Neurotrophins as neurobiological correlates of analytic visual information processing and migraine

Marzia Buonfiglio1, Pamela Rosso2, Elena Fico2, Marta Armentano3, Ludovico Alisi3, Filippo Brighina4, Marcella Nebbioso3, Vittorio Di Piero5, Alessandro Lambiase3, Francesco Di Sabato1, Paola Tirassa2

1Headache Center, Department of Clinical Medicine, Policlinico Umberto I, Sapienza University of Rome, Italy; 2Institute of Biochemistry and Cell Biology (IBBC) - National Research Council (CNR), Rome, Italy; 3Department of Sense Organs, Sapienza University of Rome, Italy; 4Department of Biomedicine, Neuroscience and Advanced Diagnostic (BIND), University of Palermo, Italy; 5Department of Neurological Sciences, Sapienza University of Rome, Italy.

Summary. The present study aims to clarify whether salivary and serum nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels might reflect the cognitive processing style of healthy subjects and migraine sufferers. All subjects underwent the recording of visual evoked potentials (VEP) to evaluate visual habituation. Dosing of plasmatic and salivary levels of NGF and BDNF was performed as well. Our research provides insights into the role of neurotrophins and the analytic style of processing visual information in pain mechanisms, potentially identifying them as targets for new integrated therapeutic strategies, both pharmacological and non-pharmacological, for primary headaches.

Key words. Neurotrophins, cognitive style, migraine, visual evoked potentials.

Le neurotrofine come correlati neurobiologici dell’elaborazione analitica delle informazioni visive e dell’emicrania.

Riassunto. Il presente studio mira a chiarire se i livelli salivari e sierici del fattore di crescita nervoso (NGF) e del fattore neurotrofico derivato dal cervello (BDNF) possano riflettere lo stile di elaborazione cognitiva dei soggetti sani e di quelli affetti da emicrania. Tutti i soggetti sono stati sottoposti alla registrazione dei potenziali evocati visivi (VEP) per valutare l’abituazione visiva. È stata inoltre effettuata la misurazione dei livelli plasmatici e salivari di NGF e BDNF. La nostra ricerca fornisce approfondimenti sul ruolo delle neurotrofine e dello stile analitico di elaborazione delle informazioni visive nei meccanismi del dolore, identificandole potenzialmente come bersagli per nuove strategie terapeutiche integrate, sia farmacologiche sia non farmacologiche, per il trattamento delle cefalee primarie.

Parole chiave. Emicrania, neurotrofine, potenziali evocati visivi, stile cognitivo.

Introduction

As demonstrated by Roger Sperry in the 1980s1, the two cerebral hemispheres exhibit distinct mechanisms for processing information. Specifically, the left hemisphere predominantly supports an analytic mode of thinking, characterized by step-by-step processing with attention to detail, while the right hemisphere is involved in global or holistic thought processes. The analytic cognitive processing style is defined by heightened activation of attention and memory, along with continuous evaluation of environmental stimuli, resulting in increased demands on attentional resources2-4. It functions as a habitual and preferred mode of perceiving and encoding incoming information, often evident from childhood.2 Conversely, the global processing style favors broad and abstract thinking, typically overlooking or disregarding fine details, and relies on a holistic, intuitive approach to stimuli perception2-4. Previously, we demonstrated that an analytic visual processing style is associated with impaired visual habituation and neurological disorders such as migraine and epilepsy, highlighting its significance in the pathogenesis and therapeutic management of migraine2,3,5, and underscoring the necessity of identifying its neurobiological correlates. Among the molecules involved in cognitive processing, the neurotrophins Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF)6,7 are the most extensively studied in both animal models and humans, due to their roles in regulating brain functions and reflecting environmental changes and stimuli8-12. Within the Central Nervous System (CNS), NGF and BDNF are synthesized predominantly by neuronal cells in an activity-dependent manner8-10. Variations in their expression levels correlate not only with cognitive processing13-15 but also with stress, arousal, and coping mechanisms16. Furthermore, neurotrophins (NTs) levels in the retina and primary visual cortical areas are modulated by visual and light inputs, contributing significantly to the processing of visual information and influencing cognitive and emotional responses to visual stimuli in both physiological and pathological states11,12. Changes in NGF or BDNF concentrations have also been documented in serum/plasma, saliva, and tears of animals and humans15. Importantly, variations in circulating and secreted NTs levels are not merely epiphenomenal but can reflect NTs synthesis and release within the brain. Consequently, they may serve as indicators of central neurotransmission and neuronal plasticity7, as well as markers of specific physiological or pathological states, including pain and migraine17-19. Consistent with these findings, our previous research demonstrated that ultradian variations in circulating and salivary NTs correlate with gender-related chronotypes20 and psychophysiological traits21, thus providing insights into health and well-being profiles. The present multidisciplinary study aims to investigate whether salivary and serum NGF and BDNF levels can serve as biomarkers reflecting cognitive processing styles in healthy individuals and migraine patients.

