Alien Registration- Mcgirr, Alexander W. (Presque Isle, Aroostook County)

https://digitalmaine.com/alien_docs/33871/thumbnail.jp

Psychiatric services utilization in completed suicides of a youth centres population

BACKGROUND: From a retrospective study of youth centres (YCs) and coroner's files, we investigated youths' history of medical service utilization who died by suicide. This is the second of two papers on YCs population, the first paper having shown that the rate of psychopathology was higher in the YCs population compared to the general adolescent population. METHODS: From 1995 to 2000, 422 youths, aged 18 years and younger, died as a result of suicide in Quebec. More than one-third received services from YCs at some point. Using the provincial physician payment and hospitalization database, we examined physical and psychiatric service utilization according to time intervals, as well as hospitalization for psychiatric reasons in the individuals' lifetime and in the year preceding suicide. Suicides were matched to living YCs youths for age, sex, and geographic area. YCs controls were then subdivided into two groups based on file information pertaining to the presence or absence of suicidal behavior or ideation. RESULTS: Compared to living YCs youths, suicides had a higher rate of psychiatric service utilization in the week, month, 90 days, and year preceding suicide, as well as higher levels of lifetime hospitalization for psychiatric reasons than controls with or without a history of suicidal behavior or ideation. We found that 28.3% YCs suicides made use of psychiatric services in the year preceding suicide. CONCLUSION: The rate of psychiatric service utilization by YCs youth suicides is substantially inferior to the needs of this population. Our study underscores the need for appropriate recognition of psychiatric and suicidal problems among YCs population by social and psycho-educational professionals. At the same time, it highlights the issues of general practitioners' risk identification, psychiatric referral and treatment. Our findings suggest the need for improved organization and coordination of psychiatric services to ameliorate treatment delivery

Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition

Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modelling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4BY358C mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioural assays, PDE4BY358C mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4BY358C mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 hours, was decreased at 7 days in PDE4BY358C mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signalling by PDE4B in a very late phase of consolidation. No effect of the PDE4BY358C mutation was observed in the pre-pulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory

High-speed mesoscale cortical imaging in mouse reveals altered functional connectivity and activity dynamics in mouse models of chronic stress

Stress is a relevant etiological contributor to major mental health conditions, including, but not limited to, major depression. Stress changes brain networks with diverse consequences on arousal, valence systems, cognition, social processes such that the individual’s representation of themselves and the world is altered. Here, I characterize functional networks and changes to activity dynamics that accompany the pathological effects of stress in mouse. I do so using spontaneous activity to align with data collection from human resting state imaging. I capture a wide expanse of dorsal neocortex with millisecond timescale resolution using 1) an acute surgical preparation together with voltage sensitive dye (VSD) incubated over the entire dorsal neocortex and 2) transgenic animals expressing fluorescent sensors (iGluSnFR and GCaMP6s) of neural activity together with chronic cranial windows. I first characterize functional connectivity as measured by zero-lag interregional correlation together with longitudinal real time in vivo sampling of extracellular glutamate signals in conjunction with the chronic social defeat model of stress. This reveals stress susceptibility of a midline network, the murine default mode network, and hyperconnectivity after stress that is selectively restored by the rapid acting antidepressant, ketamine. I then examine how spontaneous cortical dynamics impact faithful representation of external stimuli by isolating a specific set of activity stereotypies resembling sensory experience and processing. Focusing on events resembling limb and whisker sensory experience in spontaneous activity, I show that the occurrence of these motifs has a lasting impact on the magnitude of sensory evoked responses. I further show using multiple models of chronic stress and manipulation of circuitry implicated in negative affect, that these motifs are susceptible to stress and that a dominant motif is upregulated after stress in proportion with emotional behavior. The upregulation of sensory motifs in stressed animals accordingly results in decreased sensory reliability. My data confirms the utility and importance of murine modelling of stress and the potential to identify common and divergent effects of specific stressors, as well as identify putative biomarkers with potential treatment relevance in humans.Medicine, Faculty ofGraduat

Pendulum Study: Active Visual Tracking Elicits Non-Selective Elevations in Cerebral Blood Flow

Neurovascular 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

A dose-response characterization of transcranial magnetic stimulation intensity and evoked potential amplitude in the dorsolateral prefrontal cortex

Abstract By combining transcranial magnetic stimulation (TMS) with electroencephalography, human cortical circuits can be directly interrogated. The resulting electrical trace contains TMS-evoked potential (TEP) components, and it is not known whether the amplitudes of these components are stimulus intensity dependent. We examined this in the left dorsolateral prefrontal cortex in nineteen healthy adult participants and extracted TEP amplitudes for the N40, P60, N120, and P200 components at 110%, 120%, and 130% of resting motor threshold (RMT). To probe plasticity of putative stimulus intensity dose-response relationships, this was repeated after participants received intermittent theta burst stimulation (iTBS; 600 pulses, 80% RMT). The amplitude of the N120 and P200 components exhibited a stimulus intensity dose-response relationship, however the N40 and P60 components did not. After iTBS, the N40 and P60 components continued to exhibit a lack of stimulus intensity dose-dependency, and the P200 dose-response was unchanged. In the N120 component, however, we saw evidence of change within the stimulus intensity dose-dependent relationship characterized by a decrease in absolute peak amplitudes at lower stimulus intensities. These data suggest that TEP components have heterogeneous dose-response relationships, with implications for standardizing and harmonizing methods across experiments. Moreover, the selective modification of the N120 dose-response relationship may provide a novel marker for iTBS plasticity in health and disease

Consistency of frontal cortex metabolites quantified by magnetic resonance spectroscopy within overlapping small and large voxels

Single voxel Magnetic Resonance Spectroscopy (MRS) quantifies metabolites within a specified volume of interest. MRS voxels are constrained to rectangular prism shapes and therefore must either define a small voxel contained within the anatomy of interest or include neighbouring tissue that is not of interest (i.e., partial volume effect). When studying cortical regions without clearly demarcated boundaries, such as the dorsolateral prefrontal cortex (DLPFC), it is unclear how representative a larger voxel is of a smaller volume within it. This study quantified total N-Acetylaspartate (tNAA), choline, glutamate, glutamate and glutamine (Glx), myo-inositol, and creatine values in two overlapping MRS voxels placed in the DLPFC, a large (30x30x30 mm3) and small (15x15x15 mm3) voxel to examine the correspondence of quantified metabolite levels to determine whether a large voxel is representative of a small voxel. Factors of signal to noise (SNR) and tissue type were specifically investigated. Spearman’s rho correlations were used to investigate the relationship between the small voxel and large voxel metabolite values. Only myo-inositol was significantly correlated between the two voxels when water-referencing was used, while all metabolites showed significant correlations when creatine-referencing was used. SNR had a minimal effect on the correspondence between voxels, while tissue type showed substantial influence. This study demonstrates substantial variability of metabolite estimates within the DLPFC and suggests that when small anatomical structures are of interest, it may be valuable to spend additional acquisition time measuring to obtain specific, localized data