A modified neural circuit framework for semantic memory retrieval with implications for circuit modulation to treat verbal retrieval deficits.

Word finding difficulty is a frequent complaint in older age and disease states, but treatment options are lacking for such verbal retrieval deficits. Better understanding of the neurophysiological and neuroanatomical basis of verbal retrieval function may inform effective interventions. In this article, we review the current evidence of a neural retrieval circuit central to verbal production, including words and semantic memory, that involves the pre-supplementary motor area (pre-SMA), striatum (particularly caudate nucleus), and thalamus. We aim to offer a modified neural circuit framework expanded upon a memory retrieval model proposed in 2013 by Hart et al., as evidence from electrophysiological, functional brain imaging, and noninvasive electrical brain stimulation studies have provided additional pieces of information that converge on a shared neural circuit for retrieval of memory and words. We propose that both the left inferior frontal gyrus and fronto-polar regions should be included in the expanded circuit. All these regions have their respective functional roles during verbal retrieval, such as selection and inhibition during search, initiation and termination of search, maintenance of co-activation across cortical regions, as well as final activation of the retrieved information. We will also highlight the structural connectivity from and to the pre-SMA (e.g., frontal aslant tract and fronto-striatal tract) that facilitates communication between the regions within this circuit. Finally, we will discuss how this circuit and its correlated activity may be affected by disease states and how this circuit may serve as a novel target engagement for neuromodulatory treatment of verbal retrieval deficits.

Effect of electroacupuncture on proBDNF/mBDNF and synaptic plasticity in rats with learning and memory impairment after cerebral ischemia-reperfusion. / ç”µé’ˆå¯¹è„‘ç¼ºè¡€å†çŒæ³¨å­¦ä¹ è®°å¿†éšœç¢å¤§é¼ æµ·é©¬è„‘æºæ€§ç¥žç»è¥å »å› å­è½¬åŒ–å’Œçªè§¦å¯å¡‘æ€§çš„å½±å“.

OBJECTIVES: To observe the effect of electroacupuncture (EA) at "Baihui" (GV20) and "Shenting" (GV24) on the rats' behavior and the transforming precursor of brain-derived neurotrophic factor (proBDNF) into mature brain-derived neurotrophic factor (mBDNF) in the hippocampus of rats with learning and memory impairment induced by cerebral ischemia-reperfusion (IR), so as to explore its mechanisms underlying improvement of learning and memory ability. METHODS: SD rats were randomly divided into blank, sham operation, model, and EA groups, with 6 rats in each group. The model of IR was established by occlusion of the middle cerebral artery. EA (1 Hz/20 Hz) was applied to GV24 and GV20 for 30 min, once daily for 14 days. The neurological function was evaluated according to the Zea Longa's score criteria 24 h after modeling and after intervention. Morris water maze test was used to detect the learning and memory function of the rats. TTC staining was used to evaluate the cerebral infarction volume on the affected side. The protein expression levels of proBDNF, mBDNF, tissue plasminogen activator (tPA), tyrosine kinase receptor B (TrkB) and p75 neurotrophin receptor (p75NTR) in hippocampal tissue were detected by Western blot. RESULTS: Compared with the sham operation group, the neurological function score, the percentage of cerebral infarction volume and the expression levels of proBDNF and p75NTR protein in hippocampus were increased (P<0.01), while the times of crossing the original platform and the total distance in the target quadrant, the expression levels of mBDNF, TrkB and tPA protein and the ratio of mBDNF/proBDNF were decreased (P<0.01, P<0.05) in the model group. Compared with the model group, the neurological function score, the percentage of cerebral infarction volume, and the expression levels of proBDNF and p75NTR protein in hippocampus were decreased (P<0.01, P<0.05), while the times of crossing the original platform, the total distance in the target quadrant, and the expression levels of mBDNF, TrkB and tPA protein and the ratio of mBDNF/proBDNF were increased (P<0.05, P<0.01) in the EA group. CONCLUSIONS: EA can alleviate learning and memory impairment in IR rats, which may be related to its function in up-regulating the expression of tPA protein and promoting the transformation of proBDNF to mBDNF, thus improving the synaptic plasticity.

