Biomedicines

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14 pages, 341 KiB

Open AccessEditorial

A Decade of Dedication: Pioneering Perspectives on Neurological Diseases and Mental Illnesses

by Masaru Tanaka and László Vécsei

Biomedicines 2024, 12(5), 1083; https://doi.org/10.3390/biomedicines12051083 - 13 May 2024

Cited by 4 | Viewed by 1792

Abstract

Welcome to Biomedicines’ 10th Anniversary Special Issue, a journey through the human mind’s labyrinth and complex neurological pathways [...] Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

Research

Jump to: Editorial, Review, Other

14 pages, 895 KiB

Open AccessArticle

Effects of Virtual Reality Cognitive Training on Neuroplasticity: A Quasi-Randomized Clinical Trial in Patients with Stroke

by Antonio Gangemi, Rosaria De Luca, Rosa Angela Fabio, Paola Lauria, Carmela Rifici, Patrizia Pollicino, Angela Marra, Antonella Olivo, Angelo Quartarone and Rocco Salvatore Calabrò

Biomedicines 2023, 11(12), 3225; https://doi.org/10.3390/biomedicines11123225 - 6 Dec 2023

Cited by 7 | Viewed by 3401

Abstract

Cognitive Rehabilitation (CR) is a therapeutic approach designed to improve cognitive functioning after a brain injury, including stroke. Two major categories of techniques, namely traditional and advanced (including virtual reality—VR), are widely used in CR for patients with various neurological disorders. More objective [...] Read more.

Cognitive Rehabilitation (CR) is a therapeutic approach designed to improve cognitive functioning after a brain injury, including stroke. Two major categories of techniques, namely traditional and advanced (including virtual reality—VR), are widely used in CR for patients with various neurological disorders. More objective outcome measures are needed to better investigate cognitive recovery after a stroke. In the last ten years, the application of electroencephalography (EEG) as a non-invasive and portable neuroimaging method has been explored to extract the hallmarks of neuroplasticity induced by VR rehabilitation approaches, particularly within the chronic stroke population. The aim of this study is to investigate the neurophysiological effects of CR conducted in a virtual environment using the VRRS device. Thirty patients with moderate-to-severe ischemic stroke in the chronic phase (at least 6 months after the event), with a mean age of 58.13 (±8.33) for the experimental group and 57.33 (±11.06) for the control group, were enrolled. They were divided into two groups: an experimental group and a control group, receiving neurocognitive stimulation using VR and the same amount of conventional neurorehabilitation, respectively. To study neuroplasticity changes after the training, we focused on the power band spectra of theta, alpha, and beta EEG rhythms in both groups. We observed that when VR technology was employed to amplify the effects of treatments on cognitive recovery, significant EEG-related neural improvements were detected in the primary motor circuit in terms of power spectral density and time-frequency domains. Indeed, EEG analysis suggested that VR resulted in a significant increase in both the alpha band power in the occipital areas and the beta band power in the frontal areas, while no significant variations were observed in the theta band power. Our data suggest the potential effectiveness of a VR-based rehabilitation approach in promoting neuroplastic changes even in the chronic phase of ischemic stroke. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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14 pages, 1342 KiB

Open AccessArticle

Gut Dysbiosis: A New Avenue for Stroke Prevention and Therapeutics

by Shin Young Park, Sang Pyung Lee, Dongin Kim and Woo Jin Kim

Biomedicines 2023, 11(9), 2352; https://doi.org/10.3390/biomedicines11092352 - 23 Aug 2023

Cited by 7 | Viewed by 2893

Abstract

A stroke is a serious life-threatening condition and a leading cause of death and disability that happens when the blood vessels to part of the brain are blocked or burst. While major advances in the understanding of the ischemic cascade in stroke was [...] Read more.

A stroke is a serious life-threatening condition and a leading cause of death and disability that happens when the blood vessels to part of the brain are blocked or burst. While major advances in the understanding of the ischemic cascade in stroke was made over several decades, limited therapeutic options and high mortality and disability have caused researchers to extend the focus toward peripheral changes beyond brain. The largest proportion of microbes in human body reside in the gut and the interaction between host and microbiota in health and disease is well known. Our study aimed to explore the gut microbiota in patients with stroke with comparison to control group. Fecal samples were obtained from 51 subjects: 25 stroke patients (18 hemorrhagic, 7 ischemic) and 26 healthy control subjects. The variable region V3–V4 of the 16S rRNA gene was sequenced using the Illumina MiSeq platform. PICRUSt2 was used for prediction of metagenomics functions. Our results show taxonomic dysbiosis in stroke patients in parallel with functional dysbiosis. Here, we show that stroke patients have (1) increased Parabacteroides and Escherichia_Shigella, but decreased Prevotella and Fecalibacterium; (2) higher transposase and peptide/nickel transport system substrate-binding protein, but lower RNA polymerase sigma-70 factor and methyl-accepting chemotaxis protein, which are suggestive of malnutrition. Nutrients are essential regulators of both host and microbial physiology and function as key coordinators of host–microbe interactions. Manipulation of nutrition is expected to alleviate gut dysbiosis and prognosis and improve disability and mortality in the management of stroke. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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19 pages, 2566 KiB

Open AccessArticle

The Secretome of Human Dental Pulp Stem Cells and Its Components GDF15 and HB-EGF Protect Amyotrophic Lateral Sclerosis Motoneurons against Death

by Richard Younes, Youssef Issa, Nadia Jdaa, Batoul Chouaib, Véronique Brugioti, Désiré Challuau, Cédric Raoul, Frédérique Scamps, Frédéric Cuisinier and Cécile Hilaire

Biomedicines 2023, 11(8), 2152; https://doi.org/10.3390/biomedicines11082152 - 30 Jul 2023

