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Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry Volume III

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (31 March 2025) | Viewed by 24401

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Dr. Masaru Tanaka

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Danube Neuroscience Research Laboratory, HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged (HUN-REN-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary
Interests: depression; anxiety; dementia pain; and their comorbidities nature; and translational research in neurological diseases and psychiatric disorders
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Dr. Simone Battaglia

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1. Department of Psychology, University of Turin, Turin, Italy
2. Center for Studies and Research in Cognitive Neuroscience, Department of Psychology, University of Bologna, Bologna, Italy
Interests: NIBS techniques; TMS; skin conductance; heart rate variability; fear conditioning; fear learning; learning; neuropsychology; prefrontal cortex; amygdala; hippocampus; anxiety; depression; working memory; PTSD; skin conductance responses; psychophysiology; error-related negativity; EEG; tDCS; Alzheimer’s disease; PIT; stress-related disorders; Parkinson’s disease; resilience; memory; neurologic patients; cognitive decisions; fMRI; translational and molecular psychiatry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This is the third volume of the Special Issue "Crosstalk between Depression, Anxiety, and Dementia: Comorbidity in Behavioral Neurology and Neuropsychiatry".

In the realm of neurodegenerative and psychiatric diseases, symptoms such as depression, anxiety, dementia, and chronic pain span a spectrum and commonly coexist among patients. These illnesses pose significant research challenges due to their polygenic etiologies, multifactorial causative factors, heterogeneous pathogenesis, and diverse mental and behavioral manifestations. The range of diseases exhibiting these symptoms includes Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease and amyotrophic lateral sclerosis, infectious prion disease, stroke sequelae, and psychiatric disorders such as depressive disorder, substance abuse disorder, bipolar disorder, anxiety disorder, schizophrenia, somatic symptom disorder, autism spectrum disorder, post-traumatic stress disorder, and hyperactive attention deficit disorder.

This Special Issue aims to shed light on the latest research pertaining to the comorbidity of depression, anxiety, dementia, and chronic pain in various diseases. We cordially invite authors to contribute original research articles focusing on, but not limited to the following:

Etiology, pathogenesis, and progression mechanisms;
Early diagnosis including the use of biomarkers, bio-imaging, and biosensors;
Prophylactic, disease-modifying, and therapeutic strategies, as well as novel targets;
Novel drug discovery and development, naturally driven biomedicines, natural bioactive molecules, and vaccines;
Antidepressants, anti-anxiolytics, cognitive enhancers, and analgesics;
Nanobiotechnology, nanosimilars, and nanobiosimilars;
Preclinical in vitro models and animal models;
Bench-to-bedside translational research;
Bedside-to-bench translational research.

Review articles including expert opinions, systematic analysis, metanalysis, and other statistical and analytical methods are also welcome.

Dr. Masaru Tanaka
Dr. Simone Battaglia
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Related Special Issue

Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry 2.0 in Biomedicines (16 articles)

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Research

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12 pages, 581 KiB

Open AccessArticle

Physical Inactivity Amplifies the Link Between Anxiety, Depression, and Neck Pain in Breast Cancer Survivors

by Guilherme H. D. Grande, Paloma Ferrero-Hernández, Leonardo R. de Oliveira, Vitória M. Danno B. Ramos, Mariana R. Palma, Rubens Vidal, Anna A. P. M. Oishi, Gerson Ferrari and Diego G. D. Christofaro

Biomedicines 2025, 13(5), 1089; https://doi.org/10.3390/biomedicines13051089 - 30 Apr 2025

