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ABSTRACT Purpose Executive functions (EFs) are a set of advanced cognitive functions essential for human survival and behavioral regulation. Understanding neurophysiological mechanisms of EFs as well as exploring methods to enhance them are still challenging problems in cognitive neuroscience. In recent years, transcranial magnetic stimulation (TMS) has been widely used in the field of EF research and has made notable progress. This article aimed to discuss the impact of TMS technology on EF research from both basic and applied research perspectives. Methods We searched for literature on TMS and EFs published in the last decade (2013–2023) and reviewed how TMS has been applied in the field of EF. Findings We found that the combination of TMS with neuroimaging techniques was helpful in exploring the brain mechanisms of EFs and investigating the executive dysfunctions caused by other neuropsychiatric disorders. Moreover, TMS could be considered as one of the most important techniques to enhance EFs among patient populations, even healthy people, with high safety and credibility. Meanwhile, we discussed the application of TMS in the research of EFs and made suggestions for future research directions. We suggested that a multidisciplinary structure of methods such as epigenetics and endocrinology could be integrated with TMS for investigating deeper in EF domains, and a substantial number of high‐quality clinical studies are required to further elucidate the effects of TMS on EFs. Conclusions TMS holds great promise for gaining insight into investigating the neural mechanisms of EFs and improving executive functions among different populations.

Background: Deficits in associative memory (AM) are the earliest and most prominent feature of Alzheimer's disease (AD) and demonstrate a clear cause of distress for patients and their families. Objective: The present study aimed to determine AM enhancements following accelerated intermittent theta-burst stimulation (iTBS) in patients with AD. Methods: In a randomized, double-blind, sham-controlled design, iTBS was administered to the left dorsolateral prefrontal cortex (DLPFC) of patients with AD for 14 days. Measurements included AM (primary outcome) and a comprehensive neuropsychological battery. Patients were evaluated at baseline, following the intervention (week 2), and 8 weeks after treatment cessation (week 10). Results: Sixty patients with AD were initially enrolled; 47 completed the trial. The active group displayed greater AM improvements compared with the sham group at week 2 (P = 0.003), which was sustained at week 10. Furthermore, higher Mini-Mental State Examination (MMSE) scores at baseline were associated with greater AM improvements at weeks 2 and 10. For the independent iTBS group, this correlation predicted improvements in AM (P

Carbonic anhydrases (CAs) are a family of ubiquitous metal enzymes catalyzing the reversible conversion of CO2 and H2O to HCO3− with the release of a proton. They play an important role in pH regulation and in the balance of body fluids and are involved in several functions such as homeostasis regulation and cellular respiration. For these reasons, they have been studied as targets for the development of agents for treating several pathologies. CA inhibitors have been used in therapy for a long time, especially as diuretics and for the treatment of glaucoma, and are being investigated for application in other pathologies including obesity, cancer, and epilepsy. On the contrary, CAs activators are still poorly studied. They are proposed to act as additional (other than histidine) proton shuttles in the rate-limiting step of the CA catalytic cycle, which is the generation of the active hydroxylated enzyme. Recent studies highlight the involvement of CAs activation in brain processes essential for the transmission of neuronal signals, suggesting CAs activation might represent a potential therapeutic approach for the treatment of Alzheimer's disease and other conditions characterized by memory impairment and cognitive problems. Actually, some compounds able to activate CAs have been identified and proposed to potentially resolve problems related to neurodegeneration. This review reports on the primary literature regarding the potential of CA activators for treating neurodegeneration-related diseases. [ABSTRACT FROM AUTHOR]

