Spontaneous cortical dynamics from the first years to the golden years.

In the largest and most expansive lifespan magnetoencephalography (MEG) study to date (n = 434, 6 to 84 y), we provide critical data on the normative trajectory of resting-state spontaneous activity and its temporal dynamics. We perform cutting-edge analyses to examine age and sex effects on whole-brain, spatially-resolved relative and absolute power maps, and find significant age effects in all spectral bands in both types of maps. Specifically, lower frequencies showed a negative correlation with age, while higher frequencies positively correlated with age. These correlations were further probed with hierarchical regressions, which revealed significant nonlinear trajectories in key brain regions. Sex effects were found in absolute but not relative power maps, highlighting key differences between outcome indices that are generally used interchangeably. Our rigorous and innovative approach provides multispectral maps indicating the unique trajectory of spontaneous neural activity across the lifespan, and illuminates key methodological considerations with the widely used relative/absolute power maps of spontaneous cortical dynamics.

Neuromodulatory effects of parietal high-definition transcranial direct-current stimulation on network-level activity serving fluid intelligence.

Fluid intelligence (Gf) involves rational thinking skills and requires the integration of information from different cortical regions to resolve novel complex problems. The effects of non-invasive brain stimulation on Gf have been studied in attempts to improve Gf, but such studies are rare and the few existing have reached conflicting conclusions. The parieto-frontal integration theory of intelligence (P-FIT) postulates that the parietal and frontal lobes play a critical role in Gf. To investigate the suggested role of parietal cortices, we applied high-definition transcranial direct current stimulation (HD-tDCS) to the left and right parietal cortices of 39 healthy adults (age 19-33 years) for 20 min in three separate sessions (left active, right active and sham). After completing the stimulation session, the participants completed a logical reasoning task based on Raven's Progressive Matrices during magnetoencephalography. Significant neural responses at the sensor level across all stimulation conditions were imaged using a beamformer. Whole-brain, spectrally constrained functional connectivity was then computed to examine the network-level activity. Behaviourally, we found that participants were significantly more accurate following left compared to right parietal stimulation. Regarding neural findings, we found significant HD-tDCS montage-related effects in brain networks thought to be critical for P-FIT, including parieto-occipital, fronto-occipital, fronto-parietal and occipito-cerebellar connectivity during task performance. In conclusion, our findings showed that left parietal stimulation improved abstract reasoning abilities relative to right parietal stimulation and support both P-FIT and the neural efficiency hypothesis. KEY POINTS: Abstract reasoning is a critical component of fluid intelligence and is known to be served by multispectral oscillatory activity in the fronto-parietal cortices. Recent studies have aimed to improve abstract reasoning abilities and fluid intelligence overall through behavioural training, but the results have been mixed. High-definition transcranial direct-current stimulation (HD-tDCS) applied to the parietal cortices modulated task performance and neural oscillations during abstract reasoning. Left parietal stimulation resulted in increased accuracy and decreased functional connectivity between occipital regions and frontal, parietal, and cerebellar regions. Future studies should investigate whether HD-tDCS alters abstract reasoning abilities in those who exhibit declines in performance, such as healthy ageing populations.

Effects of endogenous testosterone on oscillatory activity during verbal working memory in youth.

Testosterone levels sharply rise during the transition from childhood to adolescence and these changes are known to be associated with changes in human brain structure. During this same developmental window, there are also robust changes in the neural oscillatory dynamics serving verbal working memory processing. Surprisingly, whereas many studies have investigated the effects of chronological age on the neural oscillations supporting verbal working memory, none have probed the impact of endogenous testosterone levels during this developmental period. Using a sample of 89 youth aged 6-14 years-old, we collected salivary testosterone samples and recorded magnetoencephalography during a modified Sternberg verbal working memory task. Significant oscillatory responses were identified and imaged using a beamforming approach and the resulting maps were subjected to whole-brain ANCOVAs examining the effects of testosterone and sex, controlling for age, during verbal working memory encoding and maintenance. Our primary results indicated robust testosterone-related effects in theta (4-7 Hz) and alpha (8-14 Hz) oscillatory activity, controlling for age. During encoding, females exhibited weaker theta oscillations than males in right cerebellar cortices and stronger alpha oscillations in left temporal cortices. During maintenance, youth with greater testosterone exhibited weaker alpha oscillations in right parahippocampal and cerebellar cortices, as well as regions across the left-lateralized language network. These results extend the existing literature on the development of verbal working memory processing by showing region and sex-specific effects of testosterone, and are the first results to link endogenous testosterone levels to the neural oscillatory activity serving verbal working memory, above and beyond the effects of chronological age.

