Autism is a complex neurodevelopmental condition characterized by repetitive behaviors, impaired social communication, and various associated conditions such as depression and anxiety. Its multifactorial etiology includes genetic, environmental, dietary, and gastrointestinal contributions. Pathologically, Autism is linked to mitochondrial dysfunction, oxidative stress, neuroinflammation, and neurotransmitter imbalances involving GABA, glutamate, dopamine, and oxytocin. Propionic acid (PRPA) is a short-chain fatty acid produced by gut bacteria, influencing central nervous system functions. Elevated PRPA levels can exacerbate Autism-related symptoms by disrupting metabolic processes and crossing the blood–brain barrier. Our research investigates the neuroprotective potential of Genistein (GNT), an isoflavone compound with known benefits in neuropsychiatric and neurodegenerative disorders, through modulation of the AC/cAMP/CREB/PKA signaling pathway and mitochondrial ETC complex (I-IV) function. In silico analyses revealed GNT’s high affinity for these targets. Subsequent in vitro and in vivo experiments using a PRPA-induced rat model of autism demonstrated that GNT (40 and 80 mg/kg., orally) significantly improves locomotion, neuromuscular coordination, and cognitive functions in PRPA-treated rodents. Behavioral assessments showed reduced immobility in the forced swim test, enhanced Morris water maze performance, and restored regular locomotor activity. On a molecular level, GNT restored levels of key signaling molecules (AC, cAMP, CREB, PKA) and mitochondrial complexes (I-V), disrupted by PRPA exposure. Additionally, GNT reduced neuroinflammation and apoptosis, normalized neurotransmitter levels, and improved the complete blood count profile. Histopathological analyses confirmed that GNT ameliorated PRPA-induced brain injuries, restored normal brain morphology, reduced demyelination, and promoted neurogenesis. The study supports GNT’s potential in autism treatment by modulating neural pathways, reducing inflammation, and restoring neurotransmitter balance.
{"title":"Therapeutic efficacy of Genistein in activation of neuronal AC/cAMP/CREB/PKA and mitochondrial ETC-Complex pathways in experimental model of autism: Evidence from CSF, blood plasma and brain analysis","authors":"Manjeet kumar , Sidharth Mehan , Aakash Kumar , Tarun Sharma , Zuber Khan , Aarti Tiwari , Ghanshyam Das Gupta , Acharan S. Narula","doi":"10.1016/j.brainres.2024.149251","DOIUrl":"10.1016/j.brainres.2024.149251","url":null,"abstract":"<div><div>Autism is a complex neurodevelopmental condition characterized by repetitive behaviors, impaired social communication, and various associated conditions such as depression and anxiety. Its multifactorial etiology includes genetic, environmental, dietary, and gastrointestinal contributions. Pathologically, Autism is linked to mitochondrial dysfunction, oxidative stress, neuroinflammation, and neurotransmitter imbalances involving GABA, glutamate, dopamine, and oxytocin. Propionic acid (PRPA) is a short-chain fatty acid produced by gut bacteria, influencing central nervous system functions. Elevated PRPA levels can exacerbate Autism-related symptoms by disrupting metabolic processes and crossing the blood–brain barrier. Our research investigates the neuroprotective potential of Genistein (GNT), an isoflavone compound with known benefits in neuropsychiatric and neurodegenerative disorders, through modulation of the AC/cAMP/CREB/PKA signaling pathway and mitochondrial ETC complex (I-IV) function. In silico analyses revealed GNT’s high affinity for these targets. Subsequent in vitro and in vivo experiments using a PRPA-induced rat model of autism demonstrated that GNT (40 and 80 mg/kg., orally) significantly improves locomotion, neuromuscular coordination, and cognitive functions in PRPA-treated rodents. Behavioral assessments showed reduced immobility in the forced swim test, enhanced Morris water maze performance, and restored regular locomotor activity. On a molecular level, GNT restored levels of key signaling molecules (AC, cAMP, CREB, PKA) and mitochondrial complexes (I-V), disrupted by PRPA exposure. Additionally, GNT reduced neuroinflammation and apoptosis, normalized neurotransmitter levels, and improved the complete blood count profile. Histopathological analyses confirmed that GNT ameliorated PRPA-induced brain injuries, restored normal brain morphology, reduced demyelination, and promoted neurogenesis. The study supports GNT’s potential in autism treatment by modulating neural pathways, reducing inflammation, and restoring neurotransmitter balance.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149251"},"PeriodicalIF":2.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.brainres.2024.149262
Jenna Parker , Jose M. Moris , Lily C. Goodman , Vineet K. Paidisetty , Vicente Vanegas , Haley A. Turner , Daniel Melgar , Yunsuk Koh
The prevalence of Alzheimer’s disease (AD) among adults has continued to increase over the last two decades, which has sparked a significant increase in research that focuses on the topic of “brain health.” While AD is partially determined by a genetic predisposition, there are still numerous pathophysiological factors that require further research. This research requirement stems from the acknowledgment that AD is a multifactorial disease that to date, cannot be prevented. Therefore, addressing and understanding the potential AD risk factors is necessary to increase the quality of life of an aging population. To raise awareness of critical pathways that impact AD progression, this review manuscript describes AD etiologies, structural impairments, and biomolecular changes that can significantly increase the risk of AD. Among them, a special highlight is given to inflammasomes, which have been shown to bolster neuroinflammation. Alike, the role of brain-derived neurotrophic factor, an essential neuropeptide that promotes the preservation of cognition is presented. In addition, the functional role of neurovascular units to regulate brain health is highlighted and contrasted to inflammatory conditions, such as cellular senescence, vascular damage, and increased visceral adiposity, who all increase the risk of neuroinflammation. Altogether, a multifactorial interventional approach is warranted to reduce the risk of AD.