Deficits in associative memory (AM) are the earliest and most prominent feature of Alzheimer's disease (AD) and demonstrate a clear cause of distress for patients and their families. The present study aimed to determine AM enhancements following accelerated intermittent theta-burst stimulation (iTBS) in patients with AD. In a randomized, double-blind, sham-controlled design, iTBS was administered to the left dorsolateral prefrontal cortex (DLPFC) of patients with AD for 14 days. Measurements included AM (primary outcome) and a comprehensive neuropsychological battery. Patients were evaluated at baseline, following the intervention (week 2), and 8 weeks after treatment cessation (week 10). Sixty patients with AD were initially enrolled; 47 completed the trial. The active group displayed greater AM improvements compared with the sham group at week 2 (P = 0.003), which was sustained at week 10. Furthermore, higher Mini-Mental State Examination (MMSE) scores at baseline were associated with greater AM improvements at weeks 2 and 10. For the independent iTBS group, this correlation predicted improvements in AM (P < 0.001) and identified treatment responders with 92% accuracy. Most of the neuropsychological tests were markedly improved in the active group. In particular, the Montreal Cognitive Assessment and MMSE in the active group increased by 2.8 and 2.3 points, respectively, at week 2, while there was no marked change in the sham group. In the present study, accelerated iTBS of the DLPFC demonstrated an effective and well-tolerated complementary treatment for patients with AD, especially for individuals with relatively high MMSE scores. • Accelerate iTBS of the left DLPFC showed an effective and well-tolerated complementary treatment to improve symptoms and cognitive in AD patients. • The MoCA and MMSE in active group increased 2.8 and 2.3 points after two-weeks treatment. • The ameliorating effects were more effective and robust among patients with high MMSE score in baseline. [ABSTRACT FROM AUTHOR]

Carbonic anhydrases (CAs) are a family of ubiquitous metal enzymes catalyzing the reversible conversion of CO2 and H2O to HCO3− with the release of a proton. They play an important role in pH regulation and in the balance of body fluids and are involved in several functions such as homeostasis regulation and cellular respiration. For these reasons, they have been studied as targets for the development of agents for treating several pathologies. CA inhibitors have been used in therapy for a long time, especially as diuretics and for the treatment of glaucoma, and are being investigated for application in other pathologies including obesity, cancer, and epilepsy. On the contrary, CAs activators are still poorly studied. They are proposed to act as additional (other than histidine) proton shuttles in the rate-limiting step of the CA catalytic cycle, which is the generation of the active hydroxylated enzyme. Recent studies highlight the involvement of CAs activation in brain processes essential for the transmission of neuronal signals, suggesting CAs activation might represent a potential therapeutic approach for the treatment of Alzheimer’s disease and other conditions characterized by memory impairment and cognitive problems. Actually, some compounds able to activate CAs have been identified and proposed to potentially resolve problems related to neurodegeneration. This review reports on the primary literature regarding the potential of CA activators for treating neurodegeneration-related diseases.

Four human (h) carbonic anhydrase isoforms (CA, EC 4.2.1.1), hCA I, II, IV, and VII, were investigated for their activation profile with piperazines belonging to various classes, such as N-aryl-, N-alkyl-, N-acyl-piperazines as well as 2,4-disubstituted derivatives. As the activation mechanism involves participation of the activator in the proton shuttling between the zinc-coordinated water molecule and the external milieu, these derivatives possessing diverse basicity and different scaffolds were appropriate for being investigated as CA activators (CAAs). Most of these derivatives showed CA activating properties against hCA I, II, and VII (cytosolic isoforms) but were devoid of activity against the membrane-associated hCA IV. For hCA I, the KAs were in the range of 32.6–131 µM; for hCA II of 16.2–116 µM, and for hCA VII of 17.1–131 µM. The structure-activity relationship was intricate and not easy to rationalize, but the most effective activators were 1-(2-piperidinyl)-piperazine (KA of 16.2 µM for hCA II), 2-benzyl-piperazine (KA of 17.1 µM for hCA VII), and 1-(3-benzylpiperazin-1-yl)propan-1-one (KA of 32.6 µM for hCA I). As CAAs may have interesting pharmacologic applications in cognition and for artificial tissue engineering, investigation of new classes of activators may be crucial for this relatively new research field.

