Steven E. Prince

Neural correlates of relational memory: successful encoding and retrieval of semantic and perceptual associations

Using event-related functional magnetic resonance imaging, we identified brain regions involved in successful relational memory (RM) during encoding and retrieval for semantic and perceptual associations or in general, independent of phase and content. Participants were scanned while encoding and later retrieving associations between pairs of words (semantic RM) or associations between words and fonts (perceptual RM). Encoding success activity (ESA) was identified by comparing study-phase activity for items subsequently remembered (hits) versus forgotten (misses) and retrieval success activity (RSA) by comparing test-phase activity for hits versus misses. The study yielded three main sets of findings. First, ESA-RSA differences were found within the medial temporal lobes (MTLs) and within the prefrontal cortex (PFC). Within the left MTL, ESA was greater in the anterior hippocampus, and RSA was greater in the posterior parahippocampal cortex/hippocampus. This finding is consistent with the notion of an encoding-retrieval gradient along the longitudinal MTL axis. Within the left PFC, ESA was greater in ventrolateral PFC, and RSA was greater in dorsolateral and anterior PFC. This is the first evidence of a dissociation in successful encoding and retrieval activity within left PFC. Second, consistent with the transfer-appropriate processing principle, some ESA regions were reactivated during RSA in a content-specific manner. For semantic RM, these regions included the left ventrolateral PFC, whereas for perceptual RM, they included occipitoparietal and right parahippocampal regions. Finally, only one region in the entire brain was associated with RM in general (i.e., for both semantic and perceptual ESA and RSA): the left hippocampus. This finding highlights the fundamental role of the hippocampus in RM.

When less means more: deactivations during encoding that predict subsequent memory

In event-related functional MRI (fMRI) studies, greater activity for items that are subsequently remembered (R-items) than for items that are subsequently forgotten (F-items), or Dm effect (Difference in memory), has been attributed to successful encoding operations. In contrast, regions showing a reverse DM effect (revDM = F-items > R-items) have been linked to detrimental processes leading to forgetting. Yet, revDMs may reflect not only activations for F-items (aFs) but also deactivations for R-items (dRs), and the latter alternative is more likely to reflect beneficial rather than detrimental encoding processes. To investigate this issue, we used a paradigm that included a fixation baseline and could distinguish between the two types of revDMs (aF vs. dR). Participants were scanned while encoding semantic associations between words or perceptual associations between words and fonts, and their memory was measured with associative recognition tests. For both semantic and perceptual encoding, dR effects were found in dorsolateral prefrontal, temporoparietal, and posterior midline regions. In contrast with a prior study that attributed revDMs in these regions to detrimental processes, the present results suggest that these effects reflect beneficial processes, that is, the efficient reallocation of neurocognitive resources. At the same time, aF effects were found in other regions, such as the insula, and these are more consistent with an interpretation in terms of detrimental processes. Whereas most fMRI studies of encoding have focused on activation increases, the present study indicates that activation decreases are also critical for successful learning of new information.

Effects of Aging on the Neural Correlates of Successful Item and Source Memory Encoding

To investigate the neural basis of age-related source memory (SM) deficits, young and older adults were scanned with fMRI while encoding faces, scenes, and face-scene pairs. Successful encoding activity was identified by comparing encoding activity for subsequently remembered versus forgotten items or pairs. Age deficits in successful encoding activity in hippocampal and prefrontal regions were more pronounced for SM (pairs) as compared with item memory (faces and scenes). Age-related reductions were also found in regions specialized in processing faces (fusiform face area) and scenes (parahippocampal place area), but these reductions were similar for item and SM. Functional connectivity between the hippocampus and the rest of the brain was also affected by aging; whereas connections with posterior cortices were weaker in older adults, connections with anterior cortices, including prefrontal regions, were stronger in older adults. Taken together, the results provide a link between SM deficits in older adults and reduced recruitment of hippocampal and prefrontal regions during encoding. The functional connectivity findings are consistent with a posterior-anterior shift with aging previously reported in several cognitive domains and linked to functional compensation.

