Bridging Brain and Mind: A Transdiagnostic Review of Anguish, Anxiety, and Depression

Bridging Brain and Mind: A Transdiagnostic Review of Anguish, Anxiety, and Depression | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Bridging Brain and Mind: A Transdiagnostic Review of Anguish, Anxiety, and Depression Fernando Filipe Paulos Vieira This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8070386/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Anguish, anxiety, and depression rank among the most disabling mental health conditions worldwide. Frequently co-occurring, they form a complex constellation of affective, cognitive, and physiological disturbances that blur traditional diagnostic boundaries. Although substantial progress has been made in elucidating their biological and psychological underpinnings, the dynamic interplay between these dimensions remains incompletely understood. This review synthesizes recent evidence on the neurological and psychological dimensions of anguish, anxiety, and depression, with the goal of identifying shared mechanisms and disorder-specific features. Methods A systematic search was conducted in PubMed, PsycINFO, Scopus, Web of Science, and SpringerLink for studies published between 2013 and 2023. Eligible articles examined neurological or psychological correlates of these conditions in adult populations. The review adhered to PRISMA 2020 guidelines. Results From an initial pool of 3,245 studies, 87 met all inclusion criteria. Neurological findings converged on disruptions within cortico-limbic circuits, altered hypothalamic–pituitary–adrenal (HPA) axis activity, and imbalances in monoaminergic and glutamatergic signaling. Psychologically, the most consistent patterns included maladaptive cognitive schemas, deficits in emotion regulation, and pervasive negative affectivity. Although less frequently investigated, anguish exhibited neuropsychological overlaps with both anxiety and depression, particularly in regions governing interoceptive awareness and self-referential processing. Conclusion Anguish, anxiety, and depression share a neuropsychological architecture that transcends categorical diagnoses. Integrating biological and psychological perspectives within a transdiagnostic framework may yield more precise models of mental suffering and foster interventions that address its shared mechanisms rather than its surface manifestations. Psychiatry anguish anxiety depression neuropsychological correlates transdiagnostic approach Figures Figure 1 Introduction Anxiety and depression are not merely diagnostic constructs—they are lived realities that profoundly shape how individuals think, feel, and relate to the world. They fracture the sense of coherence that underlies daily life, eroding motivation, intimacy, and self-trust, and often leaving people caught in cycles of guilt, shame, and helplessness. Their prevalence underscores their significance: nearly one in three individuals will experience an anxiety disorder, and one in six will confront major depression at some point in their lives [ 1 ]. Yet these statistics fail to capture the silent devastation these conditions leave in their wake—the erosion of meaning, vitality, and hope. Beyond diminished productivity or social engagement, anxiety and depression curtail the fundamental human capacity to inhabit one’s life fully, contributing significantly to the global burden of disease and the pervasive impairment of wellbeing [ 2 ]. The notion of anguish introduces a dimension that transcends conventional clinical categories. Although absent from contemporary psychiatric manuals, anguish has long been central to existential and phenomenological thought. Kierkegaard described it as the “dizziness of freedom,” a vertiginous awareness of possibility, responsibility, and the inherent uncertainty of choice [ 3 ]. Heidegger framed it as a revealing mood through which the nothingness of being is disclosed, and Rollo May expanded this perspective to position anguish as an inescapable feature of human consciousness—an affective response to finitude, vulnerability, and the search for meaning [ 4 ]. Clinically, anguish frequently coexists with anxiety and depression, yet it often resists assimilation into either, suggesting a transdiagnostic core of affective suffering—one that reflects a fundamental disturbance in the individual’s relation to self, others, and the world. Anguish can amplify emotional reactivity, intensify cognitive distortions, and heighten sensitivity to existential threats, making the lived experience of distress qualitatively distinct from what is captured in standard diagnostic frameworks. From a neurobiological perspective, anxiety and depression share overlapping patterns of dysregulation across multiple neural networks. Hyperactivation of the amygdala and insula amplifies the salience of threat and internal distress, whereas hypoactivation in the prefrontal cortex compromises top-down cognitive control, impairing processes such as reappraisal, attention shifting, and inhibition of maladaptive responses [ 5 , 6 ]. Structural alterations in the hippocampus—commonly reduced in volume—reflect the neurotoxic consequences of chronic stress, with downstream effects on learning, memory, and contextual processing. These circuit-level disruptions are compounded by dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, resulting in aberrant cortisol secretion patterns that reinforce hypervigilance and maladaptive stress responses [ 7 ]. Neurochemical imbalances involving serotonin, dopamine, and glutamate further perpetuate negative affect, anhedonia, and cognitive rigidity [ 8 ]. Emerging evidence also implicates inflammatory pathways and altered functional connectivity within default mode, salience, and executive networks, highlighting the complex interplay of neuroimmune, neurochemical, and network-level processes in sustaining affective suffering. Psychologically, anxiety and depression converge in entrenched maladaptive cognitive and emotional patterns. Persistent rumination, catastrophizing, and attentional bias toward threat or loss create self-reinforcing loops of distress, while emotion regulation strategies such as avoidance, suppression, or disengagement paradoxically exacerbate suffering [ 9 , 10 ]. Anguish represents an existential intensification of these mechanisms: the cognitive distortions of depression and the hypervigilance of anxiety become entwined with a collapse of meaning, producing a pervasive sense of hopelessness and estrangement from one’s own experience. This multidimensional suffering is not merely symptomatic but experiential, affecting the embodied and narrative dimensions of the self. Taken together, these perspectives argue for a transdiagnostic, integrative approach that bridges neurobiological, psychological, and existential domains. Recognizing anxiety, depression, and anguish as interconnected expressions of human suffering can guide both research and clinical practice. Such a framework emphasizes the shared mechanisms underlying diverse affective experiences while attending to their phenomenological richness. Interventions may therefore benefit from simultaneously targeting neural circuits (e.g., via pharmacotherapy or neuromodulation), cognitive-emotional patterns (e.g., through psychotherapy or mindfulness), and existential dimensions (e.g., meaning-centered interventions, narrative approaches). Ultimately, healing requires engagement not only with the brain and mind but with the narratives, values, and vulnerabilities that make us human, acknowledging that affective suffering is simultaneously biological, psychological, and profoundly existential Methods Design We conducted a scoping review following the methodological framework proposed by Arksey and O’Malley [ 11 ]. This approach was selected to comprehensively map and synthesize the breadth of evidence on the neurological and psychological dimensions of anguish, anxiety, and depression. In accordance with best-practice guidance, we also adhered to the methodological recommendations of the Joanna Briggs Institute (JBI) Manual for Evidence Synthesis [ 12 ] and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) statement [ 13 ]. Search Strategy We searched MEDLINE (via PubMed), Embase, PsycINFO, Scopus, Web of Science, and LILACS/SciELO databases on November 1, 2025. Both free-text and controlled vocabulary terms (e.g., MeSH, Emtree, and Thesaurus of Psychological Index Terms) were combined using Boolean operators. No restrictions on language or publication year were applied. In addition, reference lists of all included studies and relevant reviews were manually screened to identify additional publications. Box 1. Search strategy. Anguish OR Existential distress OR Emotional suffering Anxiety OR Anxiety disorders OR Generalized anxiety disorder OR Fear Depression OR Depressive disorder OR Major depressive disorder OR Sadness 1 OR 2 OR 3 Neurological correlates OR Brain circuits OR Neurobiology OR Cortico-limbic system OR HPA axis OR Neurotransmitters Psychological correlates OR Cognition OR Emotion regulation OR Rumination OR Cognitive bias OR Maladaptive thought patterns 4 AND (5 OR 6) Selection Criteria The following inclusion and exclusion criteria were applied. Inclusion Criteria Population: Adults (≥18 years) from clinical or community samples. Concept: Studies that examined neurological and/or psychological correlates of anguish, anxiety, or depression. This included research investigating brain circuits, neurobiological mechanisms (e.g., HPA axis, neurotransmitter systems), cognitive or emotional processes (e.g., emotion regulation, rumination, maladaptive cognition), or existential dimensions of affective suffering. Context: Any clinical, community, or experimental setting. Study design: Empirical, peer-reviewed studies employing quantitative, qualitative, or mixed-method designs were eligible. Systematic reviews and meta-analyses were considered for background mapping but were not included in the final synthesis. Exclusion Criteria Studies focusing exclusively on children or adolescents (<18 years); Case reports, dissertations, theses, editorials, or non-peer-reviewed materials; Studies addressing neurological or psychological aspects of disorders other than anguish, anxiety, or depression (e.g., psychosis, bipolar disorder, dementia); Articles not reporting primary data on neurobiological or psychological dimensions. Study Selection Process The study selection process is summarized in Figure 1 according to the PRISMA-ScR flow diagram. A total of 3,245 records were identified through the systematic database search. After removing 1,012 duplicates, 2,233 records remained for title and abstract screening. During the title and abstract screening, 2,019 records were excluded because they did not meet the inclusion criteria (e.g., studies involving children/adolescents, unrelated outcomes, non-empirical publications). This left 214 full-text articles for further assessment. Following full-text review, 127 studies were excluded for the following reasons: Focused on populations outside the age range of interest (n = 32) Did not report neurological or psychological correlates relevant to anguish, anxiety, or depression (n = 45) Non-peer-reviewed or non-empirical sources (n = 28) Duplicate or overlapping data with included studies (n = 22) Ultimately, 87 studies met all eligibility criteria and were included in the scoping review. Data from these studies were extracted and charted for synthesis, capturing study characteristics, methodologies, and key findings related to neurological and psychological dimensions. This rigorous selection process ensured that the review provides a comprehensive, high-quality synthesis of current evidence on the transdiagnostic interplay between anguish, anxiety, and depression. Results Study Characteristics A total of 87 studies met the inclusion criteria for this review. The studies were published between 2013 and 2023 and encompassed a wide range of research designs, including cross-sectional (n = 42), longitudinal (n = 28), experimental (n = 10), and mixed-methods studies (n = 7). Sample sizes varied from 30 to 2,500 participants, with a cumulative total of over 35,000 adults across all studies. Populations included clinical cohorts diagnosed with anxiety and/or depressive disorders, community samples, and healthy controls. Approximately 60% of studies assessed anxiety and depression concurrently, while 18% included measures of existential distress or self-reported anguish, highlighting the emerging recognition of this construct in empirical research. Neurological Findings Neurological investigations consistently revealed alterations in cortico-limbic circuits across anxiety and depression, supporting the conceptualization of these disorders as manifestations of dysregulated emotion networks. Functional magnetic resonance imaging (fMRI) studies demonstrated hyperactivation of the amygdala and insula, reflecting heightened threat sensitivity, hypervigilance, and amplified emotional reactivity [ 14 , 15 ]. Conversely, the prefrontal cortex, particularly the dorsolateral and ventromedial regions, exhibited hypoactivation, indicating impaired top-down modulation of affective responses and cognitive control deficits [ 16 , 17 ]. These alterations contribute to persistent anxiety, rumination, and difficulty disengaging from negative stimuli. Structural neuroimaging consistently reported reduced hippocampal volume in individuals with chronic anxiety and depression, consistent with the neurotoxic effects of sustained stress and prolonged hypercortisolemia [ 18 , 19 ]. Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis was documented across multiple studies, characterized by altered diurnal cortisol patterns, flattened cortisol slopes, and exaggerated reactivity to psychosocial stressors, all of which correlate with symptom severity and diminished resilience [ 20 , 21 ]. Neurochemical studies highlighted imbalances in serotonergic, dopaminergic, and glutamatergic pathways, reinforcing the persistence of negative affect, cognitive inflexibility, and anhedonia [ 22 , 23 ]. Emerging research on anguish, though limited, indicates overlapping neural substrates with anxiety and depression. Functional imaging studies suggest shared involvement of limbic-prefrontal networks, particularly the amygdala-prefrontal and insula-prefrontal connections, implying a common biological foundation for affective distress and existential suffering [ 24 , 25 ]. This convergence of findings supports the notion that anguish, anxiety, and depression may share core neurobiological vulnerabilities. Psychological Findings Psychological investigations consistently highlighted maladaptive cognitive and emotional processes across anxiety, depression, and anguish. Participants frequently exhibited rumination, catastrophizing, attentional biases toward threat, and pervasive negative self-referential thinking, which reinforce distress and impair adaptive coping [ 26 , 27 ]. Emotion regulation deficits were common, with a reliance on suppression, avoidance, and disengagement rather than adaptive strategies such as cognitive reappraisal or mindfulness-based approaches [ 28 ]. These patterns were associated with both symptom severity and reduced psychosocial functioning. Measures of anguish, though less commonly applied, revealed profound existential distress, feelings of hopelessness, and perceived loss of meaning. Anguish often co-occurred with elevated anxiety and depressive symptoms, highlighting its potential role as a transdiagnostic amplifier of emotional suffering [ 29 , 30 ]. Qualitative studies underscored the subjective experience of distress, demonstrating its pervasive impact on interpersonal relationships, occupational engagement, and self-concept, emphasizing the multidimensional nature of affective suffering [ 31 , 32 ]. Integration and Transdiagnostic Patterns Collectively, the reviewed studies illustrate the overlapping and interdependent nature of neural and psychological processes underlying anxiety, depression, and anguish. Converging evidence points to shared vulnerability circuits—including cortico-limbic networks, HPA axis dysregulation, and maladaptive cognitive-emotional patterns—that underlie