Prenatal cannabis exposure in the clinic and laboratory: What do we know and where do we need to go?

Coincident with the legalisation of cannabis in many nations, rates of cannabis use during pregnancy have increased. Like prior investigations on smoking and alcohol, understanding how prenatal cannabis exposure (PCE) impacts offspring outcomes across the lifespan will be critical for informing choices for pregnant people, clinicians, and policy makers alike. A thorough characterization of the life-long impacts is especially urgent for supporting all of these stakeholders in the decision-making process. While studies in humans bring forth the most direct information, it can be difficult to parse the impact of PCE from confounding variables. Laboratory studies in animal models can provide experimental designs that allow for causal inferences to be drawn, however there can be challenges in designing experiments with external validity in mirroring real-world exposure, as well as challenges translating results from the laboratory back to the clinic. In this literature review, we first highlight what is known about patterns of cannabis use during pregnancy. We then seek to lay out updates to the current understanding of the impact of PCE on offspring development informed by both human and nonhuman animal experiments. Finally we highlight opportunities for information exchange among the laboratory, clinic, and policy, identifying gaps to be filled by future research.

Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia.

Recent studies have reported early cerebellar and subcortical impact in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the cerebello-subcortical circuitry in FTD has been understudied despite its essential role in cognition and behaviors related to FTD symptomatology. The present study aims to investigate the association between cerebellar and subcortical atrophy, and neuropsychiatric symptoms across genetic mutations. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative including mutation carriers and noncarrier first-degree relatives of known symptomatic carriers. Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed, and partial least squares analyses (PLS) were used to link morphometry and behavior. In presymptomatic C9orf72 expansion carriers, thalamic atrophy was found compared to noncarriers, suggesting the importance of this structure in FTD prodromes. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to neuropsychiatric symptoms, with significant overlap in brain/behavior patterns, but also specificity for each genetic mutation group. The largest differences were in the cerebellar atrophy (larger extent in C9orf72 expansion group) and more prominent amygdalar volume reduction in the MAPT group. Brain scores in the C9orf72 expansion carriers and MAPT carriers demonstrated covariation patterns concordant with atrophy patterns detectable up to 20 years before expected symptom onset. Overall, these results demonstrated the important role of the subcortical structures in genetic FTD symptom expression, particularly the cerebellum in C9orf72 and the amygdala in MAPT carriers.

Examining litter specific variability in mice and its impact on neurodevelopmental studies.

Our current understanding of litter variability in neurodevelopmental studies using mice may limit translation of neuroscientific findings. Higher variance of measures across litters than within, often termed intra-litter likeness, may be attributable to both pre- and postnatal environment. This study aimed to assess the litter-effect within behavioral assessments (2 timepoints) and anatomy using T1-weighted magnetic resonance images across 72 brain region volumes (4 timepoints) (36 C57bl/6J inbred mice; 7 litters: 19F/17M). Between-litter comparisons of brain and behavioral measures and their associations were evaluated using univariate and multivariate techniques. A power analysis using simulation methods was then performed on modeled neurodevelopment and to evaluate trade-offs between number-of-litters, number-of-mice-per-litter, and sample size. Our results show litter-specific developmental effects, from the adolescent period to adulthood for brain structure volumes and behaviors, and for their associations in adulthood. Our power simulation analysis suggests increasing the number-of-litters in experimental designs to achieve the smallest total sample size necessary for detecting different rates of change in specific brain regions. Our results demonstrate how litter-specific effects may influence development and that increasing the litters to the total sample size ratio should be strongly considered when designing neurodevelopmental studies.

Dynamic association of the first identifiable symptom with rapidity of progression to first-episode psychosis.

BACKGROUND: Rapid progression from the first identifiable symptom to the onset of first-episode psychosis (FEP) allows less time for early intervention. The aim of this study was to examine the association between the first identifiable symptom and the subsequent speed of illness progression. METHODS: Data were available for 390 patients attending a catchment-based early intervention service for FEP. Exposure to non-psychotic and subthreshold psychotic symptoms was retrospectively recorded using semi-structured interviews. Outcomes following the onset of the first identifiable symptom were (1) time to onset of FEP and (2) symptom incidence rate (i.e. number of symptoms emerging per person-year until FEP onset). These outcomes were respectively analyzed with Cox proportional hazards and negative binomial regressions. RESULTS: After Bonferroni correction, having a subthreshold psychotic (v. non-psychotic) symptom as the first symptom was not associated with time to FEP onset [hazard ratio (HR) = 1.39; 95% CI 0.94-2.04] but was associated with higher symptom incidence [incidence rate ratio (IRR) = 1.92; 95% CI 1.10-3.48]. A first symptom of suspiciousness was associated with shorter time to FEP onset (HR = 2.37; 95% CI 1.38-4.08) and higher symptom incidence rate (IRR = 3.20; 95% CI 1.55-7.28) compared to other first symptoms. In contrast, a first symptom of self-harm was associated with lower symptom incidence rate (IRR = 0.06; 95% CI 0.01-0.73) compared to other first symptoms. Several associations between symptoms and illness progression were moderated by the age at symptom onset. CONCLUSIONS: Appreciating the content and timing of early symptoms can identify windows and treatment targets for early interventions in psychosis.

