Associations of prior concussion severity with brain microstructure using mean apparent propagator magnetic resonance imaging.

Magnetic resonance imaging (MRI) diffusion studies have shown chronic microstructural tissue abnormalities in athletes with history of concussion, but with inconsistent findings. Concussions with post-traumatic amnesia (PTA) and/or loss of consciousness (LOC) have been connected to greater physiological injury. The novel mean apparent propagator (MAP) MRI is expected to be more sensitive to such tissue injury than the conventional diffusion tensor imaging. This study examined effects of prior concussion severity on microstructure with MAP-MRI. Collegiate-aged athletes (N = 111, 38 females; ≥6 months since most recent concussion, if present) completed semistructured interviews to determine the presence of prior concussion and associated injury characteristics, including PTA and LOC. MAP-MRI metrics (mean non-Gaussian diffusion [NG Mean], return-to-origin probability [RTOP], and mean square displacement [MSD]) were calculated from multi-shell diffusion data, then evaluated for associations with concussion severity through group comparisons in a primary model (athletes with/without prior concussion) and two secondary models (athletes with/without prior concussion with PTA and/or LOC, and athletes with/without prior concussion with LOC only). Bayesian multilevel modeling estimated models in regions of interest (ROI) in white matter and subcortical gray matter, separately. In gray matter, the primary model showed decreased NG Mean and RTOP in the bilateral pallidum and decreased NG Mean in the left putamen with prior concussion. In white matter, lower NG Mean with prior concussion was present in all ROI across all models and was further decreased with LOC. However, only prior concussion with LOC was associated with decreased RTOP and increased MSD across ROI. Exploratory analyses conducted separately in male and female athletes indicate associations in the primary model may differ by sex. Results suggest microstructural measures in gray matter are associated with a general history of concussion, while a severity-dependent association of prior concussion may exist in white matter.

Split-slice training and hyperparameter tuning of RAKI networks for simultaneous multi-slice reconstruction.

PURPOSE: Simultaneous multi-slice acquisitions are essential for modern neuroimaging research, enabling high temporal resolution functional and high-resolution q-space sampling diffusion acquisitions. Recently, deep learning reconstruction techniques have been introduced for unaliasing these accelerated acquisitions, and robust artificial-neural-networks for k-space interpolation (RAKI) have shown promising capabilities. This study systematically examines the impacts of hyperparameter selections for RAKI networks, and introduces a novel technique for training data generation which is analogous to the split-slice formalism used in slice-GRAPPA. METHODS: RAKI networks were developed with variable hyperparameters and with and without split-slice training data generation. Each network was trained and applied to five different datasets including acquisitions harmonized with Human Connectome Project lifespan protocol. Unaliasing performance was assessed through L1 errors computed between unaliased and calibration frequency-space data. RESULTS: Split-slice training significantly improved network performance in nearly all hyperparameter configurations. Best unaliasing results were achieved with three layer RAKI networks using at least 64 convolutional filters with receptive fields of 7 voxels, 128 single-voxel filters in the penultimate RAKI layer, batch normalization, and no training dropout with the split-slice augmented training dataset. Networks trained without the split-slice technique showed symptoms of network over-fitting. CONCLUSIONS: Split-slice training for simultaneous multi-slice RAKI networks positively impacts network performance. Hyperparameter tuning of such reconstruction networks can lead to further improvements in unaliasing performance.

Optimization of q-space sampling for mean apparent propagator MRI metrics using a genetic algorithm.

Mean Apparent Propagator (MAP) MRI is a recently introduced technique to estimate the diffusion probability density function (PDF) robustly. Using the estimated PDF, MAP MRI then calculates zero-displacement and non-Gaussianity metrics, which might better characterize tissue microstructure compared to diffusion tensor imaging or diffusion kurtosis imaging. However, intensive q-space sampling required for MAP MRI limits its widespread adoption. A reduced q-space sampling scheme that maintains the accuracy of the derived metrics would make it more practical. A heuristic approach for acquiring MAP MRI with fewer q-space samples has been introduced earlier with scan duration of less than 10 minutes. However, the sampling scheme was not optimized systematically to preserve the accuracy of the model metrics. In this work, a genetic algorithm is implemented to determine optimal q-space subsampling schemes for MAP MRI that will keep total scan time under 10 min. Results show that the metrics derived from the optimized schemes more closely match those computed from the full set, especially in dense fiber tracts such as the corpus callosum.

