Medial Temporal Lobe Activation Research Articles

Age-related neural changes underlying long-term recognition of musical sequences.

Aging is often associated with decline in brain processing power and neural predictive capabilities. To challenge this notion, we used magnetoencephalography (MEG) and magnetic resonance imaging (MRI) to record the whole-brain activity of 39 older adults (over 60 years old) and 37 young adults (aged 18-25 years) during recognition of previously memorised and varied musical sequences. Results reveal that when recognising memorised sequences, the brain of older compared to young adults reshapes its functional organisation. In fact, it shows increased early activity in sensory regions such as the left auditory cortex (100 ms and 250 ms after each note), and only moderate decreased activity (350 ms) in medial temporal lobe and prefrontal regions. When processing the varied sequences, older adults show a marked reduction of the fast-scale functionality (250 ms after each note) of higher-order brain regions including hippocampus, ventromedial prefrontal and inferior temporal cortices, while no differences are observed in the auditory cortex. Accordingly, young outperform older adults in the recognition of novel sequences, while no behavioural differences are observed with regards to memorised ones. Our findings show age-related neural changes in predictive and memory processes, integrating existing theories on compensatory neural mechanisms in non-pathological aging.

The effect of feedback timing on category learning and feedback processing in younger and older adults.

Corrective feedback can be received immediately after an action or with a temporal delay. Neuroimaging studies suggest that immediate and delayed feedback are processed by the striatum and medial temporal lobes (MTL), respectively. Age-related changes in the striatum and MTL may influence the efficiency of feedback-based learning in older adults. The current study leverages event-related potentials (ERPs) to evaluate age-related differences in immediate and delayed feedback processing and consequences for learning. The feedback-related negativity (FRN) captures activity in the frontostriatal circuit while the N170 is hypothesized to reflect MTL activation. 18 younger (Myears = 24.4) and 20 older (Myears = 65.5) adults completed learning tasks with immediate and delayed feedback. For each group, learning outcomes and ERP magnitudes were evaluated across timing conditions. Younger adults learned better than older adults in the immediate timing condition. This performance difference was associated with a typical FRN signature in younger but not older adults. For older adults, impaired processing of immediate feedback in the striatum may have negatively impacted learning. Conversely, learning was comparable across groups when feedback was delayed. For both groups, delayed feedback was associated with a larger magnitude N170 relative to immediate feedback, suggesting greater MTL activation. Delaying feedback may increase MTL involvement and, for older adults, improve category learning. Age-related neural changes may differentially affect MTL- and striatal-dependent learning. Future research can evaluate the locus of age-related learning differences and how feedback can be manipulated to optimize learning across the lifespan.

Interactions between physical exercise, associative memory, and genetic risk for Alzheimer's disease.

The ε4 allele of the APOE gene heightens the risk of late onset Alzheimer's disease. ε4 carriers, may exhibit cognitive and neural changes early on. Given the known memory-enhancing effects of physical exercise, particularly through hippocampal plasticity via endocannabinoid signaling, here we aimed to test whether a single session of physical exercise may benefit memory and underlying neurophysiological processes in young ε3 carriers (ε3/ε4 heterozygotes, risk group) compared with a matched control group (homozygotes for ε3). Participants underwent fMRI while learning picture sequences, followed by cycling or rest before a memory test. Blood samples measured endocannabinoid levels. At the behavioral level, the risk group exhibited poorer associative memory performance, regardless of the exercising condition. At the brain level, the risk group showed increased medial temporal lobe activity during memory retrieval irrespective of exercise (suggesting neural compensatory effects even at baseline), whereas, in the control group, such increase was only detectable after physical exercise. Critically, an exercise-related endocannabinoid increase correlated with task-related hippocampal activation in the control group only. In conclusion, healthy young individuals carrying the ε4 allele may present suboptimal associative memory performance (when compared with homozygote ε3 carriers), together with reduced plasticity (and functional over-compensation) within medial temporal structures.

