A wide range of neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and prion diseases, share common mechanisms such as neuronal loss, apoptosis, mitochondrial dysfunction, oxidative stress, and inflammation. Intervention strategies using plant-derived bioactive compounds have been offered as a form of treatment for these debilitating conditions, as there are currently no remedies to prevent, reverse, or halt the progression of neuronal loss. Rutin, a glycoside of the flavonoid quercetin, is found in many plants and fruits, especially buckwheat, apricots, cherries, grapes, grapefruit, plums, and oranges. Pharmacological studies have reported the beneficial effects of rutin in many disease conditions, and its therapeutic potential in several models of NDs has created considerable excitement. Here, we have summarized the current knowledge on the neuroprotective mechanisms of rutin in various experimental models of NDs. The mechanisms of action reviewed in this article include reduction of proinflammatory cytokines, improved antioxidant enzyme activities, activation of the mitogen-activated protein kinase cascade, downregulation of mRNA expression of PD-linked and proapoptotic genes, upregulation of the ion transport and antiapoptotic genes, and restoration of the activities of mitochondrial complex enzymes. Taken together, these findings suggest that rutin may be a promising neuroprotective compound for the treatment of NDs.

We have investigated whether a 1:1 combination of botanical extracts enriched in eitherΔ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, is neuroprotective in Huntington's disease (HD), using an experimental model of this disease generated by unilateral lesions of the striatum with the mitochondrial complex II inhibitor malonate. This toxin damages striatal neurons by mechanisms that primarily involve apoptosis and microglial activation. We monitored the extent of this damage and the possible preservation of the striatal parenchyma by treatment with a Sativex-like combination of phytocannabinoidsusing different histological and biochemical markers. Results were as follows: (i) malonate increased the volume of edema measured by in vivo NMR imaging and the Sativex-like combination of phytocannabinoids partially reduced this increase; (ii) malonate reduced the number of Nissl-stained cells, while enhancing the number of degenerating cells stained with FluoroJade-B, and the Sativex-like combination of phytocannabinoids reversed both effects; (iii) malonate caused a strong glial activation (i.e., reactive microglia labeled with Iba-1, and astrogliosis labeled with GFAP) and the Sativex-like combination of phytocannabinoids attenuated both responses; and (iv) malonate increased the expression of inducible nitric oxide synthase and the neurotrophin IGF-1, and both responses were attenuated after the treatment with the Sativex-like combination of phytocannabinoids. We also wanted to establish whether targets within the endocannabinoid system (i.e., CB(1) and CB(2) receptors) are involved in the beneficial effects induced in this model by the Sativex-like combination of phytocannabinoids. This we did using selective antagonists for both receptor types (i.e., SR141716 and AM630) combined with the Sativex-like phytocannabinoid combination. Our results indicated that the effects of this combination are blocked by these antagonists and hence that they do result from an activation of both CB(1) and CB(2) receptors. In summary, this study provides preclinical evidence in support ofa beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying signs of disease progression in a proinflammatory model of HD, which adds to previous data obtained in models priming oxidative mechanisms of striatal injury. However, the interest here is that, in contrast with these previous data, we have now obtained evidence that both CB(1) and CB(2) receptors appear to be involved in the effects produced by a Sativex-like phytocannabinoid combination, thus stressing the broad-spectrum properties of Sativex that may combine activity at the CB(1) and/or CB(2) receptors with cannabinoid receptor-independent actions.

Sesamol (SML) obtained from sesame seeds (Sesamum indicum, Linn, Pedaliaceae) has been used as a traditional health food in India and other countries since a long time. Besides its good antioxidant activity, SML is currently receiving considerable attention in relation to neurological disorders. Therefore, the present study has been designed to explore the protective role of SML in 3-nitropropionic acid (3-NP)-induced neurotoxicity in animals. Male rats were given 3-NP (10 mg/kg) treatment for 14 days. Various behavioral observations (body weight, locomotor activity), oxidative damage (lipid peroxidation, nitrite level, superoxide dismutase, and catalase enzyme), and mitochondrial enzyme complex functions were also assessed in the striatum, cortex, and hippocampal regions of the brain. 3-NP treatment significantly impaired locomotor activity, motor coordination, body weight, oxidative damage, and mitochondrial enzyme complex functions as compared with vehicle-treated groups. SML (5, 10, and 20 mg/kg) pre-treatment significantly improved body weight, locomotor activity, motor coordination, and attenuated oxidative damage in different regions of rat brain. Besides these, SML treatment also significantly improved mitochondrial enzymes in all regions of the brain as compared with the respective control (3-NP) group. The present study suggests that SML could be used as effective agents in the management of Huntington's disease.

