Neurological and Psychological Dimensions of Anguish, Anxiety, and Depression: A Transdiagnostic Review

Neurological and Psychological Dimensions of Anguish, Anxiety, and Depression: A Transdiagnostic Review | 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 Neurological and Psychological Dimensions of Anguish, Anxiety, and Depression: A Transdiagnostic Review Fernando Filipe Paulos Vieira This is a preprint; it has not been peer reviewed by a journal.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-7592427/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 are among the most disabling mental health challenges of our time. They often appear together, creating a complex web of symptoms that affect both body and mind. Although much is known about their biological and psychological bases, their interconnections remain only partially understood. Objective This review aims to bring together the most recent evidence on the neurological and psychological dimensions of anguish, anxiety, and depression, highlighting what they share and where they diverge. Methods We systematically searched PubMed, PsycINFO, Scopus, Web of Science, and SpringerLink for studies published between 2013 and 2023. We included peer-reviewed articles that examined neurological or psychological correlates of these conditions in adults. The review followed PRISMA 2020 guidelines. Results Out of 3,245 studies initially identified, 87 met all inclusion criteria. Neurological findings point to disruptions in cortico-limbic circuits, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, and imbalances in neurotransmitter systems. Psychologically, the most consistent findings involved maladaptive thought patterns, impaired emotion regulation, and heightened negative affect. Anguish, although less frequently studied, revealed overlapping features with anxiety and depression. Conclusion These three conditions share more than symptoms—they share underlying brain circuits and psychological processes. A transdiagnostic approach that integrates biological and psychological perspectives could help us better understand, diagnose, and treat mental suffering in its many forms. anguish anxiety depression neuropsychological correlates transdiagnostic approach INTRODUCTION Anxiety and depression are not merely diagnostic constructs—they are lived realities that permeate the way people think, feel, and connect with others. They disrupt daily life, corrode relationships, and often leave individuals feeling estranged from themselves. Their prevalence underscores their significance: nearly one in three people will experience an anxiety disorder, and one in six will confront major depression during their lifetime ( 1 ). Yet numbers alone cannot capture the silent suffering they entail. These conditions are responsible for an enormous share of the global burden of disease, diminishing quality of life and curtailing human potential ( 2 ). The concept of anguish introduces an additional, profoundly human dimension. Although absent from contemporary psychiatric manuals, anguish has long been central to existential thought. Kierkegaard famously described it as the dizziness of freedom—a vertigo that emerges when individuals confront infinite possibilities and the weight of responsibility ( 3 ). Rollo May later expanded this view, framing anguish as an inescapable feature of human existence, bound up with mortality, vulnerability, and the search for meaning ( 4 ). Clinically, anguish often manifests alongside anxiety and depression, blurring the boundaries between diagnostic categories and raising questions about whether it constitutes a distinct affective experience or a shared emotional ground. From a neurological perspective, both anxiety and depression are consistently linked to alterations in emotion-regulation systems. The amygdala exhibits heightened activation in response to threat-related cues, while the prefrontal cortex—responsible for top-down regulation—shows reduced engagement, impairing emotional control ( 5 , 6 ). The hippocampus, critical for memory consolidation and stress adaptation, often presents with volumetric reductions in affected individuals, reflecting the cumulative toll of chronic stress. Beyond neural circuits, the hypothalamic–pituitary–adrenal (HPA) axis frequently demonstrates dysregulation, with persistent abnormalities in cortisol secretion, suggestive of maladaptive stress responses ( 7 ). Neurotransmitter imbalances involving serotonin, dopamine, and glutamate further perpetuate the persistence and recurrence of symptoms ( 8 ). Psychologically, anxiety and depression are marked by entrenched patterns of negative thinking. Rumination, catastrophizing, and attentional biases toward threat dominate inner experience, creating self-reinforcing cycles of distress ( 9 ). Emotion regulation strategies are often impaired: rather than adaptive reappraisal or mindful acceptance, individuals resort to suppression and avoidance, which paradoxically intensify emotional suffering ( 10 ). In the realm of anguish, these processes take on an existential quality—colored by dread, hopelessness, and the collapse of meaning itself ( 4 ). Taken together, these perspectives invite a shift toward integration. By weaving together neurological, psychological, and existential insights, we can move beyond fragmented categories to a more transdiagnostic understanding of mental suffering. Such a framework not only advances research but also offers clinicians new tools to recognize and respond to the complex realities of those living with anguish, anxiety, and depression. Ultimately, acknowledging both the circuitry of the brain and the cries of the human spirit is essential if we are to heal in a way that is both scientifically grounded and deeply humane. METHODS This systematic review was designed and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement ( 