Declarative Learning Mechanisms Support Declarative but Not Probabilistic Feedback-Based Learning in Children with Developmental Language Disorder (DLD).

Declarative and probabilistic feedback-based learning was evaluated in 8-12-year-old school-age children with developmental language disorder (DLD; n = 14) and age-matched children with typical development (TD; n = 15). Children performed a visual two-choice word-learning task and a visual probabilistic classification task while their electroencephalogram (EEG) was recorded non-invasively from the scalp. Behavioral measures of accuracy and response to feedback, and electrophysiological responses to feedback were collected and compared between the two groups. While behavioral data indicated poorer performance by children with DLD in both learning paradigms, and similar response patterns to positive and negative feedback, electrophysiological data highlighted processing patterns in the DLD group that differed by task. More specifically, in this group, feedback processing in the context of declarative learning, which is known to be dominated by the medial temporal lobe (MTL), was associated with enhanced N170, an event-related brain potential (ERP) associated with MTL activation. The N170 amplitude was found to be correlated with declarative task performance in the DLD group. During probabilistic learning, known to be governed by the striatal-based learning system, the feedback-related negativity (FRN) ERP, which is the product of the cortico-striatal circuit dominated feedback processing. Within the context of probabilistic learning, enhanced N170 was associated with poor learning in the TD group, suggesting that MTL activation during probabilistic learning disrupts learning. These results are interpreted within the context of a proposed feedback parity hypothesis suggesting that in children with DLD, the system that dominates learning (i.e., MTL during declarative learning and the striatum during probabilistic learning) dominates and supports feedback processing.

60 Neural Correlates of the Self-Reference Effect: Neuronal Mechanisms Supporting Self-Referential Encoding

Objective:Self-concept is a mental representation of the self—an internal sense of personal identity. This complex representation is unique to the human mind. Behavioral studies on self-concept have demonstrated that self-relevant information is remembered better than other types of information, a phenomenon commonly known as the “self-reference effect” (SRE). However, the underlying neural mechanisms of SRE remain largely unknown.Participants and Methods:Here, we recorded neural activity from ∼600 neurons from 15 neurosurgical epilepsy patients, who were implanted with depth electrodes for seizure monitoring. The SRE paradigm consisted of an incidental learning (encoding) task and subsequent memory recognition test. During the incidental learning task, participants were asked to rate various personality traits in three distinct encoding conditions: the self, a friend, and a celebrity. In the recognition part of the task, participants were asked to distinguish between traits that were presented during the encoding phase (old) and traits that were not presented (new).Results:Our behavioral findings showed the highest memory accuracy on the recognition test for traits that were associated with the “self” condition, which is consistent with previous studies on SRE. Additionally, we found that traits associated with the “friend” category were more accurately recognized than those associated with a celebrity, indicating that personally familiar information—even if not self-related— improves memory recognition. Through single-unit analyses from target brain regions, including the medial temporal lobe (MTL) and medial prefrontal cortex (mPFC), we identified unique patterns of neural activity during the memory encoding phase, specifically increased responses during self-referential encoding in a subset of the neuronal population.Conclusions:Future analyses will explore the relationship between increased MTL activity during self-referential encoding and improved memory recognition of traits rated in relation to the self, and network interactions between MTL and mPFC in self-oriented memory processes.

Paving the Way for Memory Enhancement: Development and Examination of a Neurofeedback System Targeting the Medial Temporal Lobe.

Neurofeedback (NF) shows promise in enhancing memory, but its application to the medial temporal lobe (MTL) still needs to be studied. Therefore, we aimed to develop an NF system for the memory function of the MTL and examine neural activity changes and memory task score changes through NF training. We created a memory NF system using intracranial electrodes to acquire and visualise the neural activity of the MTL during memory encoding. Twenty trials of a tug-of-war game per session were employed for NF and designed to control neural activity bidirectionally (Up/Down condition). NF training was conducted with three patients with drug-resistant epilepsy, and we observed an increasing difference in NF signal between conditions (Up-Down) as NF training progressed. Similarities and negative correlation tendencies between the transition of neural activity and the transition of memory function were also observed. Our findings demonstrate NF's potential to modulate MTL activity and memory encoding. Future research needs further improvements to the NF system to validate its effects on memory functions. Nonetheless, this study represents a crucial step in understanding NF's application to memory and provides valuable insights into developing more efficient memory enhancement strategies.

