The potential role of nutritional components in improving brain function among patients with Alzheimer’s disease: a meta-analysis of RCT studies
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* Tarfa Albrahim

## Abstract

**Objectives:** To find out the potential role of nutritional components in improving brain function among patients with Alzheimer’s disease (AD).

**Methods:** The correlation between nutrition and cerebral function in cases of AD has been the focus of 19 prospective randomised controlled trials (RCTs) with a combined research sample of 2297 patients. These RCTs are subject to systematic review and meta-analysis in the current paper.

**Results:** Findings showed that chain-free secondary saturated fatty acids (SFA) and trans fatty acids (TFA) occurred in higher concentrations in AD patients’ brains than in controls. Furthermore, neuroinflammation was caused by remodelling of the lipid membrane and AD patients’ cognitive function was impacted by alterations in tyrosine, tryptophan, purine, and tocopherol pathway metabolomics. Moreover, in cases of mild-to-moderate AD, reduction in functionality was induced by administration of alpha-tocopherol for more than 12 months. Consumption of Souvenaid helps in synaptic synthesis, which enhances functional connectivity. Furthermore, consumption of the B vitamins folate, cobalamin and pyridoxine at dosages of 0.8 mg, 0.5 mg and 20 mg per day, respectively, over a period of one year resulted in lower plasma tHcy levels and brain atrophy.

**Conclusion:** Chain-free SFA and TFA occur in greater amounts in the brains of individuals with AD than in those without AD.

Life expectancy has recently increased enormously throughout the world, owing to development in medical sciences. As a result, the ageing population has expanded quickly, causing a phenomenal rise in the prevalence of late-life cognitive diseases like AD and vascular dementia (VaD).1-3 Besides impacting cognition in ageing individuals, causing the brain to become atrophied and disrupting learning, cognitive, reasoning and communication capabilities, such conditions are also a significant burden from a social and economic perspective.4 Dementia occurs in 5-8% of people older than 65, 15-20% of those older than 75 and 25-50% of those older than 85 years of age.5 Age, gender, head trauma and CVD risk factors (e. g. cardiac disease, diabetes, high blood pressure, depression, high cholesterol, sedentarism, smoking, alcohol drinking) are among the known sporadic AD risk factors that are not of genetic origin.6-8

The creation of medication capable of deferring AD onset by disrupting and mitigating A synthesis has been the aim of a number of clinical research trials and empirical work and has attracted ample annual investment from pharmaceutical companies. Even though such medication is yet to be formulated, drugs for symptom management do exist.9 Thus, the approach toward drug development for AD, as well as the therapeutic role of nutrition in preventing AD, need to be reconsidered.

Evidence has been produced that AD risk and progression are diminished by diet-related components like antioxidants,10,11 vitamins,12-14 polyphenols,15,16 and omega-3 fatty acids.17,18 By contrast, saturated fatty acids19 and simple carbohydrates20 are considered to increase likelihood of AD development.21 The RCTs carried out in the period 2010-2018 were reviewed in this paper to investigate whether AD patients’ cognitive function can be enhanced based on nutritional constituents. To this end, a meta-analysis was conducted to establish the extent to which cerebral function in AD cases was influenced by nutrition-based treatments. Furthermore, subgroup meta-analyses were also carried out to determine conformance to nutrition plans, proportion of deaths due to general causes and AD, respectively, body weight (BW), lean body mass (LBW), life expectancy, quality of life (QoL), and development of additional neurodegenerative diseases.

## Methods

The literature was searched and around 2657 relevant studies were found, of which 294 were chosen for additional inspection on the basis of scrutiny of their titles and abstracts according to the established eligibility criteria. 275 out of the 294 were not included in the review and meta-analysis, leaving a final number of 23 studies that satisfied the inclusion and exclusion criteria.

The work conducted by Sofi and colleagues22 on prospective RCTs analysing whether nutritional components influenced cerebral function in AD cases informed the research approach adopted in the present study. Thus, a combination of free text and MeSH terms (e. g. “Alzheimer’s disease”, “Alzheimer’s dementia”, “type 2 diabetes”, “nutrition”, “nutrient”, “medical food”, “randomised, double-blind controlled trial”, “randomised, controlled trial”, “randomised clinical trial”, “prospective”) was employed to search four electronic databases (i.e. PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials) for articles written in English and published between 2010 and 2018. Furthermore, to enrich the available data, the references from the chosen studies were screened as well. The most recent article was selected in cases where more than one article on the same study was available. A hierarchical strategy involving inspection of titles and abstracts coupled with accessibility of full-text article was adopted to determine whether the articles were relevant.