Intermittent theta-burst stimulation (iTBS) is emerging as a noninvasive therapeutic strategy for Alzheimer's disease (AD). Recent advances highlighted a new accelerated iTBS (aiTBS) protocol, consisting of multiple sessions per day and higher overall pulse doses, in brain modulation. To examine the possibility of applying the aiTBS in treating AD patients, we enrolled 45 patients in AD at early clinical stages, and they were randomly assigned to either receive real or sham aiTBS. Neuropsychological scores were evaluated before and after treatment. Moreover, we detected cortical excitability and oscillatory activity changes in AD, by the single-pulse TMS in combination with EEG (TMS-EEG). Real stimulation showed markedly better performances in the group average of Auditory Verbal Learning Test scores compared to baseline. TMS-EEG revealed that aiTBS has reinforced this memory-related cortical mechanism by increasing cortical excitability and beta oscillatory activity underlying TMS target. We also found an enhancement of local natural frequency after aiTBS treatment. The novel findings implicated that high-dose aiTBS targeting left DLPFC is rapid-acting, safe, and tolerable in AD patients. Furthermore, TMS-related increase of specific neural oscillation elucidates the mechanisms of the AD cognitive impairment ameliorated by aiTBS., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

There is ample evidence that phosphodiesterase 4 (PDE4) inhibition can improve memory performance in animal studies. In the present study, we examined the acute effects of the PDE4 inhibitor roflumilast on memory performance in healthy individuals (60–80 years of age). We tested the effects of acute roflumilast administration (100, 250, 1000 μg) in a double-blind, placebo-controlled, 4-way crossover design. Participants were first screened for their verbal word memory performance to ensure normal memory performance (within 0.5 standard deviation from norm score; n = 20) Drug effects on memory performance were tested in a verbal memory test and a spatial memory test. Reported side effects of drug treatment were registered. Roflumilast (100 μg) improved the delayed recall performance of the participants (Cohen's d, 0.69). No effects were observed in the spatial memory task. Roflumilast was well tolerated at this low dose. Although no clear adverse side effects were reported at the low dose, mild adverse events (including headache, dizziness, insomnia, and diarrhea) were reported after the 1000 μg dose. The present study provides first evidence that the PDE4 inhibitor roflumilast improves verbal memory performance in old participants. The current data encourage further development of PDE4 inhibitors for improving memory. • Phosphodiesterase type 4 (PDE4) breaks down cAMP, which plays a crucial role in neuronal plasticity. • A vast amount of animal studies has shown improved learning and memory with PDE4 inhibitors. • The PDE4 inhibitor roflumilast improved the delayed verbal memory recall in healthy old participants. [ABSTRACT FROM AUTHOR]

Copyright of Revista de Derecho y Genoma Humano is the property of Dykinson SL and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Four human (h) carbonic anhydrase isoforms (CA, EC 4.2.1.1), hCA I, II, IV, and VII, were investigated for their activation profile with piperazines belonging to various classes, such as N-aryl-, N-alkyl-, N-acyl-piperazines as well as 2,4-disubstituted derivatives. As the activation mechanism involves participation of the activator in the proton shuttling between the zinc-coordinated water molecule and the external milieu, these derivatives possessing diverse basicity and different scaffolds were appropriate for being investigated as CA activators (CAAs). Most of these derivatives showed CA activating properties against hCA I, II, and VII (cytosolic isoforms) but were devoid of activity against the membrane-associated hCA IV. For hCA I, the KAs were in the range of 32.6-131 µM; for hCA II of 16.2-116 µM, and for hCA VII of 17.1-131 µM. The structure-activity relationship was intricate and not easy to rationalize, but the most effective activators were 1-(2-piperidinyl)-piperazine (KA of 16.2 µM for hCA II), 2-benzyl-piperazine (KA of 17.1 µM for hCA VII), and 1-(3-benzylpiperazin-1-yl)propan-1-one (KA of 32.6 µM for hCA I). As CAAs may have interesting pharmacologic applications in cognition and for artificial tissue engineering, investigation of new classes of activators may be crucial for this relatively new research field. [ABSTRACT FROM AUTHOR]

