Breaking (musical) boundaries by investigating brain dynamics of event segmentation during real-life music-listening.

The perception of musical phrase boundaries is a critical aspect of human musical experience: It allows us to organize, understand, derive pleasure from, and remember music. Identifying boundaries is a prerequisite for segmenting music into meaningful chunks, facilitating efficient processing and storage while providing an enjoyable, fulfilling listening experience through the anticipation of upcoming musical events. Expanding on Sridharan et al.'s [Neuron 55, 521-532 (2007)] work on coarse musical boundaries between symphonic movements, we examined finer-grained boundaries. We measured the fMRI responses of 18 musicians and 18 nonmusicians during music listening. Using general linear model, independent component analysis, and Granger causality, we observed heightened auditory integration in anticipation to musical boundaries, and an extensive decrease within the fronto-temporal-parietal network during and immediately following boundaries. Notably, responses were modulated by musicianship. Findings uncover the intricate interplay between musical structure, expertise, and cognitive processing, advancing our knowledge of how the brain makes sense of music.

Brain representations of affective valence and intensity in sustained pleasure and pain.

Pleasure and pain are two fundamental, intertwined aspects of human emotions. Pleasurable sensations can reduce subjective feelings of pain and vice versa, and we often perceive the termination of pain as pleasant and the absence of pleasure as unpleasant. This implies the existence of brain systems that integrate them into modality-general representations of affective experiences. Here, we examined representations of affective valence and intensity in an functional MRI (fMRI) study (n = 58) of sustained pleasure and pain. We found that the distinct subpopulations of voxels within the ventromedial and lateral prefrontal cortices, the orbitofrontal cortex, the anterior insula, and the amygdala were involved in decoding affective valence versus intensity. Affective valence and intensity predictive models showed significant decoding performance in an independent test dataset (n = 62). These models were differentially connected to distinct large-scale brain networks-the intensity model to the ventral attention network and the valence model to the limbic and default mode networks. Overall, this study identified the brain representations of affective valence and intensity across pleasure and pain, promoting a systems-level understanding of human affective experiences.

Targeted neurostimulation reverses a spatiotemporal biomarker of treatment-resistant depression.

Major depressive disorder (MDD) is widely hypothesized to result from disordered communication across brain-wide networks. Yet, prior resting-state-functional MRI (rs-fMRI) studies of MDD have studied zero-lag temporal synchrony (functional connectivity) in brain activity absent directional information. We utilize the recent discovery of stereotyped brain-wide directed signaling patterns in humans to investigate the relationship between directed rs-fMRI activity, MDD, and treatment response to FDA-approved neurostimulation paradigm termed Stanford neuromodulation therapy (SNT). We find that SNT over the left dorsolateral prefrontal cortex (DLPFC) induces directed signaling shifts in the left DLPFC and bilateral anterior cingulate cortex (ACC). Directional signaling shifts in the ACC, but not the DLPFC, predict improvement in depression symptoms, and moreover, pretreatment ACC signaling predicts both depression severity and the likelihood of SNT treatment response. Taken together, our findings suggest that ACC-based directed signaling patterns in rs-fMRI are a potential biomarker of MDD.

Evaluating the impact of short educational videos on the cortical networks for mathematics.

Many teaching websites, such as the Khan Academy, propose vivid videos illustrating a mathematical concept. Using functional magnetic resonance imaging, we asked whether watching such a video suffices to rapidly change the brain networks for mathematical knowledge. We capitalized on the finding that, when judging the truth of short spoken statements, distinct semantic regions activate depending on whether the statements bear on mathematical knowledge or on other domains of semantic knowledge. Here, participants answered such questions before and after watching a lively 5-min video, which taught them the rudiments of a new domain. During the video, a distinct math-responsive network, comprising anterior intraparietal and inferior temporal nodes, showed intersubject synchrony when viewing mathematics course rather than control courses in biology or law. However, this experience led to minimal subsequent changes in the activity of those domain-specific areas when answering questions on the same topics a few minutes later. All taught facts, whether mathematical or not, led to domain-general repetition enhancement, particularly prominent in the cuneus, posterior cingulate, and posterior parietal cortices. We conclude that short videos do not suffice to induce a meaningful lasting change in the brain's math-responsive network, but merely engage domain-general regions possibly involved in episodic short-term memory.