The articles had to be RCTs published in full and written in English to be included in the review. Furthermore, participants had to be older than 60 years of age and administered nutritional intervention for more than one month during therapy, without consideration for nutritional condition (i.e. well-nourished, malnourished, malnutrition risk). A standardised method of data extraction was used to derive a number of baseline attributes from the initial articles (e. g. main author, publication date, cohort nationality, sample size, number of outcomes, follow-up interval, age at entry, gender, results), which were incorporated in the meta-analysis. Data collection was undertaken by 2 investigators, with the third author (AC) intervening in the event of lack of agreement between the 2. Conformance to nutrition plans, proportion of deaths due to general causes and AD, respectively, body weight (BW), lean body mass (LBW), life expectancy, and quality of life (QoL) constituted the targeted outcomes.

## Statistical analysis

The non-parametric statistical test known as Cochran’s Q statistic and intended to assess if treatments yield the same outcomes was conducted to determine how heterogeneous the results of the chosen articles were. Heterogeneity was reflected by a *p*-value of less than 0.10, while the degree of heterogeneity was measured based on the I2 statistic and considered to be low for 25%, moderate for 50% and high for 75%. Furthermore, the combined incidence of MI and the equivalent odds and hazards ratios were calculated. The DerSimonian-Laird random-effects framework was applied when articles were markedly heterogeneous, whereas the fixed-effects framework was applied in all other cases. Two-tailed values were reported and the statistical significance of results was indicated by a *p*-value of less than 0.05, meaning that the confidence interval (C.I.) was 95%. A strategy of leave-one-out (LOO) sensitivity analysis was used where heterogeneity was high, with articles being eliminated successively to determine how they affected the combined results. The software program Review Manager (REVMAN) 5.3 Copenhagen (The Nordic Cochrane Center, The Cochrane Collaboration, 2014) was employed to conduct every statistical test.

## Results

### Patients characteristics

**Figure 1** shows the study selection procedure. **Table 1** provides the baseline features associated with AD and control cases. As can be seen in this table, the 23 chosen articles were published in the period 2010-2018, comprised a combined number of 2632 AD patients and 2441 controls, and the research was conducted in the US, Germany, Italy, France, the Netherlands, the UK, Sweden, Belgium, Spain, Singapore, and Norway. Male individuals accounted for 37.1% of the overall number participants (i.e. n=1305), and the patients had an average age of 75.8 years old.

View this table:
[Table 1](http://nsj.org.sa/content/25/1/4/T1)

Table 1 
Key features of the articles chosen for review.

### Primary outcomes. Single antioxidants

According to the values of Chi2 (2.86, *p* = 0.70) and I2 (0%), 5 articles concluded that the RCTs did not have marked heterogeneity regarding single antioxidant usage. Furthermore, single antioxidant and control did not differ regarding coenzyme Q (CoQ) concentration (MDIFF: -0.11: 95% CI, -0.65-0.43; *p* = 0.70; I2=0%), as revealed by the random-effects model employed **(Table**2**)**.

View this table:
[Table 2](http://nsj.org.sa/content/25/1/4/T2)

Table 2 
Comparison of single, composite antioxidant between AD patients and control group.

### Composite antioxidants

According to the values of Chi2 (10.10, *p* = 0.80) and I2 (90%), 2 articles concluded that the RCTs did not have marked heterogeneity regarding composite antioxidant usage. Furthermore, composite antioxidant and control did not differ regarding the MMSE score at 16 weeks (MDIFF: 0.68: 95% CI, -4.70-6.06; *p* = 0.80; I2=90%), as revealed by the random-effects model employed **(Table**2**)**.

### Omega-3

The 3 articles that examined Omega-3 found that the trials were not greatly heterogeneous, as reflected in the values of 2 (0.25, *p* = 0.70) and I2 (0%). Furthermore, Omega-3 and control did not differ regarding the MMSE score between baseline and 18 weeks (MDIFF: 0.13: 95% CI, -0.52-0.77; *p* = 0.70; I2 = 0%), as revealed by the random-effects model employed **(Table**3**)**.