Starting from enantiomerically pure amino acids, 1,4-diazepanes with various substituents in 1, 2, and 4-position were synthesized following the late stage diversification strategy. The key step in the formation of the seven-membered ring was the intramolecular EDC coupling of amino acids 15 , 26 , and 39 . The configuration in 2-position does not influence the σ 1 affinity and selectivity over related receptors. A cyclohexylmethyl or a butyl group are the preferred substituents in 4-position, whereas a methyl moiety in 2-position and a (substituted) benzyl moiety in 1-position result in the highest σ 1 affinity. These results fit nicely to the reported σ 1 pharmacophore models. The compounds did not inhibit the structurally related fungal enzyme sterol Δ 8,7 -isomerase, but showed inhibition of diverse enzymes in late cholesterol biosynthesis at high concentrations. In a screening against more than 50 target proteins, (2 S )-1-benzyl-4-(4-methoxybenzyl)-2-methyl-1,4-diazepane (( S )- 28b , K i (σ 1 ) = 0.86 nM) showed a clean receptor profile. The dose dependent potentiation of electrically stimulated contractions of guinea pig vas deferens indicates σ 1 agonistic activity of ( S )- 28b . Even at a dose of 100 mg/kg ( S )- 28b did not induce severe toxic or behavioral effects in the Irwin screen. Clear cognition enhancing effects were observed for ( S )- 28b after inducing amnesia by scopolamine. [ABSTRACT FROM AUTHOR]

Cocoa flavanols (CF) positively influence physiological processes in ways that suggest their consumption may improve aspects of cognitive function. This study investigated the acute cognitive and subjective effects of CF consumption during sustained mental demand. In this randomized, controlled, double-blinded, balanced, three period crossover trial 30 healthy adults consumed drinks containing 520 mg, 994 mg CF and a matched control, with a three-day washout between drinks. Assessments included the state anxiety inventory and repeated 10-min cycles of a Cognitive Demand Battery comprising of two serial subtraction tasks (Serial Threes and Serial Sevens), a Rapid Visual Information Processing (RVIP) task and a ‘mental fatigue’ scale, over the course of 1 h. Consumption of both 520 mg and 994 mg CF significantly improved Serial Threes performance. The 994 mg CF beverage significantly speeded RVIP responses but also resulted in more errors during Serial Sevens. Increases in self-reported ‘mental fatigue’ were significantly attenuated by the consumption of the 520 mg CF beverage only. This is the first report of acute cognitive improvements following CF consumption in healthy adults. While the mechanisms underlying the effects are unknown they may be related to known effects of CF on endothelial function and blood flow. [ABSTRACT FROM PUBLISHER]

The article presents research on psychological aspects of exercise. The effects of moderate and moderately intense exercise on cognitive flexibility and feeling states are examined. Results of a random controlled trial indicate that those persons who engaged in either form of exercise had enhancement of both cognitive flexibility and their feeling states.

Defects in processing speed and memory are common in multiple sclerosis (MS) patients. In other populations, amphetamines have been shown to enhance cognition, but their use is limited by adverse behavioral effects. The l-isomer may have equivalent cognition enhancement with less adverse effects due to decreased potency in subcortical areas. The aim of this study was to assess the safety and efficacy of l-amphetamine sulfate in the treatment of cognitive dysfunction in MS. This was a 2:1 randomized, placebo-controlled, double-blind trial, involving 33 MS clinics across the USA. One hundred and fifty-one clinically definite MS patients with documented cognitive dysfunction who were relapse free for ≥90 days, with an Expanded Disability Status Scale (EDSS) ≤6.5, and with no other medical/psychiatric condition that may cause psychological dysfunction were randomized to 30 mg of oral l-amphetamine sulfate or placebo for 29 days, including a dose escalation period. A history of cardiac disease, uncontrolled hypertension or electrocardiograph abnormalities resulted in exclusion. The primary outcomes were the Subject Global Assessment of Change and Symbol Digit Modalities Test (SDMT). Secondary outcomes were the results from the California Verbal Learning Test, second edition (CVLT2), Brief Visual Memory Test-Revised (BVMTR), and Paced Auditory Serial Addition Test (PASAT). One hundred and thirty-six subjects completed the study. No differences were found at baseline in demographics or in the results of the neuropsychological tests. After treatment, the active group performed significantly better for total learning ( P = 0.041) and delayed recall ( P < 0.01) on the BVMTR, and for delayed recall ( P = 0.012) on the CVLT2. Five patients (four from the treatment group, one placebo) withdrew due to intolerable adverse events. l-amphetamine sulfate was associated with improved learning and memory and was well tolerated in this study. However, because the positive findings were observed on secondary outcome measures, the study requires replication before l-amphetamine sulfate can be recommended for the treatment of cognitive impairment in MS. [ABSTRACT FROM AUTHOR]