Hydrogen sulfide mitigates memory impairments via the restoration of glutamatergic neurons in a mouse model of hemorrhage shock and resuscitation.

Impaired long-term memory, a complication of traumatic stress including hemorrhage shock and resuscitation (HSR), has been reported to be associated with multiple neurodegenerations. The ventral tegmental area (VTA) participates in both learned appetitive and aversive behaviors. In addition to being prospective targets for the therapy of addiction, depression, and other stress-related diseases, VTA glutamatergic neurons are becoming more widely acknowledged as powerful regulators of reward and aversion. This study revealed that HSR exposure induces memory impairments and decreases the activation in glutamatergic neurons, and decreased ß power in the VTA. We also found that optogenetic activation of glutamatergic neurons in the VTA mitigated HSR-induced memory impairments, and restored ß power. Moreover, hydrogen sulfide (H2S), a gasotransmitter with pleiotropic roles, has neuroprotective functions at physiological concentrations. In vivo, H2S administration improved HSR-induced memory deficits, elevated c-fos-positive vesicular glutamate transporters (Vglut2) neurons, increased ß power, and restored the balance of γ-aminobutyric acid (GABA) and glutamate in the VTA. This work suggests that glutamatergic neuron stimulation via optogenetic assay and exogenous H2S may be useful therapeutic approaches for improving memory deficits following HSR.

Oral administration of bacterial probiotics improves Helicobacter pylori-induced memory impairment in rats: Insights from behavioral and biochemical investigations.

There are numerous evidence supporting the association between Helicobacter pylori (H. pylori) infection and the occurrence of cognitive deficits in humans. In this regard, treatment of H. pylori infection has been suggested as an effective strategy to decelerate the neurodegenerative processes of memory deficits in AD patients. Numerous studies support the beneficial effects of probiotics on various pathological conditions, particularly cognitive deficits, however, this concern has not been addressed in relation to the memory impairment induced by H. pylori infection. In the present study, we aimed to reveal whether oral administration of two bacterial probiotics (including Lactobacillus rhamnosus and Lactobacillus plantarum), could ameliorate H. pylori-induced memory deficits at behavioral level in rats. Besides, cellular mechanisms were investigated by biochemical methods to find out how probiotic effects are mediated in hippocampal circuitry. Male Wistar rats were infected by H. pylori for 3 consecutive days, then probiotic treatment was done for the next 3 days and after a drug-free period (12 days), animals were assessed by Morris Water Maze and Novel Object Recognition tests. Finally, rats were euthanized by CO2 and hippocampal tissues were excised for biochemical measurements. Results indicated that H. pylori infection markedly impairs memory function in rats which is associated with alterations of oxidative, inflammatory, neurotrophic, and cholinergic markers. Interestingly, treatment with either of the probiotics alone or in combination, significantly improved the H. pylori-induced memory deficits and this was associated with restoration of balance in biochemical factors within the hippocampal neurons.

Electroconvulsive therapy disrupts functional connectivity between hippocampus and posterior default mode network.

BACKGROUND: The mechanisms underlying memory deficits after electroconvulsive therapy (ECT) remain unclear but altered functional interactions between hippocampus and neocortex may play a role. OBJECTIVES: To test whether ECT reduces functional connectivity between hippocampus and posterior regions of the default mode network (DMN) and to examine whether altered hippocampal-neocortical functional connectivity correlates with memory impairment. A secondary aim was to explore if these connectivity changes are present 6 months after ECT. METHODS: In-patients with severe depression (n = 35) received bitemporal ECT. Functional connectivity of the hippocampus was probed with resting-state fMRI before the first ECT-session, after the end of ECT, and at a six-month follow-up. Memory was assessed with the Verbal Learning Test - Delayed Recall. Seed-based connectivity analyses established connectivity of four hippocampal seeds, covering the anterior and posterior parts of the right and left hippocampus. RESULTS: Compared to baseline, three of four hippocampal seeds became less connected to the core nodes of the posterior DMN in the week after ECT with Cohen's d ranging from -0.9 to -1.1. At the group level, patients showed post-ECT memory impairment, but individual changes in delayed recall were not correlated with the reduction in hippocampus-DMN connectivity. At six-month follow-up, no significant hippocampus-DMN reductions in connectivity were evident relative to pre-ECT, and memory scores had returned to baseline. CONCLUSION: ECT leads to a temporary disruption of functional hippocampus-DMN connectivity in patients with severe depression, but the change in connectivity strength is not related to the individual memory impairment.

