A two-week period of detraining reduces hippocampal volume in regularly active young adults: a structural MRI study

doi:10.21203/rs.3.rs-6810285/v1

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A two-week period of detraining reduces hippocampal volume in regularly active young adults: a structural MRI study

https://doi.org/10.21203/rs.3.rs-6810285/v1

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Background

Regular physical activity (PA) confers numerous benefits to both peripheral and cerebral health, including enhanced cardiovascular and muscular function, as well as improved cognitive performance and neuroplasticity. The hippocampus, a brain region highly sensitive to the effects of PA, has been consistently shown to undergo structural enhancements with sustained exercise. However, the impact of physical detraining—the cessation or significant reduction of regular PA—on hippocampal structure remains largely unexplored, particularly in humans. This study aimed to investigate whether a 14-day period of voluntary exercise reduction leads to measurable structural changes in the hippocampus, and whether these changes are associated with anxiety symptomatology.

Results

Repeated-measures ANCOVAs, controlling for physical fitness index and degree of PA reduction, revealed a significant decrease in hippocampal gray matter volume following detraining, especially in individuals with greater PA reduction. Notably, post-detraining anxiety levels were lower in participants who showed larger reductions in hippocampal volume. Correlational analyses supported this association.

Conclusions

These findings suggest that even short-term interruptions in regular physical activity may prompt rapid structural changes in the hippocampus, modulated by the extent of detraining. The observed relationship between hippocampal volume reduction and decreased anxiety points to stress regulation as a potential mechanism. Further research is warranted to explore the functional significance and potential reversibility of these neuroplastic changes.

anxiety

detraining

exercise cessation

hippocampus

Magnetic Resonance Imaging

physical activity

Regular physical activity (PA), which refers to bodily movement produced by skeletal muscle that requires energy expenditure, offers numerous benefits both at the peripheral and cerebral levels [1]. In particular, physical exercise, a subcategory of physical activity that is planned, structured, repetitive, and performed with the intent to improve physical fitness [2], has been demonstrated to provide the greatest benefits [3]. From a peripheral perspective, both exercise and PA enhance cardiovascular function, muscular strength, and joint mobility, as well as regulate metabolism, contributing to a higher quality of life and the prevention of chronic diseases such as diabetes or hypertension [4–9]. At the cerebral level, physical exercise has a significant impact on cognitive health and neuroplasticity. Recent studies have demonstrated that exercise promotes neurogenesis, particularly in the hippocampus, a brain region crucial for memory and learning [10]. Moreover, exercise improves cerebral blood flow (CBF) and increases the release of neurotrophic factors such as BDNF (brain derived neurotrophic factor), which are essential for neuronal survival, synaptic plasticity, and overall mental health [11].

These positive effects of exercise not only benefit cognitive function in healthy individuals but also have been observed to aid those patients with hippocampal damage such as those with mild cognitive impairment [12], suggesting that exercise can be an effective intervention to delay or prevent the progression of neurodegenerative diseases such Alzheimer’s [13]. MRI studies have shown that exercise and increased PA are associated with increased hippocampal volume and improved functional connectivity in brain regions that are typically affected in Alzheimer’s disease, potentially reducing the risk or delaying its onset [14–16]. However, it is important to note that the cognitive benefits of exercise tend to be more sustainable when a regular exercise routine is maintained over time [17].

Despite maintaining an overall physically active lifestyle, most individuals experience specific periods in life—such as during holidays, recovery from illness, or intentional rest—in which exercise is drastically reduced. Despite the growing body of evidence supporting the benefits of exercise, the effects of the reduction in exercise practice remain relatively underexplored. Most existing studies have focused on older adults and suggest that the partial or complete loss of training-induced adaptations can lead to a range of adverse changes. These include declines in muscle quality [18], reductions in lean body mass, increases in fat mass and abdominal adiposity [19], as well as decreased muscle strength in both upper and lower limbs and reduced functional capacity [20]. The consequences of exercise cessation have been widely documented, particularly at the cardiovascular level—with reductions in VO₂max, blood and plasma volume, and increases in blood pressure and heart rate—alongside metabolic effects such as decreased insulin sensitivity [21]. Moreover, cognitive studies have revealed that exercise cessation was associated with a decline in some but not all the cognitive functions [22], such as verbal fluency [23], inhibition [24], working memory [25], and cognitive flexibility [26], among others in older adults’ samples.

