Entorhinal volume, aerobic fitness, and recognition memory in healthy young adults: A voxel-based morphometry study
Introduction
The beneficial effects of cardio-respiratory fitness, aerobic exercise, and environmental enrichment on brain health and cognition are well documented (e.g. see van Praag et al., 2000; Cotman and Berchtold, 2002; Cotman et al., 2007 for reviews). For example, aerobic exercise and environmental enrichment are thought to improve learning and memory and to induce changes in the morphology of many brain structures, notably the hippocampus, through a variety of mechanisms. Most of this knowledge, however, is inferred from rodent models, which have focused eminently on effects in the dentate gyrus (DG), a sub-region of the hippocampus. Comparatively fewer direct observations have been made in humans. We therefore take a translational approach considering putative physical and neural correlates of exercise adaptation cross-sectionally in healthy young adults.
In rodents, both exercise and environmental enrichment have been shown to upregulate birth and survival rates of adult born neuronal and glial cells in the DG of the hippocampus, as well as improve performance on hippocampal dependent memory tasks (Creer et al., 2010, Falls et al., 2010, Fordyce and Farrar, 1991, Kempermann et al., 1997, O'Callaghan et al., 2007, Uda et al., 2006, Van Praag et al., 1999, Van Praag et al., 2005). More generally, environmental enrichment has also been linked to increased cortical thickness across the brain, most notably in posterior regions and the entorhinal cortex (EC) (Diamond et al., 1976, Diamond et al., 1987, Greer et al., 1982a, Greer et al., 1982b; reviewed in Mohammed et al., 2002). Exercise-induced brain plasticity is thought to be regulated in part by the complex, pleiotropic actions of different neurotrophins, namely brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1). These neurotrophins are associated with synaptic plasticity, neuronal survival, and differentiation (Kang and Schuman, 1995, McAllister et al., 1999, Trejo et al., 2001; see Cotman et al., 2007 for a review). In animal models BDNF mRNA expression, while highest in the hippocampus, is also high in EC and perirhinal cortex (Conner et al., 1997, Okuno et al., 1999).
Owing to the adult neurogenesis hypothesis, animal models have primarily targeted the DG and the hippocampal memory system. Exercise not only affects the DG, however, but also other regions of the medial temporal lobes (MTLs), especially hippocampal subfield CA1 and the EC (Neeper et al., 1996, Stranahan et al., 2007). Specifically, structural changes have been observed in these regions in the form of increased dendritic spine density in basal dendrites of pyramidal neurons in entorhinal layer III and in basal and apical CA1 neurons after two months of voluntary wheel running (Stranahan et al., 2007). These findings stand on their own, but also integrate well with the literature on neurogenesis, given that the EC has direct projections to the DG and CA1 via layers II and III, respectively (Steward and Scoville, 1976, Van Hoesen and Pandya, 1975, Witter et al., 1988, Witter et al., 1989), and entorhinal input may be needed to integrate newborn DG neurons into existing functional networks (Vivar et al., 2012). In addition, angiogenesis could also affect hippocampal and/or entorhinal structure following exercise training. Angiogenesis and neurogenesis are upregulated cooperatively (Palmer et al., 2000), resulting in enhanced formation of new blood vessels that support newborn neurons. Together, these findings suggest that aerobic exercise and cardio-respiratory fitness may directly alter the structure of the MTL more broadly.
It is plausible that angiogenesis, adult neurogenesis, and neurotrophin-mediated plasticity may underlie aerobic exercise-related changes in MTL function and structure in humans. Although these hypotheses cannot be assessed directly in living individuals, evidence for adult neurogenesis has been observed in postmortem human tissue (Eriksson et al., 1998). In addition, increased cerebral blood volume (CBV) in the DG (and somewhat in the EC) has been linked to exercise, providing a possible correlate of exercise-induced neurogenesis in mice and by extension, perhaps in humans (Pereira et al., 2007). In support of these ideas, recent human studies indicate that aerobic exercise training and cardio-respiratory fitness may be positively correlated with hippocampal volume (Erickson et al., 2009, Erickson et al., 2011b) and hippocampal cerebral blood flow in healthy older adults (Maass et al., 2015b). In turn, changes in hippocampal volume following the exercise intervention were correlated with changes in serum BDNF (Erickson et al., 2011b). Previous work from our lab suggests that effects of aerobic fitness and serum BDNF interact to support episodic recognition memory (Whiteman et al., 2014) in a task we have shown to recruit the hippocampus and perirhinal/EC (Schon et al., 2004, Schon et al., 2005). Additionally, increased cardio-respiratory fitness is associated with greater volume of the parahippocampal gyrus in Alzheimer's disease patients (Honea et al., 2009), and aerobic exercise consistently appears as one of the most effective interventions to attenuate cognitive decline in geriatric populations (Barnes & Yaffe, 2011; Burns et al., 2008). In younger cohorts, exercise-induced gains in cardio-respiratory fitness have been linked to better relational memory in children (Chaddock et al., 2010), and better learning of a virtual Morris Water Maze task in adolescents (Herting and Nagel, 2012).