Improvement of spatial learning and memory deficits by intranasal administration of human olfactory ecto-mesenchymal stem cells in an Alzheimer's disease rat model.

Mesenchymal stem cells therapy provides a new perspective of therapeutic approaches in the treatment of neurodegenerative diseases. The present study aimed to investigate the effects of intranasally transplanted human "olfactory ecto-mesenchymal stem cells" (OE-MSCs) in Alzheimer's disease (AD) rats. In this study, we isolated OE-MSCs from human olfactory lamina propria and phenotypically characterized them using immunocytochemistry and flow cytometry. The undifferentiated OE-MSCs were transplanted either by intranasal (IN) or intrahippocampal (IH) injection to rat models of AD, which were induced by injecting amyloid-beta (Aß) intrahippocampally. Behavioral, histological, and molecular assessments were performed after a three-month recovery period. Based on the results, intranasal administration of OE-MSCs significantly reduced Aß accumulation and neuronal loss, improved learning and memory impairments, and increased levels of BDNF (brain-derived neurotrophic factor) and NMDAR (N-methyl-D-Aspartate receptors) in the AD rat model. These changes were more significant in animals who received OE-MSCs by intranasal injection. The results of this study suggest that OE-MSCs have the potential to enhance cognitive function in AD, possibly mediated by BDNF and the NMDA receptors.

Health Information Technology Supporting Adherence Memory Disorder Patients: A Systematic Literature Review.

BACKGROUND: People with memory disorders have difficulty adhering to treatments. With technological advances, it remains important to investigate the potential of health information technology (HIT) in supporting medication adherence among them. OBJECTIVES: This review investigates the role of HIT in supporting adherence to medication and therapies among patients with memory issues. It also captures the factors that impact technology adherence interventions. METHODS: We searched the literature for relevant publications published until March 15, 2023, using technology to support adherence among patients with memory issues (dementia, Alzheimer's, amnesia, mild cognitive impairment, memory loss, etc.). The review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We conducted a quality assessment of the papers following the Mixed Methods Appraisal Tool. RESULTS: Fifteen studies were included after carefully reviewing the 3,773 articles in the search. Methodological quality, as appraised, ranged from 80 to 100% with eight studies rated 100%. The studies overall did not have a high risk of bias. Thus, all of the 15 studies were included. Technologies investigated were classified into four groups based on their impact: therapeutic patient education, simplifying treatment regimens, early follow-up visits and short-term treatment goals, and reminder programs. Different technologies were used (automatic drug dispensers or boxes, mobile health-based interventions, game-based interventions, e-health-based interventions, patient portals, and virtual reality). The factors impacting patients' adherence to technology-based treatment and medication were clustered into human-computer interaction and integration challenges. CONCLUSION: This study contributes to the literature by classifying the technologies that supported medication adherence among patients with memory issues in four groups. It also explores and presents the possible limitations of existing solutions to drive future research in supporting care for people with memory disorders.

Enriched environment ameliorates fear memory impairments induced by sleep deprivation via inhibiting PIEZO1/calpain/autophagy signaling pathway in the basal forebrain.

AIMS: To verify the hypothesis that an enriched environment (EE) alleviates sleep deprivation-induced fear memory impairment by modulating the basal forebrain (BF) PIEZO1/calpain/autophagy pathway. METHODS: Eight-week-old male mice were housed in a closed, isolated environment (CE) or an EE, before 6-h total sleep deprivation. Changes in fear memory after sleep deprivation were observed using an inhibitory avoidance test. Alterations in BF PIEZO1/calpain/autophagy signaling were detected. The PIEZO1 agonist Yoda1 or inhibitor GsMTx4, the calpain inhibitor PD151746, and the autophagy inducer rapamycin or inhibitor 3-MA were injected into the bilateral BF to investigate the pathways involved in the memory-maintaining role of EE in sleep-deprived mice. RESULTS: Mice housed in EE performed better than CE mice in short- and long-term fear memory tests after sleep deprivation. Sleep deprivation resulted in increased PIEZO1 expression, full-length tropomyosin receptor kinase B (TrkB-FL) degradation, and autophagy, as reflected by increased LC3 II/I ratio, enhanced p62 degradation, increased TFEB expression and nuclear translocation, and decreased TFEB phosphorylation. These molecular changes were partially reversed by EE treatment. Microinjection of Yoda1 or rapamycin into the bilateral basal forebrain induced excessive autophagy and eliminated the cognition-protective effects of EE. Bilateral basal forebrain microinjection of GsMTx4, PD151746, or 3-MA mimicked the cognitive protective and autophagy inhibitory effects of EE in sleep-deprived mice. CONCLUSIONS: EE combats sleep deprivation-induced fear memory impairments by inhibiting the BF PIEZO1/calpain/autophagy pathway.