View this table:
[Table 3](http://nsj.org.sa/content/25/1/4/T3)

Table 3 
Comparison of Omega 3, Polymeric formula and Docosahexaenoic Acid between AD patients and control group.

### Polymeric formula

The 3 articles that examined polymeric formula usage found that the trials were not greatly heterogeneous, as reflected in the values of 2 (0.12, *p* = 0.94) and I2 (0%). Furthermore, the polymeric formula and control did not differ regarding the treatment intervention (MDIFF: 0.06: 95% CI, -1.39-1.50; *p* = 0.94; I2 =0%), as revealed by the random-effects model employed **(Table**3**)**.

### Docosahexaenoic acid (DHA)

The 9 articles that examined DHA usage found that the trials were not greatly heterogeneous, as reflected in the values of 2 (26.77, *p* = 0.16) and I2 (78%). Furthermore, the AD and control cases did not differ regarding the DHA usage (MDIFF: -0.56: 95% CI, -1.34-0.23; *p* = 0.16; I2 =78%), as revealed by the random-effects model employed **(Table**3**)**.

### Vitamin C

The 3 articles that examined vitamin C usage found that the trials were not greatly heterogeneous, as reflected in the values of 2 (5.90, *p* = 0.40) and I2 (83%). Furthermore, the AD and control cases did not differ regarding the vitamin C usage (MDIFF: -3036.54: 95% CI, -10095.76-4.022.68; *p* = 0.40; I2=83%), as revealed by the random-effects model employed **(Table**4**)**.

View this table:
[Table 4](http://nsj.org.sa/content/25/1/4/T4)

Table 4 
Comparison of Vitamin C, E, B12, Folate, Plasma total homocysteine (tHcy) between AD patients and control group

### Vitamin E

The 4 articles that examined vitamin E usage found that the trials were not greatly heterogeneous, as reflected in the values of Chi2 (3.35, *p* = 0.47) and I2 (70%). Furthermore, the AD and control cases did not differ regarding the vitamin E usage (MDIFF: -27.55: 95% CI, -101.71-46.60; *p* = 0.47; I2=70%), as revealed by the random-effects model employed **(Table**4**)**.

### Secondary outcomes. Plasma total homocysteine (tHcy)

The 4 articles that examined the tHcy levels found that the trials were not greatly heterogeneous, as reflected in the values of 2 (181.22, *p* = 0.31) and I2 (99%). Furthermore, the AD and control cases did not differ regarding the tHcy levels (MDIFF: 383.81: 95% CI, -353.62-1121.24; *p* = 0.31; I2=99%), as revealed by the random-effects model employed **(Table**4**)**.

### Vitamin B12

The 4 articles that examined vitamin B12 usage found that the trials were not greatly heterogeneous, as reflected in the values of 2 (49.29, *p* = 0.39) and I2 (98%). Furthermore, the AD and control cases did not differ regarding the vitamin B12 usage (MDIFF: -2.73: 95% CI, -8.91-3.44; *p* = 0.39; I2=98%), as revealed by the random-effects model employed **(Table**4**)**.

### Folate

The 4 articles that examined folate usage found that the trials were not greatly heterogeneous, as reflected in the values of 2 (37.20, *p* = 0.31) and I2 (97%). Furthermore, the AD and control cases did not differ regarding folate usage (MDIFF: 10.47: 95% CI, -9.81-30.76; *p* = 0.31; I2= 97%), as revealed by the random-effects model employed **(Table**4**)**.