Hemodynamic transient and functional connectivity follow structural connectivity and cell type over the brain hierarchy.

The neural circuit of the brain is organized as a hierarchy of functional units with wide-ranging connections that support information flow and functional connectivity. Studies using MRI indicate a moderate coupling between structural and functional connectivity at the system level. However, how do connections of different directions (feedforward and feedback) and regions with different excitatory and inhibitory (E/I) neurons shape the hemodynamic activity and functional connectivity over the hierarchy are unknown. Here, we used functional MRI to detect optogenetic-evoked and resting-state activities over a somatosensory pathway in the mouse brain in relation to axonal projection and E/I distribution. Using a highly sensitive ultrafast imaging, we identified extensive activation in regions up to the third order of axonal projections following optogenetic excitation of the ventral posteriomedial nucleus of the thalamus. The evoked response and functional connectivity correlated with feedforward projections more than feedback projections and weakened with the hierarchy. The hemodynamic response exhibited regional and hierarchical differences, with slower and more variable responses in high-order areas and bipolar response predominantly in the contralateral cortex. Electrophysiological recordings suggest that these reflect differences in neural activity rather than neurovascular coupling. Importantly, the positive and negative parts of the hemodynamic response correlated with E/I neuronal densities, respectively. Furthermore, resting-state functional connectivity was more associated with E/I distribution, whereas stimulus-evoked effective connectivity followed structural wiring. These findings indicate that the structure-function relationship is projection-, cell-type- and hierarchy-dependent. Hemodynamic transients could reflect E/I activity and the increased complexity of hierarchical processing.

Chinese Verbal Fluency Deficiency in Temporal Lobe Epilepsy with and without Hippocampal Sclerosis: A Multiscale Study.

To test a Chinese character version of the phonemic verbal fluency task in patients with temporal lobe epilepsy (TLE) and assess the verbal fluency deficiency pattern in TLE with and without hippocampal sclerosis, a cross-sectional study was conducted including 30 patients with TLE and hippocampal sclerosis (TLE-HS), 28 patients with TLE and without hippocampal sclerosis (TLE-NHS), and 29 demographically matched healthy controls (HC). Both sexes were enrolled. Participants finished a Chinese character verbal fluency (VFC) task during functional MRI. The activation/deactivation maps, functional connectivity, degree centrality, and community features of the left frontal and temporal regions were compared. A neural network classification model was applied to differentiate TLE-HS and TLE-NHS using functional statistics. The VFC scores were correlated with semantic fluency in HC while correlated with phonemic fluency in TLE-NHS. Activation and deactivation deficiency was observed in TLE-HS and TLE-NHS (p < 0.001, k ≥ 10). Functional connectivity, degree centrality, and community features of anterior inferior temporal gyri were impaired in TLE-HS and retained or even enhanced in TLE-NHS (p < 0.05, FDR-corrected). The functional connectivity was correlated with phonemic fluency (p < 0.05, FDR-corrected). The neural network classification reached an area under the curve of 0.90 in diagnosing hippocampal sclerosis. The VFC task is a Chinese phonemic verbal fluency task suitable for clinical application in TLE. During the VFC task, functional connectivity of phonemic circuits was impaired in TLE-HS and was enhanced in TLE-NHS, representing a compensative phonemic searching strategy applied by patients with TLE-NHS.

Subtitled speech: the neural mechanisms of ticker-tape synaesthesia.

The acquisition of reading modifies areas of the brain associated with vision and with language, in addition to their connections. These changes enable reciprocal translation between orthography and the sounds and meaning of words. Individual variability in the pre-existing cerebral substrate contributes to the range of eventual reading abilities, extending to atypical developmental patterns, including dyslexia and reading-related synaesthesias. The present study is devoted to the little-studied but highly informative ticker-tape synaesthesia, in which speech perception triggers the vivid and irrepressible perception of words in their written form in the mind's eye. We scanned a group of 17 synaesthetes and 17 matched controls with functional MRI, while they listened to spoken sentences, words, numbers or pseudowords (Experiment 1), viewed images and written words (Experiment 2) or were at rest (Experiment 3). First, we found direct correlates of the ticker-tape synaesthesia phenomenon: during speech perception, as ticker-tape synaesthesia was active, synaesthetes showed over-activation of left perisylvian regions supporting phonology and of the occipitotemporal visual word form area, where orthography is represented. Second, we provided support to the hypothesis that ticker-tape synaesthesia results from atypical relationships between spoken and written language processing: the ticker-tape synaesthesia-related regions overlap closely with cortices activated during reading, and the overlap of speech-related and reading-related areas is larger in synaesthetes than in controls. Furthermore, the regions over-activated in ticker-tape synaesthesia overlap with regions under-activated in dyslexia. Third, during the resting state (i.e. in the absence of current ticker-tape synaesthesia), synaesthetes showed increased functional connectivity between left prefrontal and bilateral occipital regions. This pattern might reflect a lowered threshold for conscious access to visual mental contents and might imply a non-specific predisposition to all synaesthesias with a visual content. These data provide a rich and coherent account of ticker-tape synaesthesia as a non-detrimental developmental condition created by the interaction of reading acquisition with an atypical cerebral substrate.

