Investigating the role of Gamma-aminobutyric acid (GABA) in sedation: a combinedelectrophysiological, haemodynamicand spectroscopic study in humans

A better understanding of the mechanisms of anaesthesia and sedation are expected not only to improve the understanding of the neural correlates of consciousness but also to help improve safety from the complications of anaesthesia/ sedation and develop safer drugs and objective brain function monitoring systems. Neuroimaging modalities such as functional MRI, magnetoencephalography and MR spectroscopy provide complimentary information about brain functions and can help interrogate brain activity in a living human brain. Most anaesthetic drugs act by enhancing the inhibitory actions of GABA in the brain. Most neuroimaging research has focused on anaesthetic-induced unconsciousness, with only few investigating the earliest levels of sedation-induced altered consciousness. The work in this thesis used a range of advanced neuroimaging modalities to investigate the role of GABA (through a GABA-ergic drug, propofol), during mild sedation, in humans. This was performed as a series of experiments within two, sequential, scanning sessions, MEG followed by fMRI, in the same participants. Propofol resulted in a dissociation of the visual gamma band response (decreased evoked, increased induced power). This was related to a reduced BOLD fMRI response but there were no changes in MRS detectable GABA concentration. Response to multisensory stimulation also revealed interesting changes with MEG and fMRI. Functional connectivity analyses showed changes in connectivities of the posterior cingulate cortex (key hub of default-mode network) and thalamus with each other and other key brain regions. Resting state networks were identified with MEG too, which revealed interesting increases in connectivity in certain band- limited networks while motor networks showed no change. Perfusion fMRI using arterial spin labelling revealed a global and regional reduction in perfusion, highlighting some of the key regions (frontal cortex, precuenus, PCC and thalamus) involved in sedation

Evaluation of Guava (Psidium guajava L.) Varieties and Standardization of Recipe for Nectar Preparation

The nectar prepared from guava variety L-49 had highest ascorbic acid, pH and non-reducing sugar. The recipe with 20 per cent pulp, 0.3 per cent acidity and 17°Brix (TSS) recorded highest organoleptic score. The acidity, TSS, total and reducing sugar of nectar showed an increasing trend during the progress of storage upto five months under ambient conditions. However, these chemical constituents did not change markedly until five months of storage as compared to fresh nectar at the time of preparation

Oscillatory dynamics in ischaemic pain

Background: The pain experience relies on integration of brain activity across different areas1, including somatosensory, insular, cingulate, prefrontal cortices, thalamus, subcortical areas and brainstem that belong to different functional systems of the brain but are transiently functionally connected (FC) during pain processing2 Pain is associated with complex spatial, temporal and spectral patterns of brain activity3 measured by Magnetoencephalography. Previous imaging has shown altered connectivity between sensorimotor cortex and resting state networks during tourniquet pain4. We aim to demonstrate oscillatory and FC alterations across our tonically painful experimental stimulus. Methods: This was a pilot study with 5 participants. Approval was obtained from Cardiff University School of Psychology ethics committee (EC.17.12.12.5171). Post-ischaemia isometric forearm exercises result in a severe, deep aching pain; closely simulating pathological pain. Pain was rated on a scale 0-10 (0=no pain10= worst possible pain) whenever this changed during the experiment. Data analysis assessed alpha (7-14Hz), beta (15-30Hz), gamma (6090Hz) frequency bands during rest, early pain, late pain and post pain, epoched into 60 trials of 5 second duration. Pre-processing was performed using fieldtrip and beamformed using DICS. We extracted virtual electrodes from left somatosensory cortex (SI), secondary somatosensory cortex, anterior cingulate cortex (ACC), insula and prefrontal cortex using AAL atlas and extracted alpha, beta and gamma amplitude in each ROI across 4 time periods. Connectivity was assessed between pairs of regions. Results: No substantial connectivity changes were seen. Increases in alpha and beta amplitudes were seen in the ACC, during transition from early to late pain phase with increases in gamma amplitude occurring in four participants. Oscillatory increases coincided with moderate to severe pain ratings. Increases in oscillatory activity in the ACC may reflect pain-anxiety interaction due to the tonically painful nature of the pain stimulus and therefore comparable to clinical chronic pain5. Conclusions Ischaemic tourniquet pain may be an experimental surrogate for chronic pain evoking oscillatory brain changes in previously reported pain regions in the brain. Although we were unable to demonstrate alterations to FC we intend to perform whole brain network connectivity with future dataset

Mild propofol sedation reduces frontal lobe and thalamic cerebral blood flow: An arterial spin labeling study

