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Converging evidence from biopsychosocial research in humans and animals demonstrates that chronic sensory stimulation (via excessive screen exposure) affects brain development increasing the risk of cognitive, emotional, and behavioural disorders in adolescents and young adults. Emerging evidence suggests that some of these effects are similar to those seen in adults with symptoms of mild cognitive impairment (MCI) in the early stages of dementia, including impaired concentration, orientation, acquisition of recent memories (anterograde amnesia), recall of past memories (retrograde amnesia), social functioning, and self-care. Excessive screen time is known to alter gray matter and white volumes in the brain, increase the risk of mental disorders, and impair acquisition of memories and learning which are known risk factors for dementia. Chronic sensory overstimulation (i.e., excessive screen time) during brain development increases the risk of accelerated neurodegeneration in adulthood (i.e., amnesia, early onset dementia). This relationship is affected by several mediating/moderating factors (e.g., IQ decline, learning impairments and mental illness). We hypothesize that excessive screen exposure during critical periods of development in Generation Z will lead to mild cognitive impairments in early to middle adulthood resulting in substantially increased rates of early onset dementia in later adulthood. We predict that from 2060 to 2100, the rates of Alzheimer’s disease and related dementias (ADRD) will increase significantly, far above the Centres for Disease Control (CDC) projected estimates of a two-fold increase, to upwards of a four-to-six-fold increase. The CDC estimates are based entirely on factors related to the age, sex, race and ethnicity of individuals born before 1950 who did not have access to mobile digital technology during critical periods of brain development. Compared to previous generations, the average 17–19-year-old spends approximately 6 hours a day on mobile digital devices (MDD) (smartphones, tablets, and laptop computers) whereas individuals born before 1950 at the same age spent zero. Our estimates include the documented effects of excessive screen time on individuals born after 1980, Millennials and Generation Z, who will be the majority of individuals ≥65 years old. An estimated 4-to-6-fold increase in rates of ADRD post-2060 will result in widespread societal and economic distress and the complete collapse of already overburdened healthcare systems in developed countries. Preventative measures must be set in place immediately including investments and interventions in public education, social policy, laws, and healthcare.

It has been proposed that the small volume of a dendritic spine can amplify Ca2+signals during synaptic transmission. Accordingly, we have performed calculations to determine whether the activation of N-methyl-D-aspartate (NMDA) type glutamate receptors during synaptic transmission results in significant elevation in intracellular Ca2+levels, permitting optical detection of synaptic signals within a single spine. Simple calculations suggest that the opening of even a single NMDA receptor would result in the influx of ~ 310 000 Ca2+ions into the small volume of a spine, producing changes in Ca2+levels that are readily detectable using high affinity Ca2+indicators such as fura-2 or fluo-3. Using fluorescent Ca2+indicators, we have imaged local Ca2+transients mediated by NMDA receptors in spines and dendritic shafts attributed to spontaneous miniature synaptic activity. Detailed analysis of these quantal events suggests that the current triggering these transients is attributed to the activation of <10 NMDA receptors. The frequency of these miniature synaptic Ca2+transients is not randomly distributed across synapses, as some synapses can display a >10-fold higher frequency of transients than others. As expected for events mediated by NMDA receptors, miniature synaptic Ca2+transients were suppressed by extracellular Mg2+at negative membrane potentials; however, the Mg2+block could be removed by depolarization.Key words: miniature release, N-methyl-D-aspartate (NMDA), calcium, glutamate, spine.

The purpose of this study was to determine whether white matter microstructure measured by diffusion magnetic resonance imaging (dMRI) provides independent information about baseline level or change in executive function (EF) or memory (MEM) in older adults with and without cognitive impairment. Longitudinal data was acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study from phases GO and 2 (2009–2015). ADNI participants included were diagnosed as cognitively normal (n = 46), early mild cognitive impairment (MCI) (n = 48), late MCI (n = 29), and dementia (n = 39) at baseline. We modeled the association between dMRI-based global white matter mean diffusivity (MD) and baseline level and change in EF and MEM composite scores, in models controlling for baseline bilateral hippocampal volume, regional cerebral FDG PET metabolism and global cerebral AV45 PET uptake. EF and MEM composite scores were measured at baseline, 6, 12, 24 and 36 months. In the baseline late MCI and dementia groups, greater global MD was associated with lesser baseline EF, but not EF change nor MEM baseline or change. As expected, lesser hippocampal volume and lesser FDG PET metabolism was associated with greater rates of EF and MEM decline. In ADNI-GO/2 participants, white matter integrity provided independent information about current executive function, but was not sensitive to future cognitive change. Since individuals experiencing executive function declines progress to dementia more rapidly than those with only memory impairment, better biomarkers of future executive function decline are needed. Highlights • In the ADNI cohort, MRI and PET predictors of baseline and change in executive function were tested. • Global mean diffusivity was associated with baseline, but not change in, executive function. • Diffusion MRI provides independent information on current executive function in older adults.

