Migraine is a common and disabling neurological disorder characterized by recurrent headache attacks accompanied by various neurological and systemic symptoms. Globally, migraine affects approximately 14–15% of the population and represents one of the leading causes of years lived with disability.¹ Beyond headache pain, migraine is increasingly recognized as a complex brain disorder associated with cognitive, emotional, and sensory disturbances.

Traditionally, cognitive impairment in migraine has been studied primarily during the ictal phase, when patients experience acute headache attacks. During this phase, individuals frequently report difficulties with concentration, attention, and information processing.² However, emerging evidence suggests that cognitive dysfunction may also persist during the interictal period, when patients are not experiencing active migraine attacks.³

Attention, vigilance, and executive functions are particularly vulnerable cognitive domains in migraine patients. These functions play a critical role in everyday activities, including decision-making, problem-solving, and sustained concentration. Deficits in these domains can significantly impact academic performance, occupational productivity, and overall quality of life.⁴

Several neuropsychological studies have demonstrated that migraine patients perform worse on tests of sustained attention and executive functioning compared with healthy controls.⁵ Functional neuroimaging research has further revealed altered activity in brain regions associated with cognitive processing, including the prefrontal cortex, anterior cingulate cortex, and thalamus.⁶ These findings suggest that migraine may involve widespread neural network dysfunction beyond the classical pain pathways.

Chronic migraine, defined as headache occurring on at least 15 days per month for more than three months, is associated with particularly severe cognitive disturbances.⁷ Repeated migraine attacks and persistent central sensitization may contribute to cumulative neurological changes that impair cognitive functioning.⁸ In contrast, patients with episodic migraine generally experience fewer headache days and may exhibit milder cognitive deficits.

Another important consideration is the potential reversibility of migraine-related cognitive impairment. Preventive migraine therapies, including pharmacological agents such as beta-blockers, antiepileptics, and antidepressants, aim to reduce the frequency and severity of migraine attacks.⁹ By stabilizing neuronal excitability and reducing cortical hyperresponsiveness, these treatments may also improve cognitive functioning.¹⁰

Longitudinal studies investigating the effect of preventive therapy on cognitive performance in migraine patients remain limited. Some investigations have reported significant improvements in attention and executive functioning following effective migraine prophylaxis.¹¹ However, other studies suggest that certain cognitive deficits may persist even after clinical improvement in headache frequency.¹²

The mechanisms underlying interictal cognitive dysfunction in migraine remain incompletely understood. Proposed explanations include cortical spreading depression, altered neurotransmitter signaling, and structural brain changes associated with repeated migraine attacks.¹³ Additionally, comorbid conditions such as anxiety, depression, and sleep disturbances may further contribute to cognitive impairment.¹⁴

Understanding interictal cognitive dysfunction in migraine has important clinical implications. Cognitive symptoms may significantly contribute to functional disability, yet they are often underrecognized in routine clinical practice. Early identification and appropriate management of these deficits may improve patient outcomes and quality of life.¹⁵

In the present study, we aimed to evaluate interictal dysfunctions of attention, vigilance, and executive functions in patients with chronic and episodic migraine using standardized neuropsychological assessments. Furthermore, we investigated whether these cognitive deficits improve following preventive migraine therapy over a longitudinal follow-up period.

Introduction

Migraine is a common and disabling neurological disorder characterized by recurrent headache attacks accompanied by various neurological and systemic symptoms. Globally, migraine affects approximately 14–15% of the population and represents one of the leading causes of years lived with disability.¹ Beyond headache pain, migraine is increasingly recognized as a complex brain disorder associated with cognitive, emotional, and sensory disturbances.