Learning new words via feedback-Association between feedback-locked ERPs and recall performance-An exploratory study.

Feedback learning is thought to involve the dopamine system and its projection sites in the basal ganglia and anterior cingulate cortex (ACC), regions associated with procedural learning. Under certain conditions, such as when feedback is delayed, feedback-locked activation is pronounced in the medial temporal lobe (MTL), which is associated with declarative learning. In event-related potential research, the feedback-related negativity (FRN) has been linked to immediate feedback processing, while the N170, possibly reflecting MTL activity, has been related to delayed feedback processing. In the current study, we performed an exploratory investigation on the relation between N170 and FRN amplitude and memory performance in a test for declarative memory (free recall), also exploring the role of feedback delay. To this end, we adapted a paradigm in which participants learned associations between non-objects and non-words with either immediate or delayed feedback, and added a subsequent free recall test. We indeed found that N170, but not FRN amplitudes, depended on later free recall performance, with smaller amplitudes for later remembered non-words. In an additional analysis with memory performance as dependent variable, the N170, but not the FRN amplitude predicted free recall, modulated by feedback timing and valence. This finding shows that the N170 reflects an important process during feedback processing, possibly related to expectations and their violation, but is distinct from the process reflected by the FRN.

Dopamine differentially modulates medial temporal lobe activity and behavior during spatial navigation in young and older adults

Aging is associated with changes in spatial navigation behavior. In addition to an overall performance decline, older adults tend to rely more on proximal location cue information than on environmental boundary information during spatial navigation compared to young adults. The fact that older adults are more susceptible to errors during spatial navigation might be partly attributed to deficient dopaminergic modulation of hippocampal and striatal functioning. Hence, elevating dopamine levels might differentially modulate spatial navigation and memory performance in young and older adults. In this work, we administered levodopa (L-DOPA) in a double-blind within-subject, placebo-controlled design and recorded functional neuroimaging while young and older adults performed a 3D spatial navigation task in which boundary geometry or the position of a location cue were systematically manipulated. An age by intervention interaction on the neural level revealed an upregulation of brain responses in older adults and a downregulation of responses in young adults within the medial temporal lobe (including hippocampus and parahippocampus) and brainstem, during memory retrieval. Behaviorally, L-DOPA had no effect on older adults’ overall memory performance; however, older adults whose spatial memory improved under L-DOPA also showed a shift towards more boundary processing under L-DOPA. In young adults, L-DOPA induced a decline in spatial memory performance in task-naïve participants. These results are consistent with the inverted-U-shaped hypothesis of dopamine signaling and cognitive function and suggest that increasing dopamine availability improves hippocampus-dependent place learning in some older adults.

Decoding human spontaneous spiking activity in medial temporal lobe from scalp EEG

Linking scalp electroencephalography (EEG) signals and spontaneous firing activity from deep nuclei in humans is not trivial. To examine this, we analyzed simultaneous recordings of scalp EEG and unit activity in deeply located sites recorded overnight from patients undergoing pre-surgical invasive monitoring. We focused on modeling the within-subject average unit activity of two medial temporal lobe areas: amygdala and hippocampus. Linear regression model correlates the units' average firing activity to spectral features extracted from the EEG during wakefulness or non-REM sleep. We show that changes in mean firing activity in both areas and states can be estimated from EEG (Pearson r>0.2, p≪0.001). Region specificity was shown with respect to other areas. Both short- and long-term fluctuations in firing rates contributed to the model accuracy. This demonstrates that scalp EEG frequency modulations can predict changes in neuronal firing rates, opening a new horizon for non-invasive neurological and psychiatric interventions.

The medial temporal lobe supports the quality of visual short-term memory representation.

