According to the world statistical data, headaches are widespread and lead to significant limitations [1-2]. The Harvard Medical School claims over 300 types of headaches, but only about 10% have a known cause [3]. According to the World Health Organization (WHO), 50-75% of adults aged 18–65 years have experienced a headache in the last year [4]. The International Classification of Headache (ICHD) is essential in diagnosis and treatment of headache. The second version of this classification has been widely used In Russia (ICHD-2, 2003), when a Russian-language version was formulated and adapted. The third version (ICHD-3) was adopted in 2018. This system is currently used in practical and scientific activities. According to the ICHD-3 data, all headaches are divided into primary, secondary headaches and cranial neuralgia [5]. It is believed that 95% of patients experience primary headache, and the most common (30–78%) clinical form is tension-type headache (TTH) [6, 7]. Arterial hypertension (AH) is the most common (40-44%) vascular disease accompanied by headache in adult population of Europe and Russia [8, 9]. Expert community is focused on the issues of early diagnosis and reduction of risk of hypertension, and masked hypertension is a clinical variant of essential hypertension with mean ambulatory blood pressure (BP) >130/80 mm Hg and/or mean daily BP >135/85 mm Hg and/or mean nighttime BP >120/70 mm Hg with normal clinical blood pressure. Some authors distinguish hemodynamic phenotypes of masked hypertension: isolated systolic, isolated diastolic, systolic-diastolic masked hypertension [10]. Headaches in AH are diverse in nature and fundamentally differ from TTH [11]. AH-related headache is often associated with elevated BP [12]. At the same time, there is an opinion that this is a clinical manifestation of TTH in a comorbid patient [13]. It is believed that headache is a result of functional changes in cerebral system, neurotransmitters controlling pain, while the brain-derived neurotrophic factor (BDNF) is essential in regulation of these processes [14]. Psychoemotional disorders (anxiety, depression) cause neurotrophic changes in brain including decrease of BDNF [15, 16]. Some studies indicate an importance of BDNF in regulation of neuronal plasticity [17]. Moreover, this factor is involved in pathophysiology of some neurological and psychiatric diseases, such as depression, post-traumatic stress and chronic pain [15]. There is evidence that BDNF can penetrate the blood-brain barrier [18]. BDNF level is often analyzed in blood serum, since experiments on pigs and rodents revealed a positive correlation between the level of BDNF in brain and peripheral blood [19]. The relationship between neurotrophic factors and primary cephalalgia continues to be studied, in particular, in cluster headache and migraine [20]. At the same time, the effect of BDNF on severity of headache in patients with TTH and masked hypertension has not been studied enough.

The purpose of the study was to analyze the clinical features of headache and the role of brain-derived neurotrophic factor (BDNF) in young patients with arterial normotension and masked arterial hypertension.

Material and methods

We examined 128 patients aged 18 — 44 years (mean 34.1±5.9) who were treated at the 1477 Naval Clinical Hospital of the Russian Ministry of Defense (Vladivostok) between 2017 and 2021. To establish the diagnosis, we used the ICHD-3 criteria (2018) and clinical guidelines of the Russian Cardiology Society “Arterial hypertension in adults (2016)".

Inclusion criteria: male and female patients aged 18–44 years without other comorbidities, and whose clinical manifestations met the criteria for masked hypertension or TTH; no intake of antidepressants, hypotensive, neuroprotective and nootropic drugs throughout the entire period of survey; complaints of headache; headache NRS score < 8 points; an informed consent for examination. The control group included 30 healthy people without complaints and normal blood pressure.

Exclusion criteria: pain syndromes of other localization, acute or aggravation of chronic somatic disease, mental disorders, organic neurological disease, alcohol and drug abuse, no consent for examination.

The ethics committee approved the study. The last one was performed in accordance with Good Clinical Practice and the principles of the Declaration of Helsinki. Upon inclusion, all participants signed an informed consent.

All participants were divided into 4 groups: group 1 (control group) — 30 healthy people (mean age 34.2 ± 4.8 years) without any complaints and normal blood pressure (true normotension); group 2 — 32 patients (mean age 34.6±5.6 years) with recurrent TTH and normal blood pressure; group 3 — 32 patients (mean age 34.4±5.8 years) with masked systolic hypertension and headache; group 4 — 34 patients (mean age 34.2±5.7 years) with masked diastolic hypertension and headache.

Numerical rating scale was used to assess headache intensity. Masked arterial hypertension was diagnosed using 24-hour blood pressure monitoring and monitoring at home with analysis of BP and headache diary. Spielberger-Khanin scale and Beck Depression Inventory were used to assess psychological state.

We analyzed serum BDNF by enzyme immunoassay in the morning on an empty stomach. Blood was taken from the cubital vein into a 10 ml tube and then centrifuged at 1000 g for 20 min. Aliquoted samples were preserved at -80°C for up to 3 months, and enzyme immunoassay was performed using ELISA Kit reagents (USA).

