High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment

Abstract

Functional magnetic resonance imaging (fMRI) studies have observed hyperactivity in the hippocampal region in individuals with Mild Cognitive Impairment (MCI). However, the actual source of such hyperactivity is not well understood. Studies of aged rats observed similar hyperactive signals in the CA3 region of the hippocampus that correlated with spatial memory deficits and, in particular, with their ability to represent novel environments as being distinct from familiar ones (pattern separation). In this study, we tested the hypothesis that patients with amnestic MCI (aMCI) have deficits in pattern separation, along with hyperactive fMRI BOLD activity in the CA3 region of the hippocampus. We used high-resolution fMRI during a continuous recognition task designed to emphasize pattern separation. We conducted hippocampal subfieldlevel region of interest analyses to test for dysfunctional activity in aMCI patients. We found that patients showed impaired performance on trials that taxed their pattern separation abilities. We also observed hyperactive BOLD signals in the CA3/dentate and hypoactive signals in the entorhinal cortex during the separation condition. In a high-resolution morphometric analysis of hippocampal subfields, aMCI patients also had smaller CA3/dentate and CA1 volumes (no difference in the subiculum). The CA3/dentate region bilaterally also exhibited the largest shape deformations in aMCI patients, suggesting that this locus is affected early in the course of the disease. These findings suggest that structural and functional changes in the CA3/dentate region of the hippocampus contribute to the deficits in episodic memory that are observed in patients with aMCI. The functional hyperactivity may be evidence for a dysfunctional encoding mechanism, consistent with the predictions of computational models of hippocampal learning.

Functional connectivity with the retrosplenial cortex predicts cognitive aging in rats

“…Pharmacological treatments that dampen this excess activity (e.g., low-dose administration of the antiepileptic drug levetiracetam) rescue memory, suggesting that these neurophysiological and cognitive signatures of hippocampal aging are causally related (50). Human fMRI studies, founded in part on this preclinical animal work, have documented elevated activity in the hippocampus of older subjects with corresponding memory deficits (51). Moreover, both effects are reversed by the same pharmacological intervention that proved beneficial in aged rats (52).…”

Object and spatial mnemonic interference differentially engage lateral and medial entorhinal cortex in humans

“…In addition to similar object lures, which have been used extensively in our prior investigations of interference resolution in humans (14,(49)(50)(51), we designed a set of spatial lures based on varying metric distance (7,52). We defined a high-similarity lure as an identical object occurring one grid space from its original location, and a low-similarity lure as an identical object occurring two grid spaces from its original location.…”

The cognitive neuroscience of ageing

“…Recent research has focused on understanding what might underlie this over-activity. For example, one recent study 175 examined subregions of the hippocampus using high resolution fMRI to explore the CA3 region, thought to be involved in pattern separation during memory. Participants with MCI showed over-recruitment of the CA3 region, but not other regions, relative to controls, as well as impaired pattern separation ability, consistent with the idea of a dysfunctional encoding mechanism due to early neuropathological changes in this hippocampal region.…”