Omnipresence of the sensorimotor-association axis topography in the human connectome.

Low-dimensional representations are increasingly used to study meaningful organizational principles within the human brain. Most notably, the sensorimotor-association axis consistently explains the most variance in the human connectome as its so-called principal gradient, suggesting that it represents a fundamental organizational principle. While recent work indicates these low dimensional representations are relatively robust, they are limited by modeling only certain aspects of the functional connectivity structure. To date, the majority of studies have restricted these approaches to the strongest connections in the brain, treating weaker or negative connections as noise despite evidence of meaningful structure among them. The present work examines connectivity gradients of the human connectome across a full range of connectivity strengths and explores the implications for outcomes of individual differences, identifying potential dependencies on thresholds and opportunities to improve prediction tasks. Interestingly, the sensorimotor-association axis emerged as the principal gradient of the human connectome across the entire range of connectivity levels. Moreover, the principal gradient of connections at intermediate strengths encoded individual differences, better followed individual-specific anatomical features, and was also more predictive of intelligence. Taken together, our results add to evidence of the sensorimotor-association axis as a fundamental principle of the brain's functional organization, since it is evident even in the connectivity structure of more lenient connectivity thresholds. These more loosely coupled connections further appear to contain valuable and potentially important information that could be used to improve our understanding of individual differences, diagnosis, and the prediction of treatment outcomes.

Hippocampal-targeted Theta-burst Stimulation Enhances Associative Memory Formation.

The hippocampus plays a critical role in episodic memory, among other cognitive functions. However, few tools exist to causally manipulate hippocampal function in healthy human participants. Recent work has targeted hippocampal-cortical networks by performing TMS to a region interconnected with the hippocampus, posterior inferior parietal cortex (pIPC). Such hippocampal-targeted TMS enhances associative memory and influences hippocampal functional connectivity. However, it is currently unknown which stages of mnemonic processing (encoding or retrieval) are affected by hippocampal-targeted TMS. Here, we examined whether hippocampal-targeted TMS influences the initial encoding of associations (vs. items) into memory. To selectively influence encoding and not retrieval, we performed continuous theta-burst TMS before participants encoded object-location associations and assessed memory after the direct effect of stimulation dissipated. Relative to control TMS and baseline memory, pIPC TMS enhanced associative memory success and confidence. Item memory was unaffected, demonstrating a selective influence on associative versus item memory. The strength of hippocampal-pIPC functional connectivity predicted TMS-related memory benefits, which was mediated by parahippocampal and retrosplenial cortices. Our findings indicate that hippocampal-targeted TMS can specifically modulate the encoding of new associations into memory without directly influencing retrieval processes and suggest that the ability to influence associative memory may be related to the fidelity of hippocampal TMS targeting. These results support the notion that pIPC TMS may serve as a potential tool for manipulating hippocampal function in healthy participants. Nonetheless, future work combining hippocampal-targeted continuous theta-burst TMS with neuroimaging is needed to better understand the neural basis of TMS-induced memory changes.

Persistence of Amygdala-Hippocampal Connectivity and Multi-Voxel Correlation Structures During Awake Rest After Fear Learning Predicts Long-Term Expression of Fear.

After encoding, memories undergo a process of consolidation that determines long-term retention. For conditioned fear, animal models postulate that consolidation involves reactivations of neuronal assemblies supporting fear learning during postlearning "offline" periods. However, no human studies to date have investigated such processes, particularly in relation to long-term expression of fear. We tested 24 participants using functional MRI on 2 consecutive days in a fear conditioning paradigm involving 1 habituation block, 2 acquisition blocks, and 2 extinction blocks on day 1, and 2 re-extinction blocks on day 2. Conditioning blocks were preceded and followed by 4.5-min rest blocks. Strength of spontaneous recovery of fear on day 2 served as a measure of long-term expression of fear. Amygdala connectivity primarily with hippocampus increased progressively during postacquisition and postextinction rest on day 1. Intraregional multi-voxel correlation structures within amygdala and hippocampus sampled during a block of differential fear conditioning furthermore persisted after fear learning. Critically, both these main findings were stronger in participants who exhibited spontaneous recovery 24 h later. Our findings indicate that neural circuits activated during fear conditioning exhibit persistent postlearning activity that may be functionally relevant in promoting consolidation of the fear memory.

Persistence of hippocampal multivoxel patterns into postencoding rest is related to memory.

