The influence of neuroactive steroids on cortical evoked response potentials and attentive performance of cognitive tasks in young adults – A cross-sectional study

INTRODUCTION

Neuroactive steroids (NASs) are naturally produced substances that alter neurotransmitter receptors in the brain to rapidly alter neuronal excitability. They play a vital role in controlling many brain processes such as emotion, cognition, and behavior. The impact of NASs on the focus and productivity of young people is currently being extensively investigated. NAS interacts with neurotransmitter receptors and affects the generation of electrical signals and communication between nerve cells, thus playing a crucial role in the regulation of cognitive and learning processes. While the role of NAS is predominantly studied in the context of neurological disorders, extensive research is necessary to fully comprehend its role in the brain’s response to various conditions. Below is an elaborate analysis of how NASs and their ratios may influence attention and performance in this specific population.^[1,2] The sulfate form of dehydroepiandrostenedione-sulfate (DHEA-S) has been linked to enhancements in mood, memory, and cognitive function, highlighting the importance of DHEA. They mitigate the impact of cortisol and, perhaps, improve performance under stressful situations. Progesterone, a steroid, has been shown to have a tranquilizing effect on the brain and has been demonstrated to affect memory and attention processes.^[3,4] The hypothalamic-pituitary-adrenal (HPA) axis may be regulated by neuroactive hormones, especially DHEA, which decreases the impact of stress on cognitive function. NASs can affect attentional processes by influencing the neurotransmitter systems. DHEA has shown the ability to enhance attentional function, maybe by mitigating the detrimental impact of cortisol on the brain.^[5] The impact on memory and executive functioning varies and is contingent on the particular neurosteroid and its concentration. DHEA is often linked to improved working memory and executive function. The balance between NASs is crucial for maintaining homeostasis. An effective method for assessing the impact of stress on cognitive performance involves analyzing the DHEA-to-cortisol ratio, with cortisol serving as an indicator of stress. A higher ratio of DHEA to cortisol is often associated with enhanced cognitive function and a heightened capacity to manage stress.^[6] NASs modify the capacity of neurons to generate electrical signals and transfer information between them, thereby influencing cognition. Hence, this study aimed to determine the impact of NASs on cortical-evoked response potentials and the attentive performance of cognitive tasks.

MATERIALS AND METHODS

This cross-sectional observational study was conducted in the Department of Physiology Outpatient Unit of the Medical Sciences, Institute of National Importance for a period of 6 months (October 2023–March 2024). Ethical approval was obtained from the institutional ethical committee before conducting the study (IEC certificate no: AIIMS/MG/IEC/2022-23/228). Participants were given a comprehensive explanation of the study objectives and methodologies, and written consent was obtained according to the guidelines set by the Institutional Review Board.

This study adopted an analytical technique using a cross-sectional design. The sample size was estimated using the formula: N = (Za/2)² s²/d², where s is the standard deviation (SD) obtained from the pilot study and d is the accuracy of the estimate or how close it is to the true mean. Za/2 normal deviates from the two-tailed alternative hypothesis at a level of significance. A pilot study conducted on five young adults resulted in an SD of 5, with a probability of 95%, and at an error rate of 5%, the minimum sample size required was estimated to be 24 subjects, and after an allowance of 20% for non-respondents is assumed, the corrected sample required was 30 subjects. Accordingly, 30 young healthy adult male participants with ages ranging from 21.5 to 31.9 years who willingly consented to participate in the examination were included in the study. A comprehensive medical history was obtained, encompassing information regarding existing medical conditions and drugs taken over the past 6 months. Subsequently, comprehensive clinical and systemic evaluation was performed. The study excluded those with pre-existing cardiovascular diseases, unstable coronary syndromes, or those engaged in vigorous athletic training, as they may act as confounders.

Blood samples were collected to assess the levels of neuroactive hormones, specifically cortisol, and DHEA-S, using aseptic techniques and preserved in vials containing ethylenediaminetetraacetic acid anticoagulant at a concentration of approximately 1.5 mg/mL. This sample was collected after administering a validated questionnaire to measure perceived stress, emotions, and mood. DHEA-S and cortisol concentrations were measured using fully automated electrochemical luminescence immunoassay technology on the ROCHE COBAS E 411. Subsequently, the research focus shifted toward event-related potentials (ERPs) data, particularly to analyze the P300 component exclusively. Eysenck explained that cognitive performance was determined by the time taken to respond and the proportion of the maximal possible accuracy of the task.^[7] Each participant was then given a battery of cognitive tests performed on the Stroop test, Trial Making test, and Mini-mental state examination (MMSE). P300 - cortical evoked response potential was used for neurophysiological measure of cognitive function.

