Multi-modal characterization of rapid anterior hippocampal volume increase associated with aerobic exercise

“and white matter segmentations were performed using FMRIB’s Automated Segmentation Tool (FAST) (Zhang et al., 2001) without smoothing.”

“A recent longitudinal study has demonstrated that one year of aerobic exercise has a direct causal role in increasing the volume of the hippocampus in sedentary older adults (Erickson et al., 2011).”

“Rating of Perceived Exertion (RPE) was also monitored (Borg, 1970).”

“The first is that LME separately and effectively models variance due to within and between subject factors (Fitzmaurice et al., 2011; Verbeke and Molenberghs, 2009).”

“…estimated V ̇ O 2 max was calculated by performing a linear fit between Heart Rate (HR) and V ̇ O 2 scores during the test and projecting the V ̇ O 2 value at the participant’s age-predicted heart rate maximum (208 − 0.7 * Age, Tanaka et al., 2001; American College of Sports Medicine, 2006).”

“Boundary Based Registration (BBR) was use for alignments of EPI images to MPRAGE scans Greve and Fischl (2009).”

“For example, it has been shown that aerobic exercise increases the rate of neurogenesis in the dentate gyrus region of the rodent hippocampus and increases cerebral blood volume (CBV) in the same region in humans (Pereira et al., 2007; van Praag et al., 1999a,b).”

“In the hippocampus, exercise alone leads to increased production of new neurons while exercise paired with environmental enrichment leads to greater survival of new neurons (van Praag et al., 2000, 2005).”

“It is interesting to note that our results differ from previously published studies in rodents that have shown a robust vascular change within the hippocampus after a prolonged period of exercise (Pereira et al., 2007; Van der Borght et al., 2009; van Praag et al., 2005).”

“Histological examination of the hippocampus reveals three obvious subdivision along the longitudinal axis: the head, the body, and the tail (Duvernoy, 2005; Strange et al., 2014), with the body being somewhat longer than the other two segments.”

“…to relate the morphometric measurements commonly used in neuroimaging to underlying changes in the neural tissue elicited by other behavioral training paradigms (Lerch et al., 2011; Sampaio-Baptista et al., 2013), but little is known about what drives these changes in humans (Zatorre et al., 2012).”

“…2005; Barbier et al., 2001), thus it would obviously increase if vasculature increased, but a myelin change would not be predicted to change CBV. • SWI images show lower intensity in highly vascularized regions (Haacke et al., 2004), thus an decrease in SWI would support an increase in vasculature.”

“We also measuredMD and FA which have been used in other studies to draw conclusions about axonal orientation, integrity, and myelination within white matter regions where fibers are bundled with coherent orientation (Scholz et al., 2009) though aspects of this interpretation are controversial (Mädler et al.”

“Neuronal activity-dependent changes in myelination have been observed in cell culture (Wake et al., 2011; Fields, 2010) as well as in recent in vivo experiments (Gibson et al., 2014).”

“However, another measure that has been used to measure myelin, the T1/T2 ratio (Glasser and Van Essen, 2011), did show an increase in the anterior hippocampus (Z = 1.54).”

“For example, it has been shown that aerobic exercise increases the rate of neurogenesis in the dentate gyrus region of the rodent hippocampus and increases cerebral blood volume (CBV) in the same region in humans (Pereira et al., 2007; van Praag et al., 1999a,b).”

“This result is particularly relevant given the growing recognition of the importance of lifestyle during middle age for lifelong cognitive health (Wilson et al., 2002; Karp et al., 2006; Young et al., 2015).”

“• T2 is similarly significantly higher in vasculature than in myelin-rich regions (Stanisz et al., 2005; Wansapura et al., 1999), thus a similar prediction applies.”

“One potential substrate for exercise-mediated volume increases that is relatively accessible with neuroimaging methods is increased vasculature (i.e. angiogenesis), possibly accompanied by neurogenesis (Black et al., 1990; Pereira et al., 2007).”

“All tasks were administered using paper and pencil except for the digit span test which was administered by computer using the PEBL software package (Mueller and Piper, 2014) in a stepwise fashion as described in Woods et al. (2010).”