Adaptive coding of reward in schizophrenia, its change over time and relationship to apathy.

Adaptive coding of reward is the process by which neurons adapt their response to the context of available compensations. Higher rewards lead to a stronger brain response, but the increase of the response depends on the range of available rewards. A steeper increase is observed in a narrow range and a more gradual slope in a wider range. In schizophrenia, adaptive coding appears to be affected in different domains, especially in the reward domain. Here, we tested adaptive coding of reward in a large group of patients with schizophrenia (n = 86) and control subjects (n = 66). We assessed: (i) the association between adaptive coding deficits and symptoms; (ii) the longitudinal stability of deficits (the same task was performed 3 months apart); and (iii) the stability of results between two experimental sites. We used functional MRI and the monetary incentive delay task to assess adaptation of participants to two different reward ranges: a narrow range and a wide range. We used a region-of-interest analysis to evaluate adaptation within striatal and visual regions. Patients and control subjects underwent a full demographic and clinical assessment. We found reduced adaptive coding in patients, with a decreased slope in the narrow reward range with respect to that of control participants, in striatal but not visual regions. This pattern was observed at both research sites. Upon retesting, patients increased their narrow-range slopes, showing improved adaptive coding, whereas control subjects slightly reduced them. At retesting, patients with overly steep slopes in the narrow range also showed higher levels of negative symptoms. Our data confirm deficits in reward adaptation in schizophrenia and reveal an effect of practice in patients, leading to improvement, with steeper slopes upon retesting. However, in some patients, an excessively steep slope may result in poor discriminability of larger rewards, owing to early saturation of the brain response. Together, the loss of precision of reward representation in new (first exposure, underadaptation) and more familiar (retest, overadaptation) situations might contribute to the multiple motivational symptoms in schizophrenia.

Impaired value-based decision-making in Parkinson's disease apathy.

Apathy is a common and disabling complication of Parkinson's disease characterized by reduced goal-directed behaviour. Several studies have reported dysfunction within prefrontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision-making. Specifically, these neuromodulators have overlapping contributions to encoding the value of decisions, and influence whether to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesized that apathy in Parkinson's disease should be associated with an impairment in value-based learning. Using a four-armed restless bandit reinforcement learning task, we studied decision-making in 75 volunteers; 53 patients with Parkinson's disease, with and without clinical apathy, and 22 age-matched healthy control subjects. Patients with apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patient's apathy severity measured using the Lille Apathy Rating Scale (R = -0.46, P < 0.001). Computational modelling of the patient's choices confirmed the apathy group made decisions that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration, which also correlated with apathy scores (R = -0.5, P < 0.001). We went on to acquire functional MRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age-matched controls performing the Restless Bandit Task. Analysis of the functional MRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinson's disease, which was more marked in apathy, but not predictive of their individual apathy severity. Using a model-based categorization of choice type, decisions to explore lower value bandits in the apathy group activated prefrontal cortex to a similar degree to the age-matched controls. In contrast, Parkinson's patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched control subjects, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinson's disease.

The neural representation of body part concepts.

Neuropsychological and neuroimaging studies provide evidence for a degree of category-related organization of conceptual knowledge in the brain. Some of this evidence indicates that body part concepts are distinctly represented from other categories; yet, the neural correlates and mechanisms underlying these dissociations are unclear. We expand on the limited prior data by measuring functional magnetic resonance imaging responses induced by body part words and performing a series of analyses investigating the cortical representation of this semantic category. Across voxel-level contrasts, pattern classification, representational similarity analysis, and vertex-wise encoding analyses, we find converging evidence that the posterior middle temporal gyrus, the supramarginal gyrus, and the ventral premotor cortex in the left hemisphere play important roles in the preferential representation of this category compared to other concrete objects.