Glycemic control level alters working memory neural dynamics in adults with type 2 diabetes.

Poor glycemic control in type 2 diabetes has been associated with accentuated age-related cognitive decline, although the underlying neural mechanisms are not well understood. The current study sought to identify the impact of glycemic control on the neural dynamics serving working memory in adults with type 2 diabetes. Participants (n = 34, ages = 55-73) performed a working memory task while undergoing MEG. Significant neural responses were examined relative to poorer (A1c > 7.0%) or tighter glycemic control (A1c < 7.0%). Those with poorer glycemic control showed diminished responses within left temporal and prefrontal regions during encoding and showed diminished responses within right occipital cortex during maintenance but showed an enhanced activity in the left temporal, occipital, and cerebellar regions during maintenance. Notably, left temporal activity in encoding and left lateral occipital activity in maintenance significantly predicted performance on the task such that diminished temporal activity led to longer reaction times, which were driven by the poorer glycemic control group. Greater lateral occipital activity during maintenance was associated with both lower accuracy and longer reaction times across all participants. These findings suggest that glycemic control has a robust impact on the neural dynamics serving working memory, with distinct effects by subprocess (e.g. encoding vs. maintenance) and direct effects on behavior.

Convergent and divergent oscillatory aberrations during visuospatial processing in HIV-related cognitive impairment and Alzheimer's disease.

Adults with HIV frequently develop a form of mild cognitive impairment known as HIV-associated neurocognitive disorder (HAND), but presumably cognitive decline in older persons with HIV could also be attributable to Alzheimer's disease (AD). However, distinguishing these two conditions in individual patients is exceedingly difficult, as the distinct neural and neuropsychological features are poorly understood and most studies to date have only investigated HAND or AD spectrum (ADS) disorders in isolation. The current study examined the neural dynamics underlying visuospatial processing using magnetoencephalography (MEG) in 31 biomarker-confirmed patients on the ADS, 26 older participants who met criteria for HAND, and 31 older cognitively normal controls. MEG data were examined in the time-frequency domain, and a data-driven approach was utilized to identify the neural dynamics underlying visuospatial processing. Both clinical groups (ADS/HAND) were significantly less accurate than controls on the task and exhibited stronger prefrontal theta oscillations compared to controls. Regarding disease-specific alterations, those with HAND exhibited stronger alpha oscillations than those on the ADS in frontoparietal and temporal cortices. These results indicate both common and unique neurophysiological alterations among those with ADS disorders and HAND in regions serving visuospatial processing and suggest the underlying neuropathological features are at least partially distinct.

Developmental differences in functional organization of multispectral networks.

Assessing brain connectivity during rest has become a widely used approach to identify changes in functional brain organization during development. Generally, previous works have demonstrated that brain activity shifts from more local to more distributed processing from childhood into adolescence. However, the majority of those works have been based on functional magnetic resonance imaging measures, whereas multispectral functional connectivity, as measured using magnetoencephalography (MEG), has been far less characterized. In our study, we examined spontaneous cortical activity during eyes-closed rest using MEG in 101 typically developing youth (9-15 years old; 51 females, 50 males). Multispectral MEG images were computed, and connectivity was estimated in the canonical delta, theta, alpha, beta, and gamma bands using the imaginary part of the phase coherence, which was computed between 200 brain regions defined by the Schaefer cortical atlas. Delta and alpha connectivity matrices formed more communities as a function of increasing age. Connectivity weights predominantly decreased with age in both frequency bands; delta-band differences largely implicated limbic cortical regions and alpha band differences in attention and cognitive networks. These results are consistent with previous work, indicating the functional organization of the brain becomes more segregated across development, and highlight spectral specificity across different canonical networks.