The quality of short-term memory (STM) underlies our ability to recall the exact details of a recent event, yet how the human brain enables this core cognitive function remains poorly understood. Here we use multiple experimental approaches to test the hypothesis that the quality of STM, such as its precision or fidelity, relies on the medial temporal lobe (MTL), a region commonly associated with the ability to distinguish similar information remembered in long-term memory. First, with intracranial recordings, we find that delay-period MTL activity retains item-specific STM content that is predictive of subsequent recall precision. Second, STM recall precision is associated with an increase in the strength of intrinsic MTL-to-neocortical functional connections during a brief retention interval. Finally, perturbing the MTL through electrical stimulation or surgical removal can selectively reduce STM precision. Collectively, these findings provide converging evidence that the MTL is critically involved in the quality of STM representation.

Sex differences in longitudinal changes of episodic memory-related brain activity and cognition in cognitively unimpaired older adults with a family history of Alzheimer’s disease

Episodic memory decline is an early symptom of Alzheimer’s disease (AD) – a neurodegenerative disease that has a higher prevalence rate in older females compared to older males. However, little is known about why these sex differences in prevalence rate exist. In the current longitudinal task fMRI study, we explored whether there were sex differences in the patterns of memory decline and brain activity during object-location (spatial context) encoding and retrieval in a large sample of cognitively unimpaired older adults from the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer’s Disease (PREVENT-AD) program who are at heightened risk of developing AD due to having a family history (+FH) of the disease. The goal of the study was to gain insight into whether there are sex differences in the neural correlates of episodic memory decline, which may advance knowledge about sex-specific patterns in the natural progression to AD. Our results indicate that +FH females performed better than +FH males at both baseline and follow-up on neuropsychological and task fMRI measures of episodic memory. Moreover, multivariate data-driven task fMRI analysis identified generalized patterns of longitudinal decline in medial temporal lobe activity that was paralleled by longitudinal increases in lateral prefrontal cortex, caudate and midline cortical activity during successful episodic retrieval and novelty detection in +FH males, but not females. Post-hoc analyses indicated that higher education had a stronger effect on +FH females neuropsychological scores compared to +FH males. We conclude that higher educational attainment may have a greater neuroprotective effect in older +FH females compared to +FH males.

Multiple traces and altered signal-to-noise in systems consolidation: Evidence from the 7T fMRI Natural Scenes Dataset

The brain mechanisms of memory consolidation remain elusive. Here, we examine blood-oxygen-level-dependent (BOLD) correlates of image recognition through the scope of multiple influential systems consolidation theories. We utilize the longitudinal Natural Scenes Dataset, a 7-Tesla functional magnetic resonance imaging human study in which ∼135,000 trials of image recognition were conducted over the span of a year among eight subjects. We find that early- and late-stage image recognition associates with both medial temporal lobe (MTL) and visual cortex when evaluating regional activations and a multivariate classifier. Supporting multiple-trace theory (MTT), parts of the MTL activation time course show remarkable fit to a 20-y-old MTT time-dynamical model predicting early trace intensity increases and slight subsequent interference (R2 > 0.90). These findings contrast a simplistic, yet common, view that memory traces are transferred from MTL to cortex. Next, we test the hypothesis that the MTL trace signature of memory consolidation should also reflect synaptic "desaturation," as evidenced by an increased signal-to-noise ratio. We find that the magnitude of relative BOLD enhancement among surviving memories is positively linked to the rate of removal (i.e., forgetting) of competing traces. Moreover, an image-feature and time interaction of MTL and visual cortex functional connectivity suggests that consolidation mechanisms improve the specificity of a distributed trace. These neurobiological effects do not replicate on a shorter timescale (within a session), implicating a prolonged, offline process. While recognition can potentially involve cognitive processes outside of memory retrieval (e.g., re-encoding), our work largely favors MTT and desaturation as perhaps complementary consolidative memory mechanisms.