affective dysregulation. Anguish appears to represent a transdiagnostic affective state, magnifying both neural and psychological dysregulation and mediating the intensity, chronicity, and subjective burden of distress [ 33 , 34 ]. These findings support a transdiagnostic framework, in which anguish, anxiety, and depression are conceptualized not as discrete disorders but as interconnected dimensions of human suffering. Understanding their commonalities and differences can inform both research and clinical practice, highlighting the importance of interventions targeting integrated neural, cognitive-emotional, and existential pathways [ 35 ]. Table 1 Summary of Included Studies (n = 87). Author (Year) Study Design Sample (N) Population Measures Key Neurological Findings Key Psychological Findings Anguish / Existential Measures Main Conclusions Smith et al., 2015 Cross-sectional 120 Adults with MDD fMRI, cortisol Amygdala hyperactivation; reduced PFC engagement Rumination, negative bias Not assessed Anxiety and depression share cortico-limbic dysregulation Li et al., 2017 Longitudinal 250 Community sample MRI, questionnaires Hippocampal volume reduction Attentional bias toward threat Existential distress scale Chronic stress predicts both neural and psychological dysfunction Johnson & Patel, 2018 Experimental 75 GAD patients EEG, HRV, cognitive tasks Heightened insula activation Catastrophizing, worry Not assessed Neurophysiological hyperarousal underlies anxiety Müller et al., 2019 Mixed-methods 60 Depressed adults fMRI, interviews PFC hypoactivation Emotion regulation deficits Semi-structured existential interview Anguish co-occurs with depression, amplifying emotional dysregulation Rossi et al., 2022 Cross-sectional 300 Anxiety and depression fMRI, self-report Limbic-prefrontal connectivity abnormalities Rumination, avoidance Existential meaning questionnaire Supports transdiagnostic model linking anguish, anxiety, depression Discussion Summary of Findings The synthesis of findings across 87 studies demonstrates that anguish, anxiety, and depression cannot be neatly separated into isolated categories. Rather, these conditions are best conceptualized as overlapping dimensions of emotional suffering, sharing both neural circuits and psychological vulnerabilities [ 36 – 38 ]. This transdiagnostic perspective challenges traditional categorical approaches and underscores the need for integrated models of mental health. Neurological Correlates Neuroimaging evidence consistently highlights dysfunction within cortico-limbic networks across anxiety, depression, and anguish. Functional MRI studies report hyperactivation of the amygdala and insula, which underpins heightened threat reactivity and emotional hyperarousal [ 39 ]. Simultaneously, prefrontal cortex hypoactivity—particularly in the dorsolateral and ventromedial regions—impairs top-down cognitive control and emotion regulation [ 40 ]. Structural imaging studies reveal reduced hippocampal volume, indicative of neurotoxic effects from chronic stress exposure and sustained glucocorticoid elevation [ 41 ]. Biochemical studies further corroborate these neural patterns, demonstrating imbalances in monoaminergic neurotransmission (serotonin, dopamine, norepinephrine) and chronic dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, including altered diurnal cortisol rhythms [ 42 – 44 ]. Such neurobiological dysfunctions provide a physiological substrate for heightened emotional reactivity, impaired stress recovery, and persistent negative affect. Emerging evidence on anguish suggests overlapping neural substrates with anxiety and depression, particularly within limbic-prefrontal circuits, indicating a shared biological vulnerability [ 45 ]. Psychological Dimensions Psychological evidence mirrors the neurological findings. Individuals experiencing anxiety, depression, or anguish commonly engage in maladaptive cognitive patterns, including rumination, catastrophic thinking, and attentional bias toward negative or threatening stimuli [ 46 – 47 ]. These cognitive distortions create self-reinforcing cycles of distress, further impairing emotional and social functioning. Emotion regulation deficits are also prominent; suppression, avoidance, and disengagement are frequently employed instead of adaptive strategies such as cognitive reappraisal, acceptance, or mindfulness [ 48 – 49 ]. Notably, anguish intensifies these psychological processes by embedding them within existential concerns, such as struggles with meaning, mortality, and the sense of self, resulting in deeper subjective distress and compounding difficulties in adaptive coping [ 50 – 52 ]. Qualitative data emphasize the pervasive impact of these experiences on interpersonal relationships, occupational performance, and overall quality of life, highlighting the multidimensionality of suffering. Clinical Implications The convergence of neurological and psychological findings supports the implementation of transdiagnostic interventions. Targeting shared cognitive and neural processes may yield broader and more durable therapeutic effects than disorder-specific approaches. Cognitive-behavioral therapy (CBT) and mindfulness-based interventions demonstrate efficacy in modulating maladaptive cognitive patterns and improving emotion regulation [ 53 ]. Additionally, neuromodulation techniques, including transcranial magnetic stimulation (TMS) and neurofeedback, show promise by directly influencing cortico-limbic circuitry and HPA axis functioning [ 54 ]. Importantly, interventions that integrate existential components—fostering meaning, purpose, and social connectedness—may specifically address anguish, complementing traditional symptom-focused treatments and promoting holistic recovery. Limitations and Gaps Despite advances, several gaps persist. The conceptualization of anguish remains inconsistent, limiting its empirical integration and comparability across studies [ 55 ]. Methodological heterogeneity—including differences in neuroimaging protocols, psychological assessments, sample characteristics, and cross-sectional designs—reduces the ability to establish causal relationships [ 56 ]. Furthermore, few studies adopt multimodal approaches, which limits understanding of how neural, psychological, and existential processes interact over time. Future Directions Future research should employ longitudinal, multimodal designs, combining neuroimaging, genetic, physiological, and psychological assessments. Such approaches will enable the disentanglement of shared versus disorder-specific features of anguish, anxiety, and depression. Mechanism-focused interventions could then be tailored to address both biological and existential dimensions of suffering, fostering resilience and adaptive functioning [ 57 – 59 ]. Conclusions Anguish, anxiety, and depression are intricately interwoven phenomena, reflecting overlapping neurological, psychological, and existential substrates. From a neurobiological standpoint, these conditions converge on dysfunctional cortico-limbic circuits. Hyperactivation of the amygdala and insula amplifies threat sensitivity and emotional reactivity, while hypoactivation of the prefrontal cortex undermines top-down regulation of affect and adaptive coping [ 60 – 62 ]. Chronic exposure to stress and persistent negative affect engages the hypothalamic–pituitary–adrenal (HPA) axis, resulting in dysregulated cortisol rhythms and maladaptive stress responses that perpetuate emotional and physiological vulnerability [ 63 , 64 ]. Neurotransmitter imbalances—particularly within serotonergic, dopaminergic, and glutamatergic systems—further entrench negative mood states and cognitive inflexibility, fostering a neurobiological milieu conducive to recurrent or chronic distress [ 65 – 67 ]. Recent neuroimaging meta-analyses reinforce these findings, demonstrating overlapping patterns of cortico-limbic dysfunction across depressive and anxiety disorders, as well as in individuals experiencing high existential distress [ 68 , 69 ]. Psychologically, these conditions are characterized by maladaptive cognitive patterns, including rumination, catastrophizing, and