The transformation of new experiences into lasting memories is thought to be mediated by postencoding reactivation or the reexpression of activity patterns that characterize prior encoding experiences during subsequent offline periods. Although hippocampal reactivation has been well-described in the rodent, evidence for postencoding persistence of hippocampal encoding patterns has yet to be described in humans. Using functional MRI, we examined the persistence of multivoxel hippocampal encoding patterns into postencoding rest periods. To characterize activity patterns, we computed the pairwise multivoxel correlation structure (MVCS) across hippocampal voxels during two distinct encoding tasks as well as during pre- and postencoding rest periods. We found that the hippocampal MVCS for each encoding task was more similar to the MVCS during immediate postencoding rest periods compared with a preencoding, baseline rest period. Additionally, using a principal component decomposition approach, we found that the strongest encoding patterns showed evidence of preferential persistence into immediate postencoding rest periods. Finally, the extent to which the strongest encoding patterns showed evidence of preferential persistence into immediate postencoding rest significantly correlated with later memory for stimuli seen during encoding. Taken together, these results provide strong evidence for hippocampal reactivation in humans, which was measured by the persistence of hippocampal encoding patterns into immediate postencoding rest periods, and importantly, provide a possible link between this persistence and memory consolidation.

Fast connectivity gradient approximation: maintaining spatially fine-grained connectivity gradients while reducing computational costs.

Brain connectome analysis suffers from the high dimensionality of connectivity data, often forcing a reduced representation of the brain at a lower spatial resolution or parcellation. This is particularly true for graph-based representations, which are increasingly used to characterize connectivity gradients, capturing patterns of systematic spatial variation in the functional connectivity structure. However, maintaining a high spatial resolution is crucial for enabling fine-grained topographical analysis and preserving subtle individual differences that might otherwise be lost. Here we introduce a computationally efficient approach to establish spatially fine-grained connectivity gradients. At its core, it leverages a set of landmarks to approximate the underlying connectivity structure at the full spatial resolution without requiring a full-scale vertex-by-vertex connectivity matrix. We show that this approach reduces computational time and memory usage while preserving informative individual features and demonstrate its application in improving brain-behavior predictions. Overall, its efficiency can remove computational barriers and enable the widespread application of connectivity gradients to capture spatial signatures of the connectome. Importantly, maintaining a spatially fine-grained resolution facilitates to characterize the spatial transitions inherent in the core concept of gradients of brain organization.

Structured memory representations develop at multiple time scales in hippocampal-cortical networks.

Influential views of systems memory consolidation posit that the hippocampus rapidly forms representations of specific events, while neocortical networks extract regularities across events, forming the basis of schemas and semantic knowledge. Neocortical extraction of schematic memory representations is thought to occur on a protracted timescale of months, especially for information that is unrelated to prior knowledge. However, this theorized evolution of memory representations across extended timescales, and differences in the temporal dynamics of consolidation across brain regions, lack reliable empirical support. To examine the temporal dynamics of memory representations, we repeatedly exposed human participants to structured information via sequences of fractals, while undergoing longitudinal fMRI for three months. Sequence-specific activation patterns emerged in the hippocampus during the first 1-2 weeks of learning, followed one week later by high-level visual cortex, and subsequently the medial prefrontal and parietal cortices. Schematic, sequence-general representations emerged in the prefrontal cortex after 3 weeks of learning, followed by the medial temporal lobe and anterior temporal cortex. Moreover, hippocampal and most neocortical representations showed sustained rather than time-limited dynamics, suggesting that representations tend to persist across learning. These results show that specific hippocampal representations emerge early, followed by both specific and schematic representations at a gradient of timescales across hippocampal-cortical networks as learning unfolds. Thus, memory representations do not exist only in specific brain regions at a given point in time, but are simultaneously present at multiple levels of abstraction across hippocampal-cortical networks.

The tie that binds: temporal coding and adaptive emotion.

Emotions are temporally dynamic, but the persistence of emotions outside of their appropriate temporal context is detrimental to health and well-being. Yet, precisely how temporal coding and emotional processing interact remains unclear. Recently unveiled temporal context representations in the hippocampus, entorhinal cortex (EC), and prefrontal cortex (PFC) support memory for what happened when. Here, we discuss how these neural temporal representations may interact with densely interconnected amygdala circuitry to shape emotional functioning. We propose a neuroanatomically informed framework suggesting that high-fidelity temporal representations linked to dynamic experiences promote emotion regulation and adaptive emotional memories. Then, we discuss how newly-identified synaptic and molecular features of amygdala-hippocampal projections suggest that intense, amygdala-dependent emotional responses may distort temporal-coding mechanisms. We conclude by identifying key avenues for future research.