Cognitive stimulation as a mechanism linking socioeconomic status and neural function supporting working memory: a longitudinal fMRI study.

Childhood experiences of low socioeconomic status are associated with alterations in neural function in the frontoparietal network and ventral visual stream, which may drive differences in working memory. However, the specific features of low socioeconomic status environments that contribute to these disparities remain poorly understood. Here, we examined experiences of cognitive deprivation (i.e. decreased variety and complexity of experience), as opposed to experiences of threat (i.e. violence exposure), as a potential mechanism through which family income contributes to alterations in neural activation during working memory. As part of a longitudinal study, 148 youth between aged 10 and 13 years completed a visuospatial working memory fMRI task. Early childhood low income, chronicity of low income in early childhood, and current income-to-needs were associated with task-related activation in the ventral visual stream and frontoparietal network. The association of family income with decreased activation in the lateral occipital cortex and intraparietal sulcus during working memory was mediated by experiences of cognitive deprivation. Surprisingly, however, family income and deprivation were not significantly related to working memory performance, and only deprivation was associated with academic achievement in this sample. Taken together, these findings suggest that early life low income and associated cognitive deprivation are important factors in neural function supporting working memory.

White matter microstructure and functional connectivity in the brains of infants with Turner syndrome.

Turner syndrome, caused by complete or partial loss of an X-chromosome, is often accompanied by specific cognitive challenges. Magnetic resonance imaging studies of adults and children with Turner syndrome suggest these deficits reflect differences in anatomical and functional connectivity. However, no imaging studies have explored connectivity in infants with Turner syndrome. Consequently, it is unclear when in development connectivity differences emerge. To address this gap, we compared functional connectivity and white matter microstructure of 1-year-old infants with Turner syndrome to typically developing 1-year-old boys and girls. We examined functional connectivity between the right precentral gyrus and five regions that show reduced volume in 1-year old infants with Turner syndrome compared to controls and found no differences. However, exploratory analyses suggested infants with Turner syndrome have altered connectivity between right supramarginal gyrus and left insula and right putamen. To assess anatomical connectivity, we examined diffusivity indices along the superior longitudinal fasciculus and found no differences. However, an exploratory analysis of 46 additional white matter tracts revealed significant group differences in nine tracts. Results suggest that the first year of life is a window in which interventions might prevent connectivity differences observed at later ages, and by extension, some of the cognitive challenges associated with Turner syndrome.

Leveraging the adolescent brain cognitive development study to improve behavioral prediction from neuroimaging in smaller replication samples.

Neuroimaging is a popular method to map brain structural and functional patterns to complex human traits. Recently published observations cast doubt upon these prospects, particularly for prediction of cognitive traits from structural and resting state functional magnetic resonance imaging (MRI). We leverage baseline data from thousands of children in the Adolescent Brain Cognitive DevelopmentSM Study to inform the replication sample size required with univariate and multivariate methods across different imaging modalities to detect reproducible brain-behavior associations. We demonstrate that by applying multivariate methods to high-dimensional brain imaging data, we can capture lower dimensional patterns of structural and functional brain architecture that correlate robustly with cognitive phenotypes and are reproducible with only 41 individuals in the replication sample for working memory-related functional MRI, and ~ 100 subjects for structural and resting state MRI. Even with 100 random re-samplings of 100 subjects in discovery, prediction can be adequately powered with 66 subjects in replication for multivariate prediction of cognition with working memory task functional MRI. These results point to an important role for neuroimaging in translational neurodevelopmental research and showcase how findings in large samples can inform reproducible brain-behavior associations in small sample sizes that are at the heart of many research programs and grants.

What makes an event significant: an fMRI study on self-defining memories.