Transgenic mice that overexpress the mutant human SOD1 gene (hSOD1) serve as an animal model for amyotrophic lateral sclerosis (ALS). Age and sex are recognized as risk factors for ALS, but physical activity remains controversial. Therefore, we investigated the effect of exercise on the phenotype of male and female hSOD1 mice. Onset of disease, progression of disease and survival were measured in low-copy and high-copy hSOD1 mice that were randomized to an exercise or sedentary group. We found that onset of disease was different for the two sexes: significantly earlier in male than in female hSOD1 mice. Exercise delayed the onset of disease in female but not in male hSOD1 mice. Also, exercise delayed the total survival time in female high-copy hSOD1 mice. Muscle morphometry and motor neuron counts were similar in all experimental groups at the end of training. Sedentary female hSOD1 mice showed more frequently irregular estrous cycles suggesting a higher estrogen exposure in exercising female mice. These results suggest a possible neuroprotective effect of female sex hormones and support the view that ALS patients should not avoid regular exercise.

We applied rhythmic binaural sound to Parkinson's Disease (PD) patients to investigate its influence on several symptoms of this disease and on Electrophysiology (Electrocardiography and Electroencephalography (EEG)). We conducted a double-blind, randomized controlled study in which rhythmic binaural beats and control were administered over two randomized and counterbalanced sessions (within-subjects repeated-measures design). Patients ([Formula: see text], age [Formula: see text], stage I-III Hoehn&Yahr scale) participated in two sessions of sound stimulation for 10[Formula: see text]min separated by a minimum of 7 days. Data were collected immediately before and after both stimulations with the following results: (1) a decrease in theta activity, (2) a general decrease in Functional Connectivity (FC), and (3) an improvement in working memory performance. However, no significant changes were identified in the gait performance, heart rate or anxiety level of the patients. With regard to the control stimulation, we did not identify significant changes in the variables analyzed. The use of binaural-rhythm stimulation for PD, as designed in this study, seems to be an effective, portable, inexpensive and noninvasive method to modulate brain activity. This influence on brain activity did not induce changes in anxiety or gait parameters; however, it resulted in a normalization of EEG power (altered in PD), normalization of brain FC (also altered in PD) and working memory improvement (a normalizing effect). In summary, we consider that sound, particularly binaural-rhythmic sound, may be a co-assistant tool in the treatment of PD, however more research is needed to consider the use of this type of stimulation as an effective therapy.

BACKGROUND:Cannabidiol (CBD)-based treatments for several diseases, including Tourette's syndrome, multiple sclerosis, epilepsy, movement disorders and glaucoma, are proving to be beneficial and the scientific clinical background of the drug is continuously evolving.

OBJECTIVES:To investigate the short-term effect of CBD-enriched hemp oil for relieving symptoms and improving the life quality (QOL) in young girls with adverse drug effects (ADRs) following human papillomavirus (HPV) vaccine.

METHODS:In this anecdotal, retrospective,"compassionate-use", observational, open-label study, 12 females (age 12-24 years) with severe somatoform and dysautonomic syndrome following HPV vaccination were given sublingual CBD-rich hemp oil drops, 25 mg/kg per day supplemented by 2-5 mg/ml CBD once a week until a maximum dose of 150 mg/ml CBD per day was reached over a 3 month period. Patients' quality of life was evaluated using the medical outcome short-form health survey questionnaire (SF-36).

RESULTS:Two patients dropped out due to iatrogenic adverse events and another two patients stopped the treatment early due to lack of any improvement. SF-36 showed significant benefits in the physical component score (P<0.02), vitality (P<0.03) and social role functioning (P<0.02) after the treatment. The administration of hemp oil also significantly reduced body pain according to the SF-36 assessment. No significant differences from the start of treatment to several months post-treatment were detected in role limitations due to emotional reactions (P = 0.02).