Alpha oscillations in left perisylvian cortices support semantic processing and predict performance.

Semantic processing is the ability to discern and maintain conceptual relationships among words and objects. While the neural circuits serving semantic representation and controlled retrieval are well established, the neuronal dynamics underlying these processes are poorly understood. Herein, we examined 25 healthy young adults who completed a semantic relation word-matching task during magnetoencephalography (MEG). MEG data were examined in the time-frequency domain and significant oscillatory responses were imaged using a beamformer. Whole-brain statistical analyses were conducted to compare semantic-related to length-related neural oscillatory responses. Time series were extracted to visualize the dynamics and were linked to task performance using structural equation modeling. The results indicated that participants had significantly longer reaction times in semantic compared to length trials. Robust MEG responses in the theta (3-6 Hz), alpha (10-16 Hz), and gamma (64-76 Hz and 64-94 Hz) bands were observed in parieto-occipital and frontal cortices. Whole-brain analyses revealed stronger alpha oscillations in a left-lateralized network during semantically related relative to length trials. Importantly, stronger alpha oscillations in the left superior temporal gyrus during semantic trials predicted faster responses. These data reinforce existing literature and add novel temporal evidence supporting the executive role of the semantic control network in behavior.

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.

Spontaneous sensorimotor beta power and cortical thickness uniquely predict motor function in healthy aging.

BACKGROUND: Spontaneous beta activity in the primary motor cortices has been shown to increase in amplitude with advancing age, and that such increases are tightly coupled to stronger motor-related beta oscillations during movement planning. However, the relationship between these age-related changes in spontaneous beta in the motor cortices, local cortical thickness, and overall motor function remains unclear. METHODS: We collected resting-state magnetoencephalography (MEG), high-resolution structural MRI, and motor function scores using a neuropsychological battery from 126 healthy adults (56 female; age range = 22-72 years). MEG data were source-imaged and a whole-brain vertex-wise regression model was used to assess age-related differences in spontaneous beta power across the cortex. Cortical thickness was computed from the structural MRI data and local beta power and cortical thickness values were extracted from the sensorimotor cortices. To determine the unique contribution of age, spontaneous beta power, and cortical thickness to the prediction of motor function, a hierarchical regression approach was used. RESULTS: There was an increase in spontaneous beta power with age across the cortex, with the strongest increase being centered on the sensorimotor cortices. Sensorimotor cortical thickness was not related to spontaneous beta power, above and beyond age. Interestingly, both cortical thickness and spontaneous beta power in sensorimotor regions each uniquely contributed to the prediction of motor function when controlling for age. DISCUSSION: This multimodal study showed that cortical thickness and spontaneous beta activity in the sensorimotor cortices have dissociable contributions to motor function across the adult lifespan. These findings highlight the complexity of interactions between structure and function and the importance of understanding these interactions in order to advance our understanding of healthy aging and disease.

Individual differences in amygdala volumes predict changes in functional connectivity between subcortical and cognitive control networks throughout adolescence.

