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.”

“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).”

“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).”

“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).”

“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).”

“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.”

“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).”

“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.”

“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).”

“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…”