Panic disorder (PD) is a chronic anxiety disorder characterized by recurrent, unexpected episodes of intense fear or anxiety. These panic attacks are accompanied by various autonomic nervous system symptoms, including palpitations, sweating, trembling, shortness of breath, chest discomfort, nausea, dizziness, and fear of death [1]. Due to persistent anticipatory anxiety about future attacks, patients commonly avoid specific places or situations. As a result, these symptoms significantly impair patients’ daily lives, social and occupational functioning, leading to a marked reduction in quality of life [2]. Epidemiological studies estimate the lifetime prevalence of panic attacks of 28.3%, with 4.7% meeting the diagnostic criteria for PD. The disorder primarily affects young adults in their 20s and 30s, a period of peak social and occupational activity, with women showing 2-3 times higher prevalence than men [3]. Additionally, PD frequently co-occurs with other psychiatric conditions such as major depression, generalized anxiety disorder, and social phobia [4].

Research on the neurobiological mechanisms of PD has focused on abnormalities within the fear network. In particular, dysfunctional sensory information processing between the cortex and brainstem is recognized as a key pathophysiological feature [5]. This network involves interconnected structures, including the prefrontal cortex (PFC), hippocampus, and amygdala, which play a crucial role in processing emotions such as fear and anxiety. Hyperactivation of the amygdala stimulates the hypothalamic-pituitary-adrenal axis, increasing cortisol secretion, and amplifies autonomic nervous system responses through the periaqueductal gray (PAG), locus coeruleus, and parabrachial nucleus, leading to core symptoms of panic attacks such as tachycardia and hyperventilation [6-8]. While PFC typically inhibits excessive amygdala activity to mitigate anxiety and fear, this regulatory function appears to be impaired in PD patients [6,9,10].

Although our understanding of the pathophysiological mechanisms underlying PD has evolved, clinical diagnosis still heavily relies on patients’ subjective symptom reports and psychological assessments [11]. This reliance on subjective measures limits the objectivity and reliability of diagnoses. In this context, electroencephalography (EEG) is gaining attention as a non-invasive tool capable of measuring real-time brain electrical activity. In particular, quantitative electroencephalography (QEEG) objectively evaluates changes in brain activity across various frequency bands by quantifying EEG data through mathematical algorithms like Fourier transform [12]. This approach offers objective and quantifiable biomarkers to support psychiatric diagnosis, complementing current subjective assessments [13,14].

Currently, the clinical utility of QEEG has been well established in attention-deficit/hyperactivity disorder [15], and it is increasingly being applied to other psychiatric conditions. Recent reports suggest that QEEG may also show characteristic findings in post-traumatic stress disorder, including increased gamma and delta activity [16]. However, research in PD remains relatively limited, making it difficult to identify consistent findings [17,18]. Studies on QEEG in PD face methodological challenges, as the unpredictable nature of panic attacks makes it challenging to directly measure EEG changes during an attack. Given that patients with PD often experience persistent anticipatory anxiety and chronic arousal even between attacks, understanding changes in brain activity in the resting state holds significant importance.

Although studies on QEEG in PD remain limited, existing findings have generally reported increased beta activity, decreased alpha activity, and increased delta activity in the frontal regions. Increased beta activity and decreased alpha activity were thought to reflect possible deficiency in top-down regulatory control over anxiety. Additionally, increased beta activity reflected a state of high excitability, anticipatory anxiety and maintenance of a hypervigilant cognitive state. A paradoxical shift towards slow wave delta activity was thought to reflect altered brainstem evoked response and physiological hyperarousal [19-25].

Among these oscillatory changes, beta frequency wave (12-30 Hz) warrants particular attention because it encompasses sub-bands that differ in their functional roles. Beta waves (12-25 Hz) are known to play a crucial role in maintaining attention, behavior control, and cognitive regulation [26], whereas high beta activity (25-30 Hz) has been associated with heightened stress, hyperarousal, and anxiety [27,28]. In healthy individuals, exposure to fear-inducing stimuli has been shown to elicit increased high-beta activity in the frontal region [28]. Clinically, elevated high beta activity has been observed in various anxiety-related conditions, including generalized anxiety disorder and phobias, as well as in major depressive disorder comorbid with prominent anxiety symptoms [29,30]. This functional distinction between beta sub-bands may be relevant for understanding PD.

However, most QEEG studies on PD have analyzed beta waves (12-30 Hz) as a single frequency band [17,20,25], which may have obscured the potential differences between arousal-related high-beta activity and regulatory beta activity. Given that PD is characterized by persistent autonomic hyperarousal and impaired prefrontal regulation, distinguishing between these beta frequency bands may provide a more nuanced understanding of the neurophysiological mechanisms of PD.

Therefore, this study aimed to explore the QEEG characteristics of patients with PD in a resting state, with a particular focus on differentiating beta and high beta waves to better elucidate the role of high beta activity in PD. Based on previous studies reporting elevated beta wave activity in PD [17,20,25], this study hypothesized that both beta and high beta activity would be elevated in the PD group compared to the healthy controls (HC) group, with a more pronounced increase in high beta activity. Additionally, changes in alpha, theta, and delta waves were analyzed to provide a more comprehensive understanding of neural activity associated with PD.

This study explored the electrophysiological mechanisms underlying PD through QEEG analysis during the resting state. Notably, high beta activity was broadly elevated across all regions (frontal, central, and posterior), whereas beta activity showed a more region-specific increase confined to the frontal cortex, consistent with previous research and confirming our hypothesis [17,20,36].