{"title":"A multifactorial lens on risk factors promoting the progression of Alzheimer’s disease","authors":"Jenna Parker , Jose M. Moris , Lily C. Goodman , Vineet K. Paidisetty , Vicente Vanegas , Haley A. Turner , Daniel Melgar , Yunsuk Koh","doi":"10.1016/j.brainres.2024.149262","DOIUrl":"10.1016/j.brainres.2024.149262","url":null,"abstract":"<div><div>The prevalence of Alzheimer’s disease (AD) among adults has continued to increase over the last two decades, which has sparked a significant increase in research that focuses on the topic of “brain health.” While AD is partially determined by a genetic predisposition, there are still numerous pathophysiological factors that require further research. This research requirement stems from the acknowledgment that AD is a multifactorial disease that to date, cannot be prevented. Therefore, addressing and understanding the potential AD risk factors is necessary to increase the quality of life of an aging population. To raise awareness of critical pathways that impact AD progression, this review manuscript describes AD etiologies, structural impairments, and biomolecular changes that can significantly increase the risk of AD. Among them, a special highlight is given to inflammasomes, which have been shown to bolster neuroinflammation. Alike, the role of brain-derived neurotrophic factor, an essential neuropeptide that promotes the preservation of cognition is presented. In addition, the functional role of neurovascular units to regulate brain health is highlighted and contrasted to inflammatory conditions, such as cellular senescence, vascular damage, and increased visceral adiposity, who all increase the risk of neuroinflammation. Altogether, a multifactorial interventional approach is warranted to reduce the risk of AD.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149262"},"PeriodicalIF":2.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.brainres.2024.149268
Regina Andressa Caetano , Joelma Alves , Thiago A. Smaniotto , Francisco Daroda Dutra , Eduardo Z.B. de Assis , Luisa Soares Pedroso , Ariadni Peres , Alessandra G. Machado , Rachel Krolow , Pauline Maciel August , Cristiane Matté , Marina Seady , Marina C. Leite , Brenda G. Machado , Carolina Marques , Laura Saraiva , Randriely Merscher Sobreira de Lima , Carla Dalmaz
<div><div>Early exposure to stressors affects how the organism reacts to stimuli, its emotional state throughout life, and how it deals with emotional memories. Consequently, it may affect susceptibility to psychopathology later in life. We used an animal model of early stress by maternal separation to study its potential impact on the extinction of aversive memories and anxiety-like behavior in adulthood, as well as its effects on mitochondrial functionality, inflammatory and astrocytic markers in the amygdala. We also assessed whether a diet enriched with linseed oil, known for its high content in omega-3 fats, could be used to attenuate the behavioral and neurochemical effects of early stress. Litters of Wistar rats were divided into controls (intact) or subjected to maternal separation (MS). They were subdivided into two groups receiving isocaloric diets enriched in soy or linseed oils at weaning. In adulthood, the animals were exposed to the open field and the elevated plus maze, to evaluate exploratory activity and anxiety-like behavior. They were also trained in a context of fear conditioning, and afterward subjected to an extinction session, followed by a test session to evaluate the extinction memory. Amygdalae were evaluated for inflammatory cytokines (interleukin (IL)-1beta, IL-6, and tumor-necrose factor (TNF)-alpha), mitochondrial functionality, and astrocyte markers (glial fibrillary acidic protein − GFAP, S100B, and glutamine synthetase activity). MS induced anxiety-like behavior in the elevated plus-maze, which was reversed by a diet enriched in linseed oil offered from weaning. When testing the memory of an extinction session of fear conditioning, MS animals showed more freezing behavior. MS males receiving a linseed oil-enriched diet had lower functional mitochondria in the amygdala. In addition, MS led to increased inflammatory cytokines, particularly IL-1beta, and the diet enriched in linseed oil further increased these levels in MS animals. MS also increased S100B levels. These results point to a higher emotionality presented by MS animals, with higher levels of inflammatory cytokines and S100B. While a diet enriched in linseed oil attenuated anxiety-like behavior, it further altered amygdala IL-1beta and reduced mitochondria functionality, particularly in males. MS also increased glutamine synthetase activity in the amygdala, and this effect was higher when the animals received a diet enriched in linseed oil, particularly in females. In conclusion, these results point to MS effects on emotional behavior, and neurochemical alterations in the amygdala, with sex-specific effects. Although a diet enriched in linseed oil appears to be able to reverse some of MS behavioral effects, these results must be considered with caution, since biochemical parameters could be worsened in MS animals receiving a linseed oil-enriched diet. This knowledge is important for the understanding of mechanisms of action of strategies aiming to reverse