Adolescence is a critical period of structural and functional neural maturation among regions serving the cognitive control of emotion. Evidence suggests that this process is guided by developmental changes in amygdala and striatum structure and shifts in functional connectivity between subcortical (SC) and cognitive control (CC) networks. Herein, we investigate the extent to which such developmental shifts in structure and function reciprocally predict one another over time. 179 youth (9-15 years-old) completed annual MRI scans for three years. Amygdala and striatum volumes and connectivity within and between SC and CC resting state networks were measured for each year. We tested for reciprocal predictability of within-person and between-person changes in structure and function using random-intercept cross-lagged panel models. Within-person shifts in amygdala volumes in a given year significantly and specifically predicted deviations in SC-CC connectivity in the following year, such that an increase in volume was associated with decreased SC-CC connectivity the following year. Deviations in connectivity did not predict changes in amygdala volumes over time. Conversely, broader group-level shifts in SC-CC connectivity were predictive of subsequent deviations in striatal volumes. We did not see any cross-predictability among amygdala or striatum volumes and within-network connectivity measures. Within-person shifts in amygdala structure year-to-year robustly predicted weaker SC-CC connectivity in subsequent years, whereas broader increases in SC-CC connectivity predicted smaller striatal volumes over time. These specific structure function relationships may contribute to the development of emotional control across adolescence.

Eyes-closed versus eyes-open differences in spontaneous neural dynamics during development.

BACKGROUND: Assessing brain activity during rest has become a widely used approach in developmental neuroscience. Extant literature has measured resting brain activity both during eyes-open and eyes-closed conditions, but the difference between these conditions has not yet been well characterized. Studies, limited to fMRI and EEG, have suggested that eyes-open versus -closed conditions may differentially impact neural activity, especially in visual cortices. METHODS: Spontaneous cortical activity was recorded using MEG from 108 typically developing youth (9-15 years-old; 55 female) during separate sessions of eyes-open and eyes-closed rest. MEG source images were computed, and the strength of spontaneous neural activity was estimated in the canonical delta, theta, alpha, beta, and gamma bands, respectively. Power spectral density maps for eyes-open were subtracted from eyes-closed rest, and then submitted to vertex-wise regression models to identify spatially specific differences between conditions and as a function of age and sex. RESULTS: Relative alpha power was weaker in the eyes-open compared to -closed condition, but otherwise eyes-open was stronger in all frequency bands, with differences concentrated in the occipital cortex. Relative theta power became stronger in the eyes-open compared to the eyes-closed condition with increasing age in frontal cortex. No differences were observed between males and females. CONCLUSIONS: The differences in relative power from eyes-closed to -open conditions are consistent with changes observed in task-based visual sensory responses. Age differences occurred in relatively late developing frontal regions, consistent with canonical attention regions, suggesting that these differences could be reflective of developmental changes in attention processes during puberty. Taken together, resting-state paradigms using eyes-open versus -closed produce distinct results and, in fact, can help pinpoint sensory related brain activity.

Differential impact of movement on the alpha and gamma dynamics serving visual processing.

Visual processing is widely understood to be served by a decrease in alpha activity in occipital cortices, largely concurrent with an increase in gamma activity. Although the characteristics of these oscillations are well documented in response to a range of complex visual stimuli, little is known about how these dynamics are impacted by concurrent motor responses, which is problematic as many common visual tasks involve such responses. Thus, in the current study, we used magnetoencephalography (MEG) and modified a well-established visual paradigm to explore the impact of motor responses on visual oscillatory activity. Thirty-four healthy adults viewed a moving gabor (grating) stimulus that was known to elicit robust alpha and gamma oscillations in occipital cortices. Frequency and power characteristics were assessed statistically for differences as a function of movement condition. Our results indicated that occipital alpha significantly increased in power during movement relative to no movement trials. No differences in peak frequency or power were found for gamma responses between the two movement conditions. These results provide valuable evidence of visuomotor integration and underscore the importance of careful task design and interpretation, especially in the context of complex visual processing, and suggest that even basic motor responses alter occipital visual oscillations in healthy adults.NEW & NOTEWORTHY Processing of visual stimuli is served by occipital alpha and gamma activity. Many studies have investigated the impact of visual stimuli on motor cortical responses, but few studies have systematically investigated the impact of motor responses on visual oscillations. We found that when participants are asked to move in response to a visual stimulus, occipital alpha power was modulated whereas gamma responses were unaffected. This suggests that these responses have dissociable roles in visuomotor integration.