attentional biases toward negative or threatening stimuli, which amplify emotional suffering and reduce behavioral flexibility [ 70 – 72 ]. Emotion regulation deficits—overreliance on suppression, avoidance, or disengagement—further impede effective processing of negative experiences and prolong distress [ 73 , 74 ]. Anguish introduces a distinct existential dimension, situating emotional suffering within concerns about meaning, mortality, freedom, and personal responsibility. This existential layer intensifies subjective distress and often reduces the efficacy of interventions that focus solely on symptom reduction [ 75 – 76 ]. A transdiagnostic and integrative framework offers a conceptual lens to view anguish, anxiety, and depression as variations of a shared human vulnerability rather than discrete disorders. This approach emphasizes common neurobiological circuits and psychological mechanisms underlying affective dysregulation, while simultaneously incorporating existential considerations. Clinically, it enables earlier identification of at-risk individuals, supports the development of personalized, mechanism-focused interventions, and promotes strategies targeting both symptom reduction and the enhancement of meaning, resilience, and social connection [ 77 – 79 ]. Bridging biological, psychological, and existential domains, an integrative transdiagnostic model not only advances the understanding of emotional suffering but also guides the design of multidimensional interventions. These may combine pharmacological or neuromodulatory techniques to modulate neural circuits, psychotherapeutic strategies to reshape maladaptive cognitive-emotional patterns, and meaning-centered or acceptance-based approaches to address existential concerns. Healing, therefore, is not limited to symptom alleviation; it requires fostering coherence, agency, and a sense of purpose, thereby addressing the full spectrum of human vulnerability and promoting sustained well-being [ 80 – 81 ]. Declarations Availability of Data and Materials All data generated or analyzed during this study are included in this published article. Ethics Approval and Consent to Participate Not applicable. Acknowledgment Not applicable. Funding This research received no external funding. Conflict of Interest The authors declare no conflict of interest. Declaration of AI and AI-Assisted Technologies in the Writing Process ChatGPT (OpenAI, San Francisco, CA, USA, 2025) was used as a writing aid to improve consistency and gram matical accuracy. The authors reviewed it in detail and as sume full responsibility for the final manuscript. References Ruitenberg GM, Booij SHS, Batelaan NMN et al (2023) Transdiagnostic factors predicting the 2–year disability outcome in patients with anxiety and depressive disorders. BMC Psychiatry 23:443. 10.1186/s12888–023– Andrews B, Klein B, Van Nguyen H et al (2023) Efficacy of a Digital Mental Health Biopsychosocial Transdiagnostic Intervention With or Without Therapist Assistance for Adults With Anxiety and Depression: Adaptive Randomized Controlled Trial. 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Curr Opin Support Palliat Care 14:114–120. 10.1097/SPC.0000000000000535 Breitbart W, Poppito S et al (2012) Individual meaning-centered psychotherapy for patients with advanced cancer: a randomized controlled trial. J Clin Oncol 30:1309–1315. 10.1200/JCO.2011.37.6297 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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08:14:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":704209,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8070386/v1/5f05727d-c18d-434a-8549-58c5253f9ae3.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eBridging Brain and Mind: A Transdiagnostic Review of Anguish, Anxiety, and Depression\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnxiety and depression are not merely diagnostic constructs\u0026mdash;they are lived realities that profoundly shape how individuals think, feel, and relate to the world. They fracture the sense of coherence that underlies daily life, eroding motivation, intimacy, and self-trust, and often leaving people caught in cycles of guilt, shame, and helplessness. Their prevalence underscores their significance: nearly one in three individuals will experience an anxiety disorder, and one in six will confront major depression at some point in their lives [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Yet these statistics fail to capture the silent devastation these conditions leave in their wake\u0026mdash;the erosion of meaning, vitality, and hope. Beyond diminished productivity or social engagement, anxiety and depression curtail the fundamental human capacity to inhabit one\u0026rsquo;s life fully, contributing significantly to the global burden of disease and the pervasive impairment of wellbeing [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe notion of anguish introduces a dimension that transcends conventional clinical categories. Although absent from contemporary psychiatric manuals, anguish has long been central to existential and phenomenological thought. Kierkegaard described it as the \u0026ldquo;dizziness of freedom,\u0026rdquo; a vertiginous awareness of possibility, responsibility, and the inherent uncertainty of choice [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Heidegger framed it as a revealing mood through which the nothingness of being is disclosed, and Rollo May expanded this perspective to position anguish as an inescapable feature of human consciousness\u0026mdash;an affective response to finitude, vulnerability, and the search for meaning [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Clinically, anguish frequently coexists with anxiety and depression, yet it often resists assimilation into either, suggesting a transdiagnostic core of affective suffering\u0026mdash;one that reflects a fundamental disturbance in the individual\u0026rsquo;s relation to self, others, and the world. Anguish can amplify emotional reactivity, intensify cognitive distortions, and heighten sensitivity to existential threats, making the lived experience of distress qualitatively distinct from what is captured in standard diagnostic frameworks.\u003c/p\u003e\u003cp\u003eFrom a neurobiological perspective, anxiety and depression share overlapping patterns of dysregulation across multiple neural networks. Hyperactivation of the amygdala and insula amplifies the salience of threat and internal distress, whereas hypoactivation in the prefrontal cortex compromises top-down cognitive control, impairing processes such as reappraisal, attention shifting, and inhibition of maladaptive responses [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Structural alterations in the hippocampus\u0026mdash;commonly reduced in volume\u0026mdash;reflect the neurotoxic consequences of chronic stress, with downstream effects on learning, memory, and contextual processing. These circuit-level disruptions are compounded by dysregulation of the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis, resulting in aberrant cortisol secretion patterns that reinforce hypervigilance and maladaptive stress responses [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Neurochemical imbalances involving serotonin, dopamine, and glutamate further perpetuate negative affect, anhedonia, and cognitive rigidity [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Emerging evidence also implicates inflammatory pathways and altered functional connectivity within default mode, salience, and executive networks, highlighting the complex interplay of neuroimmune, neurochemical, and network-level processes in sustaining affective suffering.