More unexplored are the effects of cessation of training on the human brain structure and function. Most of the literature has been run in animals and results have revealed a rebound effect in the neurogenesis of the hippocampus following exercise cessation that diminished to a level lower than found in the sedentary group or even at baseline levels [27–29]. This research showed a significant reduction in immature neuron density in the hippocampus of mice after 5 to 8 weeks of exercise cessation, attributed to decreased cell survival rather than impaired proliferation or maturation. In another study, Morgan and colleagues [30] revealed that exercise cessation led to changes in hippocampal gene expression, particularly in genes related to neuroplasticity, inflammation, and metabolism.

In humans, the investigation of the effects of exercise reduction has predominantly been focused on mental health and psychological outcomes [31], reporting increased anxiety [32] and depressive symptoms [33]. However, the structural and functional consequences of exercise reduction on the human brain have not been elucidated yet. To the best of our knowledge, there is only one study in humans to date that has investigated the effects of short-term exercise cessation on cerebral mechanisms such as cerebral blood flow (CBF) [34]. In this study, a decrease in resting CBF was observed in eight brain regions—including the bilateral hippocampus, inferior temporal gyrus, fusiform gyrus, inferior parietal lobule, lingual gyrus, precuneus, and cerebellum—after just 10 days of detraining in a sample of master athletes aged 50 to 80 with a history of long-term endurance training. These findings suggest that even short-term exercise cessation may compromise brain function by reducing blood supply to areas critical for memory and cognition.

Given the detrimental impact of exercise cessation on human cognition and on brain health observed in animals, as well as the paucity of knowledge existing in young adults, there is a need to further investigate the effects of a period of exercise cessation specifically on hippocampal structure in this population. Moreover, expanding the knowledge beyond the psychological effects of detraining could help to understand the mechanisms behind brain changes. Thus, the main objective of this study is to determine whether a two-week period of exercise cessation leads to measurable structural changes in the hippocampus assessed by MRI. Furthermore, if such changes are observed, the secondary aim is to examine their association with anxiety symptomatology. Based on existing research, we hypothesized that a 14-day period of voluntary exercise cessation would result in a significant reduction in hippocampal gray matter volume, and that this reduction could be partially modulated by increased anxiety levels induced by detraining.

2.1. Participants

Twenty-two healthy young adults (12 females), with a mean age of 23 years (SD = 3.7, range 18–29), participated in the study after providing written informed consent. Participants were recruited from the student community at Universitat Jaume I through poster advertisements, social networks, and word of mouth. All were right-handed and achieved a minimum scaled score of 7 on the Matrix Reasoning subtest of the Wechsler Adult Intelligence Scale, 4th edition (WAIS-IV) [35], ensuring adequate intellectual functioning. The majority (92%) of participants had completed or were involved in tertiary education, including a bachelor’s degree (68%) or a master’s/doctoral degree (24%). The remaining 8% had vocational training studies. Additionally, none of the participants reported a history of psychiatric or neurological disorders or brain injury involving loss of consciousness. The study was approved by the Ethical Committee of Universitat Jaume I (CD/11/2021), and all volunteers received monetary compensation for their participation.

Given our focus on investigating the effects of exercise detraining on brain structure, it was essential to select participants who were regular exercisers. Therefore, all participants were pre-selected from a pool of volunteers based on their responses to the exercise-related questions in a screening questionnaire. Participants self-reported their daily PA levels according to the following question: “In your daily life, how would you describe yourself: as someone who does not exercise or exercises very little (sedentary), as someone who exercises occasionally, without following a fixed schedule (moderate); as someone who exercises regularly more than once a week with a fixed schedule (active); or as someone who dedicates more than 12 hours per week to exercise (athlete)?” All participants were also specifically asked to report the number of hours per week they dedicated to exercise. This questionnaire also collected data on demographic information, education, handedness, medical conditions, and MRI compatibility. Individuals were eligible for the study if they reported being physically active, regularly engaging in structured exercise more than once per week—including aerobic training, resistance training at the gym, team sports, or other forms of planned PA—and maintaining a consistent training schedule. Those who engaged in professional sport practice or dedicated more than 12 hours per week to physical exercise (n = 8) were also included. Thus, participants who were selected based on being regularly active or identified as athletes, were explicitly instructed to refrain voluntarily from engaging in regular physical exercise during the second and third week of the study.