## Discussion

### Primary outcomes

Single antioxidants, including ascorbic acid (AA) and vitamin E, Souvenaid, vitamin E and memantine, vitamins E and C, and CoQ, were investigated in five of the reviewed articles,23-27 none of which differed significantly (*p* = 0.70) according to statistical analysis. The response of brain functionality to alpha-tocopherol, memantine and their combination was investigated by Dysken and colleagues23 in cases of mild-to-moderate AD; findings suggested that, by contrast to controls, the 152 participants with AD administered 2000 IU/d alpha-tocopherol for 5 years suffered moderate reduction in functionality, but administration of neither 20 mg/d memantine nor alpha-tocopherol combined with memantine had any impact on the Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) scale. Meanwhile, the biochemical and clinical impact of AA and vitamin E on 12 participants with AD was examined by Arlt and colleagues,24 who found that cognitive function was not altered significantly by administration of 1000 mg/d AA and 400 IU/d vitamin E alongside cholinesterase inhibitor for 12 months, according to the Mini-Mental State Examination (MMSE). Nevertheless, following 4 weeks, there was an improvement in the concentration of CSF antioxidant, while following 12 months, there was a decrease in CSF lipid oxidation. In the study by Ringma and colleagues,25 the focus was on the ability of the polyphenolic compound with antioxidant effects called curcumin C3 complex administered in 2 or 4 g/d to decrease beta-amyloid accumulation in a number of 32 participants with mild-to-moderate AD over a duration of 24 weeks. No discrepancies of note were observed in the AD Assessment Scale - Cognitive Subscale (ADAS-Cog), secondary outcomes, including the Neuropsychiatric Inventory (NPI), the ADCS-ADL scale, or Ab1-42, t-tau, p-tau181 or F2-isoprostane concentrations in CSF. Another study employed a sample of 78 patients to explore how oxidative stress, CSF biomarkers and ADCS-ADL responded to vitamin E (800 IU/d), vitamin C (500 mg/d), a-lipoic acid (ALA) (900 mg/d) and CoQ administered thrice daily for 16 weeks. The patients administered vitamins E and C and ALA showed 19% lower levels of F2-isoprostane, although AB42, tau and P-tau181 levels in CSF did not differ significantly. Nevertheless, the patients administered vitamins E and C and ALA did exhibit a more rapid decrease in the MMSE score, which is worrying from a safety perspective.26 Electroencephalography (EEG) was employed by De Waal and colleagues27 to determine how the beta band of the brain of 179 patients responded to the isocaloric control product Souvenaid administered in 125 ml/d for 24 weeks. Results indicated that the control group displayed a reduction in brain networks, whereas the active group displayed no alteration.

The effects of the composite antioxidants vitamin E / vitamin C / ALA and curcumin were investigated in 2 studies.26,28 No significant differences (*p* = 0.80) were observed in these studies. The primary outcome evaluated in both these studies was peripheral F2-isoprostane concentration. Galasko et al26 2012 reported a 19% decline in levels of F2-isoprostane in the E/C/ALA group, while Shinto et al28 2014 did not find any significant evidence. Nevertheless, one study28 judged that administration of Omega-3 FA had a negative impact on the MMSE score, while administration of Omega-3 FA combined with ALA had a negative effect not only on the MMSE score but also on the IADL score.

The impact of Omega-3 FA and DHA on AD was investigated in three studies.28-30 Statistical analysis revealed no significant effects of these substances (*p* = 0.70) in any of these studies. In keeping with the results obtained by Quinn and colleagues and Shinto and colleagues,28,30 regarding the DHA influence on the ADAS-cog score, Faxén-Irving and colleagues29 found that the concentration of plasma transthyretin (TTR), which is related to AB plaque decrease in the brain, was increased by DHA supplementation. Therefore, degeneration of cognition and functionality in cases of mild-to-moderate AD is not markedly diminished by administration of 2 g/d DHA of algal extract origin or consumption of 765 mg/d of fish with high levels of Omega-3 FA.

Polymeric formula usage was addressed in 3 studies,31-33 and all of them indicated that it had no substantial impact on participants with AD (*p* = 0.94). Meanwhile, the clinical product Souvenaid was investigated by 2 studies,31,33 which reported better tolerance of the food by AD patients. Kamphuis et al., 2011 31 reported a higher ADAS-cog score in patients with a high baseline ADAS-cog score and effects directly associated with its regular intake. Shah et al., 201333 do not report any significant change in ADAS-cog score upon consumption of Souvenaid for a period of 24 weeks. Ringman et al25 designed a nutrient formula using folate, vitamin E, cobalamin, SAM, NAC, and acetyl-L-carnitine. The IADL score of participants with AD was not substantially enhanced by the nutrient formula, although the dementia rating scale was improved.