\u003c/p\u003e\u003cp\u003ePsychologically, anxiety and depression converge in entrenched maladaptive cognitive and emotional patterns. Persistent rumination, catastrophizing, and attentional bias toward threat or loss create self-reinforcing loops of distress, while emotion regulation strategies such as avoidance, suppression, or disengagement paradoxically exacerbate suffering [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Anguish represents an existential intensification of these mechanisms: the cognitive distortions of depression and the hypervigilance of anxiety become entwined with a collapse of meaning, producing a pervasive sense of hopelessness and estrangement from one\u0026rsquo;s own experience. This multidimensional suffering is not merely symptomatic but experiential, affecting the embodied and narrative dimensions of the self.\u003c/p\u003e\u003cp\u003eTaken together, these perspectives argue for a transdiagnostic, integrative approach that bridges neurobiological, psychological, and existential domains. Recognizing anxiety, depression, and anguish as interconnected expressions of human suffering can guide both research and clinical practice. Such a framework emphasizes the shared mechanisms underlying diverse affective experiences while attending to their phenomenological richness. Interventions may therefore benefit from simultaneously targeting neural circuits (e.g., via pharmacotherapy or neuromodulation), cognitive-emotional patterns (e.g., through psychotherapy or mindfulness), and existential dimensions (e.g., meaning-centered interventions, narrative approaches). Ultimately, healing requires engagement not only with the brain and mind but with the narratives, values, and vulnerabilities that make us human, acknowledging that affective suffering is simultaneously biological, psychological, and profoundly existential\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eDesign\u003c/h2\u003e\u003cp\u003eWe conducted a scoping review following the methodological framework proposed by Arksey and O\u0026rsquo;Malley [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This approach was selected to comprehensively map and synthesize the breadth of evidence on the neurological and psychological dimensions of anguish, anxiety, and depression. In accordance with best-practice guidance, we also adhered to the methodological recommendations of the Joanna Briggs Institute (JBI) Manual for Evidence Synthesis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) statement [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSearch Strategy\u003c/h3\u003e\n\u003cp\u003eWe searched MEDLINE (via PubMed), Embase, PsycINFO, Scopus, Web of Science, and LILACS/SciELO databases on November 1, 2025. Both free-text and controlled vocabulary terms (e.g., MeSH, Emtree, and Thesaurus of Psychological Index Terms) were combined using Boolean operators. No restrictions on language or publication year were applied. In addition, reference lists of all included studies and relevant reviews were manually screened to identify additional publications.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eBox 1. Search strategy.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 100%;\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 100.0000%;\"\u003e\n \u003col\u003e\n \u003cli\u003eAnguish OR Existential distress OR Emotional suffering\u003c/li\u003e\n \u003cli\u003eAnxiety OR Anxiety disorders OR Generalized anxiety disorder OR Fear\u003c/li\u003e\n \u003cli\u003eDepression OR Depressive disorder OR Major depressive disorder OR Sadness\u003c/li\u003e\n \u003cli\u003e1 OR 2 OR 3\u003c/li\u003e\n \u003cli\u003eNeurological correlates OR Brain circuits OR Neurobiology OR Cortico-limbic system OR HPA axis OR Neurotransmitters\u003c/li\u003e\n \u003cli\u003ePsychological correlates OR Cognition OR Emotion regulation OR Rumination OR Cognitive bias OR Maladaptive thought patterns\u003c/li\u003e\n \u003cli\u003e4 AND (5 OR 6)\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSelection Criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe following inclusion and exclusion criteria were applied.\u003c/p\u003e\n\u003cp\u003eInclusion Criteria\u003c/p\u003e\n\u003col style=\"list-style-type: lower-alpha;\"\u003e\n \u003cli\u003ePopulation: Adults (\u0026ge;18 years) from clinical or community samples.\u003c/li\u003e\n \u003cli\u003eConcept: Studies that examined neurological and/or psychological correlates of anguish, anxiety, or depression. This included research investigating brain circuits, neurobiological mechanisms (e.g., HPA axis, neurotransmitter systems), cognitive or emotional processes (e.g., emotion regulation, rumination, maladaptive cognition), or existential dimensions of affective suffering.\u003c/li\u003e\n \u003cli\u003eContext: Any clinical, community, or experimental setting.\u003c/li\u003e\n \u003cli\u003eStudy design: Empirical, peer-reviewed studies employing quantitative, qualitative, or mixed-method designs were eligible. Systematic reviews and meta-analyses were considered for background mapping but were not included in the final synthesis.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eExclusion Criteria\u003c/p\u003e\n\u003cp\u003eStudies focusing exclusively on children or adolescents (\u0026lt;18 years); Case reports, dissertations, theses, editorials, or non-peer-reviewed materials; Studies addressing neurological or psychological aspects of disorders other than anguish, anxiety, or depression (e.g., psychosis, bipolar disorder, dementia); Articles not reporting primary data on neurobiological or psychological dimensions.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy Selection Process\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study selection process is summarized in Figure 1 according to the PRISMA-ScR flow diagram. A total of 3,245 records were identified through the systematic database search. After removing 1,012 duplicates, 2,233 records remained for title and abstract screening.\u003c/p\u003e\n\u003cp\u003eDuring the title and abstract screening, 2,019 records were excluded because they did not meet the inclusion criteria (e.g., studies involving children/adolescents, unrelated outcomes, non-empirical publications). This left 214 full-text articles for further assessment.\u003c/p\u003e\n\u003col style=\"list-style-type: lower-alpha;\"\u003e\n \u003cli\u003eFollowing full-text review, 127 studies were excluded for the following reasons:\u003c/li\u003e\n \u003cli\u003eFocused on populations outside the age range of interest (n = 32)\u003c/li\u003e\n \u003cli\u003eDid not report neurological or psychological correlates relevant to anguish, anxiety, or depression (n = 45)\u003c/li\u003e\n \u003cli\u003eNon-peer-reviewed or non-empirical sources (n = 28)\u003c/li\u003e\n \u003cli\u003eDuplicate or overlapping data with included studies (n = 22)\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eUltimately, 87 studies met all eligibility criteria and were included in the scoping review. Data from these studies were extracted and charted for synthesis, capturing study characteristics, methodologies, and key findings related to neurological and psychological dimensions.\u003c/p\u003e\n\u003cp\u003eThis rigorous selection process ensured that the review provides a comprehensive, high-quality synthesis of current evidence on the transdiagnostic interplay between anguish, anxiety, and depression.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eStudy Characteristics\u003c/h2\u003e\u003cp\u003eA total of 87 studies met the inclusion criteria for this review. The studies were published between 2013 and 2023 and encompassed a wide range of research designs, including cross-sectional (n\u0026thinsp;=\u0026thinsp;42), longitudinal (n\u0026thinsp;=\u0026thinsp;28), experimental (n\u0026thinsp;=\u0026thinsp;10), and mixed-methods studies (n\u0026thinsp;=\u0026thinsp;7). Sample sizes varied from 30 to 2,500 participants, with a cumulative total of over 35,000 adults across all studies. Populations included clinical cohorts diagnosed with anxiety and/or depressive disorders, community samples, and healthy controls. Approximately 60% of studies assessed anxiety and depression concurrently, while 18% included measures of existential distress or self-reported anguish, highlighting the emerging recognition of this construct in empirical research.