Medial Temporal Lobe Activation Research Articles

Increased Intrinsic Activity of Medial-Temporal Lobe Subregions is Associated with Decreased Cortical Thickness of Medial-Parietal Areas in Patients with Alzheimer's Disease Dementia.

In Alzheimer's disease (AD), disrupted connectivity between medial-parietal cortices and medial-temporal lobes (MTL) is linked with increased MTL local functional connectivity, and parietal atrophy is associated with increased MTL memory activation. We hypothesized that intrinsic activity in MTL subregions is increased and associated with medial-parietal degeneration and impaired memory in AD. To test this hypothesis, resting-state-functional and structural-MRI was assessed in 22 healthy controls, 22 mild cognitive impairment patients, and 21 AD-dementia patients. Intrinsic activity was measured by power-spectrum density of blood-oxygenation-level-dependent signal, medial-parietal degeneration by cortical thinning. In AD-dementia patients, intrinsic activity was increased for several right MTL subregions. Raised intrinsic activity in dentate gyrus and cornu ammonis 1 was associated with cortical thinning in posterior cingulate cortices, and at-trend with impaired delayed recall. Critically, increased intrinsic activity in the right entorhinal cortex was associated with ipsilateral posterior cingulate degeneration. Our results provide evidence that in AD, intrinsic activity in MTL subregions is increased and associated with medial-parietal atrophy. Results fit a model in which medial-parietal degeneration contributes to MTL dysconnectivity from medial-parietal cortices, potentially underpinning disinhibition-like changes in MTL activity.

Decoding Episodic Retrieval Processes: Frontoparietal and Medial Temporal Lobe Contributions to Free Recall.

Neuroimaging studies of recognition memory have identified distinct patterns of cortical activity associated with two sets of cognitive processes: Recollective processes supporting retrieval of information specifying a probe item's original source are associated with the posterior hippocampus, ventral posterior parietal cortex, and medial pFC. Familiarity processes supporting the correct identification of previously studied probes (in the absence of a recollective response) are associated with activity in anterior medial temporal lobe (MTL) structures including the perirhinal cortex and anterior hippocampus, in addition to lateral prefrontal and dorsal posterior parietal cortex. Here, we address an open question in the cognitive neuroscientific literature: To what extent are these same neurocognitive processes engaged during an internally directed memory search task like free recall? We recorded fMRI activity while participants performed a series of free recall and source recognition trials, and we used a combination of univariate and multivariate analysis techniques to compare neural activation profiles across the two tasks. Univariate analyses showed that posterior MTL regions were commonly associated with recollective processes during source recognition and with free recall responses. Prefrontal and posterior parietal regions were commonly associated with familiarity processes and free recall responses, whereas anterior MTL regions were only associated with familiarity processes during recognition. In contrast with the univariate results, free recall activity patterns characterized using multivariate pattern analysis did not reliably match the neural patterns associated with recollective processes. However, these free recall patterns did reliably match patterns associated with familiarity processes, supporting theories of memory in which common cognitive mechanisms support both item recognition and free recall.

Changes in spatial cognition and brain activity after a single dose of testosterone in healthy women

Studies have consistently shown that males perform better than females on several spatial tasks. Animal and human literature suggests that sex hormones have an important role in both establishing and maintaining this difference. The aim of the present study was to examine the effects of exogenous testosterone on spatial cognition and brain activity in healthy women. A cross-sectional, double-blind, randomized, placebo-controlled study was performed in 42 healthy young women who either received one dose of 0.5mg sublingual testosterone or placebo. They then learned a virtual environment and performed navigation tasks during functional magnetic resonance imaging (fMRI). Subsequently, their knowledge of the virtual environment, self-reported navigation strategy, and mental rotation abilities were measured. The testosterone group had improved representations of the directions within the environment and performed significantly better on the mental rotation task compared to the placebo group, but navigation success and navigation strategy were similar in the two groups. Nevertheless, the testosterone group had significantly increased activity within the medial temporal lobe during successful navigation compared to the placebo group, and a positive correlation between testosterone load and medial temporal lobe activity was found. Fetal testosterone levels, measured as second-to-fourth digit length ratio, interacted significantly with parahippocampal activity and tended towards giving higher mental rotation task scores. These results demonstrated that testosterone had a limited effect pertaining specifically to spatial cognition involving 3D-visualization in healthy women, while complex behaviors such as navigation, relying more on learned strategies, were not altered despite increased neuronal activity in relevant brain regions.