Filter-probe diffusion imaging improves spinal cord injury outcome prediction.

OBJECTIVE: Diffusion-weighted imaging (DWI) is a powerful tool for investigating spinal cord injury (SCI), but has limited specificity for axonal damage, which is the most predictive feature of long-term functional outcome. In this study, a technique designed to detect acute axonal injury, filter-probe double diffusion encoding (FP-DDE), is compared with standard DWI for predicting long-term functional and cellular outcomes. METHODS: This study extends FP-DDE to predict long-term functional and histological outcomes in a rat SCI model of varying severities (n = 58). Using a 9.4T magnetic resonance imaging (MRI) system, a whole-cord FP-DDE spectroscopic voxel was acquired in 3 minutes at the lesion site and compared to DWI at 48 hours postinjury. Relationships with chronic (30-day) locomotor and histological outcomes were evaluated with linear regression. RESULTS: The FP-DDE measure of parallel diffusivity (ADC|| ) was significantly related to chronic hind limb locomotor functional outcome (R2 = 0.63, p < 0.0001), and combining this measurement with acute functional scores demonstrated prognostic benefit versus functional testing alone (p = 0.0007). Acute ADC|| measurements were also more closely related to the number of injured axons measured 30 days after the injury than standard DWI. Furthermore, acute FP-DDE images showed a clear and easily interpretable pattern of injury that closely corresponded with chronic MRI and histology observations. INTERPRETATION: Collectively, these results demonstrate FP-DDE benefits from greater specificity for acute axonal damage in predicting functional and histological outcomes with rapid acquisition and fully automated analysis, improving over standard DWI. FP-DDE is a promising technique compatible with clinical settings, with potential research and clinical applications for evaluation of spinal cord pathology. Ann Neurol 2018;83:37-50.

Analysis of errors in diffusion kurtosis imaging caused by slice crosstalk in simultaneous multi-slice imaging.

Simultaneous multi-slice (SMS) imaging techniques accelerate diffusion MRI data acquisition. However, slice separation is imperfect and results in residual signal leakage between the simultaneously excited slices. The resulting consistent bias may adversely affect diffusion model parameter estimation. Although this bias is usually small and might not affect the simplified diffusion tensor model significantly, higher order diffusion models such as kurtosis are likely to be more susceptible to such effects. In this work, two SMS reconstruction techniques and an alternative acquisition approach were tested to quantify the effects of slice crosstalk on diffusion kurtosis parameters. In reconstruction, two popular slice separation algorithms, slice GRAPPA and split-slice GRAPPA, are evaluated to determine the effect of slice leakage on diffusion kurtosis metrics. For the alternative acquisition, the slice pairings were varied across diffusion weighted images such that the signal leakage does not come from the same overlapped slice for all diffusion encodings. Simulation results demonstrated the potential benefits of randomizing the slice pairings. However, various experimental factors confounded the advantages of slice pair randomization. In volunteer experiments, region-of-interest analyses found high metric errors with each of the SMS acquisitions and reconstructions in the brain white matter.

Chronic differences in white matter integrity following sport-related concussion as measured by diffusion MRI: 6-Month follow-up.

Recent studies demonstrated evidence of physiological changes in the brain following sport-related concussion (SRC) that persisted beyond the point at which athletes achieved full symptom recovery. Diffusion MRI techniques have been used to study brain white matter (WM) changes following SRC; however, longitudinal studies that follow injured athletes from the acute to chronic stages of injury are sparse. The current study explores potential persisting effects of the injury, which serves as a follow-up to our previous work that reported WM changes in the acute and subacute phase of SRC recovery. Concussed high school and collegiate football players (n = 17) and well-matched teammate controls (n = 20) were followed up at 6 months postinjury with diffusion tensor (DTI) and diffusion kurtosis imaging (DKI) as well as measures of self-reported symptoms, cognitive functioning, and balance. Results of tract-based spatial statistics (TBSS) analyses revealed continued widespread decreased mean and axial diffusivity compared to control subjects in 6-month follow-up scans. On the other hand, kurtosis metrics, which were significantly higher in concussed athletes in the acute phase, had normalized. WM tract regions-of-interest (ROIs) were created from significant clusters in the TBSS analysis, and linear mixed effects (LME) analyses were used to look at longitudinal changes in these ROIs over time. LME analyses revealed few time × group interactions indicating findings were relatively stable over time. In addition, acute concussion symptoms predicted diffusivity measures at 6 months postinjury. Findings indicate that DTI and DKI may be useful tools in assessing concussion severity, recovery, and possible long-term effects of concussion.

