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Neurobiological and psychological models of learning emphasize the importance of prediction errors (surprises) for memory formation. These effects have focused on memory for information surrounding a momentary surprising event; however, it is less clear whether surprise that unfolds across multiple events and timescales impacts memory. We asked basketball fans about their most positive and negative autobiographical memories of individual plays, games, and seasons, allowing surprise measurements spanning seconds, hours, and months. We used advanced analytics on National Basketball Association play-by-play data and betting odds spanning 17 seasons, >22K games, >5.6M plays to compute and align the estimated surprise values of each memory. We found that surprising events biased positive memories on the scale of seconds and months and negative memories across all three timescales. Critically, game and season memories could not be explained by surprise at shorter timescales, suggesting that long-term, multi-event surprise influences memory. These results expand the role of surprise in models of learning and reinforce its relevance in real-world domains.

According to most memory theories, encoding involves continuous communication between the hippocampus and neocortex leaving the temporal dynamics of hippocampal-neocortical interactions often overlooked. Recent work has shown that we perceive complex events in our lives as dynamic, with relatively distinct starting and stopping points known as event boundaries. Event boundaries may be important for memory, as they are associated with increased activity in the hippocampus, and extended neocortical regions (the posterior cingulate cortex, lateral parietal cortex, and parahippocampal cortex). Our objective was to determine how functional connectivity between the hippocampus and neocortical regions during the encoding of naturalistic events (movies) related to subsequent retrieval and retention of those events. Participants encoded two 16-minute cartoon movies during fMRI scanning. After encoding, participants freely recalled one of the movies immediately, and the other after a 2-day delay. We quantified hippocampal-neocortical functional connectivity (FC) at time windows around each event onset, middle, and offset, and compared these FC measures with subsequent recall. These analyses revealed that higher FC between the hippocampus and the posterior medial network (PMN) at an event’s offset related to whether that event was subsequently recalled. In contrast, mid-event connectivity between the hippocampus and PMN was associated with poorer memory. Furthermore, hippocampal-PMN offset connectivity predicted not only whether events were retained in memory, but also the degree to which these events could be recalled in detail after a 2-day delay. These data demonstrate that the relationship between memory encoding and hippocampal-neocortical interaction is more dynamic than suggested by most memory theories, and they converge with recent modeling work suggesting that event offset is an optimal time for encoding.

The neurobiology of major depressive disorder (MDD) remains incompletely understood, and many individuals fail to respond to standard treatments. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) has emerged as a promising antidepressant therapy. However, the heterogeneity of response underscores a pressing need for biomarkers of treatment outcome. We acquired resting state functional magnetic resonance imaging (rsfMRI) data in 47 MDD individuals prior to 5–8 weeks of rTMS treatment targeted using the F3 beam approach and in 29 healthy comparison subjects. The caudate, prefrontal cortex, and thalamus showed significantly lower blood oxygenation level‐dependent (BOLD) signal power in MDD individuals at baseline. Critically, individuals who responded best to treatment were associated with lower pre‐treatment BOLD power in these regions. Additionally, functional connectivity (FC) in the default mode and affective networks was associated with treatment response. We leveraged these findings to train support vector machines (SVMs) to predict individual treatment responses, based on learned patterns of baseline FC, BOLD signal power and clinical features. Treatment response (responder vs. nonresponder) was predicted with 85–95% accuracy. Reduction in symptoms was predicted to within a mean error of ±16% (r = .68, p

Life’s events are scattered throughout time, yet we often recall different events in the context of an integrated narrative. Prior research suggests that the hippocampus, which supports memory for past events, can sometimes support integration of overlapping associations or separate events, but the conditions which lead to hippocampus-dependent memory integration are unclear. We used functional brain imaging to test whether the ability to form a larger narrative (narrative coherence) drives hippocampal memory integration. During encoding of fictional stories, the hippocampus supported patterns of activity, including activity at boundaries between events, which were more similar between distant events that formed one coherent narrative, compared with events taken from unrelated narratives. Twenty-four hours later, the hippocampus preferentially supported detailed recall of coherent narrative events, through reinstatement of hippocampal activity patterns from encoding. These findings reveal a key function of the hippocampus: the dynamic integration of events into a narrative structure for memory.