“Animal and human studies provide a number of candidate mechanisms for exercise-driven or experience-dependent change in brain structure Voss et al. (2013).”

“…that these two underlying mechanisms would produce predictable but distinct changes in T1, T2, QSM, SWI, WM, and CBV, due to the different sensitivities of these MR measures to different tissue components (Deistung et al., 2013; Haacke et al., 2004; Lutti et al., 2013; Whittall et al., 1997).”

“In T1-weighted MRI scan, myelin is most apparent in the white matter, however there are also a considerable number of myelinated fibers within hippocampal grey matter (Benes et al., 1994).”

“Habitual aerobic exercise has been widely associated with greater cognitive performance in older adults as well as adolescents (Kramer and Erickson, 2007; Anderson-Hanley et al., 2012; Benedict et al., 2012; Aberg et al., 2009; Young et al., 2015).”

“Phase maps were unwrapped using Phase Region Expanding Labeller for Unwrapping Discrete Estimates (PRELUDE) (Jenkinson, 2003).”

“Neuronal activity-dependent changes in myelination have been observed in cell culture (Wake et al., 2011; Fields, 2010) as well as in recent in vivo experiments (Gibson et al., 2014).”

“…the majority of our imaging measures supported an increase in myelination within anterior hippocampus, the lack of an increase in T1 is a surprising and notable exception as many investigators consider R1 (1/T1) to be the best MR measure of myelin content (Stüber et al., 2014; Lutti et al., 2013).”

“…of several recent critical reviews of longitudinal neuroimaging approaches (Bernal-Rusiel et al., 2013; Thomas and Baker, 2012; Thomas et al., 2009; Aarts et al., 2014), all longitudinal analyses in this study have been conducted in the subject’s native space, avoiding potential confounds due to…”

“Two ME-MPRAGE scans with and without contrast agent (1 mm isotropic voxels, TR = 2530 ms, TI = 1200 ms, TE = 1.69, 3.55, 5.41 and 7.27 ms, matrix size = 256 × 256 × 176, and GRAPPA factor = 2; van der Kouwe et al., 2008).”

“This result is particularly relevant given the growing recognition of the importance of lifestyle during middle age for lifelong cognitive health (Wilson et al., 2002; Karp et al., 2006; Young et al., 2015).”

“These and other studies have shown that myelination changes can occur in a time frame much less than the six-week intervention used here (Yeung et al., 2014; Gibson et al., 2014).”

“QSM maps were then computed by implementing the highly computationally efficient thresholded k-space division (TKD) (Shmueli et al., 2009; Schweser et al., 2013) modification of the dipole-inversion approach (Salomir et al.”

“As previous studies have shown that hippocampal plasticity tends to be focused in the anterior head portion (Erickson et al., 2011; Sagi et al., 2012), we focused our analysis on the anterior quarter of the hippocampus.”

“This result is particularly relevant given the growing recognition of the importance of lifestyle during middle age for lifelong cognitive health (Wilson et al., 2002; Karp et al., 2006; Young et al., 2015).”

“Although a number of studies have reported change in brain volumes with exercise interventions in older adults (Erickson et al., 2011; Anderson-Hanley et al., 2012), effects in young to middle aged adults have not been well studied.”

“We note that it has been recently demonstrated that an increase in head motion could result in artifactual changes in segmented volumes (Reuter et al., 2014).”

“• QSM has been shown to be dark in myelin-rich regions and bright in blood-rich regions (Deistung et al., 2013; Stuber and Turner, 2010), thus making clear predictions for both a myelin and vasculature change.”

“However, there is little evidence on the effects of exercise on the brain in early to middle adulthood, despite clear relevance of this question to lifelong cognitive health (Voelcker-Rehage and Niemann, 2013).”

“QSM maps were then computed by implementing the highly computationally efficient thresholded k-space division (TKD) (Shmueli et al., 2009; Schweser et al., 2013) modification of the dipole-inversion approach (Salomir et al., 2003; Marques and Bowtell, 2005).”

“…to relate the morphometric measurements commonly used in neuroimaging to underlying changes in the neural tissue elicited by other behavioral training paradigms (Lerch et al., 2011; Sampaio-Baptista et al., 2013), but little is known about what drives these changes in humans (Zatorre et al., 2012).”