Materials and methods

Participants and study design

This study aimed to analyze NGF and BDNF profiles in saliva and serum samples from healthy subjects and migraine patients recruited from the Ophthalmology Clinic and the Headache Center at Policlinico Umberto I Hospital (Rome, Italy), respectively. The study received ethical approval from the local ethics committee (Ref. 7809 Prot. 0042/2025), and all participants provided written informed consent. The study procedures complied with the Declaration of Helsinki. All enrolled subjects underwent ophthalmological evaluations, confirming the absence of concomitant ocular diseases. Participants were unrelated, without any personal or familial history of neurological or psychiatric conditions, and had no current allergic, infectious, or inflammatory disorders. Recruited volunteers reported not taking regular medications, not smoking cannabis or nicotine, having no history of alcohol or drug addiction, not being heavy alcohol drinkers (as defined by the National Institute on Alcohol Abuse and Alcoholism - NIAAA), and having abstained from alcohol in the past 48 hours. Female participants were included during the first week following menstruation.

Psychological evaluation

Psychological data were collected through a structured clinical diagnostic interview divided into three sessions for each participant, along with two standardized psychological tests: the Sternberg-Wagner Self-Assessment Inventory and the Learning Styles Questionnaire. Detailed methodologies for psychological assessments are provided in Supplementary Material 1. These instruments allowed the assessment of each participant’s preferred cognitive style.

Electrophysiological evaluation

Visual evoked potentials (VEP) were recorded in both migraine patients and healthy subjects. Migraineurs underwent VEP recordings during the interictal period, at least 48 hours before or after a migraine attack. Habituation was quantified as the difference in the average amplitudes between the 50th and the 200th stimulation. Comprehensive details regarding VEP recording procedures are included in Supplementary Material 2.

Saliva and serum sample collection and NTs measurement

The methodology to analyze the NGF and BDNF concentration in the human saliva and blood follows a protocol standardized in our laboratory and described in previous studies11,15,20. Briefly, the saliva and serum samples were collected between 9:00 and 11:00 a.m. on the same day as ophthalmological evaluations. Blood samples (10 ml) were drawn from each subject’s antecubital vein and allowed to clot at room temperature before serum was separated by centrifugation. Saliva samples were collected via passive drooling into plastic tubes and centrifuged at 10,000 rpm for 10 minutes. Both serum and saliva samples were stored at -80 °C until analysis. NGF and BDNF concentrations in serum and saliva samples were measured using human-specific immunoassay kits (R&D Systems, Minneapolis, Usa). All assays were performed in triplicate following the manufacturer’s protocols, utilizing recommended buffers, diluents, and substrates. Optical density was measured using a microtiter plate reader (Dynatech MR5000; PBI International, Dynatech International, Edgewood, NY, Usa) at 450 nm. Intra- and inter-assay coefficients of variation were below 7%. NTs concentrations (pg/ml) were calculated based on standard curves provided by the assay.

