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Whole-body vibration (WBV) therapy is a way of passive exercise in which subjects are exposed to mild and well-controlled mechanical vibrations through a vibrating platform. For a long time, studies have focused on the effects and applications of WBV to enhance musculoskeletal performance in athletes and patients suffering from musculoskeletal disorders. Recent evidence points toward the positive effect of WBV on the brain and its therapeutic potential in brain disorders. Research being done in the field gradually reveals cellular and molecular mechanisms underlying WBV affecting the body and brain. Particularly, the influence of WBV on immune and brain function is a growing field that warrants an up-to-date and integrated review. Immune function is closely intertwined with brain functioning and plays a significant role in various brain disorders. Dysregulation of the immune response is linked to conditions such as neuroinflammation, neurodegenerative diseases, and mood disorders, highlighting the crucial connection between the immune system and the brain. This review aims to explore the impact of WBV on the cellular and molecular pathways involved in immune and brain functions. Understanding the effects of WBV at a cellular and molecular level will aid in optimizing WBV protocols to improve its therapeutic potential for brain disorders.

Background: Beneficial effects of whole-body vibration (WBV) on brain and musculoskeletal health in mice have been demonstrated, but underlying mechanisms remain relatively unrevealed. WBV improves attention and memory performance in mice, putatively through stimulation of the cholinergic system. Here, we investigated the effects of WBV on the septo-hippocampal cholinergic system. Methods: Young C57BL/6 mice (8 weeks old) were subjected to 10 min WBV/day (mechanical vibration: 30 Hz; ~0.1-μm peak-to-peak displacement), 5X/week for 5 weeks. In Experiment 1, choline acetyltransferase (ChAT)-immunoreactivity in the septum and hippocampus was analyzed either 2 or 24 h after the last WBV session. Pseudo-WBV-treated mice (same handling procedure as WBV, but no vibrations) served as controls. In Experiment 2, the longitudinal profile of ChAT-immunoreactivity was analyzed in the hippocampus after 1, 2, 3, 4, or 5 weeks of WBV. In addition, synaptophysin immunostaining was performed at either 2 and 5 weeks of WBV. Mice housed 1/cage during the entire experiment served as controls. The balance-beam test was used to monitor the functional impact of WBV. In Experiment 3, a Y-maze reference-memory test was performed after 5 weeks of WBV to obtain a functional cognitive outcome measure of WBV. Pseudo-WBV treated mice served as controls. Results: In Experiment 1, ChAT-immunoreactivity was significantly enhanced after the last WBV session of the 5-week period. This was found in the septum, Cornu Ammonis 1 (CA1), CA3, and dentate gyrus, and was dependent on layer and time-point (2 or 24 h). Experiment 2 revealed that, ChAT-immunoreactivity was lower after 2 weeks of WBV, whereas it was significantly higher after 5 weeks (similar to in Experiment 1). Immunostaining for synaptophysin, a marker for synaptic density, was also significantly higher after 5 weeks of WBV, but not significantly lower after 2 weeks, as was ChAT. WBV-treated groups performed significantly better than did controls on the balance beam from week 3 onwards. Experiment 3 showed that WBV-treated mice had better spatial-reference memory performance in the Y-maze test than did pseudo-WBV controls. Conclusions: Our results indicate that WBV stimulates the septo-hippocampal cholinergic system in a gradual and dynamic way that may contribute to improved spatial-memory performance. This finding suggests that WBV, by upregulation of the septo-hippocampal cholinergic system, may be considered a valuable therapeutic strategy to enhance brain functions in aging, neurodegenerative, and other brain diseases.

Whole body vibration (WBV) is a form of passive exercise that offers an alternative physical training to aged individuals with limitations in their physical and mental capabilities. The aim of the present study was to explore the therapeutic potential of five weeks of WBV on anxiety-like behaviors as well as learning and memory abilities in senescent thirty months old rats. Animals were exposed to 5 min vibration twice per day, five times per week during the five consecutive weeks. Pseudo WBV treated animals served as controls. After five weeks of WBV treatment, animals were tested for anxiety-like behavior by the open field test and for spatial and object memory functions by the novel and spatial object recognition tests, respectively. As a result, anxiety-like and exploratory behaviors were significantly improved in the WBV treated group compared to the pseudo WBV group. Furthermore, WBV treatment increased discrimination performance in both spatial and object memory function testing. These results indicate that WBV treatment in thirty months old rats seems to have comparable beneficial effects on age-related emotional and cognitive performance as what has been reported in younger age groups.

