The Role of Aerobic Glycolysis in the Resting Human Brain

The human brain accounts for 2% of total body weight, though it consumes 20% of the body\u27s energy supply. Most of this energy is provided by the complete oxidation of glucose to carbon dioxide and water, though some fraction of glucose undergoes aerobic glycolysis without concomitant oxidative phosphorylation. Elevation in neuronal activity increases aerobic glycolysis due to the disproportionate increase in blood flow and glucose utilization greater than oxygen consumption. Since aerobic glycolysis produces significantly less energy than complete oxidation of glucose, its role in cellular activities has been overlooked, though its presence in the resting brain has been known for several decades. In this thesis, we investigate three aspects of resting aerobic glycolysis using positron emission tomography. First, we characterize the regional distribution of aerobic glycolysis in the awake, eyes closed human brain. We show that brain regions with high levels of functional activity in the resting state, including the default network and prefrontal cortex, have elevated aerobic glycolysis. In addition, we show that aerobic glycolysis is modulated by prior task performance. Performance of a complex visuomotor rotation learning task increases aerobic glycolysis in premotor cortex for several hours following task completion. Further, we show that regional brain metabolism is correlated to neurotransmitter receptor density. Aerobic glycolysis is highest in regions with a balanced density of excitatory and inhibitory receptors. Taken together, these results demonstrate the functional significance of resting aerobic glycolysis and its modulation by transient functional activity. These data provide supporting evidence for the synaptic homeostasis hypothesis, indicating elevation in brain metabolism, specifically aerobic glycolysis, during wakefulness associated with alterations in synaptic strength and receptor density

Development of Low-Frequency Repetitive Transcranial Magnetic Stimulation as a Tool to Modulate Visual Disorders: Insights from Neuroimaging

Repetitive transcranial magnetic stimulation (rTMS) has become a popular neuromodulation technique, increasingly employed to manage several neurological and psychological conditions. Despite its popular use, the underlying mechanisms of rTMS remain largely unknown, particularly at the visual cortex. Moreover, the application of rTMS to modulate visual-related disorders is under-investigated. The goal of the present research was to address these issues. I employ a multitude of neuroimaging techniques to gain further insight into neural mechanisms underlying low-frequency (1 Hz) rTMS to the visual cortex. In addition, I begin to develop and refine clinical low-frequency rTMS protocols applicable to visual disorders as an alternative therapy where other treatment options are unsuccessful or where there are simply no existing therapies. One such visual disorder that can benefit from rTMS treatment is the perception of visual hallucinations that can occur following visual pathway damage in otherwise cognitively healthy individuals. In Chapters 23, I investigate the potential of multiday low-frequency rTMS to the visual cortex to alleviate continuous and disruptive visual hallucinations consequent to occipital injury. Combining rTMS with magnetic resonance imaging techniques reveals functional and structural cortical changes that lead to the perception of visual hallucinations; and rTMS successfully attenuates these anomalous visual perceptions. In Chapters 45, I compare the effects of alternative doses of low-frequency rTMS to the visual cortex on neurotransmitter levels and intrinsic functional connectivity to gain insight into rTMS mechanisms and establish the most effective protocol. Differential dose-dependent effects are observed on neurotransmitter levels and functional connectivity that suggest the choice of protocol critically depends on the neurophysiological target. Collectively, this work provides a basic framework for the use of low-frequency rTMS and neuroimaging in clinical application for visual disorders

Muscarinic attenuation of mnemonic rule representation in macaque dorsolateral prefrontal cortex during a pro- and anti-saccade task

Maintenance of context is necessary for execution of appropriate responses to diverse environmental stimuli. The dorsolateral prefrontal cortex (DLPFC) plays a pivotal role in executive function, including working memory and representation of abstract rules, and is modulated by the ascending cholinergic system through nicotinic and muscarinic receptors. Muscarinic receptors’ effect on local primate DLPFC neural activity in vivo during cognitive tasks remains poorly understood. Here we examined the effects of muscarinic receptor blockade on rule-related activity in the macaque prefrontal cortex by combining iontophoretic application of the general muscarinic receptor antagonist scopolamine with single-unit recordings while monkeys performed a rule-guided saccade task. We found that scopolamine reduced overall neuronal firing rate and impaired rule discriminability of task-selective cells. Saccade and visual direction selectivity measures were also reduced by muscarinic antagonism. These results demonstrate that blockade of muscarinic receptors in dorsolateral prefrontal cortex creates deficits in working memory representation of rules in primates

