A healthy mind in a healthy body: Effects of arteriosclerosis and other risk factors on cognitive aging and dementia.

In this review we start from the assumption that, to fully understand cognitive aging, it is important to embrace a holistic view, integrating changes in bodily, brain, and cognitive functions. This broad view can help explain individual differences in aging trajectories and could ultimately enable prevention and remediation strategies. As the title of this review suggests, we claim that there are not only indirect but also direct effects of various organ systems on the brain, creating cascades of phenomena that strongly contribute to age-related cognitive decline. Here we focus primarily on the cerebrovascular system, because of its direct effects on brain health and close connections with the development and progression of Alzheimer's Disease and other types of dementia. We start by reviewing the main cognitive changes that are often observed in normally aging older adults, as well as the brain systems that support them. Second, we provide a brief overview of the cerebrovascular system and its known effects on brain anatomy and function, with a focus on aging. Third, we review genetic and lifestyle risk factors that may affect the cerebrovascular system and ultimately contribute to cognitive decline. Lastly, we discuss this evidence, review limitations, and point out avenues for additional research and clinical intervention.

Dietary flavanols improve cerebral cortical oxygenation and cognition in healthy adults.

Cocoa flavanols protect humans against vascular disease, as evidenced by improvements in peripheral endothelial function, likely through nitric oxide signalling. Emerging evidence also suggests that flavanol-rich diets protect against cognitive aging, but mechanisms remain elusive. In a randomized double-blind within-subject acute study in healthy young adults, we link these two lines of research by showing, for the first time, that flavanol intake leads to faster and greater brain oxygenation responses to hypercapnia, as well as higher performance only when cognitive demand is high. Individual difference analyses further show that participants who benefit from flavanols intake during hypercapnia are also those who do so in the cognitive challenge. These data support the hypothesis that similar vascular mechanisms underlie both the peripheral and cerebral effects of flavanols. They further show the importance of studies combining physiological and graded cognitive challenges in young adults to investigate the actions of dietary flavanols on brain function.

Reorganization of neural systems mediating peripheral visual selective attention in the deaf: An optical imaging study.

Theories of brain plasticity propose that, in the absence of input from the preferred sensory modality, some specialized brain areas may be recruited when processing information from other modalities, which may result in improved performance. The Useful Field of View task has previously been used to demonstrate that early deafness positively impacts peripheral visual attention. The current study sought to determine the neural changes associated with those deafness-related enhancements in visual performance. Based on previous findings, we hypothesized that recruitment of posterior portions of Brodmann area 22, a brain region most commonly associated with auditory processing, would be correlated with peripheral selective attention as measured using the Useful Field of View task. We report data from severe to profoundly deaf adults and normal-hearing controls who performed the Useful Field of View task while cortical activity was recorded using the event-related optical signal. Behavioral performance, obtained in a separate session, showed that deaf subjects had lower thresholds (i.e., better performance) on the Useful Field of View task. The event-related optical data indicated greater activity for the deaf adults than for the normal-hearing controls during the task in the posterior portion of Brodmann area 22 in the right hemisphere. Furthermore, the behavioral thresholds correlated significantly with this neural activity. This work provides further support for the hypothesis that cross-modal plasticity in deaf individuals appears in higher-order auditory cortices, whereas no similar evidence was obtained for primary auditory areas. It is also the only neuroimaging study to date that has linked deaf-related changes in the right temporal lobe to visual task performance outside of the imaging environment. The event-related optical signal is a valuable technique for studying cross-modal plasticity in deaf humans. The non-invasive and relatively quiet characteristics of this technique have great potential utility in research with clinical populations such as deaf children and adults who have received cochlear or auditory brainstem implants.

Battery-free, stretchable optoelectronic systems for wireless optical characterization of the skin.