Long-term learning transforms prefrontal cortex representations during working memory.

The role of the lateral prefrontal cortex (lPFC) in working memory (WM) is debated. Non-human primate (NHP) electrophysiology shows that the lPFC stores WM representations, but human neuroimaging suggests that the lPFC controls WM content in sensory cortices. These accounts are confounded by differences in task training and stimulus exposure. We tested whether long-term training alters lPFC function by densely sampling WM activity using functional MRI. Over 3 months, participants trained on both a WM and serial reaction time (SRT) task, wherein fractal stimuli were embedded within sequences. WM performance improved for trained (but not novel) fractals and, neurally, delay activity increased in distributed lPFC voxels across learning. Item-level WM representations became detectable within lPFC patterns, and lPFC activity reflected sequence relationships from the SRT task. These findings demonstrate that human lPFC develops stimulus-selective responses with learning, and WM representations are shaped by long-term experience, which could reconcile competing accounts of WM functioning.

Causal Contribution of Awake Post-encoding Processes to Episodic Memory Consolidation.

Stable representations of past experience are thought to depend on processes that unfold after events are initially encoded into memory. Post-encoding reactivation and hippocampal-cortical interactions are leading candidate mechanisms thought to support memory retention and stabilization across hippocampal-cortical networks. Although putative consolidation mechanisms have been observed during sleep and periods of awake rest, the direct causal contribution of awake consolidation mechanisms to later behavior is unclear, especially in humans. Moreover, it has been argued that observations of putative consolidation processes are epiphenomenal and not causally important, yet there are few tools to test the functional contribution of these mechanisms in humans. Here, we combined transcranial magnetic stimulation (TMS) and fMRI to test the role of awake consolidation processes by targeting hippocampal interactions with lateral occipital cortex (LOC). We applied theta-burst TMS to LOC (and a control site) to interfere with an extended window (approximately 30-50 min) after memory encoding. Behaviorally, post-encoding TMS to LOC selectively impaired associative memory retention compared to multiple control conditions. In the control TMS condition, we replicated prior reports of post-encoding reactivation and memory-related hippocampal-LOC interactions during periods of awake rest using fMRI. However, post-encoding LOC TMS reduced these processes, such that post-encoding reactivation in LOC and memory-related hippocampal-LOC functional connectivity were no longer present. By targeting and manipulating post-encoding neural processes, these findings highlight the direct contribution of awake time periods to episodic memory consolidation. This combined TMS-fMRI approach provides an opportunity for causal manipulations of human memory consolidation.

Awake Reactivation of Prior Experiences Consolidates Memories and Biases Cognition.

After experiences are encoded into memory, post-encoding reactivation mechanisms have been proposed to mediate long-term memory stabilization and transformation. Spontaneous reactivation of hippocampal representations, together with hippocampal-cortical interactions, are leading candidate mechanisms for promoting systems-level memory strengthening and reorganization. While the replay of spatial representations has been extensively studied in rodents, here we review recent fMRI work that provides evidence for spontaneous reactivation of nonspatial, episodic event representations in the human hippocampus and cortex, as well as for experience-dependent alterations in systems-level hippocampal connectivity. We focus on reactivation during awake post-encoding periods, relationships between reactivation and subsequent behavior, how reactivation is modulated by factors that influence consolidation, and the implications of persistent reactivation for biasing ongoing perception and cognition.

Understanding perirhinal contributions to perception and memory: Evidence through the lens of selective perirhinal damage.

Although a memory systems view of the medial temporal lobe (MTL) has been widely influential in understanding how memory processes are implemented, a large body of work across humans and animals has converged on the idea that the MTL can support various other decisions, beyond those involving memory. Specifically, recent work suggests that perception of and memory for visual representations may interact in order to support ongoing cognition. However, given considerations involving lesion profiles in neuropsychological investigations and the correlational nature of fMRI, the precise nature of representations supported by the MTL are not well understood in humans. In the present investigation, three patients with highly specific lesions to MTL were administered a task that taxed perceptual and mnemonic judgments with highly similar face stimuli. A striking double dissociation was observed such that I.R., a patient with a cyst localized to right posterior PRc, displayed a significant impairment in perceptual discriminations, whereas patient A.N., an individual with a lesion in right posterior parahippocampal cortex and the tail of the right hippocampus, and S.D., an individual with bilateral hippocampal damage, did not display impaired performance on the perceptual task. A.N. and S.D. did, however, show impairments in memory performance, whereas patient I.R. did not. These results causally implicate right PRc in successful perceptual oddity judgments, however they suggest that representations supported by PRc are not necessary for correct mnemonic judgments, even in situations of high featural overlap.