Attenuated interoceptive processing in individuals with major depressive disorder and high repetitive negative thinking

Repetitive negative thinking (RNT) is a transdiagnostic symptom associated with poor outcomes in major depressive disorder (MDD). MDD is characterized by altered interoception, which has also been associated with poor outcomes. The present study investigated whether RNT is directly associated with altered interoceptive processing. Interoceptive awareness toward the heart and stomach was probed on the Visceral Interoceptive Attention (VIA) task with fMRI in MDD individuals who were propensity-matched on the severity of depression and anxiety symptoms and relevant demographics but different in RNT intensity (High RNT [H-RNT, n = 48] & Low RNT [L-RNT, n = 49]), and in matched healthy volunteers (HC, n = 27). Both H-RNT and L-RNT MDD individuals revealed reduced stomach interoceptive processing compared to HC in the left medial frontal region and insular cortex (H-RNT: β = −1.04, L-RNT: β = −0.97), perirhinal cortex (H-RNT: β = −0.99, L-RNT: β = −1.03), and caudate nucleus (H-RNT: β = −1.06, L-RNT: β = −0.89). However, H-RNT was associated with decreased right medial temporal lobe activity including the hippocampus and amygdala during stomach interoceptive trials (β = −0.61) compared to L-RNT. Insular interoceptive processing was similar in H-RNT and L-RNT participants (β = −0.07, p = 0.92). MDD individuals with high RNT exhibited altered gastric interoceptive responses in brain areas that are important for associating the information with specific contexts and emotions. Attenuated interoceptive processing may contribute to RNT generation, non-adaptive information processing, action selection, and thus poor treatment outcome.

Brain activity patterns underlying memory confidence.

The primary aim of this review is to examine the brain activity patterns that are related to subjectively perceived memory confidence. We focus on the main brain regions involved in episodic memory: the medial temporal lobe (MTL), prefrontal cortex (PFC), and posterior parietal cortex (PPC), and relate activity in their subregions to memory confidence. How this brain activity in both the encoding and retrieval phase is related to (subsequent) memory confidence ratings will be discussed. Specifically, encoding related activity in MTL regions and ventrolateral PFC mainly shows a positive linear increase with subsequent memory confidence, while dorsolateral and ventromedial PFC activity show mixed patterns. In addition, encoding‐related PPC activity seems to only have indirect effects on memory confidence ratings. Activity during retrieval in both the hippocampus and parahippocampal cortex increases with memory confidence, especially during high‐confident recognition. Retrieval‐related activity in the PFC and PPC show mixed relationships with memory confidence, likely related to post‐retrieval monitoring and attentional processes, respectively. In this review, these MTL, PFC, and PPC activity patterns are examined in detail and related to their functional roles in memory processes. This insight into brain activity that underlies memory confidence is important for our understanding of brain–behaviour relations and memory‐guided decision making.

Alcohol use disorder and mild cognitive impairment: Shared neural signatures during an episodic memory task

AbstractBackgroundAlcohol Use Disorder (AUD) has previously been identified as a risk factor for Alzheimer’s disease and cognitive impairment. However, the mechanisms underlying the connection between AUD and Alzheimer’s disease remain unclear. Episodic memory is impaired in both AUD and mild cognitive impairment (MCI), and is associated with the transition from MCI to Alzheimer’s disease. This study used functional magnetic resonance imaging (fMRI) to compare activation during encoding of an episodic memory task in mid‐life AUD subjects to subjects with mild cognitive impairment (MCI), a prodromal stage of Alzheimer’s disease.MethodParticipants included 14 AUD subjects age 45 to 65 (M = 56 years), and 14 MCI subjects age 45 to 85 (M = 67 years). Healthy control subjects were matched to AUD and MCI groups by age and sex. Images were acquired on a 3T Siemens Prisma (3 mm3 voxels, TR = 1.1s, TE = 30 ms). During the fMRI task, participants viewed pictures of faces and objects and were instructed to remember these pictures for later. Activation maps were produced through general linear model analysis using cluster correction thresholding (Z>3.3, p = .05) in FSL (version 6.0).ResultsAUD and MCI groups showed reduced extent of BOLD activation during encoding versus baseline (Figure 1). Compared to matched controls, AUD and MCI subjects showed less medial temporal lobe (amygdala), brainstem, and thalamus activation. Additionally, AUD subjects did not exhibit the frontal activation that was present in MCI and matched controls.ConclusionsGiven the small sample sizes, caution should be taken in interpreting these results. Nonetheless, these preliminary findings suggest that mid‐life AUD subjects show similar patterns of reduced activation during episodic encoding to those with MCI. Reduced medial temporal lobe activation may represent vulnerability to Alzheimer’s disease, which is present in both MCI and AUD. Explanations for the differences in frontal activation might include compensatory mechanisms in MCI or executive dysfunction in AUD. Future analyses will aim to disentangle these effects by examining the relationship between BOLD signal activation and behavioral outcomes.