Characteristics of the study sample are presented below in Table 1.

Table 1
*Descriptive participant data collected at baseline*. Means, standard deviations, and ranges for demographic, anthropometric, cardiovascular, and fitness-related variables in the study sample
N = 22	Mean	SD	Minimum	Maximum
Age (years)	23.32	3.72	18.00	29.00
Self-reported PA (h/week)	10.33	4.28	4.00	20.00
BMI (kg/m2)	22.74	2.81	19.14	31.42
Abdominal circumference (cm)	71.13	7.68	58.00	87.80
Hip circumference (cm)	91.20	5.97	79.80	101.00
SBP (mmHg)	119.29	14.87	98.00	148.00
DBP (mmHg)	68.48	6.39	59.00	83.00
Heart rate (bpm)	76.38	10.99	52.00	92.00
VO₂max (mL/kg/min)	49.23	7.11	37.90	63.10
Jump Test (cm)	35.07	9.63	19.32	52.78
Left handgrip strength (kg)	35.07	9.31	21.20	51.40
Right handgrip strength (kg)	37.76	13.73	21.30	78.20
Note. BMI = Body mass index; bpm = Beats per minute; DBP = Diastolic blood pressure; mmHg = Millimeters of mercury; PA = Physical activity; SBP = Systolic blood pressure; VO₂max = Maximal oxygen uptake.

2.2. Exercise reduction and monitoring of protocol adherence

PA levels were objectively monitored using GENEActiv accelerometers (Activinsights Ltd., Kimbolton, UK) over a three-week period, comprising three distinct time points: baseline (a week of habitual PA), the first week of exercise reduction, and the second week of voluntary cessation period. Participants wore the device continuously on their non-dominant (left) wrist for 24 hours a day. At baseline, PA was tracked for seven consecutive days leading up to the first MRI session. The exercise reduction phase began immediately after this scan, during which all structured training was voluntarily discontinued or substantially reduced. Participants were explicitly instructed to avoid engaging in moderate or vigorous exercise.

To ensure continuous data collection and adherence to the protocol, the accelerometers were replaced after the first 7 days of the 14-day reduction period to prevent battery depletion. The GENEActiv device is waterproof and includes a triaxial microelectromechanical sensor that detects motion and gravitational acceleration with equal sensitivity across all axes. It also features a body temperature sensor to distinguish wear from non-wear periods, and has demonstrated strong reliability, with intra- and inter-instrument coefficients of variation of 1.4% and 2.1%, respectively, and has been validated for assessing PA in young adults [36]. Data were recorded at 100 Hz, stored in gravitational units (1 g = 9.81 m/s²), and converted into 1-second epochs using GENEActiv Post-Processing Software (v2.2).

PA intensity was classified using validated cut-off points: light PA ranged from 217 to 644 g, moderate PA (MPA) from 645 to 1810 g, and vigorous PA (VPA) for values ≥ 1811 g. For the purposes of this study, only moderate and vigorous PA were analyzed, as they best reflect structured exercise. The reduction in moderate-to-vigorous physical activity (MVPA) during the exercise cessation period was quantified using the following formula: [baseline MPA + 5 × baseline VPA] – [post-detraining MPA + 5 × post-detraining VPA], where the constant 5 serves as a weighting factor to emphasize the contribution of each intensity level.

