Distinct neurophysiological correlates of the fMRI BOLD signal in the hippocampus and neocortex.

Functional magnetic resonance imaging (fMRI) is among the foremost methods for mapping human brain function but provides only an indirect measure of underlying neural activity. Recent findings suggest that the neurophysiological correlates of the fMRI blood-oxygen-level-dependent (BOLD) signal might be regionally specific. We examined the neurophysiological correlates of the fMRI BOLD signal in the hippocampus and neocortex, where differences in neural architecture might result in a different relationship between the respective signals. Fifteen human neurosurgical patients (10 female, 5 male) implanted with depth electrodes performed a verbal free recall task while electrophysiological activity was recorded simultaneously from hippocampal and neocortical sites. The same patients subsequently performed a similar version of the task during a later fMRI session. Subsequent memory effects (SMEs) were computed for both imaging modalities as patterns of encoding-related brain activity predictive of later free recall. Linear mixed-effects modelling revealed that the relationship between BOLD and gamma-band SMEs was moderated by the lobar location of the recording site. BOLD and high gamma (70-150 Hz) SMEs positively covaried across much of the neocortex. This relationship was reversed in the hippocampus, where a negative correlation between BOLD and high gamma SMEs was evident. We also observed a negative relationship between BOLD and low gamma (30-70 Hz) SMEs in the medial temporal lobe more broadly. These results suggest that the neurophysiological correlates of the BOLD signal in the hippocampus differ from those observed in the neocortex.Significance Statement:The blood-oxygen-level-dependent (BOLD) signal forms the basis of fMRI but provides only an indirect measure of neural activity. Task-related modulation of BOLD signals are typically equated with changes in gamma-band activity; however, relevant empirical evidence comes largely from the neocortex. We examined neurophysiological correlates of the BOLD signal in the hippocampus, where the differing neural architecture might result in a different relationship between the respective signals. We identified a positive relationship between encoding-related changes in BOLD and gamma-band activity in frontal and parietal cortex. This effect was reversed in the hippocampus, where BOLD and gamma-band effects negatively covaried. These results suggest regional variability in the transfer function between neural activity and the BOLD signal in the hippocampus and neocortex.

Age Differences In Retrieval-Related Reinstatement Reflect Age-Related Dedifferentiation At Encoding.

Age-related reductions in neural selectivity have been linked to cognitive decline. We examined whether age differences in the strength of retrieval-related cortical reinstatement could be explained by analogous differences in neural selectivity at encoding, and whether reinstatement was associated with memory performance in an age-dependent or an age-independent manner. Young and older adults underwent fMRI as they encoded words paired with images of faces or scenes. During a subsequent scanned memory test participants judged whether test words were studied or unstudied and, for words judged studied, also made a source memory judgment about the associated image category. Using multi-voxel pattern similarity analyses, we identified robust evidence for reduced scene reinstatement in older relative to younger adults. This decline was however largely explained by age differences in neural differentiation at encoding; moreover, a similar relationship between neural selectivity at encoding and retrieval was evident in young participants. The results suggest that, regardless of age, the selectivity with which events are neurally processed at the time of encoding can determine the strength of retrieval-related cortical reinstatement.

Neural Differentiation is Moderated by Age in Scene-Selective, 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.

Comparison of fMRI correlates of successful episodic memory encoding in temporal lobe epilepsy patients and healthy controls.