Default mode network connectivity in stable vs progressive mild cognitive impairment

Objective: Dysfunction of the default mode network (DMN) has been identified in prior cross-sectional fMRI studies of Alzheimer disease (AD) and mild cognitive impairment (MCI); however, no studies have examined its utility in predicting future cognitive decline. Methods: fMRI scans during a face–name memory task were acquired from a cohort of 68 subjects (25 normal control, 31 MCI, and 12 AD). Subjects with MCI were followed for 2.4 years (±0.8) to determine progression to AD. Maps of DMN connectivity were compared with a template DMN map constructed from elderly normal controls to obtain goodness-of-fit (GOF) indices of DMN expression. Indices were compared between groups and correlated with cognitive decline. Results: GOF indices were highest in normal controls, intermediate in MCI, and lowest in AD (p < 0.0001). In a predictive model (that included baseline GOF indices, age, education, Mini-Mental State Examination score, and an index of DMN gray matter volume), the effect of GOF index on progression from MCI to dementia was significant. In MCI, baseline GOF indices were correlated with change from baseline in functional status (Clinical Dementia Rating–sum of boxes) (r = −0.40, p < 0.04). However, there was no additional predictive value for DMN connectivity when baseline delayed recall was included in the models. Conclusions: fMRI connectivity indices distinguish patients with MCI who undergo cognitive decline and conversion to AD from those who remain stable over a 2- to 3-year follow-up period. Our data support the notion of different functional brain connectivity endophenotypes for “early” vs “late” MCI, which are associated with different baseline memory scores and different rates of progression and conversion.

Attention-related activity during episodic memory retrieval: a cross-function fMRI study

In functional neuroimaging studies of episodic retrieval (ER), activations in prefrontal, parietal, anterior cingulate, and thalamic regions are typically attributed to episodic retrieval processes. However, these activations are also frequent during visual attention (VA) tasks, suggesting that their role in ER may reflect attentional rather than mnemonic processes. To investigate this possibility, we directly compared brain activity during ER and VA tasks using event-related fMRI. The ER task was a word recognition test with a retrieval mode component, and the VA task was a target detection task with a sustained attention component. The study yielded three main findings. First, a common fronto-parietal-cingulate-thalamic network was found for ER and VA, suggesting that the involvement of these regions during ER reflects general attentional processes. This idea is compatible with some of the interpretations proposed in the ER literature (e.g. postretrieval monitoring), which may be rephrased in terms of attentional processes. Second, several subregions were differentially involved in ER versus VA. For example, the frontopolar cortex and the precuneus were more activated for ER than for VA, possibly reflecting retrieval mode and processing of internally generated stimuli, respectively. Finally, the study yielded an unexpected finding: some medial temporal lobe regions were similarly activated for ER and VA. This finding suggests that the medial temporal lobes may be involved in indexing representations within the focus of consciousness, regardless of whether they are mnemonic or perceptual. Overall, the present results suggest that many of the activations attributed to specific cognitive processes, such as episodic memory, may actually reflect more general cognitive operations.

Posterior midline and ventral parietal activity is associated with retrieval success and encoding failure

The ventral part of lateral posterior parietal cortex (VPC) and the posterior midline region (PMR), including the posterior cingulate cortex and precuneus, tend to show deactivation during demanding cognitive tasks, and have been associated with the default mode of the brain. Interestingly, PMR and VPC activity has been associated with successful episodic retrieval but also with unsuccessful episodic encoding. However, the differential contributions of PMR and VPC to retrieval vs. encoding has never been demonstrated within-subjects and within the same experiment. Here, we directly tested the prediction that PMR and VPC activity should be associated with retrieval success but with encoding failure. Consistent with this prediction, we found across five different fMRI experiments that, during retrieval, activity in these regions is greater for hits than misses, whereas during encoding, it is greater for subsequent misses than hits. We also found that these regions overlap with the ones that show deactivations during conscious rest. Our findings further aid in clarifying the role of the default mode regions in learning and memory.

Neurobehavioral mechanisms of human fear generalization.

While much research has elucidated the neurobiology of fear learning, the neural systems supporting the generalization of learned fear are unknown. Using functional magnetic resonance imaging (fMRI), we show that regions involved in the acquisition of fear support the generalization of fear to stimuli that are similar to a learned threat, but vary in fear intensity value. Behaviorally, subjects retrospectively misidentified a learned threat as a more intense stimulus and expressed greater skin conductance responses (SCR) to generalized stimuli of high intensity. Brain activity related to intensity-based fear generalization was observed in the striatum, insula, thalamus/periacqueductal gray, and subgenual cingulate cortex. The psychophysiological expression of generalized fear correlated with amygdala activity, and connectivity between the amygdala and extrastriate visual cortex was correlated with individual differences in trait anxiety. These findings reveal the brain regions and functional networks involved in flexibly responding to stimuli that resemble a learned threat. These regions may comprise an intensity-based fear generalization circuit that underlies retrospective biases in threat value estimation and overgeneralization of fear in anxiety disorders.