Prediction Errors for Aversive Events Shape Long-Term Memory Formation through a Distinct Neural Mechanism.

Prediction errors (PEs) have been known for decades to guide associative learning, but their role in episodic memory formation has been discovered only recently. To identify the neural mechanisms underlying the impact of aversive PEs on long-term memory formation, we used functional magnetic resonance imaging, while participants saw a series of unique stimuli and estimated the probability that an aversive shock would follow. Our behavioral data showed that negative PEs (i.e., omission of an expected outcome) were associated with superior recognition of the predictive stimuli, whereas positive PEs (i.e., presentation of an unexpected outcome) impaired subsequent memory. While medial temporal lobe (MTL) activity during stimulus encoding was overall associated with enhanced memory, memory-enhancing effects of negative PEs were linked to even decreased MTL activation. Additional large-scale network analyses showed PE-related increases in crosstalk between the "salience network" and a frontoparietal network commonly implicated in memory formation for expectancy-congruent events. These effects could not be explained by mere changes in physiological arousal or the prediction itself. Our results suggest that the superior memory for events associated with negative aversive PEs is driven by a potentially distinct neural mechanism that might serve to set these memories apart from those with expected outcomes.

Rapid Sequential Implication of the Human Medial Temporal Lobe in Memory Encoding and Recognition.

The medial temporal lobe (MTL) is crucial for memory encoding and recognition. The time course of these processes is unknown. The present study juxtaposed encoding and recognition in a single paradigm. Twenty healthy subjects performed a continuous recognition task as brain activity was monitored with a high-density electroencephalography. The task presented New pictures thought to evoke encoding. The stimuli were then repeated up to 4 consecutive times to produce over-familiarity. These repeated stimuli served as “baseline” for comparison with the other stimuli. Stimuli later reappeared after 9–15 intervening items, presumably associated with new encoding and recognition. Encoding-related differences in evoked response potential amplitudes and in spatiotemporal analysis were observed at 145–300 ms, whereby source estimation indicated MTL and orbitofrontal activity from 145 to 205 ms. Recognition-related activity evoked by late repetitions occurred at 405–470 ms, implicating the MTL and neocortical structures. These findings indicate that encoding of information is initiated before it is recognized. The result helps to explain modifications of memories over time, including false memories, confabulation, and consolidation.

Cerebral perfusion changes in chronic dizziness: A single-photon emission computed tomography study.

Background and purposeDizziness may persist even after the causative vestibular imbalance subsides. Although the precise mechanism of chronic dizziness is unknown, various cerebral activity changes associated with it have been reported. To understand its mechanism in the absence of the causative vestibular imbalance, we compared cerebral changes in chronic dizziness with and without persistent vestibular imbalance.MethodsBetween September 2014 and March 2020, we examined regional cerebral blood flow (rCBF) in 12 patients having chronic post-lateral medullary infarction dizziness with persistent brainstem vestibular imbalance and 23 patients having chronic dizziness without currently active vestibular imbalance using single-photon emission computed tomography (SPECT) with 99m Technetium-ethyl cysteinate dimer. Further, we analyzed the SPECT images using a voxel-based group comparison.ResultsWe observed a decreased rCBF in the occipital lobe and increased rCBF in the medial and inferior parts of the temporal lobe in patients having chronic dizziness with and without active vestibular imbalance compared to healthy controls. However, only patients having chronic dizziness without active vestibular imbalance exhibited increased rCBF in the frontal lobe, including the orbitofrontal cortex.ConclusionThis is the first study to highlight the difference in rCBF changes between patients having chronic dizziness with and without active vestibular imbalance. Decreased occipital lobe activity and increased medial and inferior temporal lobe activity may be related to keeping dizziness perception triggered regardless of the presence or absence of active vestibular imbalance, whereas increased frontal lobe activity may explain the dizziness background to persist after the disappearance of vestibular imbalance.