{"title":"Impacts of linseed oil diet on anxiety and memory extinction after early life stress: A sex-specific analysis of mitochondrial dysfunction, astrocytic markers, and inflammation in the amygdala","authors":"Regina Andressa Caetano , Joelma Alves , Thiago A. Smaniotto , Francisco Daroda Dutra , Eduardo Z.B. de Assis , Luisa Soares Pedroso , Ariadni Peres , Alessandra G. Machado , Rachel Krolow , Pauline Maciel August , Cristiane Matté , Marina Seady , Marina C. Leite , Brenda G. Machado , Carolina Marques , Laura Saraiva , Randriely Merscher Sobreira de Lima , Carla Dalmaz","doi":"10.1016/j.brainres.2024.149268","DOIUrl":"10.1016/j.brainres.2024.149268","url":null,"abstract":"<div><div>Early exposure to stressors affects how the organism reacts to stimuli, its emotional state throughout life, and how it deals with emotional memories. Consequently, it may affect susceptibility to psychopathology later in life. We used an animal model of early stress by maternal separation to study its potential impact on the extinction of aversive memories and anxiety-like behavior in adulthood, as well as its effects on mitochondrial functionality, inflammatory and astrocytic markers in the amygdala. We also assessed whether a diet enriched with linseed oil, known for its high content in omega-3 fats, could be used to attenuate the behavioral and neurochemical effects of early stress. Litters of Wistar rats were divided into controls (intact) or subjected to maternal separation (MS). They were subdivided into two groups receiving isocaloric diets enriched in soy or linseed oils at weaning. In adulthood, the animals were exposed to the open field and the elevated plus maze, to evaluate exploratory activity and anxiety-like behavior. They were also trained in a context of fear conditioning, and afterward subjected to an extinction session, followed by a test session to evaluate the extinction memory. Amygdalae were evaluated for inflammatory cytokines (interleukin (IL)-1beta, IL-6, and tumor-necrose factor (TNF)-alpha), mitochondrial functionality, and astrocyte markers (glial fibrillary acidic protein − GFAP, S100B, and glutamine synthetase activity). MS induced anxiety-like behavior in the elevated plus-maze, which was reversed by a diet enriched in linseed oil offered from weaning. When testing the memory of an extinction session of fear conditioning, MS animals showed more freezing behavior. MS males receiving a linseed oil-enriched diet had lower functional mitochondria in the amygdala. In addition, MS led to increased inflammatory cytokines, particularly IL-1beta, and the diet enriched in linseed oil further increased these levels in MS animals. MS also increased S100B levels. These results point to a higher emotionality presented by MS animals, with higher levels of inflammatory cytokines and S100B. While a diet enriched in linseed oil attenuated anxiety-like behavior, it further altered amygdala IL-1beta and reduced mitochondria functionality, particularly in males. MS also increased glutamine synthetase activity in the amygdala, and this effect was higher when the animals received a diet enriched in linseed oil, particularly in females. In conclusion, these results point to MS effects on emotional behavior, and neurochemical alterations in the amygdala, with sex-specific effects. Although a diet enriched in linseed oil appears to be able to reverse some of MS behavioral effects, these results must be considered with caution, since biochemical parameters could be worsened in MS animals receiving a linseed oil-enriched diet. This knowledge is important for the understanding of mechanisms of action of strategies aiming to reverse ","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149268"},"PeriodicalIF":2.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.brainres.2024.149263
Chaofan Sui , Meng Li , Qihao Zhang , Jing Li , Yian Gao , Xinyue Zhang , Na Wang , Changhu Liang , Lingfei Guo
Objective
Compared with those in type 2 diabetes mellitus (T2DM) patients without diabetic peripheral neuropathy (DPN), alterations in brain iron levels in the basal ganglia (an iron-rich region) and motor and cognitive dysfunction in T2DM patients with DPN have not been fully elucidated. We aimed to explore changes in brain iron levels in the basal ganglia in T2DM patients with DPN using quantitative susceptibility mapping (QSM).
Methods
Thirty-four patients with DPN, fifty-five patients with diabetes without DPN (non-DPN, NDPN), and fifty-one healthy controls (HCs) were recruited and underwent cognitive and motor assessments, blood biochemical tests, and brain QSM imaging. One-way ANOVA was applied to evaluate the variations in cognitive, motor and blood biochemical indicators across the three groups. Then, we performed multiple linear regression analysis to identify the possible factors associated with the significant differences in susceptibility values of the basal ganglia subregions between the two T2DM groups.
Results
Susceptibility values in the putamen and the caudate nucleus were greater in the T2DM patients than in the HCs (DPN patients vs. HCs, p < 0.05; NDPN patients vs. HCs, p < 0.05, FDR correction), and there were no significant differences between the DPN patients and NDPN patients. Multiple linear regression analysis revealed that age and history of diabetes played crucial roles in brain iron deposition in the putamen and the caudate nucleus. Notably, DPN in T2DM patients had no effect on brain iron deposition in the putamen or the caudate nucleus. The susceptibility values of the putamen was positively correlated with the Timed Up and Go test score and negatively correlated with gait speed, the Montreal Cognitive Assessment score, and the Symbol Digit Modalities Test score in T2DM patients.
Conclusions
Iron-based susceptibility in the putamen, measured by QSM, can reflect motor function in T2DM patients and might indicate micropathological changes in brain tissue in T2DM patients.