Idiopathic epilepsy in the dog: Reasons for referral and assessment from the owner's perspective

Seizures are the most common neurological disorder in small animal medicine, of which 40 to 50% of affected dogs are diagnosed as having idiopathic epilepsy. Dogs with epilepsy represent a large proportion of the caseload for the neurology service of the Small Animal Hospital of University of the Glasgow Veterinary School (SAH-UGVS). The aims of this study were to clarify the reasons for owners requesting a second opinion for dogs with idiopathic epilepsy. This was undertaken by reviewing seizure management regimens instigated at primary veterinary clinics and examining the owners' perspective of the reasons for referral and the seizure management regimen used in SAH-UGVS. Information from the owners' perspective was also thought of value to clinicians in assessing seizure management regimens and could potentially raise issues of relevance to dogs with epilepsy and their owners, which may be the basis for developing an alternative assessment of long-term seizure treatment in veterinary medicine. A total of 48 dogs referred to SAH-UGVS between March 1999 and April 2001 for evaluation of seizures and diagnosed or tentatively diagnosed with idiopathic epilepsy were included in this study. Breed, gender, age at the onset of seizure activity, seizure type, reasons for referral and previous antiepileptic drug (AED) therapy were reviewed for these cases. For 32 cases, the owners' perspective on reasons for referral to and the seizure management regimen used in SAH-UGVS, as well as the exploration of other issues relevant to dogs and their owners, were sought by mailed questionnaires. Behavioural changes were reported by 11 respondents to the first questionnaire, and the second mailed survey was undertaken to clarify the nature and potential causes of behavioural changes in these patients. The study demonstrated that "dogs' quality of life", "adequate seizure frequency" and "acceptable AED side effects" were the three main concepts considered important by owners in assessing the outcomes of seizure management. Furthermore, owning an epileptic dog did not have a major impact on owners' work/day-to-day activities and free time. The majority of owners did not consider the administration of the medication a nuisance and coped well with administering medication more than once daily. For more than half of owners, regular veterinary examination and blood sampling for serum AED concentrations monitoring did not cause a significant problem. Further diagnostic procedures did help most owners understand their dogs' condition and provided owners with more confidence in AED therapy adjustment and accepting the balance between AED efficacy and side effects. The majority of owners agreed the cost of further diagnostic procedures was worthwhile. The study suggests that in both undergraduate and post-graduate education, the value of measuring AED serum concentrations, as well as the use of bromide in canine epilepsy, should be emphasised. The study also demonstrated that dogs on potassium bromide alone exhibited fewer side effects than dogs on phenobarbitone. A relatively large proportion of cases studied exhibited behavioural changes, which mainly appeared to be AED-related. Clinicians should be aware of the potential for behavioural change in idiopathic epileptic patients on AED therapy. Once patients exhibit AED-related behavioural changes, a dose reduction or discontinuation of the particular AED may be necessary