The asymmetry of the fusiform face area is a stable individual characteristic that underlies the left-visual-field superiority for faces.

Recognition of faces is better when faces are presented in the left than right-visual-field. Furthermore, this perceptual asymmetry is a stable individual characteristic. Although it has been commonly assumed that the right hemispheric dominance for face processing underlies this left-visual-field superiority in face recognition, this neural-behavioral association has never been directly demonstrated. Here we applied functional MRI (fMRI) to measure the magnitude of the asymmetric response to faces for each subject. To determine whether the asymmetric neural response to faces is stable across sessions, subjects returned for a second fMRI session. In addition, subjects performed a behavioral experiment outside the scanner where they had to recognize centrally presented chimeric faces, which presented different identities in the right- and left-visual-field. This task yielded a measure of the magnitude of the left-visual-field bias for each subject. Our findings show that the magnitude of the asymmetry of the face-selective area in the fusiform gyrus (FFA) is highly consistent for each individual across scans. We then show that the behavioral left-visual-field asymmetry, measured outside the scanner, was strongly and specifically correlated with the asymmetry of the FFA across subjects, but not with other face-specific or nearby object-general regions. Our findings provide the first empirical evidence for the prevalent idea that perceptual asymmetries in face recognition are associated with the well-known hemispheric asymmetry for faces. We conclude that the FFA asymmetry is a highly stable individual characteristic that underlies the well-established left-visual-field superiority for face recognition.

What's in a face? Effects of stimulus duration and inversion on face processing in schizophrenia.

A number of studies show deficits in early-stage visual processing in schizophrenia. Deficits are also seen at more complex levels, such as ability to discriminate faces. This study investigated the "face inversion" effect, which reflects intrinsic cortical processing within the ventral visual stream, as well as contrast sensitivity, which reflects low-level visual processing, in order to evaluate integrity of specific stages of face processing in schizophrenia. Patients with schizophrenia and controls discriminated between pairs of upright or inverted faces or houses that had been manipulated to differ in the shape of the parts or the spatial distance among parts. The duration threshold for above chance performance on upright stimuli was obtained for patients using a house discrimination task. Contrast sensitivity was assessed for gratings of three spatial frequencies ranging from 0.5 to 21 cycles/degree. Patients needed significantly longer time to obtain 70% correct for upright stimuli and showed decreased contrast sensitivity. Increased duration threshold correlated with reduced contrast sensitivity to low (magnocellular-biased) but not medium or high spatial frequency stimuli. Using increased durations, patients showed significant inversion effects that were equivalent to those of controls on the face part and spacing tasks. Like controls, patients did not show inversion effects on the house tasks. These findings show that patients have difficulty integrating visual information as shown by increased duration thresholds. However, when faces were presented at these longer duration thresholds, patients showed the same relative processing ability for upright vs. inverted faces as controls, suggesting preserved intrinsic processing within cortical face processing regions. Similar inversion effects for face part and spacing for both groups suggest that they are using the same holistic face processing mechanism.

Spontaneous cognitive processes and the behavioral validation of time-varying brain connectivity.

In cognitive neuroscience, focus is commonly placed on associating brain function with changes in objectively measured external stimuli or with actively generated cognitive processes. In everyday life, however, many forms of cognitive processes are initiated spontaneously, without an individual's active effort and without explicit manipulation of behavioral state. Recently, there has been increased emphasis, especially in functional neuroimaging research, on spontaneous correlated activity among spatially segregated brain regions (intrinsic functional connectivity) and, more specifically, on intraindividual fluctuations of such correlated activity on various time scales (time-varying functional connectivity). In this Perspective, we propose that certain subtypes of spontaneous cognitive processes are detectable in time-varying functional connectivity measurements. We define these subtypes of spontaneous cognitive processes and review evidence of their representations in time-varying functional connectivity from studies of attentional fluctuations, memory reactivation, and effects of baseline states on subsequent perception. Moreover, we describe how these studies are critical to validating the use of neuroimaging tools (e.g., fMRI) for assessing ongoing brain network dynamics. We conclude that continued investigation of the behavioral relevance of time-varying functional connectivity will be beneficial both in the development of comprehensive neural models of cognition, and in informing on best practices for studying brain network dynamics.

