Dopamine and memory dedifferentiation in aging.

The dedifferentiation theory of aging proposes that a reduction in the specificity of neural representations causes declines in complex cognition as people get older, and may reflect a reduction in dopaminergic signaling. The present pharmacological fMRI study investigated episodic memory-related dedifferentiation in young and older adults, and its relation to dopaminergic function, using a randomized placebo-controlled double-blind crossover design with the agonist Bromocriptine (1.25mg) and the antagonist Sulpiride (400mg). We used multi-voxel pattern analysis to measure memory specificity: the degree to which distributed patterns of activity distinguishing two different task contexts during an encoding phase are reinstated during memory retrieval. As predicted, memory specificity was reduced in older adults in prefrontal cortex and in hippocampus, consistent with an impact of neural dedifferentiation on episodic memory representations. There was also a linear age-dependent dopaminergic modulation of memory specificity in hippocampus reflecting a relative boost to memory specificity on Bromocriptine in older adults whose memory was poorer at baseline, and a relative boost on Sulpiride in older better performers, compared to the young. This differed from generalized effects of both agents on task specificity in the encoding phase. The results demonstrate a link between aging, dopaminergic function and dedifferentiation in the hippocampus.This research was funded mainly by a Fellowship to AMM from Research into Ageing, UK, and by an RCUK Academic Fellowship at the University of Edinburgh. Some of the research was conducted by Hunar Abdulrahman as part of a dissertation for the MSc in Neurosciences at the University of Edinburgh. The research was also supported by a Human Brain Project grant from the National Institute of Mental Health and the National Institute of Biomedical Imaging & Bioengineering. PCF was supported by a Wellcome Trust Senior Fellowship in Clinical Science, and by the Bernard Wolfe Health Neuroscience Fund. ETB is a part-time (50%) employee and shareholder of GSK. AMM is a member of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative, Grant number G0700704/84698.This is the accepted manuscript. The final version is available at http://dx.doi.org/10.1016/j.neuroimage.2015.03.03

Norm-based coding of voice identity in human auditory cortex

Listeners exploit small interindividual variations around a generic acoustical structure to discriminate and identify individuals from their voice—a key requirement for social interactions. The human brain contains temporal voice areas (TVA) [1] involved in an acoustic-based representation of voice identity [2, 3, 4, 5 and 6], but the underlying coding mechanisms remain unknown. Indirect evidence suggests that identity representation in these areas could rely on a norm-based coding mechanism [4, 7, 8, 9, 10 and 11]. Here, we show by using fMRI that voice identity is coded in the TVA as a function of acoustical distance to two internal voice prototypes (one male, one female)—approximated here by averaging a large number of same-gender voices by using morphing [12]. Voices more distant from their prototype are perceived as more distinctive and elicit greater neuronal activity in voice-sensitive cortex than closer voices—a phenomenon not merely explained by neuronal adaptation [13 and 14]. Moreover, explicit manipulations of distance-to-mean by morphing voices toward (or away from) their prototype elicit reduced (or enhanced) neuronal activity. These results indicate that voice-sensitive cortex integrates relevant acoustical features into a complex representation referenced to idealized male and female voice prototypes. More generally, they shed light on remarkable similarities in cerebral representations of facial and vocal identity

Neural differentiation is moderated by age in scene- but not face-selective cortical regions

The aging brain is characterized by neural dedifferentiation, an apparent decrease in the functional selectivity of category-selective cortical regions. Age-related reductions in neural differentiation have been proposed to play a causal role in cognitive aging. Recent findings suggest, however, that age-related dedifferentiation is not equally evident for all stimulus categories and, additionally, that the relationship between neural differentiation and cognitive performance is not moderated by age. In light of these findings, in the present experiment, younger and older human adults (males and females) underwent fMRI as they studied words paired with images of scenes or faces before a subsequent memory task. Neural selectivity was measured in two scene-selective (parahippocampal place area (PPA) and retrosplenial cortex (RSC)] and two face-selective [fusiform face area (FFA) and occipital face area (OFA)] regions using both a univariate differentiation index and multivoxel pattern similarity analysis. Both methods provided highly convergent results, which revealed evidence of age-related reductions in neural dedifferentiation in scene-selective but not face-selective cortical regions. Additionally, neural differentiation in the PPA demonstrated a positive, age-invariant relationship with subsequent source memory performance (recall of the image category paired with each recognized test word). These findings extend prior findings suggesting that age-related neural dedifferentiation is not a ubiquitous phenomenon, and that the specificity of neural responses to scenes is predictive of subsequent memory performance independently of age