Combination of fMRI and PET reveals the beneficial effect of three-phase enriched environment on post-stroke memory deficits by enhancing plasticity of brain connectivity between hippocampus and peri-hippocampal cortex.

AIM: The three-phase enriched environment (EE) intervention paradigm has been shown to improve learning and memory function after cerebral ischemia, but the neuronal mechanisms are still unclear. This study aimed to investigate the hippocampal-cortical connectivity and the metabolic interactions between neurons and astrocytes to elucidate the underlying mechanisms of EE-induced memory improvement after stroke. METHODS: Rats were subjected to permanent middle cerebral artery occlusion (pMCAO) or sham surgery and housed in standard environment or EE for 30 days. Memory function was examined by Morris water maze (MWM) test. Magnetic resonance imaging (MRI) was conducted to detect the structural and functional changes. [18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) was conducted to detect brain energy metabolism. PET-based brain connectivity and network analysis was performed to study the changes of hippocampal-cortical connectivity. Astrocyte-neuron metabolic coupling, including gap junction protein connexin 43 (Cx43), glucose transporters (GLUTs), and monocarboxylate transporters (MCTs), was detected by histological studies. RESULTS: Our results showed EE promoted memory function improvement, protected structure integrity, and benefited energy metabolism after stroke. More importantly, EE intervention significantly increased functional connectivity between the hippocampus and peri-hippocampal cortical regions, and specifically regulated the level of Cx43, GLUTs and MCTs in the hippocampus and cortex. CONCLUSIONS: Our results revealed the three-phase enriched environment paradigm enhanced hippocampal-cortical connectivity plasticity and ameliorated post-stroke memory deficits. These findings might provide some new clues for the development of EE and thus facilitate the clinical transformation of EE.

Memory and Traumatic Brain Injury: Assessment and Management Practices of Speech-Language Pathologists.

PURPOSE: Memory impairments are among the most commonly reported deficits and among the most frequent rehabilitation targets for individuals with traumatic brain injury (TBI). Memory and learning are also critical for rehabilitation success and broader long-term outcomes. Speech-language pathologists (SLPs) play a central role in memory management for individuals with TBI across the continuum of care. Yet, little is known about the current practice patterns of SLPs for post-TBI memory disorders. This study aims to examine the clinical management of memory disorders in adults with TBI by SLPs and identify opportunities to improve post-TBI memory outcomes. METHOD: SLPs from across the continuum of care were recruited to complete an online survey. The survey assessed key practice areas specific to memory and memory disorders post-TBI, including education and training, knowledge and confidence, and assessment and treatment patterns. RESULTS: Surveys from 155 SLPs were analyzed. Results revealed that TBI-specific training remains low in the field. Respondents varied in their practice patterns in assessing and treating memory disorders. Most SLPs do not appear to have access to appropriate standardized assessments to measure unique forms of memory. Respondents also reported a range of barriers and opportunities to advance memory outcomes following TBI and provided suggestions of areas in which they would like to see more basic and clinical research. CONCLUSIONS: These findings establish a baseline of the current practices for clinical management of memory impairment in adults with TBI by SLPs. Improved opportunities for clinician training, the development of a single tool to assess multiple forms of memory, better access to existing memory assessments, and implementation of evidence-based interventions promise to lead to improved memory outcomes for individuals with TBI.

Human Presenilin-1 delivered by AAV9 rescues impaired γ-secretase activity, memory deficits, and neurodegeneration in Psen mutant mice.