Daily dynamics of blood pressure was assessed according to international guidelines. We carried out a 24-hour BP monitoring using portable device BPLab V.05.02.00 (Russia) with oscillometric BP measurements in decompression phase. Monitoring was started at 9-10 am, the intervals between measurements were 15 min during the day and 30 min at night. We assessed mean daily systolic and diastolic blood pressure, pressure during the day and at night. Generally accepted parameters in healthy people were used as reference values.

Statistical analysis was performed using descriptive statistics (median (Me) and 95% confidence interval (CI)), non-parametric Mann-Whitney test, Spearman's rank correlation coefficient. According to Shapiro-Wilk test, distribution of BP values was close to normal. Differences were significant at p-value <0.05. Data analysis was performed in R environment.

Analysis and interpretation of data were partially supported by the RFBR grant 19-29-01077.

Results

All patients underwent SMAD. According to these data, 62 patients (48.4%) had normal office BP (true normotension). All patients with true normotension were included in the 1^st and 2^nd groups: group 1 consisting of 30 (23.4%) healthy people without any complaints (control group) and group 2 consisting of 32 (25.0%) people with headaches (5 — 12 episodes per a month).

Masked hypertension was observed in 66 (51.6%) patients. Some patients had predominant systolic hypertension, some patients — diastolic hypertension. Considering predominant systolic or diastolic hypertension, we divided these patients into two groups: group 3 — 32 (25.0%) patients with systolic masked hypertension, group 4 — 34 (26.6%) patients with diastolic masked hypertension. Hemodynamic phenotypes were verified using a combination of modern methods for biomedical data processing (UMAP and DBSCAN) that made it possible to identify two clusters with high accuracy (Davies-Bouldin index 0.72): systolic masked hypertension — 32 (48.5%), diastolic masked hypertension — 35 (51.5%) (Table 1).

Table 1. Indicators of daily monitoring of blood pressure in individuals with normal blood pressure, masked arterial hypertension

Note. Data are presented as median and 95% confidence interval; BP — blood pressure; SBP — systolic blood pressure; DBP — diastolic blood pressure; p₀ — differences between the groups of masked hypertension and normal blood pressure.

In the 2^nd group (32 people including 11 (34.4%) men and 21 (65.6%) women), duration of disease was 3.2±1.3 years. Mean number of pain episodes was 8.4±3.9, duration of pain attacks — 7.9±4.5 hours. Mean NRS score of headache was 5.6±1.6. At the same time, 28 (78.1%) patients associated pain with psycho-emotional stress. Cephalgia was bilateral, had compressive nature and mainly involved frontal, temporal and parietal regions. In 7 people (21.9%), tension and soreness of pericranial muscles were revealed. These patients denied association of headache with psycho-emotional factors and believed that it occurs after prolonged static muscle tension (prolonged work on the computer or after sleep). There were no complaints of nausea, vomiting and dizziness. Mean Spielberger-Khanin score was 45.4±5.3 (high personal anxiety). Mean situational anxiety accounted for 37.4±4.3 points (moderate anxiety). Mean BDI score was 12.9±1.1 (mild depression). In the 3^rd group (32 people including 19 (59.4%) men and 13 (40.6%) women), duration of disease was 2.8±1.3 years. Mean number of pain episodes per a month was 9.4±3.8. Mean duration of pain attacks was 13.2±5.8 hours. NRS score of headache was 6.5±1.4. In case of complaints typical for TTH, patients additionally presented complaints of diverse nature. Thus, 23 (71.8%) patients characterized headache as throbbing, 15 (46.9%) patients reported fever and numbness of the face, 10 (31.3%) patients noted unsteadiness when walking, 9 patients (28.1%) had impaired concentration of attention, 7 (21.9%) patients — non-systemic dizziness, 7 (21.9%) patients — mild nausea, 5 (16.1%) patients — feeling of lightheadedness. Tension and soreness of pericranial muscles after prolonged static loads were detected in 4 (12.5%) patients. Mean number of complaints per a patient in this group was 2.2. Mean Spielberger-Khanin score of personal anxiety was 39.4±4.5 (moderate). There was high situational anxiety (47.5±4.7 points). Mean BDI score was 13.8±1.2 (mild depression). In the 4^th group (34 people including 15 (44.1%) men and 19 (55.9%) women), duration of disease was 3.3±1.1 years. Mean number of headache episodes was 12±1.7. Mean duration of pain attacks was 22.3±6.8 hours, NRS score of headache — 6.1±1.4 points. Twenty-two (62.9%) patients had heaviness in the head, 13 (37.1%) patients — heaviness in occipital region; 11 (31.4%) patients — unsteadiness when walking; 7 (20.0%) patients — delayed reaction, 6 (17.1%) patients — nausea, 5 (14.3%) patients — feeling of lightheadedness. Tension and soreness of pericranial muscles were detected in 5 (14.7%) patients. Mean number of complaints in this group was 2.1. Spielberger-Khanin score of personal anxiety was 48.6±5.8, situational anxiety — 46.4±3.1 (high anxiety). Mean BDI score was 19.1±1.2 (moderate depression). Anxiety and depressive symptoms are described in Table 2.