The use of quantitative T(1) mapping in neuroscience and neurology has raised strong interest in the development of T(1)-mapping techniques that can measure T(1) in the whole brain, with high accuracy and precision and within short imaging and computation times. Here, we present a new inversion-recovery (IR) based T(1)-mapping method using a standard 3D magnetization-prepared rapid gradient-echo (MPRAGE) sequence. By varying only the inversion time (TI), but keeping other parameters constant, MPRAGE image signals become linear to exp(-TI/T(1)), allowing for accurate T(1) estimation without flip angle correction. We also show that acquiring data at just 3 TIs, with the three different TI values optimized, gives maximum T(1) precision per unit time, allowing for new efficient approaches to measure and compute T(1). We demonstrate the use of our method at 7 T to obtain 3D T(1) maps of the whole brain in common marmosets at 0.60mm resolution and within 11 min. T(1) maps from the same individuals were highly reproducible across different days. Across subjects, the peak of cerebral gray matter T(1) distribution was 1735±52 ms, and the lower edge of cerebral white matter T(1) distribution was 1270±43 ms. We found a significant decrease of T(1) in both gray and white matter of the marmoset brain with age over a span of 14 years, in agreement with previous human studies. This application illustrates that MPRAGE-based 3D T(1) mapping is rapid, accurate and precise, and can facilitate high-resolution anatomical studies in neuroscience and neurological diseases.

Robust and reproducible source mapping with magnetoencephalography is particularly challenging at the individual level. We evaluated a receiver-operating characteristic reliability (ROC-r) method for automated production of volumetric MEG maps in single-subjects. ROC-r provides quality assurance comparable to that offered by goodness-of-fit (GoF) and confidence volume (CV) for equivalent current dipole (ECD) modeling.ROC-r utilizes within-session reproducibility for quality assurance, latency identification, and thresholding of volumetric source maps. We tested ROC-r on simulated and real MEG with a strongly focal source, using somatosensory evoked fields (SEFs) elicited by bilateral median nerve stimulation (MNS). For quality assurance, the ROC-r reliable fraction (FR) was compared to the ECD GoF and CV. Peak beamformer locations and latencies identified by ROC-r were compared to the ECD for co-localization accuracy.The predominant component of the SEF response occurred around 35ms, contralateral to the MNS.FR and 1/CV were more strongly correlated (mean Pearson's correlation: 0.76; 95% CI 0.60-0.87) than FR and GoF (0.65; 95% CI 0.32-0.85). There was no difference in the latency of the peak GoF (35.0+/-0.6ms), CV (34.8+/-0.7ms) and FR (35.5+/-0.8ms). The ECD fits and ROC-r peaks co-localized to within a mean (median) distance of 8.3+/-5.9mm (6.2mm).ROC-r volumetric mapping co-localized closely with the standard ECD approach. This analysis can be added to any whole-brain MEG source imaging protocol, and is especially useful for single-subject mapping. Additionally, the development of FR as an analogue to GoF or CV for volumetric mapping is a critical improvement for clinical applications.