Traditionally, cognitive impairment in migraine has been studied primarily during the ictal phase, when patients experience acute headache attacks. During this phase, individuals frequently report difficulties with concentration, attention, and information processing.² However, emerging evidence suggests that cognitive dysfunction may also persist during the interictal period, when patients are not experiencing active migraine attacks.³

Attention, vigilance, and executive functions are particularly vulnerable cognitive domains in migraine patients. These functions play a critical role in everyday activities, including decision-making, problem-solving, and sustained concentration. Deficits in these domains can significantly impact academic performance, occupational productivity, and overall quality of life.⁴

Several neuropsychological studies have demonstrated that migraine patients perform worse on tests of sustained attention and executive functioning compared with healthy controls.⁵ Functional neuroimaging research has further revealed altered activity in brain regions associated with cognitive processing, including the prefrontal cortex, anterior cingulate cortex, and thalamus.⁶ These findings suggest that migraine may involve widespread neural network dysfunction beyond the classical pain pathways.

Chronic migraine, defined as headache occurring on at least 15 days per month for more than three months, is associated with particularly severe cognitive disturbances.⁷ Repeated migraine attacks and persistent central sensitization may contribute to cumulative neurological changes that impair cognitive functioning.⁸ In contrast, patients with episodic migraine generally experience fewer headache days and may exhibit milder cognitive deficits.

Another important consideration is the potential reversibility of migraine-related cognitive impairment. Preventive migraine therapies, including pharmacological agents such as beta-blockers, antiepileptics, and antidepressants, aim to reduce the frequency and severity of migraine attacks.⁹ By stabilizing neuronal excitability and reducing cortical hyperresponsiveness, these treatments may also improve cognitive functioning.¹⁰

Longitudinal studies investigating the effect of preventive therapy on cognitive performance in migraine patients remain limited. Some investigations have reported significant improvements in attention and executive functioning following effective migraine prophylaxis.¹¹ However, other studies suggest that certain cognitive deficits may persist even after clinical improvement in headache frequency.¹²

The mechanisms underlying interictal cognitive dysfunction in migraine remain incompletely understood. Proposed explanations include cortical spreading depression, altered neurotransmitter signaling, and structural brain changes associated with repeated migraine attacks.¹³ Additionally, comorbid conditions such as anxiety, depression, and sleep disturbances may further contribute to cognitive impairment.¹⁴

Understanding interictal cognitive dysfunction in migraine has important clinical implications. Cognitive symptoms may significantly contribute to functional disability, yet they are often underrecognized in routine clinical practice. Early identification and appropriate management of these deficits may improve patient outcomes and quality of life.¹⁵

In the present study, we aimed to evaluate interictal dysfunctions of attention, vigilance, and executive functions in patients with chronic and episodic migraine using standardized neuropsychological assessments. Furthermore, we investigated whether these cognitive deficits improve following preventive migraine therapy over a longitudinal follow-up period.

Materials and Methods

Study Design and Setting

This study was conducted as a prospective longitudinal case–control investigation at the Department of Neurology, Kalinga Institute of Medical Sciences (KIMS), Bhubaneswar, Odisha, India. The objective was to evaluate interictal cognitive dysfunction in patients with migraine and to assess changes in cognitive performance following preventive therapy.

The study was carried out over a 22-month period from March 2024 to January 2026. Patients presenting to the neurology outpatient department or admitted for inpatient care with a diagnosis of migraine were screened for eligibility.

Study Population

A total of 680 individuals were screened during the study period. After applying predefined inclusion and exclusion criteria, 420 patients with migraine were included in the final analysis. Additionally, 200 healthy individuals without a history of migraine or neurological disorders were recruited as controls.

Controls were matched with cases for age, sex, and educational level to minimize potential confounding effects on cognitive performance.

Migraine patients were categorized into two groups:

• Chronic migraine (n = 110)
• Episodic migraine (n = 310)

Diagnostic Criteria

Migraine diagnosis was established according to the International Classification of Headache Disorders, 3rd edition (ICHD-3).

• Episodic migraine: Headache occurring on fewer than 15 days per month
• Chronic migraine: Headache occurring on 15 or more days per month for at least three months, with at least 8 days exhibiting migraine features

All diagnoses were confirmed by experienced neurologists following detailed clinical evaluation.