Prognostic Value of Posteromedial Cortex Deactivation in Mild Cognitive Impairment

Background Normal subjects deactivate specific brain regions, notably the posteromedial cortex (PMC), during many tasks. Recent cross-sectional functional magnetic resonance imaging (fMRI) data suggests that deactivation during memory tasks is impaired in Alzheimers disease (AD). The goal of this study was to prospectively determine the prognostic significance of PMC deactivation in mild cognitive impairment (MCI). Methodology/Principal Findings 75 subjects (34 MCI, 13 AD subjects and 28 controls) underwent baseline fMRI scanning during encoding of novel and familiar face-name pairs. MCI subjects were followed longitudinally to determine conversion to AD. Regression and analysis of covariance models were used to assess the effect of PMC activation/deactivation on conversion to dementia as well as in the longitudinal change in dementia measures. At longitudinal follow up of up to 3.5 years (mean 2.5±0.79 years), 11 MCI subjects converted to AD. The proportion of deactivators was significantly different across all groups: controls (79%), MCI-Nonconverters (73%), MCI-converters (45%), and AD (23%) (p<0.05). Mean PMC activation magnitude parameter estimates, at baseline, were negative in the control (−0.57±0.12) and MCI-Nonconverter (−0.33±0.14) groups, and positive in the MCI-Converter (0.37±0.40) and AD (0.92±0.30) groups. The effect of diagnosis on PMC deactivation remained significant after adjusting for age, education and baseline Mini-Mental State Exam (p<0.05). Baseline PMC activation magnitude was correlated with change in dementia ratings from baseline. Conclusion Loss of physiological functional deactivation in the PMC may have prognostic value in preclinical AD, and could aid in profiling subgroups of MCI subjects at greatest risk for progressive cognitive decline.

Distinguishing the Neural Correlates of Episodic Memory Encoding and Semantic Memory Retrieval

Episodic memory and semantic memory interact very closely. In particular, episodic memory encoding (EE) tends to elicit semantic memory retrieval (SR), and vice versa. Thus, similar activations for EE and SR in functional neuroimaging studies may reflect shared memory processes, or they may reflect the fact that EE and SR are usually confounded. To address this issue, we used a factorial functional magnetic resonance imaging approach to disentangle the neural correlates of EE and SR. Within the left temporal lobe, the hippocampus was associated with successful EE, whereas a posterior lateral region was associated with successful SR. Within the left inferior prefrontal cortex, a posterior region was involved in SR, a mid region was involved in both SR and EE, and an anterior region was involved in EE, but only when SR was also high. Thus, the neural correlates of EE and SR are dissociable but interact in specific brain regions.

Encoding and retrieving faces and places: Distinguishing process- and stimulus-specific differences in brain activity

Among the most fundamental issues in cognitive neuroscience is how the brain may be organized into process-specific and stimulus-specific regions. In the episodic memory domain, most functional neuroimaging studies have focused on the former dimension, typically investigating the neural correlates of various memory processes. Thus, there is little information about what role stimulus-specific brain regions play in successful memory processes. To address this issue, the present event-related fMRI study used a factorial design to focus on the role of stimulus-specific brain regions, such as the fusiform face area (FFA) and parahippocampal place area (PPA) in successful encoding and retrieval processes. Searching within regions sensitive to faces or places, we identified areas similarly involved in encoding and retrieval, as well as areas differentially involved in encoding or retrieval. Finally, we isolated regions associated with successful memory, regardless of stimulus and process type. There were three main findings. Within face sensitive regions, anterior medial PFC and right FFA displayed equivalent encoding and retrieval success processes whereas left FFA was associated with successful encoding rather than retrieval. Within place sensitive regions, left PPA displayed equivalent encoding and retrieval success processes whereas right PPA was associated with successful encoding rather than retrieval. Finally, medial temporal and prefrontal regions were associated with general memory success, regardless of stimulus or process type. Taken together, our results clarify the contribution of different brain regions to stimulus- and process-specific episodic memory mechanisms.