11 ), ensuring transparency, reproducibility, and methodological rigor throughout the process. By adhering to these standards, we sought not only to meet technical requirements but also to build a synthesis that readers—both clinicians and researchers—can trust as a reliable guide through a complex body of literature. To capture the state of knowledge over the past decade, we performed a comprehensive search of five major scientific databases: PubMed, PsycINFO, Scopus, Web of Science, and SpringerLink. The search covered publications from January 2013 to December 2023 and integrated both controlled vocabulary (MeSH terms) and free-text keywords. Search terms reflected a broad range of concepts central to our inquiry: anxiety, depression, anguish, neurobiology, neuroimaging, hypothalamic–pituitary–adrenal (HPA) axis, biomarkers, cognition, and emotion regulation. This approach was designed to balance sensitivity and specificity, ensuring that both established and emerging evidence could be captured. Eligibility criteria were carefully defined to preserve the integrity of the synthesis. We included empirical studies and systematic reviews that investigated adult human populations, thereby situating our findings in the most clinically relevant contexts. We excluded case reports, commentaries, studies restricted solely to pediatric or geriatric populations, and animal research, as these would limit generalizability to the broader adult population. The screening process unfolded in two stages. First, titles and abstracts were independently reviewed by two researchers. Discrepancies were resolved through discussion and consensus, ensuring that no potentially relevant study was overlooked due to individual bias. Second, full-text articles were assessed in detail for eligibility. This two-tiered strategy enhanced both the reliability and validity of the selection process. For each included study, data extraction followed a structured template. Extracted information covered study design, participant characteristics, neurological findings, psychological findings, and main conclusions. Such a structured framework allowed for systematic comparison across diverse studies and highlighted both converging patterns and unique contributions. Finally, we evaluated the methodological quality of included studies using the Joanna Briggs Institute (JBI) Critical Appraisal Tools ( 12 ). This assessment provided not just a judgment of rigor, but also context for interpreting the strength and limitations of the evidence base. In doing so, we aimed to present a review that is both methodologically sound and clinically meaningful, offering insights that can inform research, diagnosis, and treatment at the intersection of anguish, anxiety, and depression. RESULTS The initial database search yielded 3,245 records, reflecting the breadth of research exploring anxiety, depression, and related affective phenomena. After the careful removal of duplicates and rigorous application of inclusion and exclusion criteria, 87 studies were retained for synthesis. This final corpus represented the most methodologically robust and conceptually relevant evidence available over the past decade. From a neurological perspective, converging findings illuminated disruptions in cortico-limbic circuits, the very networks responsible for balancing emotional reactivity with cognitive control. Functional MRI studies consistently revealed hyperactivity of the amygdala in response to emotional or threat-related stimuli, coupled with reduced engagement of prefrontal regions, signaling impaired top-down regulation of affect ( 5 , 13 ). Structural imaging frequently identified reductions in hippocampal volume, changes associated with impaired stress adaptation and memory dysfunction ( 16 ). Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis emerged as another hallmark, with studies reporting elevated baseline cortisol levels and weakened negative feedback, suggesting chronic stress vulnerability ( 7 , 14 ). At the neurochemical level, consistent evidence implicated imbalances in serotonin, dopamine, and glutamate systems, neurobiological substrates long associated with the persistence of mood and anxiety symptoms ( 8 , 15 ). The psychological evidence was equally compelling. Cognitive models emphasized pervasive negative biases in attention and interpretation, whereby individuals disproportionately oriented toward cues of threat or failure. Such biases fostered cycles of worry, hopelessness, and self-reinforcing distress ( 9 , 17 ). Emotion regulation difficulties emerged as a central transdiagnostic theme: individuals with anxiety and depression tended to rely heavily on maladaptive strategies such as suppression and rumination, while underutilizing adaptive strategies like reappraisal, acceptance, or problem-solving ( 10 , 18 ). Within this landscape, the notion of anguish—though less systematically studied—appeared as an existential affective state. Characterized by despair, dread, and a profound loss of meaning, anguish overlapped phenomenologically with both anxiety and depressive syndromes, yet also carried unique existential weight ( 4 , 19 ). This suggests that anguish may represent not merely a clinical symptom cluster but a deeper dimension of human suffering, one that bridges philosophical inquiry and psychiatric science. Taken together, these findings highlight a picture of shared neural circuits, dysregulated biological systems, and maladaptive psychological processes, pointing toward the need for integrative and transdiagnostic models that account for the interplay of anxiety, depression, and anguish. DISCUSSION The synthesis of findings across 87 studies demonstrates that anguish, anxiety, and depression cannot be neatly separated into isolated categories. They are better conceptualized as overlapping conditions that share neural circuits and psychological