Recent advances in materials, mechanics, and electronic device design are rapidly establishing the foundations for health monitoring technologies that have "skin-like" properties, with options in chronic (weeks) integration with the epidermis. The resulting capabilities in physiological sensing greatly exceed those possible with conventional hard electronic systems, such as those found in wrist-mounted wearables, because of the intimate skin interface. However, most examples of such emerging classes of devices require batteries and/or hard-wired connections to enable operation. The work reported here introduces active optoelectronic systems that function without batteries and in an entirely wireless mode, with examples in thin, stretchable platforms designed for multiwavelength optical characterization of the skin. Magnetic inductive coupling and near-field communication (NFC) schemes deliver power to multicolored light-emitting diodes and extract digital data from integrated photodetectors in ways that are compatible with standard NFC-enabled platforms, such as smartphones and tablet computers. Examples in the monitoring of heart rate and temporal dynamics of arterial blood flow, in quantifying tissue oxygenation and ultraviolet dosimetry, and in performing four-color spectroscopic evaluation of the skin demonstrate the versatility of these concepts. The results have potential relevance in both hospital care and at-home diagnostics.

Read My Lips: Brain Dynamics Associated with Audiovisual Integration and Deviance Detection.

Information from different modalities is initially processed in different brain areas, yet real-world perception often requires the integration of multisensory signals into a single percept. An example is the McGurk effect, in which people viewing a speaker whose lip movements do not match the utterance perceive the spoken sounds incorrectly, hearing them as more similar to those signaled by the visual rather than the auditory input. This indicates that audiovisual integration is important for generating the phoneme percept. Here we asked when and where the audiovisual integration process occurs, providing spatial and temporal boundaries for the processes generating phoneme perception. Specifically, we wanted to separate audiovisual integration from other processes, such as simple deviance detection. Building on previous work employing ERPs, we used an oddball paradigm in which task-irrelevant audiovisually deviant stimuli were embedded in strings of non-deviant stimuli. We also recorded the event-related optical signal, an imaging method combining spatial and temporal resolution, to investigate the time course and neuroanatomical substrate of audiovisual integration. We found that audiovisual deviants elicit a short duration response in the middle/superior temporal gyrus, whereas audiovisual integration elicits a more extended response involving also inferior frontal and occipital regions. Interactions between audiovisual integration and deviance detection processes were observed in the posterior/superior temporal gyrus. These data suggest that dynamic interactions between inferior frontal cortex and sensory regions play a significant role in multimodal integration.

Noninvasive diffusive optical imaging of the auditory response to birdsong in the zebra finch.

Songbirds communicate by learned vocalizations with concomitant changes in neurophysiological and genomic activities in discrete parts of the brain. Here, we tested a novel implementation of diffusive optical imaging (also known as diffuse optical imaging, DOI) for monitoring brain physiology associated with vocal signal perception. DOI noninvasively measures brain activity using red and near-infrared light delivered through optic fibers (optodes) resting on the scalp. DOI does not harm subjects, so it raises the possibility of repeatedly measuring brain activity and the effects of accumulated experience in the same subject over an entire life span, all while leaving tissue intact for further study. We developed a custom-made apparatus for interfacing optodes to the zebra finch (Taeniopygia guttata) head using 3D modeling software and rapid prototyping technology, and applied it to record responses to presentations of birdsong in isoflurane-anesthetized zebra finches. We discovered a subtle but significant difference between the hemoglobin spectra of zebra finches and mammals which has a major impact in how hemodynamic responses are interpreted in the zebra finch. Our measured responses to birdsong playback were robust, highly repeatable, and readily observed in single trials. Responses were complex in shape and closely paralleled responses described in mammals. They were localized to the caudal medial portion of the brain, consistent with response localization from prior gene expression, electrophysiological, and functional magnetic resonance imaging studies. These results define an approach for collecting neurophysiological data from songbirds that should be applicable to diverse species and adaptable for studies in awake behaving animals.

Effects of alcohol on sequential information processing: evidence for temporal myopia.