Mutations in the Presenilin (PSEN1 and PSEN2) genes are the major cause of early-onset familial Alzheimer's disease (FAD). Presenilin (PS) is the catalytic subunit of the γ-secretase complex, which cleaves type I transmembrane proteins, such as Notch and the amyloid precursor protein (APP), and plays an evolutionarily conserved role in the protection of neuronal survival during aging. FAD PSEN1 mutations exhibit impaired γ-secretase activity in cell culture, in vitro, and knockin (KI) mouse brains, and the L435F mutation is the most severe in reducing γ-secretase activity and is located closest to the active site of γ-secretase. Here, we report that introduction of the codon-optimized wild-type human PSEN1 cDNA by adeno-associated virus 9 (AAV9) results in broadly distributed, sustained, low to moderate levels of human PS1 (hPS1) expression and rescues impaired γ-secretase activity in the cerebral cortex of Psen mutant mice either lacking PS or expressing the Psen1 L435F KI allele, as evaluated by endogenous γ-secretase substrates of APP and recombinant γ-secretase products of Notch intracellular domain and Aß peptides. Furthermore, introduction of hPS1 by AAV9 alleviates impairments of synaptic plasticity and learning and memory in Psen mutant mice. Importantly, AAV9 delivery of hPS1 ameliorates neurodegeneration in the cerebral cortex of aged Psen mutant mice, as shown by the reversal of age-dependent loss of cortical neurons and elevated microgliosis and astrogliosis. These results together show that moderate hPS1 expression by AAV9 is sufficient to rescue impaired γ-secretase activity, synaptic and memory deficits, and neurodegeneration caused by Psen mutations in mouse models.

Efficacy and Safety of Repetitive Transcranial Magnetic Stimulation for Poststroke Memory Disorder: A Meta-Analysis and Systematic Review.

BACKGROUND: Patients with post-stroke memory disorder (PSMD) have poor quality of life and it is necessary to identify more beneficial stimulation protocols for treatment with repetitive transcranial magnetic stimulation (rTMS). This meta-analysis was conducted to investigate the efficacy and safety of rTMS for improving memory performance, global cognition, and activities of daily living (ADL) among patients with PSMD. METHODS: The PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, China Science and Technology Journal Database, and Wanfang databases were screened to identify relevant randomized controlled trials. The primary outcome was memory performance; secondary outcomes included global cognition, ADL, and adverse events. STATA software was used to perform data synthesis. RESULTS: Five articles with a total of 192 participants were included. The results indicated that rTMS was superior to control treatments for improving memory performance (mean difference [MD] = 1.73, 95% CI [Confidence Interval] [0.85, 2.60], p < 0.001), global cognition (MD = 2.44, 95% CI [0.96, 3.93], p < 0.001), and ADL (MD = 10.29, 95% CI [5.10, 15.48], p < 0.001). No significant differences were found between the low-frequency (LF) and high-frequency (HF) rTMS subgroups (p = 0.47, I2 = 0.00%) or between the sham rTMS and non-rTMS subgroups (p = 0.94, I2 = 0.00%). Four studies did not reported adverse events. CONCLUSIONS: rTMS may improve memory function, global cognition, and the ability to perform ADL in patients with PSMD. LF-rTMS and HF-rTMS may have equal efficacy for treatment of PSMD. Future studies should consider extending the follow-up period to explore the safety and long-term efficacy of rTMS for treatment of PSMD and the appropriate choice of placebo for clinical trials of this treatment.

Physical activity in a swimming pool attenuates memory impairment by reducing glutamate and inflammatory cytokines and increasing BDNF in the brain of mice with type 2 diabetes.