Self-defining memories are highly significant personal memories that contribute to an individual's life story and identity. Previous research has identified 4 key subcomponents of self-defining memories: content, affect, specificity, and self-reflection. However, these components were not tested under functional neuroimaging. In this study, we first explored how self-defining memories distinguish themselves from everyday memories (non-self-defining) through their associated brain activity. Next, we evaluated the different self-defining memory subcomponents through their activity in the underlying brain system. Participants recalled both self-defining and non-self-defining memories under functional MRI and evaluated the 4 subcomponents for each memory. Multivoxel pattern analysis uncovered a brain system closely related to the default mode network to discriminate between self-defining and non-self-defining memories. Representational similarity analysis revealed the neural coding of each subcomponent. Self-reflection was coded mainly in the precuneus, middle and inferior frontal gyri, and cingulate, lateral occipital, and insular cortices. To a much lesser extent, content coding was primarily in the left angular gyrus and fusiform gyrus. No region was found to represent information on affect and specificity. Our findings highlight the marked difference in brain processing between significant and non-significant memories, and underscore self-reflection as a predominant factor in the formation and maintenance of self-defining memories, inviting a reassessment of what constitutes significant memories.

Linguistic modulation of the neural encoding of phonemes.

Speech comprehension entails the neural mapping of the acoustic speech signal onto learned linguistic units. This acousto-linguistic transformation is bi-directional, whereby higher-level linguistic processes (e.g. semantics) modulate the acoustic analysis of individual linguistic units. Here, we investigated the cortical topography and linguistic modulation of the most fundamental linguistic unit, the phoneme. We presented natural speech and "phoneme quilts" (pseudo-randomly shuffled phonemes) in either a familiar (English) or unfamiliar (Korean) language to native English speakers while recording functional magnetic resonance imaging. This allowed us to dissociate the contribution of acoustic vs. linguistic processes toward phoneme analysis. We show that (i) the acoustic analysis of phonemes is modulated by linguistic analysis and (ii) that for this modulation, both of acoustic and phonetic information need to be incorporated. These results suggest that the linguistic modulation of cortical sensitivity to phoneme classes minimizes prediction error during natural speech perception, thereby aiding speech comprehension in challenging listening situations.

Resting state functional connectome in breast cancer patients with fear of cancer recurrence.

This study aimed to investigate network-level brain functional changes in breast cancer patients and their relationship with fear of cancer recurrence (FCR). Resting-state functional MRI was collected from 43 patients with breast cancer and 40 healthy controls (HCs). Graph theory analyses, whole-brain voxel-wise functional connectivity strength (FCS) analyses and seed-based functional connectivity (FC) analyses were performed to identify connection alterations in breast cancer patients. Correlations between brain functional connections (i.e. FCS and FC) and FCR level were assessed to further reveal the neural mechanisms of FCR in breast cancer patients. Graph theory analyses indicated a decreased clustering coefficient in breast cancer patients compared to HCs (P = 0.04). Patients with breast cancer exhibited significantly higher FCS in both higher-order function networks (frontoparietal, default mode, and dorsal attention systems) and primary somatomotor networks. Among the hyperconnected regions in breast cancer, the left inferior frontal operculum demonstrated a significant positive correlation with FCR. Our findings suggest that breast cancer patients exhibit less segregation of brain function, and the left inferior frontal operculum is a key region associated with FCR. This study offers insights into the neural mechanisms of FCR in breast cancer patients at the level of brain connectome.

Low blood concentration of alcohol enhances activity related to stopping failure in the right inferior frontal cortex.

This study investigated the effects of low doses of alcohol, which are acceptable for driving a car, on inhibitory control and neural processing using the stop-signal task (SST) in 17 healthy right-handed social drinkers. The study employed simultaneous functional magnetic resonance imaging and electromyography (EMG) recordings to assess behavioral and neural responses under conditions of low-dose alcohol (breath-alcohol concentration of 0.15 mg/L) and placebo. The results demonstrated that even a small amount of alcohol consumption prolonged Go reaction times in the SST and modified stopping behavior, as evidenced by a decrease in the frequency and magnitude of partial response EMG that did not result in button pressing during successful inhibitory control. Furthermore, alcohol intake enhanced neural activity during failed inhibitory responses in the right inferior frontal cortex, suggesting its potential role in behavioral adaptation following stop-signal failure. These findings suggest that even low levels of alcohol consumption within legal driving limits can greatly impact both the cognitive performance and brain activity involved in inhibiting responses. This research provides important evidence on the neurobehavioral effects of low-dose alcohol consumption, with implications for understanding the biological basis of impaired motor control and decision-making and potentially informing legal guidelines on alcohol consumption.

Functional and structural abnormalities of the speech disorders: a multimodal activation likelihood estimation meta-analysis.