{"title":"Increased brain iron deposition in the basial ganglia is associated with cognitive and motor dysfunction in type 2 diabetes mellitus","authors":"Chaofan Sui , Meng Li , Qihao Zhang , Jing Li , Yian Gao , Xinyue Zhang , Na Wang , Changhu Liang , Lingfei Guo","doi":"10.1016/j.brainres.2024.149263","DOIUrl":"10.1016/j.brainres.2024.149263","url":null,"abstract":"<div><h3>Objective</h3><div>Compared with those in type 2 diabetes mellitus (T2DM) patients without diabetic peripheral neuropathy (DPN), alterations in brain iron levels in the basal ganglia (an iron-rich region) and motor and cognitive dysfunction in T2DM patients with DPN have not been fully elucidated. We aimed to explore changes in brain iron levels in the basal ganglia in T2DM patients with DPN using quantitative susceptibility mapping (QSM).</div></div><div><h3>Methods</h3><div>Thirty-four patients with DPN, fifty-five patients with diabetes without DPN (non-DPN, NDPN), and fifty-one healthy controls (HCs) were recruited and underwent cognitive and motor assessments, blood biochemical tests, and brain QSM imaging. One-way ANOVA was applied to evaluate the variations in cognitive, motor and blood biochemical indicators across the three groups. Then, we performed multiple linear regression analysis to identify the possible factors associated with the significant differences in susceptibility values of the basal ganglia subregions between the two T2DM groups.</div></div><div><h3>Results</h3><div>Susceptibility values in the putamen and the caudate nucleus were greater in the T2DM patients than in the HCs (DPN patients vs. HCs, p < 0.05; NDPN patients vs. HCs, p < 0.05, FDR correction), and there were no significant differences between the DPN patients and NDPN patients. Multiple linear regression analysis revealed that age and history of diabetes played crucial<!--> <!-->roles in brain iron deposition in the putamen and the caudate nucleus. Notably, DPN in T2DM patients had no effect on brain iron deposition in the putamen or the caudate nucleus. The susceptibility values of the putamen was positively correlated with the Timed Up and Go test score and negatively correlated with gait speed, the Montreal Cognitive Assessment score, and the Symbol Digit Modalities Test score in T2DM patients.</div></div><div><h3>Conclusions</h3><div>Iron-based susceptibility in the putamen, measured by QSM, can reflect motor function in T2DM patients and might indicate micropathological changes in brain tissue in T2DM patients.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149263"},"PeriodicalIF":2.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.brainres.2024.149267
Márcia da-Silva, Ana Rita Pereira, Adriana Sampaio, Joana Coutinho, Alberto J. González-Villar
Affective touch is mediated by specialized receptors sensitive to gentle and slow touch called C-tactile afferents (CT). The activation of these receptors has shown promise in reducing subjective pain ratings, however, how this type of touch can affect central sensitization processes is poorly studied. This work aimed to investigate if affective touch is able to modulate pain sensitization and its electrophysiological correlates during Temporal Summation of Second Pain (TSSP), a phenomenon characterized by an increase in pain perception due to repeated noxious stimuli.
Thirty-seven participants underwent a TSSP protocol involving three conditions: TSSP alone, TSSP during vibrotactile stimulation, and TSSP during CT stimulation (administered with a brush mounted in a robot arm). We measured subjective pain ratings, electroencephalographic (N2-P2 complex) and electrocardiographic activity during these conditions.
Participants reported a significantly lower increase of pain during CT stimulation compared to vibrotactile stimulation, but not to TSSP alone. In addition, TSSP was reduced when administered in the ipsilateral arm compared to the other somatosensory stimulation. Subjective reports of attention towards painful stimuli, amplitude of the N2-P2 complex, and heart rate were also reduced during CT stimulation. Conclusion: Our results indicated that the activation of CT receptors may reduce sensitization compared to other types of somatosensory stimulation, which is possibly related to the reduction of the attention devoted to nociceptive stimulation. Our results suggest that activation of CT receptors may alleviate the occurrence of central pain sensitization.
{"title":"The effects of C-tactile stimulation on temporal summation of second pain: A study of the central and peripheral neural correlates","authors":"Márcia da-Silva, Ana Rita Pereira, Adriana Sampaio, Joana Coutinho, Alberto J. González-Villar","doi":"10.1016/j.brainres.2024.149267","DOIUrl":"10.1016/j.brainres.2024.149267","url":null,"abstract":"<div><div>Affective touch is mediated by specialized receptors sensitive to gentle and slow touch called C-tactile afferents (CT). The activation of these receptors has shown promise in reducing subjective pain ratings, however, how this type of touch can affect central sensitization processes is poorly studied. This work aimed to investigate if affective touch is able to modulate pain sensitization and its electrophysiological correlates during Temporal Summation of Second Pain (TSSP), a phenomenon characterized by an increase in pain perception due to repeated noxious stimuli.</div><div>Thirty-seven participants underwent a TSSP protocol involving three conditions: TSSP alone, TSSP during vibrotactile stimulation, and TSSP during CT stimulation (administered with a brush mounted in a robot arm). We measured subjective pain ratings, electroencephalographic (N2-P2 complex) and electrocardiographic activity during these conditions.</div><div>Participants reported a significantly lower increase of pain during CT stimulation compared to vibrotactile stimulation, but not to TSSP alone. In addition, TSSP was reduced when administered in the ipsilateral arm compared to the other somatosensory stimulation. Subjective reports of attention towards painful stimuli, amplitude of the N2-P2 complex, and heart rate were also reduced during CT stimulation. <u>Conclusion</u>: Our results indicated that the activation of CT receptors may reduce sensitization compared to other types of somatosensory stimulation, which is possibly related to the reduction of the attention devoted to nociceptive stimulation. Our results suggest that activation of CT receptors may alleviate the occurrence of central pain sensitization.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149267"},"PeriodicalIF":2.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.brainres.2024.149255
Jibrin Sammani Usman, Thomson Wai-Lung Wong, Shamay Sheung Mei Ng
Introduction
Successful execution of normal activities in various populations warrants the performance of dual tasks (DTs). DTs involve motor and cognitive tasking with the involvement of various brain areas. Transcranial direct current stimulation (tDCS) has been used for regulating the excitability of brain cortical regions. The purpose of this review was to evaluate the available scientific evidence on the effects of tDCS combined with concurrent DT walking on mobility, gait and cognition in older adults (OAs) with and without Parkinson’s disease (PD).
