Multispectral brain connectivity during visual attention distinguishes controlled from uncontrolled hypertension.

Hypertension-related changes in brain function place individuals at higher risk for cognitive impairment and Alzheimer's disease. The existing functional neuroimaging literature has identified important neural and behavioural differences between normotensive and hypertensive individuals. However, previously-used methods (i.e. magnetic resonance imaging, functional near-infrared spectroscopy) rely on neurovascular coupling, which is a useful but indirect measure of neuronal activity. Furthermore, most studies fail to distinguish between controlled and uncontrolled hypertensive individuals, who exhibit significant behavioural and clinical differences. To partially remedy this gap in the literature, we used magnetoencephalography (MEG) to directly examine neuronal activity that is invariant to neurovascular coupling changes induced by hypertension. Our study included 52 participants (19 healthy controls, 15 controlled hypertensives, 18 uncontrolled hypertensives) who completed a modified flanker attention task during MEG. We identified significant oscillatory neural responses in two frequencies (alpha: 8-14 Hz, gamma: 48-60 Hz) for imaging and used grand-averaged images to determine seeds for whole-brain connectivity analysis. We then conducted Fisher-z tests for each pair of groups, using the relationship between the neural connectivity and behavioural attention effects. This highlighted a distributed network of regions associated with cognitive control and selective attention, including frontal-occipital and interhemispheric occipital connections. Importantly, the inferior frontal cortex exhibited a unique neurobehavioural relationship that distinguished the uncontrolled hypertensive group from the controlled hypertensive and normotensive groups. This is the first investigation of hypertension using MEG and identifies critical whole-brain connectivity differences based on hypertension profiles. KEY POINTS: Structural and functional changes in brain circuitry scale with hypertension severity and increase the risk of cognitive impairment and Alzheimer's disease. We harness the excellent spatiotemporal precision of magnetoencephalography (MEG) to directly quantify dynamic functional connectivity in healthy control, controlled hypertensive and uncontrolled hypertensive groups during a flanker task. In the first MEG study of hypertension, we show that there are neurobehavioural relationships that distinguish the uncontrolled hypertensive group from healthy and controlled hypertensive group in the prefrontal cortex. These results provide novel insights into the differential impact of hypertension on brain dynamics underlying selective attention.

Developmentally sensitive multispectral cortical connectivity profiles serving visual selective attention.

Throughout childhood and adolescence, the brain undergoes significant structural and functional changes that contribute to the maturation of multiple cognitive domains, including selective attention. Selective attention is crucial for healthy executive functioning and while key brain regions serving selective attention have been identified, their age-related changes in neural oscillatory dynamics and connectivity remain largely unknown. We examined the developmental sensitivity of selective attention circuitry in 91 typically developing youth aged 6 - 13 years old. Participants completed a number-based Simon task while undergoing magnetoencephalography (MEG) and the resulting data were preprocessed and transformed into the time-frequency domain. Significant oscillatory brain responses were imaged using a beamforming approach, and task-related peak voxels in the occipital, parietal, and cerebellar cortices were used as seeds for subsequent whole-brain connectivity analyses in the alpha and gamma range. Our key findings revealed developmentally sensitive connectivity profiles in multiple regions crucial for selective attention, including the temporoparietal junction (alpha) and prefrontal cortex (gamma). Overall, these findings suggest that brain regions serving selective attention are highly sensitive to developmental changes during the pubertal transition period.

The co-use of nicotine and prescription psychostimulants: A review of their behavioral and neuropharmacological interactions.