RESULTS

Figure 1 presents the following measurements: The average age is 21 years, the height is 1.70 m, the weight is 62.47 kg, the resting heart rate is 81.03 beats/min, the systolic blood pressure is 116.77 mmHg, and the diastolic blood pressure is 74.90 mmHg. Figure 2 shows that the measurements are as follows: Cortisol level is 7.13 ± 3.04 μg/dL, DHEA-S level is 350.34 ± 89.74 μg/dL, Cortisol/DHEA-S ratio is 0.023 ± 0.01, Stroop test correctness of response for congruent trials is 98.93 ± 1.11%, for incongruent trials is 96.77 ± 2.02%, Stroop test RT for congruent trials is 23.83 ± 5.27 s, for incongruent trials is 31.1 ± 5.78 s, TMT-A score is 23.93 ± 4.56, TMT-B score is 49.73 ± 8.02, MMSE score is 29.33 ± 0.71, and P300 latency is 312.97 ± 35.98 ms. Participants with elevated levels of DHEA-S demonstrated better performance, indicated by higher accuracy percentages and quicker RTs. Lower P300 latencies were associated with faster RTs and improved response accuracy, leading to better cognitive performance. Individuals with reduced attention and performance exhibited a notably elevated Cortisol/DHEA-S ratio.

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Figure 1:

Basic parameter of the participants. RHR: Resting heart rate, SBP: Systolic blood pressure, DBP: Diastolic blood pressure. X-axis: Age in years, height in cm, weight in kg, RHR in beats/min, SBP in mmHg, DBP in mmHg. Y-axis: Numerical values in relation with X-axis parameters.

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Figure 2:

Cognitive parameter. DHEA-S: Dehydroepiandrostenedionesulfate, TMT: Trail-making test, MMSE: Mini-mental state examination, RT: Reaction time. Y-axis: Numerical values in relation with X-axis parameters.

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The ratio of cortisol to DHEA-S has the potential to influence RTs for incongruent trials. This is suggested by a t-value of 2.54 and a P = 0.09, both of which signal a tendency toward statistical significance. However, when considering a significance threshold of 0.05, this effect does not meet the requirements for statistical significance. The t-values of 3.98 and P = 0.15 suggest a significant trend, indicating a potential influence of the cortisol/DHEA-S ratio on TMT-B completion times.

The statistical analysis reveals a significant difference (t = 2.41, P = 0.02) between the groups with high and low DHEA-S values on the MMSE scores. These data suggest that there exists a positive correlation between higher levels of DHEA-S and improved cognitive performance. The t-value of 2.56, along with a P = 0.01, indicates a statistically significant correlation between cortisol levels and MMSE scores. Higher cortisol levels may be associated with improved cognitive performance. The correlation between the cortisol to DHEA-S ratio and MMSE scores is statistically significant, as indicated by the t-value of 1.77 and P = 0.04 [Table 1].

In general, the majority of cognitive markers do not exhibit statistically significant associations with levels of NASs. Nevertheless, noteworthy discoveries have been made: MMSE scores exhibit a substantial correlation with DHEA-S, cortisol, and the cortisol/DHEA-S ratio, indicating a possible connection between these neuroactive hormones and cognitive function as a whole. In addition, there is a notable correlation between the cortisol/DHEA-S ratio and RTs in the Stroop test, namely during incongruent trials. This highlights the necessity for additional research in this field.

DISCUSSION

The important findings of this study include cortisol levels of 7.13 ± 3.04 μg/dL and DHEA-S levels of 350.34 ± 89.74 μg/dL, with a cortisol/DHEA-S ratio of 0.023 ± 0.01. Higher DHEA-S scores correlate with better cognitive performance, faster RTs, and greater accuracy. Lower P300 latencies are associated with improved cognitive response times. Although the cortisol/DHEA-S ratio showed a trend toward influencing RTs and TMT-B completion times, these were not statistically significant. Higher DHEA-S and cortisol levels were significantly correlated with better MMSE scores, suggesting a positive association between these hormones and cognitive function.

