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BackgroundThis study aimed to investigate the efficacy of circuits-based paired associative stimulation (PAS) in adults with amnestic mild cognitive impairment (aMCI).MethodsWe conducted a parallel-group, randomised, controlled clinical trial. Initially, a cohort of healthy subjects was recruited to establish the cortical-hippocampal circuits by tracking white matter fibre connections using diffusion tensor imaging. Subsequently, patients diagnosed with aMCI, matched for age and education, were randomly allocated in a 1:1 ratio to undergo a 2-week intervention, either circuit-based PAS or sham PAS. Additionally, we explored the relationship between changes in cognitive performance and the functional connectivity (FC) of cortical-hippocampal circuits.ResultsFCs between hippocampus and precuneus and between hippocampus and superior frontal gyrus (orbital part) were most closely associated with the Auditory Verbal Learning Test (AVLT)_N5 score in 42 aMCI patients, thus designated as target circuits. The AVLT_N5 score improved from 2.43 (1.43) to 5.29 (1.98) in the circuit-based PAS group, compared with 2.52 (1.44) to 3.86 (2.39) in the sham PAS group (p=0.003; Cohen’s d=0.97). A significant decrease was noted in FC between the left hippocampus and left precuneus in the circuit-based PAS group from baseline to postintervention (p=0.013). Using a generalised linear model, significant group×FC interaction effects for the improvements in AVLT_N5 scores were found within the circuit-based PAS group (B=3.4, p=0.017).ConclusionsCircuit-based PAS effectively enhances long-term delayed recall in adults diagnosed with aMCI, which includes individuals aged 50–80 years. This enhancement is potentially linked to the decreased functional connectivity between the left hippocampus and left precuneus.Trial registration numberChiCTR2100053315; Chinese Clinical Trial Registry.

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).

Preclinical and human studies suggest that hippocampal dysfunction is a key factor in the onset of psychosis. People at Clinical High Risk for psychosis (CHR-P) present with a clinical syndrome that can include social withdrawal and have a 20–35% risk of developing psychosis in the next 2 years. Recent research shows that resting hippocampal blood flow is altered in CHR-P individuals and predicts adverse clinical outcomes, such as non-remission/transition to frank psychosis. Previous work in healthy males indicates that a single dose of intranasal oxytocin has positive effects on social function and marked effects on resting hippocampal blood flow. The present study examined the effects of intranasal oxytocin on hippocampal blood flow in CHR-P individuals. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using pseudo-continuous Arterial Spin Labelling on 2 occasions, once after 40IU intranasal oxytocin and once after placebo. The effects of oxytocin on left hippocampal blood flow were examined in a region-of-interest analysis of data acquired at 22–28 and at 30–36 minutes post-intranasal administration. Relative to placebo, administration of oxytocin was associated with increased hippocampal blood flow at both time points (p = .0056; p = .034), although the effect at the second did not survive adjustment for the effect of global blood flow. These data indicate that oxytocin can modulate hippocampal function in CHR-P individuals and therefore merits further investigation as a candidate novel treatment for this group.

Background Cognitive impairment is a prominent feature that adversely affects the long-term prognosis of schizophrenia; yet effective clinical strategies for treatment remain limited. Disruptions in the tricarboxylic acid (TCA) cycle and functional brain abnormalities in the hippocampus may underlie cognitive deficits, although the intrinsic connections between these factors have yet to be fully elucidated. Notably, metformin, a biguanide anti-hyperglycemic agent, has been shown to improve several cognitive domains in patients with schizophrenia and may have the potential to regulate the TCA cycle. Previously, we found the cognitive improvement effect of adding metformin. In this study, we will further explore the relationship between cognitive improvement and TCA cycle metabolites and brain function. Methods This study included 58 patients with schizophrenia who were in similar clinical conditions and assigned to 24-week 1500 mg metformin add-on treatment or the control group. We used the liquid chromatography tandem mass spectrometry (LC–MS/MS) method to detect the levels of key TCA cycle metabolites in the blood of schizophrenia patients, conducted MRI scans, and assessed clinical condition using the Positive and Negative Syndrome Scale (PANSS) and cognitive performance using the Chinese version of MATRICS Consensus Cognitive Battery (MCCB). Results Twenty-four weeks of metformin treatment downregulated levels of upstream lactic acid (− 80.81 (− 96.85, − 64.77) μg/mL at week 24) and pyruvic acid (− 17.51 (− 20.52, − 14.49) μg/mL at week 24), while upregulating levels of other seven downstream metabolites in TCA cycle (all p values < 0.001). Functional connectivity between left caudal hippocampus and right medio ventral occipital cortex (week 12, between-group difference =  − 0.334), and right caudal hippocampus and right middle frontal gyrus (week 24, between-group difference = 0.284) were significantly different between groups ( p  < 0.001). Moreover, metformin-improved cognition (working memory and verbal learning) and hippocampal functional connectivity (right caudal hippocampus and right middle frontal gyrus) were associated with changes in TCA cycle metabolites. Limitation Limited sample size and follow-up time, and lack of in-depth mechanism exploration. Conclusions Our results suggested that repurposing of metformin may have the potential to improve cognition by regulating energy metabolism pathways. Clinical trials registration NCT03271866. Graphical Abstract