Investigating the "two-hit hypothesis": Effects of prenatal maternal immune activation and adolescent cannabis use on neurodevelopment in mice.

Prenatal exposure to maternal immune activation (MIA) and chronic adolescent cannabis use are both risk factors for neuropsychiatric disorders. However, exposure to a single risk factor may not result in major mental illness, indicating that multiple exposures may be required for illness onset. Here, we examine whether combined exposure to prenatal MIA and adolescent delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, lead to enduring neuroanatomical and behavioural changes in adulthood. Mice were prenatally exposed to viral mimetic, poly I:C (5 mg/kg), or vehicle at gestational day (GD) 9, and postnatally exposed to chronic THC (5 mg/kg, intraperitoneal) or vehicle during adolescence (postnatal day [PND]28-45). Longitudinal magnetic resonance imaging (MRI) was performed pre-treatment, PND 25, post-treatment, PND 50, and in adulthood, PND85, followed by behavioural tests for anxiety-like, social, and sensorimotor gating. Post-mortem assessment of cannabinoid (CB)1 and 2 receptor expressing cells was performed in altered regions identified by MRI (anterior cingulate and somatosensory cortices, striatum, and hippocampus). Subtle deviations in neurodevelopmental trajectory and subthreshold anxiety-like behaviours were observed in mice exposed to both risk factors. Sex-dependent effects were observed in patterns of shared brain-behaviour covariation, indicative of potential sex differences in response to MIA and THC. Density of CB1 and CB2 receptor positive cells was significantly decreased in all mice exposed to MIA, THC, or both. These findings suggest that there may be a cumulative effect of risk factor exposure on gross neuroanatomical development, and that the endocannabinoid system may be sensitive to both prenatal MIA, adolescent THC, or the combination.

The impact of the Siemens Tim Trio to Prisma upgrade and the addition of volumetric navigators on cortical thickness, structure volume, and 1H-MRS indices: An MRI reliability study with implications for longitudinal study designs.

Many magnetic resonance imaging (MRI) measures are being studied longitudinally to explore topics such as biomarker detection and clinical staging. A pertinent concern to longitudinal work is MRI scanner upgrades. When upgrades occur during the course of a longitudinal MRI neuroimaging investigation, there may be an impact on the compatibility of pre- and post-upgrade measures. Similarly, subject motion is another issue that may be detrimental to MRI work and embedding volumetric navigators (vNavs) within acquisition sequences has emerged as a technique that allows for prospective motion correction. Our research group recently underwent an upgrade from a Siemens MAGNETOM 3T Tim Trio system to a Siemens MAGNETOM 3T Prisma Fit system. The goals of the current work were to: 1) investigate the impact of this upgrade on commonly used structural imaging measures and proton magnetic resonance spectroscopy indices ("Prisma Upgrade protocol") and 2) examine structural imaging measures in a sequence with vNavs alongside a standard acquisition sequence ("vNav protocol"). While high reliability was observed for most of the investigated MRI outputs, suboptimal reliability was observed for certain indices. Across the scanner upgrade, increases in frontal, temporal, and cingulate cortical thickness (CT) and thalamus volume, along with decreases in parietal CT and amygdala, globus pallidus, hippocampus, and striatum volumes, were observed. No significant impact of the upgrade was found in 1H-MRS analyses. Further, CT estimates were found to be larger in MPRAGE acquisitions compared to vNav-MPRAGE acquisitions mainly within temporal areas, while the opposite was found mostly in parietal brain regions. The results from this work should be considered in longitudinal study designs and comparable prospective motion correction investigations are warranted in cases of marked head movement.

A systematic review of neuroimaging and acute cannabis exposure in age-of-risk for psychosis.