2.3. Cardiorespiratory Fitness Testing

Participants underwent a graded exercise test to exhaustion on a treadmill (h/p/cosmos® 150/50 LC, Italy) to assess cardiorespiratory fitness. A modified Bruce protocol [37] was applied, which started with a 2-minutes warm-up, then speed was set at 6.0 km/h and increased 1km/h every 3 minutes until volitional exhaustion while inclination was constant at a 1%, followed by a 2-minutes cool-down period. Standardized verbal encouragement was given throughout the test. Participants wore a chest heart rate monitor (POLAR T34, Polar Electro OY, Helsinki, Finland) during the test. Maximal oxygen uptake (VO₂max) was measured for each participant using a breath-by-breath FitMate™ PRO system (Cosmed, Rome, Italy), which has been previously validated against the classic Douglas bag technique [38].

2.4. Muscular Strength

Upper limb muscular strength was measured using a hand dynamometer with an adjustable grip (TKK 5101 Grip D; Takey, Tokyo, Japan) [39]. Participants were instructed to squeeze the dynamometer gradually and continuously for a minimum of 2 seconds, alternating between the right and left hands. The maximum force exerted by each hand was recorded in kilograms-force, and the average of the scores from both handgrip tests was used in the analyses.

Lower limb muscular strength was assessed by performing the countermovement jump test on the Chronojump jump mat (Chronojump Boscosystem, Barcelona, Spain) [40]. Participants were required to place their hands on their hips, and from a standing position performed a quick downward movement, bending their knees to a 90-degree angle, and then jumping upward as high as possible. Jump height data was recorded twice, and the best performance was used in the analyses.

2.5. Physical fitness index

A physical fitness index (PFI) was calculated by averaging the standardized measurements (Mean = 0; SD = 1) from the administered tests mentioned above. Thus, the final formula for the PFI is: [(upper limb strength z-score + lower limb strength z-score + cardiorespiratory fitness z-score) / 3]. Higher z-scores in this index indicate better overall physical condition.

2.6. Anxiety state assessment

Participants’ state anxiety was assessed on two occasions—prior to the exercise reduction and immediately after the 14-day cessation period—using the State scale of the State-Trait Anxiety Inventory [41].

2.7. MRI Data Acquisition

MRI data were acquired using a 3T General Electric Signa Architect scanner (Waukesha, WI, USA) equipped with a 48-channel head coil. Participants were positioned supine inside the scanner, with cushions placed to minimize head motion. A high-resolution T1-weighted BRAVO anatomical image was obtained for each participant, covering the entire brain (TE = 3.0 ms, TR = 7.4 ms, FOV = 240 mm, phase FOV = 100%, flip angle = 8º, inversion time = 600 ms, matrix = 240 × 240, voxel size = 0.5 × 0.5 mm, slice spacing = 0.5 mm, slice thickness = 1 mm). The acquisition time for this sequence was 2 minutes and 24 seconds, yielding 300 volumes with a strictly sagittal scan plane orientation.

MRI scans were performed at two time points: baseline and immediately after the 14-day exercise cessation period. The second scan took place in the morning following the final day of reduced activity.

2.8. Image Processing

Anatomical T1-weighted images were initially reoriented by aligning the origin point (0, 0, 0) with the anterior-posterior commissure line, followed by preprocessing using the Computational Anatomy Toolbox (CAT12; v12.9, r2577; www.neuro.uni-jena.de/cat/) within the Statistical Parametric Mapping software (SPM12; v7771; www.fil.ion.ucl.ac.uk/spm/software/spm12/) under Matlab R2018b (v9.5). Following the standard preprocessing pipeline, we utilized the CAT12 “segment” module and adhered to the recommended steps outlined in the manual: 1) segmenting the original images into gray matter (GM), white matter (WM), and cerebrospinal fluid using tissue probability maps provided by SPM; 2) conducting affine registration and regularization based on the International Consortium for Brain Mapping (ICBM) template; 3) normalizing the GM segments to the Montreal Neurological Institute (MNI) template using DARTEL; and 4) applying modulation based on the affine and non-linear components (SPM default) derived from the spatial MNI normalization. After preprocessing, data quality was assessed using the CAT12 "Check sample homogeneity for long. Data" module. No outliers were identified.

