Histologic validation of locus coeruleus MRI contrast in post-mortem tissue.

The locus coeruleus (LC) noradrenergic system regulates arousal and modulates attention through its extensive projections across the brain. LC dysfunction has been implicated in a broad range of neurodevelopmental, neurodegenerative and psychiatric disorders, as well as in the cognitive changes observed during normal aging. Magnetic resonance imaging (MRI) has been used to characterize the human LC (elevated contrast relative to surrounding structures), but there is limited understanding of the factors underlying putative LC contrast that are critical to successful biomarker development and confidence in localizing nucleus LC. We used ultra-high-field 7 T magnetic resonance imaging (MRI) to acquire T1-weighted microscopy resolution images (78 µm in-plane resolution) of the LC from post-mortem tissue samples. Histological analyses were performed to characterize the distribution of tyrosine hydroxylase (TH) and neuromelanin in the scanned tissue, which allowed for direct comparison with MR microscopy images. Our results indicate that LC-MRI contrast corresponds to the location of neuromelanin cells in LC; these also correspond to norepinephrine neurons. Thus, neuromelanin appears to serve as a natural contrast agent for nucleus LC that can be used to localize nucleus LC and may have the potential to characterize neurodegenerative disease.

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.

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 Heschl's 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.

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 LC's 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.

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.

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.