance: a combined brain imaging and personality investigation.

BACKGROUND: Previous investigations revealed that the impact of task-irrelevant emotional distraction on ongoing goal-oriented cognitive processing is linked to opposite patterns of activation in emotional and perceptual vs. cognitive control/executive brain regions. However, little is known about the role of individual variations in these responses. The present study investigated the effect of trait anxiety on the neural responses mediating the impact of transient anxiety-inducing task-irrelevant distraction on cognitive performance, and on the neural correlates of coping with such distraction. We investigated whether activity in the brain regions sensitive to emotional distraction would show dissociable patterns of co-variation with measures indexing individual variations in trait anxiety and cognitive performance. METHODOLOGY/PRINCIPAL FINDINGS: Event-related fMRI data, recorded while healthy female participants performed a delayed-response working memory (WM) task with distraction, were investigated in conjunction with behavioural measures that assessed individual variations in both trait anxiety and WM performance. Consistent with increased sensitivity to emotional cues in high anxiety, specific perceptual areas (fusiform gyrus--FG) exhibited increased activity that was positively correlated with trait anxiety and negatively correlated with WM performance, whereas specific executive regions (right lateral prefrontal cortex--PFC) exhibited decreased activity that was negatively correlated with trait anxiety. The study also identified a role of the medial and left lateral PFC in coping with distraction, as opposed to reflecting a detrimental impact of emotional distraction. CONCLUSIONS: These findings provide initial evidence concerning the neural mechanisms sensitive to individual variations in trait anxiety and WM performance, which dissociate the detrimental impact of emotion distraction and the engagement of mechanisms to cope with distracting emotions. Our study sheds light on the neural correlates of emotion-cognition interactions in normal behaviour, which has implications for understanding factors that may influence susceptibility to affective disorders, in general, and to anxiety disorders, in particular.

Interior pathways of the North Atlantic meridional overturning circulation.

To understand how our global climate will change in response to natural and anthropogenic forcing, it is essential to determine how quickly and by what pathways climate change signals are transported throughout the global ocean, a vast reservoir for heat and carbon dioxide. Labrador Sea Water (LSW), formed by open ocean convection in the subpolar North Atlantic, is a particularly sensitive indicator of climate change on interannual to decadal timescales. Hydrographic observations made anywhere along the western boundary of the North Atlantic reveal a core of LSW at intermediate depths advected southward within the Deep Western Boundary Current (DWBC). These observations have led to the widely held view that the DWBC is the dominant pathway for the export of LSW from its formation site in the northern North Atlantic towards the Equator. Here we show that most of the recently ventilated LSW entering the subtropics follows interior, not DWBC, pathways. The interior pathways are revealed by trajectories of subsurface RAFOS floats released during the period 2003-2005 that recorded once-daily temperature, pressure and acoustically determined position for two years, and by model-simulated 'e-floats' released in the subpolar DWBC. The evidence points to a few specific locations around the Grand Banks where LSW is most often injected into the interior. These results have implications for deep ocean ventilation and suggest that the interior subtropical gyre should not be ignored when considering the Atlantic meridional overturning circulation.

The G-protein-coupled receptor kinases beta ARK1 and beta ARK2 are widely distributed at synapses in rat brain.

The beta-adrenergic receptor kinase (beta ARK) phosphorylates the agonist-occupied beta-adrenergic receptor to promote rapid receptor uncoupling from Gs, thereby attenuating adenylyl cyclase activity. Beta ARK-mediated receptor desensitization may reflect a general molecular mechanism operative on many G-protein-coupled receptor systems and, particularly, synaptic neurotransmitter receptors. Two distinct cDNAs encoding beta ARK isozymes were isolated from rat brain and sequenced. The regional and cellular distributions of these two gene products, termed beta ARK1 and beta ARK2, were determined in brain by in situ hybridization and by immunohistochemistry at the light and electron microscopic levels. The beta ARK isozymes were found to be expressed primarily in neurons distributed throughout the CNS. Ultrastructurally, beta ARK1 and beta ARK2 immunoreactivities were present both in association with postsynaptic densities and, presynaptically, with axon terminals. The beta ARK isozymes have a regional and subcellular distribution consistent with a general role in the desensitization of synaptic receptors.

Functional parcellation of attentional control regions of the brain.

Recently, a number of investigators have examined the neural loci of psychological processes enabling the control of visual spatial attention using cued-attention paradigms in combination with event-related functional magnetic resonance imaging. Findings from these studies have provided strong evidence for the involvement of a fronto-parietal network in attentional control. In the present study, we build upon this previous work to further investigate these attentional control systems. In particular, we employed additional controls for nonattentional sensory and interpretative aspects of cue processing to determine whether distinct regions in the fronto-parietal network are involved in different aspects of cue processing, such as cue-symbol interpretation and attentional orienting. In addition, we used shorter cue-target intervals that were closer to those used in the behavioral and event-related potential cueing literatures. Twenty participants performed a cued spatial attention task while brain activity was recorded with functional magnetic resonance imaging. We found functional specialization for different aspects of cue processing in the lateral and medial subregions of the frontal and parietal cortex. In particular, the medial subregions were more specific to the orienting of visual spatial attention, while the lateral subregions were associated with more general aspects of cue processing, such as cue-symbol interpretation. Additional cue-related effects included differential activations in midline frontal regions and pretarget enhancements in the thalamus and early visual cortical areas.

Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues.

Brain tumors are typically resistant to conventional chemotherapeutics, most of which initiate apoptosis upstream of mitochondrial cytochrome c release. In this study, we demonstrate that directly activating apoptosis downstream of the mitochondria, with cytosolic cytochrome c, kills brain tumor cells but not normal brain tissue. Specifically, cytosolic cytochrome c is sufficient to induce apoptosis in glioblastoma and medulloblastoma cell lines. In contrast, primary neurons from the cerebellum and cortex are remarkably resistant to cytosolic cytochrome c. Importantly, tumor tissue from mouse models of both high-grade astrocytoma and medulloblastoma display hypersensitivity to cytochrome c when compared with surrounding brain tissue. This differential sensitivity to cytochrome c is attributed to high Apaf-1 levels in the tumor tissue compared with low Apaf-1 levels in the adjacent brain tissue. These differences in Apaf-1 abundance correlate with differences in the levels of E2F1, a previously identified activator of Apaf-1 transcription. ChIP assays reveal that E2F1 binds the Apaf-1 promoter specifically in tumor tissue, suggesting that E2F1 contributes to the expression of Apaf-1 in brain tumors. Together, these results demonstrate an unexpected sensitivity of brain tumors to postmitochondrial induction of apoptosis. Moreover, they raise the possibility that this phenomenon could be exploited therapeutically to selectively kill brain cancer cells while sparing the surrounding brain parenchyma.