Abstract Background Alzheimer’s disease (AD) is the core cause of dementia in elderly populations. One of the main hallmarks of AD is extracellular amyloid beta (Aβ) accumulation (APP-pathology) associated with glial-mediated neuroinflammation. Whole-Body Vibration (WBV) is a passive form of exercise, but its effects on AD pathology are still unknown. Methods Five months old male J20 mice (n = 26) and their wild type (WT) littermates (n = 24) were used to investigate the effect of WBV on amyloid pathology and the healthy brain. Both J20 and WT mice underwent WBV on a vibration platform or pseudo vibration treatment. The vibration intervention consisted of 2 WBV sessions of 10 min per day, five days per week for five consecutive weeks. After five weeks of WBV, the balance beam test was used to assess motor performance. Brain tissue was collected to quantify Aβ deposition and immunomarkers of astrocytes and microglia. Results J20 mice have a limited number of plaques at this relatively young age. Amyloid plaque load was not affected by WBV. Microglia activation based on IBA1-immunostaining was significantly increased in the J20 animals compared to the WT littermates, whereas CD68 expression was not significantly altered. WBV treatment was effective to ameliorate microglia activation based on morphology in both J20 and WT animals in the Dentate Gyrus, but not so in the other subregions. Furthermore, GFAP expression based on coverage was reduced in J20 pseudo-treated mice compared to the WT littermates and it was significantly reserved in the J20 WBV vs. pseudo-treated animals. Further, only for the WT animals a tendency of improved motor performance was observed in the WBV group compared to the pseudo vibration group. Conclusion In accordance with the literature, we detected an early plaque load, reduced GFAP expression and increased microglia activity in J20 mice at the age of ~ 6 months. Our findings indicate that WBV has beneficial effects on the early progression of brain pathology. WBV restored, above all, the morphology of GFAP positive astrocytes to the WT level that could be considered the non-pathological and hence “healthy” level. Next experiments need to be performed to determine whether WBV is also affective in J20 mice of older age or other AD mouse models.

Many living organisms of the animal kingdom have the fundamental ability to form and retrieve memories. Most information is initially stored as short-term memory, which is then converted to a more stable long-term memory through a process called memory consolidation. At the neuronal level, synaptic plasticity is crucial for memory storage. It includes the formation of new spines, as well as the modification of existing spines, thereby tuning and shaping synaptic efficacy. Cofilin critically contributes to memory processes as upon activation, it regulates the shape of dendritic spines by targeting actin filaments. We previously found that prolonged activation of cofilin in hippocampal neurons attenuated the formation of long-term object-location memories. Because the modification of spine shape and structure is also essential for short-term memory formation, we determined whether overactivation of hippocampal cofilin also influences the formation of short-term memories. To this end, mice were either injected with an adeno-associated virus expressing catalytically active cofilin, or an eGFP control, in the hippocampus. We show for the first time that cofilin overactivation improves short-term memory formation in the object-location memory task, without affecting anxiety-like behavior. Surprisingly, we found no effect of cofilin overactivation on AMPA receptor expression levels. Altogether, while cofilin overactivation might negatively impact the formation of long-lasting memories, it may benefit short-term plasticity.

Abstract Women with cardiovascular disease may be more susceptible to concomitant mental health problems, such as depression and cognitive decline. Exercise training has beneficial effects on the cardiovascular system as well as on mental functions. Aim of the present study was to study the effects of exercise training on heart, brain and behavior in the isoproterenol (ISO) model in middle-aged female rats. Twelve months old female Wistar rats were submitted to ISO injections (70 mg/kg s.c., on two consecutive days) or received saline. One week later, rats were assigned to either exercise training (treadmill running) or control handling for five weeks. During the last 7 days, tests were performed regarding depressive-like behavior and cognitive function. Then, rats were sacrificed and heart and brains were dissected for (immuno)histochemistry. ISO-induced cardiac effects were eminent from cardiac fibrosis and declined cardiac function. Exercise training reversed cardiac damage and partly restored ISO-induced cardiac dysfunction. However, ISO treatment could not be associated with neuroinflammation, nor impaired hippocampal neurogenesis or neuronal function. Accordingly, no cognitive impairment or depressive-like behavior were observed. Actually, hippocampal microglia hyper-ramification was observed after ISO. Exercise left neuroinflammation and behavior merely unaltered, and even reduced neuronal function. Our data indicated that the cardiac damage after ISO in middle-aged female rats, and the subsequent beneficial effects of five weeks exercise training on the heart, were not reflected in changes in the brain nor in altered behavior.