“Segmentation of the hippocampus for each visit was performed on individual subject MPRAGE images (without contrast) in native space using the Freesurfer hippocampal subfield segmentation pipeline (Van Leemput et al., 2009).”

“• CBV is a direct measure of blood volume (Wenz et al., 1996; Lu et al., 2005; Barbier et al., 2001), thus it would obviously increase if vasculature increased, but a myelin change would not be predicted to change CBV. • SWI images show lower intensity in highly vascularized regions (Haacke et al.,…”

“QSM maps were then computed by implementing the highly computationally efficient thresholded k-space division (TKD) (Shmueli et al., 2009; Schweser et al., 2013) modification of the dipole-inversion approach (Salomir et al., 2003; Marques and Bowtell, 2005).”

“Habitual aerobic exercise has been widely associated with greater cognitive performance in older adults as well as adolescents (Kramer and Erickson, 2007; Anderson-Hanley et al., 2012; Benedict et al., 2012; Aberg et al., 2009; Young et al., 2015).”

“All tasks were administered using paper and pencil except for the digit span test which was administered by computer using the PEBL software package (Mueller and Piper, 2014) in a stepwise fashion as described in Woods et al. (2010).”

“Background phase was estimated using the Morphology Enabled Dipole Inversion (MEDI) technique (Liu et al., 2011); residual phase maps representing underlying variations due to microstructural inhomogeneities in susceptibility were produced by subtracting the estimated background from the unwrapped…”

“Longitudinal LME modeling has been demonstrated to be a be superior technique to more common alternatives such as repeated measure ANOVA or simple paired T-test in that it provides more statistical power and is robust in the face ofmissing data (Bernal-Rusiel et al., 2013).”

“…the majority of our imaging measures supported an increase in myelination within anterior hippocampus, the lack of an increase in T1 is a surprising and notable exception as many investigators consider R1 (1/T1) to be the best MR measure of myelin content (Stüber et al., 2014; Lutti et al., 2013).”

“In rats, some efforts have been made to relate the morphometric measurements commonly used in neuroimaging to underlying changes in the neural tissue elicited by other behavioral training paradigms (Lerch et al., 2011; Sampaio-Baptista et al., 2013), but little is known about what drives these changes in humans (Zator…”

“It is possible that such mechanisms explain the changes in myelin associated with experience that have been reported in several recent imaging studies (Blumenfeld-Katzir et al., 2011; Sampaio-Baptista et al., 2013).”

“The method we used to quantify T1 has been recently criticized as suffering from inaccuracies due to RF field inhomogeneities (Lankford and Does, 2013; Stikov et al., 2014).”

“Neuronal activity-dependent changes in myelination have been observed in cell culture (Wake et al., 2011; Fields, 2010) as well as in recent in vivo experiments (Gibson et al., 2014).”

“…and FA which have been used in other studies to draw conclusions about axonal orientation, integrity, and myelination within white matter regions where fibers are bundled with coherent orientation (Scholz et al., 2009) though aspects of this interpretation are controversial (Mädler et al., 2008).”

“It is interesting to note that our results differ from previously published studies in rodents that have shown a robust vascular change within the hippocampus after a prolonged period of exercise (Pereira et al., 2007; Van der Borght et al., 2009; van Praag et al., 2005).”

“SWI signal in myelinated regions depends on a number of factors, such as the orientation of the fibers with respect to the field (Deistung et al., 2013; Lutti et al., 2013; Lee et al., 2012), thus no clear prediction with respect to myelin change can be made.”

“In light of several recent critical reviews of longitudinal neuroimaging approaches (Bernal-Rusiel et al., 2013; Thomas and Baker, 2012; Thomas et al., 2009; Aarts et al., 2014), all longitudinal analyses in this study have been conducted in the subject’s native space, avoiding potential confounds…”

“Measures of cardiovascular fitness have been shown to increase after as little as one week of exercise training (Hickson et al., 1981).”

“All scans were acquired using “Auto Align” to minimize variability in slice positioning (van der Kouwe et al., 2005).”

“QSM maps were then computed by implementing the highly computationally efficient thresholded k-space division (TKD) (Shmueli et al., 2009; Schweser et al., 2013) modification of the dipole-inversion approach (Salomir et al.”