Nine studies28,30,33-39 reported on the effect of DHA. In these studies, no significant (*p* = 0.16) difference was reported in its use by AD patients. Both Quinn et al28, 2020 and Shinto et al30 2014 reported no significant effect of the consumption of DHA (2 gram/day) and omega-3 FA (675 mg DHA and 975 mg EPA/d) on cognitive function of either AD patients or normal subjects. According to Scheltens et al39consumption of Souvenaid (125 ml/day) does not statistically improve IADL score, ADAS-cog score, QoL, or Interview-Based Impression of Change coupled with Caregiver Input or Neuropsychiatric Inventory, but did lead to markedly better activities of delayed verbal recall. Meanwhile, DHA concentration in AD patients’ brains were analysed by three studies,34,35,37 which found that AD patients had significantly less DHA than individuals without AD. By contrast, DHA was reported by Fraser and colleagues36 to be more or less the same in cases with and without AD. Fonteh et al35 reported high levels of even chain-free SFAs and TFAs in AD patients and 37 showed varying concentrations of lipid in the brain, resulting in lipid membrane remodeling and leading to neuroinflammation in AD patients. Similarly, Astarita et al34 showed dysfunction in the synthesis of DHA by the liver, resulting in low levels of DHA in the brains of AD patients.

The results of three studies24,40,41 indicated that cognitive function in cases of mild-to-moderate AD was not noticeably affected by AA (*p* = 0.40). More specifically, Arlt and colleagues24 revealed that administration of 1000 mg/d of AA and 400 IU/d of vitamin E for 12 months did not lead to considerably better cognitive function. Meanwhile, Kaddurah-Daouk and colleagues40 observed that participants with AD exhibited alterations in the metabolomics of the tyrosine, tryptophan, purine, and tocopherol pathways, which play a central role in normal cognitive function. Finally, Scheltens et al., 201241 assessed the impact of medicinal food, concluding that regular consumption of Souvenaid (125 ml/day) for 24 weeks results in better functional connectivity as a result of synaptic formation.

The impact of vitamin E administration on AD was addressed by four studies,23,39-41 but none of them reported any marked influence (*p* = 0.47). In terms of a-tocopherol, Kaddurah-Daouk et al., 201140 reported modifications in the tocopherol pathway in AD patients, which is crucial for proper cognitive function. By promoting synaptic links and enhancing the ability to undertake activities of delayed verbal recall, administration of 125 ml/d Souvenaid for 12 and 24 weeks led to better functional connectivity, according to Scheltens and colleagues.39,41 On the other hand, no alterations were noted in the IADL score, ADAS-cog score, QoL, and Interview-Based Impression of Change coupled with Caregiver Input.

### Secondary Outcomes

Four studies42-45 reported on the levels of plasma total homocysteine. However, no significant difference (*p* = 0.31) was identified between patients with AD and control individuals. All the studies reported on the effect of daily consumption of vitamin B (0.8 mg B9, 0.5 mg B12 and 20 mg B6) on plasma tHcy and reported that when baseline tHcy levels were above 11 µmol/L, significant effects were observed on reducing gray matter atrophy of the brain and on stable cognitive function (CLOX). Similarly, when B9 and B12 were administered at dosages of 5 and 1 mg daily, respectively, for 2 years, plasma tHcy levels were reduced.

Four studies42-45 reported on the effect of vitamin B12 on the development of MCI into AD. Statistical analysis showed no significant evidence of an effect on this change (*p* = 0.39). From the studies of Douaud et al42, de Jager et al43, and Smith et al45 it can be seen that vitamin B12 (0.5 mg/d) administered in combination with other B vitamins significantly lowers brain atrophy in MCI patients. However, such results are evident only in patients with high baseline plasma tHcy levels (>11 µmol/L). According to Kwok et al., 2011,44 when vitamin B12 is given at a dosage of 0.5 mg per day for 2 years in combination with folic acid, it results in a significant reduction in plasma tHcy levels. On the other hand, neuropsychological scores, including the Mattis Dementia Rating Scale (MDRS), the Neuropsychiatric Inventory and the Cornell Scale for Depression in Dementia, did not display notable modifications.

Four studies42-45 reported on the use of folate. Statistical analysis of these studies revealed no significant evidence (*p* = 0.31) of its effect on patients with AD. From all four studies42,43,45 it is evident that consumption of vitamin B9 (20 mg/d) for a period over 1 year significantly reduces plasma tHcy levels and brain atrophy. Similarly, the findings of Kwok et al44 2011 reveal that when 5 mg of B9 was orally administered for a period of 2 years, plasma tHcy levels decreased significantly. By contrast, neuropsychological scores, including the MDRS, the Neuropsychiatric Inventory and the Cornell Scale for Depression in Dementia, did not exhibit any alterations. Additionally, as previously mentioned, the effectiveness of vitamin B9 was based on baseline plasma tHcy levels.