2.9. Hippocampal GM volume extraction and Statistical Analyses

2.9.1. Hippocampal volume extraction

To test our hypothesis, hippocampal GM volumes (in mL) were extracted in two distinct ways using the ROI Tools module of CAT12. First, whole left and right hippocampal volumes were obtained by selecting the “Estimate mean value inside ROI for external analysis” option, employing the Neuromorphometrics atlas (http://neuromorphometrics.com/). The extracted volumes were then exported to IBM SPSS Statistics for Windows, Version 28.0 (Armonk, NY: IBM Corp.), and summed to generate a single bilateral hippocampal volume value per participant.

Subsequently, to later investigate the location of potential volumetric changes with greater anatomical specificity, the same extraction procedure was repeated using the CobrA atlas [42] (https://www.cobralab.ca/atlases), which segments the hippocampus into five subregions per hemisphere: Cornu Ammonis 1 (CA1), Cornu Ammonis 2 and 3 (CA2/CA3), and Cornu Ammonis 4 (CA4), also knowns as Dentate Gyrus (DG), Subiculum, and Stratum Radiatum/Lacunosum/Moleculare (SR/SL/SM). As with the previous step, left and right subfield volumes were summed to obtain bilateral values for each hippocampal subregion for further analysis.

2.9.2. Statistical analyses

To examine potential changes in total hippocampal volume across sessions (baseline vs. post-detraining), a repeated-measures ANCOVA in IBM SPSS Statistics for Windows, Version 28.0. (Armonk, NY: IBM Corp.) was performed. Session was treated as the within-subject factor, while PFI and reduction in MVPA were included as covariates. Additionally, to explore the effects with greater anatomical specificity, we conducted a similar repeated-measures MANCOVA, this time including the volume of each hippocampal subfield (as defined by the CobrA atlas) as within-subject factors. The same covariates as in the previous analysis—PFI and MVPA reduction—were included in the model.

On the other hand, to explore whether there were behavioral changes related to anxiety experienced before and after exercise cessation, we calculated the difference in STAI-State scores using the following formula: ΔSTAI = (STAI-State pre – STAI-State post–detraining). This difference score was then correlated with the changes in hippocampal volumes to investigate their potential relationship. To this end, Spearman correlations were conducted using the difference scores for both variables.

3.1. Quantifying Reduction in Physical Activity

The reduction in moderate-to-vigorous physical activity (MVPA) (See Fig. 1) was quantified using the MVPA reduction formula: [baseline Moderate PA (MPA) + 5 × baseline Vigorous PA (VPA)] – [post-detraining MPA + 5 × post-detraining VPA].The mean MVPA reduction (See Fig. 1) value was 32.66 minutes/day (SD = 30.01), with a range from − 28.28 to 97.74 minutes/day. Thirteen percent of the sample did not exhibit significant reductions in physical activity, as they were unable to refrain from engaging in it. In one case, this was due to an unexpected event (a music concert that led to an increase in physical activity compared to baseline levels), and in the remaining two cases, participants reported non-compliance with the exercise cessation protocol, stating that they were unable to abstain from physical activity during the designated period. The distribution of this variable met the assumptions of normality. The reduction amounted to a total of 12.38 minutes per day (SD = 14.48) of MPA and 4.05 minutes per day (SD = 4.58) of VPA.

3.2. Hippocampal Volume Changes Following Detraining

We ran a repeated-measures ANCOVA to examine potential changes in hippocampal volume, with session (baseline vs. post–PA cessation) as a within-subject factor, and PFI and MVPA reduction included as covariates. The analysis revealed a significant main effect of session [F (1,19) = 6.25, p = .022], indicating a decrease in hippocampal volume following the physical activity restriction period. Importantly, this effect was moderated by a significant interaction between session and MVPA reduction [F (1,19) = 13.22, p = .002], suggesting that the greater the reduction in physical activity, the greater the decrease in hippocampal volume (see Fig. 2).

Additionally, we ran a similar MANCOVA analysis including the volume for each subfield of the hippocampus as within-subjects factor. This analysis revealed a significant interaction between session and MVPA reduction for CA1 volume [F (1,19) = 9.21, p = .007], for the CA4 [F (1,19) = 5.50, p = 0.030] and for the Subiculum [F (1,19) = 7.03, p = .016]. All these effects reflected a reduction of hippocampal volume as MVPA reduction increased.

