The sign effect in temporal discounting does not require the hippocampus.

When considering future outcomes, humans tend to discount gains more than losses. This phenomenon, referred to as the temporal discounting sign effect, is thought to result from the greater anticipated emotional impact of waiting for a negative outcome (dread) compared to waiting for a positive outcome (mixture of savoring and impatience). The impact of such anticipatory emotions has been proposed to rely on episodic future thinking. We evaluated this proposal by examining the presence and magnitude of a sign effect in the intertemporal decisions of individuals with hippocampal amnesia, who are severely impaired in their ability to engage in episodic mental simulation, and by comparing their patterns of choices to those of healthy controls. We also measured loss aversion, the tendency to assign greater value to losses compared to equivalent gains, to verify that any reduction in the sign effect in the hippocampal lesion group could not be explained by a group difference in loss aversion. Results showed that participants with hippocampal amnesia exhibited a sign effect, with less discounting of monetary losses compared to gains, that was similar in magnitude to that of controls. Loss aversion, albeit greater in the hippocampal compared to the control group, did not account for the sign effect. These results indicate that the sign effect does not depend on the integrity of hippocampally mediated episodic processes. They suggest instead that the impact of anticipatory emotions can be factored into decisions via semantic future thinking, drawing on non-contextual knowledge about oneself.

Less is more: Smaller hippocampal subfield volumes predict greater improvements in posttraumatic stress disorder symptoms over 2 years.

Posttraumatic stress disorder (PTSD) is a heterogeneous disorder, and symptom severity varies over time. Neurobiological factors that predict PTSD symptoms and their chronicity remain unclear. This study investigated whether the volume of the hippocampus and its subfields, particularly cornu ammonis (CA) 1, CA3, and dentate gyrus, are associated with current PTSD symptoms and whether they predict PTSD symptom changes over 2 years. We examined clinical and structural magnetic resonance imaging measures from 252 trauma-exposed post-9/11 veterans (159 with Time 1 PTSD diagnosis) during assessments approximately 2 years apart. Automated hippocampal subfield segmentation was performed with FreeSurfer Version 7.1, producing 19 bilateral subfields. PTSD symptoms were measured at each assessment using the Clinician-Administered PTSD Scale-IV (CAPS). All models included total intracranial volume as a covariate. First, similar to previous reports, we showed that smaller overall hippocampal volume was associated with greater PTSD symptom severity at Time 1. Notably, when examining regions of interest (CA1, CA3, dentate gyrus), we found that smaller Time 1 hippocampal volumes in the bilateral CA1-body and CA2/3-body predicted decreased PTSD symptom severity at Time 2. These findings were not accounted for by combat exposure or treatment history. Additionally, both Time 1 CA1-body and CA2/3-body volume showed unique associations with changes in avoidance/numbing, but not with changes in reexperiencing or hyperarousal symptoms. This supports a more complex and nuanced relationship between hippocampal structure and PTSD symptoms, where during the posttrauma years bigger may not always mean better, and suggests that the CA1-body and CA2/3-body are important factors in the maintenance of PTSD symptoms. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Future thinking in PTSD: Preliminary evidence for altered event construction.

Using a future event fluency task, the current study sought to examine future event construction in PTSD and to identify clinical profiles associated with altered event construction. Thirty-eight trauma exposed war-zone veterans with (n=25) and without (n=13) PTSD generated within one minute as many positive and negative future events as possible in the near and distant future. The PTSD group generated fewer specific, but not generic, events than the no-PTSD group, a difference that was amplified for positive events as a result of comorbid depression. Clinical correlates of event construction varied as a function of event valence.

Blood-based DNA methylation and exposure risk scores predict PTSD with high accuracy in military and civilian cohorts.

Background: Incorporating genomic data into risk prediction has become an increasingly useful approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p-0.003), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD. Conclusion: Results, especially those from the eMRS, reinforce earlier findings that methylation and trauma are interconnected and can be leveraged to increase the correct classification of those with vs. without PTSD. Moreover, our models can potentially be a valuable tool in predicting the future risk of developing PTSD. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting the condition and, relatedly, improve their performance in independent cohorts.

