B6 - Food for the Brain

B6

The Role of B6 in Brain Health

B6 is an essential water-soluble vitamin, and must be obtained from the diet due to humans inability to synthesize it themselves – good dietary sources include fish, legumes, nuts, bananas & potatoes. The primary symptoms of vitamin B6 deficiency are neurological, with identified brain-specific symptoms of B6 deficiency including irritability, impaired alertness, autonomic dysfunction & convulsions (Dakshinamurti et al., 2013). Furthermore, pyridoxal 5′-phosphate (PLP), the metabolically active form of vitamin B6, plays an essential role in brain metabolism as a cofactor in numerous enzyme reactions. This document presents findings from scientific journals, exploring the role of vitamin B6 on brain health. Effort was made to identify the mechanisms in which B6 supports brain function, though these are not yet transparent in all areas.

Inclusion Criteria

Papers were peer-reviewed, full text articles and to have been published between 2011-2021, though cited works within these texts are also referenced.

Neuroprotective role

Vitamin B6 is associated with functions of the nervous system, with its deficiency possibly resulting in neurological disorders including convulsions and epileptic encephalopathy (Ahmad et al., 2013; Lee et al., 2015). B6 is attributed a neuroprotective role which appears to be mainly linked with its ability to regulate the glutamatergic system and thus gamma‐aminobutyric acid (GABA) levels, a key inhibitory neurotransmitter in the central nervous system. Vitamin B6 is an indispensable in the synthesis of GABA (from glutamate), utilising the PLP-dependent enzyme glutamic acid decarboxylyase (Ramos et al., 2017). Increased levels of glutamate, an excitatory neurotransmitter, can be linked with seizures, and similarly the application of GABA or B6 can end or reduce seizure activity (Calderón‐Ospina & Nava‐Mesa, 2020). For example, in infants with ARX-deficient encephalopathy, the intake of PLP can effectively improve GABA deficiency and inhibit epileptic seizures (Kwong et al., 2019). Recent research also supports the role of B6 as a neuroprotective agent, finding that B6 (and vitamin B12) significantly reduced the incidence, relative risk and severity of vincristine-induced peripheral neuropathy (VIPN). Since VIPN develops as a result of two proposed mechanisms, neurodegeneration and oxidative stress (Sisignano et al., 2014) it seems likely that these underlie the process in which Bis beneficial

Homocysteine hypothesis, Cognition & Alzheimer’s Disease

As B6 is an essential homocysteine re-methylation cofactor, deficiency can disrupt the remethylation cycle of homocysteine to methionine. This leads to elevated plasma homocysteine which can result in far-reaching health impairments from prenatal development to late adulthood (Miller, 2003). Homocysteine is a physiological amino acid produced from protein break-down, and can develop into a pathological condition called hyperhomocysteinemia if these exceed certain levels (Cordaro et al,. 2021).  Supplementation with B vitamins, including vitamin B6, has been shown to reduce blood homocysteine levels. For example, a recent meta-analysis (Olaso‐Gonzalez et al., 2021) examined the impact of B vitamin supplementation on homocysteine levels in patients with mild cognitive impairment and found clinically relevant and statistically significant decreases in homocysteine across the four studies including B6 in their intervention, irrespective of the duration (Lee et al., 2016; de Jager et al., 2012; Schroecksnadel et al., 2006; Lehmann et al., 2003). 

Studies have linked elevated plasma homocysteine concentrations with hippocampal atrophy, the wasting away of an area of the brain required for consolidation of memories (den Heijer et al., 2003). With hyperhomocysteinaemia proposed as mechanism in the development Alzheimer’s disease, it is widely suggested that high homocysteine concentrations may have direct neurotoxic effects, resulting in apoptosis and possibly impairing pathways associated with cognition (McGarel et al., 2015; Walker et al., 2012; Clarke et al., 1998). For example, randomised trials in older adults have shown a reduced rate of brain atrophy through MRI after intervention with high-dose folic acid, vitamin B12 and vitamin B(Smith et al., 2010; Douaud et al., 2013). Further evidence originates from the VITACOG trial in Oxford, in which B vitamins appeared to slow cognitive decline in people with mild cognitive impairment, particularly those with elevated homocysteine (de Jager et al., 2012).