Medial temporal lobe activity associated with the successful retrieval of destination memory.

Destination memory is the process of remembering to whom we tell particular things. Although recent behavioral studies have clarified the cognitive nature of destination memory, the neural mechanisms underlying destination memory retrieval remain unclear. We used functional magnetic resonance imaging (fMRI) to determine whether the medial temporal lobe (MTL), a structure that has been implicated in recollection-based memory, is activated during the successful retrieval of destination information. During a study phase before fMRI scanning, the subjects told a series of facts to either a woman or a man. During fMRI scanning, the subjects were asked to judge whether each fact presented was old or new, and if they judged it as old, to indicate, including a confidence rating (high or low), whether the subjects had told that fact to either a man or a woman. We found that successful destination retrieval, when compared to failed destination retrieval, was associated with increased activity in the parahippocampal gyrus. We also found that the confidence level (high vs. low) for destination memory retrieval was associated with increased activity in another (posterior) region of the parahippocampal gyrus. The present study suggests that the successful retrieval of destination information depends highly on MTL-mediated recollection processes.

A Meta-Analysis of fMRI Activation Differences during Episodic Memory in Alzheimer's Disease and Mild Cognitive Impairment.

Functional MRI (fMRI) has the potential to be used as a tool to detect biomarkers related to classifying Alzheimer's disease (AD) and its prodromal stage, mild cognitive impairment (MCI). Previous meta-analyses suggest that during episodic memory tasks, MCI patients exhibit hyperactivation in the medial temporal lobe (MTL) while AD patients exhibit hypoactivation, compared to healthy older adults (HOAs). However, these previous studies have methodological weaknesses that limit the generalizability of the results. This quantitative meta-analysis re-examines the activation associated with episodic memory in AD and MCI as compared to cognitively normal populations to assess these commonly cited activation differences. A whole-brain activation likelihood estimation based meta-analysis was conducted on fMRI studies that examined episodic memory in HOA (n = 200), MCI (n = 131), and AD populations (n = 89; total n = 409). Diffuse activation was exhibited in the HOA sample, while activation was more limited in the clinical populations. Additionally, the HOA sample showed more activation in the right hippocampus compared to the AD sample. The MCI studies showed greater activation in the cerebellum compared to the HOA sample, potentially indicating a compensatory mechanism for verbal encoding. MTL hypoactivation in the AD sample is consistent with previous studies, but more evidence of MCI hyperactivation is needed before considering MTL activation as an early biomarker for the AD disease process.

Human aging alters the neural computation and representation of space

The hippocampus and striatum are core neural circuits involved in spatial learning and memory. Although both neural systems support spatial navigation, experimental and theoretical evidence indicate that they play different roles. In particular, whereas hippocampal place cells generate allocentric neural representations of space that are sensitive to geometric information, striatum-dependent learning is influenced by local landmarks. How human aging affects these different neural representations, however, is still not well understood. In this paper, we combined virtual reality, computational modeling, and neuroimaging to investigate the effects of age upon the neural computation and representation of space in humans. We manipulated the geometry and local landmarks of a virtual environment and examined the effects on memory performance and brain activity during spatial learning. In younger adults, both behavior and brain activity in the medial-temporal lobe were consistent with predictions of a computational model of hippocampus-dependent boundary processing. In contrast, older adults' behavior and medial-temporal lobe activity were primarily influenced by local cue information, and spatial learning was more associated with activity in the caudate nucleus rather than the hippocampus. Together these results point to altered spatial representations and information processing in the hippocampal–striatal circuitry with advancing adult age, which may contribute to spatial learning and memory deficits associated with normal and pathological aging.

Telling true from false: cannabis users show increased susceptibility to false memories.