Maintenance of Procedural Motor Memory across Brief Rest Periods Requires the Hippocampus.

Research on the role of the hippocampus in memory acquisition has generally focused on active learning. But to understand memory, it is at least as important to understand processes that happen offline, during both wake and sleep. In a study of patients with amnesia, we previously demonstrated that although a functional hippocampus is not necessary for the acquisition of procedural motor memory during training session, it is required for its offline consolidation during sleep. Here, we investigated whether an intact hippocampus is also required for the offline consolidation of procedural motor memory while awake. Patients with amnesia due to hippocampal damage (n = 4, all male) and demographically matched controls (n = 10, 8 males) trained on the finger tapping motor sequence task. Learning was measured as gains in typing speed and was divided into online (during task execution) and offline (during interleaved 30 s breaks) components. Amnesic patients and controls showed comparable total learning, but differed in the pattern of performance improvement. Unlike younger adults, who gain speed across breaks, both groups gained speed only while typing. Only controls retained these gains over the breaks; amnesic patients slowed down and compensated for these losses during subsequent typing. In summary, unlike their peers, whose motor performance remained stable across brief breaks in typing, amnesic patients showed evidence of impaired access to motor procedural memory. We conclude that in addition to being necessary for the offline consolidation of motor memories during sleep, the hippocampus maintains access to motor memory across brief offline periods during wake.

Imagining emotional future events in PTSD: clinical and neurocognitive correlates.

Emotional future thinking serves important functions related to goal pursuit and emotion regulation but has been scantly studied in posttraumatic stress disorder (PTSD). The current study sought to characterize emotional future thinking in PTSD and to identify clinical and neurocognitive profiles associated with potential alterations in the level of detail in narratives of imagined future events. Fifty-eight, trauma-exposed, war-zone veterans, who were classified into current PTSD, past PTSD, and no-PTSD groups, were asked to vividly imagine future events in response to positive and negative cue words occurring in the near and distant future. These narratives were scored for internal (i.e., pertaining to the main event) and external (i.e., tangential to the main event) details. Participants also performed neurocognitive tasks of generative ability, working memory, and relational verbal memory. Linear mixed modeling revealed that the current and past PTSD groups generated fewer internal details than the no-PTSD group across positive and negative cue words and across temporal proximity. Partial least squares analysis revealed that symptom severity for all PTSD clusters was inversely associated with production of internal details, albeit with the association relatively weaker for intrusion symptoms. Among the neurocognitive tasks, only relational verbal memory was associated with production of internal details. These findings suggest, as predicted, that functional avoidance may underlie reduced detail generation but also point to potential additional mechanisms to be further investigated. That future event simulation remains overgeneral even when PTSD symptoms abate highlights the importance of addressing alterations in future thinking in this population.

The Hippocampus Contributes to Temporal Discounting When Delays and Rewards Are Experienced in the Moment.