Speech disorders are associated with different degrees of functional and structural abnormalities. However, the abnormalities associated with specific disorders, and the common abnormalities shown by all disorders, remain unclear. Herein, a meta-analysis was conducted to integrate the results of 70 studies that compared 1843 speech disorder patients (dysarthria, dysphonia, stuttering, and aphasia) to 1950 healthy controls in terms of brain activity, functional connectivity, gray matter, and white matter fractional anisotropy. The analysis revealed that compared to controls, the dysarthria group showed higher activity in the left superior temporal gyrus and lower activity in the left postcentral gyrus. The dysphonia group had higher activity in the right precentral and postcentral gyrus. The stuttering group had higher activity in the right inferior frontal gyrus and lower activity in the left inferior frontal gyrus. The aphasia group showed lower activity in the bilateral anterior cingulate gyrus and left superior frontal gyrus. Across the four disorders, there were concurrent lower activity, gray matter, and fractional anisotropy in motor and auditory cortices, and stronger connectivity between the default mode network and frontoparietal network. These findings enhance our understanding of the neural basis of speech disorders, potentially aiding clinical diagnosis and intervention.

Combining CRISPR-Cas9 and brain imaging to study the link from genes to molecules to networks.

Receptors, transporters, and ion channels are important targets for therapy development in neurological diseases, but their mechanistic role in pathogenesis is often poorly understood. Gene editing and in vivo imaging approaches will help to identify the molecular and functional role of these targets and the consequence of their regional dysfunction on the whole-brain level. We combine CRISPR-Cas9 gene editing with in vivo positron emission tomography (PET) and functional MRI (fMRI) to investigate the direct link between genes, molecules, and the brain connectome. The extensive knowledge of the Slc18a2 gene encoding the vesicular monoamine transporter (VMAT2), involved in the storage and release of dopamine, makes it an excellent target for studying the gene network relationships while structurally preserving neuronal integrity and function. We edited the Slc18a2 in the substantia nigra pars compacta of adult rats and used in vivo molecular imaging besides behavioral, histological, and biochemical assessments to characterize the CRISPR-Cas9-mediated VMAT2 knockdown. Simultaneous PET/fMRI was performed to investigate molecular and functional brain alterations. We found that stage-specific adaptations of brain functional connectivity follow the selective impairment of presynaptic dopamine storage and release. Our study reveals that recruiting different brain networks is an early response to the dopaminergic dysfunction preceding neuronal cell loss. Our combinatorial approach is a tool to investigate the impact of specific genes on brain molecular and functional dynamics, which will help to develop tailored therapies for normalizing brain function.

Differential Laminar Activation Dissociates Encoding and Retrieval in the Human Medial and Lateral Entorhinal Cortex.

The hierarchically organized structures of the medial temporal lobe are critically important for episodic memory function. Accumulating evidence suggests dissociable information processing pathways are maintained throughout these structures including in the medial and lateral entorhinal cortex. Cortical layers provide an additional dimension of dissociation as the primary input to the hippocampus derives from layer 2 neurons in the entorhinal cortex, whereas the deeper layers primarily receive output from the hippocampus. Here, novel high-resolution T2-prepared functional MRI methods were successfully used to mitigate susceptibility artifacts typically affecting MRI signals in this region providing uniform sensitivity across the medial and lateral entorhinal cortex. During the performance of a memory task, healthy human subjects (age 25-33 years, mean age 28.2 ± 3.3 years, 4 female) showed differential functional activation in the superficial and deep layers of the entorhinal cortex associated with task-related encoding and retrieval conditions, respectively. The methods provided here offer an approach to probe layer-specific activation in normal cognition and conditions contributing to memory impairment.SIGNIFICANCE STATEMENT This study provides new evidence for differential neuronal activation in the superficial versus deep layers of the entorhinal cortex associated with encoding and retrieval memory processes, respectively, in cognitively normal adults. The study further shows that this dissociation can be observed in both the medial and the lateral entorhinal cortex. The study was achieved by using a novel functional MRI method allowing us to measure robust functional MRI signals in both the medial and lateral entorhinal cortex that was not possible in previous studies. The methodology established here in healthy human subjects lays a solid foundation for subsequent studies investigating layer-specific and region-specific changes in the entorhinal cortex associated with memory impairment in various conditions such as Alzheimer's disease.