Methods
The PubMed, PEDro, Cochrane Library, Embase and Web databases of Science were searched for relevant articles published from their beginning until date. Randomized controlled trials were retrieved, and their methodological quality and risk of bias were evaluated using the PEDro scale and the Cochrane risk-of-bias tool respectively. Qualitative and quantitative synthesis were used to analyze the data.
Results
Five studies were included in the review. The results revealed that in individuals with PD, active tDCS with concurrent DT walking has more potential to significantly improve DT cost to gait speed (p < 0.05), and the proportion of correct responses during DT time up and go test (TUG)count (p = 0.004). DT walking with concurrent tDCS has potential to significantly improve DT [gait speed count (p = 0.03), cadence (p = 0.0005), double limb support time (DBST) (p < 0.0001), and single-task (ST) cadence (p = 0.008)]. Significant improvements were observed in the DT costs for stride time (p < 0.0001), DBST (p = 0.03), stride time variability (p < 0.00001), and swing time variability (p = 0.002) with the active tDCS combined with concurrent DT training in OAs.
Conclusions
The effects of tDCS combined with concurrent DT walking or training on cognitive, gait and mobility outcomes in OAs with or without PD can be better explained by the DTW training itself. However, tDCS could produce some specific effects in particular outcomes and scenarios.
{"title":"Effects of transcranial direct current stimulation combined with concurrent dual-task walking on mobility, gait, and cognitive outcomes: A systematic review","authors":"Jibrin Sammani Usman, Thomson Wai-Lung Wong, Shamay Sheung Mei Ng","doi":"10.1016/j.brainres.2024.149255","DOIUrl":"10.1016/j.brainres.2024.149255","url":null,"abstract":"<div><h3>Introduction</h3><div>Successful execution of normal activities in various populations warrants the performance of dual tasks (DTs). DTs involve motor and cognitive tasking with the involvement of various brain areas. Transcranial direct current stimulation (tDCS) has been used for regulating the excitability of brain cortical regions. The purpose of this review was to evaluate the available scientific evidence on the effects of tDCS combined with concurrent DT walking on mobility, gait and cognition in older adults (OAs) with and without Parkinson’s disease (PD).</div></div><div><h3>Methods</h3><div>The PubMed, PEDro, Cochrane Library, Embase and Web databases of Science were searched for relevant articles published from their beginning until date. Randomized controlled trials were retrieved, and their methodological quality and risk of bias were evaluated using the PEDro scale and the Cochrane risk-of-bias tool respectively. Qualitative and quantitative synthesis were used to analyze the data.</div></div><div><h3>Results</h3><div>Five studies were included in the review. The results revealed that in individuals with PD, active tDCS with concurrent DT walking has more potential to significantly improve DT cost to gait speed (p < 0.05), and the proportion of correct responses during DT time up and go test (TUG)<sub>count</sub> (p = 0.004). DT walking with concurrent tDCS has potential to significantly improve DT [gait speed <sub>count</sub> (p = 0.03), cadence (p = 0.0005), double limb support time (DBST) (p < 0.0001), and single-task (ST) cadence (p = 0.008)]. Significant improvements were observed in the DT costs for stride time (p < 0.0001), DBST (p = 0.03), stride time variability (p < 0.00001), and swing time variability (p = 0.002) with the active tDCS combined with concurrent DT training in OAs.</div></div><div><h3>Conclusions</h3><div>The effects of tDCS combined with concurrent DT walking or training on cognitive, gait and mobility outcomes in OAs with or without PD can be better explained by the DTW training itself. However, tDCS could produce some specific effects in particular outcomes and scenarios.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149255"},"PeriodicalIF":2.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.brainres.2024.149264
Gibbeum Kim , Rafay A. Khan , Yihsin Tai , Somayeh Shahsavarani , Fatima T. Husain
Tinnitus is a phantom auditory sensation that commonly co-occurs with hearing loss. Both tinnitus and hearing loss can impact the quality of life, emotional well-being, and cognitive functioning of the affected individuals. While previous studies have highlighted structural alterations in hearing loss and/or tinnitus, the fundamental neural mechanisms underpinning tinnitus severity remain poorly understood. In this study, we conducted a voxel-based morphometry to investigate gray matter (GM) volume differences among groups of participants with varying tinnitus severity and hearing status, and controls within a large sample. We observed reduced GM volume in the left anterior insula and right planum polare in participants with hearing loss, regardless of their tinnitus status, compared to normal hearing controls. We noted decreased GM volume in the bilateral anterior and posterior insula for those with tinnitus and normal hearing compared to a normal hearing control group. Further, the tinnitus with hearing loss group showed decreased GM volume in the left planum polare, left inferior temporal gyrus, bilateral anterior temporal gyri, and right superior frontal gyrus compared to the normal hearing control group, suggesting a combined effect of hearing loss and tinnitus. While tinnitus severity did not show a significant overall effect, there was a significant positive correlation between tinnitus distress and GM volume in bilateral planum polare. Our findings enhance the understanding of structural brain changes related to hearing loss and tinnitus, and advance the overall knowledge of tinnitus pathophysiology, which can contribute to the development of more effective treatments for tinnitus.
