Cognitive Recovery Research Articles

The neurocognitive correlates of DTI indicators of white matter disorganization in pediatric moderate-to-severe traumatic brain injury

IntroductionNeuroimaging has expanded our understanding of pediatric brain disorders in which white matter organization and connectivity are crucial to functioning. Paralleling the known pathobiology of many neurodevelopmental disorders, traumatic brain injury (TBI) in childhood can alter trajectories of brain development. Specifically, diffusion tensor imaging (DTI) studies in TBI have demonstrated white matter (WM) abnormalities that suggest microstructural disruptions that may underlie atypical neurodevelopment. The neurocognitive correlates of these previous findings will be explored in this study.MethodsIndicators of WM organization were collected in 44 pediatric patients with moderate/severe TBI and 76 controls over two post-injury time points: T1 (8–20 weeks) and T2 (54–96 weeks). Our previous work identified two TBI subgroups based on information processing differences: one with slower interhemispheric transfer times (IHTT) of visual information than controls and another with comparable IHTT. We extend this prior work by evaluating neurocognitive trajectories associated with divergent WM structure post-injury in slow and normal IHTT TBI subgroups.ResultsAt T1, both TBI subgroups performed significantly worse than controls on a norm-referenced working memory index (WMI), but only the Normal IHTT TBI subgroup significantly improved over the 12-month follow-up period (p = 0.014) to match controls (p = 0.119). In contrast, the Slow IHTT TBI subgroup did not show any recovery in working memory performance over time and performed more poorly than the control group (p < 0.001) at T2. Improvement in one of the two WMI subtests was associated with DTI indicators of WM disorganization in CC tracts to the precentral, postcentral, frontal, and parietal cortices. IHTT and WM mean diffusivity predicted 79% of the variance in cognitive recovery from T1 to T2 when also accounting for other known predictors of TBI recovery.DiscussionIn the year following TBI, some pediatric patients experienced persisting working memory disturbance while others exhibited recovery; stratification was based on an event-related potential marker. More or less improvement in neurocognition was also associated with the degree of WM disorganization. IHTT, measured post-acutely after TBI, and progression of WM disorganization over time predicted neurocognitive trajectories at the chronic timeframe - potentially representing a prognostic biomarker.

The Comparison of Two Multitasking Approaches to Cognitive Training in Patients after Coronary Bypass Surgery: Theta Activity Changes and <i>sLORETA</i> Analysis Data

The study investigated the changes in theta activity and localization of its sources by standardized low resolution brain electromagnetic tomography (sLORETA) in patients who have underwent two variants of multitasking cognitive training (CT) in the early postoperative period of coronary artery bypass grafting (CABG). Two groups were formed in a pseudo-random way, which differed according to the type of motor problem used: CT I (n = 27) – a postural balance task and CT II (n = 27) – a simple visual-motor reaction. Cognitive tasks were the same for both groups (counting backwards, verbal fluency, and unusual uses for common objects). Daily sessions of CT were held from the 3rd to 4th day after CABG, with a duration of 5 minutes on the 1st day of training and up to 20 minutes on the 6th to 7th day of training. The current density of theta rhythm sources was lower before CABG than after surgery in the CT II group only. The most significant differences are in the Brodmann area 31, the parietal occipital lobes and precuneus, which may indicate damage associated with cardiac surgery. This effect was not observed in the CT I group. The results of our study demonstrated the informativeness of sLORETA indicators to determine an effective cognitive recovery option after CABG. The reduction of the severity of damaging effects of CABG during training using cognitive tasks and postural balance task was shown. Further research is needed to determine the optimal mode and duration of cognitive training to maximize the functional reserves of such patients.