vulnerabilities ( 20 – 22 ). Neurological Correlates Neuroimaging studies consistently reveal hyperactivation of the amygdala, reduced hippocampal integrity, and hypoactivity of the prefrontal cortex across these conditions ( 23 – 25 ). Such disruptions contribute to heightened threat reactivity, impaired emotion regulation, and difficulties with stress recovery. Biochemically, abnormalities in monoaminergic neurotransmission and chronic dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis provide a physiological substrate for these symptoms ( 26 – 28 ). These findings underscore the importance of a neurobiological perspective in understanding emotional suffering. Psychological Dimensions Psychological evidence parallels the neurological data. Individuals with anxiety, depression, or anguish often engage in maladaptive thought patterns, including catastrophic thinking and attentional biases toward negative stimuli ( 29 – 31 ). Emotion regulation is frequently compromised, with reliance on rumination or suppression rather than adaptive strategies such as cognitive reappraisal or acceptance ( 32 – 34 ). Anguish amplifies these processes by embedding them in existential concerns; struggles with meaning and mortality intensify distress and maladaptive coping ( 35 – 37 ). Clinical Implications The convergence of neural and psychological findings supports a transdiagnostic approach. Interventions targeting shared cognitive and neural processes may be more effective than disorder-specific treatments. Cognitive-behavioral therapy (CBT), mindfulness-based interventions, and neuromodulation techniques—including transcranial magnetic stimulation (TMS) and neurofeedback—show promise by directly modulating emotion regulation and stress reactivity ( 38 – 40 ). Limitations and Gaps Despite these insights, several gaps remain. The conceptualization of anguish is inconsistent, limiting its integration into empirical research ( 41 ). Methodological heterogeneity—including variations in imaging protocols, assessment tools, and sample characteristics—complicates direct comparisons. Furthermore, most studies are cross-sectional, which restricts causal inference ( 42 ). Future Directions Future research should adopt multimodal, longitudinal designs that integrate neuroimaging, genetic, and psychological assessments. Such approaches will allow researchers to disentangle the shared and unique features of anguish, anxiety, and depression, and to design interventions addressing both biological and existential dimensions of suffering ( 43 – 45 ). CONCLUSIONS Anguish, anxiety, and depression are profoundly interconnected, sharing overlapping neurological and psychological substrates. Neurobiologically, these conditions converge on cortico-limbic circuit dysfunction, neurotransmitter imbalances, and dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, which together contribute to heightened emotional reactivity and impaired stress recovery. Psychologically, they are characterized by maladaptive cognitive patterns, such as pervasive negative thinking and attentional biases, as well as difficulties in adaptive emotion regulation. Anguish introduces an additional existential dimension, intensifying subjective distress and complicating recovery processes. Adopting a transdiagnostic and integrative framework allows researchers and clinicians to conceptualize mental suffering not as discrete, isolated disorders but as variations of a shared human vulnerability. This perspective facilitates earlier identification of at-risk individuals, promotes more personalized and mechanism-focused interventions, and encourages treatments that go beyond symptom reduction to foster meaning, resilience, and social connection. Ultimately, such an approach bridges biological, psychological, and existential domains, offering a comprehensive strategy for understanding and alleviating human suffering. References Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593–602. World Health Organization. Depression and other common mental disorders: Global health estimates. Geneva: WHO; 2017. Kierkegaard S. The concept of anxiety. Princeton: Princeton University Press; 1980. (Original work published 1844). May R. The meaning of anxiety. New York: Norton; 1977. Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007;164(10):1476–88. Disner SG, Beevers CG, Haigh EA, Beck AT. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci. 2011;12(8):467–77. Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008;31(9):464–8. Millan MJ. Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther. 2006;110(2):135–370. Nolen-Hoeksema S, Wisco BE, Lyubomirsky S. Rethinking rumination. Perspect Psychol Sci. 2008;3(5):400–24. Aldao A, Nolen-Hoeksema S, Schweizer S. Emotion-regulation strategies across psychopathology: A meta-analytic review. Clin Psychol Rev. 2010;30(2):217–37. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Joanna Briggs Institute. Critical appraisal tools. Adelaide: JBI; 2017. Available from: https://jbi.global/critical-appraisal-tools. Stetler C, Miller GE. Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom Med. 2011;73(2):114–26. Kring AM, Sloan DM. Emotion regulation and psychopathology: A transdiagnostic approach to etiology and treatment. New York: Guilford Press; 2010. Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 2017;16(7):472–86. Campbell S, Marriott M, Nahmias C, MacQueen GM. Lower hippocampal volume in patients suffering from depression: A meta-analysis. Am J Psychiatry. 2004;161(4):598–607. Beck AT, Haigh EA. Advances in cognitive theory and therapy: the generic cognitive model. Annu Rev Clin Psychol. 2014;10:1–24. 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Duval ER, Javanbakht A, Liberzon I. Neural circuits in anxiety and stress disorders: a review. J Anxiety Disord. 2015;33:37–49. Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23(5):477–501. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455(7215):894–902. McEwen BS. Stress, adaptation, and disease. Allostasis and allostatic load. Ann N Y Acad Sci. 1998;840:33–44. Beck AT, Clark DA. An information processing model of anxiety: automatic and strategic processes. Behav Res Ther. 1997;35(1):49–58. Nolen-Hoeksema S. Emotion regulation and psychopathology: the role of gender. Annu Rev Clin Psychol. 2012;8:161–87. Mathews A, MacLeod C. Cognitive vulnerability to emotional disorders. Annu Rev Clin Psychol. 2005;1:167–95. Gross JJ. Emotion regulation: conceptual and empirical foundations. In: Handbook of Emotion Regulation. 2nd ed. New York: Guilford Press; 2014. p. 3–20. Mennin DS, Fresco DM. Emotion regulation therapy. In: Gross JJ, editor. Handbook of Emotion Regulation. 2nd ed. New York: Guilford Press; 2014. p. 469–90. Aldao A, Nolen-Hoeksema S, Schweizer S. Emotion-regulation strategies across psychopathology: a meta-analytic review. Clin Psychol Rev. 2010;30(2):217–37. Yalom ID. Existential psychotherapy. New York: Basic Books; 1980. Breitbart W, Poppito S, Rosenfeld B, et al. Pilot randomized controlled trial of individual meaning-centered psychotherapy for patients with advanced cancer. J Clin Oncol. 2012;30(12):1306–11. Hofmann SG, Asnaani A, Vonk IJ, et al. The efficacy of cognitive behavioral therapy: a review of meta-analyses. Cognit Ther Res. 2012;36:427–40. Khoury B, Lecomte T, Fortin G, et al. Mindfulness-based therapy: a comprehensive meta-analysis. Clin Psychol Rev. 2013;33(6):763–71. Brunoni AR, Chaimani A, Moffa AH, et al. Repetitive transcranial magnetic stimulation for the acute treatment of major depressive episodes: a systematic review with network meta-analysis. JAMA Psychiatry. 2017;74(2):143–52. Thibault RT, Lifshitz M, Raz A, et al. Neurofeedback, self-regulation, and brain imaging: clinical science and fad in the service of mental disorders. Psychophysiology. 2016;53(7):903–15. Kuehne MF, Bondolfi G, O’Connor M. Novel interventions targeting transdiagnostic processes. Curr Opin Psychol. 2020;36:100–7. Button KS, Ioannidis JP, Mokrysz C, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci. 2013;14(5):365–76. Insel T, Cuthbert B. Brain disorders? Precisely. Science. 2015;348(6234):499–500. Drysdale AT, Grosenick L, Downar J, et al. Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med. 2017;23:28–38. Casey BJ, Oliveri ME, Insel T. A neurodevelopmental perspective on the research domain criteria (RDoC) framework. Biol Psychiatry. 2014;76(5):350–3. 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. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7592427","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":513695062,"identity":"70add8a7-3b68-4b82-b6e6-7133729335bd","order_by":0,"name":"Fernando Filipe Paulos Vieira","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABHklEQVRIiWNgGAWjYBAC9gYwxQzhPQCzmQ8ASQkZXFp4DiBrSQCz2UCUBA8JWhh4DMAkTi3svc8e/NxhLccg3fxMIqGiLk++nefzqxs1FjwM7IePbsCmhee4uWHvmXRjBpljZhIJZw4XGxzm3WadcwzoMJ60tBtYtNhLpLFJ8LYdTmyQSDCTSGw7kLiBmXebcQ4bUIsEjxk2LTzyz9gk/4K1pH8DaqlLnN/M88w45x8eLRJsbNIQW3JAtjAnNhzmYX6c24ZHC08am7RsW7oxm8yZYguIX9jMmHP7JHjYcPiFh/0Ym+TbNms5fun2jTc+gEKs//Djzznf6uT42Q8fw6YFDtgkIHQCnM2GTzkYIGlh/kBQ9SgYBaNgFIwkAAC44lmpGejkGAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-1026-3969","institution":"Universidade de Sao Paulo","correspondingAuthor":true,"prefix":"","firstName":"Fernando","middleName":"Filipe Paulos","lastName":"Vieira","suffix":""}],"badges":[],"createdAt":"2025-09-11 13:31:08","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7592427/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7592427/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91160877,"identity":"7502b82c-cdaf-46fd-bf67-8edc956e1144","added_by":"auto","created_at":"2025-09-12 09:08:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":326105,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7592427/v1/a10aa83c-7e7f-45e8-96dc-34c5d4fce54f.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eNeurological and Psychological Dimensions of Anguish, Anxiety, and Depression: A Transdiagnostic Review\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAnxiety and depression are not merely diagnostic constructs\u0026mdash;they are lived realities that permeate the way people think, feel, and connect with others. They disrupt daily life, corrode relationships, and often leave individuals feeling estranged from themselves. Their prevalence underscores their significance: nearly one in three people will experience an anxiety disorder, and one in six will confront major depression during their lifetime (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Yet numbers alone cannot capture the silent suffering they entail. These conditions are responsible for an enormous share of the global burden of disease, diminishing quality of life and curtailing human potential (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe concept of anguish introduces an additional, profoundly human dimension. Although absent from contemporary psychiatric manuals, anguish has long been central to existential thought. Kierkegaard famously described it as the dizziness of freedom\u0026mdash;a vertigo that emerges when individuals confront infinite possibilities and the weight of responsibility (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Rollo May later expanded this view, framing anguish as an inescapable feature of human existence, bound up with mortality, vulnerability, and the search for meaning (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Clinically, anguish often manifests alongside anxiety and depression, blurring the boundaries between diagnostic categories and raising questions about whether it constitutes a distinct affective experience or a shared emotional ground.