{"title":"Gray matter volumetric changes in tinnitus: The impact of hearing loss and severity","authors":"Gibbeum Kim , Rafay A. Khan , Yihsin Tai , Somayeh Shahsavarani , Fatima T. Husain","doi":"10.1016/j.brainres.2024.149264","DOIUrl":"10.1016/j.brainres.2024.149264","url":null,"abstract":"<div><div>Tinnitus is a phantom auditory sensation that commonly co-occurs with hearing loss. Both tinnitus and hearing loss can impact the quality of life, emotional well-being, and cognitive functioning of the affected individuals. While previous studies have highlighted structural alterations in hearing loss and/or tinnitus, the fundamental neural mechanisms underpinning tinnitus severity remain poorly understood. In this study, we conducted a voxel-based morphometry to investigate gray matter (GM) volume differences among groups of participants with varying tinnitus severity and hearing status, and controls within a large sample. We observed reduced GM volume in the left anterior insula and right planum polare in participants with hearing loss, regardless of their tinnitus status, compared to normal hearing controls. We noted decreased GM volume in the bilateral anterior and posterior insula for those with tinnitus and normal hearing compared to a normal hearing control group. Further, the tinnitus with hearing loss group showed decreased GM volume in the left planum polare, left inferior temporal gyrus, bilateral anterior temporal gyri, and right superior frontal gyrus compared to the normal hearing control group, suggesting a combined effect of hearing loss and tinnitus. While tinnitus severity did not show a significant overall effect, there was a significant positive correlation between tinnitus distress and GM volume in bilateral planum polare. Our findings enhance the understanding of structural brain changes related to hearing loss and tinnitus, and advance the overall knowledge of tinnitus pathophysiology, which can contribute to the development of more effective treatments for tinnitus.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149264"},"PeriodicalIF":2.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.brainres.2024.149266
Caroline Amaral Machado , Bruna da Silva Oliveira , João Luís Vieira Monteiro de Barros , Heliana de Barros Fernandes , Eliana Cristina de Brito Toscano , Lucas Miranda Kangussu , Pedro Pires Goulart Guimarães , Ana Cristina Simões e Silva , Antonio Lucio Teixeira , Aline Silva de Miranda
The Renin Angiotensin System (RAS) plays a pathophysiological role in traumatic brain injury (TBI) but the evidence of its involvement in mild TBI (mTBI) is still limited. We aimed at investigating the levels of components from both the classical and counter-regulatory axis of the RAS in a mTBI animal model. Mice with mTBI displayed enhanced ACE/Ang II/AT1R axis ipsilateral- and contralaterally to the trauma in the hippocampus and prefrontal cortex during acute (24 and 72 h) and later (30 days) timepoints. Increase in Ang-(1–7) levels alongside reduction in Mas receptor expression in hippocampus and prefrontal cortex was also observed after injury. Conversely, mTBI-mice presented higher expression of AT2 receptor in the contralateral hippocampus and the ipsilateral prefrontal cortex. Importantly, treatment with telmisartan, an AT1R blocker, and perindopril, an ACE inhibitor, were able to prevent mTBI-associated locomotor activity impairment and anxiety-like behavior, corroborating the involvement of RAS in the pathophysiology of mTBI. We provided original evidence that components of classical and alternative RAS axes undergo alterations in key brain areas following a mTBI in a time and hemisphere dependent manner. Our findings also open new avenues for investigating the therapeutic potential of RAS components in mTBI.