Table 2. The level of anxiety-depressive symptoms in patients of all groups

Note. * — p<0.05. ** — p<0.01 (significant differences compared to the control group).

In the 1^st group, serum BDNF was 11.6±2 ng/ml. At the same time, there were no any complaints, anxiety and depressive symptoms. In the 2^nd group, mean serum BDNF was 9.2±1.8 ng/ml, in the 3^rd group — 8.2±2.9 ng/ml, in the 4^th group — 5.5±1.7 ng/ml. Thus, mean serum BDNF is lower in the 2^nd and 3^rd groups compared to the 1^st group but it significantly higher than in the 4^th group. Mild depression was typical in the 2^nd and 3^rd groups, while moderate depression was common in the 4^th group. Serum BDNF is presented in Table 3. Correlation between serum BDNF and severity of depression is presented in the Figure.

Table 3. Serum BDNF level of all groups

Note. * — p<0.05; BDNF — brain-derived neurotrophic factor.

The dependence of the serum BDNF level in patients with CTTH and the level of depression on the Beck Depression Inventory.

We found a significant correlation (R= -0.63, p<0.05) between BDI score and serum BDNF in the 4^th group compared to the control group. There was no significant correlation between BDI score and serum BDNF in the 2^nd and 3^rd groups (R₂= -0.24, R₃= -0.37, p>0.05). In the 4^th group, high personal and situational anxiety inversely correlated with serum BDNF (personal anxiety R₄= -0.52 / situational anxiety R₄= -0.49). In the 2^nd and 3^rd groups, personal and situational anxiety was lower while serum BDNF was higher. No significant inverse correlation was obtained (personal anxiety R₂= -0.24 / situational anxiety R₂= -0.17; personal anxiety R₃= –0.16 / situational anxiety R₃= –0.26) (Table 4).

Table 4. Correlation between serum the BDNF level and the severity of anxiety-depressive symptoms in patients of all groups

Note. * — p<0.05; BDNF — brain-derived neurotrophic factor.

We found that 62 (48.9%) patients had normal office blood pressure (true normotension). Of these, 51.6% (32 people) had complaints that met the criteria for episodic frequent TTH, and 30 (48.4%) people were healthy. In 66 people, 24-hour monitoring revealed masked hypertension. As mentioned above, patients were divided into two hemodynamic phenotypes depending on predominant systolic or diastolic hypertension. These patients presented a large number of diverse complaints in addition to TTH. Thus, patients with systolic hypertension indicated recurrent headaches characterized by bilateral throbbing, as well as fever and numbness of the face, impaired concentration, non-systemic dizziness and feeling of lightheadedness in addition to complaints typical for TTH. In addition to complaints typical for TTH, patients with diastolic hypertension complained of heaviness in the head, occipital region, unsteady gait, general weakness and slow reactions, which were also combined under the general term "headache".

In patients with masked hypertension, complaints often arose or intensified after self-control blood pressure measurement when the measurement results were subjectively assessed as elevated figures. It increased situational anxiety and led to depressive symptoms. This was especially true for patients with diastolic hypertension. Patients with systolic hypertension and pulsating pain more often diagnosed themselves with pseudohypertensive crisis and used antihypertensive drugs after control measurements.

We studied serum BDNF in all patients. Serum BDNF in the control group (no complaints, anxiety and depressive symptoms) was recognized as normal. Serum BDNF was slightly reduced in patients with episodic frequent TTH and those with comorbid systolic hypertension and episodic frequent TTH. Serum BDNF was significantly lower in patients with comorbid TTH and diastolic hypertension compared to the control group. However, no significant differences compared to the 2^nd and 3^rd groups were observed.

We analyzed correlation between serum BDNF and severity of anxiety and depressive symptoms in the 1^st and 4^th groups. There was a significant inverse correlation between serum BDNF and BDI score of depression (R=0.63, p<0.05), Spielberger-Khanin score of personal anxiety (R=0.52, p<0.05) and situational anxiety (R=0.49, p<0.05). In the 2^nd and 3^rd groups, there was no significant correlation between serum BDNF, severity of depression and anxiety (p<0.05). We can assume that reduced serum BDNF is a result of chronic pain process and dysregulation of antinociceptive system, while neurotrophic factor is involved in pathogenesis of pain syndrome.

Conclusion

Headache corresponds to TTH in patients with normal office blood pressure (true normotension). Patients with masked hypertension presented complaints typical for TTH and additionally diverse complaints that depended on hemodynamic phenotype of masked hypertension and did not meet the criteria for TTH. BDNF was significantly reduced in patients with TTH and comorbid TTH and isolated systolic masked arterial hypertension compared to the control group. However, serum BDNF did not significantly correlated with severity of depression, personal and situational anxiety.

Serum BDNF was significantly reduced in patients with comorbid TTH and diastolic masked arterial hypertension. These ones had high Spielberg-Khanin score of personal and situational anxiety, as well as moderate depression. This can indicate dysregulation of limbic-reticular complex, in particular, antinociceptive system.

Financing. The study was partially supported by the RFBR grant 19-29-01077.

The authors declare no conflicts of interest.