Kelly C. Harris

In-Vivo Mapping of the Human Locus Coeruleus

The locus coeruleus (LC) is a brainstem structure that has widespread cortical and sub-cortical projections to modulate states of attention. Our understanding of the LCs role in both normal attention and clinical populations affected by disrupted attention would be advanced by having in vivo functional and structural markers of the human LC. Evidence for LC activation can be difficult to interpret because of uncertainty about whether brainstem activity can be accurately localized to the LC. High resolution T1-turbo spin echo (T1-TSE) magnetic resonance imaging (MRI) (in-plane resolution of 0.4 mm x 0.4 mm) was used in this study to characterize the location and distribution probability of the LC across 44 adults ranging in age from 19 to 79 years. Utilizing a study-specific brainstem template, the individual brainstems were aligned into standard space, while preserving variations in LC signal intensity. Elevated T1-TSE signal was observed in the rostral pons that was strongly correlated with the position and concentration of LC cells previously reported in a study of post-mortem brains (r=0.90). The elevated T1-TSE signal was used to produce a probabilistic map of the LC in standard Montreal Neurological Institute (MNI) coordinate space. This map can be used to test hypotheses about the LC in human structural and functional imaging studies. Such efforts will contribute to our understanding of attention systems in normal and clinical populations.

Speech Recognition in Younger and Older Adults: A Dependency on Low-Level Auditory Cortex

A common complaint of older adults is difficulty understanding speech, especially in challenging listening environments. In addition to well known declines in the peripheral auditory system that reduce audibility, age-related changes in central auditory and attention-related systems are hypothesized to have additive negative effects on speech recognition. We examined the extent to which functional and structural differences in speech- and attention-related cortex predicted differences in word recognition between 18 younger adults (19–39 years) and 18 older adults (61–79 years). Subjects performed a word recognition task in an MRI scanner where the intelligibility of words was parametrically varied. Older adults exhibited significantly poorer word recognition in a challenging listening condition compared with younger adults. An anteromedial Heschls gyrus/superior temporal gyrus (HG/STG) region, engaged by the word recognition task, exhibited age group differences in gray matter volume and predicted word recognition in younger and older adults. Age group differences in anterior cingulate (ACC) activation were also observed. The association between HG gray matter volume, word recognition, and ACC activation was present after controlling for hearing loss. In younger and older adults, causal path modeling analyses demonstrated that individual variation in left HG/STG morphology affected word recognition performance, which was reflected by error monitoring activity in the dorsal ACC. These results have clinical implications for rehabilitation and suggest that some of the perceptual difficulties experienced by older adults are due to structural changes in HG/STG. More broadly, the results suggest the possibility that aging may exaggerate developmental limitations on the ability to recognize speech.

Age-Related Changes in Processing Speed: Unique Contributions of Cerebellar and Prefrontal Cortex

Age-related declines in processing speed are hypothesized to underlie the widespread changes in cognition experienced by older adults. We used a structural covariance approach to identify putative neural networks that underlie age-related structural changes associated with processing speed for 42 adults ranging in age from 19 to 79 years. To characterize a potential mechanism by which age-related gray matter changes lead to slower processing speed, we examined the extent to which cerebral small vessel disease influenced the association between age-related gray matter changes and processing speed. A frontal pattern of gray matter and white matter variation that was related to cerebral small vessel disease, as well as a cerebellar pattern of gray matter and white matter variation were uniquely related to age-related declines in processing speed. These results demonstrate that at least two distinct factors affect age-related changes in processing speed, which might be slowed by mitigating cerebral small vessel disease and factors affecting declines in cerebellar morphology.

Age-related differences in gap detection: Effects of task difficulty and cognitive ability

Differences in gap detection for younger and older adults have been shown to vary with the complexity of the task or stimuli, but the factors that contribute to these differences remain unknown. To address this question, we examined the extent to which age-related differences in processing speed and workload predicted age-related differences in gap detection. Gap detection thresholds were measured for 10 younger and 11 older adults in two conditions that varied in task complexity but used identical stimuli: (1) gap location fixed at the beginning, middle, or end of a noise burst and (2) gap location varied randomly from trial to trial from the beginning, middle, or end of the noise. We hypothesized that gap location uncertainty would place increased demands on cognitive and attentional resources and result in significantly higher gap detection thresholds for older but not younger adults. Overall, gap detection thresholds were lower for the middle location as compared to beginning and end locations and were lower for the fixed than the random condition. In general, larger age-related differences in gap detection were observed for more challenging conditions. That is, gap detection thresholds for older adults were significantly larger for the random condition than for the fixed condition when the gap was at the beginning and end locations but not the middle. In contrast, gap detection thresholds for younger adults were not significantly different for the random and fixed condition at any location. Subjective ratings of workload indicated that older adults found the gap detection task more mentally demanding than younger adults. Consistent with these findings, results of the Purdue Pegboard and Connections tests revealed age-related slowing of processing speed. Moreover, age group differences in workload and processing speed predicted gap detection in younger and older adults when gap location varied from trial to trial; these associations were not observed when gap location remained constant across trials. Taken together, these results suggest that age-related differences in complex measures of auditory temporal processing may be explained, in part, by age-related deficits in processing speed and attention.