Given this background, it is likely that entorhinal-dependent memory is associated with cardio-respiratory fitness and related mechanisms, but a direct link has not yet been established with entorhinal structure in humans. Establishing such a connection is of interest given that the EC provides the primary input to the hippocampus during episodic memory encoding. The present study reports on a subsample of participants from Whiteman et al. (2014) that participated in a magnetic resonance imaging (MRI) study to examine associations between aerobic capacity and volumes of structures in the medial temporal lobe (MTL) memory system. Healthy young participants underwent a standard graded treadmill test to measure cardiorespiratory fitness (Bruce et al., 1963, Thompson et al., 2010), provided blood samples to assay serum BDNF concentration, and performed an episodic recognition memory task (Schon et al., 2004, Whiteman et al., 2014). We used region-of-interest (ROI) based voxel-based morphometry (VBM; Ashburner and Friston, 2000) to analyze regional gray matter volume in the EC and hippocampus in an unbiased manner. We predicted that volume in these structures would be positively associated with cardiorespiratory fitness. In addition, based on our previous work (Whiteman et al., 2014), we hypothesized that serum BDNF would also predict MTL volumes. Here, we report evidence for a relationship between aerobic fitness and gray matter volume in the EC. We also report that performance on our recognition memory task was correlated with average volume in both the hippocampus and EC; we did not find relationships between gray matter volume and serum BDNF.
Section snippets
Participants
One hundred and fourteen healthy young participants were recruited from the Boston University student community. A random sub-sample of this cohort (sixty-one individuals) was recruited to participate in an MRI study; the full sample is described in Whiteman et al. (2014). Of this sub-sample, 16 did not meet inclusion/exclusion criteria, and forty-five participants were enrolled. Ten participants voluntarily withdrew or were lost to contact, and two were excluded due to equipment malfunction,
Fitness and entorhinal gray matter volume
Results from our primary VBM analysis showed that gray matter volume in a region of the right EC composed of 157 voxels was positively associated with aerobic fitness (Table 2; Fig. 2a). This was the only region that showed a correlation with aerobic fitness when controlling for the effects of memory accuracy, BDNF, total intra-cranial volume, gender, and RER ≥ 1.15 for our primary ROI-based VBM analysis. Based on the permutation distribution, the observed result is significant in both height (P <
Discussion
With the present study, we examined the relationships between aerobic fitness, serum BDNF, recognition memory, and gray matter volume in the entorhinal–hippocampal memory system. Our data suggest that volume in the EC may be positively associated with aerobic fitness and recognition memory performance, but not with serum BDNF. These results provide translational support for rodent models on exercise, neurogenesis, and the entorhinal–hippocampal memory system.
Motivation for this general line of
Conclusions
We have successfully tested the hypothesis that effects of aerobic exercise on structure in the hippocampal–entorhinal formation observed in rodents can be translated to healthy young adult humans. Consistent with work on environmental enrichment in rodents, our data demonstrated a positive association between fitness and volume in the right EC. Here we have also reported evidence for correlations between volume in both entorhinal cortices and performance on an episodic recognition memory task.
Acknowledgments
This work was supported by a Pathway to Independence Award to K.S. (NIH K99AG036845 and NIH R00AG036845), the Boston University Clinical and Translational Science Institute (CTSI; UL1-TR000157), the Boston University Center for Biomedical Imaging (CBI), and a Student Research Award from the Boston University Undergraduate Research Opportunities Program to A.S.W. We would like to thank Drs. Xuemei He and Tai Chen for performing and overseeing the BDNF ELISAs, respectively, and the staff of the
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2022, Brain and CognitionCitation Excerpt :Our finding regarding the memory–brain association was only marginal because of our stringent α rate; however, this study revealed preliminary evidence that in humans, the entorhinal cortex plays a key role in the retention of social information, which is a finding that is consistent with the results obtained through animal models. However, our findings on the inverse associations between memory measures and the entorhinal cortex in healthy YAs are inconsistent with those of studies that suggested positive associations between entorhinal cortex involvement and memory performance (Whiteman et al., 2016); nevertheless, they are consistent with those of several studies that reported a correlation between memory performance and hippocampal volume from a developmental perspective (Foster et al., 1999; Pruessner, Pruessner, Hellhammer, Pike, & Lupien, 2007; Van Petten, 2004). Foster et al. (1999) proposed the following neurobiological explanation for the inverse memory–brain association: the insufficient neural pruning of the hippocampus during childhood and adolescence may reduce mnemonic efficiency in healthy young people [however, see (Courchesne et al., 2000; Giedd et al., 1999; Sowell, Trauner, Gamst, & Jernigan, 2002)].
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2020, Trends in NeurosciencesCitation Excerpt :RCTs that examine hippocampal volume changes in young and middle age adults are also scarce [25–27]. However, there is cross-sectional evidence in these groups that provides support for a link between exercise and related constructs (e.g., cardiorespiratory fitness), hippocampal volume, and cognitive performance in healthy children (9–10 years old), adolescents, and young and middle-aged adults (but not yet in very young children) [28–31]. More work is needed to assess whether hippocampal volumetric and functional changes can be detected in the context of RCTs in lesser-studied age groups and what, if any, specific intervention parameters are required to do so.
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