DEVELOPMENT OF CORTICAL GABA CIRCUITRY: IDENTIFYING PERIODS OF VULNERABILITY TO SCHIZOPHRENIA

The development of cognitive functioning is disrupted in many individuals who will later be diagnosed with schizophrenia, lagging behind healthy comparison subjects by 1-2 standard deviations at clinical onset. Cognitive dysfunction often appears years before clinical onset, is the best predictor of functional outcome, and is increasingly recognized as a central feature of schizophrenia. The domains of cognitive functioning affected in schizophrenia are mediated, at least in part, by prefrontal cortex (PFC) GABA neurons, which show molecular alterations in postmortem studies in schizophrenia. One common environmental risk factor for schizophrenia is chronic cannabis use, which disrupts cognitive function most prominently during adolescence, a time of flux in PFC circuitry that may be a sensitive period for the effects of cannabis use on neural circuit maturation. Parvalbumin (PV)-containing GABA neurons may be particularly vulnerable to risk factors for schizophrenia since they are altered in the disease, important for neural activity associated with cognitive functioning, and have a lengthy period of postnatal maturation. However, the nature of PV neuron subtype-specific developmental changes is not clear. Therefore, this dissertation focuses on understanding the timing of altered expression profiles of GABA-related mRNA levels in schizophrenia, the impact of chronic cannabis exposure during adolescence on GABA circuits of the monkey PFC, and the cell type-specific nature of postnatal maturation of influential GABAergic connections. Indeed, we find that the profile of GABA transmission markers in postmortem PFC tissue in schizophrenia can be explained by disrupted development of their mRNA levels; that chronic exposure to the psychoactive compound in cannabis during adolescence alters the GABAergic mRNA levels in monkey PFC; and that two populations of PV neurons have distinctive modes of maturation in monkey PFC

Accidental intradural injection during attempted epidural block -A case report-

Several cases of accidental subdural injection have been reported, but only few of them are known to be accidental intradural injection during epidural block. Therefore we would like to report our experience of accidental intradural injection. A 68-year-old female was referred to our pain clinic due to severe metastatic spinal pain. We performed a diagnostic epidural injection at T9/10 interspace under the C-arm guided X-ray view. Unlike the usual process of block, onset was delayed and sensory dermatomes were irregular range. We found out a dense collection of localized radio-opaque contrast media on the reviewed X-ray findings. These are characteristic of intradural injection and clearly different from the narrow wispy bands of contrast in the subdural space

Proof-of-concept study of compartmentalized lung ventilation using system for asymmetric flow regulation (SAFR)

Asymmetrical distribution of acute lung injury in mechanically ventilated patients can result in a heterogeneity of gas distribution between different regions, potentially worsening ventilation-perfusion matching. Furthermore, overdistension of healthier, more compliant lung regions can lead to barotrauma and limit the effect of increased PEEP on lung recruitment. We propose a System for Asymmetric Flow Regulation (SAFR) which, combined with a novel double lumen endobronchial tube (DLT) may offer individualized lung ventilation to the left and right lungs, better matching each lung's mechanics and pathophysiology. In this preclinical experimental model, the performance of SAFR on gas distribution in a two-lung simulation system was tested. Our results indicate that SAFR may be a technically feasible and potentially clinically useful although further research is warranted

Neurobehavioral risk factors influence prevalence and severity of hazardous substance use in youth at genetic and clinical high risk for psychosis