Statistical analysis

Statistical analyses were conducted using the open-source software JASP [JASP Team. JASP Version 0.19.3]. The normality of data distributions was evaluated using the Shapiro-Wilk test. Psychological measures, electrophysiological scores, and NTs expression levels were analyzed using the Kruskal-Wallis test, followed by Dunn’s post hoc comparisons with Bonferroni correction. All data are expressed as mean ± SD. Correlation analyses between NTs levels and both psychological and ophthalmological variables were performed using Pearson or Spearman correlation tests, when appropriate. A p-value <0.05 was considered statistically significant.

Results

Study population

The study recruited a total of 8 healthy subjects characterized by an analytic cognitive style (HA), 8 healthy subjects with a global cognitive style (HG), and 16 migraine patients. Migraine patients were further categorized into migraine without aura (MWOA, n=8) and migraine with aura (MWA, n=8). Patients consulting the headache center were diagnosed according to the International Classification of Headache Disorders, 2nd edition (ICHD-II, 2004). Mean age did not significantly differ among groups: HA group (52.78±17.88 years), HG group (50.5±14.10 years), MWOA group (46±9.76 years), and MWA group (52.25±8.02 years) (p=0.769). All participants enrolled in the study were female.

Psychological characteristics of the study’s group

The Sternberg-Wagner Self-Assessment Inventory results for analytic cognitive style were significantly different among groups: HA group scored 6.89±0.33, HG group 2.13±0.64, MWOA group 6.50±0.58, and MWA group 6.75±0.50 (p<0.001). For global cognitive style, scores were as follows: HA group 1.78±0.67, HG group 6.38±0.52, MWOA group 1.50±0.58, and MWA group 2.50±1.00 (p<0.001).

The Mariani test results, evaluating visual, auditory, analytic, and global cognitive styles, are presented in Supplementary Material 3 and confirm the findings from the Sternberg inventory. Both migraine groups (MWA, MWOA) showed higher analytic style scores and lower global style scores compared to the HG group, similar to the HA group. Regarding visual and auditory cognitive styles, both migraine groups scored higher than the global group in the visual style, mirroring the HA group. However, the MWA group scored higher than both MWOA patients and the HA group in the auditory cognitive style category.

Visual evoked potentials

VEP results, averaged across both eyes, were analyzed by calculating the amplitude difference between the 50th and 200th stimulations (Delta stimulation). Mean Delta stimulation values were 3.42±2.65 for the healthy analytic group, -2.60±2.69 for the healthy global group, 3.37±1.16 for the migraine without aura group, and 1.84±1.78 for the migraine with aura group. The Kruskal-Wallis test revealed statistically significant differences among groups (p<0.001). Post- hoc analysis using Dunn’s multiple comparison test identified significant differences between the healthy analytic and healthy global groups (p<0.001), and between the healthy global group and both migraine groups (migraine without aura, p<0.001; migraine with aura, p=0.001). However, no significant differences were found between the healthy analytic group and either migraine group (migraine without aura, p=1.000; migraine with aura, p=0.390), nor between the migraine with aura and migraine without aura groups (p=0.905).

Serum and salivary levels of NGF

Different levels of NGF were measured in the serum and saliva of healthy subjects and migraine patients, as illustrated in figures 1A and 1B, respectively. In serum, no significant difference between the analytic (42,11±3,74 pg/ml) and global healthy groups (45,44 ±4,86 pg/ml) were found. Both migraine patients with (120,10±10,82 pg/ml) and without aura (100,50±4,55 pg/ml) showed high levels of NGF when compared to global and analytic control groups (p<0.001). The small difference in the serum of NGF levels reported in the migraine groups also results statistically significant (p<0.001) (figure 1A).