A recent study analyzed the plasma concentrations of DHEA, DHEA-S, cortisol, dissociative psychological symptoms, and military performance in 41 physically fit individuals enrolled in the combat diver qualification course; a favorable connection was observed between elevated levels of DHEA and DHEA-S and enhanced performance on the underwater navigation test. Furthermore, a notable negative correlation was observed between symptoms of stress-induced dissociation and elevated levels of DHEA and DHEA-S.^[9] An analysis of NASs, such as pregnenolone and DHEA, and their ratios, particularly about cortisol, provides valuable insights into their impact on attention and cognitive performance in young persons. Van Broekhoven and Verkes found that administering allopregnanolone in moderate doses can enhance concentration by reducing anxiety. However, higher doses of the drug can impair attention due to its sedative qualities, indicating that the effect on cognitive function is dependent on the dosage.^[10] Eser et al. confirmed that the modulation of gamma-aminobutyric acid A (GABA-A) receptors by allopregnanolone is crucial for its effects on anxiety and attention.^[11] This study also offered valuable insights into the neuronal mechanisms that underlie these effects. Wolf and Kirschbaum conducted a study that demonstrated that incorporating DHEA into one’s diet can improve cognitive abilities, namely working memory and attention, particularly in young individuals experiencing stress.^[12] According to the scientists, the negative effect of DHEA on cortisol plays a significant role in enhancing cognitive function.^[12] Alhaj et al. reported similar findings, suggesting that DHEA enhances cognitive performance and mood.^[13] This provides evidence that the regulation of cortisol levels using DHEA may have a beneficial effect on cognitive function.

Morgan et al. found a connection between a higher DHEA/cortisol ratio and enhanced cognitive performance as well as an increased capacity to manage stress.^[14] This finding indicates that it is crucial to maintain a balanced level of these neurosteroids for optimal cognitive health. Guazzo et al. found that individuals with a higher DHEA/cortisol ratio demonstrated enhanced memory function and reduced levels of anxiety.^[15] This discovery provides evidence that this ratio can be regarded as a reliable indication of cognitive well-being. Majewska et al. and Paul and Purdy investigated the influence of neurosteroids on GABA-A receptors, which subsequently modulate inhibitory control and cognitive functions.^[16,17] The research highlights the importance of neurosteroids, specifically allopregnanolone, in regulating attention and performance. Dubrovsky examined the relationship between neurosteroids and N-methyl-Daspartate (NMDA) receptors, which play critical roles in synaptic plasticity and memory. Neurosteroids can enhance cognitive processes by controlling the activation of NMDA receptors, as demonstrated by this interaction.^[18] Sapolsky et al. investigated the role of neurosteroids in regulating the HPA axis and stress management.^[19] Neurosteroids like DHEA were highlighted as having the ability to mitigate the detrimental effects of cortisol on the brain, hence safeguarding cognitive functioning during periods of stress. Yen and Laughlin presented proof that the administration of DHEA reduces cortisol levels and improves cognitive performance, especially in stressful situations.^[20] To address the variability in neurosteroid levels and their influence on cognitive function, future research must prioritize personalized treatments. Studies conducted by Ritsner et al. and Marx et al. suggested that differences in the processing of neurosteroids and the initial levels of these substances in individuals could offer useful insights for the development of tailored treatment approaches.^[21,22] Comprehensive investigation is required to fully understand the long-lasting effects of neurosteroid modulation on cognitive function. Wolf and Kirschbaum and Morgan et al. propose utilizing longitudinal designs to investigate temporal changes and assess the enduring efficacy of cognitive enhancers.^[9,12] Supplementing neurosteroids in clinical research has demonstrated promise in enhancing cognitive impairment and attention deficits. Eser et al. and Guazzo et al.^[11,15] emphasize the therapeutic capacity of neurosteroids in the treatment of conditions such as attention deficit hyperactivity disorder (ADHD) and anxiety disorders.

CONCLUSION

This study conclusively illustrates the neuroprotective and neuroinhibitory effects of DHEA-S and cortisol. The anti-glucocorticoid activity of DHEA-S was confirmed by the inverse ratio of cortisol to DHEA-S. Our findings support existing data indicating that the immediate effects of neurosteroids do not involve interactions with traditional steroid hormone receptors responsible for gene transcription. Neurosteroids have been shown to directly influence the function of ligand-gated ion channels, particularly GABA-A receptors, and possess characteristics of inducing anxiety, promoting seizures, increasing memory, stimulating neurogenesis, and providing neuroprotection. Suppression of GABA-A receptor activity: The enhanced activity of NMDA receptors may be used in the future to build powerful analogs as a translational and rational approach to neurological diseases.