CONCLUSIONS:This study demonstrated the safety and tolerability of CBD-rich hemp oil and the primary efficacy endpoint. Randomized controlled trials are warranted to characterize the safety profile and efficacy of this compound.

The aim of this study was to observe the grey matter (GM) tissue changes of ischemic stroke patients, to explore the therapy responses and possible mechanism of acupuncture. 21 stroke patients were randomly assigned to receive either acupuncture plus conventional (Group A) or only conventional (Group B) treatments for 4 weeks. All patients in both groups accepted resting-state functional magnetic resonance (fMRI) scan before and after treatment, and the voxel-based morphometry (VBM) analysis was performed to detect the cerebral grey structure changes. The modified Barthel index (MBI) was used to evaluate the therapeutic effect. Compared with the patients in Group B, the patients in Group A exhibited a more significant enhancement of the changes degree of MBI from pre- to post-treatment intervention. VBM analyses found that after treatment the patients in Group A showed extensive changes in GMV. In Group A, the left frontal lobe, precentral gyrus, superior parietal gyrus, anterior cingulate cortex, and middle temporal gyrus significantly increased, and the right frontal gyrus, inferior parietal gyrus, and middle cingulate cortex decreased (<0.05, corrected). In addition, left anterior cingulate cortex and left middle temporal gyrus are positively related to the increase in MBI score (<0.05, corrected). In Group B, right precentral gyrus and right inferior frontal gyrus increased (<0.05, corrected). In conclusion, acupuncture can evoke pronounced structural reorganization in the frontal areas and the network of DMN areas, which may be the potential therapy target and the potential mechanism where acupuncture improved the motor and cognition recovery.

BACKGROUND:The primary objective of this trial is to investigate the effects of a short-term exercise program on neuropsychiatric signs and symptoms in acute hospital dementia care.

METHODS:Within a hospital-based randomized controlled trial, the intervention group conducted a 2-week exercise program with four 20-min exercise sessions on 3 days per week. The control group conducted a social stimulation program. Effects on neuropsychiatric signs and symptoms were measured via the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change, the Neuropsychiatric Inventory, and the Cohen-Mansfield Agitation Inventory. Theantipsychotic and sedative dosage was quantified by olanzapine and diazepam equivalents.

RESULTS:Eighty-five patients were randomized via minimization to an intervention group (IG) and a control group (CG). Seventy patients (82%) (mean age 80 years, 33 females, mean Mini Mental State Examination score 18.3 points) completed the trial. As compared to the CG (n = 35), the IG (n = 35) showed significantly reduced neuropsychiatric signs and symptoms. Especially, agitated behavior and lability improved. There were no between-group differences concerning antipsychotic and benzodiazepine medication.

CONCLUSIONS:This exercise program is easily applicable in hospital dementia care and significantly reduces neuropsychiatric signs and symptoms in patients suffering from predominantly moderate stages of dementia.

TRIAL REGISTRATION:German Clinical Trial Register DRKS00006740 . Registered 28 October 2014.

OBJECTIVE:To probe the mechanism of acupuncture for anti-aging.

METHODS:In the senescence accelerated mouse the SAMP10 and the SAMR1, by using RT-PCR and DIG-labeled Northern blot technique, the expression differences of HSP84 and HSP86 genes in whole brain, cortex and hippocampus in the 4 groups,8-month SAMR1 control group, 8-month SAMP10 control group, 8-month SAMP10 acupuncture group and 8-month SAMP10 non-point acupuncture group were investigated.

RESULTS:In the SAMP10 control group, the expression of HSP84 and HSP86 were down-regulated in the whole brain, the cortex and the hippocampus, and they were up-regulated after acupuncture, tending to the normal group.

CONCLUSION:Brain aging of the SAMP10 mouse is related with abnormal expression of HSP84 and HSP86 genes, and acupuncture can strengthen the protection of cells, inhibit apoptosis and anti-oxidative stress through regulating expression of HSP84 and HSP86, hence anti-aging.

OBJECTIVE:To probe the mechanism of acupuncture for anti-aging.

METHODS:In the senescence accelerated mouse the SAMP10 and the SAMR1, by using RT-PCR and DIG-labeled Northern blot technique, the expression differences of HSP84 and HSP86 genes in whole brain, cortex and hippocampus in the 4 groups,8-month SAMR1 control group, 8-month SAMP10 control group, 8-month SAMP10 acupuncture group and 8-month SAMP10 non-point acupuncture group were investigated.