Table 2
*Hippocampal volumes (in mL) before and after the detraining period.* Means, standard deviations, and repeated measures ANCOVA results are presented. Statistical tests include the main effect of session (pre vs. post), and interaction effects between session and PFI, and session and MVPA reduction
	Pre (ml.) Mean ± SD	Post (ml.) Mean ± SD	F (Sess.)	P	F (Sess.*PFI)	P	F (Sess.* Red.)	P
CA1	0.792 ± 0.056	0.788 ± 0.055	1.941	.180	1.344	.261	9.208	.007
CA2/CA3	0.131 ± 0.011	0.129 ± 0.010	.283	.601	.251	.622	.054	.819
CA4/ DG	0.644 ± 0.042	0.645 ± 0.044	3.853	.0.64	4.043	.059	5.500	.030
Subiculum	0.276 ± 0.031	0.275 ± 0.029	2.455	.134	1.587	.223	7.026	.016
Stratum	0.487 ± 0.037	0.483 ± 0.034	.098	.758	0.20	.890	3.991	.060
^aValues are expressed in milliliters. Session = comparison between pre- and post-detraining

^bStatistically significant values (p < 0.05) are reported in bold.

Note

MVPA = Moderate-to-vigorous physical activity; PFI = Physical Fitness Index; Red. = MVPA reduction. Sess.= Session.

3.3. Anxiety changes

STAI-State scores obtained before and after the two-week period of PA reduction did not meet the assumptions of normality. Therefore, a Wilcoxon signed-rank T test was conducted to compare baseline and post–PA reduction scores, revealing no statistically significant difference between sessions.

To explore potential associations with individual differences, Spearman rank-order correlations were performed between the difference in STAI-State scores (ΔSTAI) and key variables: PFI, MVPA reduction, and changes in hippocampal volume. Among these, only the correlation with total hippocampal volume change reached statistical significance, ρ (21) = –.47, p = .028. Specifically, greater reductions in hippocampal volume were associated with smaller decreases in STAI-State scores (see Fig. 3). Importantly, when analyzing hippocampal subfields separately, the correlation was also significant for the CA4/dentate gyrus (CA4/DG) subfield, ρ (21) = –.45, p = .036.

The primary aim of this study was to investigate the effects of exercise cessation on brain hippocampus in regularly active young adults. Our findings revealed that after a 14-day period of exercise cessation, compared to the measurements taken prior to the detraining, gray matter volume decreased in the hippocampus, especially in those individuals with a larger reduction in physical activity. This effect is especially observed in the anterior part of the hippocampus. Additionally, the decrement in hippocampus volume (especially in CA4/DG) was negatively associated with anxiety change after detraining.

The present study provides clear evidence in healthy and young humans that the reduction of exercise is associated with alterations in the hippocampal structure, with emotion regulation being one of the possible mechanisms involved in these changes. These findings contribute to the limited body of literature on the effects of exercise cessation on brain structure in young adults. Research on this area remains limited, and, as far as we are aware, this is the first study to use structural MRI to assess the impact of exercise cessation on brain architecture, while also rigorously controlling the PA of the participants throughout the study. Using accelerometer measurements, our sample showed a differential reduction in PA, with an average decrease of approximately 4 hours in MVPA over a two-week period. This reduction led to a slight decrease in hippocampal volume, particularly among participants who exhibited greater reductions in PA.

It is well established that physical exercise promotes neurogenesis, synaptic plasticity, and increases gray matter volume, particularly in the hippocampus, which enhances memory and learning [11, 14, 16, 43]. However, research on the effects of exercise cessation is sparse, and the reversibility of long-term training benefits remains unclear. Our results are consistent with a previous study showing the effects of stopping physical exercise on the blood support of the human brain measured with arterial spin labelling [34], which found that a 10-day cessation of regular exercise in master athletes reduced resting blood flow in both hippocampi. This reduction in CBF may be linked to our findings of decreased gray matter volume in these areas. We may speculate that exercise cessation leads to slight increases in resting heart rate and blood pressure, which in turn elevates metabolic demands and may reduce cerebral perfusion, particularly in hippocampal regions [44]. Thus, as an adequate CBF is essential for delivering oxygen and nutrients, supporting neural health, and maintaining structural integrity, a reduction in blood flow following exercise cessation may impair these processes over time, potentially leading to diminished gray matter volume, as observed in our study.