BackgroundFemales with cardiovascular disease seem more vulnerable to develop concomitant mental problems, such as depression and cognitive decline. Although exercise is shown beneficial in cardiovascular disease as well as in mental functions, these patients may be incapable or unmotivated to perform exercise. Whole body vibration (WBV) could provide a passive alternative to exercise. Aim of the present study was to compare WBV to exercise after isoproterenol (ISO)-induced myocardial damage in female rats, regarding effects on heart, brain and behavior.MethodsOne week after ISO (70 mg/kg s.c., on 2 consecutive days) or saline injections, 12 months old female rats were assigned to WBV (10 minutes daily), treadmill running (30 minutes daily) or pseudo intervention for 5 weeks. During the last 10 days, behavioral tests were performed regarding depressive-like behavior, cognitive function, and motor performance. Rats were sacrificed, brains and hearts were dissected for (immuno)histochemistry.ResultsSignificant ISO-induced cardiac collagen deposition (0.67 ± 0.10 vs 0.18 ± 0.03%) was absent after running (0.45 ± 0.26 vs 0.46 ± 0.08%), but not after WBV (0.83 ± 0.12 vs 0.41 ± 0.05%). However, WBV as well as running significantly reduced hippocampal (CA3) collagen content in ISO-treated rats. Significant regional differences in hippocampal microglia activity and brain derived neurotrophic factor (BDNF) expression were observed. Significant ISO-induced CA1 microglia activation was reduced after WBV as well as running, while opposite effects were observed in the CA3; significant reduction after ISO that was restored by WBV and running. Both WBV and running reversed the ISO-induced increased BDNF expression in the CA1, Dentate gyrus and Hilus, but not in the CA3 area. Whereas running had no significant effect on behavior in the ISO-treated rats, WBV may be associated with short-term spatial memory in the novel location recognition test.ConclusionAlthough the female rats did not show the anticipated depressive-like behavior or cognitive decline after ISO, our data indicated regional effects on neuroinflammation and BDNF expression in the hippocampus, that were merely normalized by both WBV and exercise. Therefore, apart from the potential concern about the lack of cardiac collagen reduction, WBV may provide a relevant alternative for physical exercise.

Abstract Whole body vibration (WBV) is a form of passive exercise by the stimulation of mechanical vibration platform. WBV has been extensively investigated through clinical studies with main focus on the musculoskeletal system. However, pre-clinical data in the context of behavior, memory and motor functions with aged rodents are limited. The aim of this experiment was to investigate the dose dependent effects of a five weeks long WBV intervention with an aged animal model including anxiety-related behavior, memory and motor functions, as well as markers of (neuro)inflammation. Male Wistar rats (18 months) underwent 5 or 20 min daily vibration exposure or pseudo-treatment (i.e.: being subjected to the same environmental stimuli for 5 or 20 min, but without exposure to vibrations) 5 times per week. After 5 weeks treatment, cognitive functions, anxiety-like behavior and motor performance were evaluated. Finally, brain tissue was collected for immunohistological purposes to evaluate hippocampal (neuro)inflammation. Animals with 20 min daily session of WBV showed a decrease in their anxiety-like behavior and improvement in their spatial memory. Muscle strength in the grip hanging test was only significantly improved by 5 min daily WBV treatments, whereas motor coordination in the balance beam test was not significantly altered. Microglia activation showed a significant decrease in the CA1 and Dentate gyrus subregions by both dose of WBV. In contrast, these effects were less pronounced in the CA3 and Hilus subregions, where only 5 min dose showed a significant effect on microglia activation. Our results indicate, that WBV seems to be a comparable strategy on age-related anxiety, cognitive and motor decline, as well as alleviating age-related (neuro)inflammation.

Recent research in rodents and humans revealed that Whole-Body Vibration (WBV) is beneficial for cognitive functions. However, the optimal WBV conditions are not established: contrary to vertical WBV, side-alternating WBV was not investigated before. The present study investigated the short-term effects of side-alternating WBV in standing and sitting posture on specific cognitive function of young adults. We used a balanced cross-over design. Sixty healthy young adults (mean age 21.7 ± 2.0 years, 72% female) participated. They were exposed to three bouts of two-minute side-alternating WBV (frequency 27 Hz) and three control conditions in two different sessions. In one session a sitting posture was used and in the other session a standing (semi-squat) posture. After each condition selective attention and inhibition was measured with the incongruent condition of the Stroop Color-Word Interference Test. WBV significantly (p = 0.026) improved selective attention and inhibition in the sitting posture, but not in the standing posture. The sitting posture was perceived as more comfortable, joyous and less exhaustive as compared to the standing posture. This study demonstrated that side-alternating WBV in sitting posture improves selective attention and inhibition in healthy young adults. This indicates that posture moderates the cognitive effect of WBV, although the effects are still small. Future studies should focus on the working mechanisms and further optimization of settings, especially in individuals who are unable to perform active exercise.

Abstract Acute sympathetic stress can result in cardiac fibrosis, but may also lead to mental dysfunction. Exercise training after isoproterenol (ISO)-induced acute sympathetic stress was investigated regarding cardiac damage, neuroinflammation, brain function and behavior. Male Wistar rats (12 months) received ISO or saline. One week later, treadmill running or control handling (sedentary) started. After 4 weeks, cognitive- and exploratory behavior were evaluated, and heart and brain tissues were analyzed regarding cardiac damage, hippocampal neuroinflammation and neuronal function. ISO did not affect cognitive performance nor hippocampal function. However, ISO reduced anxiety, coinciding with locally reduced microglia (processes) size in the hippocampus. Exercise in ISO rats reversed anxiety, did not affect microglia morphology, but increased brain function. Thus, exercise after ISO did not affect cardiac damage, cognition or hippocampal neuroinflammation, but normalized anxiety. Increased localized BDNF expression may indicate improved brain function.