Influence of aging on the neural correlates of autobiographical, episodic, and semantic memory retrieval

We used fMRI to assess the neural correlates of autobiographical, semantic, and episodic memory retrieval in healthy young and older adults. Participants were tested with an eventrelated paradigm in which retrieval demand was the only factor varying between trials. A spatio-temporal partial least square analysis was conducted to identify the main patterns of activity characterizing the groups across conditions. We identified brain regions activated by all three memory conditions relative to a control condition. This pattern was expressed equally in both age groups and replicated previous findings obtained in a separate group of younger adults. We also identified regions whose activity differentiated among the different memory conditions. These patterns of differentiation were expressed less strongly in the older adults than in the young adults, a finding that was further confirmed by a barycentric discriminant analysis. This analysis showed an age-related dedifferentiation in autobiographical and episodic memory tasks but not in the semantic memory task or the control condition. These findings suggest that the activation of a common memory retrieval network is maintained with age, whereas the specific aspects of brain activity that differ with memory content are more vulnerable and less selectively engaged in older adults. Our results provide a potential neural mechanism for the well-known age differences in episodic/autobiographical memory, and preserved semantic memory, observed when older adults are compared with younger adults

Causes and Consequences of Dedifferentiation in the Aging Brain.

Cognitive performance declines across the adult lifespan. According to the dedifferentiation hypothesis of cognitive aging, age-related cognitive impairments reflect reductions in the fidelity of neural representations. However, behavioral tests of this hypothesis have yielded mixed results. Thus, the present research sought to explore age-related dedifferentiation using pattern classification of neural activity, which may yield a more direct measure of representational fidelity. Three studies examined age differences in the fidelity of the neural representations of visual stimuli, motor actions, and cognitive task sets, respectively. Study 1 showed that multi-voxel activation patterns evoked by presentation of face and house stimuli were less distinctive in older adults than in young adults. No regions showed greater distinctiveness in older adults than in young adults, and the spatial pattern of category information was similar across age groups, suggesting that older adults do not compensate for low- fidelity representations in visual cortex by forming higher-fidelity representations elsewhere in the brain. Study 2 extended these results to the domain of motor control, using multi-voxel pattern analysis to distinguish between left- and right-hand finger movements. Older adults showed reduced distinctiveness throughout a network of regions related to motor representation and control; again, no regions showed greater distinctiveness in older adults. Study 3 further investigated age differences in neural representations in the context of verbal and spatial working memory tasks. Results from memory encoding and retrieval were consistent with Studies 1 and 2, with reduced discrimination of verbal versus spatial information in older adults. In contrast, results from working memory maintenance showed that representational fidelity was decreased in older adults at high levels of task demand but increased in older adults at low levels of demand. Overall, results from perceptual and motor tasks were consistent with the dedifferentiation hypothesis, while results from memory maintenance were more consistent with compensation-related accounts of cognitive aging. These results suggest that both dedifferentiation- and compensation-based accounts can explain some phenomena, but that neither theory can offer a comprehensive account of age differences in neural representation. Future research should investigate the generalizability of the present results across analysis methods, cognitive tasks, and participant populations.PhDPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107180/1/jmcarp_1.pd

Assessing neural tuning for object perception in schizophrenia and bipolar disorder with multivariate pattern analysis of fMRI data.