Viewed by 600

Abstract

Background and Objectives: Breast cancer can cause significant changes in both physical and mental health, leading to conditions such as low back pain, neck pain (musculoskeletal pain), anxiety, and depression. Women with this diagnosis tend to subsequently decrease their levels of physical activity, which can contribute to the emergence of musculoskeletal dysfunction. With this in mind, the aim of the present study was to analyze the relationship between physical activity levels (active vs. inactive), neck and low back pain in women breast cancer survivors in association with anxiety and depression. Methods: This cross-sectional study was conducted with 128 women breast cancer survivors. The prevalence of neck pain stratified by anxiety and depression status was higher in women physically inactive than in active women; however, there was no statistically significant difference. Results: Symptoms of anxiety and depression were associated with neck pain only in physically inactive women. No associations were observed between anxiety and depression and low back pain regardless of physical activity levels. Conclusions: This study demonstrates significant results for the association between physical activity level, anxiety and depression, and neck pain in women breast cancer survivors. However, the same association was not found for low back pain. Full article

(This article belongs to the Special Issue Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry Volume III)

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15 pages, 559 KiB

Open AccessArticle

Periodontal Indices as Predictors of Cognitive Decline: Insights from the PerioMind Colombia Cohort

by Catalina Arévalo-Caro, Diego López, Jose Antonio Sánchez Milán, Cristina Lorca, María Mulet, Humberto Arboleda, Sergio Losada Amaya, Aida Serra and Xavier Gallart-Palau

Biomedicines 2025, 13(1), 205; https://doi.org/10.3390/biomedicines13010205 - 15 Jan 2025

Cited by 3 | Viewed by 2733

Abstract

Background: Poor oral health and periodontitis have been epidemiologically linked to cognitive decline and mild cognitive impairment (MCI) in older adults. However, specific metrics directly linking these clinical signs are exceedingly limited. Methods: To address this gap and develop novel tools to help clinicians identify individuals at risk of cognitive decline, we established the PerioMind Colombia Cohort, comprising elderly Colombian subjects who underwent comprehensive neurocognitive and periodontal evaluations. Results: The results revealed that subjects diagnosed with MCI exhibited significantly higher scores in specific periodontal indices, including gingival erythema and pocket depth parameters. The predictive model identified positive associations with MCI, with gingival erythema showing the strongest correlation, followed by the presence of periodontitis and variations in pocket depth measurements. Additionally, lower educational attainment was associated with a higher likelihood of being classified in the periodontitis-MCI group. Conclusions: Here, we show that specific altered periodontal metrics are associated with MCI diagnosis, and the generated results provide defined metric ranges for identifying individuals at risk. Upon validation in larger cohorts, the findings reported here could offer dental practitioners and clinicians innovative tools to identify individuals at risk of MCI and age-related dementias through routine oral health assessments, thereby enabling more accessible and highly sought-after early intervention strategies in both developing and developed countries. Full article

(This article belongs to the Special Issue Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry Volume III)

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14 pages, 1210 KiB

Open AccessArticle

From Mild Cognitive Impairment to Dementia: The Impact of Comorbid Conditions on Disease Conversion

by Federico Menegon, Fabiola De Marchi, Davide Aprile, Iacopo Zanelli, Greta Decaroli, Cristoforo Comi and Giacomo Tondo

Biomedicines 2024, 12(8), 1675; https://doi.org/10.3390/biomedicines12081675 - 26 Jul 2024

Cited by 4 | Viewed by 2252

Abstract

The conversion from mild cognitive impairment (MCI) to dementia is influenced by several factors, including comorbid conditions such as metabolic and vascular diseases. Understanding the impact of these comorbidities can help in the disease management of patients with a higher risk of progressing to dementia, improving outcomes. In the current study, we aimed to analyze data from a large cohort of MCI (n = 188) by principal component analysis (PCA) and cluster analysis (CA) to classify patients into distinct groups based on their comorbidity profile and to predict the risk of conversion to dementia. From our analysis, four clusters emerged. CA showed a significantly higher rate of disease progression for Cluster 1, which was predominantly characterized by extremely high obesity and diabetes compared to other clusters. In contrast, Cluster 3, which was defined by a lower prevalence of all comorbidities, had a lower conversion rate. Cluster 2, mainly including subjects with traumatic brain injuries, showed the lowest rate of conversion. Lastly, Cluster 4, including a high load of hearing loss and depression, showed an intermediate risk of conversion. This study underscores the significant impact of specific comorbidity profiles on the progression from MCI to dementia, highlighting the need for targeted interventions and management strategies for individuals with these comorbidity profiles to potentially delay or prevent the onset of dementia. Full article