Previous studies on the neurocognitive impact of cannabis use have found working and declarative memory deficits that tend to normalize with abstinence. An unexplored aspect of cognitive function in chronic cannabis users is the ability to distinguish between veridical and illusory memories, a crucial aspect of reality monitoring that relies on adequate memory function and cognitive control. Using functional magnetic resonance imaging, we show that abstinent cannabis users have an increased susceptibility to false memories, failing to identify lure stimuli as events that never occurred. In addition to impaired performance, cannabis users display reduced activation in areas associated with memory processing within the lateral and medial temporal lobe (MTL), and in parietal and frontal brain regions involved in attention and performance monitoring. Furthermore, cannabis consumption was inversely correlated with MTL activity, suggesting that the drug is especially detrimental to the episodic aspects of memory. These findings indicate that cannabis users have an increased susceptibility to memory distortions even when abstinent and drug-free, suggesting a long-lasting compromise of memory and cognitive control mechanisms involved in reality monitoring.

Studying memory encoding to promote reliable engagement of the medial temporal lobe at the single-subject level.

The medial temporal lobe (MTL)—comprising hippocampus and the surrounding neocortical regions—is a targeted brain area sensitive to several neurological diseases. Although functional magnetic resonance imaging (fMRI) has been widely used to assess brain functional abnormalities, detecting MTL activation has been technically challenging. The aim of our study was to provide an fMRI paradigm that reliably activates MTL regions at the individual level, thus providing a useful tool for future research in clinical memory-related studies. Twenty young healthy adults underwent an event-related fMRI study consisting of three encoding conditions: word-pairs, face-name associations and complex visual scenes. A region-of-interest analysis at the individual level comparing novel and repeated stimuli independently for each task was performed. The results of this analysis yielded activations in the hippocampal and parahippocampal regions in most of the participants. Specifically, 95% and 100% of participants showed significant activations in the left hippocampus during the face-name encoding and in the right parahippocampus, respectively, during scene encoding. Additionally, a whole brain analysis, also comparing novel versus repeated stimuli at the group level, showed mainly left frontal activation during the word task. In this group analysis, the face-name association engaged the HP and fusiform gyri bilaterally, along with the left inferior frontal gyrus, and the complex visual scenes activated mainly the parahippocampus and hippocampus bilaterally. In sum, our task design represents a rapid and reliable manner to study and explore MTL activity at the individual level, thus providing a useful tool for future research in clinical memory-related fMRI studies.

Levels of processing in working memory: differential involvement of frontotemporal networks.

How does the brain maintain to-be-remembered information in working memory (WM), particularly when the focus of attention is drawn to processing other information? Cognitive models of WM propose that when items are displaced from focal attention recall involves retrieval from long-term memory (LTM). In this fMRI study, we tried to clarify the role of LTM in performance on a WM task and the type of representation that is used to maintain an item in WM during rehearsal-filled versus distractor-filled delays. Participants made a deep or shallow levels-of-processing (LOP) decision about a single word at encoding and tried to recall the word after a delay filled with either rehearsal of the word or a distracting math task. Recalling one word after 10 sec of distraction demonstrated behavioral and neural indices of retrieval from LTM (i.e., LOP effects and medial-temporal lobe activity). In contrast, recall after rehearsal activated cortical areas that reflected reporting the word from focal attention. In addition, areas that showed an LOP effect at encoding (e.g., left ventrolateral VLPFC and the anterior temporal lobes [ATLs]) were reactivated at recall, especially when recall followed distraction. Moreover, activity in left VLPFC during encoding, left ATL during the delay, and left hippocampus during retrieval predicted recall success after distraction. Whereas shallow LOP and rehearsal-related areas supported active maintenance of one item in focal attention, the behavioral processes and neural substrates that support LTM supported recall of one item after it was displaced from focal attention.

Neural activity in the medial temporal lobe reveals the fidelity of mental time travel.

Neural circuitry in the medial temporal lobe (MTL) is critically involved in mental time travel, which involves the vivid retrieval of the details of past experience. Neuroscientific theories propose that the MTL supports memory of the past by retrieving previously encoded episodic information, as well as by reactivating a temporal code specifying the position of a particular event within an episode. However, the neural computations supporting these abilities are underspecified. To test hypotheses regarding the computational mechanisms supported by different MTL subregions during mental time travel, we developed a computational model that linked a blood oxygenation level-dependent signal to cognitive operations, allowing us to predict human performance in a memory search task. Activity in the posterior MTL, including parahippocampal cortex, reflected how strongly one reactivates the temporal context of a retrieved memory, allowing the model to predict whether the next memory will correspond to a nearby moment in the study episode. A signal in the anterior MTL, including perirhinal cortex, indicated the successful retrieval of list items, without providing information regarding temporal organization. A hippocampal signal reflected both processes, consistent with theories that this region binds item and context information together to form episodic memories. These findings provide evidence for modern theories that describe complementary roles of the hippocampus and surrounding parahippocampal and perirhinal cortices during the retrieval of episodic memories, shaping how humans revisit the past.

