44 research outputs found
Contributions and complexities from the use of in-vivo animal models to improve understanding of human neuroimaging signals.
Many of the major advances in our understanding of how functional brain imaging signals relate to neuronal activity over the previous two decades have arisen from physiological research studies involving experimental animal models. This approach has been successful partly because it provides opportunities to measure both the hemodynamic changes that underpin many human functional brain imaging techniques and the neuronal activity about which we wish to make inferences. Although research into the coupling of neuronal and hemodynamic responses using animal models has provided a general validation of the correspondence of neuroimaging signals to specific types of neuronal activity, it is also highlighting the key complexities and uncertainties in estimating neural signals from hemodynamic markers. This review will detail how research in animal models is contributing to our rapidly evolving understanding of what human neuroimaging techniques tell us about neuronal activity. It will highlight emerging issues in the interpretation of neuroimaging data that arise from in-vivo research studies, for example spatial and temporal constraints to neuroimaging signal interpretation, or the effects of disease and modulatory neurotransmitters upon neurovascular coupling. We will also give critical consideration to the limitations and possible complexities of translating data acquired in the typical animals models used in this area to the arena of human fMRI. These include the commonplace use of anaesthesia in animal research studies and the fact that many neuropsychological questions that are being actively explored in humans have limited homologues within current animal models for neuroimaging research. Finally we will highlighting approaches, both in experimental animals models (e.g. imaging in conscious, behaving animals) and human studies (e.g. combined fMRI-EEG), that mitigate against these challenges
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Therapeutic Target Identification, Validation and Drug Discovery for Traumatic Brain Injury
Traumatic Brain Injury (TBI) is a recognized cause of long-term disability worldwide with mild TBI accounting for 80% of all head traumas. Growing evidence links mTBI, and particularly repetitive mTBI (r-mTBI), with long lasting pathological and cognitive deficits that can serve as a risk factor for neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease, Chronic Traumatic Encephalopathy and others. So far, there is no FDA-approved treatment to mitigate the consequences of r-mTBI, mainly due to the lack of an effective therapeutic target and a poor translatability of existing preclinical studies, which fail to mimic heterogeneous nature of TBI. In the current thesis, I used a mouse model of r-mTBI which was treated with two different drugs, nilvadipine and anatabine, that have been previously shown to decrease inflammation and neurodegenerative mechanisms and improve cognition. To address the heterogenous nature of r-mTBI, I used several cohorts of mice which vary in age at injury (young vs old), number of hits (5 vs 24), acute or chronic duration of treatment, and the time of the first treatment intervention post injury (immediate vs delayed). I have found that both nilvadipine and anatabine, in their respective treatment paradigms, improved cognitive deficits, decreased neuroinflammation, and reduced tau pathology. Moreover, nilvadipine was equally effective in both young and old 5-hit r-mTBI mice during the acute treatment. Anatabine was shown to be effective as a delayed treatment starting at 3 months after the last injury in r-mTBI mice with both 5 and 24 hits. We further conducted a phosphoproteome analysis to identify common alterations in response to r-mTBI and tested therapeutics. Despite a high heterogeneity of the phosphoproteome profile between the analyzed cohorts, our data identified several molecules (ARPP21, Syt-1) which were equally altered in response to treatment in all r-mTBI cohorts and may represent potential therapeutic targets that are effective across different models of r-mTBI. Future studies will focus on the total proteome analysis and a subsequent validation of these potential targets
Radiolabelled Molecules for Brain Imaging with PET and SPECT
Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are in vivo molecular imaging methods which are widely used in nuclear medicine for diagnosis and treatment follow-up of many major diseases. These methods use target-specific molecules as probes, which are labeled with radionuclides of short half-lives that are synthesized prior to the imaging studies. These probes are called radiopharmaceuticals. The use of PET and SPECT for brain imaging is of special significance since the brain controls all the body’s functions by processing information from the whole body and the outside world. It is the source of thoughts, intelligence, memory, speech, creativity, emotion, sensory functions, motion control, and other important body functions. Protected by the skull and the blood–brain barrier, the brain is somehow a privileged organ with regard to nutrient supply, immune response, and accessibility for diagnostic and therapeutic measures. Invasive procedures are rather limited for the latter purposes. Therefore, noninvasive imaging with PET and SPECT has gained high importance for a great variety of brain diseases, including neurodegenerative diseases, motor dysfunctions, stroke, epilepsy, psychiatric diseases, and brain tumors. This Special Issue focuses on radiolabeled molecules that are used for these purposes, with special emphasis on neurodegenerative diseases and brain tumors
Diffusion tensor imaging and resting state functional connectivity as advanced imaging biomarkers of outcome in infants with hypoxic-ischaemic encephalopathy treated with hypothermia
Therapeutic hypothermia confers significant benefit in term neonates with hypoxic-ischaemic encephalopathy (HIE). However, despite the treatment nearly half of the infants develop an unfavourable outcome. Intensive bench-based and early phase clinical research is focused on identifying treatments that augment hypothermic neuroprotection. Qualified biomarkers are required to test these promising therapies efficiently.
