Mnemonic discrimination relates to perforant path integrity: An ultra-high resolution diffusion tensor imaging study

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Highlights

  • We assessed relationships between hippocampal tract integrity and mnemonic factors.

  • Age-related declines were seen for perforant path, fornix, and cingulum integrity.

  • Perforant path integrity related only to the mnemonic discrimination factor.

  • But comparable relationships were seen for the other hippocampal tracts.

  • Thus, mnemonic discrimination is likely mediated by a broad MTL network.

Abstract

Pattern separation describes the orthogonalization of similar inputs into unique, non-overlapping representations. This computational process is thought to serve memory by reducing interference and to be mediated by the dentate gyrus of the hippocampus. Using ultra-high in-plane resolution diffusion tensor imaging (hrDTI) in older adults, we previously demonstrated that integrity of the perforant path, which provides input to the dentate gyrus from entorhinal cortex, was associated with mnemonic discrimination, a behavioral outcome designed to load on pattern separation. The current hrDTI study assessed the specificity of this perforant path integrity–mnemonic discrimination relationship relative to other cognitive constructs (identified using a factor analysis) and white matter tracts (hippocampal cingulum, fornix, corpus callosum) in 112 healthy adults (20–87 years). Results revealed age-related declines in integrity of the perforant path and other medial temporal lobe (MTL) tracts (hippocampal cingulum, fornix). Controlling for global effects of brain aging, perforant path integrity related only to the factor that captured mnemonic discrimination performance. Comparable integrity–mnemonic discrimination relationships were also observed for the hippocampal cingulum and fornix. Thus, whereas perforant path integrity specifically relates to mnemonic discrimination, mnemonic discrimination may be mediated by a broader MTL network.

Introduction

A fundamental component of memory is the ability to encode a given event as distinct from even highly similar events (e.g., where did you park your car today versus yesterday?). This type of mnemonic discrimination is thought to rely on pattern separation, in which unique representations are generated for each event (see Yassa & Stark, 2011). Computational models of hippocampal function have proposed that pattern separation is mediated by the dentate gyrus (McClelland et al., 1995, Treves and Rolls, 1994, Norman and O’Reilly, 2003). In support of this view, electrophysiological studies in rodents have revealed that neurons within the dentate gyrus alter their firing rates in response to minor changes in input events (i.e., the testing environment; Leutgeb et al., 2007, Neunuebel and Knierim, 2014). Similarly small changes in inputs (i.e., images of highly similar objects) have also elicited differential activity within the dentate gyrus in functional neuroimaging studies in humans, consistent with the role of the dentate in pattern separation (Bakker et al., 2008, Lacy et al., 2011).

Importantly, the dentate gyrus operates within a broader network of medial temporal lobe (MTL) regions and their connections. The dentate gyrus primarily receives inputs (e.g., highly processed sensory information) from entorhinal cortex via the perforant path (Witter, 2007). Entorhinal cortex receives its input from neocortex via the cingulum bundle (Jones & Witter, 2007), whereas the hippocampus receives additional input from subcortical regions via the fornix (Amaral and Cowan, 1980, Swanson and Cowan, 1977). Thus, differences in pattern separation ability could be observed not only from a disruption of processing within dentate gyrus itself, but also from disrupted transfer of information via the perforant path and other MTL tracts (cingulum, fornix).

A noninvasive technique for assessing these white matter tracts in humans is diffusion tensor imaging (DTI), in which the rate of molecular water diffusion can be used to identify the orientation and “integrity” of white matter microstructure (e.g., axonal size and density, degree of myelination, coherence of fiber orientation; Beaulieu, 2002, Le Bihan, 2003). Using ultra-high in-plane resolution DTI (hrDTI), we previously calculated perforant path integrity as the amount of diffusion signal parallel to an anatomically-constrained prototypical perforant path within parahippocampal white matter (Yassa et al., 2011, Yassa et al., 2010). In healthy older adults, this measure of perforant path integrity was positively related to a behavioral index of pattern separation (i.e., mnemonic discrimination; Yassa et al., 2011), measured as the ability to discriminate highly similar lure objects from repeated objects in the Mnemonic Similarity Task (MST; Kirwan and Stark, 2007, Stark et al., 2013). More recently, we used normal resolution DTI to show that integrity of the fornix (identified using traditional tractography methods) was also related to mnemonic discrimination (measured using the MST) in adults across the lifespan (Bennett, Huffman, & Stark, 2014).

The current study aimed to assess the specificity of the perforant path integrity–mnemonic discrimination relationship relative to other cognitive constructs and white matter tracts in 112 healthy adults (20–87 years). In addition to using measures of mnemonic discrimination from the MST for comparisons to our earlier work, mnemonic and executive functioning constructs were identified using a Principal Components factor analysis of thirteen MST and neuropsychological test measures. Furthermore, we introduce a novel method for assessing tract integrity, in which integrity metrics (diffusion, anisotropy) were calculated from fibers identified as running parallel to a prototypical tract orientation, after estimating multiple (two) fiber populations per voxel. This is especially important for the perforant path whose smaller fibers traverse parahippocampal white matter, which is primarily comprised of the hippocampal cingulum. It is predicted that perforant path integrity will be particularly sensitive to the factor capturing mnemonic discrimination. The mnemonic discrimination factor is also expected to relate to integrity of addition MTL tracts (fornix), but not the non-MTL control tract (corpus callosum).

Section snippets

Participants

A lifespan sample of 112 healthy adults aged 20–87 years (51.7 ± 19.0 years, 69 female) were recruited from the University of California, Irvine and nearby Orange County communities. Prior to participation, all individuals were screened for health conditions that may interact with their neurological status (e.g., dementia, stroke, etc.), use of psychoactive medication (e.g., neuroleptics, sedatives, etc.), and contraindications for magnetic resonance imaging (MRI) scanning (e.g., having ferrous

Age-related declines in tract integrity

Because our study involved a lifespan sample, we first assessed the effect of age on tract integrity using separate simple regressions between chronological age and each integrity metric for each tract (perforant path, hippocampal cingulum, fornix, corpus callosum). Significant effects survived Bonferroni correction for multiple comparisons (p < 0.0125 across four tracts per integrity metric).

Results revealed significant age-related declines in perforant path diffusion (B = −0.31, t(110) = −3.5, p < 

Discussion

The current study revealed three main findings. First, age-related integrity declines were observed for both local (perforant path) and large-scale (hippocampal cingulum, fornix) MTL tracts. Second, after controlling for white matter aging, perforant path integrity related only to mnemonic discrimination performance (LDI, LDI-AUC, Factor 2). Third, mnemonic discrimination was also related to integrity of the hippocampal cingulum (Factor 2) and fornix (LDI), but not the corpus callosum. Taken

Acknowledgments

This work was supported by the National Institutes on Aging R01 AG034613 (Stark) and K99 AG047334 (Bennett). We thank Shauna Stark and Samantha Rutledge for their assistance in data collection.

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