Disentangling the effects of novelty, valence and trait anxiety in the bed nucleus of the stria terminalis, amygdala and hippocampus with high resolution 7T fMRI.

The hippocampus and amygdala exhibit sensitivity to stimulus novelty that is reduced in participants with inhibited temperament, which is related to trait anxiety. Although the bed nucleus of the stria terminalis (BNST) is highly connected to the amygdala and is implicated in anxiety, whether the BNST responds to novelty remains unstudied, as well as how trait anxiety may modulate this response. Additionally how novelty, stimulus negativity and trait anxiety interact to affect activity in these areas is also unclear. To address these questions, we presented participants with novel and repeated, fearful and neutral faces, while measuring brain activity via fMRI, and also assessed participants' self-reported trait anxiety. As the small size of the BNST makes assessing its activity at typical fMRI resolution difficult, we employed high resolution 7 Tesla scanning. Our results replicate findings of novelty sensitivity that is independent of valence in the hippocampus. Our results also provide novel evidence for a BNST novelty response toward neutral, but not fearful faces. We also found that the novelty response in the hippocampus and BNST was blunted in participants with high trait anxiety. Additionally, we found left amygdala sensitivity to stimulus negativity that was blunted for high trait anxiety participants. These findings extend past research on the response to novel stimuli in the hippocampus and amygdala at high resolution, and are the first to demonstrate trait anxiety modulated novelty sensitivity in the BNST that is dependent on stimulus valence.

Acute white matter changes following sport-related concussion: A serial diffusion tensor and diffusion kurtosis tensor imaging study.

Recent neuroimaging studies have suggested that following sport-related concussion (SRC) physiological brain alterations may persist after an athlete has shown full symptom recovery. Diffusion MRI is a versatile technique to study white matter injury following SRC, yet serial follow-up studies in the very acute stages following SRC utilizing a comprehensive set of diffusion metrics are lacking. The aim of the current study was to characterize white matter changes within 24 hours of concussion in a group of high school and collegiate athletes, using Diffusion Tensor and Diffusion Kurtosis Tensor metrics. Participants were reassessed a week later. At 24 hours post-injury, the concussed group reported significantly more concussion symptoms than a well-matched control group and demonstrated poorer performance on a cognitive screening measure, yet these differences were nonsignificant at the 8-day follow-up. Similarly, within 24-hours after injury, the concussed group exhibited a widespread decrease in mean diffusivity, increased axial kurtosis and, to a lesser extent, decreased axial and radial diffusivities compared with control subjects. At 8 days post injury, the differences in these diffusion metrics were even more widespread in the injured athletes, despite improvement of symptoms and cognitive performance. These MRI findings suggest that the athletes might not have reached full physiological recovery a week after the injury. These findings have significant implications for the management of SRC because allowing an athlete to return to play before the brain has fully recovered from injury may have negative consequences. Hum Brain Mapp 37:3821-3834, 2016. © 2016 Wiley Periodicals, Inc.

In vivo quantification of lumbar disc degeneration: assessment of ADC value using a degenerative scoring system based on Pfirrmann framework.

PURPOSE: To evaluate the role of apparent diffusion coefficient (ADC) as a quantitative means to assess the degree of intervertebral disc (IVD) degeneration contextually within the framework of a widely used Pfirrmann classification rather than in a direct correlation with Pfirrmann grades. METHODS: DWI and T2-weighted (T2w) of lumbar spine were acquired from nine healthy volunteers (age range 27-62 years, mean age 45 years) with a 3T MR scanner. ADC values were obtained from each of the five lumbar discs via a pixel-by-pixel ADC calculation as well as via region of interest-averaged image intensities. Disc degeneration was assessed by a scoring system via sequential application of Pfirrmann scale and use of intensity ratio of IVD/cerebrospinal fluid in T2w for discs in each Pfirrmann grade to be further separated. RESULTS: A significant correlation was observed between degenerative scores and ADC independent of how ADC was obtained (Spearman's ρ < -0.85, P < 2 × 10(-14)). CONCLUSIONS: This study demonstrates that previously perceived as an overlap in ADC value existing between different degenerative categories based on a visual inspection can be viewed as a quantitative role of ADC in assessment of disc degeneration. This reinforces the Pfirrmann classification system but also proceeds beyond mere qualitatively determining morphologic states.