Similar results have been obtained from animal research. Studies have shown that cessation of voluntary physical activity impairs hippocampal neurogenesis to a greater extent than sedentary behavior [28]. In studies characterizing this process, the same research group demonstrated that the maximum reduction in hippocampal neurogenesis occurred during the first two weeks without activity, and that by weeks 5–8, values dropped below those of the control group, exhibiting a negative rebound effect [27]. In a second experiment, their results indicated that exercise withdrawal impaired hippocampal cell survival at five weeks post-cessation, which may explain the observed rebound effect. These neurogenesis findings are consistent with our hippocampal findings. In these animal studies, it is important to note that the observed effect is not associated with an increase in stress, but rather with a decrease in mobility and exploratory activity.

Importantly, the observed reduction in hippocampal volume was influenced by the magnitude of MVPA reduction, as greater reductions were associated with larger decreases in hippocampal volume. This may be explained by the fact that MVPA has been consistently linked to neuroprotective effects, including enhanced neurogenesis, improved cerebral blood flow, and increased levels of BDNF, particularly in the hippocampus. Consequently, a significant decline in MVPA may reduce the stimulation of these neurobiological processes, making the hippocampal structure more vulnerable and leading to more pronounced volumetric changes following a detraining period. In line with these findings, previous research in older adults has shown that the neurological effects of detraining can depend on the amount of prior engagement in physical activity, with greater baseline activity levels being associated with more marked changes following inactivity [24].

Particularly, results of the current study showed a significant reduction in the volume of CA1, CA4/dentate gyrus, and subiculum of the hippocampus. This anterior localization of the hippocampus aligns with previous findings showing that the effects of exercise training are associated with structural changes in these regions [16, 45–47]. However, other studies have reported that physical activity is associated with structural changes in different hippocampal subfields [15, 28, 43] such as the CA4/dentate gyrus. The latter region is of particular interest given its role in adult neurogenesis, which is highly sensitive to physical activity levels. Evidence suggests that regular engagement in physical activity enhances neurogenesis in the dentate gyrus, mediated in part by increased levels of BDNF [43]. Therefore, the greater volume reductions observed in this subfield among individuals with larger decreases in MVPA may reflect a disruption of these activity-dependent neuroplastic processes. In the case of CA1, observed increases in volume appear to be driven by glial volume expansion [48] suggesting that the volume reductions observed following PA restriction may be attributable to the same mechanism.

The volumetric plasticity of CA1, CA4/dentate gyrus, and the subiculum is particularly intriguing due to their proposed involvement in episodic memory and spatial processing. Traditionally, these regions are key components of the trisynaptic circuit, a memory-related loop where inputs from CA3 reach CA1 before being transmitted to the subiculum and subsequently related to cortical and contralateral areas. CA1 has been closely linked to episodic memory [49, 50] and spatial navigation [51]. Likewise, the subiculum plays a significant role in memory consolidation processes [52]. The reduction in MVPA observed in our sample appears to be associated, on one hand, with a decreased demand for spatial processing and motor control, functions that are largely dependent on hippocampal pyramidal neurons [53]. Consequently, there may be a reduced need for spatial information processing mediated specifically by CA1 pyramidal neurons. On the other hand, Cherednichenko and colleagues [15] have pointed out that MVPA is typically associated with moments in which organisms engage in voluntary physical effort, which are therefore more likely to be encoded as memorable events. Therefore, a reduction in such activity may consequently lead to a decrease in the frequency of episodic events and a corresponding decline in hippocampal engagement. As a result of these processes, the observed reduction in specific hippocampal subfields volume proportional to the decrease in PA may reflect a diminished functional demand for cognitive processing in this region.

