Browsing by Author "McGirr, Alexander"
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- ItemOpen AccessDevelopment of an Experimental Platform to Enable Ultrasound Neuromodulation Studies(2022-05-09) Loree-Spacek, Jak; Pichardo, Samuel; Kiss, Zelma; McGirr, Alexander; Curiel, Laura; Murari, KartikeyaFocused ultrasound (FUS) neuromodulation is the delivery of concentrated mechanical energy into central nervous tissue at low intensity (a few W per cm^2; about as intense as imaging ultrasound, and not sufficiently intense to cause heating) with the goal of eliciting a functional change. It is of interest to applied and clinical scientists as a prospective non-invasive therapeutic intervention; it is also applicable to basic scientists as a tool for in vivo brain mapping. This work details the development of a device and accompanying system that enables the study of ultrasound-mediated neuromodulation in brain tissue samples in a setting with concurrent electrophysiology. We use a novel ultrasound focusing technique based on principles of acoustic reflection, and the first research chapter discusses the development and integration of this focusing technique. To develop and refine our design, I used finite-element modeling and iterative computer optimization techniques. The concordance of these in silico techniques with reality was verified with prototypes and hydrophone acoustic field measurements. Subsequently, several production-quality ultrasound units were produced to the specifications determined by modeling; these units exhibited performance improvements based on the results from testing prototypes, and they were characterized in terms of efficiency, electrical impedance, and ultrasonic pressure field shape. We used two independent methods to verify the absolute acoustic intensity output by our device: radiation-force absorber measurements in conjunction with wide-field hydrophone scans, and then later a calibrated hydrophone. The second research chapter of this manuscript describes the application of our system to neuroscientific experiments: I detail how we obtained early data pertaining to the ability of pulsed FUS to modulate field potential activity in acute animal brain slices. We observed an intensity-dependent modulation effect in a majority of slices tested (>50%, n=44); however, this effect was determined to be dominated by a confound and unlikely to be physiological. This course of study explored and evaluated a novel technique for obtaining an ultrasound focus; it also yielded a system that enables further experiments into interactions between FUS and brain tissue. This manuscript, the devices resulting from the work, and the documentation included in the appendices will enable continued investigations into ultrasound neuromodulation at the University of Calgary.
- ItemOpen AccessExploring the Antidepressant-like Effects of Ketamine and Synaptic Zinc in a Mouse Model of Depression(2021-01-27) Markovina, Mariya; Dyck, Richard H.; Antle, Michael C.; Sargin, Derya; McGirr, AlexanderZinc is critical for proper cellular function due to its role in protein synthesis, brain development, and neural transmission. In the brain, zinc is found at glutamatergic synapses in many regions implicated in regulating emotions. Due to its inhibitory action on glutamatergic receptors and involvement in downstream signalling pathways, zinc is thought to be an important factor in depression. Evidence has shown that in animals and humans, zinc deficiency can lead to depressive-like behaviours and zinc on its own provides antidepressant-like effects. Ketamine, a novel and effective antidepressant, also exerts inhibitory action on the same receptor as zinc and produces rapid and sustained antidepressant effects in both animals and humans. Due to their comparable effects, we aimed to see how zinc and ketamine are involved in depression pathways when examined together. Zinc is transported into synaptic vesicles by zinc transporter 3 (ZnT3). Therefore, to understand the action of synaptic zinc, we used ZnT3 KO mice, mice that lack synaptic zinc, to explore the antidepressant effects of zinc and ketamine in the brain. We compared data found in these mice to ZnT3 HT mice, mice that have approximately half the amount of zinc, and ZnT3 WT mice. The first experiment in this thesis was designed to assess the effects of ketamine treatment on synaptic zinc levels in mood-related structures. No changes in synaptic zinc levels were observed 24h or 7 days after ketamine injection, however sex differences were seen 3 days after ketamine injection. No evidence was found that ketamine causes increases in synaptic zinc levels across all mood-related brain structures. The second experiment aimed to understand the ability of ketamine to reduce depressive-like symptoms in ZnT3 animals subjected to chronic mild stress (CMS), a method of modeling depressive-like symptoms in animals. Overall, CMS was unable to induce depressive-like symptoms in mice and therefore ketamine only had a significant effect in one behavioural test. Animals subjected to stress displayed stress resilience in some tests. ZnT3 KO mice also showed greater resilience to stress than WT mice in some behavioural tests.