Acute exposure to cannabis has been associated with an array of cognitive alterations, increased risk for neuropsychiatric illness, and other neuropsychiatric sequelae including the emergence of acute psychotic symptoms. However, the brain alterations associating cannabis use and these behavioral and clinical phenotypes remains disputed. To this end, neuroimaging can be a powerful technique to non-invasively study the impact of cannabis exposure on brain structure and function in both humans and animal models. While chronic exposure studies provide insight into how use may be related to long-term outcomes, acute exposure may reveal interesting information regarding the immediate impact of use and abuse on brain circuits. Understanding these alterations could reveal the connection with symptom dimensions in neuropsychiatric disorders and, more specifically with psychosis. The purpose of the present review is to: 1) provide an update on the findings of pharmacological neuroimaging studies examining the effects of administered cannabinoids and 2) focus the discussion on studies that examine the sensitive window for the emergence of psychosis. Current literature indicates that cannabis exposure has varied effects on the brain, with the principal compounds in cannabis (delta-9-tetrahydrocannabinol and cannabidiol) altering activity across different brain regions. Importantly, we also discovered critical gaps in the literature, particularly regarding sex-dependent responses and long-term effects of chronic exposure. Certain networks often characterized as dysregulated in psychosis, like the default mode network and limbic system, were also impacted by THC exposure, identifying areas of particular interest for future work investigating the potential relationship between the two.

Timing, Distribution, and Relationship Between Nonpsychotic and Subthreshold Psychotic Symptoms Prior to Emergence of a First Episode of Psychosis.

Prospective population studies suggest that psychotic syndromes may be an emergent phenomenon-a function of severity and complexity of more common mental health presentations and their nonpsychotic symptoms. Examining the relationship between nonpsychotic and subthreshold psychotic symptoms in individuals who later developed the ultimate outcome of interest, a first episode of psychosis (FEP), could provide valuable data to support or refute this conceptualization of how psychosis develops. We therefore conducted a detailed follow-back study consisting of semistructured interviews with 430 patients and families supplemented by chart reviews in a catchment-based sample of affective and nonaffective FEP. The onset and sequence of 27 pre-onset nonpsychotic (NPS) or subthreshold psychotic (STPS) symptoms was systematically characterized. Differences in proportions were analyzed with z-tests, and correlations were assessed with negative binomial regressions. Both the first psychiatric symptom (86.24% NPS) and the first prodromal symptom (66.51% NPS) were more likely to be NPS than STPS. Patients reporting pre-onset STPS had proportionally more of each NPS than did those without pre-onset STPS. Finally, there was a strong positive correlation between NPS counts (reflecting complexity) and STPS counts (ß = 0.34, 95% CI [0.31, 0.38], P < 2 e-16). Prior to a FEP, NPS precede STPS, and greater complexity of NPS is associated with the presence and frequency of STPS. These findings complement recent arguments that the emergence of psychotic illness is better conceptualized as part of a continuum-with implications for understanding pluripotential developmental trajectories and strengthening early intervention paradigms.

Perspective-taking increases emotionality and empathy but does not reduce harmful biases against American Indians: Converging evidence from the museum and lab.

Given the problematic depictions of Native Americans and the pervasive cultural biases that exist, we sought to understand how contemporary educational practices in museums might encourage viewers to consider the context of their preconceptions rather than passively absorb conventional representations. In this two-part study, we tested whether and how viewers (mis)perceptions and interpretations of Native peoples might be influenced by encouraging empathy-specifically by taking the perspective of a Native individual depicted in a photograph they are visually analyzing. We randomly assigned participants in a lab setting (N = 120) and in a museum setting (N = 75) to one of three conditions (perspective-taking, stereotype-suppression, or control), and examined eye movements, self-reports, and verbal and written responses while participants viewed portrait photographs of American Indians. Notably, perspective-taking led viewers to interpret American Indians in a more emotional, empathetic, and human-centered manner than in control and suppression conditions. This was reflected in eye movements such that control and suppression participants attended to decorative features (e.g. jewelry) more than to the eyes of the depicted individual, whereas perspective-takers' attention was more balanced. Similarly, perspective-takers used more empathetic and emotion-related language, whereas participants in control and suppression groups used more "objective" visually-descriptive language. Crucially, regardless of condition, cultural biases were stubbornly resistant to change and, in some cases, appeared even more frequently for participants adopting others' perspectives. We argue that despite the positive outcomes associated with perspective-taking, the continued presence of cultural biases across conditions demonstrates that cultural competency-based interventions must be more complex and culturally-specific.