Although exercise is usually associated with beneficial effects on physical and mental health, patients recovering from surgery may be hampered to perform active exercise. Whole body vibration (WBV) is suggested a passive alternative for physical training. Aim of the present study was to explore the therapeutic potential of WBV compared to physical exercise during early post-surgery recovery.Male three months old Wistar rats underwent major abdominal surgery. Starting the day after surgery, rats were subjected to either daily WBV or exercise (treadmill running) for 15 consecutive days. Control rats underwent pseudo treatment. During the first week after surgery, effects of interventions were obtained from continuous recording of hemodynamic parameters, body temperature and activity (via an implanted transducer). Behavioral tests were performed during the second post-surgical week to evaluate anxiety-like behavior, short and long-term memory functions, cognitive flexibility and motor performance. Animals were sacrificed 15 days after surgery and brain tissue was collected for analysis of hippocampal neuroinflammation and neurogenesis.Surgery significantly impacted all parameters measured during the first post-surgery week, irrespective of the type of surgery. Effect on cognitive performance was limited to cognitive flexibility; both WBV and exercise prevented the surgery-induced decline. Exercise, but not WBV increased anxiety-like behavior and grip strength. WBV as well as exercise prevented the surgery-induced declined neurogenesis, but surgery-associated hippocampal neuroinflammation was not affected.Our results indicated that active exercise and WBV share similar therapeutic potentials in the prevention of surgery induced decline in cognitive flexibility and hippocampal neurogenesis. In contrast to exercise, WBV did not increase anxiety-like behavior. Since neither intervention affected hippocampal neuroinflammation, other mechanisms and/or brain areas may be involved in the behavioral effects. Taken together, we conclude that WBV may provide a relevant alternative to active exercise during the early stage of post-operative recovery.

Acute cardiac damage can be induced by isoproterenol injections in animals. The associated inflammatory response could be reflected in the brain as neuroinflammation, with potential consequences for brain function and behavior. Although cardiac responses are reported age and sex-related, for neuroinflammation and brain function this is virtually unknown. Therefore, cardiac damage and its consequences for neuroinflammation, brain function and behavior were compared in aged male and female rats. Wistar rats of 24 months of age were treated with isoproterenol (ISO, twice s.c.) or saline. Four weeks after injections, exploratory behavior and short-term memory were tested. Then, rats were sacrificed. Hearts were collected to measure cardiac damage. Brain tissue was collected to obtain measures of neuroinflammation and brain function. In male-, but not in female rats, ISO induced significant cardiac damage. Accordingly, mortality was higher in males than in females. Baseline hippocampal microglia activity was lower in females, while ISO induced neuroinflammation in both sexes, Hippocampal brain-derived neurotrophic factor expression appeared lower in females, without effects of ISO. In the open field test, ISO-treated males, but not females, displayed anxiety-like behavior. No effects of ISO were observed on short-term memory in either sex. In conclusion, sex dimorphism in effects of ISO was observed for cardiac damage and open field behavior. However, these effects could not be related to differences in hippocampal neuroinflammation or neuronal function.

Phenylketonuria (PKU) is a metabolic disorder caused by a hepatic enzyme deficiency causing high blood and brain levels of the amino acid Phenylalanine (Phe), leading to severe cognitive and psychological deficits that can be prevented, but not completely, by dietary treatment. The behavioral outcome of PKU could be affected by the gut-microbiome-brain axis, as diet is one of the major drivers of the gut microbiome composition. Gut-microbiome alterations have been reported in treated patients with PKU, although the question remains whether this is due to PKU, the dietary treatment, or their interaction. We, therefore, examined the effects of dietary Phe restriction on gut-microbiome composition and relationships with behavioral outcome in mice. Male and female BTBR Pahenu2 mice received either a control diet (normal protein, “high” Phe), liberalized Phe-restricted (33% natural protein restriction), or severe Phe-restricted (75% natural protein restriction) diet with protein substitutes for 10 weeks (n = 14 per group). Their behavioral performance was examined in an open field test, novel and spatial object location tests, and a balance beam. Fecal samples were collected and sequenced for the bacterial 16S ribosomal RNA (rRNA) region. Results indicated that PKU on a high Phe diet reduced Shannon diversity significantly and altered the microbiome composition compared with wild-type animals. Phe-restriction prevented this loss in Shannon diversity but changed community composition even more than the high-Phe diet, depending on the severity of the restriction. Moreover, on a taxonomic level, we observed the highest number of differentially abundant genera in animals that received 75% Phe-restriction. Based on correlation analyses with differentially abundant taxa, the families Entereococacceae, Erysipelotrichaceae, Porphyromonadaceae, and the genus Alloprevotella showed interesting relationships with either plasma Phe levels and/or object memory. According to our results, these bacterial taxa could be good candidates to start examining the microbial metabolic potential and probiotic properties in the context of PKU. We conclude that PKU leads to an altered gut microbiome composition in mice, which is least severe on a liberalized Phe-restricted diet. This may suggest that the current Phe-restricted diet for PKU patients could be optimized by taking dietary effects on the microbiome into account.