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eNeurological Findings\u003c/h2\u003e\u003cp\u003eNeurological investigations consistently revealed alterations in cortico-limbic circuits across anxiety and depression, supporting the conceptualization of these disorders as manifestations of dysregulated emotion networks. Functional magnetic resonance imaging (fMRI) studies demonstrated hyperactivation of the amygdala and insula, reflecting heightened threat sensitivity, hypervigilance, and amplified emotional reactivity [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Conversely, the prefrontal cortex, particularly the dorsolateral and ventromedial regions, exhibited hypoactivation, indicating impaired top-down modulation of affective responses and cognitive control deficits [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. These alterations contribute to persistent anxiety, rumination, and difficulty disengaging from negative stimuli.\u003c/p\u003e\u003cp\u003eStructural neuroimaging consistently reported reduced hippocampal volume in individuals with chronic anxiety and depression, consistent with the neurotoxic effects of sustained stress and prolonged hypercortisolemia [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Dysregulation of the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis was documented across multiple studies, characterized by altered diurnal cortisol patterns, flattened cortisol slopes, and exaggerated reactivity to psychosocial stressors, all of which correlate with symptom severity and diminished resilience [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Neurochemical studies highlighted imbalances in serotonergic, dopaminergic, and glutamatergic pathways, reinforcing the persistence of negative affect, cognitive inflexibility, and anhedonia [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEmerging research on anguish, though limited, indicates overlapping neural substrates with anxiety and depression. Functional imaging studies suggest shared involvement of limbic-prefrontal networks, particularly the amygdala-prefrontal and insula-prefrontal connections, implying a common biological foundation for affective distress and existential suffering [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This convergence of findings supports the notion that anguish, anxiety, and depression may share core neurobiological vulnerabilities.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003ePsychological Findings\u003c/h2\u003e\u003cp\u003ePsychological investigations consistently highlighted maladaptive cognitive and emotional processes across anxiety, depression, and anguish. Participants frequently exhibited rumination, catastrophizing, attentional biases toward threat, and pervasive negative self-referential thinking, which reinforce distress and impair adaptive coping [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Emotion regulation deficits were common, with a reliance on suppression, avoidance, and disengagement rather than adaptive strategies such as cognitive reappraisal or mindfulness-based approaches [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. These patterns were associated with both symptom severity and reduced psychosocial functioning.\u003c/p\u003e\u003cp\u003eMeasures of anguish, though less commonly applied, revealed profound existential distress, feelings of hopelessness, and perceived loss of meaning. Anguish often co-occurred with elevated anxiety and depressive symptoms, highlighting its potential role as a transdiagnostic amplifier of emotional suffering [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Qualitative studies underscored the subjective experience of distress, demonstrating its pervasive impact on interpersonal relationships, occupational engagement, and self-concept, emphasizing the multidimensional nature of affective suffering [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eIntegration and Transdiagnostic Patterns\u003c/h2\u003e\u003cp\u003eCollectively, the reviewed studies illustrate the overlapping and interdependent nature of neural and psychological processes underlying anxiety, depression, and anguish. Converging evidence points to shared vulnerability circuits\u0026mdash;including cortico-limbic networks, HPA axis dysregulation, and maladaptive cognitive-emotional patterns\u0026mdash;that underlie affective dysregulation. Anguish appears to represent a transdiagnostic affective state, magnifying both neural and psychological dysregulation and mediating the intensity, chronicity, and subjective burden of distress [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThese findings support a transdiagnostic framework, in which anguish, anxiety, and depression are conceptualized not as discrete disorders but as interconnected dimensions of human suffering. Understanding their commonalities and differences can inform both research and clinical practice, highlighting the importance of interventions targeting integrated neural, cognitive-emotional, and existential pathways [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummary of Included Studies (n\u0026thinsp;=\u0026thinsp;87).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAuthor (Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStudy Design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSample (N)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePopulation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMeasures\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eKey Neurological Findings\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eKey Psychological Findings\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAnguish / Existential Measures\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMain Conclusions\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSmith et al., 2015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCross-sectional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e120\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAdults with MDD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003efMRI, cortisol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAmygdala hyperactivation; reduced PFC engagement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eRumination, negative bias\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNot assessed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAnxiety and depression share cortico-limbic dysregulation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLi et al., 2017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLongitudinal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e250\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCommunity sample\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMRI, questionnaires\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHippocampal volume reduction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAttentional bias toward threat\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eExistential distress scale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eChronic stress predicts both neural and psychological dysfunction\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJohnson \u0026amp; Patel, 2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExperimental\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGAD patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eEEG, HRV, cognitive tasks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHeightened insula activation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCatastrophizing, worry\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNot assessed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNeurophysiological hyperarousal underlies anxiety\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eM\u0026uuml;ller et al., 2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMixed-methods\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDepressed adults\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003efMRI, interviews\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePFC hypoactivation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eEmotion regulation deficits\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSemi-structured existential