(This article belongs to the Special Issue Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry Volume III)

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15 pages, 3323 KiB

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Blood Plasma Markers in Depressed Mice under Chronic Social Defeat Stress

by Dmitry A. Smagin, Dmitry V. Bezryadnov, Maria G. Zavialova, Anastasia Yu. Abramova, Sergey S. Pertsov and Natalia N. Kudryavtseva

Biomedicines 2024, 12(7), 1485; https://doi.org/10.3390/biomedicines12071485 - 5 Jul 2024

Cited by 2 | Viewed by 1995

Abstract

It has previously been shown that, in mice, chronic social defeat stress in daily agonistic interactions leads to a depression-like state similar to that in depressive patients. With this model, it has become obvious that it is possible to study peripheral markers of the depression-like state in an experiment. This paper was aimed at searching for protein markers in the blood plasma of depressed mice in the chronic social conflict model, which allows for us to obtain male mice with repeated experiences of defeat. Proteomic analysis of blood plasma samples was conducted to identify proteins differentially expressed in this state. There were changes in the expression levels of the amyloid proteins SAA1, SAA4, and SAMP and apolipoproteins APOC3, APOD, and ADIPO in the blood plasma of depressed mice compared with controls (unstressed mice). Changes in the expression of serine protease inhibitors and/or proteins associated with lipid metabolism, inflammation, or immune function [ITIH4, SPA3, A1AT5, HTP (HP), CO9, and A2MG] were also found. Here, we showed that chronic social stress is accompanied by increased levels of amyloid proteins and apolipoproteins in blood plasma. A similarity was noted between the marker protein expression changes in the depressed mice and those in patients with Alzheimer’s disease. These data indicate a psychopathogenic role of chronic social stress, which can form a predisposition to neurodegenerative and/or psychoemotional disorders. Full article

(This article belongs to the Special Issue Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry Volume III)

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16 pages, 1040 KiB

Open AccessArticle

Predictive Models for the Transition from Mild Neurocognitive Disorder to Major Neurocognitive Disorder: Insights from Clinical, Demographic, and Neuropsychological Data

by Anna Tsiakiri, Christos Bakirtzis, Spyridon Plakias, Pinelopi Vlotinou, Konstantinos Vadikolias, Aikaterini Terzoudi and Foteini Christidi

Biomedicines 2024, 12(6), 1232; https://doi.org/10.3390/biomedicines12061232 - 1 Jun 2024

Cited by 4 | Viewed by 2832

Abstract

Neurocognitive disorders (NCDs) are progressive conditions that severely impact cognitive function and daily living. Understanding the transition from mild to major NCD is crucial for personalized early intervention and effective management. Predictive models incorporating demographic variables, clinical data, and scores on neuropsychological and emotional tests can significantly enhance early detection and intervention strategies in primary healthcare settings. We aimed to develop and validate predictive models for the progression from mild NCD to major NCD using demographic, clinical, and neuropsychological data from 132 participants over a two-year period. Generalized Estimating Equations were employed for data analysis. Our final model achieved an accuracy of 83.7%. A higher body mass index and alcohol drinking increased the risk of progression from mild NCD to major NCD, while female sex, higher praxis abilities, and a higher score on the Geriatric Depression Scale reduced the risk. Here, we show that integrating multiple factors—ones that can be easily examined in clinical settings—into predictive models can improve early diagnosis of major NCD. This approach could facilitate timely interventions, potentially mitigating the progression of cognitive decline and improving patient outcomes in primary healthcare settings. Further research should focus on validating these models across diverse populations and exploring their implementation in various clinical contexts. Full article

(This article belongs to the Special Issue Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry Volume III)

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13 pages, 285 KiB

Open AccessArticle

Beyond Pain Relief: Unveiling the Multifaceted Impact of Anti-CGRP/R mAbs on Comorbid Symptoms in Resistant Migraine Patients

by Alessandra Della Vecchia, Ciro De Luca, Lucrezia Becattini, Letizia Curto, Elena Ferrari, Gabriele Siciliano, Sara Gori and Filippo Baldacci