### Limitations

Although a RCT is the best method by which to minimize bias and confusion and establish causality, conducting RCTs is not always possible. However, few published RCTs have concluded that antioxidants, B vitamins, and omega-3 PUFAs do not reduce the incidence of neurodegenerative disorders or the risk of AD. The results of these RCT studies contradict the findings of observational studies, which may be due to a number of reasons, chief among them that nutrients mainly play a preventive role rather than a protective role in the onset of AD pathogenesis. Second, variations in the dosage of nutrients between epidemiological studies and RCTs lead to poor results. Suboptimal research interval, interactions between nutrients and between drugs and nutrients, lack of consideration for social and behavioural aspects, lack of homogeneity among research populations, nutrient concentrations, exposure duration, compliance with treatment, length of follow-up and primary outcome are all factors impacting RCTs.46,47 Therefore, to expand the findings obtained, secondary outcomes (e. g. conformance to nutrition plan, body weight lean body mass, QoL, life expectancy, blood biomarkers) must be assessed as well (Schueren et al., 2018). Hence, null RCT results do not automatically signify that a particular nutrient is ineffective against AD; this is because previous studies have clearly demonstrated that, if they are taken at the right time and in the right concentration, the majority of nutrients can be beneficial.

In conclusion, Chain-free SFA and TFA occur in greater amounts in the brains of individuals with AD than in those without AD. Moreover, lipid membrane remodeling results in neuroinflammation in AD patients. Additionally, poor synthesis of DHA by the liver due to dysfunction results in accelerated AD disorder. Moreover, unlike controls, AD patients’ cognitive function is susceptible to the impact of alterations in the tyrosine, tryptophan, purine and tocopherol pathway metabolomics. Additionally, individuals with mild-to-moderate AD exhibit reduction in brain functionality as a result of administration of alpha-tocopherol for more than 12 months. However, when vitamin E is taken in combination with AA and ALA, it results in a faster decline in MMSE score, which raises safety concerns. Souvenaid has been claimed by a number of epidemiological works to have a positive action and be well-tolerated by individuals with AD. However, in the present study, it was not possible to demonstrate that Souvenaid use improved beta band network and brain functionality. Nevertheless, Souvenaid can lead to better functional connectivity as it promotes synaptic synthesis. Additionally, the effects of this medicinal food are based on the baseline ADAS-cog score, i.e., the higher the score, the more pronounced the effect of Souvenaid. These studies also failed to demonstrate a positive relationship between consumption of Souvenaid and the IADL score. However, one study reported improved delayed verbal recall tasks. When Omega-3 FA is applied alone or in combination, it results in MMSE score decline. The levels of brain AB plaque are diminished by DHA administration, but this study has not observed DHA to enhance cognition and functionality. B vitamins, such as folate, cobalamin, or pyridoxine, consumed at 0.8 mg, 0.5 mg, and 20 mg levels each day, respectively, for a period of more than 1 year result in lower plasma tHcy levels and reduced brain atrophy. However, these effects are based on baseline plasma tHcy levels, which should be above 11 µmol/L. Contrary to such results, the neuropsychological scores used in this study (e. g. MDRS, Neuropsychiatric Inventory, Cornell Scale for Depression in Dementia) did not suggest that plasma tHcy had any influence on cognitive function (CLOX). There is a strong possibility that such nutrients exert their positive effects when a mixture of nutrients are consumed together instead of when one nutrient is consumed. Therefore, further research is necessary to determine how such nutrients act in synergy and try to determine how nutrients contribute to food and diet.

## Acknowledgment

*This research was funded by the Deanship of Scientific Research at Princes Nourah bint Abdulrahman University through the Fast- track Research Funding Program.*

## Footnotes

*   **Disclosure.** Authors have no conflict of interests, and the work was not supported or funded by any drug company.

*   Received May 20, 2019.
*   Accepted November 4, 2019.


*   Copyright: © Neurosciences

Neurosciences is an Open Access journal and articles published are distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC). Readers may copy, distribute, and display the work for non-commercial purposes with the proper citation of the original work.

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