Alcohol Myopia Theory (AMT) posits that alcohol restricts the focus of attention, such that behaviors are determined only by highly salient environmental cues. While AMT is most commonly understood in terms of spatial attention, the present study tested the effects of alcohol in the temporal domain of attention. Seventy-one participants consumed either a placebo beverage or one of two doses of alcohol (0.40g/kg or 0.80g/kg ETOH) before performing an auditory discrimination task while event-related potentials (ERPs) were recorded. Consistent with typical sequential effects, placebo participants showed increased P300 amplitude and slowed behavioral responses when the current target differed from the two-back tone. In contrast, alcohol caused increased P300 and response slowing when the target tone differed from the one-back tone. These findings suggest that alcohol increases the salience of more recently encountered information, consistent with the general tenets of AMT.

Rules rule! Brain activity dissociates the representations of stimulus contingencies with varying levels of complexity.

The significance of stimuli is linked not only to their nature but also to the sequential structure in which they are embedded, which gives rise to contingency rules. Humans have an extraordinary ability to extract and exploit these rules, as exemplified by the role of grammar and syntax in language. To study the brain representations of contingency rules, we recorded ERPs and event-related optical signal (EROS; which uses near-infrared light to measure the optical changes associated with neuronal responses). We used sequences of high- and low-frequency tones varying according to three contingency rules, which were orthogonally manipulated and differed in processing requirements: A Single Repetition rule required only template matching, a Local Probability rule required relating a stimulus to its context, and a Global Probability rule could be derived through template matching or with reference to the global sequence context. ERP activity at 200-300 msec was related to the Single Repetition and Global Probability rules (reflecting access to representations based on template matching), whereas longer-latency activity (300-450 msec) was related to the Local Probability and Global Probability rules (reflecting access to representations incorporating contextual information). EROS responses with corresponding latencies indicated that the earlier activity involved the superior temporal gyrus, whereas later responses involved a fronto-parietal network. This suggests that the brain can simultaneously hold different models of stimulus contingencies at different levels of the information processing system according to their processing requirements, as indicated by the latency and location of the corresponding brain activity.

Optical imaging of temporal integration in human auditory cortex.

Behavioral and physiological studies have indicated the existence of a temporal window of auditory integration (TWI), within which similar sounds are perceptually grouped. The current study exploits the combined temporal and spatial resolution of fast optical imaging (the event-related optical signal, EROS) to show that brain activity elicited by sounds within and outside the TWI differs in location and latency. In a previous event-related brain potential (ERP) study [Sable, Gratton, and Fabiani (2003) European Journal of Neuroscience, 17, 2492-2496], we found that the mismatch negativity (MMN; a brain response to acoustic irregularities) elicited by deviations in stimulus onset asynchronies (SOAs) had a unique shape when the deviant SOA was within the TWI. In the present study, we extended these ERP results using EROS. Participants heard trains of five tones. The first four tones had SOAs of 96, 192, 288 or 384 ms. The SOA of the fourth and fifth tones was either the same (standard) or one of the other three (deviant) SOAs. With a deviant SOA of 96 ms, the cortical response was approximately 2 cm anterior to responses to longer SOA deviants, and was followed by a later response that was absent in the other conditions. Similarly to the electrical MMN, the optical mismatch response amplitudes were proportional to the magnitude of interval deviance. These results, in combination with our previous findings, indicate that the temporal integration of sounds is reflected in cortical mismatch responses that differ from the typical response to interval deviance.

Reduced suppression or labile memory? Mechanisms of inefficient filtering of irrelevant information in older adults.

Cognitive aging theories emphasize the decrease in efficiency of inhibitory processes and attention control in normal aging, which, in turn, may result in reduction of working memory function. Accordingly, some of these age-related changes may be due to faster sensory memory decay or to inefficient filtering of irrelevant sensory information (sensory gating). Here, event-related brain potentials and the event-related optical signal were recorded in younger and older adults passively listening to tone trains. To determine whether age differentially affects decay of sensory memory templates over short intervals, trains were separated by delays of either 1 or 5 sec. To determine whether age affects the suppression of responses to unattended repeated stimuli, we evaluated the brain activity elicited by successive train stimuli. Some trains started with a shorter-duration stimulus (deviant trains). Results showed that both electrical and optical responses to tones were more persistent with repeated stimulation in older adults than in younger adults, whereas the effects of delay were similar in the two groups. A mismatch negativity (MMN) was elicited by the first stimulus in deviant trains. This MMN was larger for 1- than 5-sec delay, but did not differ across groups. These data suggest that age-related changes in sensory processing are likely due to inefficient filtering of repeated information, rather than to faster sensory memory decay. This inefficient filtering may be due to, or interact with, reduced attention control. Furthermore, it may increase the noise levels in the information processing system and thus contribute to problems with working memory and speed of processing.