Cited by 5 | Viewed by 1728

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable paralytic disorder caused by the progressive death of upper and lower motoneurons. Although numerous strategies have been developed to slow disease progression and improve life quality, to date only a few therapeutic treatments are [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable paralytic disorder caused by the progressive death of upper and lower motoneurons. Although numerous strategies have been developed to slow disease progression and improve life quality, to date only a few therapeutic treatments are available with still unsatisfactory therapeutic benefits. The secretome of dental pulp stem cells (DPSCs) contains numerous neurotrophic factors that could promote motoneuron survival. Accordingly, DPSCs confer neuroprotective benefits to the SOD1^G93A mouse model of ALS. However, the mode of action of DPSC secretome on motoneurons remains largely unknown. Here, we used conditioned medium of human DPSCs (DPSCs-CM) and assessed its effect on survival, axonal length, and electrical activity of cultured wildtype and SOD1^G93A motoneurons. To further understand the role of individual factors secreted by DPSCs and to circumvent the secretome variability bias, we focused on GDF15 and HB-EGF whose neuroprotective properties remain elusive in the ALS pathogenic context. DPSCs-CM rescues motoneurons from trophic factor deprivation-induced death, promotes axon outgrowth of wildtype but not SOD1^G93A mutant motoneurons, and has no impact on the spontaneous electrical activity of wildtype or mutant motoneurons. Both GDF15 and HB-EGF protect SOD1^G93A motoneurons against nitric oxide-induced death, but not against death induced by trophic factor deprivation. GDF15 and HB-EGF receptors were found to be expressed in the spinal cord, with a two-fold increase in expression for the GDF15 low-affinity receptor in SOD1^G93A mice. Therefore, the secretome of DPSCs appears as a new potential therapeutic candidate for ALS. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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12 pages, 1199 KiB

Open AccessArticle

Breaking Barriers: Artificial Intelligence Interpreting the Interplay between Mental Illness and Pain as Defined by the International Association for the Study of Pain

by Franciele Parolini, Márcio Goethel, Klaus Becker, Cristofthe Fernandes, Ricardo J. Fernandes, Ulysses F. Ervilha, Rubim Santos and João Paulo Vilas-Boas

Biomedicines 2023, 11(7), 2042; https://doi.org/10.3390/biomedicines11072042 - 20 Jul 2023

Cited by 10 | Viewed by 2617

Abstract

Low back pain is one of the main causes of motor disabilities and psychological stress, with the painful process encompassing sensory and affective components. Noxious stimuli originate on the periphery; however, the stimuli are recombined in the brain and therefore processed differently due [...] Read more.

Low back pain is one of the main causes of motor disabilities and psychological stress, with the painful process encompassing sensory and affective components. Noxious stimuli originate on the periphery; however, the stimuli are recombined in the brain and therefore processed differently due to the emotional environment. To better understand this process, our objective was to develop a mathematical representation of the International Association for the Study of Pain (IASP) model of pain, covering the multidimensional representation of this phenomenon. Data from the Oswestry disability index; the short form of the depression, anxiety, and stress scale; and pain catastrophizing daily questionnaires were collected through online completion, available from 8 June 2022, to 8 April 2023 (1021 cases). Using the information collected, an artificial neural network structure was trained (based on anomaly detection methods) to identify the patterns that emerge from the relationship between the variables. The developed model proved to be robust and able to show the patterns and the relationship between the variables, and it allowed for differentiating the groups with altered patterns in the context of low back pain. The distinct groups all behave according to the main finding that psychological and pain events are directly associated. We conclude that our proposal is effective as it is able to test and confirm the definition of the IASP for the study of pain. Here we show that the fiscal and mental dimensions of pain are directly associated, meaning that mental illness can be an enhancer of pain episodes and functionality. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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12 pages, 1572 KiB

Open AccessArticle

Age, Dose, and Locomotion: Decoding Vulnerability to Ketamine in C57BL/6J and BALB/c Mice

by Wen-Chien Chen, Tzong-Shi Wang, Fang-Yu Chang, Po-An Chen and Yi-Chyan Chen

Biomedicines 2023, 11(7), 1821; https://doi.org/10.3390/biomedicines11071821 - 25 Jun 2023

Cited by 5 | Viewed by 2121

Abstract

Ketamine has been abused as a psychedelic agent and causes diverse neurobehavioral changes. Adolescence is a critical developmental stage but vulnerable to substances and environmental stimuli. Growing evidence shows that ketamine affects glutamatergic neurotransmission, which is important for memory storage, addiction, and psychosis. [...] Read more.

Ketamine has been abused as a psychedelic agent and causes diverse neurobehavioral changes. Adolescence is a critical developmental stage but vulnerable to substances and environmental stimuli. Growing evidence shows that ketamine affects glutamatergic neurotransmission, which is important for memory storage, addiction, and psychosis. To explore diverse biological responses, this study was designed to assess ketamine sensitivity in mice of different ages and strains. Male C57BL/6J and BALB/c mice were studied in adolescence and adulthood separately. An open field test assessed motor behavioral changes. After a 30-min baseline habituation, mice were injected with ketamine (0, 25, and 50 mg/kg), and their locomotion was measured for 60 min. Following ketamine injection, the travelled distance and speed significantly increased in C57BL/6J mice between both age groups (p < 0.01), but not in BALB/c mice. The pattern of hyperlocomotion showed that mice were delayed at the higher dose (50 mg/kg) compared to the lower dose (25 mg/kg) of ketamine treatment. Ketamine accentuated locomotor activation in adolescent C57BL/6J mice compared to adults, but not in the BALB/c strain. Here, we show that ketamine-induced locomotor behavior is modulated by dose and age. The discrepancy of neurobehaviors in the two strains of mice indicates that sensitivity to ketamine is biologically determined. This study suggests that individual vulnerability to ketamine’s pharmacological responses varies biologically. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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19 pages, 1207 KiB