Cognitive recovery of post critical care patients with and without COVID-19: differences and similarities, an observational study

BackgroundCoronavirus disease (COVID-19) patients treated in an intensive care unit (ICU) are at high risk of developing cognitive impairments of a “post-intensive care syndrome” (PICS). We explored whether critically ill COVID-19 and non-COVID-19 survivors differ in their post-ICU recovery course in terms of severity and affected cognitive domains.MethodsAn observational prospective study was conducted in a German post-acute neurological early rehabilitation clinic. Critically ill patients with or without SARS-CoV-2 infection (at least mechanically ventilated for one week) underwent repeated standardized assessments during their subsequent inpatient rehabilitation stay. Cognitive functions (information processing speed, learning, recognition, short-term and working-memory, word fluency, flexibility) assigned to different domains (attention, memory, executive functions) were assessed as primary outcome. Secondary outcomes included mental (depression, anxiety) and physical (Barthel index, modified ranking scale) state.ResultsOut of 92 eligible patients (screened between June 2021 and August 2023), 34 were examined, and 30 were available for analysis (15 per group). Both groups were ventilated for a similar period (COVID-19 vs. Non-COVID-19: median: 48 vs. 53 days). Patients of COVID-19 group spend on average 10 days longer at ICU and developed slightly more complications, but subsequent inpatient rehabilitation was of comparable duration (median: 36.5 vs. 37 days). On the group-level both groups showed similar cognitive dysfunctions with striking impairments (normative T-scores < 41) in information processing speed, word fluency, flexibility, and recognition memory on admission. Significant gains until discharge were only revealed for information processing speed in both groups (main effect visit, mean difference [95%CI] − 7.5 [− 13.1, − 2.0]). Physical and mental state were also similarly affected in both groups on admission, but improved over time, indicating that overall recovery for higher-order cognitive functions is slowest. Interestingly, majority of patients stated correctly being still physically disabled, while a discrepancy was found between subjective and objective evaluation of cognitive health.ConclusionsResults suggest a substantial overlap of cognitive, mental and physical dysfunction in post-acute recovery of ICU survivors independent of SARS-CoV-2 infection which warrants further monitoring to reduce the risk of long-term burden and enable a return to previous functionality.Trial registrationRetrospectively registered at https://drks.de/search/de/trial/DRKS00025523, 21.06.2021.

Amyloid deposition and its association with depressive symptoms and cognitive functions in late-life depression: a longitudinal study using amyloid-β PET images and neuropsychological measurements

BackgroundAlthough depression is linked to an increased risk of dementia, the association between late-onset depression (LOD) and amyloid burden remains unclear. This study aimed to determine amyloid deposition in patients with LOD compared to healthy controls (HC) using amyloid-beta (Aβ) positron emission tomography (PET) images and neuropsychological assessments.MethodsForty patients first diagnosed with major depressive disorder after the age of 60 (LOD) and twenty-one healthy volunteers (HC) were enrolled. Depression and anxiety were evaluated using the 17-item Hamilton Depression Scale, Hamilton Anxiety Rating Scale, and Clinical Global Impression Scale. Cognitive function was assessed using the Korean versions of the Mini-Mental Status Examination, Montreal Cognitive Assessment, and Seoul Neuropsychological Screening Battery at baseline and 3-month follow-up. 18F-florbetapir PET images were co-registered with T1-weighted magnetic resonance images.ResultsThere was no significant difference in Aβ deposition between LOD and HC groups. No significant correlation between Aβ burden and depressive symptom severity was found in LOD patients. Higher somatic anxiety was correlated with lower Aβ burden in multiple brain regions, including the left inferior frontal lobe (p = 0.009), right anterior cingulate (p = 0.003), and right superior frontal lobe (p = 0.009). Despite cognitive recovery in areas such as attention (Digit Span Forward, p = 0.026), memory (Auditory Verbal Learning Test Recall Total, p = 0.010; Rey Complex Figure Test Delayed Recall, p = 0.039), and frontal executive function (Contrasting Program, p = 0.033) after three months of antidepressant treatment, cognitive improvement showed no association with amyloid deposition.ConclusionsThese findings suggest distinct mechanisms may underlie amyloid deposition in neurodegenerative changes associated with depression. While amyloid burden in specific brain regions negatively correlated with somatic anxiety, it showed no significant correlation with the severity of depression or overall cognitive function.

