The organic or methylated form of mercury (Hg), consisting of one methyl group bound to each atom of Hg, (methylmercury; MeHg), accounts for most of the Hg to which humans are exposed. MeHg, by virtue of its lipophilicity is highly neurotoxic to both the developing and mature central nervous system (CNS). Historically, MeHg has been implicated in high morbidity and mortality rates over the last 40 years in Japan, Iraq, Pakistan and Guatemala. The most common symptom exhibited in these exposure episodes was cerebellar ataxia. Recent in vitro studies using cultured granule cells showed that MeHg alters intracellular calcium ion ([Ca2+]i) homeostasis, potentiates reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential leading to apoptotic death of cerebellar granule neurons. To better understand the neurotoxic mechanisms of MeHg on cerebellum, changes with respect to biochemical processes in cerebellar granule cells and associated behavior changes were investigated. The aims of this dissertation were: (1) to assess mercury concentrations in mouse brain using different routes of administration and different tissue preparations, (2) to determine the behavior effects of in vivo MeHg exposure in young adult mice. (3) to understand specific biochemical processes leading to granule cell death/dysfunction due to in vivo MeHg toxicity in mice, and (4) to determine the toxic effects of in vivo MeHg exposure on mice aged between 16-20 months. The present results showed that repeated oral exposure to MeHg results in greater accumulation of Hg in brain tissue when compared to single oral or subcutaneous exposures at the same concentration of MeHg. Behavior analysis revealed that MeHg at the concentrations used in this study had profound effects on motor coordination and balance in young adult and aged mice. Investigation of biochemical processes in cerebellar granule cells of mice exposed to MeHg showed an increase in ROS generation, alteration of ([Ca2+]i (in young adult mice) and loss of MMP in young adult and aged mice. However, these changes did not lead to apoptotic cell death of granule cells at the concentrations of MeHg used and at the specific time point it was investigated in young adult mice.

The purpose of the current study is to understand the relationship between the volume of the posterior cerebellar hemispheres and cross-modality divided attention in ASD and control participants. Abnormalities in shifting, orienting, and selective attention are well reported in ASD, but few studies have examined divided attention. Furthermore, there is evidence of volumetric reduction of the posterior cerebellum in ASD. However, few studies have examined the relationship between the posterior cerebellum and behavioral performance. The current study addresses this gap in the literature through structural MRI and a neuropsychological attention task. It is hypothesized that the ASD group will have impaired divided attention abilities compared to the control group. Furthermore, within the ASD group, reduced posterior cerebellar volume is expected to be associated with impaired divided attention. The study will use multiple regression analyses. As ASD is a neurodevelopmental disability with considerable heterogeneity and unknown etiology, the current study seeks to contribute to the understanding of neural and behavioral markers of ASD. / text

The purpose of the current study is to contribute to the understanding of prenatal cerebellar pathology in autism. Reduction of Purkinje neurons is well reported in the cerebella of individual’s with autism. While there is evidence to suggest that this abnormality may be evident as early as prenatal development, no study to date has examined in the anataomical prenatal development of the cerebella in children later diagnosed with autism. The primary prediction being made is that a reduction of Purkinje neurons during prenatal development will present as reduced cerebellar size in the reports from mother’s prenatal ultrasound records. It is hypothesized that this reduction will be greater in children with an autism diagnosis compared to the records of children without an autism diagnosis. The secondary prediction will attempt to further support the link between aberrant cerebellar development and increased stereotyped behavior and repetitive interests. A retrospective analysis of prenatal ultrasound records and autism diagnostic information will test these hypotheses, predicting that records from children who have been diagnosed with an autism spectrum disorder will show reductions in transverse cerebellar diameter measurements when compared to TD peers, and that greater reductions will correlate with increased stereotypical and repetitive behaviors as measured by a standard diagnostic tool. / text

Executive functioning abilities, including abstract reasoning, are often reported as weaknesses in autism spectrum disorders (ASDs). The current study examines reasoning through a different approach by utilizing the Cattell-Horn-Carroll (CHC) theory of intelligence, which is a widely accepted, research-based model that defines reasoning or fluid intelligence (Gf) and outlines those smaller skills of which it is composed. The Woodcock-Johnson, Third Edition (WJ III) is a test battery based on CHC theory, assessing the broad and narrow abilities of the model. Young men with high-functioning autism spectrum disorders (HFASDs) and neurotypical controls were given the WJ III tasks that assess the four narrow abilities of fluid intelligence - general sequential reasoning/deductive reasoning (RG), induction/inductive reasoning (I), speed of reasoning (RE), and quantitative reasoning/math reasoning (RQ). It was hypothesized that while deductive reasoning, inductive reasoning, and reasoning speed would be lower for HFASD, math reasoning would be comparable between groups. This expectation was based on previous autism research, which has found reasoning and processing speed deficits but preserved math skills. The present study also sought to examine cerebellar volume, through structural brain imaging, and its relationship to reasoning abilities. The HFASD group was expected to have reduced cerebellar volume when compared to controls. The ASD literature contains many examples of this pattern of brain structure, with the cerebellum being the most commonly cited region of abnormality. Additionally, the cerebellum has been implicated in studies of executive functioning, and a relationship between size and performance on nonverbal reasoning tasks has been reported. Therefore, a positive correlation was hypothesized between cerebellar volume and scores on WJ III reasoning tasks. Twenty-one young adult male HFASD subjects and 21 neurotypical controls were included in the current study. The data was analyzed through the use of MANOVA/MANCOVA, t-tests, and Pearson correlations. Results supported fluid intelligence weaknesses in the HFASD sample, with significantly lower performance in speed of reasoning. Deductive and inductive reasoning abilities were also lower, though these findings did not reach significance. The data did not support decreased cerebellar volume in HFASD, nor was a relationship between fluid reasoning and volume of the cerebellum found. / text

