The cerebral cortex develops through the coordinated generation of dozens of neuronal subtypes, but the mechanisms involved remain unclear. Here we show that mouse embryonic stem cells, cultured without any morphogen but in the presence of a sonic hedgehog inhibitor, recapitulate in vitro the major milestones of cortical development, leading to the sequential generation of a diverse repertoire of neurons that display most salient features of genuine cortical pyramidal neurons. When grafted into the cerebral cortex, these neurons develop patterns of axonal projections corresponding to a wide range of cortical layers, but also to highly specific cortical areas, in particular visual and limbic areas, thereby demonstrating that the identity of a cortical area can be specified without any influence from the brain. The discovery of intrinsic corticogenesis sheds new light on the mechanisms of neuronal specification, and opens new avenues for the modelling and treatment of brain diseases. In a further attempt to prove the validity of this model, we have initiated the study of the mechanism of action of FoxG1, a forkhead box transcription factor involved in the control of cell fate decision in the developing cortex.

Dissertation (Ph.D.)--University of Toledo, 2009. / "Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Title from title page of PDF document. Table of contents (p. iv) gives incorrect starting page numbers for "Bibliography" and "Abstract". "Bibliography" starts on p. 120 (not p. 119); "Abstract" starts on p. 150. Bibliography: p. 64-70, 97-100, 120-149.

Thesis (Ph. D.)--University of California, San Diego, and San Diego State University, 2004. / Vita. Includes bibliographical references (leaves 106-120).

published_or_final_version / Electrical and Electronic Engineering / Doctoral / Doctor of Philosophy

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It is widely accepted that the cortex can be divided into a series of spatially discrete areas based on their specific laminar patterns. It is of great interest to divide the cortex into different areas in terms of both neuronal functions and cellular composition. The division of cortical areas can be reflected by the cell arrangements or cellular composition. Therefore, the cortical structure can be represented by some functional neuronal density data. Techniques on functional data analysis help to develop some measures which indicate structural changes. / In order to separate roughness from structural variations and influences of the convolutions and foldings, a method called bivariate smoothing is proposed for the noisy density data. This smoothing method is applied to four sets of cortical density data provided by Prof Petrides [1] and Scott Mackey [2]. / The first or second order derivatives of the density function reflect the change and the rate of the change of the density, respectively. Therefore, derivatives of the density function are applied to analyze the structural features as an attempt to detect indicators for boundaries of subareas of the four cortex sections. / Finally, the accuracy and limitation of this smoothing method is tested using some simulated examples.