Handgrip Strength and Cognitive Recovery in Older Stroke Survivors: A Prospective Study

Background and Objectives: Handgrip strength (HGS) is an important indicator of overall physical capability and is linked to various health outcomes in older adults. Despite extensive research on the relationship between HGS and cognitive decline, longitudinal studies on poststroke cognitive changes in relation to HGS are scarce. This study aimed to observe whether HGS at discharge from acute stroke rehabilitation affects cognitive function 6–12 months after stroke onset and to compare cognitive outcomes between patients with normal and low HGS at discharge. Materials and Methods: This prospective cohort study was conducted in the Department of Rehabilitation Medicine at a tertiary care hospital. In agreement with the Asian Working Group for Sarcopenia 2019 criteria, low muscle strength was defined as an HGS of less than 28 kg for men and less than 18 kg for women, and participants were categorized into normal and low HGS groups. Neuropsychological evaluations were conducted before discharge (approximately one month after stroke onset) and between 6 and 12 months after stroke onset. Results: The low HGS group was older and had lower Montreal Cognitive Assessment scores. However, after adjusting for covariates, the linear mixed model analysis showed no significant differences between the groups in global cognition or specific cognitive domains, except for psychomotor speed during the subacute phase. Notable improvements in language ability were observed in both groups over time, while significant improvements in executive function were observed exclusively in the low HGS group. Conclusions: This longitudinal study is the first to explore the relationship between HGS and changes in cognitive function in older adults with stroke, providing insights into physical strength and cognitive recovery during stroke rehabilitation.

Study protocol: Cerebral autoregulation, brain perfusion, and neurocognitive outcomes after traumatic brain injury -CAPCOG-TBI.

Moderate-severe traumatic brain injury (msTBI) stands as a prominent etiology of adult disability, with increased risk for cognitive impairment and dementia. Although some recovery often occurs within the first year post-injury, predicting long-term cognitive outcomes remains challenging, partly due to the significant pathophysiological heterogeneity of TBI, including acute cerebrovascular injury. The primary aim of our recently funded study, cerebral autoregulation, brain perfusion, and neurocognitive outcomes after traumatic brain injury (CAPCOG-TBI), is to determine if acute cerebrovascular dysfunction after msTBI measured using multimodal non-invasive neuromonitoring is associated with cognitive outcome at 1-year post-injury. This longitudinal observational study will be conducted at two Level 1 trauma centers in Texas, USA, and will include adult patients with msTBI, and/or mild TBI with neuroimaging abnormalities. Multimodal cerebral vascular assessment using transcranial Doppler and cerebral near-infrared spectroscopy (NIRS) will be conducted within 7-days of onset of TBI. Longitudinal outcomes, including cognitive/functional assessments (Glasgow Outcome Scale and Patient-Reported Outcomes Measurement Information System), cerebral vascular assessment, and imaging will be performed at follow-ups 3-, 6-, and 12-months post-injury. We aim to recruit 100 subjects with msTBI along with 30 orthopedic trauma controls (OTC). This study is funded by National Institute of Neurological Disease and Stroke (NINDS) and is registered on Clinicaltrial.org (NCT06480838). We anticipate that msTBI patients will exhibit impaired cerebrovascular function in the acute phase compared to the OTC group. The severity of cerebrovascular dysfunction during this stage is expected to inversely correlate with cognitive and functional outcomes at 1-year post-injury. Additionally, recovery from cerebrovascular dysfunction is expected to be linked to cognitive recovery. The results of this study could help to understand the contribution of cerebrovascular dysfunction to cognitive outcomes after TBI and pave the way for innovative vascular-focused interventions aimed at enhancing cognitive recovery and mitigating neurodegeneration following msTB. In addition, its focus toward personalized medicine to aid in the management and prognosis of TBI patients.

Sharper Minds: Cognitive Recovery After Epilepsy Surgery in Children

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Alpha coherence is a network signature of cognitive recovery from disorders of consciousness.