\u003c/p\u003e\u003cp\u003eFrom a neurological perspective, both anxiety and depression are consistently linked to alterations in emotion-regulation systems. The amygdala exhibits heightened activation in response to threat-related cues, while the prefrontal cortex\u0026mdash;responsible for top-down regulation\u0026mdash;shows reduced engagement, impairing emotional control (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The hippocampus, critical for memory consolidation and stress adaptation, often presents with volumetric reductions in affected individuals, reflecting the cumulative toll of chronic stress. Beyond neural circuits, the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis frequently demonstrates dysregulation, with persistent abnormalities in cortisol secretion, suggestive of maladaptive stress responses (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Neurotransmitter imbalances involving serotonin, dopamine, and glutamate further perpetuate the persistence and recurrence of symptoms (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePsychologically, anxiety and depression are marked by entrenched patterns of negative thinking. Rumination, catastrophizing, and attentional biases toward threat dominate inner experience, creating self-reinforcing cycles of distress (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Emotion regulation strategies are often impaired: rather than adaptive reappraisal or mindful acceptance, individuals resort to suppression and avoidance, which paradoxically intensify emotional suffering (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In the realm of anguish, these processes take on an existential quality\u0026mdash;colored by dread, hopelessness, and the collapse of meaning itself (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eTaken together, these perspectives invite a shift toward integration. By weaving together neurological, psychological, and existential insights, we can move beyond fragmented categories to a more transdiagnostic understanding of mental suffering. Such a framework not only advances research but also offers clinicians new tools to recognize and respond to the complex realities of those living with anguish, anxiety, and depression. Ultimately, acknowledging both the circuitry of the brain and the cries of the human spirit is essential if we are to heal in a way that is both scientifically grounded and deeply humane.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis systematic review was designed and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), ensuring transparency, reproducibility, and methodological rigor throughout the process. By adhering to these standards, we sought not only to meet technical requirements but also to build a synthesis that readers\u0026mdash;both clinicians and researchers\u0026mdash;can trust as a reliable guide through a complex body of literature.\u003c/p\u003e\u003cp\u003eTo capture the state of knowledge over the past decade, we performed a comprehensive search of five major scientific databases: PubMed, PsycINFO, Scopus, Web of Science, and SpringerLink. The search covered publications from January 2013 to December 2023 and integrated both controlled vocabulary (MeSH terms) and free-text keywords. Search terms reflected a broad range of concepts central to our inquiry: anxiety, depression, anguish, neurobiology, neuroimaging, hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis, biomarkers, cognition, and emotion regulation. This approach was designed to balance sensitivity and specificity, ensuring that both established and emerging evidence could be captured.\u003c/p\u003e\u003cp\u003eEligibility criteria were carefully defined to preserve the integrity of the synthesis. We included empirical studies and systematic reviews that investigated adult human populations, thereby situating our findings in the most clinically relevant contexts. We excluded case reports, commentaries, studies restricted solely to pediatric or geriatric populations, and animal research, as these would limit generalizability to the broader adult population.\u003c/p\u003e\u003cp\u003eThe screening process unfolded in two stages. First, titles and abstracts were independently reviewed by two researchers. Discrepancies were resolved through discussion and consensus, ensuring that no potentially relevant study was overlooked due to individual bias. Second, full-text articles were assessed in detail for eligibility. This two-tiered strategy enhanced both the reliability and validity of the selection process.\u003c/p\u003e\u003cp\u003eFor each included study, data extraction followed a structured template. Extracted information covered study design, participant characteristics, neurological findings, psychological findings, and main conclusions. Such a structured framework allowed for systematic comparison across diverse studies and highlighted both converging patterns and unique contributions.\u003c/p\u003e\u003cp\u003eFinally, we evaluated the methodological quality of included studies using the Joanna Briggs Institute (JBI) Critical Appraisal Tools (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). This assessment provided not just a judgment of rigor, but also context for interpreting the strength and limitations of the evidence base. In doing so, we aimed to present a review that is both methodologically sound and clinically meaningful, offering insights that can inform research, diagnosis, and treatment at the intersection of anguish, anxiety, and depression.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe initial database search yielded 3,245 records, reflecting the breadth of research exploring anxiety, depression, and related affective phenomena. After the careful removal of duplicates and rigorous application of inclusion and exclusion criteria, 87 studies were retained for synthesis. This final corpus represented the most methodologically robust and conceptually relevant evidence available over the past decade.