High-definition transcranial direct current stimulation of the occipital cortices induces polarity dependent effects within the brain regions serving attentional reorientation.

Numerous brain stimulation studies have targeted the posterior parietal cortex, a key hub of the attention network, to manipulate attentional reorientation. However, the impact of stimulating brain regions earlier in the pathway, including early visual regions, is poorly understood. In this study, 28 healthy adults underwent three high-definition transcranial direct current stimulation (HD-tDCS) visits (i.e., anodal, cathodal, and sham). During each visit, they completed 20 min of occipital HD-tDCS and then a modified Posner task during magnetoencephalography (MEG). MEG data were transformed into the time-frequency domain and significant oscillatory events were imaged using a beamformer. Oscillatory response amplitude values were extracted from peak voxels in the whole-brain maps and were statistically compared. Behaviorally, we found that the participants responded slowly when attention reallocation was needed (i.e., the validity effect), irrespective of the stimulation condition. Our neural findings indicated that cathodal HD-tDCS was associated with significantly reduced theta validity effects in the occipital cortices, as well as reduced alpha validity effects in the left occipital and parietal cortices relative to anodal HD-tDCS. Additionally, anodal occipital stimulation significantly increased gamma amplitude in right occipital regions relative to cathodal and sham stimulation. Finally, we also found a negative correlation between the alpha validity effect and reaction time following anodal stimulation. Our findings suggest that HD-tDCS of the occipital cortices has a polarity dependent impact on the multispectral neural oscillations serving attentional reorientation in healthy adults, and that such effects may reflect altered local GABA concentrations in the neural circuitry serving attentional reorientation.

Cortisol changes in healthy children and adolescents during the COVID-19 pandemic.

The Coronavirus Disease 2019 (COVID-19) pandemic has caused massive disruptions to daily life in the United States, closing schools and businesses and increasing physical and social isolation, leading to deteriorations in mental health and well-being in people of all ages. Many studies have linked chronic stress with long-term changes in cortisol secretion, which has been implicated in many stress-related physical and mental health problems that commonly emerge in adolescence. However, the physiological consequences of the pandemic in youth remain understudied. Using hair cortisol concentrations (HCC), we quantified average longitudinal changes in cortisol secretion across a four-month period capturing before, during, and after the transition to pandemic-lockdown conditions in a sample of healthy youth (n = 49). Longitudinal changes in HCC were analyzed using linear mixed-effects models. Perceived levels of pandemic-related stress were measured and compared to the physiological changes in HCC. In children and adolescents, cortisol levels significantly increased across the course of the pandemic. These youth reported a multitude of stressors during this time, although changes in HCC were not associated with self-reported levels of COVID-19-related distress. We provide evidence that youth are experiencing significant physiological changes in cortisol activity across the COVID-19 pandemic, yet these biological responses are not associated with perceived stress levels. Youth may be especially vulnerable to the deleterious impacts of chronic cortisol exposure due to their current status in the sensitive periods for development, and the incongruency between biological and psychological stress responses may further complicate these developmental problems.

Multielectrode Transcranial Electrical Stimulation of the Left and Right Prefrontal Cortices Differentially Impacts Verbal Working Memory Neural Circuitry.

Recent studies have examined the effects of conventional transcranial direct current stimulation (tDCS) on working memory (WM) performance, but this method has relatively low spatial precision and generally involves a reference electrode that complicates interpretation. Herein, we report a repeated-measures crossover study of 25 healthy adults who underwent multielectrode tDCS of the left dorsolateral prefrontal cortex (DLPFC), right DLPFC, or sham in 3 separate visits. Shortly after each stimulation session, participants performed a verbal WM (VWM) task during magnetoencephalography, and the resulting data were examined in the time-frequency domain and imaged using a beamformer. We found that after left DLPFC stimulation, participants exhibited stronger responses across a network of left-lateralized cortical areas, including the supramarginal gyrus, prefrontal cortex, inferior frontal gyrus, and cuneus, as well as the right hemispheric homologues of these regions. Importantly, these effects were specific to the alpha-band, which has been previously implicated in VWM processing. Although stimulation condition did not significantly affect performance, stepwise regression revealed a relationship between reaction time and response amplitude in the left precuneus and supramarginal gyrus. These findings suggest that multielectrode tDCS targeting the left DLPFC affects the neural dynamics underlying offline VWM processing, including utilization of a more extensive bilateral cortical network.