Background: Stroke is a leading cause of death and morbidity in all countries, yet treatment options are few. Numerous agents that were successful in animal models, failed in humans. Establishing the cause of stroke in the individual patient from the heterogeneous stroke mechanisms and measurement of clinical deficit including cognitive impairment in stroke are pivotal in successful treatment. An indigenous stroke data bank was established with specific emphasis on aetiology of stroke and higher cortical function measurement. Aim: 1. Establishment of an indigenous stroke data bank using contemporary neuroinvestigative modalities to determine stroke mechanism as precisely as possible. 2. To determine in this population, the frequency and extent of cognitive disorders in the acute and subacute stroke period, using a battery of predefined higher cortical function tests applied to all patients. 3. Collation of a comprehensive array of epidemiological, clinical, investigative and prognostic variables in complete digitised storage form. Methods: The patient population was a hospital based consecutive case series with an inpatient and outpatient stroke service in association with an acute stroke unit. A three tier investigative protocol was devised to incorporate contemporary neuroinvestigative modalities. All patients had mandatory investigations of stroke relevant blood tests, electrocardiogram, chest radiograph and brain scan. All patients were evaluated with a comprehensive battery of predefined, bedside higher cortical function tests. Standardised neurological deficit, clinical stroke scales, aetiological scales and disability scales were incorporated to quantitate deficit, stroke subtype and handicap at presentation. All patients were evaluated by the author and all information digitised by the author into the computerised registry - Durban Stroke Data Bank (DSDB). Results 1. Stroke Data Bank Issues: The first 1000 patients evaluated comprised of 561 men, 439 women, 781 Whites, 103 Asian Indians, 100 Blacks, 14 of Mixed Race and 2 other race groups. All patients had either a CT brain scan (698;69.8%), MRI brain scan (426;42.6%) or both (124;12.4%). Single Photon Emission Computed Tomography scans were performed in 104 (10.4%). Among the 23 different symptoms coded for, long tract signs, vision abnormalities and speech impairment predominated but 150 (15%) had additional other symptoms not coded for. Among the 29 different risk factors coded for, hypertension (42.1%), smoking (26.7%), cardiac illness (17.7%), Diabetes Mellitus (10.4%) and carotid stenosis (25.1%) were the most numerous. Approximately 96 different causes and possible causes of stroke were identified. The clinical ischaemic stroke classification (OCSP) revealed partial anterior circulation strokes in 447 (44.7%), posterior circulation in 258 (25.8%), total anterior circulation in 185 (18.5%) and lacunar in 82 (8.2%). The aetiological classification identified a large proportion of strokes due to "other" (253;25.3%) causes as opposed to large (264;26.4%) and small vessel disease (262;26.2%) or cardioembolism (122;12.2%). In 99 (9.9%) patients no cause could be established. The haemorrhage group was small (48;4.8%). Comparison of the clinical and aetiological classifications showed a significant difference overall (Chi square p-value=0.001). Black race had relatively higher other causes (39%) and unknown (20%) causes as did the young stroke (8-49 years) population; other (46.5%) and unknown (19.1%). Final aetiological classification differed significantly in young versus old in all categories (p=0.001) except cardioembolism (p=0.884). Admission neurological deficit (CNS) score compared to admission disability score (Rankin) showed moderate correlation with a Kappa value of 0.543. 2. Cognitive issues: One or more higher cortical function abnormalities was detected in 60.7% of non drowsy (drowsy, coma or delirious n=45) patients. The most numerous categories were aphasias (25.2%), apraxias (14.5%), amnesias (11.6%) and frontal systems syndromes (9.2%). In 76 patients, neuropsychological testing, (used as the gold standard) was performed and comparison to the HCFD test revealed a sensitivity of 80.2% (CI: 72-88%) and specificity of 100%. Cognitive impairment occurred without elementary neurological deficits (motor, sensory or visual i mpairment) in 137/608 (22.5%). Univariate and multivariate analyses of risk factors and likelihood of developing a HCFD revealed that increasing age, black race, being overweight and recent infection were independent variables at a p value of 0.05. HCFD did not differ significantly in younger versus older patients (p=0.194). Frontal system syndromes were more common in subcortical (32.3%) versus cortical (23.5%) lesions and more common in younger versus older patients (p=0.001) Conclusions: I. Cognitive disturbance is present in the majority of all types of stroke. This necessitates a reliable appraisal of this form of neurological deficit in all stroke patients in order to measure the true extent of deficit and monitor treatment and rehabilitation. This has important consequences for acute treatment trials that depend on changes in quantifiable deficit. 2. At times cognitive disturbance may be the sole presentation of stroke, unaccompanied by long tract signs. Therefore inadequate HCFD assessment may miss the deficit altogether. 3. Subcortical stroke is commonly associated with cognitive impairment - usually of a frontal system impairment. Such deficits are best correlated with functional brain scanning and not anatomical brain scanning. This is consistent with the network theory of brain functioning. 4. Risk factors for developing cognitive impairment in the indigenous stroke population included increasing age, black race, overweight body habitus and recent infection. This is an important message for the local population as the latter two are amenable to preventative measures. 5. In the young stroke population, although causes of stroke were numerous, prothrombotic states, infection associated strokes and dissection were the most numerous. All are amenable to primary preventative measures and treatable in the acute phase of stroke. 6. The Durban Stroke Data Bank showed that at least two dozen symptoms in stroke are important. In some instances, the diagnosis of stroke may be missed altogether if a wide array of symptoms are not entertained on presentation. 7. There were important black white differences in stroke with black people being younger with an increasing rate of HIV associated stroke being, documented. 8. Clinical and aetiological post investigative classification is useful in the management of stroke patients with significant differences found in all subgroups. This guides early, emergent stroke investigations and management. / Thesis (M.D.)-University of Natal, Durban, 1998.