Type 2 diabetes is a risk factor for the development of cognitive impairment. Increasing evidence suggests that regular exercise is beneficial for the treatment of clinical symptoms in diabetic patients. The current study aimed to evaluate whether increasing physical activity through swimming training can reduce memory impairment in an animal model of type 2 diabetes. Diabetes and non-diabetes mice underwent swimming training for four weeks, and then working, spatial, and recognition memory were evaluated using three behavioral tests. Body weight, glucose, and insulin resistance were monitored. We also measured inflammatory cytokines (interleukin (IL)- 6, IL-1ß, and tumor-necrosis-factor (TNF)-α), an anti-inflammatory cytokine (IL-10), and brain-derived-neurotrophic-factor (BDNF), and glutamate levels in the hippocampus or prefrontal cortex of mice. The findings showed that diabetes increased body weight, glucose, and insulin resistance, impaired working, spatial and recognition memory, increased levels of IL-6, IL-1ß, TNF-α, and glutamate levels, and decreased BDNF in the hippocampus of diabetic mice. While higher physical activity was associated with reduced body weight, glucose, and insulin resistance, attenuated memory impairment, IL-6, IL-1ß, TNF-α, and glutamate, and increased BDNF levels in the hippocampus and prefrontal cortex of diabetic mice. This study shows that swimming training can normalize body weight and glucose-insulin axis and reduce inflammation and glutamate in the hippocampus and enhance the neurotrophic system in both the hippocampus and prefrontal cortex of diabetic mice. This study also suggests that higher physical activity through swimming training can improve cognitive impairment in a mouse model of type 2 diabetes.

Biomarker-guided neuromodulation aids memory in traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of cognitive disability in adults, often characterized by marked deficits in episodic memory and executive function. Prior studies have found that direct electrical stimulation of the temporal cortex yielded improved memory in epilepsy patients, but it is not clear if these results generalize to patients with a specific history of TBI. Here we asked whether applying closed-loop, direct electrical stimulation to lateral temporal cortex could reliably improve memory in a TBI cohort. Among a larger group of patients undergoing neurosurgical evaluation for refractory epilepsy, we recruited a subset of patients with a history of moderate-to-severe TBI. By analyzing neural data from indwelling electrodes as patients studied and recalled lists of words, we trained personalized machine-learning classifiers to predict momentary fluctuations in mnemonic function in each patient. We subsequently used these classifiers to trigger high-frequency stimulation of the lateral temporal cortex (LTC) at moments when memory was predicted to fail. This strategy yielded a 19% boost in recall performance on stimulated as compared with non-stimulated lists (P = 0.012). These results provide a proof-of-concept for using closed-loop stimulation of the brain in treatment of TBI-related memory impairment.

Multisensory Stimulation Reverses Memory Impairment in Adrß3KO Male Mice.

Norepinephrine plays an important role in modulating memory through its beta-adrenergic receptors (Adrß: ß1, ß2 and ß3). Here, we hypothesized that multisensory stimulation would reverse memory impairment caused by the inactivation of Adrß3 (Adrß3KO) with consequent inhibition of sustained glial-mediated inflammation. To test this, 21- and 86-day-old Adrß3KO mice were exposed to an 8-week multisensory stimulation (MS) protocol that comprised gustatory and olfactory stimuli of positive and negative valence; intellectual challenges to reach food; the use of hidden objects; and the presentation of food in ways that prompted foraging, which was followed by analysis of GFAP, Iba-1 and EAAT2 protein expression in the hippocampus (HC) and amygdala (AMY). The MS protocol reduced GFAP and Iba-1 expression in the HC of young mice but not in older mice. While this protocol restored memory impairment when applied to Adrß3KO animals immediately after weaning, it had no effect when applied to adult animals. In fact, we observed that aging worsened the memory of Adrß3KO mice. In the AMY of Adrß3KO older mice, we observed an increase in GFAP and EAAT2 expression when compared to wild-type (WT) mice that MS was unable to reduce. These results suggest that a richer and more diverse environment helps to correct memory impairment when applied immediately after weaning in Adrß3KO animals and indicates that the control of neuroinflammation mediates this response.

Design and baseline characteristics of the Cognitive and Aerobic Resilience for the Brain (CARB) study.