Alpha (8-12 Hz) frequency band oscillations are among the most informative features in electroencephalographic (EEG) assessment of patients with disorders of consciousness (DoC). Because interareal alpha synchrony is thought to facilitate long-range communication in healthy brains, coherence measures of resting-state alpha oscillations may provide insights into a patients capacity for higher-order cognition beyond channel-wise estimates of alpha power. In multi-channel EEG, global coherence methods may be used to augment standard spectral analysis methods by both estimating the strength and identifying the structure of coherent oscillatory networks. We performed global coherence analysis in 95 separate clinical EEG recordings (28 healthy controls and 33 patients with acute or chronic DoC, 25 of whom returned for follow-up) collected between two academic medical centers. We found that posterior alpha coherence is associated with recovery of higher-level cognition. We developed a measure of network organization, based on the distance between eigenvectors of the alpha cross-spectral matrix, that detects recovery of posterior alpha networks. In patients who have emerged from a minimally conscious state, we showed that coherence-based alpha networks are reconfigured prior to restoration of alpha power to resemble those seen in healthy controls. This alpha network measure performs well in classifying recovery from DoC (AUC = 0.78) compared to common representations of functional connectivity using the weighted phase lag index (AUC = 0.50 - 0.57). Lastly, we observed that activity within these alpha networks is suppressed during positive responses to task-based EEG command-following paradigms, supporting the potential utility of this biomarker to detect covert cognition. Our findings suggest that restored alpha networks may represent a sensitive early signature of cognitive recovery in patients with DoC. Therefore, network detection methods may augment the utility of EEG assessments for DoC.

Postoperative Electroacupuncture Boosts Cognitive Function Recovery after Laparotomy in Mice.

Postoperative cognitive dysfunction (POCD) is a common complication that affects memory, executive function, and processing speed postoperatively. The pathogenesis of POCD is linked to excessive neuroinflammation and pre-existing Alzheimer's disease (AD) pathology. Previous studies have shown that acupuncture improves cognition in the early phase of POCD. However, POCD can last for longer periods (up to weeks and years). The long-term effects of acupuncture are unknown. In this study, we hypothesized that electroacupuncture (EA) could reduce inflammation and cognitive dysfunction induced by laparotomy over a longer period. We characterized the effects of postoperative EA on cognitive changes and investigated the underlying molecular mechanisms in mice. Laparotomy was performed in 3-month-old mice followed by daily EA treatment for 2 weeks. Our data indicated that laparotomy induced prolonged impairment in memory and executive functions, which were mitigated by postoperative EA. EA also reduced tau phosphorylation and suppressed the activation of tau-related kinases and glia, with effects comparable to ibuprofen. These findings demonstrate the beneficial effects of EA in a mouse model of POCD, suggesting that EA's ability to suppress neuroinflammation may contribute to its protective effects. In conclusion, EA may be a viable non-pharmacological intervention for managing POCD in different phases of the medical condition.

Improvement in edema and cognitive recovery after moderate traumatic brain injury with the neurosteroid prodrug NTS-104

Neuroactive steroids reduce mortality, decrease edema, and improve functional outcomes in preclinical and clinical traumatic brain injury (TBI) studies. In this study, we tested the efficacy of two related novel neuroactive steroids, NTS-104 and NTS-105, in a rat model of TBI. NTS-104 is a water-soluble prodrug of NTS-105, a partial progesterone receptor agonist. To investigate the effects of NTS-104 on TBI recovery, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion injury or sham surgery and were treated with vehicle or NTS-104 (10 ​mg/kg, intramuscularly) at 4, 10, 24, and 48 ​h post-TBI. The therapeutic time window was also assessed using the neuroactive steroid NTS-105 (3 ​mg/kg, intramuscularly). Edema in the parietal cortex and hippocampus, measured at 3 days post-injury (DPI), was reduced by NTS-104 and NTS-105. NTS-105 was effective in reducing edema when given at 4, 10, or 24 ​h post-injury. Sensorimotor deficits in the cylinder test at 3 DPI were ameliorated by NTS-104 and NTS-105 treatment. Cognitive recovery, assessed with cue and contextual fear conditioning and retention of the water maze task assessed subacutely 1–3 weeks post-injury, also improved with NTS-104 treatment. Cortical and hippocampal atrophy at 22 DPI did not improve, indicating that NTS-104/NTS-105 may promote post-TBI cognitive recovery by controlling edema and other processes. These results demonstrate that NTS-104/NTS-105 is a promising therapeutic approach to improve motor and cognitive recovery after moderate TBI.