Although elevation of homocysteine levels is well-established as a risk factor for dementia, controversy currently exists regarding whether B6-mediated reduction of homocysteine levels can directly benefit cognitive function (McCleery et al., 2018). A recent comprehensive meta-analysis shows this, finding that, unlike folate (B9), higher intake of B6 was not associated with lower dementia risk and that B6 deficiency was not a risk factor for dementia and cognitive decline (Wang et al., 2021). This has not been an uncommon finding, with reviews and meta-analyses published over the last 15 years providing insufficient conclusive evidence to support the hypothesis or calling for further high-quality long-term trials on this topic. One such meta-analysis however, the paper by Clarke et al (2014) was in fact criticised due to choice of trials, the cognitive assessment tools, and the analysis and interpretation of data. Thus, though it shone light onto the ambiguous nature of the research, the findings are not extensively accepted (Garrard et al., 2015). Some other review articles have included both prevention and treatment, mixing separate topics into the same analysis (Balk et al., 2007; Ford et al 2012), however a recent well-conducted meta-analysis (Behrens et al., 2020) came to the same overall conclusion as Clarke et al (2014); no significant effect of B vitamins (including B6) in slowing cognitive decline was observed regarding primary outcomes both in healthy and cognitively-impaired individuals. 

Studies highlighting positive results from Bor composite B vitamin supplementation (including B9 and B12) should not be discounted, though definitely interpreted with caution or expanded on in future research. For example, recent research shows that a high dietary intake of Bcould reduce cognitive impairment in neuromyelitis disease (Rezaeimanesh et al., 2020). Existing research proves the interplay of B6 with other cognition and brain health to be extremely complex, even suggesting that effects on cognition might not be recognizable in healthy older subjects with normal B6 blood levels (Jannusch et al., 2017). Harris et al (2015) further reported a dissociation of multivitamin supplementation effects in healthy older adults: while blood levels could be improved via supplementation, no effect on cognitive performance was found. As summarised by Moore et al (2018) in their exploration of new directions in the ageing brain, further appropriately designed randomised trials are needed, particularly targeting individuals with low B-vitamin status/most risk of cognitive decline as they are most likely to benefit from improved cognitive health.

Neurotransmitter Metabolism: Depression & Anxiety 

PLP-dependent enzymes are involved in the metabolism of the neurotransmitters dopamine, noradrenaline, serotonin, glycine, D-serine, glutamate, γ-aminobutyrate (GABA) and histamine (Clayton, 2006). Since its role in metabolism makes it a rate-limiting cofactor in the neurotransmitter synthesis, B6 deficiency is widely considered to lead to brain function impairment and underpins the proposed link between B6 and mental health outcomes. In comparison to vitamins B12 and B9, a limited number of studies have considered the protective role of vitamin B6 against depression (Moore et al., 2018), and despite some research suggests its inverse association with vitamin B6 biomarker status (plasma PLP) (Skarupski et al., 2010; Merete et al., 2008), the overall evidence available to date is still somewhat ambiguous in nature. 

A meta-analysis by Almeida et al (2015) showed no conclusive benefits of B6 supplementation on depressive symptoms, though one included trial (Almeida et al., 2014) found prolonged use of the combination of folic acid, vitamin B12, and vitamin B6 to enhance response to antidepressant treatment over one year, and decreased relapse risk amongst those who had recovered after three months. Thus, although the meta-analysis failed to suggest that short term use of vitamins ameliorated depressive symptoms, prolonged consumption could reduce severity and the onset of clinically significant depression symptoms in particular populations. This also highlights the potential for B6 to have a synergistic effect when combined with other B vitamins, and should considered when evaluating research in B vitamins more broadly.

