Hypertension Impacts the Oscillatory Dynamics Serving the Encoding Phase of Verbal Working Memory.

BACKGROUND: Chronic hypertension is known to be a major contributor to cognitive decline, with executive function and working memory being among the domains most commonly affected. Despite the growing literature on such dysfunction in patients with hypertension, the underlying neural processes are poorly understood. METHODS: In this cross-sectional study, we examine these neural processes by having participants with controlled hypertension, uncontrolled hypertension, and healthy controls perform a verbal working memory task during magnetoencephalography. Neural oscillations associated with the encoding and maintenance components of the working memory task were imaged and statistically evaluated among the 3 groups. RESULTS: Differences related to hypertension emerged during the encoding phase, where the hypertension groups exhibited weaker α-ß oscillatory responses compared with controls in the left parietal cortices, whereas such oscillatory activity differed between the 2 hypertension groups in the right prefrontal regions. Importantly, these neural responses in the prefrontal and parietal cortices during encoding were also significantly associated with behavioral performance across all participants. CONCLUSIONS: Overall, our data suggest that hypertension is associated with neurophysiological abnormalities during working memory encoding, whereas the neural processes serving maintenance seem to be preserved. The right hemispheric neural responses likely reflected compensatory processing, which patients with controlled hypertension may use to achieve verbal working memory function at the level of controls, as opposed to the uncontrolled hypertension group where diminished resources may have limited such additional recruitment.

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.

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.

Better with age: Developmental changes in oscillatory activity during verbal working memory encoding and maintenance.

Numerous investigations have characterized the oscillatory dynamics serving working memory in adults, but few have probed its relationship with chronological age in developing youth. We recorded magnetoencephalography during a modified Sternberg verbal working memory task in 82 youth participants aged 6-14 years old. Significant oscillatory responses were identified and imaged using a beamforming approach and the resulting whole-brain maps were probed for developmental effects during the encoding and maintenance phases. Our results indicated robust oscillatory responses in the theta (4-7 Hz) and alpha (8-14 Hz) range, with older participants exhibiting stronger alpha oscillations in left-hemispheric language regions. Older participants also had greater occipital theta power during encoding. Interestingly, there were sex-by-age interaction effects in cerebellar cortices during encoding and in the right superior temporal region during maintenance. These results extend the existing literature on working memory development by showing strong associations between age and oscillatory dynamics across a distributed network. To our knowledge, these findings are the first to link chronological age to alpha and theta oscillatory responses serving working memory encoding and maintenance, both across and between male and female youth; they reveal robust developmental effects in crucial brain regions serving higher order functions.

Regular cannabis use alters the neural dynamics serving complex motor control.

Cannabis is the most widely used recreational drug in the United States and regular use has been linked to deficits in attention and memory. However, the effects of regular use on motor control are less understood, with some studies showing deficits and others indicating normal performance. Eighteen users and 23 nonusers performed a motor sequencing task during high-density magnetoencephalography (MEG). The MEG data was transformed into the time-frequency domain and beta responses (16-24 Hz) during motor planning and execution phases were imaged separately using a beamformer approach. Whole-brain maps were examined for group (cannabis user/nonuser) and time window (planning/execution) effects. As expected, there were no group differences in task performance (e.g., reaction time, accuracy, etc.). Regular cannabis users exhibited stronger beta oscillations in the contralateral primary motor cortex compared to nonusers during the execution phase of the motor sequences, but not during the motor planning phase. Similar group-by-time window interactions were observed in the left superior parietal, right inferior frontal cortices, right posterior insular cortex, and the bilateral motor cortex. We observed differences in the neural dynamics serving motor control in regular cannabis users compared to nonusers, suggesting regular users may employ compensatory processing in both primary motor and higher-order motor cortices to maintain adequate task performance. Future studies will need to examine more complex motor control tasks to ascertain whether this putative compensatory activity eventually becomes exhausted and behavioral differences emerge.

Developmental alterations in the neural oscillatory dynamics underlying attentional reorienting.

The neural and cognitive processes underlying the flexible allocation of attention undergo a protracted developmental course with changes occurring throughout adolescence. Despite documented age-related improvements in attentional reorienting throughout childhood and adolescence, the neural correlates underlying such changes in reorienting remain unclear. Herein, we used magnetoencephalography (MEG) to examine neural dynamics during a Posner attention-reorienting task in 80 healthy youth (6-14 years old). The MEG data were examined in the time-frequency domain and significant oscillatory responses were imaged in anatomical space. During the reorienting of attention, youth recruited a distributed network of regions in the fronto-parietal network, along with higher-order visual regions within the theta (3-7 Hz) and alpha-beta (10-24 Hz) spectral windows. Beyond the expected developmental improvements in behavioral performance, we found stronger theta oscillatory activity as a function of age across a network of prefrontal brain regions irrespective of condition, as well as more limited age- and validity-related effects for alpha-beta responses. Distinct brain-behavior associations between theta oscillations and attention-related symptomology were also uncovered across a network of brain regions. Taken together, these data are the first to demonstrate developmental effects in the spectrally-specific neural oscillations serving the flexible allocation of attention.