Open AccessArticle

Age-Related Effects of Exogenous Melatonin on Anxiety-like Behavior in C57/B6J Mice

by Sofia Nasini, Sara Tidei, Atea Shkodra, Danilo De Gregorio, Marco Cambiaghi and Stefano Comai

Biomedicines 2023, 11(6), 1705; https://doi.org/10.3390/biomedicines11061705 - 13 Jun 2023

Cited by 4 | Viewed by 2111

Abstract

The synthesis of melatonin (MLT) physiologically decreases during aging. Treatment with MLT has shown anxiolytic, hypnotic, and analgesic effects, but little is known about possible age-dependent differences in its efficacy. Therefore, we studied the effects of MLT (20 mg/kg, intraperitoneal) on anxiety-like behavior [...] Read more.

The synthesis of melatonin (MLT) physiologically decreases during aging. Treatment with MLT has shown anxiolytic, hypnotic, and analgesic effects, but little is known about possible age-dependent differences in its efficacy. Therefore, we studied the effects of MLT (20 mg/kg, intraperitoneal) on anxiety-like behavior (open field (OFT), elevated plus maze (EPMT), three-chamber sociability, and marble-burying (MBT) tests), and the medial prefrontal cortex (mPFC)-dorsal hippocampus (dHippo) circuit in adolescent (35–40 days old) and adult (three-five months old) C57BL/6 male mice. MLT did not show any effect in adolescents in the OFT and EPMT. In adults, compared to vehicles, it decreased locomotor activity and time spent in the center of the arena in the OFT and time spent in the open arms in the EPMT. In the MBT, no MLT effects were observed in both age groups. In the three-chamber sociability test, MLT decreased sociability and social novelty in adults, while it increased sociability in adolescents. Using local field potential recordings, we found higher mPFC-dHippo synchronization in the delta and low-theta frequency ranges in adults but not in adolescents after MLT treatment. Here, we show age-dependent differences in the effects of MLT in anxiety paradigms and in the modulation of the mPFC-dHippo circuit, indicating that when investigating the pharmacology of the MLT system, age can significantly impact the study outcomes. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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16 pages, 2720 KiB

Open AccessArticle

UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib

by Bin Chen, Md. Mahmudul Hasan, Hengsen Zhang, Qing Zhai, A. S. M. Waliullah, Yashuang Ping, Chi Zhang, Soho Oyama, Mst. Afsana Mimi, Yuna Tomochika, Yu Nagashima, Tomohiko Nakamura, Tomoaki Kahyo, Kenji Ogawa, Daita Kaneda, Minoru Yoshida and Mitsutoshi Setou

Biomedicines 2023, 11(6), 1685; https://doi.org/10.3390/biomedicines11061685 - 10 Jun 2023

Cited by 6 | Viewed by 3381

Abstract

Ubiquitin-like 3 (UBL3) acts as a post-translational modification (PTM) factor and regulates protein sorting into small extracellular vesicles (sEVs). sEVs have been reported as vectors for the pathology propagation of neurodegenerative diseases, such as α-synucleinopathies. Alpha-synuclein (α-syn) has been widely studied for its [...] Read more.

Ubiquitin-like 3 (UBL3) acts as a post-translational modification (PTM) factor and regulates protein sorting into small extracellular vesicles (sEVs). sEVs have been reported as vectors for the pathology propagation of neurodegenerative diseases, such as α-synucleinopathies. Alpha-synuclein (α-syn) has been widely studied for its involvement in α-synucleinopathies. However, it is still unknown whether UBL3 interacts with α-syn, and is influenced by drugs or compounds. In this study, we investigated the interaction between UBL3 and α-syn, and any ensuing possible functional and pathological implications. We found that UBL3 can interact with α-syn by the Gaussia princeps based split luciferase complementation assay in cells and immunoprecipitation, while cysteine residues at its C-terminal, which are considered important as PTM factors for UBL3, were not essential for the interaction. The interaction was upregulated by 1-methyl-4-phenylpyridinium exposure. In drug screen results, the interaction was significantly downregulated by the treatment of osimertinib. These results suggest that UBL3 interacts with α-syn in cells and is significantly downregulated by epidermal growth factor receptor (EGFR) pathway inhibitor osimertinib. Therefore, the UBL3 pathway may be a new therapeutic target for α-synucleinopathies in the future. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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21 pages, 2331 KiB

Open AccessArticle

Unlocking the Secrets: Exploring the Biochemical Correlates of Suicidal Thoughts and Behaviors in Adults with Autism Spectrum Conditions

by Ivan Mirko Cremone, Benedetta Nardi, Giulia Amatori, Lionella Palego, Dario Baroni, Danila Casagrande, Enrico Massimetti, Laura Betti, Gino Giannaccini, Liliana Dell'Osso and Barbara Carpita

Biomedicines 2023, 11(6), 1600; https://doi.org/10.3390/biomedicines11061600 - 31 May 2023

Cited by 8 | Viewed by 2596

Abstract

Involving 1 million people a year, suicide represents one of the major topics of psychiatric research. Despite the focus in recent years on neurobiological underpinnings, understanding and predicting suicide remains a challenge. Many sociodemographical risk factors and prognostic markers have been proposed but [...] Read more.