Numerical working memory alters alpha-beta oscillations and connectivity in the parietal cortices.

Although the neural bases of numerical processing and memory have been extensively studied, much remains to be elucidated concerning the spectral and temporal dynamics surrounding these important cognitive processes. To further this understanding, we employed a novel numerical working memory paradigm in 28 young, healthy adults who underwent magnetoencephalography (MEG). The resulting data were examined in the time-frequency domain prior to image reconstruction using a beamformer. Whole-brain, spectrally-constrained coherence was also employed to determine network connectivity. In response to the numerical task, participants exhibited robust alpha/beta oscillations in the bilateral parietal cortices. Whole-brain statistical comparisons examining the effect of numerical manipulation during memory-item maintenance revealed a difference centered in the right superior parietal cortex, such that oscillatory responses during numerical manipulation were significantly stronger than when no manipulation was necessary. Additionally, there was significantly reduced cortico-cortical coherence between the right and left superior parietal regions during the manipulation compared to the maintenance trials, indicating that these regions were functioning more independently when the numerical information had to be actively processed. In sum, these results support previous studies that have implicated the importance of parietal regions in numerical processing, but also provide new knowledge on the spectral, temporal, and network dynamics that serve this critical cognitive function during active working memory maintenance.

Hippocampal and parahippocampal volumes vary by sex and traumatic life events in children

Background: Childhood trauma is reliably associated with smaller hippocampal volume in adults; however, this finding has not been shown in children, and even less is known about how sex and trauma interact to affect limbic structural development in children. Methods: Typically developing children aged 9 to 15 years who completed a trauma history questionnaire and structural T1-weighted MRI were included in this study (n = 172; 85 female, 87 male). All children who reported 4 or more traumas (n = 36) composed the high trauma group, and all children who reported 3 or fewer traumas (n = 136) composed the low trauma group. Using multivariate analysis of covariance, we compared FreeSurfer-derived structural MRI volumes (normalized by total intracranial volume) of the amygdalar, hippocampal and parahippocampal regions by sex and trauma level, controlling for age and study site. Results: We found a significant sex × trauma interaction, such that girls with high trauma had greater volumes than boys with high trauma. Follow-up analyses indicated significantly increased volumes for girls and generally decreased volumes for boys, specifically in the hippocampal and parahippocampalregions for the high trauma group; we observed no sex differences in the low trauma group. We noted no interaction effect for the amygdalae. Limitations: We assessed a community sample and did not include a clinical sample. We did not collect data about the ages at which children experienced trauma. Conclusion: Results revealed that psychological trauma affects brain development differently in girls and boys. These findings need to be followed longitudinally to elucidate how structural differences progress and contribute to well-known sex disparities in psychopathology.

Neural dynamics of verbal working memory processing in children and adolescents.

Development of cognitive functions and the underlying neurophysiology is evident throughout childhood and adolescence, with higher order processes such as working memory (WM) being some of the last cognitive faculties to fully mature. Previous functional neuroimaging studies of the neurodevelopment of WM have largely focused on overall regional activity levels rather than the temporal dynamics of neural component recruitment. In this study, we used magnetoencephalography (MEG) to examine the neural dynamics of WM in a large cohort of children and adolescents who were performing a high-load, modified verbal Sternberg WM task. Consistent with previous studies in adults, our findings indicated left-lateralized activity throughout the task period, beginning in the occipital cortices and spreading anterior to include temporal and prefrontal cortices during later encoding and into maintenance. During maintenance, the occipital alpha increase that has been widely reported in adults was found to be relatively weak in this developmental sample, suggesting continuing development of this component of neural processing, which was supported by correlational analyses. Intriguingly, we also found sex-specific developmental effects in alpha responses in the right inferior frontal region during encoding and in parietal and occipital cortices during maintenance. These findings suggested a developmental divergence between males and females in the maturation of neural circuitry serving WM during the transition from childhood to adolescence.