RESULTS:In the SAMP10 control group, the expression of HSP84 and HSP86 were down-regulated in the whole brain, the cortex and the hippocampus, and they were up-regulated after acupuncture, tending to the normal group.

CONCLUSION:Brain aging of the SAMP10 mouse is related with abnormal expression of HSP84 and HSP86 genes, and acupuncture can strengthen the protection of cells, inhibit apoptosis and anti-oxidative stress through regulating expression of HSP84 and HSP86, hence anti-aging.

Melatonin is a neurohormone whose levels are significantly reduced or absent in Alzheimer's disease (AD) patients. In these patients, acetylcholinesterase inhibitors (AChEI) are the major drug class used for their treatment; however, they present unwanted cholinergic side effects and have provided limited efficacy in clinic. Because combination therapy is being extensively used to treat different pathological diseases such as cancer or acquired immune deficiency syndrome, we posed this study to evaluate if melatonin in combination with an AChEI, galantamine, could provide beneficial properties in a novel in vitro model of AD. Thus, we subjected organotypic hippocampal cultures (OHCs) to subtoxic concentrations ofβ-amyloid (0.5 μM βA) plus okadaic acid (1 nM OA), for 4 days. This treatment increased by 95 % cell death, which was mainly apoptotic as shown by positive TUNEL staining. In addition, the combination of βA/OA increased Thioflavin S aggregates, hyperphosphorylation of Tau, oxidative stress (increased DCFDA fluorescence), and neuroinflammation (increased IL-1β and TNFα). Under these experimental conditions, melatonin (1-1000 nM) and galantamine (10-1000 nM), co-incubated with the toxic stimuli, caused a concentration-dependent neuroprotection; maximal neuroprotective effect was achieved at 1 μM of melatonin and galantamine. Most effective was the finding that combination of sub-effective concentrations of melatonin (1 nM) and galantamine (10 nM) provided a synergic anti-apoptotic effect and reduction of most of the AD-related pathological hallmarks observed in the βA/OA model. Therefore, we suggest that supplementation of melatonin in combination with lower doses of AChEIs could be an interesting strategy for AD patients.

Alzheimer's disease (AD) is associated with cognitive deficits and behavioral disorders such as anxiety and depression. Recent clinical and experimental studies have demonstrated that swimming exercise could be a potential therapy for cognitive and behavioral disorders. The prevalence of anxiety and depression is increasing among patients with AD; hence, further studies are needed to develop therapies for these behavioral abnormalities. The purpose of this study was to evaluate the effects of swimming exercise on memory impairment, anxiety, and depression-like behaviors in a mouse model of sporadic Alzheimer-like disease. Eight days after AD induction by streptozotocin (STZ), mice were subjected to the swimming exercise for four weeks. To assess cognitive functions, anxiety- and depression-related behaviors in animals, Y-maze, novel object recognition, open field, zero maze, sucrose preference, and forced swim tests were used. To understand the possible mechanisms, amyloid-β (Aβ)-42, brain-derived neurotrophic factor (BDNF), glutamate, malondialdehyde (MDA), tumor-necrosis-factor (TNF)-α, and interleukin (IL)-6 levels were measured in the hippocampus. The results of this study indicate that STZ administration impaired cognitive functions, increased anxiety- and depression-related behaviors, and elevated Aβ-42, glutamate, MDA, TNF-α, and IL-6 levels in the hippocampus of mice. In contrast, swimming exercise significantly reversed these neurobehavioral disorders, increased BDNF, and decreased both glutamate and TNF-α in the hippocampus of STZ-treated mice. Overall, these findings provide some support for the idea that swimming exercise might be associated with reduced neurobehavioral disorders in patients with Alzheimer's disease. However, further clinical studies on this topic are required to confirm and validate these findings.

Zinc and vitamin C supplementation of the body is important for CNS functioning. Zinc ions are involved in the neurotransmission (signal transmission from acetylcholine, catecholamine, serotonin, prostaglandin receptors) and in ubiquitin-related protein degradation. Zinc deficits are associated with Alzheimer's disease and depression. Zinc supplementation (10-30 mg daily) improves neurologic recovery rate in patients with stroke and brain injury, has a positive impact on memory and reduces hyperactivity in children. Vitamin C, a zinc synergist, maintains antioxidant resources of the brain, synaptic activity and detoxification. Vitamin C in dose 130-500 mg daily should be used to prevent dementia and neurodegenerative pathology.