In addition to its roles in spatial processing and episodic memory, the hippocampus is also involved in stress regulation. Previous studies have shown that chronic stress can lead to a reduction in hippocampal volume [54], a phenomenon that has also been documented in psychiatric conditions such as post-traumatic stress disorder (PTSD) [55–57] and depression [58]. The dentate gyrus of the hippocampus is one of the few regions where neurogenesis persists into adulthood, a process known to be modulated by various factors, including chronic stress and physical activity [59, 60]. A notable finding of the present study is the association between hippocampal volume and changes in state anxiety scores (STAI-State), suggesting a possible link between structural plasticity in the hippocampus and fluctuations in emotional state. At the group level, a slight but non-significant increase in STAI-State scores was observed, which appears to be moderated by the decrease in hippocampal volume. Specifically, participants who showed greater reductions in hippocampal volume—particularly in the CA4/dentate gyrus (CA4/DG) subfield—tended to exhibit smaller changes in STAI-State scores. This pattern may reflect a compensatory mechanism in response to mood fluctuations caused by the absence of regular physical activity such as exercise.

In summary, the present study provides novel evidence of the negative impact that a short-term reduction in physical activity can have on hippocampal volume in young adults who are regularly engaged in physical exercise training. Our findings indicate that even a relatively brief two-week period of detraining is sufficient to induce measurable decreases in gray matter volume in the hippocampus. Notably, this effect was more pronounced in individuals who experienced greater reductions in their physical activity levels during the intervention period.

These results are particularly relevant in light of the fact that temporary interruptions in exercise routines—due to holidays, injury, illness, or lifestyle changes—are common in everyday life. The observed volumetric reductions in the hippocampus may reflect a decrease in the cognitive and physiological demands placed on this brain region, as well as a reduction in hippocampal engagement in functions such as spatial processing, episodic memory encoding, and stress regulation. Future research should aim to replicate and extend these results using larger and more diverse samples, longer follow-up periods, and neuroimaging approaches capable of disentangling the specific contributions of hippocampal subfields. Such work will be essential to fully understand the time course, mechanisms, and functional implications of hippocampal changes in response to physical activity fluctuations.

Ethics approval and consent to participate

All procedures were conducted in accordance with the guidelines and regulations approved by the Research Ethics Committee of Universitat Jaume I (CD/11/2021). Written informed consent was obtained from all participants in line with the approved protocol, and they received monetary compensation for their participation.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by two grants from the Generalitat Valenciana (PROMETEO/2017/109, CIPROM/2023/58) and by the Spanish State Research Agency (PID2019-108198GB-I00, PID2023-150776NB-I00). AC was supported by a pre-doctoral graduate program grant (PREDOC/2020/38. Universitat Jaume I).

Author’s contributions

A.C: Writing – review & editing, Writing – original draft, Visualization, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. M.B-P: Supervision, Methodology, Investigation, Formal analysis, Data curation. MR.B-V: Writing – review & editing, Supervision, Resources, Methodology, Investigation, Data curation, Conceptualization. D.M-U: Writing – review & editing, Supervision, Methodology, Investigation, Data curation, Conceptualization. C.A: Writing –review & editing, Writing – original draft, Visualization, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Acknowledgments

We would like to express our gratitude to all the participants for their collaboration in this study, as well as to the radiography technicians at the ASCIRES-Castellón clinic for their assistance during data acquisition.

Availability of data and materials

The datasets generated and analyzed during the current study are available in the Open Science Framework (OSF) repository at https://osf.io/fdtyc/

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A two-week period of detraining reduces hippocampal volume in regularly active young adults: a structural MRI study

Status:

Version 1

Abstract

Background

Results

Conclusions

Figures

1. Introduction

2. Methods

2.1. Participants

2.2. Exercise reduction and monitoring of protocol adherence

2.3. Cardiorespiratory Fitness Testing

2.4. Muscular Strength

2.5. Physical fitness index

2.6. Anxiety state assessment

2.7. MRI Data Acquisition

2.8. Image Processing

2.9. Hippocampal GM volume extraction and Statistical Analyses

2.9.1. Hippocampal volume extraction

2.9.2. Statistical analyses

3. Results

3.1. Quantifying Reduction in Physical Activity

3.2. Hippocampal Volume Changes Following Detraining

3.3. Anxiety changes

4. Discussion

5. Conclusion

Declarations

References

Additional Declarations

Status:

Version 1