Recently, Kafeshani et al (2020) explored the correlation between B6 intake with depression and anxiety among 3362 adults and found lower vitamin B6 in the diet of the women to be associated with increased risk of suffering from anxiety and depression. Since the impact of B6 on mental health was clearly supported here, a suggested approach to tackle such disorders involves improvement of nutritional status. Vitamin B6 has also been found to have a positive effect on reducing postpartum depression scores among at-risk mothers, providing some support for its clinical use in this specific population (Khodadad et al., 2021). 

Interestingly, a very recent systematic review and meta-analysis (Wu et al., 2021) assessed 9 articles investigating the association between dietary vitamin B6 and depression risk and found mixed results across studies. 9 of the 14 studies indicated that dietary vitamin B6 was not associated with depression, whereas results from the other 5 studies (Park et al., 2017; Kim et al., 2015; Watanabe et al., 2012; Murakami et al., 2010) indicated a significant inverse association between intake of vitamin B6 and depression, in articles published from 2010, articles conducted in Asia, and studies performed in adolescents. Further research, particularly robust randomized controlled trials with larger samples, are necessary to provide further supporting evidence for B6 clinical potential in mental health, and to determine the exact mechanism at play (since numerous neurotransmitters are synthesised with B6-involvement).

Alleviation of Symptoms Associated with Autism

Several interventions are used to treat autism, which is associated with social, communication and cognitive difficulties. Among them, vitamin B6 has been found to be beneficial in decreasing behavioural problems, improving appropriate behaviour, and supporting brain wave activity in autistic individuals (Mousain-Bosc et al., 2006). Although the exact pathogenesis is largely unknown, the mechanisms responsible for the efficacy of vitamin B6 is evidently relevant to certain neurotransmitter systems that are impaired in the presentation of individuals with Autism (Sato, 2018). Dopamine dysfunction occurs within dopamine brain regions involved in reward processing, including the ventral striatum (Dichter et al, 2012; Scott‐Van Zeeland et al 2010), therefore since B6 is required for the conversion of L-dopa into dopamine, supplementation can promote dopamine synthesis (Cellini et al., 2014). This could modulate the dopamine system, resulting in the improvement of autistic symptoms (Sato, 2018). 

Previous attempts to evaluate the efficacy of vitamin B6 in autism have in fact raised doubts about its clinical effectiveness and have failed to produce consistent findings (Findling et al., 1997; Gogou & Kolios, 2017). Proessionals have stressed that the clinical meaning of evidence, as it stood at the time of publication, was indetermined and that nutritional supplements for autism lacked sufficient and substantial support evidence (Kummer & Harsányi, 2011). Another worthy consideration is of the potential adverse effects when evaluating research as a basis for  clinical use, particularly considering that excessive doses of B6 have been associated with irritability, hypersensitivity to sounds and peripheral neuropathy (Kummer & Harsányi, 2011; Nye & Brice, 2005; Schechtman, 2007). 

With this in mind however, a more recent randomised, double blind, placebo controlled study of magnesium & B6 (Khan et al., 2021) shows promise. Significant neurobehavioural improvement was found among children with autism (with hyperactivity and irritability) in intervention compared to control group, with overall improvement in symptoms associated with autism, as well as specific domain improvements e.g. emotion and cognition. Since autism is highly heterogeneous (David et al., 2016) it is also important to consider subgroups who may show responsiveness to vitamin B6. For example, Obara et al (2018) presented data indicating that common variables may be able to identify subgroups that exhibit responsiveness to specific treatment: hypersensitivity to sound, clumsiness, and plasma glutamine level. Nevertheless, further studies to determine the predictive value of this are warranted, with the addition of a larger sample size. 

Genes mediating vitamin B6 homeostasis have also been implicated in autism. A recent study using mice has uncovered a key role for gut microbiota in regulation of autism-like social behaviour by mediating vitamin B6 metabolism, suggesting new strategies for understanding and support of individuals with autism (Li et al., 2020). According to the authors, a more alkaline environment in the gut, of individuals possessing a certain gene (EPHB6considered a candidate gene for autism), might have decreased absorption of vitamin B6. However, further research is required to uncover how the changed bacterial composition affects the gut pH and vitamin B6 levels in the blood & faeces, and the exact mechanisms resulting in symptoms associated with autism.