- ItemOpen AccessInvestigating the impact of skull vibrations during focused ultrasound neuromodulation and methods to mitigate them(2022-07-21) Hesselink, Jake Willem; Kizz, Zelma; Pichardo, Samuel; McGirr, Alexander; Yan, JunFocused ultrasound (FUS) neuromodulation offers the potential to non-invasively alter brain activity at targets throughout the brain, circumventing limitations of other neurostimulation techniques. FUS likely modulates neural tissue excitability through acoustic radiation force (ARF). The ultrasound signal exerts a mechanical force with dynamics of the carrier envelope, determined by the pulse repetition frequency (PRF). Thus, PRF has been tied both to modulatory effects of FUS and indirect auditory activation caused by FUS delivery through the skull. This auditory confound challenged motor responses to FUS, a common proxy measure of neuromodulation efficacy in rodents, and presents a hurdle for translation. Auditory activation has been linked to skull vibrations related to the PRF. Randomized PRF could prevent constructive interference of skull vibrations caused by ARF and minimize possible sensitivity of the skull to vibrate at PRFs. We hypothesized that randomizing the PRF would reduce skull vibrations without affecting motor response rates. We also hypothesized that while FUS delivery may cause skull vibrations, this auditory artifact was not the cause of motor responses and FUS neuromodulation would produce motor activity more reliably than piezoelectrically-induced skull vibrations. This study first aimed to record the amplitude of skull vibrations during FUS over a range of PRF values to assess the likelihood of skull vibrations depending on PRF. Second, vibrations were compared between randomized and fixed PRF conditions. Lastly, motor responses to FUS neuromodulation were compared between fixed PRF, random PRF, a positive control of air-puff stimulation, a sham condition, and vibration induction via a piezoelectric actuator. To obtain motor responses, isoflurane anesthesia was reduced during stimulus delivery. Motor activity was recorded via video and electromyography. A contact microphone recorded skull vibrations. The results of this work revealed the influence of PRF on skull vibrations and suggested that they do not significantly impact motor responses to FUS neuromodulation. The random PRF method slightly reduced skull vibrations and may be adapted in future studies of the neuromodulatory effects of FUS.
- ItemOpen AccessPendulum Study: Active Visual Tracking Elicits Non-Selective Elevations in Cerebral Blood Flow(2019-04) Hodge, Sarah V. L.; Spence, Emma E. M.; Suraj, Rejitha; McGirr, Alexander; Phillips, Aaron AlexanderNeurovascular coupling (NVC) describes the effective matching of cerebral blood flow (CBF) to regions of neuro-metabolic demand. There is increasing interest to assess human NVC for both basic research and its potential role in vascular-cognitive impairment. The clinical utility of NVC relies on a standardized protocol for which the driving metabolic demands are highly-selective. Various research groups deploy divergent strategies to elicit visual NVC responses, including inactive processes (visual grating), passive visual tracking (target with predictable motion) and active visual tracking (target with unpredictable motion). These strategies differ in degree of cognitive and metabolic demand and may elicit different NVC responses, thus precluding study comparison. The present NVC assessment evaluated temporal and regional responsiveness of blood flow (transcranial Doppler) to the visual cortex [via the posterior cerebral artery (PCA)] and blood pressure (Finapres NOVA) during visual stimulation in 19 healthy subjects while also measuring middle cerebral artery (MCA) blood flow. Visual stimulation included 10 cycles of 30 seconds with eyes closed, followed by 30 seconds with eyes open tracking a moving computerized target. Each subject completed three trials of passive tracking and three trials of active tracking (114 NVC protocols, 1140 individual hyperemias). A custom eye-scanning apparatus followed eye motion to quantify visual target-tracking vigilance. Additional custom software was used to quantify NVC. The data demonstrated that active tracking elicited greater NVC responses compared to passive tracking. Specifically, there was 26% greater change in the mean elevation of PCA blood velocity (p=<0.000) and 13% greater peak NVC response (p<0.01). The MCA response was also greater during active tracking (mean response 111% greater, peak response 41% greater; both p<0.001). Visual target-tracking vigilance was linearly correlated to the degree of hyperemia in the MCA and PCA, as well blood pressure during NVC. It was observed that active and passive visual tracking elicit different NVC responses and cannot be reliably compared. That PCA and MCA responses were greater with active tracking suggests an elevated global CBF (i.e. not selective to regions perfused by the PCA) that may result from recruitment of brain centres responsible for sustained attention and executive function. In other words, active tracking leads to non-selective elevations in global CBF and greater target-tracking vigilance impacts the NVC response. These findings are a critical step to better understand and standardize the evaluation of NVC in humans and for potential clinical deployment of NVC assessments.
- ItemOpen AccessSpatial, temporal, and circuit-specific activation patterns of basolateral amygdala projection neurons during stress(2023-07) Aukema, Robert; Hill, Matthew; Borgland, Stephanie; Bains, Jaideep; Bruchas, Michael; McGirr, AlexanderIn humans and rodents, the amygdala is rapidly activated by stress and hyperactivated in conditions of pathological stress or trauma. However, there is a striking lack of information of the anatomical specificity of amygdala subregions and circuits explicitly activated by stress, and of its role in governing typical responses to stress such as hypothalamic-pituitary-adrenal (HPA) axis activation. The overarching aim of this thesis was to conduct a systematic investigation of the spatial, temporal, and circuit-specific activation patterns of basolateral amygdala (BLA) projection neurons during exposure to acute stress. Additionally, we explicitly tested the role of the BLA in activation of the HPA axis, as this remains a poorly understood process. Chapter 1 describes how the BLA is anatomically well-situated for cognitive evaluation of emotional stimuli and describes the role of the BLA in diverse behavioural and physiological processes via efferent projections to many different brain structures. Chapter 2 identifies a common BLA subregion that is responsive to stressful stimuli, albeit with distinct temporal activation patterns, and which bidirectionally influences HPA axis activity. Chapter 3 maps the topographical distribution of six different populations of projection neurons throughout the BLA, and demonstrates that, although widely activated by stress exposure, inhibition of isolated populations does not influence HPA axis activity. Chapter 4 investigates the topographical distribution and stress-induced activation of BLA neurons expressing corticotropin-releasing hormone receptor type I (CRHR1), which, just like discrete circuits, does not influence HPA axis activity on its own. Together, this emphasizes the heterogeneity of BLA projection populations, while providing evidence that a large, diverse population of BLA projection neurons are activated by exposure to acute psychological stress.