Phosphodiesterase (PDE) inhibitors prevent the breakdown of the second messengers, cyclic AMP (cAMP) and cyclic GMP (cGMP), and are currently studied as possible targets for cognitive enhancement. Earlier studies indicated beneficial effects of PDE inhibitors in object recognition. In this study we tested the effects of three PDE inhibitors on spatial memory as assessed in a place and object recognition task. Furthermore, as both cAMP and cGMP are known vasodilators, the effects of PDE inhibition on cognitive functions could be explained by enhancement of cerebrovascular function. We examined this possibility by measuring the effects of PDE5 and PDE4 inhibitor treatment on local cerebral blood flow and glucose utilization in rats using [14C]-iodoantipyrine and [14C]-2-deoxyglucose quantitative autoradiography, respectively. In the spatial location task, PDE5 inhibition (cGMP) with vardenafil enhanced only early phase consolidation, PDE4 inhibition (cAMP) with rolipram enhanced only late phase consolidation, and PDE2 inhibition (cAMP and cGMP) with Bay 60–7550 enhanced both consolidation processes. Furthermore, PDE5 inhibition had no cerebrovascular effects in hippocampal or rhinal areas. PDE4 inhibition increased rhinal, but not hippocampal blood flow, whereas it decreased glucose utilization in both areas. In general, PDE5 inhibition decreased the ratio between blood flow and glucose utilization, indicative of general oligaemia; whereas PDE4 inhibition increased this ratio, indicative of general hyperemia. Both oligaemic and hyperemic conditions are detrimental for brain function and do not explain memory enhancement. These results underscore the specific effects of cAMP and cGMP on memory consolidation (object and spatial memory) and provide evidence that the underlying mechanisms of PDE inhibition on cognition are independent of cerebrovascular effects.Neuropsychopharmacology (2009) 34, 1914–1925; doi:10.1038/npp.2009.24; published online 4 March 2009 [ABSTRACT FROM AUTHOR]

Therapeutic approaches for Alzheimer’s disease (AD) are guided by four disease characteristics: amyloid plaques, neurofibrillar tangles (NFT), neurodegeneration, and dementia. Amyloid plaques are composed largely of 4 kDa β-amyloid (Aβ) peptides, with the more amyloidogenic, 42 amino acid form (Aβ42) as the primary species. Because multiple, rare mutations that cause early-onset, familial AD lead to increased production or aggregation of Aβ42, amyloid therapeutics aim to reduce the amount of toxic Aβ42 aggregates. Amyloid-based therapies include γ-secretase inhibitors and modulators, BACE inhibitors, aggregation blockers, catabolism inducers, and anti-Aβ biologics. Tangles are composed of paired helical filaments of hyperphosphorylated tau protein. Tau-based therapeutics include kinase inhibitors, microtubule stabilizers, and catabolism inducers. Therapeutic strategies for neurodegeneration target multiple mechanisms, including excitotoxicity, mitochondrial dysfunction, oxidative damage, and inflammation or stimulation of neuronal viability. Although not disease modifying, cognition enhancers are important to treat the symptom of dementia. Strategies for cognition enhancement include cholinesterase inhibitors, and other approaches to enhance the signaling of cholinergic and glutamatergic neurons. In summary, plaques, tangles, neurodegeneration and dementia guide the development of multiple therapeutic approaches for AD and are the subject of this review. [ABSTRACT FROM AUTHOR]