Aging is a progressive process leading to functional decline in many domains. Recent studies have shown that physical exercise (PE) has a positive influence on the progression of age-related functional decline, including motor and brain functions. Whole body vibration (WBV) is a form of passive stimulation by mechanical vibration platforms, which offers an alternative for PE interventions, especially for aged individuals. WBV has been demonstrated to mimic the beneficial effects of PE on the musculoskeletal system, as well on the central nervous system. However, preclinical data with aged rodents are very limited. Hence, the purpose of this experiment was to investigate the effects of a 5-week WBV intervention with an aged animal model on memory functions, anxiety-related behavior, and motor performance. The 18-month old male (N = 14) and female (N = 14) Wistar rats were divided into two groups, namely, vibration and pseudo-vibration. Animals underwent a 5-week WBV intervention protocol with low intensity (frequency of 30 Hz and amplitude of 50–200 μm) stimulation. After 5 weeks, the following cognitive and motor tests were administered: open-field, novel and spatial object recognition, grip-hanging, and balance-beam. WBV-treated rats showed a decrease in their anxiety level in the open field test compared with those in the pseudo-treated controls. In addition, WBV-treated male animals showed significantly increased rearing in the open-field test compared to their pseudo controls. Spatial memory was significantly improved by WBV treatment, whereas WBV had no effect on object memory. Regarding motor performance, both grip strength and motor coordination were improved by WBV treatment. Our results indicate that WBV seems to have comparable beneficial effects on age-related emotional, cognitive, and motor decline as what has been reported for active PE. No striking differences were found between the sexes. As such, these findings further support the idea that WBV could be considered as a useful alternative for PE in case active PE cannot be performed due to physical or mental issues.

(1) Background: When the severity of Parkinson’s Disease (PD) increases, patients often have difficulties in performing exercises. Whole-Body Vibration (WBV) may be a suitable alternative. This systematic review aims to clarify if WBV shows potential as rehabilitative therapy for PD patients. (2) Methods: We searched several databases for controlled trials investigating the effects of WBV (1) on PD populations and (2) PD neuropathological mechanisms. We included both human and animal studies and performed meta-analyses. (3) Results: The studies on PD populations (14 studies) show an overall significant, but small, effect in favor of WBV (Hedges’ g = 0.28), for which the effects on stability (Hedges’ g = 0.39) and balance (Hedges’ g = 0.30) are the most prominent. The studies on the neuropathological mechanisms (18 studies) show WBV effects on neuroinflammation (Hedges’ g = –1.12) and several specific WBV effects on neurotransmitter systems, growth factors, neurogenesis, synaptic plasticity and oxidative stress. (4) Conclusions: The effects of WBV on human PD patients remains inconclusive. Nevertheless, WBV protocols with sufficient duration (≥3 weeks), session frequency (≥3 sessions/week) and vibration frequency (≥20 Hz) show potential as a treatment method, especially for motor function. The potential of WBV for PD patients is confirmed by the effects on the neuropathological mechanisms in mostly non-PD populations. We recommend high-quality future studies on both PD patients and PD mouse models to optimize WBV protocols and to examine the neuropathological mechanisms in PD populations.

Vibrations are all around us. We can detect vibrations with sensitive skin mechanoreceptors, but our conscious awareness of the presence of vibrations is often limited. Nevertheless, vibrations play a role in our everyday life. Here, we briefly describe the function of vibration detection and how it can be used for medical applications by way of whole body vibration. Strong vibrations can be harmful, but milder vibrations can be beneficial, although to what extent and how large the clinical relevance is are still controversial. Whole body vibration can be applied via a vibrating platform, used in both animal and human research. Recent findings make clear that the mode of action is twofold: next to the rather well-known exercise (muscle) component, it also has a sensory (skin) component. Notably, the sensory (skin) component stimulating the brain has potential for several purposes including improvements in brain-related disorders. Combining these two components by selecting the optimal settings in whole body vibration has clear potential for medical applications. To realize this, the field needs more standardized and personalized protocols. It should tackle what could be considered the “Big Five” variables of whole body vibration designs: vibration amplitude, vibration frequency, method of application, session duration/frequency, and total intervention duration. Unraveling the underlying mechanisms by translational research can help to determine the optimal settings. Many systematic reviews on whole body vibration end with the conclusion that the findings are promising yet inconclusive. This is mainly because of the large variation in the “Big Five” settings between studies and incomplete reporting of methodological details hindering reproducibility. We are of the opinion that when (part of) these optimal settings are being realized, a much better estimate can be given about the true potential of whole body vibration as a medical application.