Involving 1 million people a year, suicide represents one of the major topics of psychiatric research. Despite the focus in recent years on neurobiological underpinnings, understanding and predicting suicide remains a challenge. Many sociodemographical risk factors and prognostic markers have been proposed but they have poor predictive accuracy. Biomarkers can provide essential information acting as predictive indicators, providing proof of treatment response and proposing potential targets while offering more assurance than psychological measures. In this framework, the aim of this study is to open the way in this field and evaluate the correlation between blood levels of serotonin, brain derived neurotrophic factor, tryptophan and its metabolites, IL-6 and homocysteine levels and suicidality. Blood samples were taken from 24 adults with autism, their first-degree relatives, and 24 controls. Biochemical parameters were measured with enzyme-linked immunosorbent assays. Suicidality was measured through selected items of the MOODS-SR. Here we confirm the link between suicidality and autism and provide more evidence regarding the association of suicidality with increased homocysteine (0.278) and IL-6 (0.487) levels and decreased tryptophan (−0.132) and kynurenic acid (−0.253) ones. Our results suggest a possible transnosographic association between these biochemical parameters and increased suicide risk. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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17 pages, 986 KiB

Open AccessArticle

Age-Dependent Alterations in Platelet Mitochondrial Respiration

by Zdeněk Fišar, Jana Hroudová, Martina Zvěřová, Roman Jirák, Jiří Raboch and Eva Kitzlerová

Biomedicines 2023, 11(6), 1564; https://doi.org/10.3390/biomedicines11061564 - 28 May 2023

Cited by 7 | Viewed by 2609

Abstract

Mitochondrial dysfunction is an important cellular hallmark of aging and neurodegeneration. Platelets are a useful model to study the systemic manifestations of mitochondrial dysfunction. To evaluate the age dependence of mitochondrial parameters, citrate synthase activity, respiratory chain complex activity, and oxygen consumption kinetics [...] Read more.

Mitochondrial dysfunction is an important cellular hallmark of aging and neurodegeneration. Platelets are a useful model to study the systemic manifestations of mitochondrial dysfunction. To evaluate the age dependence of mitochondrial parameters, citrate synthase activity, respiratory chain complex activity, and oxygen consumption kinetics were assessed. The effect of cognitive impairment was examined by comparing the age dependence of mitochondrial parameters in healthy individuals and those with neuropsychiatric disease. The study found a significant negative slope of age-dependence for both the activity of individual mitochondrial enzymes (citrate synthase and complex II) and parameters of mitochondrial respiration in intact platelets (routine respiration, maximum capacity of electron transport system, and respiratory rate after complex I inhibition). However, there was no significant difference in the age-related changes of mitochondrial parameters between individuals with and without cognitive impairment. These findings highlight the potential of measuring mitochondrial respiration in intact platelets as a means to assess age-related mitochondrial dysfunction. The results indicate that drugs and interventions targeting mitochondrial respiration may have the potential to slow down or eliminate certain aging and neurodegenerative processes. Mitochondrial respiration in platelets holds promise as a biomarker of aging, irrespective of the degree of cognitive impairment. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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18 pages, 11572 KiB

Open AccessArticle

Light Alcohol Consumption Promotes Early Neurogenesis Following Ischemic Stroke in Adult C57BL/6J Mice

by Jiyu Li, Chun Li, Pushpa Subedi, Xinli Tian, Xiaohong Lu, Sumitra Miriyala, Manikandan Panchatcharam and Hong Sun

Biomedicines 2023, 11(4), 1074; https://doi.org/10.3390/biomedicines11041074 - 2 Apr 2023

Cited by 6 | Viewed by 2951

Abstract

Ischemic stroke is one of the leading causes of death and disability worldwide. Neurogenesis plays a crucial role in postischemic functional recovery. Alcohol dose-dependently affects the prognosis of ischemic stroke. We investigated the impact of light alcohol consumption (LAC) on neurogenesis under physiological [...] Read more.

Ischemic stroke is one of the leading causes of death and disability worldwide. Neurogenesis plays a crucial role in postischemic functional recovery. Alcohol dose-dependently affects the prognosis of ischemic stroke. We investigated the impact of light alcohol consumption (LAC) on neurogenesis under physiological conditions and following ischemic stroke. C57BL/6J mice (three months old) were fed with 0.7 g/kg/day ethanol (designed as LAC) or volume-matched water (designed as control) daily for eight weeks. To evaluate neurogenesis, the numbers of 5-bromo-2-deoxyuridine (BrdU)⁺/doublecortin (DCX)⁺ and BrdU⁺/NeuN⁺ neurons were assessed in the subventricular zone (SVZ), dentate gyrus (DG), ischemic cortex, and ischemic striatum. The locomotor activity was determined by the accelerating rotarod and open field tests. LAC significantly increased BrdU⁺/DCX⁺ and BrdU⁺/NeuN⁺ cells in the SVZ under physiological conditions. Ischemic stroke dramatically increased BrdU⁺/DCX⁺ and BrdU⁺/NeuN⁺ cells in the DG, SVZ, ischemic cortex, and ischemic striatum. The increase in BrdU⁺/DCX⁺ cells was significantly greater in LAC mice compared to the control mice. In addition, LAC significantly increased BrdU⁺/NeuN⁺ cells by about three folds in the DG, SVZ, and ischemic cortex. Furthermore, LAC reduced ischemic brain damage and improved locomotor activity. Therefore, LAC may protect the brain against ischemic stroke by promoting neurogenesis. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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20 pages, 3771 KiB

Open AccessArticle

The Tryptophan-Kynurenine Metabolic System Is Suppressed in Cuprizone-Induced Model of Demyelination Simulating Progressive Multiple Sclerosis

by Helga Polyák, Zsolt Galla, Nikolett Nánási, Edina Katalin Cseh, Cecília Rajda, Gábor Veres, Eleonóra Spekker, Ágnes Szabó, Péter Klivényi, Masaru Tanaka and László Vécsei

Biomedicines 2023, 11(3), 945; https://doi.org/10.3390/biomedicines11030945 - 20 Mar 2023

Cited by 35 | Viewed by 10225

Abstract

Progressive multiple sclerosis (MS) is a chronic disease with a unique pattern, which is histologically classified into the subpial type 3 lesions in the autopsy. The lesion is also homologous to that of cuprizone (CPZ) toxin-induced animal models of demyelination. Aberration of the [...] Read more.