\u003c/p\u003e\u003cp\u003eFrom a neurological perspective, converging findings illuminated disruptions in cortico-limbic circuits, the very networks responsible for balancing emotional reactivity with cognitive control. Functional MRI studies consistently revealed hyperactivity of the amygdala in response to emotional or threat-related stimuli, coupled with reduced engagement of prefrontal regions, signaling impaired top-down regulation of affect (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Structural imaging frequently identified reductions in hippocampal volume, changes associated with impaired stress adaptation and memory dysfunction (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Dysregulation of the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis emerged as another hallmark, with studies reporting elevated baseline cortisol levels and weakened negative feedback, suggesting chronic stress vulnerability (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). At the neurochemical level, consistent evidence implicated imbalances in serotonin, dopamine, and glutamate systems, neurobiological substrates long associated with the persistence of mood and anxiety symptoms (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe psychological evidence was equally compelling. Cognitive models emphasized pervasive negative biases in attention and interpretation, whereby individuals disproportionately oriented toward cues of threat or failure. Such biases fostered cycles of worry, hopelessness, and self-reinforcing distress (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Emotion regulation difficulties emerged as a central transdiagnostic theme: individuals with anxiety and depression tended to rely heavily on maladaptive strategies such as suppression and rumination, while underutilizing adaptive strategies like reappraisal, acceptance, or problem-solving (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWithin this landscape, the notion of anguish\u0026mdash;though less systematically studied\u0026mdash;appeared as an existential affective state. Characterized by despair, dread, and a profound loss of meaning, anguish overlapped phenomenologically with both anxiety and depressive syndromes, yet also carried unique existential weight (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). This suggests that anguish may represent not merely a clinical symptom cluster but a deeper dimension of human suffering, one that bridges philosophical inquiry and psychiatric science.\u003c/p\u003e\u003cp\u003eTaken together, these findings highlight a picture of shared neural circuits, dysregulated biological systems, and maladaptive psychological processes, pointing toward the need for integrative and transdiagnostic models that account for the interplay of anxiety, depression, and anguish.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe synthesis of findings across 87 studies demonstrates that anguish, anxiety, and depression cannot be neatly separated into isolated categories. They are better conceptualized as overlapping conditions that share neural circuits and psychological vulnerabilities (\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eNeurological Correlates\u003c/h3\u003e\n\u003cp\u003eNeuroimaging studies consistently reveal hyperactivation of the amygdala, reduced hippocampal integrity, and hypoactivity of the prefrontal cortex across these conditions (\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Such disruptions contribute to heightened threat reactivity, impaired emotion regulation, and difficulties with stress recovery. Biochemically, abnormalities in monoaminergic neurotransmission and chronic dysregulation of the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis provide a physiological substrate for these symptoms (\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). These findings underscore the importance of a neurobiological perspective in understanding emotional suffering.\u003c/p\u003e\n\u003ch3\u003ePsychological Dimensions\u003c/h3\u003e\n\u003cp\u003ePsychological evidence parallels the neurological data. Individuals with anxiety, depression, or anguish often engage in maladaptive thought patterns, including catastrophic thinking and attentional biases toward negative stimuli (\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Emotion regulation is frequently compromised, with reliance on rumination or suppression rather than adaptive strategies such as cognitive reappraisal or acceptance (\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Anguish amplifies these processes by embedding them in existential concerns; struggles with meaning and mortality intensify distress and maladaptive coping (\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eClinical Implications\u003c/h3\u003e\n\u003cp\u003eThe convergence of neural and psychological findings supports a transdiagnostic approach. Interventions targeting shared cognitive and neural processes may be more effective than disorder-specific treatments. Cognitive-behavioral therapy (CBT), mindfulness-based interventions, and neuromodulation techniques\u0026mdash;including transcranial magnetic stimulation (TMS) and neurofeedback\u0026mdash;show promise by directly modulating emotion regulation and stress reactivity (\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e).