Alternations of vitamin D and cognitive function in first-diagnosed and drug-naïve BD patients: Physical activity as a moderator

Bipolar disorders (BD) are severe and recurrent mood diseases with high heritability and interindividual variation that affect almost 2–3 % of the global population (Bauer et al., 2018; Grande et al., 2016). BD is characterized by interepisodic mood fluctuations, cognitive impairments, psychiatric and physical comorbidities that drastically affect the quality of life for those with BD (Carvalho et al., 2014; Crump et al., 2013; Zellweger, 2019). Cognitive dysfunction in the acute phase and in the remission phase of BD has been frequently reported (Volkert et al., 2016). In addition, BD is associated with deficits in attention, executive functions, and memory, which even happens in the remission phase (Bora and Pantelis, 2015). However, the modulating mechanisms of cognitive impairment in BD are still unknown. Some neurobiological alternations such as dopamine hypothesis, voltage-gated calcium channels, white matter differentiation have been found to be connected with cognitive deficits in BD and the pathophysiology of it (Ashok et al., 2017; Brown et al., 2021; Harrison et al., 2018).

Vitamin D, known for its anti-inflammation and neuroprotection functions, is a potential agent for central pain modulation via neurophysiological pathways. The relationship between cognitive deficits and vitamin D deficiency has been investigated in recent studies (Goodwill and Szoeke, 2017). It has been found that cognitive deficits such as several neuroprogressive or psychiatric illnesses are related to vitamin D deficiency, including Alzheimer's disease, dementia, schizophrenia, depression, and attention deficit disorder (Berridge, 2017; Cortese et al., 2020; Grübler et al., 2017; Mayne and Burne, 2019).

In addition, vitamin D is also considered as a potential modulator of neurocognition. Vitamin D was reported to regulate brain function by affecting the production and release of neurotrophins, influencing synaptic plasticity, attenuating oxidative damage in nervous system, reducing neuroinflammation, and maintaining intracellular calcium homeostasis via regulating expression of relevant genes and proteins (Filgueiras et al., 2020; Fleet, 2017; Mayne and Burne, 2019). Firstly, the prenatal vitamin D insufficiency reduced cortical thickness, larger lateral ventricles, as well as inhibited expression of nerve growth factor (NGF) and neurotrophic factor (Féron et al., 2005). Secondly, deficiency of maternal vitamin D changes the neurogenesis of rat brains (Morello et al., 2018). Moreover, the proliferation of neurocytes in the sub-granular zone of the hippocampus in adults with vitamin D insufficiency rised, and neuronal differentiation was disrupted (Zhu et al., 2012a). Increasing evidence suggests that after long-term vitamin D supplementation, the cognition of patients with neurodegenerative diseases improves, especially people with AD. A transcriptomic analysis of mice's hippocampus and neocortex with 5-month vitamin D treatment found that a large number of dysregulated pathways with regard to neurotransmitter activity and inflammatory response (Landel et al., 2016). There was another experiment which revealed that vitamin D could affect cognition by reducing expressions of nuclear factor- -κB (NF-κB), brain-derived neurotrophic factor (BDNF) in the hippocampus, and blood-brain barrier (BBB) permeability in high-fat diet (HFD)-induced obese rats (Hajiluian et al., 2017). All in all, those findings illustrate that vitamin D plays a vital role in neurocognitive performance. However, there is still a lack of systematical correlation studies based on BD.

It is commonly said that vitamin D and Ca2+ showed some similar effects as pathophysiological signals in the musculoskeletal metabolism which are associated with physical activities (PA) (Zhang et al., 2020). In some studies, vitamin D was reported to be positively correlated with PA both indoors and outdoors (Fernandes and Barreto, 2017). The levels of serum vitamin D were affected by sun exposure during outdoor exercises. Additionally, some experimental evidence indicated that skeletal muscle hypertrophy caused by PA might be another crucial contribution to the increased vitamin D levels and skeletal muscle was an important storage site of vitamin D in newborn rats (Clements and Fraser, 1988). Besides, exercises-related activities are found to be associated with the increased vitamin D levels even (Jones et al., 2005). Interestingly, vitamin D could reversely induce muscle protein synthesis, causing increase of proportion of fast twitch muscle cell whose function is about high-power output and muscle development (Koundourakis et al., 2016; Wiciński et al., 2019). Close et al. reported that vitamin D3 supplementation was positively associated with the performance of some sports, including vertical jump and 10-m sprint times (Close et al., 2013).

Moreover, some studies of normal population reported benefits of PA on cognitive function, especially moderate- intensive PA like aerobic exercise (Alsubaie et al., 2020; Falck et al., 2017). A meta-analysis based on Alzheimer's disease (AD) indicated that PA and exercise could enhance cognitive function in the older with AD (Jia et al., 2019). In addition, a sample of 3 BD patients with overweight undergoing an 8-week high-intension exercise showed significant cognitive improvement in processing speed and symbol coding (Strassnig et al., 2015). Another 18-month prospective study indicated that BD patients performing more physical activity had better cognitive function (Melo et al., 2019). However, using triaxial accelerometer to collect PA information, Jennifer et al. found that there was little or no relationship between PA and cognition in BD (Burgess et al., 2022). To summarize, whether PA will actually influence cognitive function in BD patients and how it works is still unknown.

Only a few studies concentrated on exploring the association between vitamin D and cognitive impairments in patients with BD. The relationship between vitamin D and clinical symptoms in BD has been discovered in several systematic studies and analysis, but cognitive impairment was rarely mentioned (Cereda et al., 2021). A recent report pointed out that the mood balance in patients with BD could be positively influenced by an adequate intake of vitamin D (Cereda et al., 2021). In contrast, reduction in mood, depression, and anxiety symptoms is found in a randomized controlled trial of vitamin D supplementation treatment for BD (Marsh et al., 2017). For cognitive deficits, Naifar and colleagues have suggested that the level of 25-hydroxy vitamin D was higher in patients with BD and acute decompensation than in control group, and was positively associated with abstraction, attention, and memory ability (Naifar et al., 2020). Unfortunately, only a few reports investigated the potential links among PA, vitamin D, and cognition in BD. Thus, more and more systematic experiments need to be designed to explore influences of vitamin D on BD as well as the possible biological factors regulated by vitamin D, which could be potential targets for intervention in BD.

In this study, we hypothesize that BD patients has been faced with the rise of vitamin D level in the early stage of this disease, which could have impacts on cognitive function, activities or therapies which can regulate the level of vitamin D, such as exercising would be beneficial to improving cognitive impairment. Hence, the aim of our study was to investigate the effect of PA on vitamin D and cognition in patients in order to guide the physical interventions for BD in the future.

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