Long-Term Heavy Ketamine Use is Associated with Spatial Memory Impairment and Altered Hippocampal Activation

Ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, is rising in popularity as a drug of abuse. Preliminary evidence suggests that chronic, heavy ketamine use may have profound effects on spatial memory but the mechanism of these deficits is as yet unclear. This study aimed to examine the neural mechanism by which heavy ketamine use impairs spatial memory processing. In a sample of 11 frequent ketamine users and 15 poly-drug controls, matched for IQ, age, years in education. We used fMRI utilizing an ROI approach to examine the neural activity of three regions known to support successful navigation; the hippocampus, parahippocampal gyrus, and the caudate nucleus during a virtual reality task of spatial memory. Frequent ketamine users displayed spatial memory deficits, accompanied by and related to, reduced activation in both the right hippocampus and left parahippocampal gyrus during navigation from memory, and in the left caudate during memory updating, compared to controls. Ketamine users also exhibited schizotypal and dissociative symptoms that were related to hippocampal activation. Impairments in spatial memory observed in ketamine users are related to changes in medial temporal lobe activation. Disrupted medial temporal lobe function may be a consequence of chronic ketamine abuse and may relate to schizophrenia-like symptomatology observed in ketamine users.

The medial temporal lobe—conduit of parallel connectivity: a model for attention, memory, and perception

Based on the notion that the brain is equipped with a hierarchical organization, which embodies environmental contingencies across many time scales, this paper suggests that the medial temporal lobe (MTL)—located deep in the hierarchy—serves as a bridge connecting supra- to infra—MTL levels. Bridging the upper and lower regions of the hierarchy provides a parallel architecture that optimizes information flow between upper and lower regions to aid attention, encoding, and processing of quick complex visual phenomenon. Bypassing intermediate hierarchy levels, information conveyed through the MTL “bridge” allows upper levels to make educated predictions about the prevailing context and accordingly select lower representations to increase the efficiency of predictive coding throughout the hierarchy. This selection or activation/deactivation is associated with endogenous attention. In the event that these “bridge” predictions are inaccurate, this architecture enables the rapid encoding of novel contingencies. A review of hierarchical models in relation to memory is provided along with a new theory, Medial-temporal-lobe Conduit for Parallel Connectivity (MCPC). In this scheme, consolidation is considered as a secondary process, occurring after a MTL-bridged connection, which eventually allows upper and lower levels to access each other directly. With repeated reactivations, as contingencies become consolidated, less MTL activity is predicted. Finally, MTL bridging may aid processing transient but structured perceptual events, by allowing communication between upper and lower levels without calling on intermediate levels of representation.

Factors affecting reorganisation of memory encoding networks in temporal lobe epilepsy

In temporal lobe epilepsy (TLE) due to hippocampal sclerosis reorganisation in the memory encoding network has been consistently described. Distinct areas of reorganisation have been shown to be efficient when associated with successful subsequent memory formation or inefficient when not associated with successful subsequent memory. We investigated the effect of clinical parameters that modulate memory functions: age at onset of epilepsy, epilepsy duration and seizure frequency in a large cohort of patients. We studied 53 patients with unilateral TLE and hippocampal sclerosis (29 left). All participants performed a functional magnetic resonance imaging memory encoding paradigm of faces and words. A continuous regression analysis was used to investigate the effects of age at onset of epilepsy, epilepsy duration and seizure frequency on the activation patterns in the memory encoding network. Earlier age at onset of epilepsy was associated with left posterior hippocampus activations that were involved in successful subsequent memory formation in left hippocampal sclerosis patients. No association of age at onset of epilepsy was seen with face encoding in right hippocampal sclerosis patients. In both left hippocampal sclerosis patients during word encoding and right hippocampal sclerosis patients during face encoding, shorter duration of epilepsy and lower seizure frequency were associated with medial temporal lobe activations that were involved in successful memory formation. Longer epilepsy duration and higher seizure frequency were associated with contralateral extra-temporal activations that were not associated with successful memory formation. Age at onset of epilepsy influenced verbal memory encoding in patients with TLE due to hippocampal sclerosis in the speech-dominant hemisphere. Shorter duration of epilepsy and lower seizure frequency were associated with less disruption of the efficient memory encoding network whilst longer duration and higher seizure frequency were associated with greater, inefficient, extra-temporal reorganisation.