The aim of this study is to investigate and compare how 12-weeks of Tai Chi Chuan and Baduanjin exercise can modulate brain structure and memory function in older adults. Magnetic resonance imaging and memory function measurements (Wechsler Memory Scale-Chinese revised, WMS-CR) were applied at both the beginning and end of the study. Results showed that both Tai Chi Chuan and Baduanjin could significantly increase grey matter volume (GMV) in the insula, medial temporal lobe, and putamen after 12-weeks of exercise. No significant differences were observed in GMV between the Tai Chi Chuan and Baduanjin groups. We also found that compared to healthy controls, Tai Chi Chuan and Baduanjin significantly improved visual reproduction subscores on the WMS-CR. Baduanjin also improved mental control, recognition, touch, and comprehension memory subscores of the WMS-CR compared to the control group. Memory quotient and visual reproduction subscores were both associated with GMV increases in the putamen and hippocampus. Our results demonstrate the potential of Tai Chi Chuan and Baduanjin exercise for the prevention of memory deficits in older adults.

BACKGROUND:Effects of Tai Chi (TC) on specific cognitive function and mechanisms by which TC may improve cognition in older adults with amnestic mild cognitive impairment (a-MCI) remain unknown.

OBJECTIVE:To examine the effects of TC on cognitive functions and plasma biomarkers (brain-derived neurotrophic factor [BDNF], tumor necrosis factor-α [TNF-α], and interleukin-10 [IL-10]) in a-MCI.

METHODS:A total of 66 older adults with a-MCI (mean age = 67.9 years) were randomized to either a TC (n = 33) or a control group (n = 33). Participants in the TC group learned TC with a certified instructor and then practiced at home for 50 min/session, 3 times/wk for 6 months. The control group received educational material that covered information related to cognition. The primary outcome was cognitive performance, including Logical Memory (LM) delayed recall, Block Design, Digit Span, and Trail Making Test B minus A (TMT B-A). The secondary outcomes were plasma biomarkers, including BDNF, TNF-α, and IL-10.

RESULTS:At the end of the trial, performance on the LM and TMT B-A was significantly better in the TC group compared with the control group after adjusting for age, gender, and education ( P<.05). Plasma BDNF level was significantly increased for the TC group, whereas the other outcome measures were similar between the 2 groups after adjusting for age and gender ( P<.05).

CONCLUSIONS:TC training significantly improved memory and the mental switching component of executive function in older adults with a-MCI, possibly via an upregulation of BDNF.

Vascular dementia is the progressive change in blood vessels that leads to neuronal injuries in vulnerable areas induced by chronic cerebral hypoperfusion (CCH). CCH induces disruption of blood-brain barrier (BBB), and this BBB disruption can initiate the cognitive impairment and white matter injury. In the present study, we evaluated the effect of treadmill exercise on the cognitive impairment, white matter injury, and BBB disruption induced by CCH. Vascular dementia was induced by permanent bilateral common carotid arteries occlusion (BCCAO) in rats. The rats in the exercise group were made to run on a treadmill for 30min once a day for 14 weeks, starting 4 weeks after birth. Our results revealed that treadmill exercise group was alleviated the cognitive impairment and myelin degradation induced by CCH. The disruption of BBB after CCH indicates degradation of occludin, zonula occluden-1 (ZO-1), and up-regulation of matrix metalloproteinases (MMPs). Treadmill exercise may provide protective effects on BBB disruption from degradation of occludin, ZO-1, and overexpression of MMP-9 after CCH. These findings suggest that treadmill exercise ameliorates cognitive impairment and white matter injury from BBB disruption induced by CCH in rats. The present study will be valuable for means of prophylactic and therapeutic intervention for patients with CCH.