Association between intervertebral disc degeneration and endplate perfusion studied by DCE-MRI.

PURPOSE: The goal of this study was to study the association between solute transport mechanisms in cartilaginous disc endplates and the degeneration of intervertebral discs. Intervertebral disc degeneration is a multi-factorial process. It is suspected that poor nutrient delivery to discs might be a factor leading to degeneration. Several studies suggest that defects in disc endplates could lead to poor transport of nutrients. An imaging technique assessing endplate perfusion could be a valuable tool in investigating disc degeneration. There is currently no universally accepted technique assessing endplate perfusion in vivo. METHODS: Nine adult patients exhibiting varying levels of intervertebral disc degeneration were included. MRI was used to study the association between blood perfusion in 90 lumbar disc endplates and disc degeneration in 45 lumbar discs. Solute transport mechanism through endplates was assessed indirectly by dynamic contrast enhanced (DCE) MRI. T2-weighted MRI was used for conventional Pfirrmann classification. RESULTS: A positive association was observed between Pfirrmann grades and endplate DCE-MRI enhancement. A differential enhancement between cranial and caudal endplates was also observed, which increased with Pfirrmann grades. This differential enhancement was also dependent on the lumbar level. CONCLUSIONS: Increased MRI signal enhancement in the cartilaginous endplates of degenerated discs might indicate damage to the subchondral bone of the vertebral bodies. The endplate enhancement characteristic could aid in understanding the pathophysiology of disc degeneration and planning treatment more effectively.

Intervertebral disc height loss demonstrates the threshold of major pathological changes during degeneration.

PURPOSE: Quantitative MRI techniques were utilized to study intervertebral disc degeneration. Main focus was to develop a novel approach to quantify disc height loss associated with disc degeneration. Currently there is no universally accepted metric of degeneration based on measurement of disc height. Such quantitative imaging methods would complement qualitative visual assessment methods currently used and offer a valuable diagnostic tool. METHODS: 51 adult participants took part in this MRI study. T2 weighted images were used to obtain disc height index (DHI) and also a semi-quantitative metric based on relative voxel intensities. For DHI, each disc was given a score based on standard deviations from the mean DHI of healthy discs. Diffusion Weighted MRI was used to assess morphological changes in the nucleus pulposus. Conventional Pfirrmann classification was used as the gold standard to assess these quantitative approaches. RESULTS: At deviations of up to 1.5σ below normative disc height, levels of apparent diffusion coefficient (ADC) and normalized T2 intensity were maintained. Once disc compression reached 1.5σ, there was a massive drop in ADC and normalized T2 intensity. Pfirrmann degeneration scores also increased after the 1.5σ mark. CONCLUSIONS: This study provides new, unbiased quantitative imaging tools to assess disc degeneration. We observed that these quantitative MRI measures indicate a threshold beyond which major pathological changes take place concurrently. Combined information from DHI, ADC and T2 images construct a set of novel biomarkers that could be used to identify degenerating discs that are approaching the threshold and possibly intervene before major pathologic changes occur.

Changes in perfusion and diffusion in the endplate regions of degenerating intervertebral discs: a DCE-MRI study.

PURPOSE: Dynamic contrast-enhanced MRI (DCE-MRI) was used to investigate the associations between intervertebral disc degeneration and changes in perfusion and diffusion in the disc endplates. METHODS: 56 participants underwent MRI scans. Changes in DCE-MRI signal enhancement in the endplate regions were analyzed. Also, a group template was generated for the endplates and enhancement maps were registered to this template for group analysis. RESULTS: DCE-MRI enhancement changed significantly in cranial endplates with increased degeneration. A similar trend was observed for caudal endplates, but it was not significant. Group-averaged enhancement maps revealed major changes in spatial distribution of endplate perfusion and diffusion with increasing disc degeneration especially in peripheral endplate regions. CONCLUSIONS: Increased enhancement in the endplate regions of degenerating discs might be an indication of ongoing damage in these tissues. Therefore, DCE-MRI could aid in understanding the pathophysiology of disc degeneration. Moreover, it could be used in the planning of novel treatments such as stem cell therapy.

Shape of the basal ganglia in preadolescent children is associated with cognitive performance.