Progressive multiple sclerosis (MS) is a chronic disease with a unique pattern, which is histologically classified into the subpial type 3 lesions in the autopsy. The lesion is also homologous to that of cuprizone (CPZ) toxin-induced animal models of demyelination. Aberration of the tryptophan (TRP)-kynurenine (KYN) metabolic system has been observed in patients with MS; nevertheless, the KYN metabolite profile of progressive MS remains inconclusive. In this study, C57Bl/6J male mice were treated with 0.2% CPZ toxin for 5 weeks and then underwent 4 weeks of recovery. We measured the levels of serotonin, TRP, and KYN metabolites in the plasma and the brain samples of mice at weeks 1, 3, and 5 of demyelination, and at weeks 7 and 9 of remyelination periods by ultra-high-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) after body weight measurement and immunohistochemical analysis to confirm the development of demyelination. The UHPLC-MS/MS measurements demonstrated a significant reduction of kynurenic acid, 3-hydoxykynurenine (3-HK), and xanthurenic acid in the plasma and a significant reduction of 3-HK, and anthranilic acid in the brain samples at week 5. Here, we show the profile of KYN metabolites in the CPZ-induced mouse model of demyelination. Thus, the KYN metabolite profile potentially serves as a biomarker of progressive MS and thus opens a new path toward planning personalized treatment, which is frequently obscured with immunologic components in MS deterioration. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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13 pages, 1549 KiB

Open AccessArticle

The Serum Brain-Derived Neurotrophic Factor Increases in Serotonin Reuptake Inhibitor Responders Patients with First-Episode, Drug-Naïve Major Depression

by Reiji Yoshimura, Naomichi Okamoto, Enkmurun Chibaatar, Tomoya Natsuyama and Atsuko Ikenouchi

Biomedicines 2023, 11(2), 584; https://doi.org/10.3390/biomedicines11020584 - 16 Feb 2023

Cited by 7 | Viewed by 2913

Abstract

Brain-derived neurotrophic factor (BDNF) is a growth factor synthesized in the cell bodies of neurons and glia, which affects neuronal maturation, the survival of nervous system, and synaptic plasticity. BDNF play an important role in the pathophysiology of major depression (MD). The serum [...] Read more.

Brain-derived neurotrophic factor (BDNF) is a growth factor synthesized in the cell bodies of neurons and glia, which affects neuronal maturation, the survival of nervous system, and synaptic plasticity. BDNF play an important role in the pathophysiology of major depression (MD). The serum BDNF levels changed over time, or with the improvement in depressive symptoms. However, the change of serum BDNF during pharmacotherapy remains obscure in MDD. In particular, the changes in serum BDNF associated with pharmacotherapy have not yet been fully elucidated. The present study aimed to compare the changes in serum BDNF concentrations in first-episode, drug-naive patients with MD treated with antidepressants between treatment-response and treatment-nonresponse groups. The study included 35 inpatients and outpatients composed of 15 males and 20 females aged 36.7 ± 6.8 years at the Department of Psychiatry of our University Hospital. All patients met the DSM-5 diagnostic criteria for MD. The antidepressants administered included paroxetine, duloxetine, and escitalopram. Severity of depressive state was assessed using the 17-item HAMD before and 8 weeks after drug administration. Responders were defined as those whose total HAMD scores at 8 weeks had decreased by 50% or more compared to those before drug administration, while non-responders were those whose total HAMD scores had decreased by less than 50%. Here we showed that serum BDNF levels were not significantly different at any point between the two groups. The responder group, but not the non-responder group, showed statistically significant changes in serum BDNF 0 and serum BDNF 8. The results suggest that the changes of serum BDNF might differ between the two groups. The measurement of serum BDNF has the potential to be a useful predictor of pharmacotherapy in patients with first-episode, drug-naïve MD. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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19 pages, 4099 KiB

Open AccessArticle

Noradrenergic Modulation of Learned and Innate Behaviors in Dopamine Transporter Knockout Rats by Guanfacine

by Anna Volnova, Natalia Kurzina, Anastasia Belskaya, Arina Gromova, Arseniy Pelevin, Maria Ptukha, Zoia Fesenko, Alla Ignashchenkova and Raul R. Gainetdinov

Biomedicines 2023, 11(1), 222; https://doi.org/10.3390/biomedicines11010222 - 15 Jan 2023

Cited by 5 | Viewed by 2852

Abstract

Investigation of the precise mechanisms of attention deficit and hyperactivity disorder (ADHD) and other dopamine-associated conditions is crucial for the development of new treatment approaches. In this study, we assessed the effects of repeated and acute administration of α2A-adrenoceptor agonist guanfacine on innate [...] Read more.