Damage to the orbitofrontal cortex (OFC) has been associated with disinhibited or socially inappropriate behaviour and emotional irregularities in both humans and monkeys. Prominent characteristics of several personality disorder syndromes, in particular Borderline Personality Disorder (BPD), are impulsivity and affective instability. This investigation aimed to determine if certain aspects of the Borderline Personality syndrome, in particular impulsivity, are associated with OFC dysfunction. Basic questionnaires of personality, emotion, and impulsivity together with tasks sensitive to frontal lobe dysfunction that assess possible factors related to impulsivity, including time perception, sensitivity to reinforcers, and spatial working memory (SWM), were administered to OFC lesion, BPD, non-OFC prefrontal cortex lesion control, and normal control participants. OFC and BPD patients performed similarly, in that they were more impulsive, reported more inappropriate behaviours, BPD traits, anger, and less happiness than both control groups. They were also less open to experience and had a faster perception of time (in terms of time production) than normal controls. They performed differently on other tasks: BPD patients were less extraverted and conscientious and more neurotic and emotional than all other groups. OFC patients had more severe deficits in reversing stimulus-reinforcer associations compared to all other groups and had a faster perception of time (in terms of time estimation) than normal controls. Both OFC and non-OFC lesion patients had mixed lesions that included dorsolateral prefrontal cortex (DLFC) damage. Accordingly, they both had SWM deficits, a task used to control for DLFC damage, compared to normal and BPD participants. Since BPD participants were not impaired on this task and non-OFC patients did not perform poorly on the same tests that OFC patients did, the neuropsychological deficits of BPD and OFC patients could not be attributed to SWM deficits or DLFC dysfunction. The findings suggest that some of the cognitive/behavioural deficits commonly found in BPD patients are related to OFC dysfunction while others are unrelated and are perhaps related to other brain systems. The possibility of amygdala dysfunction is discussed. The similarities and dissociations found between BPD and OFC patients on certain tasks may lead to a better understanding of the aetiology of BPD and the functions of the OFC. Theoretical and therapeutic implications of the findings are discussed.

I studied how glutamate receptor-mediated responses, spatial arrangements, intrinsic properties and molecular specificity of cells serve cortical functions. I tested whether two somatosensory submodalities in the primary somatosensory (SI) cortex can be distinguished by glutamate receptor involvement in vivo. Low-threshold responses evoked by innocuous stimuli had a short-duration and long-duration component. The short-duration responses were mostly mediated by AMPA/kainate receptors and the long-duration responses involved the additional recruitment of NMDA receptors. High-threshold responses evoked by noxious stimuli were unimodal and mediated by both AMPA/kainate and NMDA receptors throughout the entire response. During noxious stimulus trials, an increase in baseline activity in SI cortical cells was observed. I attribute the changes in baseline activity to cells in the medial thalamic nuclei, which project to the SI cortex and are involved in the affective-motivational aspects of nociceptive signalling. To gain insight into the influence of synaptic organisation of a well-defined cortical area, I studied in vitro whether the intrinsic properties of two anatomically well-defined nonpyramidal cells in the hippocampus can provide clues into the modulation of neuronal signalling. During a depolarising current pulse, O-LM and O-Bi cells were distinguished by their accommodation of action potentials depending on the early or late part of the response. Also, during a hyperpolarising current pulse, O-LM cells displayed a prominent voltage 'sag' as compared to O-Bi cells. Both cell types contain somatostatin and I showed that O-LM cells express the metabotropic glutamate receptor type 1α. Although O-LM and O-Bi cells have a similar somatodendritic position their different axonal arbours imply that they are involved in the feedback modulation of the entorhinal and CA3 glutamatergic influences, respectively. I also found that contrary to previous reports not only somatostatin but also vasoactive intestinal polypeptide containing cells express mGluR1α, which might facilitate their oscillatory responses. To relate the action potential discharge of specific cortical cell classes to behaviourally relevant network activity, I also sought to identify hippocampal cells following in vivo recording. Novel information was provided for both the temporal and anatomical properties of cells not recorded previously. In particular, a putative interneuron targeting nonpyramidal cell and backprojection cell was recorded in relation to theta field events. A novel nonpyramidal projection cell was recorded in relation to sharp wave field events. A remarkable specificity was found in the dendritic and axonal patterns of these cells. The results show that distinct types of glutamate receptors are differentially involved in cortical function. The intrinsic properties and expression of mGluR1α in particular is highly specific in distinct nonpyramidal cell classes.