Beta and high-beta oscillations (13-30 Hz) play a critical role in long-range cortical communication, facilitating coordination and efficient information transfer between distributed neural networks [37]. When appropriately tuned, these rhythms help coordinate cognitive processes such as attention, memory, and emotional regulation [26]. However, elevated high-beta activity has a distinct physiological significance. It reflects sustained endogenous workload, using available free energy resources and disrupts the brain’s natural tendency toward synchronization. This keeps the brain in continuous processing away from rest, leading to increased energy consumption and persistent default mode desynchronization [27]. In the present study, elevation of high beta activity suggests that patients with PD maintain a state of anxiety and hyperarousal even at rest, reflecting compromised network efficiency.

The localized frontal beta increase observed in this study also warrants consideration. A temporary increase in beta under stress is considered as a compensatory effort to preserve cognitive control [38]. However, pathologically excessive beta wave activity indicates decreased cognitive flexibility and impaired behavioral control [26]. This pathological profile was evident in PD patients, who showed heightened frontal beta in response to anxiogenic visual stimuli [20]. Our findings suggest that patients with PD exhibit sustained compensatory activation even at rest, which may contribute to their reduced cognitive control and flexibility.

Additionally, beta waves (13-30 Hz) are closely associated with content-specific working memory, reactivating latent memory information as cortical representation within a few hundred milliseconds [39]. Given that patients with PD exhibit heightened threat sensitivity and show conditioned fear responses to stimuli that differ from the original threat [40,41], one possible interpretation is that increased beta range activity (13-30 Hz) reflects repeated reactivation of threat-related representations. Such reactivation could contribute to the persistence of anxious states, even in the absence of immediate external threats.

Notably, fMRI studies have consistently demonstrated amygdala hyperactivation in patients with PD, both during spontaneous panic attacks [42] and in response to panic-related stimuli [43]. In addition, increased prefrontal activation has been observed, particularly during emotion regulation or threat processing tasks [9,43]. This prefrontal activation was thought to reflect emotional stimulus processing and increased cognitive elaboration [9], potentially representing an impaired allocation of prefrontal resources and increased use of maladaptive regulation strategies [43], which are characteristics of anxiety disorders. Our electrophysiological findings of elevated high beta and beta activity are broadly compatible with fMRI observations in PD, showing predominantly frontal topography. This correspondence across neuroimaging modalities supports the evidence for elevated cortical activity patterns in PD.

In addition to the observed changes in beta activity, we investigated alpha activity to deepen our understanding of the neural dynamics in PD. Several studies have reported reductions in alpha activity in PD, particularly in the frontal and temporal regions during resting states [19,23,24]. Alpha oscillations are typically dominant during resting states with minimal attentional demands, reflecting a neural baseline associated with cortical disengagement and low arousal [44,45]. Reduced alpha activity in PD has been interpreted as a shift from this resting-state baseline, potentially indicating heightened cortical arousal or sustained internal alertness [19,23,24]. However, findings across studies remain inconsistent. Some studies have reported increased alpha activity along with elevated delta activity, interpreted as a compensatory mechanism to modulate internal arousal [46]. In our study, a significant group-by-region interaction emerged for alpha activity, yet further analysis revealed no significant regional differences. These findings, along with the heterogeneity of prior results, suggest that the role of alpha activity in PD remains inconclusive and warrants further investigation.

An increase in delta waves (0.5-4 Hz) was observed in this study. Typically associated with deep sleep, delta wave activity has been repeatedly reported in patients with PD. Notably, nocturnal panic attacks have been reported to occur during slow wave sleep (SWS) or during transitions from stage 2 sleep to SWS [47,48]. Additionally, paradoxical delta activity was observed in studies in which panic attacks were pharmacologically induced by sodium lactate in patients with PD [21,22]. Previous research suggests that delta wave activity is associated with primitive brain structures such as the brainstem and plays a pivotal role in immediate responses to threatening situations and in autonomic nervous system regulation. Increased delta activity in PD has been proposed to be linked to activation of structures such as the PAG, responsible for these primitive defense mechanisms [49]. Our findings provide additional clinical evidence supporting this hypothesis.

Overall, our findings suggest that PD is characterized by a state of resting hypervigilance and autonomic dysregulation, supported by increased high beta, beta, and delta activity. These alterations may reflect dysregulated interactions between cortical and subcortical systems, in which excessive cognitive control effort and heightened state of emotional reactivity persist even during rest. In particular, this fast-band profile is compatible with increased cortical activation indicative of sustained hyperarousal at rest, whereas elevated delta activity may reflect activation of autonomic hyperarousal. This electrophysiological profile suggests that aberrant high beta activity, in conjunction with delta changes, may serve as a potential neurophysiological marker of this imbalance in patients with PD.

This study has several limitations that should be acknowledged. As a retrospective study, it lacked randomization and a controlled design, making it difficult to establish clear causal relationships and increases the risk of selection bias. Additionally, the sample sizes were unbalanced between groups, and the overall sample size was relatively small, limiting the generalizability of the findings. Although adjustments were made for age and gender, other confounding variables, such as medication status were not fully standardized, which may have influenced the observed QEEG patterns.

In this study, EEG data were obtained exclusively during the resting state without standardized provocation (e.g., visual anxiety stimuli) and thus do not capture neurophysiological dynamics during actual panic attacks. Due to the limited spatial resolution of QEEG, interpretations regarding specific neuroanatomical sources should be viewed as suggestive.

Given these limitations, future research should address these methodological shortcomings. Larger, adequately powered samples determined by a priori power analyses, together with randomized controlled designs and standardized interventions would reduce bias and improve generalizability. Prospective studies should include structured assessment and reporting of medication exposure.