BackgroundElevated rates of alcohol, tobacco, and cannabis use are observed in both patients with psychotic disorders and individuals at clinical high risk for psychosis (CHR-P), and strong genetic associations exist between substance use disorders and schizophrenia. While individuals with 22q11.2 deletion syndrome (22qDel) are at increased genetic risk for psychosis, initial evidence suggests that they have strikingly low rates of substance use. In the current study, we aimed to directly compare substance use patterns and their neurobehavioral correlates in genetic and clinical high-risk cohorts.MethodsData on substance use frequency and severity, clinical symptoms, and neurobehavioral measures were collected at baseline and at 12-month follow-up visits in two prospective longitudinal cohorts: participants included 89 22qDel carriers and 65 age and sex-matched typically developing (TD) controls (40.67% male, Mage = 19.26 ± 7.84 years) and 1,288 CHR-P youth and 371 matched TD controls from the North American Prodrome Longitudinal Study-2 and 3 (55.74% male; Mage = 18.71 ± 4.27 years). Data were analyzed both cross-sectionally and longitudinally using linear mixed effects models.ResultsControlling for age, sex, and site, CHR-P individuals had significantly elevated rates of tobacco, alcohol, and cannabis use relative to TD controls, whereas 22qDel had significantly lower rates. Increased substance use in CHR-P individuals was associated with increased psychosis symptom severity, dysphoric mood, social functioning, and IQ, while higher social anhedonia was associated with lower substance use across all domains at baseline. These patterns persisted when we investigated these relationships longitudinally over one-year. CHR-P youth exhibited significantly increased positive psychosis symptoms, dysphoric mood, social functioning, social anhedonia, and IQ compared to 22qDel carriers, and lower rates of autism spectrum disorder (ASD) compared to 22qDel carriers, both at baseline and at 1 year follow-up.ConclusionIndividuals at genetic and CHR-P have strikingly different patterns of substance use. Factors such as increased neurodevelopmental symptoms (lower IQ, higher rates of ASD) and poorer social functioning in 22qDel may help explain this distinction from substance use patterns observed in CHR-P individuals

Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A "central hub" in schizophrenia pathophysiology?

Accumulating evidence points to altered GABAergic parvalbumin-expressing interneurons and impaired myelin/axonal integrity in schizophrenia. Both findings could be due to abnormal neurodevelopmental trajectories, affecting local neuronal networks and long-range synchrony and leading to cognitive deficits. In this review, we present data from animal models demonstrating that redox dysregulation, neuroinflammation and/or NMDAR hypofunction (as observed in patients) impairs the normal development of both parvalbumin interneurons and oligodendrocytes. These observations suggest that a dysregulation of the redox, neuroimmune, and glutamatergic systems due to genetic and early-life environmental risk factors could contribute to the anomalies of parvalbumin interneurons and white matter in schizophrenia, ultimately impacting cognition, social competence, and affective behavior via abnormal function of micro- and macrocircuits. Moreover, we propose that the redox, neuroimmune, and glutamatergic systems form a "central hub" where an imbalance within any of these "hub" systems leads to similar anomalies of parvalbumin interneurons and oligodendrocytes due to the tight and reciprocal interactions that exist among these systems. A combination of vulnerabilities for a dysregulation within more than one of these systems may be particularly deleterious. For these reasons, molecules, such as N-acetylcysteine, that possess antioxidant and anti-inflammatory properties and can also regulate glutamatergic transmission are promising tools for prevention in ultra-high risk patients or for early intervention therapy during the first stages of the disease

Schizophrenia: do all roads lead to dopamine or is this where they start? Evidence from two epidemiologically informed developmental rodent models

The idea that there is some sort of abnormality in dopamine (DA) signalling is one of the more enduring hypotheses in schizophrenia research. Opinion leaders have published recent perspectives on the aetiology of this disorder with provocative titles such as ‘Risk factors for schizophrenia—all roads lead to dopamine' or ‘The dopamine hypothesis of schizophrenia—the final common pathway'. Perhaps, the other most enduring idea about schizophrenia is that it is a neurodevelopmental disorder. Those of us that model schizophrenia developmental risk-factor epidemiology in animals in an attempt to understand how this may translate to abnormal brain function have consistently shown that as adults these animals display behavioural, cognitive and pharmacological abnormalities consistent with aberrant DA signalling. The burning question remains how can in utero exposure to specific (environmental) insults induce persistent abnormalities in DA signalling in the adult? In this review, we summarize convergent evidence from two well-described developmental animal models, namely maternal immune activation and developmental vitamin D deficiency that begin to address this question. The adult offspring resulting from these two models consistently reveal locomotor abnormalities in response to DA-releasing or -blocking drugs. Additionally, as adults these animals have DA-related attentional and/or sensorimotor gating deficits. These findings are consistent with many other developmental animal models. However, the authors of this perspective have recently refocused their attention on very early aspects of DA ontogeny and describe reductions in genes that induce or specify dopaminergic phenotype in the embryonic brain and early changes in DA turnover suggesting that the origins of these behavioural abnormalities in adults may be traced to early alterations in DA ontogeny. Whether the convergent findings from these two models can be extended to other developmental animal models for this disease is at present unknown as such early brain alterations are rarely examined. Although it is premature to conclude that such mechanisms could be operating in other developmental animal models for schizophrenia, our convergent data have led us to propose that rather than all roads leading to DA, perhaps, this may be where they start