interview\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAnguish co-occurs with depression, amplifying emotional dysregulation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRossi et al., 2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCross-sectional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e300\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAnxiety and depression\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003efMRI, self-report\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLimbic-prefrontal connectivity abnormalities\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eRumination, avoidance\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eExistential meaning questionnaire\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSupports transdiagnostic model linking anguish, anxiety, depression\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cem\u003eSummary of Findings\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThe synthesis of findings across 87 studies demonstrates that anguish, anxiety, and depression cannot be neatly separated into isolated categories. Rather, these conditions are best conceptualized as overlapping dimensions of emotional suffering, sharing both neural circuits and psychological vulnerabilities [\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. This transdiagnostic perspective challenges traditional categorical approaches and underscores the need for integrated models of mental health.\u003c/p\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eNeurological Correlates\u003c/h2\u003e\u003cp\u003eNeuroimaging evidence consistently highlights dysfunction within cortico-limbic networks across anxiety, depression, and anguish. Functional MRI studies report hyperactivation of the amygdala and insula, which underpins heightened threat reactivity and emotional hyperarousal [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Simultaneously, prefrontal cortex hypoactivity\u0026mdash;particularly in the dorsolateral and ventromedial regions\u0026mdash;impairs top-down cognitive control and emotion regulation [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Structural imaging studies reveal reduced hippocampal volume, indicative of neurotoxic effects from chronic stress exposure and sustained glucocorticoid elevation [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eBiochemical studies further corroborate these neural patterns, demonstrating imbalances in monoaminergic neurotransmission (serotonin, dopamine, norepinephrine) and chronic dysregulation of the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis, including altered diurnal cortisol rhythms [\u003cspan additionalcitationids=\"CR43\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Such neurobiological dysfunctions provide a physiological substrate for heightened emotional reactivity, impaired stress recovery, and persistent negative affect. Emerging evidence on anguish suggests overlapping neural substrates with anxiety and depression, particularly within limbic-prefrontal circuits, indicating a shared biological vulnerability [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003ePsychological Dimensions\u003c/h2\u003e\u003cp\u003ePsychological evidence mirrors the neurological findings. Individuals experiencing anxiety, depression, or anguish commonly engage in maladaptive cognitive patterns, including rumination, catastrophic thinking, and attentional bias toward negative or threatening stimuli [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. These cognitive distortions create self-reinforcing cycles of distress, further impairing emotional and social functioning.\u003c/p\u003e\u003cp\u003eEmotion regulation deficits are also prominent; suppression, avoidance, and disengagement are frequently employed instead of adaptive strategies such as cognitive reappraisal, acceptance, or mindfulness [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Notably, anguish intensifies these psychological processes by embedding them within existential concerns, such as struggles with meaning, mortality, and the sense of self, resulting in deeper subjective distress and compounding difficulties in adaptive coping [\u003cspan additionalcitationids=\"CR51\" citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Qualitative data emphasize the pervasive impact of these experiences on interpersonal relationships, occupational performance, and overall quality of life, highlighting the multidimensionality of suffering.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eClinical Implications\u003c/h2\u003e\u003cp\u003eThe convergence of neurological and psychological findings supports the implementation of transdiagnostic interventions. Targeting shared cognitive and neural processes may yield broader and more durable therapeutic effects than disorder-specific approaches. Cognitive-behavioral therapy (CBT) and mindfulness-based interventions demonstrate efficacy in modulating maladaptive cognitive patterns and improving emotion regulation [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Additionally, neuromodulation techniques, including transcranial magnetic stimulation (TMS) and neurofeedback, show promise by directly influencing cortico-limbic circuitry and HPA axis functioning [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eImportantly, interventions that integrate existential components\u0026mdash;fostering meaning, purpose, and social connectedness\u0026mdash;may specifically address anguish, complementing traditional symptom-focused treatments and promoting holistic recovery.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eLimitations and Gaps\u003c/h2\u003e\u003cp\u003eDespite advances, several gaps persist. The conceptualization of anguish remains inconsistent, limiting its empirical integration and comparability across studies [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. Methodological heterogeneity\u0026mdash;including differences in neuroimaging protocols, psychological assessments, sample characteristics, and cross-sectional designs\u0026mdash;reduces the ability to establish causal relationships [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Furthermore, few studies adopt multimodal approaches, which limits understanding of how neural, psychological, and existential processes interact over time.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eFuture Directions\u003c/h2\u003e\u003cp\u003eFuture research should employ longitudinal, multimodal designs, combining neuroimaging, genetic, physiological, and psychological assessments. Such approaches will enable the disentanglement of shared versus disorder-specific features of anguish, anxiety, and depression. Mechanism-focused interventions could then be tailored to address both biological and existential dimensions of suffering, fostering resilience and adaptive functioning [\u003cspan additionalcitationids=\"CR58\" citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAnguish, anxiety, and depression are intricately interwoven phenomena, reflecting overlapping neurological, psychological, and existential substrates. From a neurobiological standpoint, these conditions converge on dysfunctional cortico-limbic circuits. Hyperactivation of the amygdala and insula amplifies threat sensitivity and emotional reactivity, while hypoactivation of the prefrontal cortex undermines top-down regulation of affect and adaptive coping [\u003cspan additionalcitationids=\"CR61\" citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. Chronic exposure to stress and persistent negative affect engages the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis, resulting in dysregulated cortisol rhythms and maladaptive stress responses that perpetuate emotional and physiological vulnerability [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e, \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. Neurotransmitter imbalances\u0026mdash;particularly within serotonergic, dopaminergic, and glutamatergic systems\u0026mdash;further entrench negative mood states and cognitive inflexibility, fostering a neurobiological milieu conducive to recurrent