Cognitive Effects of Transcranial Direct Current Stimulation Plus Robotic Verticalization in Minimally Conscious State.

Transcranial direct current stimulation (tDCS) is a non-invasive therapeutic method that modulates cortical excitability and shows promising results for treating disorders of consciousness (DoCs). Robotic verticalization training (RVT) has been shown to enhance motor and cognitive recovery. This study evaluates the effects of an innovative approach combining RVT with tDCS in individuals with DoCs. Twenty-four subjects with DoCs, particularly those with chronic minimally conscious state (MCS) due to vascular or traumatic brain injury, participated in a quasi-randomized study at the Neurorehabilitation Unit, IRCCS Neurolesi (Messina, Italy). Participants were divided into either a control group (CG) receiving RVT alone or an experimental group (EG) receiving combined tDCS and RVT. Both groups underwent treatments five times weekly for four weeks, with tDCS/sham sessions over the dorsolateral prefrontal cortex (DLPFC) lasting 20 min before Erigo training sessions, which lasted 45 min. The findings indicate that combining tDCS with Erigo® Pro RTT could lead to greater improvements in cognitive functioning and P300 latency compared to the CG. These results suggest that the integrated approach of tDCS with RVT could offer significant benefits for patients with MCS, highlighting its potential to enhance cognitive recovery, such as reducing P300 latency.

Impact of pre-stroke cognitive decline on rehabilitation effectiveness and cognitive-functional status of patients in the acute period of ischemic stroke

Summary. The aim was to assess the influence of premorbid cognitive deficit on the effectiveness of rehabilitation using VR technologies and cognitive-functional status of patients in the acute period of ischemic stroke based on statistical methodology. Materials and methods: 120 patients diagnosed with ischemic stroke were examined. The IQCODE questionnaire was used to identify the patient’s cognitive decline before and the Pandas and SciPy libraries. Results: all patients had a multifunctional type of cognitive impairment with a predominant decline in the areas of executive function, memory, speech and perception. Patients of the 2nd group had a more pronounced deficit in the areas of constructive praxis, episodic memory, semantic information processing and perception. Assessment of the dynamics of cognitive impairment during therapy revealed a significant improvement in memory loss (p=0, 0034), executive dysfunction (p&lt;0.0001) and attention impairment (p=0.0001) in patients of 1st group and regression cognitive deficit in almost all cognitive areas in patients of 2nd group. Factors impeding rehabilitation in 1st group of patients were attention (r = -0,325) and perceptual disorders (r = -0,425); in 2nd group: semantic aphasia (r = -0,425), constructive apraxia (r = -0,325), speech impairment (r = — 0,375), object agnosia (r = -0,323) and IQCODE (r = -0,395). Conclusion: pre-stroke cognitive impairments are predictors of the development and progression of post-stroke cognitive deficits and reduce the possibilities of rehabilitation and cognitive recovery. The introduction of IQCODE in the diagnosis of cognitive dysfunction in the acute period of ischemic stroke is a useful tool in predicting the course and development of cognitive deficit and studying the prospects of rehabilitation programmes using VR technologies in patients with pre-stroke cognitive impairment.

INhaled Sedation versus Propofol in REspiratory failure in the Intensive Care Unit (INSPiRE-ICU1): protocol for a randomised, controlled trial

IntroductionSedation in mechanically ventilated adults in the intensive care unit (ICU) is commonly achieved with intravenous infusions of propofol, dexmedetomidine or benzodiazepines. Significant limitations associated with each can impact their...