Electrophysiologic Correlates of Intensity Discrimination In Cortical Evoked Potentials of Younger and Older Adults

When measured behaviorally, older adults with normal hearing have poorer intensity discrimination thresholds than younger adults, but only at lower frequencies. Poor intensity discrimination at lower but not higher frequencies for older adults can be associated with an age-related decline in temporal processing. The current study was designed to assess age-related effects on intensity discrimination at 500 and 3000 Hz using the cortical auditory evoked potential, N1--P2. Subjects were 10 younger and 10 older adults with normal hearing. The N1--P2 was elicited by an intensity increase in an otherwise continuous pure tone presented at 70 dB SPL. Intensity increments ranged from 0 dB to 5 dB at 500 Hz and from 0 d B to 8 d B at 3000 Hz in 1-dB steps. Intensity discrimination threshold was defined as the smallest intensity change needed to evoke an N1-P2 response. Consistent with behavioral measures, N1-P2 response thresholds were significantly higher for older subjects than younger subjects at 500 Hz but did not differ significantly at 3000 Hz. In addition, N1 and P2 latencies for older subjects were significantly prolonged at 500 Hz, but not at 3000 Hz. As intensity increments increased above threshold, amplitudes tended to be larger in older than in younger subjects, however, these differences were not statistically significant. In older subjects, response latencies and amplitudes were significantly larger at 500 Hz than at 3000 Hz. In younger subjects, response latencies and amplitudes were similar across frequency. Similar intensity discrimination thresholds and age-related differences for behavioral measures and evoked potentials support the notion that the N1-P2 measures reflect the physiological detection of intensity change which in turn relates to intensity discrimination. A possible explanation for the decreased intensity discrimination at low frequencies, and enhanced amplitudes with prolonged latencies in older subjects is an age-related decline in inhibitory control within the central auditory nervous system.

Age-related differences in sensitivity to small changes in frequency assessed with cortical evoked potentials

As part of an ongoing study of age-related changes in auditory processing, sensitivity to small changes in frequency were assessed using the cortical auditory evoked potential, P1-N1-P2, in younger and older adults with normal hearing. Behavioral measures have shown age-related differences in intensity and frequency discrimination that are larger at lower than higher frequencies. However, substantial individual differences and equivocal results among studies have been reported. This variability may reflect differences in tasks and procedures, as well as subject variables, such as hearing sensitivity and level of attention. To minimize these subject variables, the P1-N1-P2 response was investigated using a passive listening paradigm. Subjects were 10 younger and 10 older adults. The P1-N1-P2 was elicited by a 150-ms change in frequency in otherwise continuous 500-Hz and 3000-Hz pure tones presented at 70 dB SPL. P1-N1-P2 threshold was defined as the smallest change in frequency needed to evoke a P1-N1-P2 response. Furthermore, a frequency-dependent aging effect was observed for P1-N1-P2 thresholds, such that older subjects were significantly less sensitive to the frequency change than younger subjects, with significantly larger age-related differences at 500 Hz than at 3000 Hz. Age-related changes in response latencies and amplitude of the P1-N1-P2 response were also evident at 500 and 3000 Hz. These results are consistent with age-related changes in the central auditory system and suggest that changes in frequency discrimination abilities of older adults may be, in part, related to changes in preattentive levels of auditory processing.

Word Intelligibility and Age Predict Visual Cortex Activity during Word Listening

The distractibility that older adults experience when listening to speech in challenging conditions has been attributed in part to reduced inhibition of irrelevant information within and across sensory systems. Whereas neuroimaging studies have shown that younger adults readily suppress visual cortex activation when listening to auditory stimuli, it is unclear the extent to which declining inhibition in older adults results in reduced suppression or compensatory engagement of other sensory cortices. The current functional magnetic resonance imaging study examined the effects of age and stimulus intelligibility in a word listening task. Across all participants, auditory cortex was engaged when listening to words. However, increasing age and declining word intelligibility had independent and spatially similar effects: both were associated with increasing engagement of visual cortex. Visual cortex activation was not explained by age-related differences in vascular reactivity but rather auditory and visual cortices were functionally connected across word listening conditions. The nature of this correlation changed with age: younger adults deactivated visual cortex when activating auditory cortex, middle-aged adults showed no relation, and older adults synchronously activated both cortices. These results suggest that age and stimulus integrity are additive modulators of crossmodal suppression and activation.