Subsequent memory effects in schizophrenia

Differential neural activation at encoding can predict which stimuli will be subsequently remembered or forgotten, and memory deficits are pronounced in schizophrenia. We used event-related functional magnetic resonance imaging (fMRI) to investigate subsequent memory (SM) effects for visual fractals in patients with schizophrenia (n=26) and healthy controls (n=28). Participants incidentally encoded the fractals during an oddball task and 10min later they made old/new recognition memory judgments on 30 target fractals and 30 foil fractals. We found evidence for subsequent memory (SM, subsequently remembered>subsequently forgotten) effects on regional brain activation in both groups but with distinct patterns. Region of interest (ROI) analyses in controls demonstrated SM activation in both medial temporal lobe (MTL) and fusiform cortex (FF), whereas patients showed SM effects only in the FF. There were no significant between group differences in MTL activation; however, patients demonstrated greater FF activation than controls. Notably, greater FF activation during successful encoding was associated with more severe negative symptoms. Exploratory whole brain analyses in patients demonstrated SM activation in the occipital pole, lateral occipital cortex, left inferior temporal gyrus, and fusiform cortex; whereas in controls there was no significant activation that survived correction for multiple comparisons. Our findings suggest that patients, particularly those with prominent negative symptoms, may activate FF as a compensatory strategy to promote successful encoding, with relatively less reliance on MTL recruitment.

The Potentiation of Associative Memory by Emotions: An Event-Related FMRI Study

Establishing associations between pieces of information is related to the medial temporal lobe (MTL). However, it remains unclear how emotions affect memory for associations and, consequently, MTL activity. Thus, this event-related fMRI study attempted to identify neural correlates of the influence of positive and negative emotions on associative memory. Twenty-five participants were instructed to memorize 90 pairs of standardized pictures during a scanned encoding phase. Each pair was composed of a scene and an unrelated object. Trials were neutral, positive, or negative as a function of the emotional valence of the scene. At the behavioral level, participants exhibited better memory retrieval for both emotional conditions relative to neutral trials. Within the right MTL, a functional dissociation was observed, with entorhinal activation elicited by emotional associations, posterior parahippocampal activation elicited by neutral associations, and hippocampal activation elicited by both emotional and neutral associations. In addition, emotional associations induced greater activation than neutral trials in the right amygdala. This fMRI study shows that emotions are associated with the performance improvement of associative memory, by enhancing activity in the right amygdala and the right entorhinal cortex. It also provides evidence for a rostrocaudal specialization within the MTL regarding the emotional valence of associations.

Theta and high-frequency activity mark spontaneous recall of episodic memories.

Humans possess the remarkable ability to search their memory, allowing specific past episodes to be re-experienced spontaneously. Here, we administered a free recall test to 114 neurosurgical patients and used intracranial theta and high-frequency activity (HFA) to identify the spatiotemporal pattern of neural activity underlying spontaneous episodic retrieval. We found that retrieval evolved in three electrophysiological stages composed of: (1) early theta oscillations in the right temporal cortex, (2) increased HFA in the left hemisphere including the medial temporal lobe (MTL), left inferior frontal gyrus, as well as the ventrolateral temporal cortex, and (3) motor/language activation during vocalization of the retrieved item. Of these responses, increased HFA in the left MTL predicted recall performance. These results suggest that spontaneous recall of verbal episodic memories involves a spatiotemporal pattern of spectral changes across the brain; however, high-frequency activity in the left MTL represents a final common pathway of episodic retrieval.