Fast optical imaging of frontal cortex during active and passive oddball tasks.

This study used the high spatial and temporal resolution of the event-related optical signal (EROS) to investigate the timing of neuronal activity in frontal cortex during auditory target detection and passive oddball tasks. Activation in right middle frontal gyrus (MFG) peaked approximately 350 ms following rare target tones. This corresponded closely to the latency of the simultaneously recorded electrical P3 component. In addition, we found activation in left lateral MFG peaking at approximately 130 ms following tone onset for conditions that may have required response inhibition. These results correspond with activation patterns observed in similar fMRI studies, but provide temporal tags for the activated locations. These data may help bridge the gap between electrophysiological and hemodynamic measures of target detection and contribute to our understanding of the spatiotemporal dynamics of brain activity during target processing.

Latent inhibition mediates N1 attenuation to repeating sounds.

Sound repetition typically reduces auditory N1 amplitudes, more so at higher rates. This has been attributed to refractoriness of N1 generators. However, evidence that N1 attenuation is delayed 300-400 ms after the first occurrence of a repeated sound suggests an alternative process, such as inhibition, that requires 300-400 ms to become fully operational. We examined the N1 to trains of fixed-interval (100, 200, 300, 400 ms) tones for evidence of effects predicted by models of refractoriness and of latent inhibition. Regardless of interval, latency of the eliciting tone from train onset determined N1 amplitudes during the first 400 ms of the train, which decreased in this window. The results show that N1 attenuation cannot be due simply to refractoriness, which would elicit the smallest N1 to the second tone. An inhibitory neural circuit can account for these and previous results, and may be important to auditory perceptual processing.

Optimum filtering for EROS measurements.

The event-related optical signal (EROS) is a relatively new technology that provides noninvasive data about the time course of neural activity in circumscribed cortical areas. However, much still remains to be learned about the physiology and physics underlying the observed signals. We examined the instrumental and physiological noise observed in the intensity modulation and phase-delay measurements produced by a frequency domain oxymeter in response to steady-state auditory stimuli. We present here data on the effects of different filters on the between-subjects response consistency for amplitude and phase measurements. The results of these analyses may help explain some apparently discrepant results previously reported from different laboratories (Steinbrink et al., 2000), and illustrate differences between data from different types of measurements.

Sound presentation rate is represented logarithmically in human cortex.

The encoding of temporal information is critical to auditory processing. Since the mismatch negativity component of the auditory event-related brain potential is thought to reflect properties of auditory sensory memory, we used it to examine the representation of acoustic time intervals in the human cortex. The mismatch negativity occurs in response to deviations in acoustic regularities, which are stored in sensory memory. We used 16 stimulus conditions, randomly presenting short trains of tones with fixed onset-to-onset intervals of 100, 200, 300 or 400 ms (all tones in the study were identical). The first four intervals between the tones established the acoustic regularity on each train (i.e. the 'standard'). The fifth tone in each train was preceded by an interval that varied randomly among the same four intervals. If this interval was different from the standard for that trial, it violated the acoustic regularity (i.e. it was a 'deviant'). The mismatch response to the fifth tone differed significantly among stimulus conditions and was proportional to the absolute value of the logarithm of the deviant/standard interval ratio. This indicates that short acoustic time intervals are represented with a ratio scale in the human cortex. When the fifth tone occurred 100 ms after the fourth, it elicited a somewhat different, although proportional response, supporting the hypothesis that a special integration mechanism may exist for very short time intervals.