BACKGROUND: Treatments that delay progression of cognitive impairment in older adults are of great public health significance. This manuscript outlines the protocol, recruitment, baseline characteristics, and retention for a randomized controlled trial of cognitive and aerobic physical training to improve cognition in individuals with subjective cognitive dysfunction, the "Cognitive and Aerobic Resilience for the Brain" (CARB) study. METHODS: Community-dwelling, older adults with self-reported memory loss were randomly assigned to receive either computer-based cognitive training, aerobic physical training, combined cognitive and physical training, or education control. Treatment was delivered 2- to 3-times per week in 45- to 90-min sessions for 12 weeks by trained facilitators videoconferencing into subject's home. Outcome assessments of were taken at the baseline, immediately following training, and 3-months after training. RESULTS: 191 subjects were randomized into the trial (mean age, 75.5 years; 68% female; 20% non-white; mean education, 15.1 years; 30% with 1+ APOE e4 allele). The sample was generally obese, hypertensive, and many were diabetic, while cognition, self-reported mood, and activities of daily living were in the normal range. There was excellent retention throughout the trial. Interventions were completed at high rates, participants found the treatments acceptable and enjoyable, and outcome assessments were completed at high rates. CONCLUSIONS: This study was designed to determine the feasibility of recruiting, intervening, and documenting response to treatment in a population at risk for progressive cognitive decline. Older adults with self-reported memory loss were enrolled in high numbers and were well engaged with the intervention and outcome assessments.

Therapeutic advances for treating memory impairments in perinatal brain injuries with implications for cerebral palsy: a systematic review and meta-analysis of preclinical studies.

Cerebral palsy (CP) is a neurodevelopmental disorder caused by damage to the immature brain. CP is considered the main cause of physical disability in childhood. Studies have shown that memory function and emotional behaviour are significantly impaired in CP. Current thought is that interventions for neuromotor damaged play a prominent role, but neglects the memory acquisition problems that affect the functioning and quality of life of these children. This systematic review aims to map and analyse pre-clinical interventions used to treat memory formation problems resulting from CP. For this, a search was carried out in the Pubmed, Web of Science, Scopus and Lilacs databases. Then, eligibility, extraction date and evaluation of the methodological quality of the studies were determined. 52 studies were included in this review, and 27 were included in a meta-analysis. Assessing memory performance as a primary outcome, and structural and biochemical changes in the hippocampus as a secondary outcome. CP models were reported to be induced by hypoxia-ischemia, oxygen deprivation and liposaccharide (LPS) exposure, resulting in impairments in the formation of short-term and long-term memory in adult life. A reduction in escape latency and dwell time were observed in the target quadrant as well as an increase in the time needed for the rodents to find the platform in the Morris Water Maze (MWM). Brain injuries during the perinatal period are considered an insult that negatively impacts hippocampus maturation and causes impairment in memory formation in adult life. Some studies reported that regions of the hippocampus such as the dentate gyrus and cornu ammonis 1 were impaired in CP, noting an increase in oxidative stress enzymes and pro-inflammatory cytokines, associated with a reduction in BDNF and neurogenesis levels. These were reported to cause a reduction in the number of neurons and the volume of the hippocampus, in addition to an increase in astrogliosis and apoptosis of neurons and difficulties in forming new memories similar to those that occur in children with CP. Interventions that reduced neuroinflammation and the presence of free radicals were highlighted as a therapy for the memory disturbance present in CP. Preclinical studies registered treatments with oxygen interventions, resveratrol and erythropoietin, which were able to reduce the damage to the hippocampus and promote improvements in memory and behaviour. In the meta-analysis of selected studies, we observed favorable results, through effect size, for the use of oxygen interventions (SDM -6.83 95% CI [-7.91, -5.75], Z = 12.38, p = 0.03; I2 = 71%), erythropoietin (SDM -3.16 95% CI [-4.27, -2.05], Z = 5.58, p = 0.002; I2 = 82%) and resveratrol (SDM -2.42 95% CI [-3.19, - 1.66], Z = 6.21, p = 0.01; I2 = 77%), stimulating plastic responses in the hippocampus and facilitating the memory formation, with these presenting positive effects in general (SDM -2.84 95% CI [-3.10, -2.59], Z = 22.00; p < 0.00001; I2 = 92.9%). These studies demonstrate possible avenues of intervention for memory alterations in experimental models of early brain injuries, highlighting promising interventions that can facilitate the maturation of the hippocampus and memory formation and, consequently, minimize functional problems that arise during development.

The effects of endurance exercise and metformin on memory impairment caused by diabetes.