The impact of type 1 diabetes on neural activity serving attention.

Type 1 diabetes has been associated with alterations in attentional processing and other cognitive functions, and previous studies have found alterations in both brain structure and function in affected patients. However, these previous neuroimaging studies have generally examined older patients, particularly those with major comorbidities known to affect functioning independent of diabetes. The primary aim of the current study was to examine the neural dynamics of selective attention processing in a young group of patients with type 1 diabetes who were otherwise healthy (i.e., without major comorbidities). Our hypothesis was that these patients would exhibit significant aberrations in attention circuitry relative to closely matched controls. The final sample included 69 participants age 19-35 years old, 35 with type 1 diabetes and 34 matched nondiabetic controls, who completed an Eriksen flanker task while undergoing magnetoencephalography. Significant group differences in flanker interference activity were found across a network of brain regions, including the anterior cingulate, inferior parietal cortices, paracentral lobule, and the left precentral gyrus. In addition, neural activity in the anterior cingulate and the paracentral lobule was correlated with disease duration in patients with type 1 diabetes. These findings suggest that alterations in the neural circuitry underlying selective attention emerge early in the disease process and are specifically related to type 1 diabetes and not common comorbidities. These findings highlight the need for longitudinal studies in large cohorts to clarify the clinical implications of type 1 diabetes on cognition and the brain.

The mixed-lineage kinase 3 inhibitor URMC-099 facilitates microglial amyloid-ß degradation.

BACKGROUND: Amyloid-ß (Aß)-stimulated microglial inflammatory responses engage mitogen-activated protein kinase (MAPK) pathways in Alzheimer's disease (AD). Mixed-lineage kinases (MLKs) regulate upstream MAPK signaling that include p38 MAPK and c-Jun amino-terminal kinase (JNK). However, whether MLK-MAPK pathways affect Aß-mediated neuroinflammation is unknown. To this end, we investigated if URMC-099, a brain-penetrant small-molecule MLK type 3 inhibitor, can modulate Aß trafficking and processing required for generating AD-associated microglial inflammatory responses. METHODS: Aß1-42 (Aß42) and/or URMC-099-treated murine microglia were investigated for phosphorylated mitogen-activated protein kinase kinase (MKK)3, MKK4 (p-MKK3, p-MKK4), p38 (p-p38), and JNK (p-JNK). These pathways were studied in tandem with the expression of the pro-inflammatory cytokines interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α. Gene expression of the anti-inflammatory cytokines, IL-4 and IL-13, was evaluated by real-time quantitative polymerase chain reaction. Aß uptake and expression of scavenger receptors were measured. Protein trafficking was assessed by measures of endolysosomal markers using confocal microscopy. RESULTS: Aß42-mediated microglial activation pathways were shown by phosphorylation of MKK3, MKK4, p38, and JNK and by expression of IL-1ß, IL-6, and TNF-α. URMC-099 modulated microglial inflammatory responses with induction of IL-4 and IL-13. Phagocytosis of Aß42 was facilitated by URMC-099 with up-regulation of scavenger receptors. Co-localization of Aß and endolysosomal markers associated with enhanced Aß42 degradation was observed. CONCLUSIONS: URMC-099 reduced microglial inflammatory responses and facilitated phagolysosomal trafficking with associated Aß degradation. These data demonstrate a new immunomodulatory role for URMC-099 to inhibit MLK and to induce microglial anti-inflammatory responses. Thus, URMC-099 may be developed further as a novel disease-modifying AD therapy.