Conversely to serum, high NGF levels were detected in the saliva of healthy women characterized by a global cognitive style (187,28±11,18 pg/ml, p<0.001) compared to analytic subjects (53,7±6.99 pg/ml), while no differences between migraine with (103,28±5,63 pg/ml) or without aura were found (104,96±6,96 pg/ml). The saliva NGF levels of both migraine groups resulted significantly increased when compared to the analytic control group (p<0.001), and decreased compared to the global control, group (p<0.001).

The serum and saliva NGF levels in analytic subjects, which included healthy women and migraine patients, is positively correlated (Spearman’s rho=0,626 p=0,001) while no significant correlation was found by including the global healthy women (Spearman’s rho=0,112. p=0,54). Moreover, the graph in figure 1C confirms that migraine patient group exhibited higher NGF concentrations compared to healthy analytic group.




BDNF levels in serum and saliva

The results of the BDNF ELISA assays in serum and saliva are presented in figure 2A and 2B, respectively. No significant differences were found between the serum (figure 2A) or salivary (figure 2B) BDNF concentrations of the analytic (serum 512.55±105.64; saliva 156.29±31.57 pg/ml) and global healthy subjects (serum 416.99±76.917; saliva 183.46±14.36 pg/ml), while the migraine patients exhibited a different trend. Serum BDNF levels were significantly higher in both migraine patients (aura= 641.41±71.53 pg/ml; without aura= 580.16±40.07 pg/mlp<0.01) compared to global healthy subjects, while only patients with aura were significant when compared to the healthy analytic women (p<0.01). As far as the BDNF levels in saliva is concerned, only the levels in migraine patients with aura (244,80±39.88 pg/ml; p=0.001) but not those without aura (156.18±25.56 pg/ml; p=0.01) resulted significant different to both healthy groups.

Correlation analysis revealed a positive correlation between serum and salivary BDNF levels in analytic subjects, with no significant differences between healthy individuals and migraine patients (Spearman’s rho=0.440 p=0.031; figure 2C) while no significant correlation was found by including women with the global style (Spearman’s rho=0.284 p=0.115)




Correlation between NTS and delta VEP

Correlation analysis demonstrated distinct relationships between serum NTs levels and delta VEP values. Serum NGF levels did not show a significant correlation with delta VEP, whereas serum BDNF levels exhibited a positive correlation, with statistical data and significance values detailed in Supplementary materials 4.

Conversely, salivary NGF levels negatively correlated with delta VEP, while salivary BDNF did not show a significant correlation. Detailed results and significance levels of these correlations are summarized in Supplementary materials 5.

Discussion and conclusions

This multidisciplinary study aimed to analyze salivary and serum NGF and BDNF levels in healthy women and migraine patients, considering their visual information processing style. As specifically shown in the results section and focused below, we found that levels of NGF and BDNF in saliva and serum not only characterize migraine patients but also the cognitive processing style, such as the analytic and global ones, in healthy women. As highlighted by our data, migraineurs exhibited significant differences compared to both healthy groups, showing higher serum NGF levels and, conversely, lower salivary levels of this neurotrophin compared to global healthy subjects. Notably, the Analytic group and migraineurs (with and without aura) revealed a similar trend, showing significantly lower salivary NGF levels when compared to the global group (figure 1A-C). Regarding BDNF, significant higher serum levels were observed in both groups of migraineurs, versus global healthy subjects. Similarly, the analytic healthy group showed an increase, although not significant, in serum BDNF concentration in comparison with global healthy women (figure 2A-C). Taking into account the common neurophysiological and cognitive-behavioral features shared by analytic subjects and migraineurs2-4, but also the neurotrophins’ crucial role in brain plasticity and cognition, in health and diseases12,22-24, we believe these data warrant further larger scale investigation. In particular, in view of the gender differences in the ultradian levels of NGF and BDNF, and their correlation with specific psychophysiological traits20, it could be relevant to evaluate the neurotrophin profile in men with migraine, as well as to distinguish cognitive style from migraine between sexes.