Inclusion Criteria

Participants were included if they met the following criteria:

1. Age between 18 and 60 years
2. Diagnosis of chronic or episodic migraine based on ICHD-3 criteria
3. Ability to understand and perform neuropsychological assessments (The patients who had an elementary school education of at least sixth standard and could read and write)
4. Participants who had not taken any appropriate preventive therapy for migraine and using only rescue medications as required
5. Provision of written informed consent

Exclusion Criteria

Participants were excluded if any of the following were present:

• Other primary headache disorders
• Neurological diseases (e.g., epilepsy, stroke, neurodegenerative disorders)
• Major psychiatric disorders
• Substance abuse
• Significant visual or hearing impairment
• Use of medications known to affect cognitive function
• Pregnancy or lactation

A total of 260 individuals were excluded due to these criteria or incomplete clinical data.

Preventive Treatment Protocol

Following baseline assessment, patients received preventive migraine therapy according to established clinical guidelines. Treatment selection was individualized based on patient characteristics and comorbidities.

Medications included:

• Propranolol
• Topiramate
• Amitriptyline/ Nortriptyline
• Valproate/ Divalproex sodium
• Gabapentin
• Flunarizine

Patients were monitored periodically to assess adherence and treatment response. Follow-up cognitive assessment was performed after six months of therapy.

Neuropsychological Assessment

Cognitive function in patients with episodic migraine (EM) and chronic migraine (CM) was evaluated during the interictal phase, ensuring a minimum interval of 72 hours since the last headache episode or a headache-free day. Participants were instructed to notify the investigators via telephone if they developed a migraine attack within 72 hours following the assessment. If such an event occurred, the data from the prior evaluation were excluded, considering the likelihood that the patient may have been in the premonitory phase at the time of testing, and the assessment was subsequently repeated. All cognitive evaluations were conducted in a quiet and controlled hospital setting.

A structured battery of validated neuropsychological tests was used to assess multiple cognitive domains.

Global Cognitive Function

Global cognitive status was assessed using the Mini-Mental State Examination (MMSE). A score below 24 was considered indicative of cognitive impairment.

Attention

Attention was evaluated using:

• Digit Span Test (forward and backward)
• Trail Making Test Part A

Reduced digit span scores and increased completion times were interpreted as impaired attentional performance.

Vigilance (Sustained Attention) and Executive Function

Vigilance (Sustained Attention) and Executive functioning was assessed using:

• Trail Making Test Part B
• Stroop Word Test
• Stroop Color Test
• Stroop Interference Score

Higher completion times and increased interference scores indicated impairment in executive control, including inhibitory processing and cognitive flexibility.¹⁶

Controls comprised healthy volunteers drawn from hospital staff, ancillary workers, and their spouses. Those with a history of migraine, chronic tension-type headache, trigeminal autonomic cephalalgias, chronic pain syndromes or secondary headache disorders were excluded. Controls were enrolled in parallel with the cases.

Data Collection

The following variables were systematically recorded using a structured proforma:

• Age
• Sex
• Educational level
• Type of migraine (chronic/episodic)
• Duration of migraine
• Monthly frequency of migraine attacks
• Preventive therapy details
• Baseline cognitive scores (MMSE, Digit Span, TMT-A, TMT-B, CPT, Stroop tests)
• Follow-up cognitive scores after six months

Outcome Measures

Primary Outcome:

Assessment of interictal cognitive dysfunction in migraine patients compared with healthy controls

Secondary Outcome:

Evaluation of changes in cognitive performance following six months of preventive therapy

Statistical Analysis

Data were analyzed using SPSS version 26.0. Continuous variables were expressed as mean ± standard deviation, while categorical variables were presented as frequencies and percentages.

Comparisons between groups were performed using independent sample t-tests and one-way analysis of variance (ANOVA), as appropriate. The chi-square test was used for categorical variables.

Changes in cognitive performance over time were analyzed using repeated-measures ANOVA. A p-value <0.05 was considered statistically significant.