Investigation of the precise mechanisms of attention deficit and hyperactivity disorder (ADHD) and other dopamine-associated conditions is crucial for the development of new treatment approaches. In this study, we assessed the effects of repeated and acute administration of α2A-adrenoceptor agonist guanfacine on innate and learned forms of behavior of dopamine transporter knockout (DAT-KO) rats to evaluate the possible noradrenergic modulation of behavioral deficits. DAT-KO and wild type rats were trained in the Hebb–Williams maze to perform spatial working memory tasks. Innate behavior was evaluated via pre pulse inhibition (PPI). Brain activity of the prefrontal cortex and the striatum was assessed. Repeated administration of GF improved the spatial working memory task fulfillment and PPI in DAT-KO rats, and led to specific changes in the power spectra and coherence of brain activity. Our data indicate that both repeated and acute treatment with a non-stimulant noradrenergic drug lead to improvements in the behavior of DAT-KO rats. This study further supports the role of the intricate balance of norepinephrine and dopamine in the regulation of attention. The observed compensatory effect of guanfacine on the behavior of hyperdopaminergic rats may be used in the development of combined treatments to support the dopamine–norepinephrine balance. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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12 pages, 762 KiB

Open AccessArticle

Vertigo in Acute Stroke Is a Predictor of Brain Location but Is Not Related to Early Outcome: The Experience of Sagrat Cor Hospital of Barcelona Stroke Registry

by Angela d’Annunzio, Adrià Arboix, Luís García-Eroles and María-José Sánchez-López

Biomedicines 2022, 10(11), 2830; https://doi.org/10.3390/biomedicines10112830 - 6 Nov 2022

Cited by 4 | Viewed by 3593

Abstract

Background: Vertigo is an uncommon symptom among acute stroke victims. Knowledge about the clinical profile, the brain location, and the early outcome in stroke patients with cerebrovascular diseases and vertigo remains limited. Objectives: In this study, the effects of vertigo on cerebral topography [...] Read more.

Background: Vertigo is an uncommon symptom among acute stroke victims. Knowledge about the clinical profile, the brain location, and the early outcome in stroke patients with cerebrovascular diseases and vertigo remains limited. Objectives: In this study, the effects of vertigo on cerebral topography and early prognosis in cerebrovascular diseases were investigated. Methods: A comparative analysis in terms of demographics, risk factors, clinical characteristics, stroke subtypes, cerebral and vascular topography, and early outcome was performed between patients with presence or absence of vertigo on a sample of 3743 consecutive acute stroke patients available from a 24-year ongoing single-center hospital-based stroke registry. Results: Vertigo was present in 147 patients (3.9%). Multiple logistic regression analysis showed that variables independently associated with vertigo were: location in the cerebellum (OR 5.59, CI 95% 3.24–9.64), nausea or vomiting (OR 4.48, CI 95% 2.95–6.82), medulla (OR 2.87, CI 95% 1.31–6.30), pons (OR 2.39, CI 95% 1.26–4.51), basilar artery (OR 2.36, CI 95% 1.33–4.17), ataxia (OR 2.33, CI 95% 1.41–3.85), and headache (OR 2.31, CI 95% 1.53–3.49). Conclusion: The study confirmed that the presence of vertigo was not related with increased in-hospital mortality or poor prognosis at hospital discharge. Vertigo is mainly related to non-lacunar vertebrobasilar stroke with topographic localization in the cerebellum and/or brainstem. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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18 pages, 3627 KiB

Open AccessArticle

Human iPSC Modeling of Genetic Febrile Seizure Reveals Aberrant Molecular and Physiological Features Underlying an Impaired Neuronal Activity

by Stefania Scalise, Clara Zannino, Valeria Lucchino, Michela Lo Conte, Luana Scaramuzzino, Pierangelo Cifelli, Tiziano D’Andrea, Katiuscia Martinello, Sergio Fucile, Eleonora Palma, Antonio Gambardella, Gabriele Ruffolo, Giovanni Cuda and Elvira Immacolata Parrotta

Biomedicines 2022, 10(5), 1075; https://doi.org/10.3390/biomedicines10051075 - 5 May 2022

Cited by 11 | Viewed by 3341

Abstract

Mutations in SCN1A gene, encoding the voltage-gated sodium channel (VGSC) Na_V1.1, are widely recognized as a leading cause of genetic febrile seizures (FS), due to the decrease in the Na⁺ current density, mainly affecting the inhibitory neuronal transmission. Here, we [...] Read more.

Mutations in SCN1A gene, encoding the voltage-gated sodium channel (VGSC) Na_V1.1, are widely recognized as a leading cause of genetic febrile seizures (FS), due to the decrease in the Na⁺ current density, mainly affecting the inhibitory neuronal transmission. Here, we generated induced pluripotent stem cells (iPSCs)-derived neurons (idNs) from a patient belonging to a genetically well-characterized Italian family, carrying the c.434T > C mutation in SCN1A gene (hereafter SCN1A^M145T). A side-by-side comparison of diseased and healthy idNs revealed an overall maturation delay of SCN1A^M145T cells. Membranes isolated from both diseased and control idNs were injected into Xenopus oocytes and both GABA and AMPA currents were successfully recorded. Patch-clamp measurements on idNs revealed depolarized action potential for SCN1A^M145T, suggesting a reduced excitability. Expression analyses of VGSCs and chloride co-transporters NKCC1 and KCC2 showed a cellular “dysmaturity” of mutated idNs, strengthened by the high expression of SCN3A, a more fetal-like VGSC isoform, and a high NKCC1/KCC2 ratio, in mutated cells. Overall, we provide strong evidence for an intrinsic cellular immaturity, underscoring the role of mutant Na_V1.1 in the development of FS. Furthermore, our data are strengthening previous findings obtained using transfected cells and recordings on human slices, demonstrating that diseased idNs represent a powerful tool for personalized therapy and ex vivo drug screening for human epileptic disorders. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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Review

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21 pages, 1392 KiB

Open AccessReview

Fronto–Cerebellar Diaschisis and Cognitive Dysfunction after Pontine Stroke: A Case Series and Systematic Review

by Kei Shimmyo and Shigeru Obayashi

Biomedicines 2024, 12(3), 623; https://doi.org/10.3390/biomedicines12030623 - 11 Mar 2024

Cited by 2 | Viewed by 2779

Abstract

It is well known that cortical damage may affect cognitive functions, whereas subcortical damage, especially brainstem stroke, would be far less likely to cause cognitive decline, resulting in this condition being overlooked. Few studies have focused on cognitive dysfunction after a pontine stroke. [...] Read more.