BACKGROUND: Nicotine is commonly co-used with other psychostimulants. These high co-use rates have prompted much research on interactions between nicotine and psychostimulant drugs. These studies range from examination of illicitly used psychostimulants such as cocaine and methamphetamine to prescription psychostimulants used to treat attention deficit hyperactivity disorder (ADHD) such as methylphenidate (Ritalin™) and d-amphetamine (active ingredient of Adderall™). However, previous reviews largely focus on nicotine interactions with illicitly used psychostimulants with sparse mention of prescription psychostimulants. The currently available epidemiological and laboratory research, however, suggests high co-use between nicotine and prescription psychostimulants, and that these drugs interact to modulate use liability of either drug. The present review synthesizes epidemiological and experimental human and pre-clinical research assessing the behavioral and neuropharmacological interactions between nicotine and prescription psychostimulants that may contribute to high nicotine-prescription psychostimulant co-use. METHODS: We searched databases for literature investigating acute and chronic nicotine and prescription psychostimulant interactions. Inclusion criteria were that participants/subjects had to experience nicotine and a prescription psychostimulant compound at least once in the study, in addition to assessment of their interaction. RESULTS AND CONCLUSIONS: Nicotine clearly interacts with d-amphetamine and methylphenidate in a variety of behavioral tasks and neurochemical assays assessing co-use liability across preclinical, clinical, and epidemiological research. The currently available research suggests research gaps examining these interactions in women/female rodents, in consideration of ADHD symptoms, and how prescription psychostimulant exposure influences later nicotine-related outcomes. Nicotine has been less widely studied with alternative ADHD pharmacotherapy bupropion, but we also discuss this research.

Altered functional connectivity and oscillatory dynamics in polysubstance and cannabis only users during visuospatial processing.

RATIONALE AND OBJECTIVES: Cannabis use is often associated with the use of other psychoactive substances, which is subsequently linked to an increased risk for addiction. While there is a growing body of neuroimaging literature investigating the cognitive effect of long-term cannabis use, very little is known about the potential additive effects of cannabis polysubstance use. METHODS: Fifty-six adults composed of 18 polysubstance users (i.e., cannabis plus at least one other illicit substance), 19 cannabis-only users, and 19 nonusers completed a visuospatial attention task while undergoing magnetoencephalography. A data-driven approach was used to identify oscillatory neural responses, which were imaged using a beamforming approach. The resulting cortical regions were probed for group differences and used as seeds for whole-brain connectivity analysis. RESULTS: Participants exhibited robust theta, alpha, beta, and gamma responses during visuospatial processing. Statistical analyses indicated that the cannabis-only group had weaker occipital theta relative to the nonusers, and that both polysubstance and cannabis-only users had reduced spontaneous gamma in the occipital cortices during the pre-stimulus baseline period relative to nonusers. Finally, functional connectivity analyses revealed that polysubstance users had sharply reduced beta connectivity between occipital and prefrontal, as well as occipital and left temporal cortices. CONCLUSIONS: Cannabis use should be considered in a polysubstance context, as our correlational design suggests differences in functional connectivity among those who reported cannabis-only versus polysubstance use in occipital to prefrontal pathways critical to visuospatial processing and attention function. Future work should distinguish the effect of different polysubstance combinations and use more causal designs.

A comprehensive study to delineate the role of an extracellular vesicle-associated microRNA-29a in chronic methamphetamine use disorder.

Extracellular vesicles (EVs), which express a repertoire of cargo molecules (cf. proteins, microRNA, lipids, etc.), have been garnering a prominent role in the modulation of several cellular processes. Here, using both non-human primate and rodent model systems, we provide evidence that brain-derived EV (BDE) miRNA, miR-29a-3p (mir-29a), is significantly increased during chronic methamphetamine (MA) exposure. Further, miR-29a levels show significant increase both with drug-seeking and reinstatement in a rat MA self-administration model. We also show that EV-associated miR-29a is enriched in EV pool comprising of small EVs and exomeres and further plays a critical role in MA-induced inflammation and synaptodendritic damage. Furthermore, treatment with the anti-inflammatory drug ibudilast (AV411), which is known to reduce MA relapse, decreased the expression of miR-29a and subsequently attenuated inflammation and rescued synaptodendritic injury. Finally, using plasma from MUD subjects, we provide translational evidence that EV-miR29a could potentially serve as a biomarker to detect neuronal damage in humans diagnosed with MA use disorder (MUD). In summary, our work suggests that EV-associated miR-29a-3p plays a crucial role in MUD and might be used as a potential blood-based biomarker for detecting chronic inflammation and synaptic damage.