Current studies support the belief that high levels of performance and intellectual abilities are associated with increased brain size or volume. With few exceptions, this conclusion is restricted to studies of post-adolescent subjects and to cerebral cortex. There is evidence that "bigger is better" may not pertain to children and further, that there are areas of the brain in which larger structures are associated with cognitive deficits. In 50 preadolescent children (21 girls) a structural survey of the brain (VBM) was conducted to determine and locate areas in which gray matter volume was associated with poor cognitive performance. Only increased gray matter volume in particular areas of the basal ganglia and specifically the putamen was significantly associated with poor performance on tests of memory, response speed and a general marker and subtests of intelligence. Based on the VBM findings, volumetric analysis of basal ganglia structures was performed using FSL/FIRST. However, no significant changes in total volume of putamen or other basal ganglia structures were detected with this analysis. The disagreement between measures of localized gray matter differences and volumetric analysis suggested that there might be local regional deformity rather than widespread volumetric changes of the putamen. Surface analysis with FSL/FIRST demonstrated that bilateral outward deformation of the putamen, but especially the left, was associated with poor performance on several cognitive tests. Expansion of the globus pallidus and caudate nucleus also was associated with poor performance. Moreover a significant association was detected between a reliable test of language-free intelligence and topographically distinct outward and inward deformation of the putamen. Expansion and contraction of the putamen as a predictor of intelligence may explain why this association was not observed with measures of total volume. These results suggest that deformity is a sensitive measure of function, and that distortion of the basal ganglia may be a neurophenotype for risk of developmental impairment.

Quantitative analysis of the efficacy of gradient table correction on improving the accuracy of fiber tractography.

PURPOSE: Several groups suggested that the gradient table of a DTI data set should be reoriented to compensate for head motion. Although the effects of this correction were demonstrated qualitatively, its efficacy was not demonstrated quantitatively to date. The main goal of this study was to investigate the efficacy of gradient table correction on improving the accuracy of fiber tractography. METHODS: First, the effects of gradient table correction on the estimation of fractional anisotropy (FA) maps and the primary diffusion direction were quantified and compared with the inherent uncertainty in the estimation process. Then, the effects of gradient table correction on tractography were quantified. RESULTS: The corrections in FA values were only a fraction of the typical values seen in major fasciculi and inter-subject variance. The corrections to the primary diffusion direction were also much smaller than the uncertainty inherent in the estimation of its direction. However, the directional estimates were biased due to head motion and deviated fiber tracking. CONCLUSIONS: Corrections to FA values were negligible and are not expected to affect group comparisons. However, a small but consistent bias was introduced to the estimates of primary diffusion direction, which might affect brain connectivity analyses based on fiber tracking.

Ultrahigh-resolution microstructural diffusion tensor imaging reveals perforant path degradation in aged humans in vivo.

The perforant path (PP) undergoes synaptic changes in the course of aging and dementia. Previous studies attempting to assess the integrity of the PP in humans using diffusion tensor imaging (DTI) were limited by low resolution and the inability to identify PP fibers specifically. Here we present an application of DTI at ultrahigh submillimeter resolution that has allowed us to successfully identify diffusion signals unique to the PP and compare the intensity of these signals in a sample of young adults and older adults. We report direct evidence of age-related PP degradation in humans in vivo. We find no evidence of such loss in a control pathway, the alveus, suggesting that these findings are not evidence for a global decline. We also find no evidence for specific entorhinal gray matter atrophy. The extent of PP degradation correlated with performance on a word-list learning task sensitive to hippocampal deficits. We also show evidence for gray matter diffusion signals consistent with pyramidal dendrite orientation in the hippocampus and cerebral cortex. Ultrahigh-resolution microstructural DTI is a unique biomarker that can be used in combination with traditional structural and functional neuroimaging methods to enhance detection of Alzheimer disease in its earliest stages, test the effectiveness of new therapies, and monitor disease progression.

Characterization of diffusion MRI using the mean apparent propagator model in hemodialysis patients: A pilot study.