Testosterone levels mediate the dynamics of motor oscillatory coding and behavior in developing youth.

Recent investigations have studied the development of motor-related oscillatory responses to delineate maturational changes from childhood to young adulthood. While these studies included youth during the pubertal transition period, none have probed the impact of testosterone levels on motor cortical dynamics and performance. We collected salivary testosterone samples and recorded magnetoencephalography during a complex motor sequencing task in 58 youth aged 9-15 years old. The relationships between testosterone, age, task behavior, and beta (15-23 Hz) oscillatory dynamics were examined using multiple mediation modeling. We found that testosterone mediated the effect of age on movement-related beta activity. We also found that the effect of age on movement duration was mediated by testosterone and reaction time. Interestingly, the relationships between testosterone and motor performance were not mediated by beta activity in the left primary motor cortex, which may indicate the importance of higher-order motor regions. Overall, our results suggest that testosterone has unique associations with neural and behavioral indices of complex motor performance, beyond those already characterized in the literature. These findings are the first to link developmental changes in testosterone levels to maturation of beta oscillatory dynamics serving complex motor planning and execution, and specific measures of motor performance.

Left amygdala structure mediates longitudinal associations between exposure to threat and long-term psychiatric symptomatology in youth.

Traumatic experiences during childhood can have profound effects on stress sensitive brain structures (e.g., amygdala and hippocampus) and the emergence of psychiatric symptoms. Recent theoretical and empirical work has delineated dimensions of trauma (i.e., threat and deprivation) as having distinct neural and behavioral effects, although there are few longitudinal examinations. A sample of 243 children and adolescents were followed for three time points, with each assessment approximately 1 year apart (ages 9-15 years at Time 1; 120 males). Participants or their caregiver reported on youths' threat exposure, perceived stress (Time 1), underwent a T1-weighted structural high-resolution MRI scan (Time 2), and documented their subsequent psychiatric symptoms later in development (Time 3). The primary findings indicate that left amygdala volume, in particular, mediated the longitudinal association between threat exposure and subsequent internalizing and externalizing symptomatology. Greater threat exposure related to reduced left amygdala volume, which in turn differentially predicted internalizing and externalizing symptoms. Decreased bilateral hippocampal volume was related to subsequently elevated internalizing symptoms. These findings suggest that the left amygdala is highly threat-sensitive and that stress-related alterations may partially explain elevated psychopathology in stress-exposed adolescents. Uncovering potential subclinical and/or preclinical predictive biomarkers is essential to understanding the emergence, progression, and eventual targeted treatment of psychopathology following trauma exposure.

Trauma moderates the development of the oscillatory dynamics serving working memory in a sex-specific manner.

Working memory, the ability to hold items in memory stores for further manipulation, is a higher order cognitive process that supports many aspects of daily life. Childhood trauma has been associated with altered cognitive development including particular deficits in verbal working memory (VWM), but the neural underpinnings remain poorly understood. Magnetoencephalography (MEG) studies of VWM have reliably shown decreased alpha activity in left-lateralized language regions during encoding, and increased alpha activity in parieto-occipital cortices during the maintenance phase. In this study, we examined whether childhood trauma affects behavioral performance and the oscillatory dynamics serving VWM using MEG in a cohort of 9- to 15-year-old youth. All participants completed a modified version of the UCLA Trauma History Profile and then performed a VWM task during MEG. Our findings indicated a sex-by-age-by-trauma three-way interaction, whereby younger females experiencing higher levels of trauma had the lowest d' accuracy scores and the strongest positive correlations with age (i.e. older performed better). Likewise, females with higher levels of childhood trauma exhibited altered age-related alpha changes during the maintenance phase within the right temporal and parietal cortices. These findings suggest that trauma exposure may alter the developmental trajectory of neural oscillations serving VWM processing in a sex-specific way.

Alcohol use disorder and cannabis use disorder symptomatology in adolescents is associated with dysfunction in neural processing of future events.