{"title":"Involvement of Renin-Angiotensin system (RAS) components in mild traumatic brain injury","authors":"Caroline Amaral Machado , Bruna da Silva Oliveira , João Luís Vieira Monteiro de Barros , Heliana de Barros Fernandes , Eliana Cristina de Brito Toscano , Lucas Miranda Kangussu , Pedro Pires Goulart Guimarães , Ana Cristina Simões e Silva , Antonio Lucio Teixeira , Aline Silva de Miranda","doi":"10.1016/j.brainres.2024.149266","DOIUrl":"10.1016/j.brainres.2024.149266","url":null,"abstract":"<div><div>The Renin Angiotensin System (RAS) plays a pathophysiological role in traumatic brain injury (TBI) but the evidence of its involvement in mild TBI (mTBI) is still limited. We aimed at investigating the levels of components from both the classical and counter-regulatory axis of the RAS in a mTBI animal model. Mice with mTBI displayed enhanced ACE/Ang II/AT<sub>1</sub>R axis ipsilateral- and contralaterally to the trauma in the hippocampus and prefrontal cortex during acute (24 and 72 h) and later (30 days) timepoints. Increase in Ang-(1–7) levels alongside reduction in Mas receptor expression in hippocampus and prefrontal cortex was also observed after injury. Conversely, mTBI-mice presented higher expression of AT<sub>2</sub> receptor in the contralateral hippocampus and the ipsilateral prefrontal cortex. Importantly, treatment with telmisartan, an AT<sub>1</sub>R blocker, and perindopril, an ACE inhibitor, were able to prevent mTBI-associated locomotor activity impairment and anxiety-like behavior, corroborating the involvement of RAS in the pathophysiology of mTBI. We provided original evidence that components of classical and alternative RAS axes undergo alterations in key brain areas following a mTBI in a time and hemisphere dependent manner. Our findings also open new avenues for investigating the therapeutic potential of RAS components in mTBI.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149266"},"PeriodicalIF":2.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-03DOI: 10.1016/j.brainres.2024.149259
Xiaoyi Liu , Yayan Yin , Yi Shan , Wang Chao , Jingkai Li , Yue Zhang , Qiongge Li , Jing Liu , Jie Lu
Background and purpose
The oxygen extraction fraction is an essential biomarker for the assessment of brain metabolism. A recently proposed method combined with quantitative susceptibility mapping and quantitative blood oxygen level-dependent magnitude enables noninvasive mapping of the oxygen extraction fraction. Our study investigated the oxygen extraction fraction mapping variations of single-delay and multi-delay arterial spin-labeling.
Materials and methods
A total of twenty healthy participants were enrolled. The multi-echo spoiled gradient-echo, multi-delay arterial spin-labeling, and magnetization-prepared rapid gradient echo sequences were acquired at 3.0 T. The mean oxygen extraction fraction was generated under a single delay time of 1780 ms, multi-delay arterial spin-labeling of transit-corrected cerebral blood flow, and multi-delay arterial spin-labeling of arterial cerebral blood volume. The results were compared via paired t tests and the Wilcoxon test. Linear regression analyses were used to investigate the relationships among the oxygen extraction fraction, cerebral blood flow, and venous cerebral blood volume.
Results
The oxygen extraction fraction estimate with multi-delay arterial spin-labeling yielded a significantly lower value than that with single-delay arterial spin-labeling. The average values for the whole brain under single-delay arterial spin-labeling, multi-delay arterial spin-labeling of transit-corrected cerebral blood flow, and multi-delay arterial spin-labeling of arterial cerebral blood volume were 41.5 ± 1.7 % (P < 0.05), 41.3 ± 1.9 % (P < 0.001), and 40.9 ± 1.9 % (N = 20), respectively. The oxygen extraction fraction also showed a significant inverse correlation with the venous cerebral blood volume under steady-state conditions when multi-delay arterial spin-labeling was used (r = 0.5834, p = 0.0069).
Conclusion
These findings suggest that the oxygen extraction fraction is significantly impacted by the arterial spin-labeling methods used in the quantitative susceptibility mapping plus the quantitative blood oxygen level-dependent model, indicating that the differences should be accounted for when employing oxygen extraction fraction mapping based on this model in diseases.
背景和目的：氧萃取分数是评估大脑新陈代谢的重要生物标志物。最近提出的一种方法结合了定量易感性图谱和定量血氧水平相关幅度，可以无创地绘制氧萃取分数图谱。我们的研究调查了单延迟和多延迟动脉自旋标记的氧萃取分数绘图变化：材料和方法：共招募了 20 名健康参与者。在 3.0 T 下采集了多回波破坏梯度回波、多延迟动脉自旋标记和磁化准备快速梯度回波序列。在 1780 毫秒的单一延迟时间、多延迟动脉自旋标记的过境校正脑血流和多延迟动脉自旋标记的动脉脑血量条件下生成平均析氧分数。结果通过配对 t 检验和 Wilcoxon 检验进行比较。线性回归分析用于研究氧提取率、脑血流量和静脉脑血量之间的关系：结果：用多延迟动脉自旋标记法估算的氧萃取分数明显低于用单延迟动脉自旋标记法估算的氧萃取分数。单延迟动脉自旋标记法、多延迟动脉自旋标记法的过境校正脑血流量和多延迟动脉自旋标记法的动脉脑血量的全脑平均值分别为 41.5 ± 1.7 %（P 结论：多延迟动脉自旋标记法和单延迟动脉自旋标记法的全脑平均值均低于单延迟动脉自旋标记法：这些研究结果表明，氧萃取分数受定量易感性图谱加定量血氧水平依赖模型中使用的动脉自旋标记方法的显著影响，这表明在疾病中使用基于该模型的氧萃取分数图谱时应考虑这些差异。