Inferior Frontal Sensitivity to Common Speech Sounds Is Amplified by Increasing Word Intelligibility.

The left inferior frontal gyrus (LIFG) exhibits increased responsiveness when people listen to words composed of speech sounds that frequently co-occur in the English language (Vaden, Piquado, & Hickok, 2011), termed high phonotactic frequency (Vitevitch & Luce, 1998). The current experiment aimed to further characterize the relation of phonotactic frequency to LIFG activity by manipulating word intelligibility in participants of varying age. Thirty six native English speakers, 19-79 years old (mean=50.5, sd=21.0) indicated with a button press whether they recognized 120 binaurally presented consonant-vowel-consonant words during a sparse sampling fMRI experiment (TR=8 s). Word intelligibility was manipulated by low-pass filtering (cutoff frequencies of 400 Hz, 1000 Hz, 1600 Hz, and 3150 Hz). Group analyses revealed a significant positive correlation between phonotactic frequency and LIFG activity, which was unaffected by age and hearing thresholds. A region of interest analysis revealed that the relation between phonotactic frequency and LIFG activity was significantly strengthened for the most intelligible words (low-pass cutoff at 3150 Hz). These results suggest that the responsiveness of the left inferior frontal cortex to phonotactic frequency reflects the downstream impact of word recognition rather than support of word recognition, at least when there are no speech production demands.

Auditory-evoked cortical activity: contribution of brain noise, phase locking, and spectral power

Abstract Background: The N1-P2 is an obligatory cortical response that can reflect the representation of spectral and temporal characteristics of an auditory stimulus. Traditionally, mean amplitudes and latencies of the prominent peaks in the averaged response are compared across experimental conditions. Analyses of the peaks in the averaged response only reflect a subset of the data contained within the electroencephalogram (EEG) signal. We used single-trial analyses techniques to identify the contribution of brain noise, neural synchrony, and spectral power to the generation of P2 amplitude and how these variables may change across age group. This information is important for appropriate interpretation of event-related potentials (ERPs) results and in understanding of age-related neural pathologies. Methods: EEG was measured from 25 younger and 25 older normal hearing adults. Age-related and individual differences in P2 response amplitudes, and variability in brain noise, phase locking value (PLV), and spectral power (4–8 Hz) were assessed from electrode FCz. Model testing and linear regression were used to determine the extent to which brain noise, PLV, and spectral power uniquely predicted P2 amplitudes and varied by age group. Results: Younger adults had significantly larger P2 amplitudes, PLV, and power compared to older adults. Brain noise did not differ between age groups. The results of regression testing revealed that brain noise and PLV, but not spectral power were unique predictors of P2 amplitudes. Model fit was significantly better in younger than in older adults. Conclusions: ERP analyses are intended to provide a better understanding of the underlying neural mechanisms that contribute to individual and group differences in behavior. The current results support that age-related declines in neural synchrony contribute to smaller P2 amplitudes in older normal hearing adults. Based on our results, we discuss potential models in which differences in neural synchrony and brain noise can account for associations with P2 amplitudes and behavior and potentially provide a better explanation of the neural mechanisms that underlie declines in auditory processing and training benefits.

Age-related deficits in auditory temporal processing: unique contributions of neural dyssynchrony and slowed neuronal processing

This study was guided by the hypothesis that the aging central nervous system progressively loses its ability to process rapid acoustic changes that are important for speech recognition. Specifically, we hypothesized that age-related deficits in neural synchrony and neuronal oscillatory activity occur independently in older adults and disrupt auditory temporal processing. Neural synchrony is largely dependent on phase locking within the central auditory pathway, beginning at the auditory nerve. In contrast, the resonance characteristics of oscillatory activity are dependent on the integrity and structure of long range cortical connections. We tested our hypotheses by assessing age-related differences in electrophysiologic correlates of neural synchrony and peak oscillatory frequency in younger and older adults with normal hearing and determining their associations with a behavioral measure of gap detection. Phase-locking values were smaller (poorer neural synchrony) and peak alpha frequency was lower for older than younger adults and decreased as gap detection thresholds increased; variations in phase-locking values and peak alpha frequency uniquely predicted gap detection thresholds. These effects were driven, in large part, by associations in older adults. These results reveal dissociable neural mechanisms associated with distinct underlying pathology that may differentially be present in older adults and contribute to auditory processing declines.