Temporal discounting (TD) represents the mental devaluation of rewards that are available after a delay. Whether the hippocampus is critical for TD remains unclear, with marked discrepancies between animal and human studies: although animals with discrete hippocampal lesions display impaired TD, human participants with similar lesions show intact performance on classic intertemporal choice tasks. A candidate explanation for this discrepancy is that delays and rewards are experienced in the moment in animal studies but tend to be hypothetical in human studies. We tested this hypothesis by examining the performance of amnesic participants with hippocampal lesions (one female, six males) on a novel experiential intertemporal choice task that used interesting photographs occluded by thick lines as rewards (Patt et al., 2021). Using a logistic function to model indifference points data, we compared performance to that on a classic intertemporal choice task with hypothetical outcomes. Participants with hippocampal lesions displayed impaired patterns of choices in the experiential task but not in the hypothetical task. Specifically, hippocampal lesions were associated with decreased amplitude of the delay-reward trade-off, with persistent choice of the delayed option despite delay increase. These results help explain previous discrepancies across animal and human studies, indicating that the hippocampus plays a critical role in temporal discounting when the outcomes of decisions are experienced in the moment, but not necessarily when they are hypothetical.SIGNIFICANCE STATEMENT Impaired temporal discounting (TD) has been related to maladaptive behaviors, including substance dependence and nonadherence to medical treatment. There is consensus that TD recruits the brain valuation network but whether the hippocampal memory system is additionally recruited remains unclear. This study examined TD in hippocampal amnesia, providing a unique opportunity to explore the role of the hippocampus in cognition. Whereas most human studies have used hypothetical outcomes, this study used a novel experiential task with real-time delays and rewards. Results demonstrated hippocampal involvement in the experiential task, but not in a classic hypothetical task administered for comparison. These findings elucidate previous discrepancies between animal and human TD studies. This reconciliation is critical as animals serve as models of human neurocognition.

Verbal recall in amnesia: Does scene construction matter?

The hippocampus plays a critical role in episodic memory and imagination. One theoretical model posits that the hippocampus is important for scene construction, namely, the ability to conjure and maintain a scene-based representation in one's mind. To test one idea put forth by this view, we examined whether amnesia is associated with more severe impairment in memory when the to-be-remembered content places high demands on scene construction. To do so, we examined free recall performance for abstract (i.e., low scene imagery) and concrete, high scene-imagery single words in seven amnesic patients with hippocampal lesions and concomitant scene-construction deficits, and compared their performance to demographically matched healthy controls. As expected, amnesic patients were severely impaired in their free recall performance; however, their impairment did not differ as a function of word type. That is, their impairment was equally severe for words that evoke high versus low scene imagery. These findings suggest that the role of the hippocampus in verbal memory extends to content that does not place high demands on scene construction. Theoretical implications of these findings are discussed.

Leveraging Prior Knowledge to Support Short-term Memory: Exploring the Role of the Ventromedial Prefrontal Cortex.

It is well established that the ventromedial prefrontal cortex (vmPFC) plays a critical role in memory consolidation and the retrieval of remote long-term memories. Recent evidence suggests that the vmPFC also supports rapid neocortical learning and consolidation over shorter timescales, particularly when novel events align with stored knowledge. One mechanism by which the vmPFC has been proposed to support this learning is by integrating congruent information into existing neocortical knowledge during memory encoding. An important outstanding question is whether the vmPFC also plays a critical role in linking congruent information with existing knowledge before storage in long-term memory. The current study investigated this question by testing whether lesions to the vmPFC disrupt the ability to leverage stored knowledge in support of short-term memory. Specifically, we investigated the visuospatial bootstrapping effect, the phenomenon whereby immediate verbal recall of visually presented stimuli is better when stimuli appear in a familiar visuospatial array that is congruent with prior knowledge compared with an unfamiliar visuospatial array. We found that the overall magnitude of the bootstrapping effect did not differ between patients with vmPFC lesions and controls. However, a reliable bootstrapping effect was not present in the patient group alone. Post hoc analysis of individual patient performance revealed that the bootstrapping effect did not differ from controls in nine patients but was reduced in two patients. Although mixed, these results suggest that vmPFC lesions do not uniformly disrupt the ability to leverage stored knowledge in support of short-term memory.

Investigating the impact of healthy aging on memory for temporal duration and order.