To better understand documented cognitive decline in hemodialysis (HD) patients, diffusion MRI (dMRI) has been used to characterize brain anatomical deficits relative to controls. Studies to this point have primarily used diffusion tensor imaging (DTI) to model the three-dimensional diffusion of water in HD patients, with DTI parameters reflecting underlying microstructural changes of brain tissue. Since DTI has some limitations in characterizing tissue microstructure, some of which may be complicated by HD, we explored the use of the mean apparent propagator (MAP) model to describe diffusion in HD patients. We collected anatomical T1 and T2 FLAIR MRIs as well as multi-shell dMRI in ten HD participants and ten age-matched controls. The T1 and T2 FLAIR MRIs were used for tissue segmentation and identification of white matter hyperintensity, respectively. Multi-shell dMRI data were used to estimate MAP and DTI diffusion models. Each model was then used to characterize the differences between the HD cohort and the age-matched controls in normal appearing white matter, subcortical gray matter, corpus callosum (CC) and bilateral radiata (Rad). As expected, parameters of both DTI and MAP models of dMRI were significantly different in HD participants compared to controls. However, some MAP parameters suggested additional tissue microstructural changes in HD participants, such as increased axonal diameter. Measurements of non-Gaussianity indicated that MAP provided better a diffusion estimate than DTI, and MAP appeared to provide a more accurate measure of anisotropy in Rad, based on measures of the Rad/CC ratio. In conclusion, parameters of the MAP and DTI models were both sensitive to changes in diffusivity in HD participants compared to controls; however, the MAP model appeared to provide additional detailed information about changes in brain tissue microstructure.

Functionally distinct regions for spatial processing and sensory motor integration in the planum temporale.

There has been much debate recently over the functional role played by the planum temporale (PT) within the context of the dorsal auditory processing stream. Some studies indicate that regions in the PT support spatial hearing and other auditory functions, whereas others demonstrate sensory-motor response properties. This multifunctionality has led to the claim that the PT is performing a common computational pattern matching operation, then routing the signals (spatial, object, sensory-motor) into an appropriate processing stream. An alternative possibility is that the PT is functionally subdivided with separate regions supporting various functions. We assess this possibility using a within subject fMRI block design. DTI data were also collected to examine connectivity. There were four auditory conditions: stationary noise, moving noise, listening to pseudowords, and shadowing pseudowords (covert repetition). Contrasting the shadow and listen conditions should activate regions specific to sensory-motor processes, while contrasting the stationary and moving noise conditions should activate regions involved in spatial hearing. Subjects (N = 16) showed greater activation for shadowing in left posterior PT, area Spt, when the shadow and listen conditions were contrasted. The motion vs. stationary noise contrast revealed greater activation in a more medial and anterior portion of left PT. Seeds from these two contrasts were then used to guide the DTI analysis in an examination of connectivity via streamline tractography, which revealed different patterns of connectivity. Findings support a heterogeneous model of the PT, with functionally distinct regions for sensory-motor integration and processes involved in auditory spatial perception.

The effects of age, memory performance, and callosal integrity on the neural correlates of successful associative encoding.

This functional magnetic resonance imaging study investigated the relationship between the neural correlates of associative memory encoding, callosal integrity, and memory performance in older adults. Thirty-six older and 18 young subjects were scanned while making relational judgments on word pairs. Neural correlates of successful encoding (subsequent memory effects) were identified by contrasting the activity elicited by study pairs that were correctly identified as having been studied together with the activity elicited by pairs wrongly judged to have come from different study trials. Subsequent memory effects common to the 2 age groups were identified in several regions, including left inferior frontal gyrus and bilateral hippocampus. Negative effects (greater activity for forgotten than for remembered items) in default network regions in young subjects were reversed in the older group, and the amount of reversal correlated negatively with memory performance. Additionally, older subjects' subsequent memory effects in right frontal cortex correlated positively with anterior callosal integrity and negatively with memory performance. It is suggested that recruitment of right frontal cortex during verbal memory encoding may reflect the engagement of processes that compensate only partially for age-related neural degradation.

Distinct pattern separation related transfer functions in human CA3/dentate and CA1 revealed using high-resolution fMRI and variable mnemonic similarity.

Producing and maintaining distinct (orthogonal) neural representations for similar events is critical to avoiding interference in long-term memory. Recently, our laboratory provided the first evidence for separation-like signals in the human CA3/dentate. Here, we extended this by parametrically varying the change in input (similarity) while monitoring CA1 and CA3/dentate for separation and completion-like signals using high-resolution fMRI. In the CA1, activity varied in a graded fashion in response to increases in the change in input. In contrast, the CA3/dentate showed a stepwise transfer function that was highly sensitive to small changes in input.