A neural substrate in the human hippocampus for linking successive events

Abstract

Memory formation requires the placement of experienced events in the same order in which they appeared. A large body of evidence from human studies indicates that structures in the medial temporal lobe are critically involved in forming and maintaining such memories, and complementing evidence from lesion and electrophysiological work in animals support these findings. However, it remains unclear how single cells and networks of cells can signal this temporal relationship between events. Here we used recordings from single cells in the human brain obtained while subjects viewed repeated presentations of cinematic episodes. We found that neuronal activity in successive time segments became gradually correlated, and, as a result, activity in a given time window became a faithful predictor of the activity to follow. This correlation emerged rapidly, within two to three presentations of an episode and exceeded both context-independent and pure stimulus-driven correlations. The correlation was specific for hippocampal neurons, did not occur in the amygdala and anterior cingulate cortex, and was found for single cells, cell pairs, and triplets of cells, supporting the notion that cell assemblies code for the temporal relationships between sensory events. Importantly, this neuronal measure of temporal binding successfully predicted subjects' ability to recall and verbally report the viewed episodes later. Our findings suggest a neuronal substrate for the formation of memory of the temporal order of events. memory formation | temporal binding | medial temporal lobe | single units | electrophysiology M emory formation includes knowledge about temporally dated events and the temporal relations of these events to each other. In human episodic memory, for example, events and concepts are linked together as they appear on the "time arrow," and in the same context in which they appeared (1-4). Many other types of memory (e.g., rote and sequence learning) require the successful encoding of the temporal relationship between events that follow in time. Case studies as well as studies using imaging techniques with human subjects have shown that formation and maintenance of such memories is mediated by different structures in the medial temporal lobe, with the hippocampus playing a major role (1-10). It is now accepted that neurons of the hippocampus are especially bound to reflect associative events, as these neurons sample inputs from a wide range of structures including sensory areas and high-order association cortices involved in recent event processing (2, 3).To study electrophysiological correlates of memory formation, research in the hippocampus of animals has focused on several paradigms that require memory for the temporal order of events (2, 11). These paradigms include learning of associations between pairs of stimuli (12-15), trace conditioning in which the unconditioned stimulus is well separated in time from the conditioned stimulus (16, 17), delayed nonmatch-to-sample (18), sequences of locations in spatial navigati...

The functional profile of the human amygdala in affective processing: Insights from intracranial recordings

“…In further support of this claim, iEEG evidence suggests human amygdala neurons encode events in dissociated segments, organized individually according to category-based or object-based stimulus features (Gelbard-Sagiv et al, 2008;Kreiman et al, 2000a;Paz et al, 2010;Quiroga et al, 2007Quiroga et al, , 2005 and semantic/affective meaning (Naccache et al, 2005;Pedreira et al, 2010;Quian Quiroga et al, 2009). Several single-neuron studies illustrate the amygdala's capacity to selectively encode object categories (Gelbard-Sagiv et al, 2008; Kreiman et al, 2002Kreiman et al, , 2000aMormann et al, 2008;Pourtois, Spinelli, et al, 2010), individual objects (Kreiman et al, 2002;Quiroga et al, 2005, Quian Quiroga et al, 2009, and abstract concepts/images from words (Br azdil et al, 2002;Cameron et al, 2001;Halgren, Babb & Rausch, et al, 1977;Heit et al, 1988;Naccache et al, 2005).…”

“…Memory formation is crucial for learning from novel relevant experiences (Rutishauser, Ross, Mamelak, & Schuman, 2010), and iEEG evidence has reliably illustrated the importance of amygdala neuronal activity in encoding, recognition and recall accuracy of objects and events ( c o r t e x 6 0 ( 2 0 1 4 ) 1 0 e3 3 Heit, Smith, & Halgren, 1988;Howard, Viskontas, Shankar, & Fried, 2012;Kreiman, Koch, & Fried, 2000b;Paz et al, 2010;Quian Quiroga, Kraskov, Koch, & Fried, 2009;Quiroga, Mukamel, Isham, Malach, & Fried, 2008, Quiroga, Reddy, Kreiman, Koch, & Fried, 2005Rutishauser et al, 2010). Importantly, this occurs independently of sensory modality (Quian Quiroga et al, 2009).…”

“…For instance, categories (e.g., animals) and specific objects (e.g., individuals) are shown to yield selective amygdala neuronal FR at encoding and recognition irrespective of presentation context and angular configurations (Gelbard-Sagiv et al, 2008;Kreiman, Fried, & Koch, 2002;Mormann et al, 2011;Quian Quiroga et al, 2009;Quiroga et al, 2005). Consequently, the amygdala may be removed from encoding contextual aspects relevant to the experienced stimulus, including temporal relationships of events and objects (Howard et al, 2012;Paz et al, 2010), spatial location of the respective stimulus (Rutishauser, Mamelak, & Schuman, 2006, Rutishauser, Schuman, & Mamelak, 2008, and even affectively neutral associative relationships (Cameron et al, 2001). Single-neuron studies by Howard et al (2012) and Paz et al (2010) both failed to show significant amygdala neural responding that would be indicative of temporal order processing of experienced events.…”

“…Consequently, the amygdala may be removed from encoding contextual aspects relevant to the experienced stimulus, including temporal relationships of events and objects (Howard et al, 2012;Paz et al, 2010), spatial location of the respective stimulus (Rutishauser, Mamelak, & Schuman, 2006, Rutishauser, Schuman, & Mamelak, 2008, and even affectively neutral associative relationships (Cameron et al, 2001). Single-neuron studies by Howard et al (2012) and Paz et al (2010) both failed to show significant amygdala neural responding that would be indicative of temporal order processing of experienced events. Furthermore, Rutishauser, Mamelak, et al (2006) and Rutishauser et al (2008) observed amygdala neurons to discriminate familiar vs. novel stimuli with negligible amygdala neuron spiking activity when recalling the spatial location of the preferred stimulus 24 h post-stimulus presentation.…”

Constructing Realistic Engrams: Poststimulus Activity of Hippocampus and Dorsal Striatum Predicts Subsequent Episodic Memory

“…Converging evidence indicates that the hippocampus is involved in relational encoding (Henke et al, 1997;Cohen et al, 1999;Davachi and Wagner, 2002;Davachi et al, 2003), a process in which separate episodic elements are bound into an integrated memory trace (Davachi and Wagner, 2002). Such episodic binding associates features over gaps not only in space but also in time (Staresina and Davachi, 2009;Paz et al, 2010), enabling the encoding of complex experiences as integral events. Studies examining this type of binding have typically focused on relatively simple stimuli to differentiate item encoding and relational encoding.…”