Framing the future first: Medial temporal lobe activation discriminates delay and acceleration framing in intertemporal choice.

People often discount future rewards, embracing smaller rewards that are delivered sooner rather than waiting for larger rewards delivered later. Previous behavioral research has demonstrated that people are more patient when options are presented as decisions to accelerate rather than delay consumption. This behavioral effect is well-established in the literature, but the underlying neural mechanisms have not been identified. We examined the neural correlates of delay and acceleration framing in intertemporal choice. We find greater activation in the hippocampus, amygdala, and anterior insula when options were framed as decisions to delay rather than accelerate consumption. These findings are consistent with theoretical accounts that posit that preferences are constructed. Specifically, the heightened activation observed in medial temporal regions may reflect more vivid representations of sooner outcomes in delay versus acceleration framing. These results provide insight into contextual effects in intertemporal choice specifically and preference construction more broadly.

Reduced Repetition Suppression in Aging is Driven by Tau-Related Hyperactivity in Medial Temporal Lobe.

Tau deposition begins in the medial temporal lobe (MTL) in aging and Alzheimer's disease (AD), and MTL neural dysfunction is commonly observed in these groups. However, the association between tau and MTL neural activity has not been fully characterized. We investigated the effects of tau on repetition suppression, the reduction of activity for repeated stimulus presentations compared to novel stimuli. We used task-based functional MRI (fMRI) to assess MTL subregional activity in 21 young adults (YA) and 45 cognitively normal human older adults (OA; total sample: 37 females, 29 males). AD pathology was measured with position emission tomography (PET), using 18F-Flortaucipir for tau and 11C-Pittsburgh compound B (PiB) for amyloid-β (Aβ). The MTL was segmented into six subregions using high-resolution structural images. We compared the effects of low tau pathology, restricted to entorhinal cortex and hippocampus (Tau- OA), to high tau pathology, also occurring in temporal and limbic regions (Tau+ OA). Low levels of tau (Tau- OA vs YA) were associated with reduced repetition suppression activity specifically in anterolateral entorhinal cortex (alEC) and hippocampus, the first regions to accumulate tau. High tau pathology (Tau+ vs Tau- OA) was associated with widespread reductions in repetition suppression across MTL. Further analyses indicated that reduced repetition suppression was driven by hyperactivity to repeated stimuli, rather than decreased activity to novel stimuli. Increased activation was associated with entorhinal tau, but not Aβ. These findings reveal a link between tau deposition and neural dysfunction in MTL, in which tau-related hyperactivity prevents deactivation to repeated stimuli, leading to reduced repetition suppression.SIGNIFICANCE STATEMENT Abnormal neural activity occurs in the medial temporal lobe (MTL) in aging and Alzheimer's disease (AD). Because tau pathology first deposits in the MTL in aging, this altered activity may be due to local tau pathology, and distinct MTL subregions may be differentially vulnerable. We demonstrate that in older adults (OAs) with low tau pathology, there are focal alterations in activity in MTL subregions that first develop tau pathology, while OAs with high tau pathology have aberrant activity throughout MTL. Tau was associated with hyperactivity to repeated stimulus presentations, leading to reduced repetition suppression, the discrimination between novel and repeated stimuli. Our data suggest that tau deposition is related to abnormal activity in MTL before the onset of cognitive decline.