Pain is a subjective experience with significant individual differences. Laboratory studies investigating pain thresholds and experimental acute pain have identified structural and functional neural correlates. However, these types of pain stimuli have limited ecological validity to real-life pain experiences. Here, we use an orthodontic procedure—the insertion of an elastomeric separator between teeth—which typically induces mild to moderate pain that peaks within 2 days and lasts several days. We aimed to determine whether the baseline structure and resting-state functional connectivity (rsFC) of key regions along the trigeminal nociceptive and pain modulatory pathways correlate with subsequent peak pain ratings. Twenty-six healthy individuals underwent structural and resting-state functional (rs-fMRI) scanning prior to the placement of a separator between the first and second molars, which was kept in place for five days. Participants recorded pain ratings three times daily on a 100-mm visual analogue scale. Peak pain was not significantly correlated with diffusion metrics of the trigeminal nerve, or grey matter volume of any brain region. Peak pain did, however, positively correlate with baseline rsFC between the thalamus contralateral to the separator and bilateral insula, and negatively correlated with connectivity between the periaqueductal gray (PAG) and core nodes of the default mode network (medial prefrontal and posterior cingulate cortices). The ascending (thalamic) nociceptive and the descending (PAG) pain modulatory pathways at baseline each explained unique variation in peak pain intensity ratings. In sum, pre-interventional functional neural architecture of both systems determined the individual pain experience to a subsequent ecologically valid pain stimulus.

Alpha-methyl-para-tyrosine (AMPT), a competitive inhibitor of tyrosine hydroxylase, can be used to deplete endogenous dopamine in humans. We examined how AMPT-induced dopamine depletion alters resting-state functional connectivity of the basal ganglia, and canonical resting-state networks, in healthy humans. Fourteen healthy participants (8 females; age [mean ± SD] = 27.93 ± 9.86) completed the study. Following dopamine depletion, the caudate showed reduced connectivity with the medial prefrontal cortex (mPFC) (Cohen's d = 1.89, p.0001). Moreover, the caudate, putamen, globus pallidus, and midbrain all showed reduced connectivity with the occipital cortex (Cohen's d = 1.48-1.90; p.0001-0.001). Notably, the dorsal caudate showed increased connectivity with the sensorimotor network (Cohen's d = 2.03, p=.002). AMPT significantly decreased self-reported motivation (t(13)=4.19, p=.001) and increased fatigue (t(13)=4.79, p=.0004). A greater increase in fatigue was associated with a greater reduction in connectivity between the substantia nigra and the mPFC (Cohen's d = 3.02, p.00001), while decreased motivation was correlated with decreased connectivity between the VTA and left sensorimotor cortex (Cohen's d = 2.03, p=.00004). These findings help us to better understand the role of dopamine in basal ganglia function and may help us better understand neuropsychiatric diseases where abnormal dopamine levels are observed.

Episodic memory is thought to depend on interactions between the hippocampus and a set of closely interconnected regions that comprise the default mode network (DMN)--a large-scale network that has been identified with resting-state fMRI. Here, using data-driven analyses of resting-state fMRI data to characterize cortico-hippocampal network connectivity, we identified a discrete set of subnetworks that interact with the hippocampus. Specifically, we found that the hippocampus closely affiliated with the DMN and with a "Medial Temporal Network" (MTN) that included regions in the medial temporal lobe and retrosplenial cortex. The DMN could be further subdivided into three subnetworks: a "Posterior Medial" Subnetwork comprised of regions in the posterior cingulate, lateral parietal, and dorsal prefrontal cortex, an "Anterior Temporal: Subnetwork comprised of regions in the temporopolar, lateral orbitofrontal, and dorsal medial prefrontal cortex, and a "Medial Prefrontal" Subnetwork comprised of regions in the ventral medial prefrontal, and entorhinal cortex. These cortico-hippocampal networks vary in their functional connectivity along the hippocampal long-axis, and analyses of an independent task-fMRI dataset revealed that the three DMN subnetworks represent different kinds of information during memory-guided decision-making. Finally, a data-driven meta-analysis of functional imaging studies of cognition suggests new hypotheses regarding the functions of the MTN and DMN subnetworks, thus providing a framework to guide future research on the neural architecture of episodic memory.