Cognitive improvement after endoscopic third ventriculostomy surgery in long-standing overt ventriculomegaly in adults.

Long-standing overt ventriculomegaly in adults (LOVA) is a chronic form of hydrocephalus that can lead to cognitive deficits. Data on the cognitive profile of patients with LOVA and cognitive outcomes of endoscopic third ventriculostomy (ETV) are, however, scarce and mostly qualitative. Twenty-three consecutive patients with LOVA hydrocephalus underwent ETV surgery, and their cognitive status was assessed before surgery, immediately after surgery, and at the 5-month follow-up. Cognitive function was assessed using a neuropsychological battery measuring 6 cognitive domains: general cognitive status, attention/executive function, language, visuospatial skills, short-term memory, and long-term memory. Cognitive reserve was also estimated through a measure of premorbid IQ to assess its potential influence together with other clinical and demographic variables. Patients with LOVA did not experience general cognitive decline but rather selective long-term memory (p < 0.001) and visuospatial skills (p = 0.001) deficits alone. Moreover, ETV surgery led to significant immediate postoperative improvement in both domains (p = 0.002 and p < 0.001 respectively), that persisted at follow-up (p < 0.001 for both). However, improvement was observed only in patients with higher premorbid IQ (p < 0.001), while the others did not improve (p > 0.532). These findings confirm the effectiveness of ETV surgery and highlight the role of cognitive reserve in promoting plasticity of brain and cognitive functions thus fostering and predicting cognitive recovery.

Neuropsychological Performance after Extended N-Pep-12 Dietary Supplementation in Supratentorial Ischemic Stroke.

Background: Cognitive deficits following ischemic stroke significantly impair quality of life, highlighting the need for effective interventions. This study evaluates the efficacy and safety of extended N-Pep-12 dietary supplementation in enhancing cognitive recovery post-stroke. Methods: In this randomized, open-label, controlled study, 106 patients with supratentorial ischemic stroke were enrolled to receive either 90mg N-Pep-12 or no supplementation daily for 360 days and were followed-up for 360 days. Cognitive function and emotional well-being were assessed using established neuropsychological scales at baseline, 90 days, and 360 days post-stroke. Safety was monitored through adverse events and mortality rates. Results: Significant improvements were observed in the N-Pep-12 group compared to controls, particularly in the Montreal Cognitive Assessment scores at both 90 and 360 days, and in the Digit Symbol Coding scores at 360 days, suggesting enhanced cognitive recovery with extended N-Pep-12 supplementation. A linear regression for a composite outcome analysis at day 360 further confirmed the efficacy of N-Pep-12 in contributing to cognitive improvement. Safety profiles were favorable, with no significant adverse effects attributed to N-Pep-12. Conclusions: Extended dietary supplementation with N-Pep-12 appears to offer a safe and effective approach to support cognitive recovery in ischemic stroke survivors. These findings underscore the potential of the supplement as an add-on intervention for managing post-stroke cognitive impairments.

A study comparing brain wave patterns of fentanyl and ketamine in adult patients undergoing minimally invasive surgery.