Temporal information, including information about temporal order and duration, is a fundamental component of event sequence memory. While previous research has demonstrated that aging can have a detrimental effect on memory for temporal order, there has been limited insight into the effect of aging on memory for durations, particularly within the context of sequences. In the current study, neurologically healthy young and older participants were administered two temporal match-mismatch tasks: one in which they were instructed on each trial to compare the temporal order or duration information of stimulus sequences presented first in a study phase and then, after a short delay, in a test phase (event sequence task); and a second in which participants were required to compare single durations or sequences of durations across study and test phases of each trial (pinwheel task). Consistent with the literature, the older participants were significantly poorer compared to their younger counterparts at making temporal order match-mismatch judgments in the event sequence task. In addition to this, data from both tasks suggested that the older adults were also less accurate at match-mismatch judgments based on duration information, with tentative evidence from the pinwheel task to suggest that this age-related effect was most prominent when the duration information was presented within a sequence. We suggest that age-related changes to medial temporal and frontal lobe function may contribute to changes in memory for temporal information in older adults, given the importance of these regions to event sequence memory.

Hippocampal Contribution to Probabilistic Feedback Learning: Modeling Observation- and Reinforcement-based Processes.

Simple probabilistic reinforcement learning is recognized as a striatum-based learning system, but in recent years, has also been associated with hippocampal involvement. This study examined whether such involvement may be attributed to observation-based learning (OL) processes, running in parallel to striatum-based reinforcement learning. A computational model of OL, mirroring classic models of reinforcement-based learning (RL), was constructed and applied to the neuroimaging data set of Palombo, Hayes, Reid, and Verfaellie [2019. Hippocampal contributions to value-based learning: Converging evidence from fMRI and amnesia. Cognitive, Affective & Behavioral Neuroscience, 19(3), 523-536]. Results suggested that OL processes may indeed take place concomitantly to reinforcement learning and involve activation of the hippocampus and central orbitofrontal cortex. However, rather than independent mechanisms running in parallel, the brain correlates of the OL and RL prediction errors indicated collaboration between systems, with direct implication of the hippocampus in computations of the discrepancy between the expected and actual reinforcing values of actions. These findings are consistent with previous accounts of a role for the hippocampus in encoding the strength of observed stimulus-outcome associations, with updating of such associations through striatal reinforcement-based computations. In addition, enhanced negative RL prediction error signaling was found in the anterior insula with greater use of OL over RL processes. This result may suggest an additional mode of collaboration between the OL and RL systems, implicating the error monitoring network.

Autobiographical memory unknown: Pervasive autobiographical memory loss encompassing personality trait knowledge in an individual with medial temporal lobe amnesia.

Autobiographical memory consists of distinct memory types varying from highly abstract to episodic. Self trait knowledge, which is considered one of the more abstract types of autobiographical memory, is thought to rely on regions of the autobiographical memory neural network implicated in schema representation, including the ventromedial prefrontal cortex, and critically, not the medial temporal lobes. The current case study introduces an individual who experienced bilateral posterior cerebral artery strokes resulting in extensive medial temporal lobe damage with sparing of the ventromedial prefrontal cortex. Interestingly, in addition to severe retrograde and anterograde episodic and autobiographical fact amnesia, this individual's self trait knowledge was impaired for his current and pre-morbid personality traits. Yet, further assessment revealed that this individual had preserved conceptual knowledge for personality traits, could reliably and accurately rate another person's traits, and could access his own self-concept in a variety of ways. In addition to autobiographical memory loss, he demonstrated impairment on non-personal semantic memory tests, most notably on tests requiring retrieval of unique knowledge. This rare case of amnesia suggests a previously unreported role for the medial temporal lobes in self trait knowledge, which we propose reflects the critical role of this neural region in the storage and retrieval of personal semantics that are experience-near, meaning autobiographical facts grounded in spatiotemporal contexts.

Trauma and posttraumatic stress disorder modulate polygenic predictors of hippocampal and amygdala volume.