Biomedicines 2024, 12(3), 677; https://doi.org/10.3390/biomedicines12030677 - 18 Mar 2024

Cited by 4 | Viewed by 2765

Abstract

The study aimed to evaluate the effects of monoclonal antibodies (mAbs) acting on the calcitonin gene-related peptide (CGRP) or its receptor (anti-CGRP/R mAbs) on migraine comorbidities of depression, anxiety, and fatigue in patients resistant to traditional therapies. The issue addressed in this study is pivotal to unveiling the role of this neurotransmitter beyond pain processing. We conducted an open-label prospective study assessing comorbidities in patients with high frequency (HFEM) and chronic migraine (CM), medication overuse headache (MOH), and resistance to traditional prophylaxis. All patients were treated with anti-CGRP/R mAbs for 3 months. Seventy-seven patients were enrolled with either HFEM (21%) or CM (79%) with or without MOH (56% and 44%, respectively). We identified 21 non-responders (27%) and 56 responders (73%), defined on the reduction ≥50% of headache frequency. The two groups were highly homogeneous for the investigated comorbidities. Disease severity in terms of headache frequency, migraine-related disability, and affective comorbid symptoms was reduced in both groups with different thresholds; allodynia and fatigue were ameliorated only in responders. We found that anti-CGRP/R antibodies improved pain together with affection, fatigue, and sensory sensitization in a cohort of migraine patients resistant to traditional prophylaxis. Our results offer novel perspectives on the early efficacy of anti-CGRP/R mAbs in difficult-to-treat patients focusing on clinical features other than pain relief. Full article

(This article belongs to the Special Issue Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry Volume III)

24 pages, 16786 KiB

Open AccessArticle

Preclinical Evidence for the Role of the Yin/Yang Angiotensin System Components in Autism Spectrum Disorder: A Therapeutic Target of Astaxanthin

by Ayat I. Samra, Ahmed S. Kamel, Dalaal M. Abdallah, Mai A. Abd El Fattah, Kawkab A. Ahmed and Hanan S. El-Abhar

Biomedicines 2023, 11(12), 3156; https://doi.org/10.3390/biomedicines11123156 - 27 Nov 2023

Cited by 2 | Viewed by 2218

Abstract

Autism spectrum disorder (ASD) prevalence is emerging with an unclear etiology, hindering effective therapeutic interventions. Recent studies suggest potential renin–angiotensin system (RAS) alterations in different neurological pathologies. However, its implications in ASD are unexplored. This research fulfills the critical gap by investigating dual arms of RAS and their interplay with Notch signaling in ASD, using a valproic acid (VPA) model and assessing astaxanthin’s (AST) modulatory impacts. Experimentally, male pups from pregnant rats receiving either saline or VPA on gestation day 12.5 were divided into control and VPA groups, with subsequent AST treatment in a subset (postnatal days 34–58). Behavioral analyses, histopathological investigations, and electron microscopy provided insights into the neurobehavioral and structural changes induced by AST. Molecular investigations of male pups’ cortices revealed that AST outweighs the protective RAS elements with the inhibition of the detrimental arm. This established the neuroprotective and anti-inflammatory axes of RAS (ACE2/Ang1-7/MasR) in the ASD context. The results showed that AST’s normalization of RAS components and Notch signaling underscore a novel therapeutic avenue in ASD, impacting neuronal integrity and behavioral outcomes. These findings affirm the integral role of RAS in ASD and highlight AST’s potential as a promising treatment intervention, inviting further neurological research implications. Full article

(This article belongs to the Special Issue Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry Volume III)