IntroductionDeficits in visual perception are well-established in schizophrenia and are linked to abnormal activity in the lateral occipital complex (LOC). Related deficits may exist in bipolar disorder. LOC contains neurons tuned to object features. It is unknown whether neural tuning in LOC or other visual areas is abnormal in patients, contributing to abnormal perception during visual tasks. This study used multivariate pattern analysis (MVPA) to investigate perceptual tuning for objects in schizophrenia and bipolar disorder.MethodsFifty schizophrenia participants, 51 bipolar disorder participants, and 47 matched healthy controls completed five functional magnetic resonance imaging (fMRI) runs of a perceptual task in which they viewed pictures of four different objects and an outdoor scene. We performed classification analyses designed to assess the distinctiveness of activity corresponding to perception of each stimulus in LOC (a functionally localized region of interest). We also performed similar classification analyses throughout the brain using a searchlight technique. We compared classification accuracy and patterns of classification errors across groups.ResultsStimulus classification accuracy was significantly above chance in all groups in LOC and throughout visual cortex. Classification errors were mostly within-category confusions (e.g., misclassifying one chair as another chair). There were no group differences in classification accuracy or patterns of confusion.ConclusionsThe results show for the first time MVPA can be used successfully to classify individual perceptual stimuli in schizophrenia and bipolar disorder. However, the results do not provide evidence of abnormal neural tuning in schizophrenia and bipolar disorder

Neural evidence for age-related differences in representational quality and strategic retrieval processes.

Mounting behavioral evidence suggests that declines in both representational quality and controlled retrieval processes contribute to episodic memory decline with age. The present study sought neural evidence for age-related change in these factors by measuring neural differentiation during encoding of paired associates and changes in regional blood oxygenation level-dependent activity and functional connectivity during retrieval conditions that placed low (intact pairs) and high (recombined pairs) demands on controlled retrieval processes. Pattern similarity analysis revealed age-related declines in the differentiation of stimulus representations at encoding, manifesting as both reduced pattern similarity between closely related events and increased pattern similarity between distinct events. During retrieval, both groups increased recruitment of areas within the core recollection network when endorsing studied pairs, including the hippocampus and angular gyrus. In contrast, only younger adults increased recruitment of, and hippocampal connectivity with, lateral prefrontal regions during correct rejections of recombined pairs. These results provide evidence for age-related changes in representational quality and in the neural mechanisms supporting memory retrieval under conditions of high, but not low, control demand

Dissociating refreshing and elaboration and their impacts on memory

Maintenance of information in working memory (WM) is assumed to rely on refreshing and elaboration, but clear mechanistic descriptions of these cognitive processes are lacking, and it is unclear whether they are simply two labels for the same process. This fMRI study investigated the extent to which refreshing, elaboration, and repeating of items in WM are distinct neural processes with dissociable behavioral outcomes in WM and long-term memory (LTM). Multivariate pattern analyses of fMRI data revealed differentiable neural signatures for these processes, which we also replicated in an independent sample of older adults. In some cases, the degree of neural separation within an individual predicted their memory performance. Elaboration improved LTM, but not WM, and this benefit increased as its neural signature became more distinct from repetition. Refreshing had no impact on LTM, but did improve WM, although the neural discrimination of this process was not predictive of the degree of improvement. These results demonstrate that refreshing and elaboration are separate processes that differently contribute to memory performance

Age differences in fMRI adaptation for sound identity and location

We explored age differences in auditory perception by measuring fMRI adaptation of brain activity to repetitions of sound identity (what) and location (where), using meaningful environmental sounds. In one condition, both sound identity and location were repeated allowing us to assess non-specific adaptation. In other conditions, only one feature was repeated (identity or location) to assess domain-specific adaptation. Both young and older adults showed comparable non-specific adaptation (identity and location) in bilateral temporal lobes, medial parietal cortex, and subcortical regions. However, older adults showed reduced domain-specific adaptation to location repetitions in a distributed set of regions, including frontal and parietal areas, and to identity repetition in anterior temporal cortex. We also re-analyzed data from a previously published 1-back fMRI study, in which participants responded to infrequent repetition of the identity or location of meaningful sounds. This analysis revealed age differences in domain-specific adaptation in a set of brain regions that overlapped substantially with those identified in the adaptation experiment. This converging evidence of reductions in the degree of auditory fMRI adaptation in older adults suggests that the processing of specific auditory “what” and “where” information is altered with age, which may influence cognitive functions that depend on this processing