The motor functions of an animal require precisely timed and coordinated sequences of movements. The cerebellum is crucial for performing these functions with precision. To investigate cerebellar computations involved in precise motor movements, behavioral paradigms such as delay eyelid conditioning have been used. Delay eyelid conditioning trains an animal to close its eye in response to a previously neutral stimulus. The timing of the eyelid closure responses suggests that the cerebellum is capable of keeping track of the elapsed time since the onset of the stimulus. This dissertation proposes a network mechanism for cerebellar timing based on biologically informed simulations of the cerebellum. In chapter 2, a simulation with over a million cells is described. This simulation approaches the observed cerebellar connectivity in several well studied mammals. Graphics processing units (GPUs) provide the computational power necessary to perform this simulation at a practical speed. This chapter describes simulation algorithms that efficiently utilize GPUs. In chapter 3, the simulation is used to explore cerebellar timing mechanisms. The lateral inhibition among cerebellar Golgi cells is observed to be a potential mechanism for robust timing. Lateral Golgi inhibition enables the simulation to better replicate animal eyelid conditioning behavior for longer inter-stimulus intervals. In chapter 4, the emergent network mechanisms of lateral Golgi inhibition are analyzed by decomposing the network into its individual components. This component analysis demonstrates that nonreciprocal connectivity (where one Golgi cell inhibits another but does not receive inhibition in return) is useful for timing. Specifically, removing nonreciprocal connectivity greatly degrades the simulation's ability to keep track of time. This implies that the aforementioned component analyses are relevant to the emergent timing mechanisms of the network. Finally, in chapter 5, this dissertation discusses the relevance and limitations of the computational approach, biological predictions, and component analysis presented in previous chapters. / text

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2001. / Härtill 6 uppsatser.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1981. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 80-95).

1. A technique for the introduction of substances into the cerebellum of the decerebrate rabbit was developed and the effects of drugs and brain extracts on the electrical activity of the cerebellum were studied using this method. 2. Extracts of cerebellar tissue were found to increase the electrical activity of the cerebellum and this action could not be attributed to Ach, histamine or to any other identified pharmacologically-active constituent of the nervous system, nor could it be attributed to a vascular action. The activity was not detected in similar concentrations in extracts of cerebral hemispheres or upper brain-stem. 3. The physical and chemical properties of the cerebellar excitatory substance were studied and attempts to purify it from crude brain extracts were made. 4. The enzymic destruction of the active factor was demonstrated and this destruction was shown to be inhibited by small amounts of strychnine. The active substance was found to be released from the cerebellum under various conditions of stimulation. 5. The active substance had no apparent effect on any of the common pharmecological preparations, not did it affect transmission at the neuromuscular junction and superior cervical ganglion. 6. The cerebellar factor was found to affect spinal reflexes and the electrical activity of the cerebral cortex. 7. Nervous tissue from six animal species was found to contain the active substance, but it was not detected in similar concentrations in tissues outside the nervous system. Its distribution in various regions of the nervous system of the dog was shown to bear an approximately inverse relationship to the distribution of choline acetylase activity and acetylcholine. 8. It has been suggested that the cerebellar factor has some claims to be considered as a non-colinergic transmitter of nerve impulses and experiments which might eventually confirm this hypothesis have been considered.

The P300 event related potential (ERP) has consistently been dissociated into separate components on the basis of scalp amplitude distribution within the auditory modality (for instance Squires et al. 1975). A parietally maximum P300 deflection being evoked in response to target stimuli in comparison with a more frontally maximum P300 deflection evoked in response to rare nontarget stimuli. Results obtained within experiment 1 and 6 demonstrated such a dissociation employing auditory stimuli within a three stimulus oddball paradigm. It did not prove possible to obtain such a dissociation of P300 deflections on the basis of scalp amplitude distribution within the visual modality. Across a number of experimental manipulations both target and rare nontarget stimuli evoked P300 deflections with similar amplitude distributions (centro-parietal maximum along the midline). Experiment 5 demonstrated that frequent stimuli similarly evoked a centro-parietal maximum amplitude distribution. It was demonstrated that both stimulus probability (Experiment 4) and the physical characteristics of the stimuli (Experiment 5) affected the mean amplitude of the evoked P300 deflection. However, the scalp amplitude distribution of the evoked deflections remained constant. Within Experiment 6 it was demonstrated that within both auditory and visual modalities P300 deflections, evoked in response to both target and rare nontarget stimuli, demonstrated an equipotential amplitude distribution within an elderly group of subjects. In addition across both modalities amplitude evoked in response to rare nontarget stimuli demonstrated an asymmetric distribution across lateral chains of electrodes. Amplitude evoked along the right chain was significantly reduced in comparison to that evoked along the left chain. It would appear that the same, or a similar combination of, underlying neural generators are responsible for the activity that may be recorded at the scalp as the P300 deflection within the visual modality.

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