Background/Aims: Reliable and valid neuropsychological tests for patients with dementia are scarce. To improve the assessment of attention and inhibitory control in dementia, we determined the feasibility, test-retest reliability, and validity of a Flanker task. Methods: Participants with all-cause diagnosed dementia (n = 22, mean age 84 years; mean Mini-Mental State Examination [MMSE] score = 19.4) performed a computerized Flanker task twice within 7 days. The Flanker task required participants to indicate the direction of target arrows flanked by congruent or incongruent arrows. Number of completed trials, accuracy, and reaction times (RTs) were recorded, and interference scores were calculated from basic scores. We examined the psychometric properties of the Flanker task and its relationship with the MMSE and Stroop test. Results: The Flanker task was feasible. Test-retest reliability was good for number of correct answers and RTs, and fair to poor for accuracy and the interference scores. The correlation of the Flanker task with Stroop and MMSE performance was fair to poor. Conclusion: The Flanker task appears to be feasible, and a reliable and valid measure of selective attention. Although the test-retest reliability for the Flanker RT interference measure was fair, future studies need to confirm its validity to measure inhibitory control in patients with dementia.

Abstract Background Dementia affects cognitive functioning, physical functioning, activities of daily living (ADLs), and quality of life (QOL). Pharmacological treatments to manage, cure or prevent dementia remain controversial. Therefore development of non-pharmacological approaches to prevent, or at least delay the onset and progression of dementia is urgently needed. Passive exercise is proposed to be such a non-pharmacological alternative. This study primarily aims to investigate the effects of three different forms of passive exercise on QOL and ADLs of institutionalized patients with dementia. The secondary aims are to assess the effects of three different forms of passive exercise on cognitive functioning and physical functioning of institutionalized patients with dementia as well as on care burden of both the primary formal and primary informal caregivers of these patients. Methods This is a multicenter randomized controlled trial. Three forms of passive exercise are distinguished; motion simulation (MSim), whole body vibration (WBV), and a combination of both MSim + WBV. Intervention effects are compared to a control group receiving regular care. Institutionalized patients with dementia follow a six-week intervention program consisting of four 4–12 min sessions a week. The primary outcome measures QOL and ADLs and secondary outcome measure care burden are assessed with questionnaires filled in by the primary formal and informal caregivers of the patient. The other secondary outcome measures cognitive and physical functioning are assessed by individual testing. The four groups are compared at baseline, after 6 weeks of intervention, and 2 weeks after the intervention has ended. Discussion This study will provide insight in the effects of different forms of passive exercise on QOL, ADLs, cognitive and physical functioning and care burden of institutionalized patients with dementia and their primary formal and informal caregivers. The results of this study might support the idea that passive exercise can be an efficient alternative for physical activity for patients not able to be or stay involved in active physical exercise. Trial registration The Netherlands National Trial Register (NTR6290). Retrospectively registered 29 March 2017.

Whole-body vibration (WBV) is an exercise modality or treatment/prophylaxis method in which subjects (humans, animals, or cells) are exposed to mechanical vibrations through a vibrating platform or device. The vibrations are defined by their direction, frequency, magnitude, duration, and the number of daily bouts. Subjects can be exposed while performing exercises, hold postures, sitting, or lying down. Worldwide, WBV has attracted significant attention, and the number of studies is rising. To interpret, compare, and aggregate studies, the correct, complete, and consistent reporting of WBV-specific data (WBV parameters) is critical. Specific reporting guidelines aid in accomplishing this goal. There was a need to expand existing guidelines because of continuous developments in the field of WBV research, including but not limited to new outcome measures regarding brain function and cognition, modified designs of WBV platforms and attachments (e.g., mounting a chair on a platform), and comparisons of animal and cell culture studies with human studies. Based on Delphi studies among experts and using EQUATOR recommendations, we have developed extended reporting guidelines with checklists for human and animal/cell culture research, including information on devices, vibrations, administration, general protocol, and subjects. In addition, we provide explanations and examples of how to report. These new reporting guidelines are specific to WBV variables and do not target research designs in general. Researchers are encouraged to use the new WBV guidelines in addition to general design-specific guidelines.

Physical inactivity has emerged as an important and risk factor for cardiovascular and metabolic diseases, independent of levels of exercise engagement. Moreover, inactivity is associated with poor brain functioning. However, little data on the effects of physical inactivity on the brain is available and few methods are suitable to investigate this matter. We tested whether preventing lid climbing and reducing cage size could be used to model physical inactivity in mice. Sixty young adult C57Bl6 mice (10 weeks old) were divided over six groups with different housing conditions: in cages of three different sizes with lids that either allowed or prevented lid climbing. Housing under these conditions was maintained for a period of 19 weeks before the mice were killed for body composition analysis. Physical fitness tests performed around 5 and 10 weeks into the intervention revealed that motor coordination in the balance beam test was reduced by 30.65%, grip strength by 8.91% and muscle stamina in the inverted screen test by 70.37% in non-climbing mice as compared to climbing controls. Preventing climbing increased visceral fat mass by 17.31%, but did not reduce muscle mass. Neither preventing climbing nor reducing cage size affected anxiety assessed in the Open Field test and the Elevated Plus Maze. We did not find any negative effect of inactivity on spatial learning and memory in the novel object location test or working memory measured with the Y-maze Alternation test. The reduced physical fitness and increase in visceral fat mass show that our inactivity method models most effects of physical inactivity that are observed in experimental and observational studies in humans. Whereas established methods such as hindlimb unloading mimic many of the effects of bed rest, our novel method can be applied to study the effects of less extreme forms of physical inactivity (i.e., sedentary behavior) in various disease models including rodent models for brain diseases (i.e., stroke, Alzheimer’s disease).