The volume of subcortical structures represents a reliable, quantitative, and objective phenotype that captures genetic effects, environmental effects such as trauma, and disease effects such as posttraumatic stress disorder (PTSD). Trauma and PTSD represent potent exposures that may interact with genetic markers to influence brain structure and function. Genetic variants, associated with subcortical volumes in two large normative discovery samples, were used to compute polygenic scores (PGS) for the volume of seven subcortical structures. These were applied to a target sample enriched for childhood trauma and PTSD. Subcortical volume PGS from the discovery sample were strongly associated in our trauma/PTSD enriched sample (n = 7580) with respective subcortical volumes of the hippocampus (p = 1.10 × 10-20), thalamus (p = 7.46 × 10-10), caudate (p = 1.97 × 10-18), putamen (p = 1.7 × 10-12), and nucleus accumbens (p = 1.99 × 10-7). We found a significant association between the hippocampal volume PGS and hippocampal volume in control subjects from our sample, but was absent in individuals with PTSD (GxE; (beta = -0.10, p = 0.027)). This significant GxE (PGS × PTSD) relationship persisted (p < 1 × 10-19) in four out of five threshold peaks (0.024, 0.133, 0.487, 0.730, and 0.889) used to calculate hippocampal volume PGSs. We detected similar GxE (G × ChildTrauma) relationships in the amygdala for exposure to childhood trauma (rs4702973; p = 2.16 × 10-7) or PTSD (rs10861272; p = 1.78 × 10-6) in the CHST11 gene. The hippocampus and amygdala are pivotal brain structures in mediating PTSD symptomatology. Trauma exposure and PTSD modulate the effect of polygenic markers on hippocampal volume (GxE) and the amygdala volume PGS is associated with PTSD risk, which supports the role of amygdala volume as a risk factor for PTSD.

Autobiographical recall of a stressful negative event in veterans with PTSD.

Posttraumatic stress disorder (PTSD) is characterised by alterations in autobiographical memory for traumatic and non-traumatic events. Studies that focus on event construction - the ability to search for and identify a specific event - have documented overgeneral memory in PTSD. However, the quality of autobiographical memory also depends on the ability to elaborate on an event once constructed by providing additional details. In a prior study, individuals with PTSD generated as many episodic (event-specific) details as trauma-exposed controls when demands on event construction were minimized, albeit the PTSD group generated more non-episodic details. The current study sought to further characterize PTSD-related alterations in event elaboration by asking participants to describe a stressful negative event specified by the experimenter, thus minimizing event construction demands. Narratives were scored for episodic and non-episodic details and relations with measures of executive function and self-reported avoidance were examined. Compared to controls, the PTSD group generated narratives with equivalent episodic detail but greater non-episodic detail, including semantic information and repeated or extended events. Non-episodic detail generation was associated with greater avoidance but not executive functions. Elaborated non-trauma memories may be perceived as overgeneral in PTSD due to greater generation of non-episodic details, rather than diminished episodic detail.

Temporal discounting when outcomes are experienced in the moment: Validation of a novel paradigm and comparison with a classic hypothetical intertemporal choice task.

When faced with intertemporal choices, people typically devalue rewards available in the future compared to rewards more immediately available, a phenomenon known as temporal discounting. Decisions involving intertemporal choices arise daily, with critical impact on health and financial wellbeing. Although many such decisions are "experiential" in that they involve delays and rewards that are experienced in real-time and can inform subsequent choices, most studies have focused on intertemporal choices with hypothetical outcomes (or outcomes delivered after all decisions are made). The present study focused on experiential intertemporal choices. First, a novel intertemporal choice task was developed and validated, using delays experienced in real time and artistic photographs as consumable perceptual rewards. Second, performance on the experiential task was compared to performance on a classic intertemporal choice task with hypothetical outcomes. Involvement of distinct processes across tasks was probed by examining differential relations to state and trait anxiety. A two-parameter logistic function framework was proposed to fit indifference point data. This approach accounts for individual variability not only in the delay at which an individual switches from choosing the delayed to more immediate option, but also in the slope of that switch. Fit results indicated that the experiential task elicited temporal discounting, with effective trade-off between delay and perceptual reward. Comparison with the hypothetical intertemporal choice task suggested distinct mechanisms: first, temporal discounting across the two tasks was not correlated; and second, state and trait anxiety both were associated with choice behavior in the experiential task, albeit in distinct ways, whereas neither was significantly associated with choice behavior in the hypothetical task. The engagement of different processes in the experiential compared to hypothetical task may align with neural evidence for the recruitment of the hippocampus in animal but not in classic human intertemporal choice studies.