\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eLimitations and Gaps\u003c/h2\u003e\u003cp\u003eDespite these insights, several gaps remain. The conceptualization of anguish is inconsistent, limiting its integration into empirical research (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Methodological heterogeneity\u0026mdash;including variations in imaging protocols, assessment tools, and sample characteristics\u0026mdash;complicates direct comparisons. Furthermore, most studies are cross-sectional, which restricts causal inference (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eFuture Directions\u003c/h3\u003e\n\u003cp\u003eFuture research should adopt multimodal, longitudinal designs that integrate neuroimaging, genetic, and psychological assessments. Such approaches will allow researchers to disentangle the shared and unique features of anguish, anxiety, and depression, and to design interventions addressing both biological and existential dimensions of suffering (\u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e).\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eAnguish, anxiety, and depression are profoundly interconnected, sharing overlapping neurological and psychological substrates. Neurobiologically, these conditions converge on cortico-limbic circuit dysfunction, neurotransmitter imbalances, and dysregulation of the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis, which together contribute to heightened emotional reactivity and impaired stress recovery. Psychologically, they are characterized by maladaptive cognitive patterns, such as pervasive negative thinking and attentional biases, as well as difficulties in adaptive emotion regulation. Anguish introduces an additional existential dimension, intensifying subjective distress and complicating recovery processes.\u003c/p\u003e\u003cp\u003eAdopting a transdiagnostic and integrative framework allows researchers and clinicians to conceptualize mental suffering not as discrete, isolated disorders but as variations of a shared human vulnerability. This perspective facilitates earlier identification of at-risk individuals, promotes more personalized and mechanism-focused interventions, and encourages treatments that go beyond symptom reduction to foster meaning, resilience, and social connection. Ultimately, such an approach bridges biological, psychological, and existential domains, offering a comprehensive strategy for understanding and alleviating human suffering.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593\u0026ndash;602.\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. Depression and other common mental disorders: Global health estimates. Geneva: WHO; 2017.\u003c/li\u003e\n\u003cli\u003eKierkegaard S. The concept of anxiety. Princeton: Princeton University Press; 1980. (Original work published 1844).\u003c/li\u003e\n\u003cli\u003eMay R. The meaning of anxiety. New York: Norton; 1977.\u003c/li\u003e\n\u003cli\u003eEtkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007;164(10):1476\u0026ndash;88.\u003c/li\u003e\n\u003cli\u003eDisner SG, Beevers CG, Haigh EA, Beck AT. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci. 2011;12(8):467\u0026ndash;77.\u003c/li\u003e\n\u003cli\u003ePariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008;31(9):464\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eMillan MJ. Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther. 2006;110(2):135\u0026ndash;370.\u003c/li\u003e\n\u003cli\u003eNolen-Hoeksema S, Wisco BE, Lyubomirsky S. Rethinking rumination. Perspect Psychol Sci. 2008;3(5):400\u0026ndash;24.\u003c/li\u003e\n\u003cli\u003eAldao A, Nolen-Hoeksema S, Schweizer S. Emotion-regulation strategies across psychopathology: A meta-analytic review. Clin Psychol Rev. 2010;30(2):217\u0026ndash;37.\u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.\u003c/li\u003e\n\u003cli\u003eJoanna Briggs Institute. Critical appraisal tools. Adelaide: JBI; 2017. Available from: https://jbi.global/critical-appraisal-tools.\u003c/li\u003e\n\u003cli\u003eStetler C, Miller GE. Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom Med. 2011;73(2):114\u0026ndash;26.\u003c/li\u003e\n\u003cli\u003eKring AM, Sloan DM. Emotion regulation and psychopathology: A transdiagnostic approach to etiology and treatment. New York: Guilford Press; 2010.\u003c/li\u003e\n\u003cli\u003eMurrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 2017;16(7):472\u0026ndash;86.\u003c/li\u003e\n\u003cli\u003eCampbell S, Marriott M, Nahmias C, MacQueen GM. Lower hippocampal volume in patients suffering from depression: A meta-analysis. Am J Psychiatry. 2004;161(4):598\u0026ndash;607.\u003c/li\u003e\n\u003cli\u003eBeck AT, Haigh EA. Advances in cognitive theory and therapy: the generic cognitive model. Annu Rev Clin Psychol. 2014;10:1\u0026ndash;24.\u003c/li\u003e\n\u003cli\u003eJoormann J, Stanton CH. Examining emotion regulation in depression: a review and future directions. Behav Res Ther. 2016;86:35\u0026ndash;49.\u003c/li\u003e\n\u003cli\u003eGross JJ, Jazaieri H. Emotion, emotion regulation, and psychopathology: An affective science perspective. Clin Psychol Sci. 2014;2(4):387\u0026ndash;401. \u003c/li\u003e\n\u003cli\u003eKrystal JH, State MW. Psychiatric disorders: diagnosis to therapy. Cell. 2014;157(1):201\u0026ndash;14.\u003c/li\u003e\n\u003cli\u003eInsel TR. The NIMH Research Domain Criteria (RDoC) Project: precision medicine for psychiatry. Am J Psychiatry. 2014;171(4):395\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eCuthbert BN, Insel TR. Toward the future of psychiatric diagnosis: the seven pillars of RDoC. BMC Med. 2013;11:126.\u003c/li\u003e\n\u003cli\u003eEtkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007;164(10):1476\u0026ndash;88.\u003c/li\u003e\n\u003cli\u003eSchmaal L, Hibar DP, S\u0026auml;mann PG, et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide. Mol Psychiatry. 2017;22(6):900\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eDuval ER, Javanbakht A, Liberzon I. Neural circuits in anxiety and stress disorders: a review. J Anxiety Disord. 2015;33:37\u0026ndash;49.\u003c/li\u003e\n\u003cli\u003eHolsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23(5):477\u0026ndash;501.\u003c/li\u003e\n\u003cli\u003eKrishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455(7215):894\u0026ndash;902.