We discuss the value of resting-state functional MR imaging (rsfMR imaging) as an emerging technique to address questions about memory and language that are central in surgery for temporal-lobe epilepsy, namely the identification and characterization of eloquent cortex to avoid surgical morbidity. The emergence of a robust set of data using rsfMR imaging has opened new avenues for exploring more direct relationships between neural networks and current cognitive function and prediction of postoperative change. These techniques are also being explored for their potential to characterize epilepsy subtypes, identify epileptic foci, and monitor treatment effects.

We have previously shown that the connectivity of the hippocampus to other regions of the default mode network (DMN) is a strong indicator of memory ability in people with temporal lobe epilepsy (TLE). Recent work in the cognitive neuroscience literature has suggested that the anterior and posterior aspects of the hippocampus have distinct connections to the rest of the DMN and may support different memory operations. Further, structural analysis of epileptogenic hippocampi has found greater atrophy, characterized by mesial temporal sclerosis, in the anterior region of the hippocampus. Here, we used resting state FMRI data to parcellate the hippocampus according to its functional connectivity to the rest of the brain in people with left lateralized TLE (LTLE) and right lateralized TLE (RTLE), and in a group of neurologically healthy controls. We found similar anterior and posterior compartments in all groups. However, there was weaker connectivity of the epileptogenic hippocampus to multiple regions of the DMN. Both TLE groups showed reduced connectivity of the posterior hippocampus to key hubs of the DMN, the posterior cingulate cortex (PCC) and the medial pre-frontal cortex (mPFC). In the LTLE group, the anterior hippocampus also showed reduced connectivity to the DMN, and this effect was influenced by the presence of mesial temporal sclerosis. When we explored brain-behavior relationships, we found that reduced connectivity of the left anterior hippocampus to the DMN hubs related to poorer verbal memory ability in people with LTLE, and reduced connectivity of the right posterior hippocampus to the PCC related to poorer visual memory ability in those with RTLE. These findings may inform models regarding functional distinctions of the hippocampal anteroposterior axis.

Recent neuroimaging studies implicate the medial temporal lobe (MTL) in nociception and pain modulation. Here, we aim to identify which subregions of the MTL are involved in human pain and to test its connectivity in a cohort of chronic low-back pain patients (CBP). We conducted 2 coordinate-based meta-analyses to determine which regions within the MTL showed consistent spatial patterns of functional activation (1) in response to experimental pain in healthy participants and (2) in chronic pain compared with healthy participants. We followed PRISMA guidelines and performed activation likelihood estimate (ALE) meta-analyses. The first meta-analysis revealed consistent activation in the right anterior hippocampus (right antHC), parahippocampal gyrus, and amygdala. The second meta-analysis revealed consistently less activation in patients' right antHC, compared with healthy participants. We then conducted a seed-to-voxel resting state functional connectivity of the right antHC seed with the rest of the brain in 77 CBP and 79 age-matched healthy participants. We found that CBP had significantly weaker antHC functional connectivity to the medial prefrontal cortex compared with healthy participants. Taken together, these data indicate that the antHC has abnormally lower activity in chronic pain and reduced connectivity to the medial prefrontal cortex in CBP. Future studies should investigate the specific role of the antHC in the development and management of chronic pain.