B6 and Schizophrenia

Another condition of interest, relevant to B6, is schizophrenia, a serious heterogenous mental disorder with symptoms including hallucinations or delusions. Deficiency in B vitamins and hyperhomocysteinemia are associated with inflammation and oxidative stress, which might subsequently contribute to the development and manifestation of schizophrenia (Misiak et al., 2013; Misiak et al., 2014; Stanger et al., 2009). Research has reported lower levels of vitamin B6 in peripheral blood in patients with schizophrenia, compared to controls (Toriumi et al., 2021). Similarly, B6 level has been found to be inversely proportional to patient’s positive and negative symptom scale (PANSS) score for symptom severity (Miyashita et al., 2014). In recent years, high-dose B6 has also been found effective in alleviating psychotic symptoms, particularly the PANSS negative and general subscales, in schizophrenic patients (Itokawa et al., 2018). Though evidence clearly supports a strong link between B6 and schizophrenia -it is extensively hypothesised that loss of B6 might contribute to the development of schizophrenia symptoms- the mechanism behind this has not yet been definitively identified.

However, recent findings by Toriumi et al (2021) have contributed to our understanding, and observed that B6 deficiency increases noradrenergic signalling. Utilising a mouse model to reflect a subpopulation of schizophrenia patients with B6 deficiency, mice who were fed a B6-lacking diet for 8 weeks (VB6− mice) showed hyperactivate noradrenergic signalling, resulting in behavioural deficits comparable to schizophrenia. A marked increase in 3-methoxy-4-hydroxyphenylglycol (MHPG) in whole brain tissue was found in VB6 − mice suggesting significantly enhanced noradrenaline metabolism, with enhanced NA release in the prefrontal cortex and the STR directly demonstrated by in vivo microdialysis. The researchers also demonstrated that chronic supplementation of B6 into the CNS by osmotic pump suppressed the enhanced noradrenaline metabolism and subsequently improved previously displayed behavioural deficits. These findings demonstrate that B6 deficiency in the CNS, (not in the peripheral, as they experimented with both), increases noradrenergic signalling in certain brain regions, which may induce schizophrenia-like behavioural deficits. The author concluded that the noradrenergic system may be hyperactivated in patients with schizophrenia who have low B6 levels, causing negative symptoms and cognitive dysfunction. 

Interestingly, no changes in GABA, dopamine and serotonin were found in the VB6− mice, despite the fact that these neurotransmitters are synthesized by enzymes dependent on B6 (Toriumi et al., 2021). Another curious finding in this recent study was that despite there being significant reduction in the PLP in the plasma of VB6− mice, only modest decline was found in the brain. Taken together, these results suggest that there is a biological mechanism to maintain B6 levels in the brain and that the noradrenergic system might be more vulnerable to B6 deficiency than other neuronal systems (since modest decline in B6 was sufficient to impair it). Despite the significant results from this study, further human studies are required, including gene expression analysis to identify molecular mechanisms underlying the observed finding that B6 deficiency increases noradrenergic signalling. 

Protective role against Mitochondria Damage

Research confirms that a lack of vitamin B6 can cause damage and toxicity to mitochondria and that appropriate supplementation of it can improve mitochondria’s energy metabolism to a certain extent (Depeint et al., 2006). This is due to the mechanistic role which PLP plays in mitochondrial functions, acting as a cofactor and participating in catalytic reactions. Polyglutamine (polyQ)-mediated mitochondria damage is one of the prime causes of polyQ toxicity, resulting in the loss of neurons and injury of non-neuronal cells. Interestingly, a recent study by Nan et al (2021) shows that treatment with vitamin B6 inhibits polyglutamine toxicity through mitochondria protection. This research supports the protective mechanism of mitochondria, explored in more dated studies, as well as indicating a promising therapeutic strategy for the treatment of polyQ disease, where pathological proteins are widely expressed in the brain.

Researcher: Hazel de Maejer, BSc Pyschology, MSc Nutrition & Behaviour (Bournemouth University)

References 

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