It is well known that cortical damage may affect cognitive functions, whereas subcortical damage, especially brainstem stroke, would be far less likely to cause cognitive decline, resulting in this condition being overlooked. Few studies have focused on cognitive dysfunction after a pontine stroke. Here, we begin with describing our nine new case reports of in-depth neuropsychological findings from patients with pontine stroke. The dominant domain of cognitive dysfunction was commonly characterized by executive dysfunction, almost in line with previous studies. The severity was relatively mild. We give an overview of the available literature on cognitive decline following a pontine stroke. This is followed by discussions regarding the prognosis of the cognitive disabilities. Based on previous neuroimaging findings, we would like to get to the core of the neuropathology underlying the cognitive declines in the context of “diaschisis”, a phenomenon of a broad range of brain dysfunctions remote from the local lesions. Specifically, our unique paper, with two modalities of neuroimaging techniques, may help us better understand the pathology. SPECT scans yield evidence of frontal and thalamic hyper-perfusion and cerebellar hypo-perfusion in patients with pontine stroke. Functional near-infrared spectroscopy, when focusing on the supplementary motor area (SMA) as one of the hyper-perfusion areas, exhibits that SMA responses may be subject to the severity of cognitive decline due to a pontine stroke and would also be related to the recovery. Finally, we posit that cognitive decline due to pontine stroke could be explained by the failure of hierarchical cognitive processing in the fronto–ponto–cerebellar–thalamic loop. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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14 pages, 1096 KiB

Open AccessReview

Rehabilitation: Neurogenic Bone Loss after Spinal Cord Injury

by Giovanna E. Leone, Donald C. Shields, Azizul Haque and Narendra L. Banik

Biomedicines 2023, 11(9), 2581; https://doi.org/10.3390/biomedicines11092581 - 20 Sep 2023

Cited by 11 | Viewed by 2906

Abstract

Osteoporosis is a common skeletal disorder which can severely limit one’s ability to complete daily tasks due to the increased risk of bone fractures, reducing quality of life. Spinal cord injury (SCI) can also result in osteoporosis and sarcopenia. Most individuals experience sarcopenia [...] Read more.

Osteoporosis is a common skeletal disorder which can severely limit one’s ability to complete daily tasks due to the increased risk of bone fractures, reducing quality of life. Spinal cord injury (SCI) can also result in osteoporosis and sarcopenia. Most individuals experience sarcopenia and osteoporosis due to advancing age; however, individuals with SCI experience more rapid and debilitating levels of muscle and bone loss due to neurogenic factors, musculoskeletal disuse, and cellular/molecular events. Thus, preserving and maintaining bone mass after SCI is crucial to decreasing the risk of fragility and fracture in vulnerable SCI populations. Recent studies have provided an improved understanding of the pathophysiology and risk factors related to musculoskeletal loss after SCI. Pharmacological and non-pharmacological therapies have also provided for the reduction in or elimination of neurogenic bone loss after SCI. This review article will discuss the pathophysiology and risk factors of muscle and bone loss after SCI, including the mechanisms that may lead to muscle and bone loss after SCI. This review will also focus on current and future pharmacological and non-pharmacological therapies for reducing or eliminating neurogenic bone loss following SCI. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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21 pages, 1894 KiB

Open AccessReview

Beyond the Microbiota: Understanding the Role of the Enteric Nervous System in Parkinson’s Disease from Mice to Human

by Martina Montanari, Paola Imbriani, Paola Bonsi, Giuseppina Martella and Antonella Peppe

Biomedicines 2023, 11(6), 1560; https://doi.org/10.3390/biomedicines11061560 - 27 May 2023

Cited by 15 | Viewed by 5018

Abstract

The enteric nervous system (ENS) is a nerve network composed of neurons and glial cells that regulates the motor and secretory functions of the gastrointestinal (GI) tract. There is abundant evidence of mutual communication between the brain and the GI tract. Dysfunction of [...] Read more.

The enteric nervous system (ENS) is a nerve network composed of neurons and glial cells that regulates the motor and secretory functions of the gastrointestinal (GI) tract. There is abundant evidence of mutual communication between the brain and the GI tract. Dysfunction of these connections appears to be involved in the pathophysiology of Parkinson’s disease (PD). Alterations in the ENS have been shown to occur very early in PD, even before central nervous system (CNS) involvement. Post-mortem studies of PD patients have shown aggregation of α-synuclein (αS) in specific subtypes of neurons in the ENS. Subsequently, αS spreads retrogradely in the CNS through preganglionic vagal fibers to this nerve’s dorsal motor nucleus (DMV) and other central nervous structures. Here, we highlight the role of the ENS in PD pathogenesis based on evidence observed in animal models and using a translational perspective. While acknowledging the putative role of the microbiome in the gut–brain axis (GBA), this review provides a comprehensive view of the ENS not only as a “second brain”, but also as a window into the “first brain”, a potentially crucial element in the search for new therapeutic approaches that can delay and even cure the disease. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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62 pages, 2744 KiB

Open AccessEditor’s ChoiceReview

NLRP3 Inflammasome’s Activation in Acute and Chronic Brain Diseases—An Update on Pathogenetic Mechanisms and Therapeutic Perspectives with Respect to Other Inflammasomes

by Anna Chiarini, Li Gui, Chiara Viviani, Ubaldo Armato and Ilaria Dal Prà

Biomedicines 2023, 11(4), 999; https://doi.org/10.3390/biomedicines11040999 - 23 Mar 2023

Cited by 14 | Viewed by 6776

Abstract

Increasingly prevalent acute and chronic human brain diseases are scourges for the elderly. Besides the lack of therapies, these ailments share a neuroinflammation that is triggered/sustained by different innate immunity-related protein oligomers called inflammasomes. Relevant neuroinflammation players such as microglia/monocytes typically exhibit a [...] Read more.