Human hippocampal processing of environmental novelty during spatial navigation

The detection and processing of novel information encountered as we explore our environment is crucial for learning and adaptive behavior. The human hippocampus has been strongly implicated in laboratory tests of novelty detection and episodic memory, but has been less well studied during more ethological tasks such as spatial navigation, typically used in animals. We examined fMRI BOLD activity as a function of environmental and object novelty as humans performed an object-location virtual navigation task. We found greater BOLD response to novel relative to familiar environments in the hippocampus and adjacent parahippocampal gyrus. Object novelty was associated with increased activity in the posterior parahippocampal/fusiform gyrus and anterior hippocampus extending into the amygdala and superior temporal sulcus. Importantly, whilst mid-posterior hippocampus was more sensitive to environmental novelty than object novelty, the anterior hippocampus responded similarly to both forms of novelty. Amygdala activity showed an increase for novel objects that decreased linearly over the learning phase. By investigating how participants learn and use different forms of information during spatial navigation, we found that medial temporal lobe (MTL) activity reflects both the novelty of the environment and of the objects located within it. This novelty processing is likely supported by distinct, but partially overlapping, sets of regions within the MTL.

Nondirective meditation activates default mode network and areas associated with memory retrieval and emotional processing

Nondirective meditation techniques are practiced with a relaxed focus of attention that permits spontaneously occurring thoughts, images, sensations, memories, and emotions to emerge and pass freely, without any expectation that mind wandering should abate. These techniques are thought to facilitate mental processing of emotional experiences, thereby contributing to wellness and stress management. The present study assessed brain activity by functional magnetic resonance imaging (fMRI) in 14 experienced practitioners of Acem meditation in two experimental conditions. In the first, nondirective meditation was compared to rest. Significantly increased activity was detected in areas associated with attention, mind wandering, retrieval of episodic memories, and emotional processing. In the second condition, participants carried out concentrative practicing of the same meditation technique, actively trying to avoid mind wandering. The contrast nondirective meditation > concentrative practicing was characterized by higher activity in the right medial temporal lobe (parahippocampal gyrus and amygdala). In conclusion, the present results support the notion that nondirective meditation, which permits mind wandering, involves more extensive activation of brain areas associated with episodic memories and emotional processing, than during concentrative practicing or regular rest.

Medial temporal lobe activation during autobiographical context memory retrieval of time and place and its dependency upon recency

The contribution of the medial temporal lobe (MTL) to the retrieval of autobiographical memories is widely accepted. Results of former patient studies and functional imaging studies suggest different involvement of the MTL during the retrieval of autobiographical context information and the remoteness of these. Varying recency, the MTL contribution during chronological and locational autobiographical context information processing was investigated in this study. Thirteen males (mean = 25 years) judged the event’s place or time in a two-choice recognition task. Subjects made significantly more errors on chronological judgments. Retrieval of chronological information activated the left MTL, while retrieval of locational information activated the MTL bilaterally. Retrieval of more recent than remote context information activated especially the right MTL. Our results underline different MTL contributions on the retrieval of autobiographical context information, depending on the content and on the remoteness of the event that took place.

Additive genetic effect of APOE and BDNF on hippocampus activity

Human memory is a highly heritable polygenic trait with complex inheritance patterns. To study the genetics of memory and memory-related diseases, hippocampal functioning has served as an intermediate phenotype. The importance of investigating gene–gene effects on complex phenotypes has been emphasized, but most imaging studies still focus on single polymorphisms. APOE ε4 and BDNF Met, two of the most studied gene variants for variability in memory performance and neuropsychiatric disorders, have both separately been related to poorer episodic memory and altered hippocampal functioning. Here, we investigated the combined effect of APOE and BDNF on hippocampal activation (N=151). No non-additive interaction effects were seen. Instead, the results revealed decreased activation in bilateral hippocampus and parahippocampus as a function of the number of APOE ε4 and BDNF Met alleles present (neither, one, or both). The combined effect was stronger than either of the individual effects, and both gene variables explained significant proportions of variance in BOLD signal change. Thus, there was an additive gene–gene effect of APOE and BDNF on medial temporal lobe (MTL) activation, showing that a larger proportion of variance in brain activation attributed to genetics can be explained by considering more than one gene variant. This effect might be relevant for the understanding of normal variability in memory function as well as memory-related disorders associated with APOE and BDNF.