This study aimed to investigate and compare the neurophysiological impacts of two widely used anesthetic agents, Fentanyl and Ketamine, on EEG power spectra during different stages of anesthesia in adult patients undergoing minimally invasive surgery. EEG data were collected from patients undergoing anesthesia with either Fentanyl or Ketamine. The data were analyzed for relative power spectrum and fast-to-slow wave power ratios, alongside Spectral Edge Frequency 95% (SEF95), at 3 key stages: pre-anesthesia, during stable anesthesia, and post-anesthesia. EEG Relative Power Spectrum: Initially, both groups exhibited similar EEG spectral profiles, establishing a uniform baseline (P > .05). Upon anesthesia induction, the Fentanyl group showed a substantial increase in delta band power (P < .05), suggesting deeper anesthesia, while the Ketamine group maintained higher alpha and beta band activity (P < .05), indicative of a lighter sedative effect. Fast and Slow Wave Power Ratios: The Fentanyl group exhibited a marked reduction in the fast-to-slow wave power ratio during anesthesia (P < .05), persisting post-anesthesia (P < .05) and indicating a lingering effect on brain activity. Conversely, the Ketamine group demonstrated a more stable ratio (P > .05), conducive to settings requiring rapid cognitive recovery. Spectral Edge Frequency 95% (SEF95): Analysis showed a significant decrease in SEF95 values for the Fentanyl group during anesthesia (P < .05), reflecting a shift towards lower frequency power. The Ketamine group experienced a less pronounced decrease (P > .05), maintaining a higher SEF95 value that suggested a lighter level of sedation. The study highlighted the distinct impacts of Fentanyl and Ketamine on EEG power spectra, with Fentanyl inducing deeper anesthesia as evidenced by shifts towards lower frequency activity and a significant decrease in SEF95 values. In contrast, Ketamine's preservation of higher frequency activity and more stable SEF95 values suggests a lighter, more dissociative anesthetic state. These findings emphasize the importance of EEG monitoring in anesthesia for tailoring anesthetic protocols to individual patient needs and optimizing postoperative outcomes.

Integrative Neuro-social cognitive Strategy Programme for Instilling REcovery (INSPIRE): a community-based cognitive remediation trial-study procotol

BackgroundAdults with schizophrenia experience a range of neurocognitive problems that affect their daily functioning. Evidence for the efficacy of cognitive remediation in schizophrenia has been established, but its implementation in under-resourced community-based settings is less well-studied. In recent years, interventions have also focused on the strategy-learning approach in favor of drill-and-practice. Moreover, there is an increasing recognition to address social cognition and negative symptoms alongside neurocognition.This study attempts to carry out cognitive remediation in a community mental health setting. The Neuropsychological and Educational Approach to Remediation (NEAR) is used as the cognitive remediation intervention. Neurocognitive and social cognitive games will be introduced during the computer-assisted cognitive exercises sessions. In addition, the instructional technique will foster the use of metacognition and cognitive strategies. Moreover, metamotivation training will be the focus of some bridging sessions to enhance motivation to engage in goal-directed learning behaviors.The aims of the study are to 1) investigate the effects of cognitive remediation on neurocognition, social cognition and functional outcomes of participants with schizophrenia/schizoaffective disorders in community mental health settings; and 2) explore the mediators for change (eg: metamotivation, metacognition and negative symptoms) in cognitive performance and functional outcomes.MethodsThis randomized controlled trial will be conducted in three Singapore Anglican Community Services (SACS) centers, where standard psychiatric rehabilitation is delivered. Participants who are randomized to the experimental arm will receive cognitive remediation and psychiatric rehabilitation, while those randomized to the control arm will receive standard psychiatric rehabilitation only. Cognitive remediation is carried out three times a week for 12 weeks. It consists of computer-assisted cognitive exercises, as well as bridging groups to aid transfer of learning to daily living. Baseline, post-intervention and eight-week follow-up measurements will be collected. Group by time differences in cognitive performance, negative symptoms, metamotivation, metacognition, functioning and recovery will be analyzed across the three time points. Mediators for improvement in cognitive performance and functioning will also be explored.DiscussionFindings of this research will add to the body of knowledge about the key therapeutic ingredients within a strategy-based cognitive remediation program and improve its implementation within under-resourced community settings.Trial registrationThis study has been registered with ClinicalTrials.gov (ID: NCT06286202). Date of registration: 29 February 2024. Date of last update: 21 May 2024.