Increasingly prevalent acute and chronic human brain diseases are scourges for the elderly. Besides the lack of therapies, these ailments share a neuroinflammation that is triggered/sustained by different innate immunity-related protein oligomers called inflammasomes. Relevant neuroinflammation players such as microglia/monocytes typically exhibit a strong NLRP3 inflammasome activation. Hence the idea that NLRP3 suppression might solve neurodegenerative ailments. Here we review the recent Literature about this topic. First, we update conditions and mechanisms, including RNAs, extracellular vesicles/exosomes, endogenous compounds, and ethnic/pharmacological agents/extracts regulating NLRP3 function. Second, we pinpoint NLRP3-activating mechanisms and known NLRP3 inhibition effects in acute (ischemia, stroke, hemorrhage), chronic (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, MS, ALS), and virus-induced (Zika, SARS-CoV-2, and others) human brain diseases. The available data show that (i) disease-specific divergent mechanisms activate the (mainly animal) brains NLRP3; (ii) no evidence proves that NLRP3 inhibition modifies human brain diseases (yet ad hoc trials are ongoing); and (iii) no findings exclude that concurrently activated other-than-NLRP3 inflammasomes might functionally replace the inhibited NLRP3. Finally, we highlight that among the causes of the persistent lack of therapies are the species difference problem in disease models and a preference for symptomatic over etiologic therapeutic approaches. Therefore, we posit that human neural cell-based disease models could drive etiological, pathogenetic, and therapeutic advances, including NLRP3’s and other inflammasomes’ regulation, while minimizing failure risks in candidate drug trials. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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20 pages, 2153 KiB

Open AccessEditor’s ChoiceReview

The Neurobiological Correlates of Gaze Perception in Healthy Individuals and Neurologic Patients

by Simone Battaglia, Jasper H. Fabius, Katarina Moravkova, Alessio Fracasso and Sara Borgomaneri

Biomedicines 2022, 10(3), 627; https://doi.org/10.3390/biomedicines10030627 - 9 Mar 2022

Cited by 53 | Viewed by 7666

Abstract

The ability to adaptively follow conspecific eye movements is crucial for establishing shared attention and survival. Indeed, in humans, interacting with the gaze direction of others causes the reflexive orienting of attention and the faster object detection of the signaled spatial location. The [...] Read more.

The ability to adaptively follow conspecific eye movements is crucial for establishing shared attention and survival. Indeed, in humans, interacting with the gaze direction of others causes the reflexive orienting of attention and the faster object detection of the signaled spatial location. The behavioral evidence of this phenomenon is called gaze-cueing. Although this effect can be conceived as automatic and reflexive, gaze-cueing is often susceptible to context. In fact, gaze-cueing was shown to interact with other factors that characterize facial stimulus, such as the kind of cue that induces attention orienting (i.e., gaze or non-symbolic cues) or the emotional expression conveyed by the gaze cues. Here, we address neuroimaging evidence, investigating the neural bases of gaze-cueing and the perception of gaze direction and how contextual factors interact with the gaze shift of attention. Evidence from neuroimaging, as well as the fields of non-invasive brain stimulation and neurologic patients, highlights the involvement of the amygdala and the superior temporal lobe (especially the superior temporal sulcus (STS)) in gaze perception. However, in this review, we also emphasized the discrepancies of the attempts to characterize the distinct functional roles of the regions in the processing of gaze. Finally, we conclude by presenting the notion of invariant representation and underline its value as a conceptual framework for the future characterization of the perceptual processing of gaze within the STS. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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Other

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14 pages, 1930 KiB

Open AccessSystematic Review

Obliviate! Reviewing Neural Fundamentals of Intentional Forgetting from a Meta-Analytic Perspective

by Olga Lucia Gamboa, Hu Chuan-Peng, Christian E. Salas and Kenneth S. L. Yuen

Biomedicines 2022, 10(7), 1555; https://doi.org/10.3390/biomedicines10071555 - 29 Jun 2022

Cited by 3 | Viewed by 2719

Abstract

Intentional forgetting (IF) is an important adaptive mechanism necessary for correct memory functioning, optimal psychological wellbeing, and appropriate daily performance. Due to its complexity, the neuropsychological processes that give birth to successful intentional forgetting are not yet clearly known. In this study, we [...] Read more.

Intentional forgetting (IF) is an important adaptive mechanism necessary for correct memory functioning, optimal psychological wellbeing, and appropriate daily performance. Due to its complexity, the neuropsychological processes that give birth to successful intentional forgetting are not yet clearly known. In this study, we used two different meta-analytic algorithms, Activation Likelihood Estimation (ALE) & Latent Dirichlet Allocation (LDA) to quantitatively assess the neural correlates of IF and to evaluate the degree of compatibility between the proposed neurobiological models and the existing brain imaging data. We found that IF involves the interaction of two networks, the main “core regions” consisting of a primarily right-lateralized frontal-parietal circuit that is activated irrespective of the paradigm used and sample characteristics and a second less constrained “supportive network” that involves frontal-hippocampal interactions when IF takes place. Additionally, our results support the validity of the inhibitory or thought suppression hypothesis. The presence of a neural signature of IF that is stable regardless of experimental paradigms is a promising finding that may open new venues for the development of effective clinical interventions. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Translational Laboratory and Experimental Medicine for the Sake of Neurological Diseases and Mental Illnesses)

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