Ethical Considerations

The study protocol was approved by the Institutional Ethics Committee of Kalinga Institute of Medical Sciences, Bhubaneswar. Written informed consent was obtained from all participants prior to enrolment. Confidentiality was maintained throughout the study. The study adhered to the principles of the Declaration of Helsinki.

Participant Characteristics

A total of 680 individuals were screened during the study period. After applying predefined eligibility criteria, 420 patients with migraine were included in the final analysis, while 260 individuals were excluded due to coexisting neurological disorders, psychiatric conditions, or incomplete clinical data.

Among the included participants, 110 (26.2%) were categorized as having chronic migraine, whereas 310 (73.8%) were classified as episodic migraine. The mean age of the study population was 34.8 ± 9.6 years, and females comprised 63.1% of the cohort.

Baseline demographic and clinical characteristics, along with the control group (n = 200), are summarized in Table 1. There were no statistically significant differences between groups with respect to age or sex distribution (p > 0.05). However, patients with chronic migraine demonstrated a significantly longer duration of illness and higher monthly headache frequency compared to those with episodic migraine (p < 0.001). Preventive therapy use was also more frequent in the chronic migraine group (p = 0.003).

Table 1. Baseline Demographic and Clinical Characteristics

Distribution of Migraine Subtypes

Episodic migraine represented the majority of cases (73.8%), whereas chronic migraine accounted for 26.2% of the study population. This distribution is illustrated in Figure 1.

Figure 1. Distribution of Migraine Subtypes

Interictal Cognitive Performance

Cognitive assessment performed during the interictal phase demonstrated significant impairment across multiple domains in migraine patients compared to healthy controls.

As shown in Table 2, individuals with chronic migraine exhibited the most pronounced deficits, followed by those with episodic migraine. Global cognitive status, assessed using the Mini-Mental State Examination (MMSE), was significantly lower in migraine groups.

Both Digit Span Forward (DS-F) and Digit Span Backward (DS-B) scores were reduced, indicating impaired attention and working memory. Trail Making Test A (TMT-A) and Test B (TMT-B) completion times were significantly prolonged, reflecting reduced processing speed and executive functioning.

In addition, performance on Stroop Word (SW), Stroop Color (SC), and Stroop Interference (SI) tasks was significantly impaired, suggesting deficits in cognitive flexibility and inhibitory control. All between-group differences were statistically significant (p < 0.001).

Table 2. Detailed Comparison of Cognitive Function Across Study Groups

Values expressed as Mean ± SD (Median; Range; IQR)

Effect of Preventive Therapy on Cognitive Outcomes

Following six months of preventive therapy, significant improvements were observed across multiple cognitive domains.

As presented in Table 3, MMSE scores showed modest but significant improvement. Both DS-F and DS-B scores increased, indicating enhanced attentional capacity and working memory (p < 0.01). Completion times for TMT-A and TMT-B decreased significantly, reflecting improved processing speed and executive functioning (p ≤ 0.001).

Performance across Stroop subtests (SW, SC, SI) also improved significantly, suggesting better cognitive flexibility and inhibitory control (p < 0.001). Despite these improvements, some deficits persisted, particularly among patients with chronic migraine.

Table 3. Changes in Cognitive Function Following Preventive Therapy

Determinants of Cognitive Dysfunction

Multivariate regression analysis was performed to identify factors associated with cognitive impairment.

As summarized in Table 4, longer duration of migraine (β = 0.31, p < 0.001), higher monthly headache frequency (β = 0.27, p = 0.002), and chronic migraine status (β = 0.34, p < 0.001) were independently associated with poorer cognitive outcomes. Among these, chronic migraine status demonstrated the strongest association.

Age and sex were not significantly related to cognitive performance (p > 0.05).

Table 4. Multivariate Regression Analysis

Graphical Representation

Comparative cognitive performance across study groups is illustrated in Figure 2, demonstrating a graded decline from healthy controls to episodic migraine and further to chronic migraine.

Summary of Findings

The findings indicate that cognitive dysfunction during the interictal phase is a consistent feature of migraine, affecting attention, working memory, processing speed, and executive functioning. The degree of impairment was more pronounced among individuals with chronic migraine compared to those with episodic migraine.

