The mouse brain after foot shock in four dimensions: Temporal dynamics at a single-cell resolution.

Acute stress leads to sequential activation of functional brain networks. A biologically relevant question is exactly which (single) cells belonging to brain networks are changed in activity over time after acute stress across the entire brain. We developed a preprocessing and analytical pipeline to chart whole-brain immediate early genes' expression-as proxy for cellular activity-after a single stressful foot shock in four dimensions: that is, from functional networks up to three-dimensional (3D) single-cell resolution and over time. The pipeline is available as an R package. Most brain areas (96%) showed increased numbers of c-fos+ cells after foot shock, yet hypothalamic areas stood out as being most active and prompt in their activation, followed by amygdalar, prefrontal, hippocampal, and finally, thalamic areas. At the cellular level, c-fos+ density clearly shifted over time across subareas, as illustrated for the basolateral amygdala. Moreover, some brain areas showed increased numbers of c-fos+ cells, while others-like the dentate gyrus-dramatically increased c-fos intensity in just a subset of cells, reminiscent of engrams; importantly, this "strategy" changed after foot shock in half of the brain areas. One of the strengths of our approach is that single-cell data were simultaneously examined across all of the 90 brain areas and can be visualized in 3D in our interactive web portal.

Alcohol use in emerging adults associated with lower rich-club connectivity and greater connectome network disorganization.

BACKGROUND: Emerging adulthood is a critical neurodevelopmental stage, with alcohol use during this period consistently associated with brain abnormalities and damage in anatomical structure and white matter integrity. However, it is less clear how alcohol use is associated with the brain's structural organization (i.e., white matter connections between anatomical regions). Recent connectome research has focused on rich-club regions, a collection of highly-interconnected hubs that are critical in brain communication and global network organization and disproportionately vulnerable to insults. METHODS: For the first time, we examined alcohol use associations with structural rich-club and connectome organization in emerging adults (N = 66). RESULTS: Greater lifetime drinks and current monthly drinks were significantly associated with lower rich-club organization (rs =-0.38, ps < 0.003) and lower rich-club connectivity (rs <-0.34, ps < 0.007). Additionally, rich-club connectivity was significantly more negatively correlated with alcohol use than connectivity among non-rich-club regions (ps < 0.035). Examining overall structural organization, greater lifetime drinks and current monthly drinks were significantly associated with lower network density (i.e., lower network resilience; rs <-0.36, ps = 0.004). Additionally, greater lifetime drinks and current monthly drinks were significantly associated with higher network segregation (i.e., network's tendency to divide into subnetworks; rs >0.33, ps<0.008). Alcohol use was not significantly associated with network integration (i.e., network's efficiency in combining information across the brain; ps > 0.064). CONCLUSIONS: Results provide novel evidence that alcohol use is associated with decreased rich-club connectivity and structural network disorganization. Given that both are critical in global brain communication, these results highlight the importance of examining alcohol use and brain relationships in emerging adulthood.

Fronto-temporal cortical atrophy in 'nyaope' combination heroin and cannabis use disorder.

Sub-Saharan Africa is one of the top three regions with the highest rates of opioid-related premature mortality. Nyaope is the street name for what is believed to be a drug cocktail in South Africa although recent research suggests that it is predominantly heroin. Nyaope powder is most commonly smoked together with cannabis, a drug-use pattern unique to the region. Due to the increasing burden of this drug in low-income communities and the absence of human structural neuroimaging data of combination heroin and cannabis use disorder, we initiated an important cohort study in order to identify neuroanatomical sequelae. Twenty-eight male nyaope users and thirty healthy, matched controls were recruited from drug rehabilitation centers and the community, respectively. T1-weighted MRI images were obtained using a 3 T General Electric Discovery and cortical thickness was examined and compared. Nyaope users displayed extensive grey matter atrophy in the right hemispheric medial orbitofrontal, rostral middle frontal, superior temporal, superior frontal, and supramarginal gyri (two-sided t-test, p < 0.05, corrected for multiple comparisons). Our findings indicate cortical abnormality in nyaope users in regions involved in impulse control, decision making, social- and self-perception, and working memory. Importantly, affected brain regions show large overlap with the pattern of cortical abnormalities shown in heroin use disorder.

Short fused? associations between white matter connections, sex steroids, and aggression across adolescence.

Functional neuroimaging studies in adults show that aggression involves reduced brain communication between subcortical and cortical areas dedicated to motivation and control, respectively. Prior research indicates that sex steroid hormone production during adolescence negatively influences the rapid development of white matter connectivity between subcortical and cortical areas during adolescence and may potentiate aggression. Here, we tested this hypothesis in 258 participants between 8 and 25 years of age by using Diffusion Weighted Imaging to examine the microstructure of white matter connections within the fronto-temporal-subcortical network. Trait aggression was measured using the Buss Perry Aggression Questionnaire and testosterone and estradiol levels were measured in saliva. Results indicated that higher levels of testosterone were associated with less white matter integrity within the fronto-temporal-subcortical network (i.e., higher mean diffusivity [MD] longitudinal [LD], and radial diffusivity [RD]). Furthermore, lower fractional anisotropy and higher MD, LD, and RD values within this network increased expressive forms of aggression and reduced inhibited forms of aggression (hostility). Our study indicates higher levels of testosterone relating to lower quality of structural cortical-subcortical connectivity, arguably resulting in a shift from inhibited towards expressive forms of aggression. Our data adds evidence to the idea that aggressive tendencies are subcortically driven, but individuals with relatively high testosterone might have lower structural connectivity within cortical control areas, resulting in a stronger tendency to act on these aggressive tendencies.

Brain connectivity in neurodegenerative diseases--from phenotype to proteinopathy.

Functional and structural connectivity measures, as assessed by means of functional and diffusion MRI, are emerging as potential intermediate biomarkers for Alzheimer disease (AD) and other disorders. This Review aims to summarize current evidence that connectivity biomarkers are associated with upstream and downstream disease processes (molecular pathology and clinical symptoms, respectively) in the major neurodegenerative diseases. The vast majority of studies have addressed functional and structural connectivity correlates of clinical phenotypes, confirming the predictable correlation with topography and disease severity in AD and frontotemporal dementia. In neurodegenerative diseases with motor symptoms, structural--but, to date, not functional--connectivity has been consistently found to be associated with clinical phenotype and disease severity. In the latest studies, the focus has moved towards the investigation of connectivity correlates of molecular pathology. Studies in cognitively healthy individuals with brain amyloidosis or genetic risk factors for AD have shown functional connectivity abnormalities in preclinical disease stages that are reminiscent of abnormalities observed in symptomatic AD. This shift in approach is promising, and may aid identification of early disease markers, establish a paradigm for other neurodegenerative disorders, shed light on the molecular neurobiology of connectivity disruption and, ultimately, clarify the pathophysiology of neurodegenerative diseases.