“Habitual aerobic exercise has been widely associated with greater cognitive performance in older adults as well as adolescents (Kramer and Erickson, 2007; Anderson-Hanley et al., 2012; Benedict et al., 2012; Aberg et al., 2009; Young et al., 2015).”

“• CBV is a direct measure of blood volume (Wenz et al., 1996; Lu et al., 2005; Barbier et al., 2001), thus it would obviously increase if vasculature increased, but a myelin change would not be predicted to change CBV. • SWI images show lower intensity in highly vascularized regions (Haacke et al.,…”

“In light of several recent critical reviews of longitudinal neuroimaging approaches (Bernal-Rusiel et al., 2013; Thomas and Baker, 2012; Thomas et al., 2009; Aarts et al., 2014), all longitudinal analyses in this study have been conducted in the subject’s native space, avoiding potential confounds…”

“The method we used to quantify T1 has been recently criticized as suffering from inaccuracies due to RF field inhomogeneities (Lankford and Does, 2013; Stikov et al., 2014).”

“…brain plasticity in humans requires exercise interventions measured in months or years, although see Sagi et al. (2012) for an example of a more rapid structural change in the hippocampus with a non-exercise intervention and Tavor et al. (2013) for an exploration of the time course of this change.”

“For example, epidemiological studies have shown that lifestyle during middle age has significant consequences for cognitive performance decades later (Wilson et al., 2002; Karp et al., 2006; Belsky et al., 2015).”

“Environmental enrichment, a less specific manipulation, has been shown to increase myelination of callosal fibres (Markham et al., 2009; Zhao et al., 2012).”

“• CBV is a direct measure of blood volume (Wenz et al., 1996; Lu et al., 2005; Barbier et al., 2001), thus it would obviously increase if vasculature increased, but a myelin change would not be predicted to change CBV. • SWI images show lower intensity in highly vascularized regions (Haacke et al.,…”

“Environmental enrichment, a less specific manipulation, has been shown to increase myelination of callosal fibres (Markham et al., 2009; Zhao et al., 2012).”

“Growth of mossy fibers in the rat hippocampus with physical exercise has been previously reported (Toscano-Silva et al., 2010), however these fibers are not myelinated.”

“Histology also requires fixation which, depending on the precise procedure used, can cause shrinkage and dehydration, potentially distorting volume measurements (Overgaard and Meden, 2000).”

“examining the effects of exercise in young-to-middle-aged adults found no change in total hippocampal volume but did find a significant increase in anterior hippocampal volume following 6 weeks of aerobic exercise (Thomas et al., 2016).”

“…has been extensively reported to have an impact on gray matter volume of the hippocampus as measured by neuroimaging (Erickson et al., 2011; Thomas et al., 2016), but the underlying cellular drivers for gross changes following exercise interventions detected using neuroimaging remain…”

“9) using a cross-over design found that 6 weeks of aerobic training for 5 days a week, 30 minutes each day, was sufficient to increase hippocampal volume (43).”

“However, a study in young to middle-age adults found that anterior hippocampal volume changes from 6 weeks of training that improved fitness increased markers of myelination rather than cerebral blood volume [67].”

“…on brain structures; in particular in the hippocampus (Pereira et al., 2007; Erickson et al., 2011; Maass et al., 2014; Niemann et al., 2014; Thomas et al., 2016), and in frontal areas (Colcombe et al., 2006; Erickson et al., 2010; Flöel et al., 2010; Voss et al., 2013; Oberlin et al.,…”

“Third, we propose an integrated reciprocal account whereby EF and health behavior are linked through a feedback loop that could confer substantial health benefits over time.”

“A single exercise session among individuals with depressive symptoms can significantly improve self-efficacy, thereby reducing negative emotions [79], while regular exercise for > 3 months can effectively reshape the central nervous system organization of patients with depression [80].”

“In younger adults, a 6-weeks exercise program was able to increase hippocampal volume (Thomas et al., 2016).”

“For example, one study demonstrated that AE stimulated hippocampal volume growth and then utilized a range of multi-modal MRI techniques to indirectly suggest that this growth may be supported by changes in myelination, rather than in vasculature (Thomas et al., 2016).”