OBJECTIVES: Diabetes has a negative effect on learning and memory performance, and it is a risk factor for Alzheimer's disease and dementia development. The present study aims to investigate the effects of two kinds of endurance exercise including high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) as well as metformin on impaired memory and learning related to streptozotocin (STZ) induced diabetes in rats. METHODS: Forty adult male rats (250 ± 20 g weight) were divided into five groups (n=8), including control, diabetic, as well as diabetic rats treated with metformin (300 mg/kg), and HIIT (20 m/min), and MICT (15 m/min) exercises. Diabetes was induced by STZ (60 mg/kg, i.p.). Serum glucose concentration and oxidative stress markers (SOD, CAT, thiol, and MDA) in the cortex and hippocampus were determined by colorimetric assay. Behavioral tests were performed with a passive avoidance test. RESULTS: The diabetic groups treated with metformin and both HIIT, and MICT exercises improved the latency and the staying time in the darkroom and lightroom. The entrance frequency into the darkroom also was restored (p<0.01-p<0.001). In both HIIT and MICT exercises as well as metformin groups the oxidative stress induced by diabetes has been reversed and attenuation of the serum glucose level has been observed compared to non-treated diabetic ones (p<0.05-p<0.001). CONCLUSIONS: The results of the present study revealed both HIIT and MICT exercises had protective effects against oxidative stress and behavioral impairments induced by diabetes and these effects were comparable to the effects of metformin.

Intracranial Self-stimulation of the Medial Forebrain Bundle Ameliorates Memory Disturbances and Pathological Hallmarks in an Alzheimer's Disease Model by Intracerebral Administration of Amyloid-ß in Rats.

No curative or fully effective treatments are currently available for Alzheimer's disease (AD), the most common form of dementia. Electrical stimulation of deep brain areas has been proposed as a novel neuromodulatory therapeutic approach. Previous research from our lab demonstrates that intracranial self-stimulation (ICSS) targeting medial forebrain bundle (MFB) facilitates explicit and implicit learning and memory in rats with age or lesion-related memory impairment. At a molecular level, MFB-ICSS modulates the expression of plasticity and neuroprotection-related genes in memory-related brain areas. On this basis, we suggest that MFB could be a promising stimulation target for AD treatment. In this study, we aimed to assess the effects of MFB-ICSS on both explicit memory as well as the levels of neuropathological markers ptau and drebrin (DBN) in memory-related areas, in an AD rat model obtained by Aß icv-injection. A total of 36 male rats were trained in the Morris water maze on days 26-30 after Aß injection and tested on day 33. Results demonstrate that this Aß model displayed spatial memory impairment in the retention test, accompanied by changes in the levels of DBN and ptau in lateral entorhinal cortex and hippocampus, resembling pathological alterations in early AD. Administration of MFB-ICSS treatment consisting of 5 post-training sessions to AD rats managed to reverse the memory deficits as well as the alteration in ptau and DBN levels. Thus, this paper reports both cognitive and molecular effects of a post-training reinforcing deep brain stimulation procedure in a sporadic AD model for the first time.

AAV-mediated neuronal expression of an scFv antibody selective for Aß oligomers protects synapses and rescues memory in Alzheimer models.

The accumulation of soluble oligomers of the amyloid-ß peptide (AßOs) in the brain has been implicated in synapse failure and memory impairment in Alzheimer's disease. Here, we initially show that treatment with NUsc1, a single-chain variable-fragment antibody (scFv) that selectively targets a subpopulation of AßOs and shows minimal reactivity to Aß monomers and fibrils, prevents the inhibition of long-term potentiation in hippocampal slices and memory impairment induced by AßOs in mice. As a therapeutic approach for intracerebral antibody delivery, we developed an adeno-associated virus vector to drive neuronal expression of NUsc1 (AAV-NUsc1) within the brain. Transduction by AAV-NUsc1 induced NUsc1 expression and secretion in adult human brain slices and inhibited AßO binding to neurons and AßO-induced loss of dendritic spines in primary rat hippocampal cultures. Treatment of mice with AAV-NUsc1 prevented memory impairment induced by AßOs and, remarkably, reversed memory deficits in aged APPswe/PS1ΔE9 Alzheimer's disease model mice. These results support the feasibility of immunotherapy using viral vector-mediated gene delivery of NUsc1 or other AßO-specific single-chain antibodies as a potential therapeutic approach in Alzheimer's disease.