Dendritic morphological development of traumatic brain injury-induced new neurons in the dentate gyrus is important for post-injury cognitive recovery and is regulated by Notch1

Traumatic brain injury (TBI) is a prevalent problem with survivors suffering from chronic cognitive impairments. Following TBI there is a series of neuropathological changes including neurogenesis. It is well established that neurogenesis in the dentate gyrus (DG) of the hippocampus is important for hippocampal dependent learning and memory functions. Following TBI, injury-enhanced hippocampal neurogenesis is believed to contribute to post-injury cognitive recovery. Behavioral function is connected to synaptic plasticity and neuronal dendritic branching is critical for successful synapse formation. To ascertain the functional contribution of injury-induced DG new neurons in post-TBI cognitive recovery, it is necessary to study their dendritic morphological development and the molecular mechanisms controlling this process. Utilizing transgenic mice with tamoxifen-induced GFP expression and Notch1 knock-out in nestin+ neural stem cells, this study examined dendritic morphology, the role of Notch1 in regulating dendritic complexity of injury-induced DG new neurons, and their association to post-TBI cognitive recovery. We found that at 8 weeks after a moderate TBI, injury-induced DG new neurons in the injured control mice displayed a similar dendritic morphology as the cells in non-injured mice accompanied with cognitive recovery. In comparison, in Notch1 conditional knock-out mice, DG new neurons in the injured mice had a significant reduction in dendritic morphological development including dendritic arbors, volume span, and number of branches in comparison to the cells in non-injured mice concomitant with persistent cognitive dysfunction. The results of this study confirm the importance of post-injury generated new neurons in cognitive recovery following TBI and the role of Notch1 in regulating their maturation process.

Orosomucoid 2 is an endogenous regulator of neuronal mitochondrial biogenesis and promotes functional recovery post-stroke

Development of functional recovery therapies is critical to reduce the global impact of stroke as the leading cause of long-term disability. Our previous studies found that acute-phase protein orosomucoid (ORM) could provide an up to 6 h therapeutic time window to reduce infarct volume in acute ischemic stroke by improving endothelial function. However, its role in neurons and functional recovery post-stroke remains largely unknown. Here, we showed that exogenous ORM administration with initial injection at 0.5 h (early) or 12 h (delayed) post-MCAO daily for consecutive 7 days significantly decreased infarct area, improved motor and cognitive functional recovery, and promoted mitochondrial biogenesis after MCAO. While neuron-specific knockout of ORM2, a dominant subtype of ORM in the brain, produced opposite effects which could be rescued by exogenous ORM. In vitro, exogenous ORM protected SH-SY5Y cells from OGD-induced damage and promoted mitochondrial biogenesis, while endogenous ORM2 deficiency worsened these processes. Mechanistically, inactivation of CCR5 or AMPK eliminated the protective effects of ORM on neuronal damage and mitochondrial biogenesis. Taken together, our findings demonstrate that ORM, mainly ORM2, is an endogenous regulator of neuronal mitochondrial biogenesis by activating CCR5/AMPK signaling pathway, and might act as a potential therapeutic target for the functional recovery post-stroke.

Activating PKA signaling increases exosome production and attenuates cerebral ischemia-reperfusion injury by regulating Cx43 expression

BackgroundConnexin 43 (Cx43) plays a crucial role in mediating intracellular communication and facitating the interaction between exosomes and recipient cells. This study investigates whether the activation of cAMP/protein kinase A (PKA) can regulate exosomal Cx43 expression and contribute to the functional recovery following ischemia-reperfusion (I/R) injury. MethodsAn intraluminal vascular occlusion was performed on Lewis rats to simulate I/R injury. Concurrently, a PKA activator (8-Bromo-cAMP, 5 mg kg-1) or PKA inhibitor (H 89 2HCl, 20 mg kg-1) was administered intravenously via the tail vein (n = 10). Exosomes were isolated from cerebrospinal fluid, and the expression of exosomal markers (CD63 and CD81) and Cx43 was analyzed using Western blot. The expression of CD63 and CD81 in astrocytes was measured to assess exosome uptake. Spatial learning and memory capability were evaluated using the Morris water maze test. Results8-Bromo-cAMP significantly increased exosome release in cerebrospinal fluid, accompanied by elevated Cx43 expression. Additionally, 8-Bromo-cAMP enhanced exosome uptake by astrocytes, alleviated blood-brain barrier damage and edema, and improved cognitive function. ConclsionsPKA activation enhances exosome production, promotes cognitive function recovery, and attenuates cerebral I/R injury by up-regulating exosomal Cx43 expression.