{"title":"Oxygen extraction fraction mapping based combining quantitative susceptibility mapping and quantitative blood oxygenation level-dependent imaging model using multi-delay PCASL","authors":"Xiaoyi Liu , Yayan Yin , Yi Shan , Wang Chao , Jingkai Li , Yue Zhang , Qiongge Li , Jing Liu , Jie Lu","doi":"10.1016/j.brainres.2024.149259","DOIUrl":"10.1016/j.brainres.2024.149259","url":null,"abstract":"<div><h3>Background and purpose</h3><div>The oxygen extraction fraction is an essential biomarker for the assessment of brain metabolism. A recently proposed method combined with quantitative susceptibility mapping and quantitative blood oxygen level-dependent magnitude enables noninvasive mapping of the oxygen extraction fraction. Our study investigated the oxygen extraction fraction mapping variations of single-delay and multi-delay arterial spin-labeling.</div></div><div><h3>Materials and methods</h3><div>A total of twenty healthy participants were enrolled. The multi-echo spoiled gradient-echo, multi-delay arterial spin-labeling, and magnetization-prepared rapid gradient echo sequences were acquired at 3.0 T. The mean oxygen extraction fraction was generated under a single delay time of 1780 ms, multi-delay arterial spin-labeling of transit-corrected cerebral blood flow, and multi-delay arterial spin-labeling of arterial cerebral blood volume. The results were compared via paired t tests and the Wilcoxon test. Linear regression analyses were used to investigate the relationships among the oxygen extraction fraction, cerebral blood flow, and venous cerebral blood volume.</div></div><div><h3>Results</h3><div>The oxygen extraction fraction estimate with multi-delay arterial spin-labeling yielded a significantly lower value than that with single-delay arterial spin-labeling. The average values for the whole brain under single-delay arterial spin-labeling, multi-delay arterial spin-labeling of transit-corrected cerebral blood flow, and multi-delay arterial spin-labeling of arterial cerebral blood volume were 41.5 ± 1.7 % (P < 0.05), 41.3 ± 1.9 % (P < 0.001), and 40.9 ± 1.9 % (N = 20), respectively. The oxygen extraction fraction also showed a significant inverse correlation with the venous cerebral blood volume under steady-state conditions when multi-delay arterial spin-labeling was used (r = 0.5834, p = 0.0069).</div></div><div><h3>Conclusion</h3><div>These findings suggest that the oxygen extraction fraction is significantly impacted by the arterial spin-labeling methods used in the quantitative susceptibility mapping plus the quantitative blood oxygen level-dependent model, indicating that the differences should be accounted for when employing oxygen extraction fraction mapping based on this model in diseases.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149259"},"PeriodicalIF":2.7,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emerging clinical and epidemiological data indicates that human immunodeficiency virus (HIV) is associated with an increased risk of stroke and aggravated brain damage. We aimed to develop a reproducible murine model of photothrombotic-stroke with HIV infection that mimics the clinical situation.
Method
To evaluate the impact of HIV infection on stroke, male C57BL/6 mice were infected with EcoHIV (p24 2-4 × 106/mouse; i.v.) or mock control. Four weeks post-infection, a stroke was induced by the photothrombotic method (pt-MCAO). After 72 h, a catwalk test was performed for gait impairments, and mice were euthanized for stroke outcomes.
Results
EcoHIV-infection exhibited a larger infarction, brain edema, higher IgG extravasation, hemorrhagic transformation, and gait impairments following pt-MCAO vs mock control. EcoHIV-infected mice showed higher levels of IFN-y and lower levels of IL-6, indicating immune activation without affecting IL-1β and MCP-1 in plasma and brain compared to mock pt-MCAO, suggesting unaltered inflammation. EcoHIV-infection showed increased oxidative stress markers (nitrotyrosine, and 4-hydroxynonenal) and thioredoxin interacting protein expression. Further, EcoHIV-infection significantly activated the microglia and astrocyte cells.
Conclusions
This animal model would be reliable and clinically relevant to future studies investigating pathophysiological mechanisms and developing new therapeutic approaches in stroke patients with HIV conditions.
{"title":"A reproducible murine model of studying HIV-associated brain damage in stroke","authors":"Mohd Salman , Golnoush Mirzahosseini , Lina Zhou , Sandip Godse , Namita Sinha , Santosh Kumar , Tauheed Ishrat","doi":"10.1016/j.brainres.2024.149256","DOIUrl":"10.1016/j.brainres.2024.149256","url":null,"abstract":"<div><h3>Background</h3><div>Emerging clinical and epidemiological data indicates that human immunodeficiency virus (HIV) is associated with an increased risk of stroke and aggravated brain damage. We aimed to develop a reproducible murine model of photothrombotic-stroke with HIV infection that mimics the clinical situation.</div></div><div><h3>Method</h3><div>To evaluate the impact of HIV infection on stroke, male C57BL/6 mice were infected with EcoHIV (p24 2-4 × 10<sup>6</sup>/mouse; i.v.) or mock control. Four weeks post-infection, a stroke was induced by the photothrombotic method (pt-MCAO). After 72 h, a catwalk test was performed for gait impairments, and mice were euthanized for stroke outcomes.</div></div><div><h3>Results</h3><div>EcoHIV-infection exhibited a larger infarction, brain edema, higher IgG extravasation, hemorrhagic transformation, and gait impairments following pt-MCAO vs mock control. EcoHIV-infected mice showed higher levels of IFN-y and lower levels of IL-6, indicating immune activation without affecting IL-1β and MCP-1 in plasma and brain compared to mock pt-MCAO, suggesting unaltered inflammation. EcoHIV-infection showed increased oxidative stress markers (nitrotyrosine, and 4-hydroxynonenal) and thioredoxin interacting protein expression. Further, EcoHIV-infection significantly activated the microglia and astrocyte cells.</div></div><div><h3>Conclusions</h3><div>This animal model would be reliable and clinically relevant to future studies investigating pathophysiological mechanisms and developing new therapeutic approaches in stroke patients with HIV conditions.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1846 ","pages":"Article 149256"},"PeriodicalIF":2.7,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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