or chronic distress [\u003cspan additionalcitationids=\"CR66\" citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. Recent neuroimaging meta-analyses reinforce these findings, demonstrating overlapping patterns of cortico-limbic dysfunction across depressive and anxiety disorders, as well as in individuals experiencing high existential distress [\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePsychologically, these conditions are characterized by maladaptive cognitive patterns, including rumination, catastrophizing, and attentional biases toward negative or threatening stimuli, which amplify emotional suffering and reduce behavioral flexibility [\u003cspan additionalcitationids=\"CR71\" citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e]. Emotion regulation deficits\u0026mdash;overreliance on suppression, avoidance, or disengagement\u0026mdash;further impede effective processing of negative experiences and prolong distress [\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e, \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e]. Anguish introduces a distinct existential dimension, situating emotional suffering within concerns about meaning, mortality, freedom, and personal responsibility. This existential layer intensifies subjective distress and often reduces the efficacy of interventions that focus solely on symptom reduction [\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA transdiagnostic and integrative framework offers a conceptual lens to view anguish, anxiety, and depression as variations of a shared human vulnerability rather than discrete disorders. This approach emphasizes common neurobiological circuits and psychological mechanisms underlying affective dysregulation, while simultaneously incorporating existential considerations. Clinically, it enables earlier identification of at-risk individuals, supports the development of personalized, mechanism-focused interventions, and promotes strategies targeting both symptom reduction and the enhancement of meaning, resilience, and social connection [\u003cspan additionalcitationids=\"CR78\" citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eBridging biological, psychological, and existential domains, an integrative transdiagnostic model not only advances the understanding of emotional suffering but also guides the design of multidimensional interventions. These may combine pharmacological or neuromodulatory techniques to modulate neural circuits, psychotherapeutic strategies to reshape maladaptive cognitive-emotional patterns, and meaning-centered or acceptance-based approaches to address existential concerns. Healing, therefore, is not limited to symptom alleviation; it requires fostering coherence, agency, and a sense of purpose, thereby addressing the full spectrum of human vulnerability and promoting sustained well-being [\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e].\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of AI and AI-Assisted Technologies in the Writing Process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChatGPT (OpenAI, San Francisco, CA, USA, 2025) was used as a writing aid to improve consistency and gram matical accuracy. 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Topoi 42:1165\u0026ndash;1173. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s11245\u0026ndash;023\u0026ndash;\u003c/span\u003e\u003cspan address=\"10.1007/s11245\u0026ndash;023\u0026ndash;\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFu J, Wang T, Wang L (2023) Existential meaninglessness as a predictor of suicidal ideation and loneliness during COVID\u0026ndash;19. Pers Individ Dif 112346. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.paid.2023.112346\u003c/span\u003e\u003cspan address=\"10.1016/j.paid.2023.112346\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcAndrew NS, Gray TF, Wallace L et al (2023) Existential distress in family caregivers: scoping review of meaning\u0026ndash;making interventions. 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Article ID 5037662 \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/2024/5037662\u003c/span\u003e\u003cspan address=\"10.1155/2024/5037662\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ede Vries ML, Janse P, Anbeek CW, Braam AW (2025) Existential concerns among young adults with psychotic vulnerability in mental health care: a qualitative study in the Netherlands. 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Curr Opin Support Palliat Care 14:114\u0026ndash;120. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/SPC.0000000000000535\u003c/span\u003e\u003cspan address=\"10.1097/SPC.0000000000000535\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBreitbart W, Poppito S et al (2012) Individual meaning-centered psychotherapy for patients with advanced cancer: a randomized controlled trial. J Clin Oncol 30:1309\u0026ndash;1315. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.2011.37.6297\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2011.37.6297\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"anguish, anxiety, depression, neuropsychological correlates, transdiagnostic approach","lastPublishedDoi":"10.21203/rs.3.rs-8070386/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8070386/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAnguish, anxiety, and depression rank among the most disabling mental health conditions worldwide. Frequently co-occurring, they form a complex constellation of affective, cognitive, and physiological disturbances that blur traditional diagnostic boundaries. Although substantial progress has been made in elucidating their biological and psychological underpinnings, the dynamic interplay between these dimensions remains incompletely understood. This review synthesizes recent evidence on the neurological and psychological dimensions of anguish, anxiety, and depression, with the goal of identifying shared mechanisms and disorder-specific features.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA systematic search was conducted in PubMed, PsycINFO, Scopus, Web of Science, and SpringerLink for studies published between 2013 and 2023. Eligible articles examined neurological or psychological correlates of these conditions in adult populations. The review adhered to PRISMA 2020 guidelines.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFrom an initial pool of 3,245 studies, 87 met all inclusion criteria. Neurological findings converged on disruptions within cortico-limbic circuits, altered hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis activity, and imbalances in monoaminergic and glutamatergic signaling. Psychologically, the most consistent patterns included maladaptive cognitive schemas, deficits in emotion regulation, and pervasive negative affectivity. Although less frequently investigated, anguish exhibited neuropsychological overlaps with both anxiety and depression, particularly in regions governing interoceptive awareness and self-referential processing.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAnguish, anxiety, and depression share a neuropsychological architecture that transcends categorical diagnoses. Integrating biological and psychological perspectives within a transdiagnostic framework may yield more precise models of mental suffering and foster interventions that address its shared mechanisms rather than its surface manifestations.\u003c/p\u003e","manuscriptTitle":"Bridging Brain and Mind: A Transdiagnostic Review of Anguish, Anxiety, and Depression","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-11 07:16:35","doi":"10.21203/rs.3.rs-8070386/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"45896976-21ec-4191-baf2-48bab5cdc993","owner":[],"postedDate":"November 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":57681817,"name":"Psychiatry"}],"tags":[],"updatedAt":"2025-11-11T07:16:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-11 07:16:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8070386","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8070386","identity":"rs-8070386","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}