Episodic processes in moral decisions: Evidence from medial temporal lobe amnesia.

Theoretical accounts of moral decision making imply distinct ways in which episodic memory processes may contribute to judgments about moral dilemmas that entail high conflict between a harmful action and a greater good resulting from such action. Yet, studies examining the status of moral judgment in amnesic patients with medial temporal lobe (MTL) lesions have yielded inconsistent results. To examine whether and how episodic processes contribute to high conflict moral decisions, amnesic patients with MTL damage and control participants were asked to judge the moral acceptability of a harmful action across two conditions that differed in the framing of the moral question. We predicted that personal (but not abstract) framing would engage episodic processes involved in mental simulation, yielding a selective impairment in MTL patients in the personal framing condition. This prediction was not confirmed as neither patients nor controls were influenced by the framing of the moral question. With the exception of a patient whose lesion extended into the amygdala bilaterally, patients were less willing than controls to endorse the utilitarian option, rejecting the harmful action despite its beneficial outcome. They also rated actions as emotionally more intense than did controls. These findings suggest that episodic processes involved in mental simulation are necessary to prospectively evaluate action-outcome contingencies.

Probabilistic value learning in medial temporal lobe amnesia.

A prevailing view in cognitive neuroscience suggests that different forms of learning are mediated by dissociable memory systems, with a mesolimbic (i.e., midbrain and basal ganglia) system supporting incremental trial-and-error reinforcement learning and a hippocampal-based system supporting episodic memory. Yet, growing evidence suggests that the hippocampus may also be important for trial-and-error learning, particularly value or reward-based learning. In the present report, we use a lesion-based neuropsychological approach to clarify hippocampal contributions to such learning. Six amnesic patients with medial temporal lobe damage and a group of healthy controls were administered a simple value-based learning task involving probabilistic trial-and-error acquisition of stimulus-response-outcome (reward or none) contingencies modeled after Li et al. (Proceedings of the National Academy of Sciences , 2011, 108 (1), 55-60). As predicted, patients were significantly impaired on the task, demonstrating reduced learning of the contingencies. Our results provide further supportive evidence that the hippocampus' role in cognition extends beyond episodic memory tasks and call for further refinement of theoretical models of hippocampal functioning.

The language of mental images: Characterizing hippocampal contributions to imageable word use during event construction.

Accumulating evidence suggests that the hippocampus plays a critical role in the creative and flexible use of language at the sentence or discourse level. Yet it is currently unclear whether the hippocampus also supports language use at the level of single words. A recent study by Hilverman et al. (2017) found that amnesic patients with hippocampal damage use less imageable words when describing autobiographical episodes compared to healthy controls, but this deficit was attributed to patients' deficits in episodic memory rather than impairments in linguistic functions of the hippocampus per se. Yet, in addition to affecting word use by way of its role in memory, the hippocampus could also impact language use more directly. The current study aimed to test this hypothesis by investigating the status of imageable word use in amnesia during two different types of language production tasks. In Experiment 1, participants constructed narratives about events depicted in visually presented pictures (picture narratives). In Experiment 2, participants constructed verbal narratives about remembered events from the past or simulated events in the future (past/future narratives). Across all types of narratives, patients produced words that were rated as having similar levels of imageability compared to controls. Importantly, this was the case both in patients' picture narratives, which did not require generating details from episodic memory and were matched to those of controls with respect to narrative content, and in patients' narratives about past/future events, which required generating details from memory and which were reduced in narrative content compared to those of controls. These results distinguish between the quantity and quality of individual linguistic details produced in amnesia during narrative construction, and suggest that the use of imageable linguistic representations does not depend on intact episodic memory and can be supported by regions outside the hippocampus.