Mechanisms of anesthetic drug-induced sedation and unconsciousness are still incompletely understood. Functional neuroimaging modalities provide a window to study brain function changes during anesthesia allowing us to explore the sequence of neuro-physiological changes associated with anesthesia. Cerebral perfusion change under an assumption of intact neurovascular coupling is an indicator of change in large-scale neural activity. In this experiment, we have investigated resting state cerebral blood flow (CBF) changes in the human brain during mild sedation, with propofol. Arterial spin labeling (ASL) provides a non-invasive, reliable, and robust means of measuring cerebral blood flow (CBF) and can therefore be used to investigate central drug effects. Mild propofol sedation-related CBF changes were studied at rest (n = 15), in a 3 T MR scanner using a PICORE-QUIPSS II ASL technique. CBF was reduced in bilateral paracingulate cortex, premotor cortex, Broca’s areas, right superior frontal gyrus and also the thalamus. This cerebral perfusion study demonstrates that propofol induces suppression of key cortical (frontal lobe) and subcortical (thalamus) regions during mild sedation

A Comparative Study of Serum Ast/Sgot Levels Among the Patients of Thyroid Disorders

Abstract: Background: Thyroid dysfunction is one of the most common endocrinological disorders. Consequentl

SYNTHESIS AND CHARACTERIZATION OF SOME METAL COMPLEXES WITH IETS AS LIGAND DERIVED FROM 2-ACETLYLINDAN-1,3-DIONE

The present investigation are based on the synthesis and characterization of metal complexes with Schiff’s bases (anils) α– (1, 3– dioxo– indan– 2–yl) – ethylidene– thiosemicarbazone(IETS) derived from 2-substituted acetyl 1, 3 - dione by condensing it with primary aryl amine (aniline) in absolute alcohol. 2-acetyl indan-1, 3-dione was prepared by claisen-condensation. The Co (II), Ni(II), Cu (II), Zn (II), Cd (II), Fe (III), V (III) and Cr (III) complexes of the Schiff’s bases have been prepared in the reactions and investigated their structures by physicochemical methods.  The formulation and structure of the ligands have been screened by their chemical analysis, IR, PMR and mass-spectral studies. The PMR spectrum of the metal complexes in quite similar to the PMR spectrum of the anil (IETS) with slight change in the position of PMR signals. The metal complexes are thermally stable at higher temperature (̴ 300o). These characteristics suggest polymeric nature of the metal complexes. The observed molar conductance values of the complexes with IETS have been found in the range 170 to 250 mhos cm2g mol-1. The mass-spectra of this IETS showed the molecular ion peak as a base peak at m/z 261. The structure of ligand has been confirmed by their mass–spectral studies. Keywords: Metal Complexes, Schiff’s bases, 2-Acetlylindan-1,3-Dion

Withaferin A inhibits lysosomal activity to block autophagic flux and induces apoptosis via energetic impairment in breast cancer cells

Withaferin A (WFA), a steroidal lactone, negatively regulates breast cancer growth however, its mechanisms of action remain largely elusive. We found that WFA blocks autophagy flux and lysosomal proteolytic activity in breast cancer cells. WFA increases accumulation of autophagosomes, LC3B-II-conversion, expression of autophagy-related proteins and autophagosome/lysosome fusion. Autolysosomes display the characteristics of acidic compartments in WFA-treated cells; however, the protein degradation activity of lysosomes is inhibited. Blockade of autophagic flux reduces the recycling of cellular fuels leading to insufficient substrates for tricarboxylic acid (TCA) cycle and impaired oxidative phosphorylation. WFA decreases expression and phosphorylation of LDHA, the key enzyme that catalyzes pyruvate-to-lactate conversion, reduces ATP levels and increases AMPK activation. AMPK-inhibition abrogates while AMPK-activation potentiates WFA's effect. WFA and 2-deoxyglucose combination elicits synergistic inhibition of breast cancer cells. Genetic-knockout of BECN1 and ATG7 fails to rescue cells from WFA-treatment; in contrast, addition of methyl pyruvate to supplement TCA cycle protects WFA-treated cells. Together, these results implicate that WFA is a potent lysosomal inhibitor; energetic impairment is required for WFA-induced apoptosis and growth-inhibition and combining WFA and 2DG is a promising therapeutic strategy for breast cancer

Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine

Cortical recordings of task-induced oscillations following subanaesthetic ketamine administration demonstrate alterations in amplitude, including increases at high-frequencies (gamma) and reductions at low frequencies (theta, alpha). To investigate the population-level interactions underlying these changes, we implemented a thalamo-cortical model (TCM) capable of recapitulating broadband spectral responses. Compared with an existing cortex-only 4-population model, Bayesian Model Selection preferred the TCM. The model was able to accurately and significantly recapitulate ketamine-induced reductions in alpha amplitude and increases in gamma amplitude. Parameter analysis revealed no change in receptor time-constants but significant increases in select synaptic connectivity with ketamine. Significantly increased connections included both AMPA and NMDA mediated connections from layer 2/3 superficial pyramidal cells to inhibitory interneurons and both GABAA and NMDA mediated within-population gain control of layer 5 pyramidal cells. These results support the use of extended generative models for explaining oscillatory data and provide in silico support for ketamine's ability to alter local coupling mediated by NMDA, AMPA and GABA-A