While anterior temporal lobe (ATL) resection is an effective treatment for temporal lobe epilepsy, surgery on the dominant hemisphere is associated with variable decline in confrontation naming. Accurate prediction of naming impairment is critical to inform clinical decision making, and while there has been some degree of success using task-based functional MRI (fMRI) paradigms, there remains a growing interest in the predictive utility of resting-state connectivity as it allows for relatively shorter scans with low task demands. Our objective was to assess the relationship between measures of preoperative resting-state connectivity and postoperative naming change in patients following left ATL resection. We compared the resting language network connectivity of each patient to a normative healthy control template using a novel measure called "matrix similarity," and found that patients with more abnormal global language-network connectivity-particularly of regions spared from surgery-showed greater postoperative naming decline than those with normative patterns of connectivity. When we interrogated the degree centrality of to-be-resected regions in a more targeted approach of the pathological temporal lobe, we found that greater functional integration of those regions with the rest of the language network at rest was related to greater decline in naming following surgery. Finally, we found that matrix similarity was a better predictor of postoperative outcome than degree within to-be-resected regions, network clustering, modularity, and language task fMRI laterality. We provide some of the first evidence that using this novel measure, a relatively short preoperative resting scan can be exploited to inform naming ability following ATL resection.

The use of fMRI to understand how cognitive processes such as language and memory are disrupted by neurological disorders is starting to bear fruit. While much of the early translational work was concerned with focal task-related activation, it is becoming increasingly clear that network properties and connectivity amongst brain regions may be a more sensitive and appropriate biomarker of functional integrity of brain networks that support cognition. Here, we discuss resting state functional MRI (rsfMRI) as an emerging technique to address questions about cognition, particularly memory and language, in the context of medial temporal lobe epilepsy (mTLE) as well as some other disorders characterized by relatively focal damage in the medial temporal lobe (MTL).

Temporal details are an important facet of our memories for events. Consistent with this, it has been demonstrated that the hippocampus, a key structure in learning and memory, is sensitive to the temporal aspects of event sequences, including temporal order, context, recency and distance. One unexplored issue is whether the hippocampus also responds to the temporal duration characteristics of an event sequence, for example, how long each event lasted for or how much time elapsed between events. To address this, we used a temporal match-mismatch detection paradigm across two functional neuroimaging studies to explore whether the human hippocampus is sensitive to the durations of events and intervals that comprise a sequence lasting on the order of seconds. On each trial participants were shown a series of four scenes during an encoding and a test phase, and had to determine whether the durations of the intervals or events were altered. We observed hippocampal sensitivity to temporal durations within event sequences. Activity was significantly greater when participants detected repeating, in comparison to novel, durations. Moreover, greater functional connectivity was observed between hippocampus and brain regions previously implicated in second and millisecond timing when durations were novel, suggesting that the hippocampus may receive duration information from these areas for use within a mnemonic context rather than generate an independent timing signal. Our novel findings suggest that the hippocampus may integrate temporal duration information when binding event sequences.

In temporal lobe epilepsy and lobectomy, deficits in emotion identification have been found consistently, but there is limited evidence for complex social inference skills such as theory of mind. Furthermore, risk factors and the specific neural underpinnings of these deficits in this population are unclear. We investigated these issues using a comprehensive range of social inference tasks (emotion identification and comprehension of sincere, deceitful and sarcastic social exchanges) in individuals with temporal lobe epilepsy or lobectomy (n = 87). We observed deficits across patient groups which were partly related to the presence of mesial temporal lobe sclerosis, early age of seizure onset and left lobectomy. A voxel-based morphometry analysis conducted in the pre-operative group confirmed the importance of the temporal lobe by showing a relationship between left hippocampal atrophy and overall social inference abilities, and between left anterior neocortex atrophy and sarcasm comprehension. These findings are in keeping with theoretical proposals that the hippocampus is critical for binding diverse elements in cognitive domains beyond canonical episodic memory operations, and that the anterior temporal cortex is a convergence zone of higher-order perceptual and emotional processes, and of stored representations. As impairments were frequent, we require further investigation of this behavioural domain and its impact on the lives of people with epilepsy.