In patients suffering from various sleep disorders and some elderly patients, sleep is disturbed with frequent but brief arousal. These events do not cause behavioral awakening, but can lead to excessive day time sleepiness. These brief arousals or microarousals (MAs) can be identified on a standard polysomnogram as a transient abrupt change of frequency, typically in the alpha and extended beta (16-40 Hz) bands. In this paper, we present a novel method to automatically detect MAs. The method is based on using the ideas of segmentation, spectral feature extraction and the identification of EEG epochs containing MA with statistical methods and decisional rules. Full-night EEG recordings from two patients are used to present some initial performance results. For this analysis, the MA events are independently scored by three experienced sleep experts. Results show the method to be promising; however, due to the large inter-scorer variations it may be necessary to tailor the detection threshold to address the varying scorer preferences (address the sensitivity/specificity tradeoffs)

Despite the widespread use of caffeine, the neuronal mechanisms underlying its stimulatory effects are not completely understood. By using c-Fos immunohistochemistry as a marker of neuronal activation, we recently showed that stimulant doses of caffeine activate arousal-promoting hypothalamic orexin (hypocretin) neurons. In the present study, we investigated whether other key neurons of the arousal system are also activated by caffeine, via dual immunostaining for c-Fos and transmitter markers. Rats were administered three doses of caffeine or saline vehicle during the light phase. Caffeine at 10 and 30 mg/kg, i.p., increased motor activities, including locomotion, compared with after saline or a higher dose, 75 mg/kg. The three doses of caffeine induced distinct dose-related patterns of c-Fos immunoreactivity in several arousal-promoting areas, including orexin neurons and adjacent neurons containing neither orexin nor melanin-concentrating hormone; tuberomammillary histaminergic neurons; locus coeruleus noradrenergic neurons; noncholinergic basal forebrain neurons that do not contain parvalbumin; and nondopaminergic neurons in the ventral tegmental area. At any dose used, caffeine induced little or no c-Fos expression in cholinergic neurons of the basal forebrain and mesopontine tegmentum; dopaminergic neurons of the ventral tegmental area, central gray, and substantia nigra pars compacta; and serotonergic neurons in the dorsal raphe nucleus. Saline controls exhibited only few c-Fos-positive cells in most of the cell groups examined. These results indicate that motor-stimulatory doses of caffeine induce a remarkably restricted pattern of c-Fos expression in the arousal-promoting system and suggest that this specific neuronal activation may be involved in the behavioral arousal by caffeine.

Summary: Purpose: To report our evaluation of interictal two epileptic spike fields on magnetoencephalography (MEG) by using invasive intracranial monitoring in a patient without lesion on magnetic resonance imaging (MRI). Methods: A 15-year-old left-handed boy with a 9-year history of refractory simple partial seizures, secondarily generalized, and a normal MRI, was studied with MEG to define magnetic spike sources, followed by invasive intracranial monitoring with subdural electrodes to delineate the epileptogenic zone and eloquent function pursuant to focal cortical excision. Results: MEG demonstrated two spike foci on the right middle frontal and inferior rolandic areas adjacent to the st sory area. Ictal recordings during prolonged invasive monit ing from subdural electrodes revealed two epileptogenic zoi in the same locations as those defined by MEG. Focal corti excision was performed of each epileptogenic zone. The patii has been seizure free for 24 months without neurologic deficit Conclusions: Magnetic source imaging is a valuable adjui in the planning of subdural grid placement in epilepsy surge particularly in patients in whom conventional imaging fails reveal a lesion.

Sleep-disordered breathing is associated with adverse clinical consequences such as daytime sleepiness and hypertension. The mechanisms behind these associations have been studied in animal models, especially rats, but intermittent stimuli such as hypoxia have been applied without reference to sleep-wake states. To determine mechanisms underlying the adverse physiological consequences of stimuli associated with sleep-disordered breathing requires criteria for detection of sleep-wake states on-line to trigger stimuli only in sleep. This study aimed to develop such a system for freely behaving rats. Twelve rats with implanted electroencephalogram and neck electromyogram electrodes were studied in the light and dark phases. Electroencephalogram frequencies in the high (20–30 Hz) and low (2–4 Hz) frequency bands distinguished non-rapid eye movement (REM) sleep, whereas neck electromyogram distinguished REM. Using these parameters in a simple algorithm led to detection accuracies of 94.5 ± 1.0 (SE) % for wakefulness, 96.2 ± 0.8% for non-REM sleep, and 92.3 ± 1.6% for REM compared with blinded human judgment. The algorithm was then used to trigger hypoxic stimuli only in sleep. Because frequency and amplitude analysis is readily performed using a variety of commercial systems, incorporation of these parameters into such an algorithm will facilitate studies investigating mechanisms underlying the physiological consequences of sleep-related respiratory stimuli in a fashion that more effectively models clinical disorders.