Two of the most commonly used substances by adolescents in the United States are cannabis and alcohol. Cannabis use disorder (CUD) and alcohol use disorder (AUD) are associated with impairments in decision-making processes. One mechanism for impaired decision-making in these individuals is thought to be an inability to adequately represent future events during decision-making. In the current study involving 112 adolescents, we used a comparative optimism task to examine the relationship between relative severity of CUD/AUD (as indexed by the CUD/AUD Identification Tests [CUDIT/AUDIT]) and atypical function within neural systems underlying affect-based neural represenation future events. Greater CUDIT scores were negatively related to responses within subgenual anterior and posterior cingulate cortex when processing high-intensity potential future positive and negative events. There was also a particularly marked negative relationship between CUD symptoms and blood oxygen level-dependent (BOLD) responses within visual and premotor cortices to high-intensity, negatively valenced potential future events. However, AUD symptom severity was not associated with dysfunction within these brain regions. These data indicate that relative risk/severity of CUD is associated with reduced responsiveness to future high-intensity events. This may impair decision-making where future significant consequences should guide response choice.

Development and sex modulate visuospatial oscillatory dynamics in typically-developing children and adolescents.

Visuospatial processing is a cognitive function that is critical to navigating one's surroundings and begins to develop during infancy. Extensive research has examined visuospatial processing in adults, but far less work has investigated how visuospatial processing and the underlying neurophysiology changes from childhood to early adolescence, which is a critical period of human development that is marked by the onset of puberty. In the current study, we examined behavioral performance and the oscillatory dynamics serving visuospatial processing using magnetoencephalography (MEG) in a cohort of 70 children and young adolescents aged 8-15 years. All participants performed a visuospatial processing task during MEG, and the resulting oscillatory responses were imaged using a beamformer and probed for developmental and sex-related differences. Our findings indicated that reaction time on the task was negatively correlated with age, and that the amplitude of theta oscillations in the medial occipital cortices increased with age. Significant sex-by-age interactions were also detected, with female participants exhibiting increased theta oscillatory activity in the right prefrontal cortex with increasing age, while male participants exhibited theta increases in the left parietal lobe/left precuneus and left supplementary motor area with increasing age. These data indicate that different nodes of the visuospatial processing network develop earlier in males compared to females (and vice versa) in this age range, which may have major implications for the developmental trajectory of behavioral performance and executive function more generally during the transition through puberty.

Differential dysfunctions related to alcohol and cannabis use disorder symptoms in reward and error-processing neuro-circuitries in adolescents.

Alcohol and cannabis are two of the most commonly used substances by adolescents and are associated with adverse medical and psychiatric outcomes. These adverse psychiatric outcomes may reflect the negative impact of alcohol and/or cannabis abuse on neural systems mediating reward and/or error detection. However, work indicative of this has mostly been conducted in adults with Alcohol and/or Cannabis Use Disorder (i.e., AUD and CUD), with relatively little work in adolescent patients. Furthermore, of the work that has been conducted in adolescents, groups were based on categorical diagnoses of AUD and/or CUD, so the relationship between AUD and/or CUD symptom severity in adolescents and neural dysfunction is unclear. We used a Monetary Incentive Delay (MID) task to examine the relationship between AUDIT and/or CUDIT scores and functional integrity of neuro-circuitries mediating reward processing and error detection within 150 adolescents. Our findings indicate that AUDIT score is negatively related to activity in reward processing neuro-circuitry in adolescents. However, CUDIT score is negatively related to activity in brain regions involved in error detection. Each of these relationships reflected a medium effect size (Partial-η2 0.09-0.14). These data suggest differential impacts of AUD and CUD on reward versus error detection neuro-circuitries within the adolescent brain.

Adolescents show differential dysfunctions related to Alcohol and Cannabis Use Disorder severity in emotion and executive attention neuro-circuitries.

Alcohol and cannabis are two substances that are commonly abused by adolescents in the United States and which, when abused, are associated with negative medical and psychiatric outcomes across the lifespan. These negative psychiatric outcomes may reflect the detrimental impact of substance abuse on neural systems mediating emotion processing and executive attention. However, work indicative of this has mostly been conducted either in animal models or adults with Alcohol and/or Cannabis Use Disorder (AUD/CUD). Little work has been conducted in adolescent patients. In this study, we used the Affective Stroop task to examine the relationship in 82 adolescents between AUD and/or CUD symptom severity and the functional integrity of neural systems mediating emotional processing and executive attention. We found that AUD symptom severity was positively related to amygdala responsiveness to emotional stimuli and negatively related to responsiveness within regions implicated in executive attention and response control (i.e., dorsolateral prefrontal cortex, anterior cingulate cortex, precuneus) as a function of task performance. In contrast, CUD symptom severity was unrelated to amygdala responsiveness but positively related to responsiveness within regions including precuneus, posterior cingulate cortex, and inferior parietal lobule as a function of task performance. These data suggest differential impacts of alcohol and cannabis abuse on the adolescent brain.