Abstract: Seventy-six plant extracts including methanolic and successive water extracts from 37 Indian medicinal plants were investigated for acetylcholinesterase (AChE) inhibitory activity (in vitro). Results indicated that methanolic extracts to be more active than water extracts. The potent AChE inhibiting methanolic plant extracts included Withania somnifera (root), Semecarpus anacardium (stem bark), Embelia ribes (Root), Tinospora cordifolia (stem), Ficus religiosa (stem bark) and Nardostachys jatamansi (rhizome). The IC50 values obtained for these extracts were 33.38, 16.74, 23.04, 38.36, 73.69 and 47.21μg/ml, respectively. These results partly substantiate the traditional use of these herbs for improvement of cognition. [Copyright &y& Elsevier]

Copyright of Ethik in der Medizin is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

ABSTRACT Phenibut (β-phenyl-γ-aminobutyric acid HCl) is a neuropsychotropic drug that was discovered and introduced into clinical practice in Russia in the 1960s. It has anxiolytic and nootropic (cognition enhancing) effects. It acts as a GABA-mimetic, primarily at GABAB and, to some extent, at GABAA receptors. It also stimulates dopamine receptors and antagonizes β-phenethylamine (PEA), a putative endogenous anxiogenic. The psychopharmacological activity of phenibut is similar to that of baclofen, a p-Cl-derivative of phenibut. This article reviews the structure-activity relationship of phenibut and its derivatives. Emphasis is placed on the importance of the position of the phenyl ring, the role of the carboxyl group, and the activity of optical isomers. Comparison of phenibut with piracetam and diazepam reveals similarities and differences in their pharmacological and clinical effects. Phenibut is widely used in Russia to relieve tension, anxiety, and fear, to improve sleep in psychosomatic or neurotic patients; as well as a pre- or post-operative medication. It is also used in the therapy of disorders characterized by asthenia and depression, as well as in post-traumatic stress, stuttering and vestibular disorders. [ABSTRACT FROM AUTHOR]

The identification and SAR development of a series of negative allosteric modulators of the GABA A α5 receptor is described. This novel series of compounds was optimised to provide analogues with high GABA A α5 binding affinity, high α5 negative allosteric modulatory activity, good functional subtype selectivity and low microsomal turnover, culminating in identification of ONO-8590580. [ABSTRACT FROM AUTHOR]

Noninvasive brain stimulation to enhance cognition is an area of increasing research interest. Theta burst stimulation (TBS) is a novel accelerated form of stimulation, which more closely mimics the brain's natural firing patterns and may have greater effects on cognitive performance. We report here the comparative assessment of the effect of conventional high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) protocols and TBS protocols on cognition enhancement in healthy controls. Sixty healthy adults (34 males and 26 females) were randomized and counterbalanced and assigned to HF-rTMS ( n  = 20), TBS ( n  = 20), or sham ( n  = 20) groups. The promotion effects of different parameters of prefrontal stimulation on working memory and executive function were compared, as assessed by performance in N-back tasks and the Wisconsin Card Sorting Test (WCST). Both HF-rTMS and intermittent TBS (iTBS) groups displayed a significant improvement in N-back tasks, with an effect size of 0.79 and 1.50, respectively. Furthermore, the iTBS group displayed a significant improvement in the WCST, with an effect size of 0.84. The iTBS group demonstrated higher effect sizes than the HF-rTMS group ( t  =   2.68, p  =   0.011), with an effect size of 0.85. However, no improvement in other tasks was observed ( p  >   0.05). Intermittent TBS has a stronger cognitive promoting effect than conventional rTMS. In summary, our findings provide direct evidence that iTBS may be a superior protocol for cognitive promotion., (Copyright © 2021 Wu et al.)

Mammalian carbonic anhydrases (CAs; EC 4.2.1.1) of which 16 isoforms are known, are involved in important physiological functions. Their inhibition is exploited pharmacologically for the treatment of many diseases (glaucoma, edema, epilepsy, obesity, hypoxic tumors, neuropathic pain, etc.) but the activators were less investigated till recently. A review on the CA activation is presented, with the activation mechanism, drug design approaches of activators and comparison of the various isoforms activation profiles being discussed. Some CAs, which are abundant in the brain, were recently demonstrated to be activatable by drug-like compounds, affording the possibility to design agents that enhance cognition, with potential therapeutic applications in aging and neurodegenerative diseases as well as tissue engineering.