Parkinson's disease (PD) is a significantly progressive neurodegenerative disease characterised by both motor and nonmotor disorders. The main pathological characteristics of PD consist of the loss of dopaminergic neurons and the formation of alpha-synuclein-containing Lewy bodies in the substantia nigra. Currently, the main therapeutic method for PD is anti-Parkinson medications, including levodopa, madopar, sirelin, and so on. However, the effect of pharmacological treatment has its own limitations, the most significant of which is that the therapeutic effect of dopaminergic treatments gradually diminishes with time. Exercise training, as an adjunctive treatment and complementary therapy, can improve the plasticity of cortical striatum and increase the release of dopamine. Exercise training has been proven to effectively improve motor disorders (including balance, gait, risk of falls and physical function) and nonmotor disorders (such as sleep impairments, cognitive function and quality of life) in PD patients. In recent years, various types of exercise training have been used to treat PD. In this review, we summarise the exercise therapy mechanisms and the protective effects of different types of exercise training on PD patients.

Physical exercise can reduce the cognitive decline associated with traumatic brain injury, yet little is known about the optimal administration schedules. Here, different protocols of voluntary wheel running were evaluated for their effects on object recognition memory (ORM), neuroprotection (NeuNcells), microglial reactivity (Iba1 staining) and neurogenesis (DCXcells) after controlled cortical impact injury (CCI). CCI-lesioned rats were divided into a sedentary group and three exercise groups: early discontinued exercise (3 weeks of exercise initiated 4 days post-injury, followed by 4 weeks in a sedentary state); delayed exercise (3 weeks of exercise initiated 4 weeks post-injury), and early continuous exercise (7 weeks of exercise starting 4 days post-injury). The deficits induced by CCI in a 24 h ORMtest were reversed in the delayed exercise group and reduced in the early discontinued and early continuous groups. The early discontinued protocol also reduced the loss of NeuNcells in the hilus, while attenuated microglial reactivity was found in the dorsal hippocampus of both the early exercising groups. Running at the end of the experiment increased the number of DCXcells in the early continuous and delayed groups, and an inverted U-shaped relationship was found between the mean daily exercise time and the amount of neurogenesis. Thus, exercise had benefits on memory both when it was commenced soon and later after injury, although the neural mechanisms implicated differed. Accordingly, the effects of exercise on memory and neurogenesis appear to not only depend on the specific temporal schedule but also, they may be influenced by the amount of daily exercise.

The objective of the present review was to evaluate whether exercise can counteract a potential high-fat diet-induced memory impairment effect. The evaluated databases included: Google Scholar, Sports Discus, Embase/PubMed, Web of Science, and PsychInfo. Studies were included if: (1) an experimental/intervention study was conducted, (2) the experiment/intervention included both a high-fat diet and exercise group, and evaluated whether exercise could counteract the negative effects of a high-fat diet on memory, and (3) evaluated memory function (any type) as the outcome measure. In total, 17 articles met the inclusionary criteria. All 17 studies (conducted in rodents) demonstrated that the high-fat diet protocol impaired memory function and all 17 studies demonstrated a counteracting effect with chronic exercise engagement. Mechanisms of these robust effects are discussed herein.

It has been demonstrated that, on their own, both exercise and stimulation from the environment can improve cognitive function and well-being in older adults. The combined effect of exercising in the outdoor environment on psychological function is less well studied. The aim of the current study was to investigate the effect of an outdoor cycling intervention on cognitive function and mental health and well-being in older adults. A total of 100 older adults took part in the study (aged 50-83), 26 of which were non-cycling controls, 36 were conventional pedal cyclists and 38 were participants using an e-bike (a bike fitted with an electric motor to provide assistance with pedaling), as part of a larger project (www.cycleboom.org). Participants took part in the study for an eight-week period, with cycling participants required to cycle at least three times a week for thirty minutes in duration for each cycle ride. Cognitive function and well-being were measured before and after the intervention period. For executive function, namely inhibition (the Stroop task) and updating (Letter Updating Task), both cycling groups improved in accuracy after the intervention compared to non-cycling control participants. E-bike participants also improved in processing speed (reaction times in go trials of the Stop-It task) after the intervention compared to non-cycling control participants. Finally, e-bike participants improved in their mental health score after the intervention compared to non-cycling controls as measured by the SF-36. This suggests that there may be an impact of exercising in the environment on executive function and mental health. Importantly, we showed a similar (sometimes larger) effect for the e-bike group compared to the pedal cyclists. This suggests that it is not just the physical activity component of cycling that is having an influence. Both pedal cycles and e-bikes can enable increased physical activity and engagement with the outdoor environment with e-bikes potentially providing greater benefits.