This thesis aims to assess advanced magnetic resonance imaging (MRI) techniques, including diffusion tensor imaging (DTI) and resting state functional MRI (fMRI) as imaging biomarkers of outcome in infants with HIE who underwent hypothermic neuroprotection.
FA values in the white matter (WM), obtained in the neonatal period and assessed by tract-based spatial statistics (TBSS), correlated with subsequent developmental quotient (DQ). However, TBSS is not suitable to study grey matter (GM), which is the primary site of injury following an acute hypoxic-ischaemic event. Therefore, a neonatal atlas-based automated tissue labelling approach was applied to segment central and cortical grey and whole brain WM. Mean diffusivity (MD) in GM structures, obtained in the neonatal period correlated with subsequent DQ. Although the central GM is the primary site of injury on conventional MRI following HIE; FA within WM tissue labels also correlated to neurodevelopmental performance scores. As DTI does not provide information on functional consequences of brain injury functional sequel of HIE was studied with resting state fMRI. Diminished functional connectivity was demonstrated in infants who suffered HIE, which associated with an unfavourable outcome.
The results of this thesis suggest that MD in GM tissue labels and FA either determined within WM tissue labels or analysed with TBSS correlate to subsequent neurodevelopmental performance scores in infants who suffered HIE treated with hypothermia and may be applied as imaging biomarkers of outcome in this population. Although functional connectivity was diminished in infants with HIE, resting state fMRI needs further study to assess its utility as an imaging biomarker following a hypoxic-ischaemic brain injury.Open Acces
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Primate Ventromedial Prefrontal Cortex and the Physiological and Behavioural Dysfunction Characteristic of Mood and Anxiety Disorders
The heterogeneity intrinsic to the ventromedial prefrontal cortex (vmPFC) is evidenced in both its anatomy and implicated function: vmPFC subregions have roles in positive affect, negative affect and autonomic/endocrine regulation. Whether different subregions serve fundamentally different functions, or whether they perform similar computations on different inputs, remains unclear. Nevertheless, the role of the vmPFC in psychopathology is widely appreciated – in mood and anxiety disorders, over-activity within constituent regions of the vmPFC is consistently implicated in symptomatology, together with its normalisation following successful treatment. However, the precise locus of change varies between studies.
The work presented in this thesis investigates the causal contributions of over-activity within two key subregions of the vmPFC – the subgenual anterior cingulate cortex (sgACC, area 25) and perigenual anterior cingulate cortex (pgACC, area 32) – in discrete dimensions of behaviour and physiology affected in psychiatric disorders. Specifically, the impact of over-activity is assessed on (i) baseline physiological function; (ii) the regulation of anticipatory, motivational and consummatory aspects of reward-related behaviour; and (iii) negative affect including fear learning, stress recovery and the intolerance of uncertainty. To provide further insight into the mechanism of action of antidepressants, the efficacy of selected treatments is tested on changes induced by over-activity of these regions.
Beyond the direct relevance of the results presented here to psychiatric disorders and their treatment, the thesis aims to emphasise the importance of broader themes associated with the measurement and quantification of emotion in preclinical animal studies. First, a multi-faceted approach is utilised enabling quantification of both the autonomic and behavioural aspects of emotion. In so doing, the experiments maintain relevance to studies which assess these correlates in isolation, both in humans (which typically measure subjective responses and physiology) and in rodents (which frequently assess behaviour in isolation). The assessment of more than one dimension of emotion confers these studies with improved power to detect maladaptive changes. Second, the experiments described were conducted in the marmoset, a new-world primate. The extensive anatomical homology between marmoset and human prefrontal cortex facilitates the forward-translation of functional results. In combination with the appropriate assays, this renders marmosets as an invaluable species to study the causal contributions of vmPFC subregions to symptoms of psychiatric disorders.
I believe that the results of these experiments provide important insights into the causal role primate vmPFC has in relation to the behavioural and physiological aspects of psychiatric symptomatology. Most importantly, I hope that they serve as the foundation for future work to further elucidate the neuropathological processes underlying mental disorders.MRC DTP Studentshi
Periodic assessment of (ET-1) and Nitric Oxide (NO) in hypertensive disorders of pregnancy (HDP)
INTRODUCTION
Hypertensive Disorders of Pregnancy (HDP) is an independent risk factor of cardiovascular (CVS) disease. Endothelin-1 (ET-1), a potent vasoconstrictor, has been identified as a pivotal mediator in both essential hypertension and HDP. Disturbances in Nitric Oxide (NO) bioavailability found in endothelial dysfunction may increase susceptibility to cardiovascular diseases.