The biological consequences of mechanical whole body vibration (WBV) on the brain are not well documented. The aim of the current study was to further investigate the effects of a 5-week WBV intervention on brain functions. Mice (C57Bl/6J males, age 15 weeks) were exposed to 30 Hz WBV sessions (10 minutes per day, 5 days per week, for a period of 5 weeks; n = 10). Controls received the same intervention without the actual vibration (n = 10). Humans (both genders, age ranging from 44-99 years) were also exposed to daily sessions of 30 Hz WBV (4 minutes per day, 4 days per week, for a period of 5 weeks; n = 18). Controls received the same protocol using a 1 Hz protocol (n = 16). Positron emission tomography imaging was performed in the mice, and revealed that glucose uptake was not changed as a consequence of the 5-week WBV intervention. Whole body vibration did, however, improve motor performance and reduced arousal-induced home cage activity. Cognitive tests in humans revealed a selective improvement in the Stroop Color-Word test. Taken together, it is concluded that WBV is a safe intervention to improve brain functioning, although the subtle effects suggest that the protocol is as yet suboptimal.

The interaction between the serotonin transporter (SERT) linked polymorphic region (5-HTTLPR) and adverse early life stressing (ELS) events is associated with enhanced stress susceptibility and risk to develop mental disorders like major depression, anxiety, and aggressiveness. In particular, human short allele carriers are at increased risk. This 5-HTTLPR polymorphism is absent in the rodent SERT gene, but heterozygous SERT knockout rodents (SERT+/−) show several similarities to the human S-allele carrier, therefore creating an animal model of the human situation. Many rodent studies investigated ELS interactions in SERT knockout rodents combined with ELS. However, underlying neuromolecular mechanisms of the (mal)adaptive responses to adversity displayed by SERT rodents remain to be elucidated. Here, we provide a comprehensive review including studies describing mechanisms underlying SERT variation × ELS interactions in rodents. Alterations at the level of translation and transcription but also epigenetic alterations considerably contribute to underlying mechanisms of SERT variation × ELS interactions. In particular, SERT+/− rodents exposed to adverse early rearing environment may be of high translational and predictive value to the more stress sensitive human short-allele carrier, considering the similarity in neurochemical alterations. Therefore, SERT+/− rodents are highly relevant in research that aims to unravel the complex psychopathology of mental disorders. So far, most studies fail to show solid evidence for increased vulnerability to develop affective-like behavior after ELS in SERT+/− rodents. Several reasons may underlie these failures, e.g., (1) stressors used might not be optimal or severe enough to induce maladaptations, (2) effects in females are not sufficiently studied, and (3) few studies include both behavioral manifestations and molecular correlates of ELS-induced effects in SERT+/− rodents. Of course, one should not exclude the (although unlikely) possibility of SERT+/− rodents not being sensitive to ELS. In conclusion, future studies addressing ELS-induced effects in the SERT+/− rodents should extensively study both long-term behavioral and (epi)genetic aspects in both sexes. Finally, further research is warranted using more severe stressors in animal models. From there on, we should be able to draw solid conclusions whether the SERT+/− exposed to ELS is a suitable translational animal model for studying 5-HTTLPR polymorphism and stress interactions.

Sleep problems have not been directly reported in phenylketonuria (PKU). In PKU, the metabolic pathway of phenylalanine is disrupted, which, among others, causes deficits in the neurotransmitters and sleep modulators dopamine, norepinephrine, and serotonin. Understanding sleep problems in PKU patients may help explain the pathophysiology of brain dysfunction in PKU patients. In this explorative study, we investigated possible sleep problems in adult treated PKU patients and untreated PKU mice. In the PKU patients, sleep characteristics were compared to healthy first degree relatives by assessment of sleep disturbances, sleep–wake patterns, and sleepiness with the help of four questionnaires: Holland sleep disorder questionnaire, Pittsburgh sleep quality index, Epworth sleepiness scale, and Munich Chronotype Questionnaire. The results obtained with the questionnaires show that PKU individuals suffer more from sleep disorders, a reduced sleep quality, and an increased latency to fall asleep and experience more sleepiness during the day. In the PKU mice, activity patterns were recorded with passive infrared recorders. PKU mice switched more often between active and non-active behavior and shifted a part of their resting behavior into the active period, confirming that sleep quality is affected as a consequence of PKU. Together, these results give the first indication that sleep problems are present in PKU. More detailed future research will give a better understanding of these problems, which could ultimately result in the improvement of treatment strategies by including sleep quality as an additional treatment target.