However, although this study is limited to women, the evidence that migraine is about 4 times prevalence in women than in males25, and that neurotrophins changes in serum are often reported in pathologies with woman prevalence11,20, also showing a specific correlation between pathological features, including cognitive impairment and visual processing15, might corroborate our findings on the neurotrophins involvement in migraine suggested by others18,19,26,27.

Consistent with our earlier studies2,3,28 we confirm that migraine is specifically associated with deficits in visual habituation and an analytic cognitive processing style. Additionally, we report for the first time that levels of salivary and serum BDNF and NGF, along with their correlations, distinctly characterize cognitive styles and migraine subtypes.

The observed correlation between salivary NGF (but not serum NGF) and delta VEP in the overall sample of women (healthy plus migraine subjects) further supports the hypothesis that salivary NGF variations are associated with habituation. Specifically, higher NGF levels correspond to better habituation (global visual processing), whereas lower NGF levels are indicative of impaired habituation (analytic visual processing)3.

The positive correlation between serum BDNF levels and delta VEP habituation, along with the correlation between serum and salivary BDNF levels in analytic cognitive style subjects, suggests that serum BDNF might reflect the habituation deficit associated with the analytic style. Elevated serum BDNF is thought to mirror cerebral activities and functions in various pathophysiological states, including stress and anxiety16,29, as well as following environmental enrichment and cognitive training9,10,29. Consequently, elevated BDNF levels in analytic subjects could reflect increased cerebral activity necessary to sustain the heightened attentional demands characteristic of this cognitive style2-5.

In addition, our study shows that levels of BDNF in the saliva of patients with migraine with aura are higher than in those without aura, and that a contemporaneous BDNF increase in serum and saliva is found only in patients with aura when compared to analytic healthy group. It is plausible that, similar to observations in Graves’ disease patients15, where serum/tear BDNF levels correlate with altered rapid visual processing scores, elevated BDNF in migraine patients with aura may reflect hyperactivation of corticolimbic pathways associated with visual stimuli, as supported by functional imaging analysis30.

These findings underline the importance of considering cognitive processing styles in control groups when investigating migraine and its subtypes, and could explain the apparently discrepancy with the studies by Fisher et al.31 and Bahtigul Holmuratova et al.27 in which the serum BDNF levels during migraine attacks is compared to migraine patients during attack-free periods or healthy subjects without differentiating their cognitive processing styles.

Clinically, the correlation between neurotrophins, cognitive style and VEP imply that peripheral NGF and BDNF profiles could serve as biomarkers to evaluate the efficacy of preventive or therapeutic migraine interventions, including non-pharmacological approaches, such as cognitive training aimed at altering their visual processing style, potentially mitigating their vulnerability to developing migraines, as previously suggested2-4.

In conclusion, our research provides valuable insights into the role of NTs and the analytic cognitive style of visual information processing in pain mechanisms, potentially identifying these, as targets for new integrated therapeutic strategies – both pharmacological and non-pharmacological – for primary headaches. Moreover, these findings may further elucidate pathways linking cognition, visual processing, and the synthesis and release of NTs, highlighting their critical role in both health and diseases.

Competing interests: the authors have no relevant financial or non-financial interests to disclose.

Author contribution. Conceptualization: Marzia Buonfiglio; Methodology: Marzia Buonfiglio, Paola Tirassa; Formal analysis and investigation: Marcella Nebbioso, Marta Armentano, Ludovico Alisi; Writing - original draft preparation: Paola Tirassa, Elena Fico, Pamela Rosso, Marzia Buonfiglio; Writing - review and editing: Paola Tirassa, Filippo Brighina, Vittorio Di Piero, Marta Armentano, Ludovico Alisi; Data analysis: Pamela Rosso, Elena Fico; Statistical analysis: Marta Armentano, Ludovico Alisi, Paola Tirassa; Supervision: Marzia Buonfiglio, Paola Tirassa, Alessandro Lambiase, Francesco Di Sabato.