“, six weeks in a younger population; [6]).”

“Similarly, exercise and good fitness level are associated with larger hippocampal volume (Thomas et al., 2016).”

“However, changes might emerge much faster than this: 26 weeks of chest and leg press [136], 138 days of aerobic exercise [137], 3 months of biking, running strength training [138], endurance training [139] and juggling [140], 6 weeks of aerobic exercise [141] and balance training [142], and even 1 week of practicing a…”

“Hippocampus”

“Physical activity and mobility have been shown to boost memory [67], improve concentration [28] and enhance creativity [39].”

“The hippocampus is our current region of interest, due to the its demonstrated malleability following mindfulness programs and other behavioral training programs lasting several weeks (Thomas et al. 2016) or even mere hours (Sagi et al. 2012).”

“…specialized techniques to segment the hippocampus into sub-regions have found that aerobic exercise may primarily affect the anterior hippocampus, including the DG, CA1, and subiculum, with weaker effects on the posterior hippocampus (Erickson et al., 2011; Maass et al., 2015; Thomas et al., 2015).”

“This result is consistent with a previous exercise intervention study in young adults that showed detectable volumetric changes in the anterior hippocampus in as little as 6 weeks of high-intensity interval exercise training (Thomas et al., 2016).”

“Prior human investigations suggested that the salutary effects on hippocampal volume elicited by greater cardiorespiratory fitness appeared to be specific to the anterior relative to the posterior region [13, 40].”

“It is therefore possible that neuroplasticity in the hippocampus of PD patients is independent of detectable changes in BDNF in the serum and mediated by other underlying mechanisms such as changes in myelination [46].”

“Further,positiveassociationsbetweenPEand hippocampalvolumehavebeenshown,inbotholder andmiddle-agedadults(Ericksonetal.,2009,2011; Thomasetal.,2016).”

“…effects of exercise on the hippocampus of young to middle-aged adult samples (e.g., Déry et al., 2013; Killgore et al., 2013; Pajonk et al., 2010; Thomas et al., 2016; Wagner et al., 2015), the majority of studies have been conducted on older adults, that is, >65 years of age (Prakash et al.,…”

“This is in 245 contrast to pre-clinical studies that have shown vol246 ume increases primarily in the DG, the site where 247 neurogenesis occurs [18], as well as human studies 248 which found pronounced increases in the hippocam249 pal head where the DG in located [3, 6].”

“volume, a brain structure that has been shown to be specifically sensitive to improved oxygen uptake following aerobic exercise [29, 30].”

“A previous exercise intervention increased hippocampal volume by about 2% (Thomas et al., 2016) in sedentary middle-aged adults.”

“However, increases in hippocampal volume have been observed in young adults (Thomas et al., 2016), confirming that the hippocampus is responsive to physical activity in younger people.”

“Results from randomized controlled trials show that exposure to events inducing enduring positive affective states cause the changes in hippocampal biomarkers (Erickson et al., 2011; Holzel et al., 2011; Thomas et al., 2016).”

“Thus, one might hypothesize that increased functional connectivity represents a basic adaptive principle that only translates to sustained neuroplasticity on a molecular or neuronal level in a biophysiological context like exercising (Thomas et al., 2016).”

“…1999; van Praag, Kempermann, & Gage, 1999) and human (Erickson et al., 2011; Jonasson et al., 2017; Maass et al., 2015; Pereira et al., 2007; Rosano et al., 2017; Thomas et al., 2016) literature, which demon- strate associations between both aerobic exercise and CRF and hippo- campal plasticity.”

“, 2020), other studies showed volume increases in anterior portions of the hippocampus after exercising (e.g., Erickson et al., 2011; Thomas et al., 2016).”

“Interventions as short as 6 weeks can result in a measurable increase in aerobic fitness 12 .”

“…volume in older adults is thought to result from the attenuation of hippocampal atrophy associated with aging (Erickson et al., 2011; Firth et al., 2018), rather than increased volume compared to baseline measurements, as seen in young adults (Nauer, Dunne, et al., 2020; Thomas et al., 2016).”