Intra-cranial electroencephalographic brain recordings (iEEG) provide a powerful tool for investigating the neural processes supporting episodic memory encoding and form the basis of experimental therapies aimed at improving memory dysfunction. However, given the invasiveness of iEEG, investigations are constrained to patients with drug-resistant epilepsy for whom such recordings are clinically indicated. Particularly in the case of temporal lobe epilepsy (TLE), neuropathology and the possibility of functional reorganization are potential constraints on the generalizability of intra-cerebral findings and pose challenges to the development of therapies for memory disorders stemming from other etiologies. Here, samples of TLE (N â€‹= â€‹16; all of whom had undergone iEEG) and age-matched healthy control (N â€‹= â€‹19) participants underwent fMRI as they studied lists of concrete nouns. fMRI BOLD responses elicited by the study words were segregated according to subsequent performance on tests of delayed free recall and recognition memory. Subsequent memory effects predictive of both successful recall and recognition memory were evident in several neural regions, most prominently in the left inferior frontal gyrus, and did not demonstrate any group differences. Behaviorally, the groups did not differ in overall recall performance or in the strength of temporal contiguity effects. However, group differences in serial position effects and false alarm rates were evident during the free recall and recognition memory tasks, respectively. Despite these behavioral differences, neuropathology associated with temporal lobe epilepsy was apparently insufficient to give rise to detectable differences in the functional neuroanatomy of episodic memory encoding relative to neurologically healthy controls. The findings provide reassurance that iEEG findings derived from experimental paradigms similar to those employed here generalize to the neurotypical population.

Ventral lateral parietal cortex and episodic memory retrieval.

With the advent of functional neuroimaging it quickly became apparent that successful episodic memory retrieval was consistently associated with enhanced activity in ventral lateral parietal cortex (VLPC), especially the left angular gyrus. Here, we selectively review recent neuropsychological and functional neuroimaging evidence relevant to the question of the functional significance of this activity. We argue that the balance of the evidence suggests that the angular gyrus supports the representation of retrieved episodic information, and that this likely reflects a more general role for the region in representing multi-modal and multi-domain information.

Dissociation between the neural correlates of recollection and familiarity in the striatum and hippocampus: Across-study convergence.

In tests of recognition memory, neural activity in the striatum has consistently been reported to differ according to the study status of the test item. A full understanding of the functional significance of striatal 'retrieval success' effects is impeded by a paucity of evidence concerning whether the effects differ according to the nature of the memory signal supporting the recognition judgment (recollection vs. familiarity). Here, we address this issue through an analysis of retrieval-related striatal activity in three independent fMRI studies (total N = 88). Recollection and familiarity were operationalized in a different way in each study, allowing the identification of test-independent, generic recollection- and familiarity-related effects. While activity in a bilateral dorsal striatal region, mainly encompassing the caudate nucleus, was enhanced equally by recollected and 'familiar only' test items, activity in bilateral ventral striatum and adjacent subgenual frontal cortex was enhanced only in response to items that elicited successful recollection. By contrast, relative to familiar items, activity in anterior hippocampus was enhanced for both recollected and novel test items. Thus, recollection- and familiarity-driven recognition memory judgments are associated with anatomically distinct patterns of retrieval-related striatal activity, and these patterns are at least partially independent of recollection and novelty effects in the hippocampus.

Recollection-related increases in functional connectivity across the healthy adult lifespan.

In young adults, recollection-sensitive brain regions exhibit enhanced connectivity with a widely distributed set of other regions during successful versus unsuccessful recollection, and the magnitude of connectivity change correlates with individual differences in recollection accuracy. Here, we examined whether recollection-related changes in connectivity and their relationship with performance varied across samples of young, middle-aged, and older adults. Psychophysiological interaction analyses identified recollection-related increases in connectivity both with recollection-sensitive seed regions and among regions distributed throughout the whole brain. The seed-based approach failed to identify age-related differences in recollection-related connectivity change. However, the whole-brain analysis revealed a number of age-related effects. Numerous pairs of regions exhibited a main effect of age on connectivity change, mostly due to decreased change with increasing age. After controlling for recollection accuracy, however, these effects of age were for the most part no longer significant, and those effects that were detected now reflected age-related increases in connectivity change. A subset of pairs of regions also exhibited an age by performance interaction, driven mostly by a weaker relationship between connectivity change and recollection accuracy with increasing age. We conjecture that these effects reflect age-related differences in neuromodulation.

Influence of response bias and internal/external source on lateral posterior parietal successful retrieval activity.