Data availability statement: the datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Consent to participate: informed consent was obtained from all individual participants included in the study.

Consent to publish: patients signed informed consent regarding publishing their data.

Ethical committee approval number: the study was approved by the local ethical committee (Rif. 7809 Prot. 0042/2025).

Acknowledgments: we are deeply grateful to Prof. Rita Levi-Montalcini for her invaluable encouragement to pursue this line of research and to her niece; Piera Levi-Montalcini, for facilitating contacts between authors from different institutions.

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Supplementary material

Supplementary material 1

Psychological evaluation

Two sessions were held with each participant. In the first session, the subject was tested, and in the second session, an interview was held to determine whether the test results coincided with the subject’s self-evaluation. A total of five 1-hour sessions, therefore, were held with each participant in the study. The Sternberg-Wagner Self-Assessment Inventory, also known as the Thinking Style Inventory (TSI), is a reliable measurement system for assessing the thinking style proposed in the theory of Sternberg and also shows good external validity2. In this diagnostic instrument, Sternberg specifies that «a style is a favorite way of thinking» and is not an ability, but a preference with which the mind controls its own activity, a differentiation in the human way of perceiving, thinking, learning, and remembering. Sternberg distinguishes the individuals who use a global style from those who use an analytic thinking style. Those who use a global style prefer to deal with issues that are relatively wide and abstract and they usually ignore or dislike details, perceiving stimuli by taking a holistic view of situations, using mostly intuition. Analytical people, on the contrary, appreciate problems that require work with details and perceive by focusing a great deal of attention on each single element of an object or a situation with, consequently, greater activation of memory and evaluation of stimuli2. Sternberg also examined the correlation of the TSI with other tests, e.g., with the Myers-Briggs type indicator and the Gregorc style delineator. Score values are assigned to categories (from very low to very high), according to the ranges, different for males and females. The Learning Styles Questionnaire (Mariani L.)2 was utilized to confirm our obtained results. This questionnaire is usually utilized in a learning context, giving us an indication of the tendency to be left/analytic or right/global hemisphere dominant or bilateral, using both about equally, and is composed of 15 items; negative scores indicate a left-brain dominance, and also focused on the visual and auditory dimensions of cognitive styles [2]. Our previous work demonstrated a very high correlation among the two test individual scores2.

Supplementary material 2

Electrophysiological evaluation

The subjects were taken to a quiet room with dimmed light. They were seated 1 m in front of a television monitor (mean luminance 250 candela/m2, colour temperature 9500 K). Stimuli were presented as a checkerboard pattern of black and white squares (8 min of arc), at a reversal frequency of 3,1 Hz. Subjects were instructed to fixate on a red dot in the middle of the screen with one eye covered by a patch. Electrodes were placed in the midline over the occipital region 2,5 cm above the inion (Oz: active electrode) and over the frontal region (Fz: reference). The ground electrode was placed on the forearm. During uninterrupted stimulation, five sequential blocks of responses were averaged for a total duration of 1,5 minutes. The five blocks of responses were analyzed in terms of peak latencies and peak-to-peak amplitudes of the maximum negative (Ni) and positive (P1) deflections determined by visual inspection. The N1 peak is defined as the most negative point between 60 and 90 ms post-stimulus, P1 as the most positive point following N1 between 80 and 120 ms post-stimulus. Habituation was expressed as the difference in amplitudes between the 50 and the 200 stimulations.

Supplementary material 3

Scores obtained from Mariani test to assess the visual, auditory, analytic, and global cognitive styles in MWA (migraine with aura) and MWOA (migraine without aura) patients and healthy subjects.




Supplementary material 4

Correlation plots illustrating the relationship between serum BDNF (A) and NGF (B) levels and delta VEP. Correlation results and statistical significance are presented in panel C.




Supplementary material 5

Correlation plots demonstrating the relationships between salivary NGF (A) and BDNF (B) levels and delta VEP. Detailed correlation results and significance values are reported in panel C.