Transient hippocampal CA1 lesions in humans impair pattern separation performance

Abstract

Day‐to‐day life involves the perception of events that resemble one another. For the sufficient encoding and retrieval of similar information, the hippocampus provides two essential computational processes. Pattern separation refers to the differentiation of overlapping memory representations, whereas pattern completion reactivates memories based on noisy or degraded input. Evidence from human and rodent studies suggest that pattern separation specifically relies on neuronal ensemble activity in hippocampal subnetworks in the dentate gyrus and CA3. Although a role for CA1 in pattern separation has been shown in animal models, its contribution in the human hippocampus remains elusive. In order to elucidate the contribution of CA1 neurons to pattern separation, we examined 14 patients with an acute transient global amnesia (TGA), a rare self‐limiting dysfunction of the hippocampal system showing specific lesions to CA1. Patients' pattern separation performance was tested during the acute amnestic phase and follow‐up using an established mnemonic similarity test. Patients in the acute phase showed a profound deficit in pattern separation (p < .05) as well as recognition memory (p < .001) that recovered during follow‐up. Specifically, patients tested in a later stage of the amnesia were less impaired in pattern separation than in recognition memory. Considering the time dependency of lesion‐associated hippocampal deficits in early and late acute stages of the TGA, we showed that the pattern separation function recovered significantly earlier than recognition memory. Our results provide causal evidence that hippocampal CA1 neurons are critical to pattern separation performance in humans.

Transient Global Amnesia: Risk Factors, Imaging Features, and Prognosis

“…The patients with TGA and lesions on DWI were further examined using fMRI. Similar to the results of previous studies, 12 , 16 , 17 , 20–25 our findings showed that the lesions on DWI were mainly located in the hippocampal CA1 area ( Figure 3 ). Seven of the patients with TGA and hippocampal lesions on DWI were right-handed, suggesting that the left cerebral hemisphere was dominant.…”

Enhanced mnemonic discrimination for emotional memories: the role of arousal in interference resolution

“…old responses given to the target items minus old responses given to the foils) as a measure of hippocampal integrity (Stark et al, 2013 ), because this index seems to be more sensitive to hippocampal dysfunctions in pathological and normal ageing (Stark et al, 2013 ; Stark, Stevenson, Wu, Rutledge, & Stark, 2015 ) as well as in various psychiatric and neurological disorders (e.g. Hanert, Pedersen, & Bartsch, 2019 ; Kirwan et al, 2012 ). Importantly, although pattern separation is a computational process, lure discrimination reflects behavioral performance on a memory test where for correct discrimination, interference resolution is needed.…”

Plasticity impairment alters community structure but permits successful pattern separation in a hippocampal network model

“…However, given our results that STDP impairment did not have a strong negative effect on learning and pattern separation, additional injury mechanisms should be explored in future work. Since damage is known to cause pattern separation deficits in both animals and humans [13,57,58], our results suggest that some additional mechanism beyond STDP impairment must contribute to those effects. Upcoming modeling studies might also examine the interplay between different plasticity algorithms since a stronger homeostatic mechanism might compensate for larger decreases in STDP-related potentiation, thereby preserving baseline untrained activity levels while exposing larger learning deficits.…”

“…These trained behaviors depend on discrimination between similar experiences. Recent findings also demonstrate that injury impairs pattern separation in humans [57,58]. The dentate is traditionally the primary focus of studies on hippocampal pattern separation because its intrinsic properties of high inhibition and parallel circuity intuitively support this filter function; however, there is growing evidence that other subregions (CA3 and CA1) also facilitate pattern separation.…”

“…The dentate is traditionally the primary focus of studies on hippocampal pattern separation because its intrinsic properties of high inhibition and parallel circuity intuitively support this filter function; however, there is growing evidence that other subregions (CA3 and CA1) also facilitate pattern separation. In fact, temporary CA1 lesions impair pattern separation in humans [58]. Since CA1 relays information processed by the hippocampus to neocortical brain regions [76], the area clearly plays an important role in the wider circuitry, making it an intuitively important subregion.…”