METHODOLOGY
Thirty six pregnant women at 30-36 weeks period of gestation from the following categories (i) pregnancy induced hypertension (PIH) (ii) chronic hypertension during pregnancy (CH) and (iii) normal pregnant women (Control). Blood pressure indices measurements and sample collection was done at antepartum (30-36 weeks), post partum (8 weeks and 12 weeks). Endothelin-1 and serum NO were measured using the Human ET-1 (Endothelin-1) and NO ELISA Kit.
RESULTS
All blood pressure indices were significantly higher in HDP patients compared to control during antenatal and post partum periods. Serum ET-1 was significantly higher in patients with HDP compared to control during antenatal until 3 months post partum. This was accompanied by significantly lower levels of serum NO in HDP patients.
CONCLUSION
Persistently high levels of ET-1 and low levels of NO up to 3 months post partum in patients with history of HDP indicate presence of persistent endothelial dysfunction despite BP normalisation in PIH patients. Long term NO/ET-1 imbalance may account for the increased CVS disease risk
Oxytocin neurone activity and release following administration of Melanotan-II in anaesthetised rats
Oxytocin release within the brain modulates several social behaviours
in animals and humans. Moreover, low central oxytocin content has been
linked to neuropsychiatric disorders, such as anxiety and autism. The
exogenous administration of oxytocin has been proposed for therapeutic
treatment, but oxytocin does not cross the blood-brain barrier (BBB) in
physiologically significant amounts. An alternative approach to oxytocin
administration is to stimulate central oxytocin release using melanocortins.
Central administration of the naturally occurring melanocortin,
α-MSH, has been shown to trigger somatodendritic oxytocin release in vitro.
Unfortunately, endogenous melanocortins also do not penetrate the BBB in
neuroactive amounts. In this study, I investigated whether systemic
administration of synthetic melanocortin receptor 3/4 (MC3/4) agonist,
Melanotan-II (MT-II), affects oxytocin neuronal activity and secretion in
anaesthetised rats. I hypothesised that systemic administration of MT-II
directly (centrally) acts on magnocellular oxytocin neurones to trigger
somatodendritic oxytocin release from neurones of the supraoptic nucleus
(SON) of the hypothalamus in vivo.
Firstly, using double immunohistochemistry against Fos protein, a
widely used marker for neural activity, and oxytocin, I showed that
intravenous (i.v.; 1 mg/kg), but not intranasal (1 and 30 μg rat),
administration of MT-II markedly induced Fos expression in magnocellular
oxytocin neurones of the SON and paraventricular nuclei (PVN) of the
hypothalamus, and this response was prevented by prior
intracerebroventricular (i.c.v.) administration of the melanocortin antagonist,
SHU-9119 (1 μg rat). In addition, brain areas receiving peripheral inputs
which are involved in the regulation of oxytocin and vasopressin release
were also analysed, showing that i.v. MT-II significantly increased Fos
expression in the nucleus tractus solitarii (NTS), but not in circumventricular
organs of the anteroventral third ventricle (AV3V) region. MT-II-induced Fos
in the NTS was not prevented by the i.c.v. melanocortin antagonist.
Then, using in vivo electrophysiology, I investigated whether i.v.
administration of MT-II affects the electrical activity of SON neurones.
Extracellular single-unit recordings from identified magnocellular neurones
of the SON showed that MT-II significantly increased the firing rate in
oxytocin neurones, however, no significant changes in firing rate were
detected in vasopressin neurones.
Finally, in vivo oxytocin release experiments showed that i.v.
administration of MT-II did not trigger somatodendritic oxytocin release
within the SON as measured by microdialysis and subsequent
radioimmunoassay. Interestingly, the i.c.v. administration of MT-II (1 μg rat)
also failed to trigger oxytocin release within the SON. The analysis of
oxytocin content in plasma revealed that the change in oxytocin
concentration was significantly greater in i.v. MT-II injected rats compared to
vehicle-injected rats.
Taken together, these results show that after i.v., but not intranasal,
administration of MT-II, the activity of magnocellular neurones of the SON is
increased. As previous studies showed that SON oxytocin neurones are
inhibited in response to direct application of melanocortin agonists, the
actions of i.v. MT-II are likely to be mediated, at least in part, indirectly by
activation of inputs from the caudal brainstem