In studies of recognition memory, regions of the lateral posterior parietal cortex exhibit greater activity (as indexed by the fMRI BOLD signal) during correct recognition of "old" (studied) items than correct rejection of "new" (unstudied) items. This effect appears to be source-sensitive, with greater activity associated with recognition of perceived than imagined events. Parietal successful retrieval activity also varies with response bias, or the tendency to be conservative about making "old" judgments. Here, we examined whether differences in response bias associated with recognition judgments of perceived and imagined events could account for source-based differences in LPPC activity. Participants perceived and imagined items in response to cue words and then at test, made recognition judgments in blocks that knowingly contained either a high or low proportion of old to new trials. While participants were indeed more conservative when making judgments about perceived than imagined events, the neuroimaging results demonstrated that response bias and source effects occurred in non-overlapping parietal regions. These findings suggest that source-based differences in LPPC activity cannot be explained by differences in response bias associated with recognizing perceived and imagined events.

Lateral posterior parietal activity during reality monitoring discriminations of memories of high and low perceptual vividness.

Regions of the lateral posterior parietal cortex (PPC) tend to be more active during recognition of previously studied items compared to correct rejection of unstudied items. Previously, we demonstrated that this effect is source-specific. While items that were encoded through visual perception elicited robust successful retrieval activity in the lateral PPC during a subsequent source memory test, items that were visually imagined did not elicit this effect. Memories of perceived events typically contain more perceptually-based contextual details than memories of imagined events. Therefore, source-based differences in lateral parietal activity might be due to a difference in the perceptual vividness of memories of perceived and imagined events. The goal of the present study was to test this hypothesis. Participants perceived and imagined items in both high and low perceptual vividness conditions. Experiment 1 demonstrated that memories for items encoded in the high vividness conditions contained significantly greater visual detail than memories encoded in the low vividness conditions. In Experiment 2, participants were scanned while they made source memory judgments about items that were previously perceived and imagined in high and low vividness conditions. Consistent with previous findings, the left lateral PPC was more active during retrieval of perceived compared to imagined events. However, lateral PPC activity did not vary according to vividness, suggesting that source effects in this region cannot be explained by a difference in the perceptual vividness of memories encoded through perception versus imagination.

Recollection-related increases in functional connectivity predict individual differences in memory accuracy.

Recollection involves retrieving specific contextual details about a prior event. Functional neuroimaging studies have identified several brain regions that are consistently more active during successful versus failed recollection-the "core recollection network." In the present study, we investigated whether these regions demonstrate recollection-related increases not only in activity but also in functional connectivity in healthy human adults. We used fMRI to compare time-series correlations during successful versus unsuccessful recollection in three separate experiments, each using a different operational definition of recollection. Across experiments, a broadly distributed set of regions consistently exhibited recollection-related increases in connectivity with different members of the core recollection network. Regions that demonstrated this effect included both recollection-sensitive regions and areas where activity did not vary as a function of recollection success. In addition, in all three experiments the magnitude of connectivity increases correlated across individuals with recollection accuracy in areas diffusely distributed throughout the brain. These findings suggest that enhanced functional interactions between distributed brain regions are a signature of successful recollection. In addition, these findings demonstrate that examining dynamic modulations in functional connectivity during episodic retrieval will likely provide valuable insight into neural mechanisms underlying individual differences in memory performance.

Lateral posterior parietal activity during source memory judgments of perceived and imagined events.

Memories of real and imagined events are qualitatively distinct, and therefore may be supported by different neural mechanisms. In the present study, we tested whether brain regions are differentially activated during source discriminations of perceived versus imagined events. During the encoding phase, subjects perceived and imagined images of objects in response to a cue word. Then, at test, they made judgments about whether old and new cue words corresponded to items that were previously perceived or imagined, or if they were new. The results demonstrated that the left lateral posterior parietal cortex and dorsolateral prefrontal cortex were significantly more active during source attributions of perceived compared to imagined events. In addition, activity in these regions was associated with successful item memory (hits>correct rejections) for perceived, but not imagined events. These findings of a source-based dissociation of successful retrieval activity have important implications regarding theories of parietal contributions to recognition memory.