Preventive therapy was associated with significant improvements across multiple cognitive domains, suggesting partial reversibility of these deficits. Additionally, longer disease duration and increased attack frequency were identified as key contributors to cognitive decline, supporting a cumulative burden effect of migraine on cognitive health.

The present study demonstrates that individuals with migraine experience measurable cognitive impairment during the interictal phase, particularly in the domains of attention, vigilance, and executive functioning. These impairments were more pronounced among patients with chronic migraine compared with episodic migraine. In addition, preventive therapy was associated with significant improvement in multiple cognitive parameters over a six-month follow-up period. These findings reinforce the concept that migraine extends beyond episodic headache and may involve persistent neurocognitive alterations.

Previous studies have shown that cognitive dysfunction in migraine is not restricted to the ictal phase but may persist during headache-free intervals. Patients have been reported to exhibit slower information processing speed and reduced memory performance compared with healthy individuals.¹⁷,¹⁸ More recent investigations have further identified deficits in attention and executive functioning, suggesting involvement of higher-order cognitive domains.¹⁹

Executive dysfunction in migraine has been consistently demonstrated in neuropsychological studies. Impairments in tasks requiring cognitive flexibility, inhibitory control, and sustained attention have been frequently observed.²⁰ These deficits are thought to reflect altered functioning in frontal cortical regions and associated neural networks responsible for executive processing. Functional neuroimaging studies have also identified abnormalities in the prefrontal cortex and anterior cingulate cortex, supporting this hypothesis.²¹ The findings of the present study are consistent with these observations, as patients showed reduced performance on Trail Making Test and Stroop Test compared with controls.

The more severe cognitive impairment observed in chronic migraine patients may be explained by mechanisms related to disease chronification. Repeated migraine episodes are known to induce central sensitization and long-term neuroplastic changes in pain-processing pathways.²² These alterations may extend to cognitive networks, particularly those governing attention and executive control, leading to more pronounced deficits in patients with higher attack frequency and longer disease duration.²³

An important observation in the present study is the improvement in cognitive performance following preventive therapy. Prophylactic treatment may reduce attack frequency and modulate neuronal excitability, thereby contributing to functional recovery of cognitive processes. Previous reports have similarly suggested that effective migraine management is associated with improvement in cognitive and functional outcomes.²⁴ However, residual deficits observed in some chronic migraine patients indicate that prolonged disease may result in partially irreversible changes.

Overall, the findings highlight that cognitive dysfunction represents a clinically relevant but often underrecognized aspect of migraine. Routine assessment of cognitive domains, particularly attention and executive function, may help identify patients at risk of functional impairment. Early initiation of preventive therapy may therefore play a key role in improving both neurological and cognitive outcomes.

Limitations

Despite the strengths of this study, certain limitations should be acknowledged. The study was conducted at a single tertiary care center, which may limit generalizability. Although standardized neuropsychological tools were used, additional domains such as language and visuospatial abilities were not assessed. Furthermore, neuroimaging techniques were not incorporated, limiting insight into underlying neural mechanisms. Future multicenter studies with larger sample sizes, longer follow-up duration, and integration of neuroimaging modalities are warranted to better elucidate the relationship between migraine and cognitive dysfunction.

The present study demonstrates that cognitive impairment involving attention, vigilance, and executive functioning is evident in patients with migraine even during the interictal phase. These deficits are more pronounced in individuals with chronic migraine, suggesting that increased disease burden contributes to greater neurocognitive involvement. Such impairments may adversely affect daily functioning and overall quality of life.

Preventive migraine therapy was associated with significant improvement in cognitive performance, indicating that appropriate prophylactic management may help mitigate both headache-related and cognitive symptoms. Early recognition and comprehensive treatment of migraine are therefore essential to reduce long-term neurological impact. Further large-scale longitudinal studies are required to clarify the mechanisms underlying migraine-related cognitive dysfunction and to optimize therapeutic strategies.

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