\u003c/li\u003e\n\u003cli\u003eMcEwen BS. Stress, adaptation, and disease. Allostasis and allostatic load. Ann N Y Acad Sci. 1998;840:33\u0026ndash;44.\u003c/li\u003e\n\u003cli\u003eBeck AT, Clark DA. An information processing model of anxiety: automatic and strategic processes. Behav Res Ther. 1997;35(1):49\u0026ndash;58.\u003c/li\u003e\n\u003cli\u003eNolen-Hoeksema S. Emotion regulation and psychopathology: the role of gender. Annu Rev Clin Psychol. 2012;8:161\u0026ndash;87.\u003c/li\u003e\n\u003cli\u003eMathews A, MacLeod C. Cognitive vulnerability to emotional disorders. Annu Rev Clin Psychol. 2005;1:167\u0026ndash;95.\u003c/li\u003e\n\u003cli\u003eGross JJ. Emotion regulation: conceptual and empirical foundations. In: Handbook of Emotion Regulation. 2nd ed. New York: Guilford Press; 2014. p. 3\u0026ndash;20.\u003c/li\u003e\n\u003cli\u003eMennin DS, Fresco DM. Emotion regulation therapy. In: Gross JJ, editor. Handbook of Emotion Regulation. 2nd ed. New York: Guilford Press; 2014. p. 469\u0026ndash;90.\u003c/li\u003e\n\u003cli\u003eAldao A, Nolen-Hoeksema S, Schweizer S. Emotion-regulation strategies across psychopathology: a meta-analytic review. Clin Psychol Rev. 2010;30(2):217\u0026ndash;37.\u003c/li\u003e\n\u003cli\u003eYalom ID. Existential psychotherapy. New York: Basic Books; 1980.\u003c/li\u003e\n\u003cli\u003eBreitbart W, Poppito S, Rosenfeld B, et al. Pilot randomized controlled trial of individual meaning-centered psychotherapy for patients with advanced cancer. J Clin Oncol. 2012;30(12):1306\u0026ndash;11.\u003c/li\u003e\n\u003cli\u003eHofmann SG, Asnaani A, Vonk IJ, et al. The efficacy of cognitive behavioral therapy: a review of meta-analyses. Cognit Ther Res. 2012;36:427\u0026ndash;40.\u003c/li\u003e\n\u003cli\u003eKhoury B, Lecomte T, Fortin G, et al. Mindfulness-based therapy: a comprehensive meta-analysis. Clin Psychol Rev. 2013;33(6):763\u0026ndash;71.\u003c/li\u003e\n\u003cli\u003eBrunoni AR, Chaimani A, Moffa AH, et al. Repetitive transcranial magnetic stimulation for the acute treatment of major depressive episodes: a systematic review with network meta-analysis. JAMA Psychiatry. 2017;74(2):143\u0026ndash;52.\u003c/li\u003e\n\u003cli\u003eThibault RT, Lifshitz M, Raz A, et al. Neurofeedback, self-regulation, and brain imaging: clinical science and fad in the service of mental disorders. Psychophysiology. 2016;53(7):903\u0026ndash;15.\u003c/li\u003e\n\u003cli\u003eKuehne MF, Bondolfi G, O\u0026rsquo;Connor M. Novel interventions targeting transdiagnostic processes. Curr Opin Psychol. 2020;36:100\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eButton KS, Ioannidis JP, Mokrysz C, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci. 2013;14(5):365\u0026ndash;76.\u003c/li\u003e\n\u003cli\u003eInsel T, Cuthbert B. Brain disorders? Precisely. Science. 2015;348(6234):499\u0026ndash;500.\u003c/li\u003e\n\u003cli\u003eDrysdale AT, Grosenick L, Downar J, et al. Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med. 2017;23:28\u0026ndash;38.\u003c/li\u003e\n\u003cli\u003eCasey BJ, Oliveri ME, Insel T. A neurodevelopmental perspective on the research domain criteria (RDoC) framework. Biol Psychiatry. 2014;76(5):350\u0026ndash;3.\u003c/li\u003e\n\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":true,"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-7592427/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7592427/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAnguish, anxiety, and depression are among the most disabling mental health challenges of our time. They often appear together, creating a complex web of symptoms that affect both body and mind. Although much is known about their biological and psychological bases, their interconnections remain only partially understood.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eThis review aims to bring together the most recent evidence on the neurological and psychological dimensions of anguish, anxiety, and depression, highlighting what they share and where they diverge.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe systematically searched PubMed, PsycINFO, Scopus, Web of Science, and SpringerLink for studies published between 2013 and 2023. We included peer-reviewed articles that examined neurological or psychological correlates of these conditions in adults. The review followed PRISMA 2020 guidelines.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eOut of 3,245 studies initially identified, 87 met all inclusion criteria. Neurological findings point to disruptions in cortico-limbic circuits, dysregulation of the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal (HPA) axis, and imbalances in neurotransmitter systems. Psychologically, the most consistent findings involved maladaptive thought patterns, impaired emotion regulation, and heightened negative affect. Anguish, although less frequently studied, revealed overlapping features with anxiety and depression.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThese three conditions share more than symptoms\u0026mdash;they share underlying brain circuits and psychological processes. A transdiagnostic approach that integrates biological and psychological perspectives could help us better understand, diagnose, and treat mental suffering in its many forms.\u003c/p\u003e","manuscriptTitle":"Neurological and Psychological Dimensions of Anguish, Anxiety, and Depression: A Transdiagnostic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-12 09:08:50","doi":"10.21203/rs.3.rs-7592427/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":"September 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-17T17:48:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-12 09:08:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7592427","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7592427","identity":"rs-7592427","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}