Magnetic Resonance Spectroscopy as applied to epilepsy

Epilepsy is the most common serious disease of the brain. Magnetic Resonance Spectroscopy (MRS) is a novel imaging technique that offers the opportunity for co-localising biochemical information relating to metabolites specific to the study of epilepsy with high resolution MRI. Aims: The work included in this thesis was undertaken with two fundamental aims. The first was to apply a standardised MRS methodology in order to gain reproducible semi-quantitative information about the variation of relevant neuro-metabolites such as gamma amino butyric acid (GABA), glutamate (as glutamate plus glutamine [GLX]), N acetyl aspartate (NAA), myo-inositol (Ins) and creatine plus phosphocreatine (Cr) within epilepsy syndromes or pathological groups. The second main aim was to test a series of hypotheses relating to the regulation of the concentrations of these metabolites in the region of epileptic seizures, immediately following seizures and associated with particular medical and surgical treatment interventions. Methods: Seven experiments were performed in this thesis. In all seven studies the findings in the patient groups were compared against results from an acquired control group made up of healthy volunteers. In the first experiment [3.1] twenty patients with temporal lobe epilepsy, with (10), and without hippocampal sclerosis were studied using multi voxel magnetic resonance spectroscopic imaging (MRSI) sequences in order to examine for differences in the obtained metabolites N acetyl aspartate (NAA), creatine plus phosphocreatine (Cr), choline containing compounds (Cho), GLX and myo-inositol (Ins) across the pathological groups and against a control population. In experiments [3.2], [3.3], [3.4] and [3.6] an MRS protocol that incorporated a double quantum filter acquisition sequence was applied in order to allow measurement of GABA+ (a combined measure of GABA plus homocarnosine) in addition to measurement of the metabolites examined in [3.1]. Studies were performed in the occipital lobes in patients with idiopathic generalised epilepsy (IGE) (n =10) or occipital lobe epilepsy (n = 10) [3.2], in the frontal lobes in patients with IGE (n = 21) and within regions of the MRI visible pathology in patients with large focal malformations of cortical development (MCD, n =10) [3.4]. In the last experiment using this technique patients with hippocampal sclerosis and temporal lobe epilepsy (n = 16) were studied in the ipsilateral and also in the contralateral temporal lobes and following temporal lobe surgery (n = 10) [3.6]. In experiment [3.5] ten patients were examined whilst taking and when not taking sodium valproate in order to further examine for an effect of this medication on the measured metabolite concentrations. In experiment [3.7] ten patients were studied immediately after an epileptic seizure and then again during a subsequent inter-ictal period in order to examine for an influence of the recent seizure on the measured concentrations of the main metabolites. Results: MRSI in the temporal lobes in patients with temporal lobe epilepsy identified low NAA in the anterior hippocampus that was most severe in those patients with hippocampal sclerosis. GLX elevation was a feature in the patients without hippocampal sclerosis. Metabolic abnormality was most marked in the anterior compared to the posterior hippocampal regions. GABA+ levels were elevated in patients with MCD and in the ipsilateral temporal lobe in temporal lobe epilepsy associated with hippocampal sclerosis but levels were not altered in patients with IGE or OLE. GLX was also elevated in MCD in the region of MRI visible abnormality and in IGE patients when measured in the frontal lobes. Low NAA was a feature of TLE and MCD. Patients with IGE showed normal NAA levels in the occipital lobes but reduced frontal lobe concentrations. Cr concentrations were abnormal in the immediate post ictal period but normalised within 120 minutes. NAA was not altered and no significant change in lactate concentrations was observed. Finally sodium valproate treatment was associated with a reduction in the levels of Ins and with unchanged NAA and GLX levels. Main Conclusions: MRS techniques demonstrate metabolite abnormalities in epileptic patients. NAA is the most sensitive metabolite marker of chronic pathology but levels are insensitive to recent seizure history. These findings repeat earlier observations of the usefulness of NAA measurement in the assessment of chronic epilepsy whilst illustrating ongoing uncertainty as to the correct patho-physiological interpretation of reduced NAA levels. Measurable changes in the combined Cr signal are detectable whilst elevated lactate is not reliably observed following brief epileptic seizures at 1.5T. This finding indicates a potential role for MRS in functional activation studies. Malformations of cortical development have abnormal levels of both GABA+ and GLX and MCD sub-types may well demonstrate different metabolite profiles. This finding suggests that MRS could be a useful tool in the MRI classification of MCD and in the pre-surgical assessment of patients with focal malformations. Following successful temporal lobe surgery levels of NAA remain unchanged but NAA/Cr levels appear to normalise in the contralateral temporal lobe. NAA and GLX/NAA levels were altered in the frontal lobes but not in the occipital lobes in Idiopathic Generalised Epilepsy. This finding provides imaging support for frontal lobe dysfunction as a cause or consequence of IGE. Metabolite levels are affected by administered antiepileptic drugs. Sodium valproate reduces the levels of MRS visible Ins levels whilst topiramate and gabapentin appear to be associated with higher GABA+ levels. These findings may be of major importance in the assessment of treatment effect or in the investigation of patients with possible drug resistance. The effect of valproate on Ins levels may become particularly interesting in the light of a growing understanding of the role of astrocyte dysfunction in a range of neurological conditions which include migraine, epilepsy, Alzheimer’s disease, motor neurone disease and in ischaemic lesions