“As well as studying the effects of long-term exercise interventions, it is also important to determine whether single bouts of physical activity influence cognitive The collation of observational (Boraxbekk et al., 2016; Fischer, 2016; Johnson et al., 2016; Oberlin et al., 2016; Sexton et al., 2016; Smith et al., 2016…”

“Because microstructural changes as well as volumetric changes could be caused by neuronal myelination (Li et al., 2017; Thomas et al., 2016), we stained for neurofilament-heavy-chain (NF-H), as part of the neuronal cytoskeleton (Lee et al., 2020) and myelinbasic-protein (MBP), which is part of…”

“[53] suggested that the hippocampal volume is modulated by aerobic exercise throughout the lifespan.”

“Previous literature has explicitly focused on studying the effects of aerobic exercise on the hippocampus (Cotman 2002; Falkai and Schmitt 2009; Chaddock-Heyman et al. 2016; Thomas et al. 2016).”

“Exercise-induced increases in hippocampal volume, measured by MRI, have been previously described in mice [30, 31] and humans [11, 32-35].”

“In the hippocampus, for example, exercise increases angiogenesis (Van der Borght et al. 2009), dendritic complexity (Redila & Christie 2006; Shih et al. 2013), spine density (Eadie et al. 2005), volume (Thomas et al. 2015), and adult neurogenesis (van Praag et al. 1999b; van Praag 2008).”

“Both Maass et al. (2015) and Thomas et al. (2016) found a specific relation between increase in CRF and increase in anterior hippocampal volume, suggesting greater sensitivity to CRF in the anterior hippocampus.”

“…the key cellular modification related to physical exercise (Andersen, Morris, Amaral, Bliss, & O’Keefe, 2007; Van Praag, 2008), in association with a buildup of the grey matter volume in the hippocampus and in the frontal regions (Colcombe et al., 2006; Kleemeyer et al., 2015; Thomas et al., 2016).”

“23 analysing cerebral blood volume did not corroborate this (Thomas et al., 2016).”

“Although most studies, particularly in older adults, have reported increases in hippocampal volume following exercise (9, 12, 73), Wagner et al.”

“Interestingly, in a previous study, Thomas et al. (2016) indicated that PE-induced hippocampal structural plasticity can occur faster than previously thought.”

“For example, human hippocampal volume has been shown to increase in response to aerobic exercise and to return to baseline after an additional six weeks without aerobic exercise [7].”

“Aerobic exercise could induce brain plasticity in early to middle adulthood, even within a relatively short timeframe of 6 weeks (Thomas et al., 2016).”

“In humans, aerobic exercise increases hippocampal volume transiently after only 6 weeks of the intervention (56).”

“Several recent studies have found the relationship between PA and brain morphology (Thomas et al., 2016; Rosano et al., 2017).”

“Thomas et al. (2016), who found hippocampal volume increases after just 6 weeks of aerobic exercise in young and middle-aged adults, argued for increased myelination.”

“…to calculate a whole hippocampus measure, and, following suggestions that exercise effects may vary along the longitudinal hippocampal axis 9,11,18,22,23 Duetopreviousstudieswiththebehavioraltaskthatindicatedacentral role of the entorhinal cortex 56 , we also analyzed the left and right…”

“…regarding the LN and the AN, referring to an integrated action among them, were analyzed in the same fifteen studies [17–19, 22– 24, 27– 30, 32 , 35– 37 Of the seventeen interventions analyzing the LN and the AN, four studies reported only functional changes, ten reported structural changes,…”

“Regarding the thalamus, three studies did not show increases in volume after physical exercise interventions [25,26,62].”

“Other studies have focused on the effect of aerobic exercise on regional brain volumes or thickness (e.g., hippocampal volume, 51 frontal gray matter volume, and cortical thickness 52,53 ), but few have examined a brain age variable that compares the volumetric information to that of a normative…”

“For instance, a longitudinal study might tr ac k c hanges in the hippocampal volume of participants who undergo a memory training pr ogr am ov er se v er al months, ther eby identifying the neural cor-r elates of tr aining-induced cognitiv e impr ov ements (Thomas et al. , 2016 ).”

“Accelerometer recordings and self-reported sleep-boundary data were collected as part 28 of a Cognitive Health in Ageing (CHA) Exercise study [9].”