Individuals with medial temporal lobe epilepsy (mTLE) often show material-specific memory impairment (verbal for left, visuospatial for right hemisphere) which can be exacerbated following surgery aimed at the epileptogenic regions of medial and anterolateral temporal cortex. There is a growing body of evidence suggesting that characterization of structural and functional integrity of these regions using MRI can aid in prediction of post-surgical risk of further memory decline. We investigated the nature of the relationship between structural and functional indices of hippocampal integrity with preoperative memory performance in a group of 26 patients with unilateral mTLE. Structural integrity was assessed using hippocampal volumes, while functional integrity was assessed using hippocampal activation during the encoding of novel scenes. We quantified structural and functional integrity in terms of asymmetry, calculated as (L - R) / (L + R). Factor scores for verbal and visual memory were calculated from a clinical database and an asymmetry score (verbal – visual) was used to characterize memory performance. We found, as expected, a significant difference between left and right mTLE groups for hippocampal volume asymmetry, with each group showing an asymmetry favoring the unaffected temporal lobe. Encoding activation asymmetry showed a similar pattern, with left mTLE patients showing activation preferential to the right hemisphere and right mTLE patients showing the reverse. Finally, we demonstrated that functional integrity mediated the relationship between structural integrity and memory performance for memory asymmetry, suggesting that even if structural changes are evident, ultimately it is the functional integrity of the tissue that most closely explains behavioral performance. Our findings argue for the incorporation of functional imaging data in clinical protocols aimed at determining the functional integrity of the MTL in surgical planning.

Recent research suggests the anterior and posterior hippocampus form part of two distinct functional neural networks. Here we investigate the structural underpinnings of this functional connectivity difference using diffusion-weighted imaging-based parcellation. Using this technique, we substantiated that the hippocampus can be parcellated into distinct anterior and posterior segments. These structurally defined segments did indeed show different patterns of resting state functional connectivity, in that the anterior segment showed greater connectivity with temporal and orbitofrontal cortex, whereas the posterior segment was more highly connected to medial and lateral parietal cortex. Furthermore, we showed that the posterior hippocampal connectivity to memory processing regions, including the dorsolateral prefrontal cortex, parahippocampal, inferior temporal and fusiform gyri and the precuneus, predicted interindividual relational memory performance. These findings provide important support for the integration of structural and functional connectivity in understanding the brain networks underlying episodic memory.

fMRI language mapping has become increasingly utilized for determining language dominance before surgical intervention for temporal lobe epilepsy (TLE). This study aimed to examine the differences between two classes of fMRI word generation tasks used in our clinic: tasks using a single word cue, referred to as simple generative tasks (SGTs), and tasks also involving sentence-level processing, referred to as sentence-level language tasks (SLTs). Specifically, we aimed to investigate the extent and laterality of activation and frontal-temporal connectivity during these language tasks and their relationship to clinical language measures. Thirty-one patients with TLE (18 patients with left TLE and 13 patients with right TLE) performed four language tasks during an fMRI scan, two SGTs and two SLTs. We found significantly greater activity for SLTs over SGTs in bilateral inferior frontal and middle temporal gyri and the left temporal pole. Sentence-level language tasks also showed greater lateralization compared with SGTs. Finally, we found that while activation extent did not correlate with clinical language tests, the degree of left frontal-temporal connectivity was significantly correlated with naming and semantic fluency performance. These correlations also were more robust for SLTs than for SGTs. Taken together, these results provide a compelling argument for including some form of SLTs in fMRI language lateralization protocols for TLE as they allow for better characterization of language networks, particularly in the temporal lobes which are at risk in surgery.