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Review

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35 pages, 1448 KiB

Open AccessReview

Neuroinflammation and Natural Antidepressants: Balancing Fire with Flora

by Ana Clara Figueiredo Godoy, Fernanda Fortes Frota, Larissa Parreira Araújo, Vitor E. Valenti, Eliana de Souza Bastos Mazuqueli Pereira, Claudia Rucco P. Detregiachi, Cristiano M. Galhardi, Flávia Cristina Caracio, Rafael S. A. Haber, Lucas Fornari Laurindo, Masaru Tanaka and Sandra M. Barbalho

Biomedicines 2025, 13(5), 1129; https://doi.org/10.3390/biomedicines13051129 - 7 May 2025

Viewed by 1506

Abstract

Background/Objectives: Major depressive disorder (MDD) is a major global health concern that is intimately linked to neuroinflammation, oxidative stress, mitochondrial dysfunction, and complicated metabolic abnormalities. Traditional antidepressants frequently fall short, highlighting the urgent need for new, safer, and more acceptable therapeutic techniques. Phytochemicals, i.e., natural antidepressants derived from plants, are emerging as powerful plant-based therapies capable of targeting many pathogenic pathways at the same time. Summary: This narrative review synthesizes evidence from preclinical and clinical studies on the efficacy of phytochemicals such as curcumin, polyphenols, flavonoids, and alkaloids in lowering depressed symptoms. Consistent data show that these substances have neuroprotective, anti-inflammatory, and antioxidant properties, altering neuroimmune interactions, reducing oxidative damage, and improving mitochondrial resilience. Particularly, polyphenols and flavonoids have great therapeutic potential because of their capacity to penetrate the blood–brain barrier, inhibit cytokine activity, and encourage neuroplasticity mediated by brain-derived neurotrophic factor (BDNF). Despite promising results, the heterogeneity in study designs, phytochemical formulations, and patient demographics highlights the importance of thorough, standardized clinical studies. Conclusions: This review identifies phytochemicals as compelling adjuvant or independent therapies in depression treatment, providing multimodal mechanisms and enhanced tolerability. Additional research into improved dosage, pharmacokinetics, long-term safety, and integrative therapy approaches is essential. Using phytotherapeutics could considerably improve holistic and customized depression care, encouraging new research routes in integrative neuroscience and clinical psychiatry. Full article

(This article belongs to the Special Issue Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry Volume III)

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22 pages, 1338 KiB

Open AccessEditor’s ChoiceReview

Advancements in Understanding and Classifying Chronic Orofacial Pain: Key Insights from Biopsychosocial Models and International Classifications (ICHD-3, ICD-11, ICOP)

by Federica Canfora, Giulia Ottaviani, Elena Calabria, Giuseppe Pecoraro, Stefania Leuci, Noemi Coppola, Mattia Sansone, Katia Rupel, Matteo Biasotto, Roberto Di Lenarda, Michele Davide Mignogna and Daniela Adamo

Biomedicines 2023, 11(12), 3266; https://doi.org/10.3390/biomedicines11123266 - 9 Dec 2023

Cited by 6 | Viewed by 4636

Abstract

In exploring chronic orofacial pain (COFP), this review highlights its global impact on life quality and critiques current diagnostic systems, including the ICD-11, ICOP, and ICHD-3, for their limitations in addressing COFP’s complexity. Firstly, this study outlines the global burden of chronic pain and the importance of distinguishing between different pain types for effective treatment. It then delves into the specific challenges of diagnosing COFP, emphasizing the need for a more nuanced approach that incorporates the biopsychosocial model. This review critically examines existing classification systems, highlighting their limitations in fully capturing COFP’s multifaceted nature. It advocates for the integration of these systems with the DSM-5’s Somatic Symptom Disorder code, proposing a unified, multidisciplinary diagnostic approach. This recommendation aims to improve chronic pain coding standardization and acknowledge the complex interplay of biological, psychological, and social factors in COFP. In conclusion, here, we highlight the need for a comprehensive, universally applicable classification system for COFP. Such a system would enable accurate diagnosis, streamline treatment strategies, and enhance communication among healthcare professionals. This advancement holds potential for significant contributions to research and patient care in this challenging field, offering a broader perspective for scientists across disciplines. Full article

(This article belongs to the Special Issue Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry Volume III)

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