Many phenylketonuria (PKU) patients cannot adhere to the severe dietary restrictions as advised by the European PKU guidelines, which can be accompanied by aggravated neuropsychological impairments that, at least in part, have been attributed to brain monoaminergic neurotransmitter deficiencies. Supplementation of large neutral amino acids (LNAA) to an unrestricted diet has previously been shown to effectively improve brain monoamines in PKU mice of various ages. To determine the additive value of LNAA supplementation to a liberalized phenylalanine-restricted diet, brain and plasma monoamine and amino acid concentrations in 10 to 16-month-old adult C57Bl/6 PKU mice on a less severe phenylalanine-restricted diet with LNAA supplementation were compared to those on a non-supplemented severe or less severe phenylalanine-restricted diet. LNAA supplementation to a less severe phenylalanine-restricted diet was found to improve both brain monoamine and phenylalanine concentrations. Compared to a severe phenylalanine-restricted diet, it was equally effective to restore brain norepinephrine and serotonin even though being less effective to reduce brain phenylalanine concentrations. These results in adult PKU mice support the idea that LNAA supplementation may enhance the effect of a less severe phenylalanine-restricted diet and suggest that cerebral outcome of PKU patients treated with a less severe phenylalanine-restricted diet may be helped by additional LNAA treatment.

Time-Place learning (TPL) refers to the ability of animals to remember important events that vary in both time and place. This ability is thought to be functional to optimize resource localization and predator avoidance in a circadian changing environment. Various studies have indicated that animals use their circadian system for TPL. However not much is known about this specific role of the circadian system in cognition. This review aims to put TPL in a broader context and to provide an overview of historical background, functional aspects and future perspectives of TPL. Recent advances have increased our knowledge on establishing TPL in a laboratory setting, leading to the development of a behavioral paradigm demonstrating the circadian nature of TPL in mice. This has enabled the investigation of circadian clock components on a functional behavioral level. Circadian TPL was found to be Cry clock gene dependent, confirming the essential role of Cry genes in circadian rhythms. In contrast, preliminary results have shown that circadian TPL is independent of Per genes. Circadian system decline with aging predicts that circadian TPL is age sensitive, potentially qualifying TPL as a functional model for episodic memory and aging. The underlying neurobiological mechanism of TPL awaits further examination. Here we discuss some putative mechanisms.

The inherited metabolic disease phenylketonuria (PKU) is characterized by increased concentrations of phenylalanine in the blood and brain, and as a consequence neurotransmitter metabolism, white matter, and synapse functioning are affected. A specific nutrient combination (SNC) has been shown to improve synapse formation, morphology and function. This could become an interesting new nutritional approach for PKU. To assess whether treatment with SNC can affect synapses, we treated PKU mice with SNC or an isocaloric control diet and wild-type (WT) mice with an isocaloric control for 12 weeks, starting at postnatal day 31. Immunostaining for post-synaptic density protein 95 (PSD-95), a post-synaptic density marker, was carried out in the hippocampus, striatum and prefrontal cortex. Compared to WT mice on normal chow without SNC, PKU mice on the isocaloric control showed a significant reduction in PSD-95 expression in the hippocampus, specifically in the granular cell layer of the dentate gyrus, with a similar trend seen in the cornus ammonis 1 (CA1) and cornus ammonis 3 (CA3) pyramidal cell layer. No differences were found in the striatum or prefrontal cortex. PKU mice on a diet supplemented with SNC showed improved expression of PSD-95 in the hippocampus. This study gives the first indication that SNC supplementation has a positive effect on hippocampal synaptic deficits in PKU mice.

Grafted islets become denervated due to the islet transplantation procedure. The aim of the present study was 1) to examine whether islet grafts in the liver, the spleen, and under the kidney capsule in rats become reinnervated following the transplantation and experimental procedures used in our laboratory, 2) whether there is any difference in reinnervation at these different sites, and 3) how these results relate to previous physiological experiments. Isogeneic isolated islets were transplanted into diabetic Albino Oxford rats, resulting in normoglycaemia. After at least 5 wk, graft-receiving organs were removed and several antibodies were employed to detect insulin, neuron-specific proteins, and cholinergic and noradrenergic nerve fibers. Islets in all three receiving organs contained viable insulin-positive B-cells. Neuron-specific enolase (NSE) as well as the growth-associated protein B-50 was observed at all sites. The cholinergic marker choline acetyltransferase (ChAT) was localized in islets grafts at all sites, but with the lowest density in the spleen. Staining for the noradrenergic markers tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH) was observed in islet grafts at all sites with the lowest density in grafts under the kidney capsule. All these neurochemical substances were most frequently observed in fibers associated with blood vessels, which may be the route along which nerves grow into the graft. It can be concluded that 1) islet grafts in the liver, in the spleen and under the kidney capsule become reinnervated; 2) the innervation pattern of the islet grafts differs only slightly from that in the control pancreatic islets; and 3) in combination with our previously physiological data, we can conclude that these nerve fibers are, at least partly, functionally active.