Brief targeted memory reactivation during the awake state enhances memory stability and benefits the weakest memories.

Reactivation of representations corresponding to recent experience is thought to be a critical mechanism supporting long-term memory stabilization. Targeted memory reactivation, or the re-exposure of recently learned cues, seeks to induce reactivation and has been shown to benefit later memory when it takes place during sleep. However, despite recent evidence for endogenous reactivation during post-encoding awake periods, less work has addressed whether awake targeted memory reactivation modulates memory. Here, we found that brief (50 ms) visual stimulus re-exposure during a repetitive foil task enhanced the stability of cued versus uncued associations in memory. The extent of external or task-oriented attention prior to re-exposure was inversely related to cueing benefits, suggesting that an internally-orientated state may be most permissible to reactivation. Critically, cueing-related memory benefits were greatest in participants without explicit recognition of cued items and remained reliable when only considering associations not recognized as cued, suggesting that explicit cue-triggered retrieval processes did not drive cueing benefits. Cueing benefits were strongest for associations and participants with the poorest initial learning. These findings expand our knowledge of the conditions under which targeted memory reactivation can benefit memory, and in doing so, support the notion that reactivation during awake time periods improves memory stabilization.

Emotional brain states carry over and enhance future memory formation.

Emotional arousal can produce lasting, vivid memories for emotional experiences, but little is known about whether emotion can prospectively enhance memory formation for temporally distant information. One mechanism that may support prospective memory enhancements is the carry-over of emotional brain states that influence subsequent neutral experiences. Here we found that neutral stimuli encountered by human subjects 9-33 min after exposure to emotionally arousing stimuli had greater levels of recollection during delayed memory testing compared to those studied before emotional and after neutral stimulus exposure. Moreover, multiple measures of emotion-related brain activity showed evidence of reinstatement during subsequent periods of neutral stimulus encoding. Both slow neural fluctuations (low-frequency connectivity) and transient, stimulus-evoked activity predictive of trial-by-trial memory formation present during emotional encoding were reinstated during subsequent neutral encoding. These results indicate that neural measures of an emotional experience can persist in time and bias how new, unrelated information is encoded and recollected.

Enhanced brain correlations during rest are related to memory for recent experiences.

Long-term storage of episodic memories is hypothesized to result from the off-line transfer of information from the hippocampus to neocortex, allowing a hippocampal-independent cortical representation to emerge. However, off-line hippocampal-cortical interactions have not been demonstrated to be linked with long-term memory. Here, using functional magnetic resonance imaging, we examined if hippocampal-cortical BOLD correlations during rest following an associative encoding task are related to later associative memory performance. Our data show enhanced functional connectivity between the hippocampus and a portion of the lateral occipital complex (LO) during rest following a task with high subsequent memory compared to pretask baseline resting connectivity. This effect is not seen during rest following a task with poor subsequent memory. Furthermore, the magnitude of hippocampal-LO correlations during posttask rest predicts individual differences in later associative memory. These results demonstrate the importance of postexperience resting brain correlations for memory for recent experiences.

Sensory contributions to impaired emotion processing in schizophrenia.

Both emotion and visual processing deficits are documented in schizophrenia, and preferential magnocellular visual pathway dysfunction has been reported in several studies. This study examined the contribution to emotion-processing deficits of magnocellular and parvocellular visual pathway function, based on stimulus properties and shape of contrast response functions. Experiment 1 examined the relationship between contrast sensitivity to magnocellular- and parvocellular-biased stimuli and emotion recognition using the Penn Emotion Recognition (ER-40) and Emotion Differentiation (EMODIFF) tests. Experiment 2 altered the contrast levels of the faces themselves to determine whether emotion detection curves would show a pattern characteristic of magnocellular neurons and whether patients would show a deficit in performance related to early sensory processing stages. Results for experiment 1 showed that patients had impaired emotion processing and a preferential magnocellular deficit on the contrast sensitivity task. Greater deficits in ER-40 and EMODIFF performance correlated with impaired contrast sensitivity to the magnocellular-biased condition, which remained significant for the EMODIFF task even when nonspecific correlations due to group were considered in a step-wise regression. Experiment 2 showed contrast response functions indicative of magnocellular processing for both groups, with patients showing impaired performance. Impaired emotion identification on this task was also correlated with magnocellular-biased visual sensory processing dysfunction. These results provide evidence for a contribution of impaired early-stage visual processing in emotion recognition deficits in schizophrenia and suggest that a bottom-up approach to remediation may be effective.