Type 2 diabetes mellitus (T2DM) affects cognition and resting-state functional connectivity (rsFC). Intranasal insulin (INI) has emerged as a potential treatment for T2DM-related cognitive decline. We aimed to evaluate the effect of INI treatment on rsFC with medio-prefrontal (mPFC) and left/right hippocampus (lHPC/rHPC), and their relationship with the cognition, hemoglobin A1c (HbA1c), and homeostatic model assessment of insulin resistance (HOMA-IR) and walking speed. An MRI sub-study of the MemAID trial was conducted, involving a 24-week treatment with either intranasal insulin or placebo. Blood oxygen level-dependent (BOLD) functional MRI (fMRI) images were acquired on eighteen DM subjects at baseline and eleven DM subjects (eight DM-INI patients and three DM-Placebo) at the end-of-treatment. Compared to DM-Placebo treated subjects, DM-INI patients showed increased mPFC-postcentral rsFC, lHPC-frontal rsFC, lHPC-postcentral rsFC, rHPC-frontal rsFC, and lHPC-mPFC rsFC (p < 0.05). The decreased HOMA-IR, which was observed in the MemAID trial, was associated with increased mPFC-basal ganglia rsFC (p < 0.05). This sub-study provides insights into potential mechanisms of INI effects on rsFC that require validation in a larger trial.

Recent evidence shows that the serotonin 2A receptor (5-hydroxytryptamine2A receptor, 5-HT2AR) is critically involved in the formation of visual hallucinations and cognitive impairments in lysergic acid diethylamide (LSD)-induced states and neuropsychiatric diseases. However, the interaction between 5-HT2AR activation, cognitive impairments and visual hallucinations is still poorly understood. This study explored the effect of 5-HT2AR activation on response inhibition neural networks in healthy subjects by using LSD and further tested whether brain activation during response inhibition under LSD exposure was related to LSD-induced visual hallucinations. In a double-blind, randomized, placebo-controlled, cross-over study, LSD (100 µg) and placebo were administered to 18 healthy subjects. Response inhibition was assessed using a functional magnetic resonance imaging Go/No-Go task. LSD-induced visual hallucinations were measured using the 5 Dimensions of Altered States of Consciousness (5D-ASC) questionnaire. Relative to placebo, LSD administration impaired inhibitory performance and reduced brain activation in the right middle temporal gyrus, superior/middle/inferior frontal gyrus and anterior cingulate cortex and in the left superior frontal and postcentral gyrus and cerebellum. Parahippocampal activation during response inhibition was differently related to inhibitory performance after placebo and LSD administration. Finally, activation in the left superior frontal gyrus under LSD exposure was negatively related to LSD-induced cognitive impairments and visual imagery. Our findings show that 5-HT2AR activation by LSD leads to a hippocampal-prefrontal cortex-mediated breakdown of inhibitory processing, which might subsequently promote the formation of LSD-induced visual imageries. These findings help to better understand the neuropsychopharmacological mechanisms of visual hallucinations in LSD-induced states and neuropsychiatric disorders.

Cannabinoids receive increasing interest as analgesic treatments. However, the clinical use of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) has progressed with justified caution, which also owes to the incomplete mechanistic understanding of its analgesic effects, in particular its interference with the processing of sensory or affective components of pain. The present placebo-controlled crossover study therefore focused on the effects of 20 mg oral THC on the connectivity between brain areas of the pain matrix following experimental stimulation of trigeminal nocisensors in 15 non-addicted healthy volunteers. A general linear model (GLM) analysis identified reduced activations in the hippocampus and the anterior insula following THC administration. However, assessment of psychophysiological interaction (PPI) revealed that the effects of THC first consisted in a weakening of the interaction between the thalamus and the secondary somatosensory cortex (S2). From there, dynamic causal modeling (DCM) was employed to infer that THC attenuated the connections to the hippocampus and to the anterior insula, suggesting that the reduced activations in these regions are secondary to a reduction of the connectivity from somatosensory regions by THC. These findings may have consequences for the way THC effects are currently interpreted: as cannabinoids are increasingly considered in pain treatment, present results provide relevant information about how THC interferes with the affective component of pain. Specifically, the present experiment suggests that THC does not selectively affect limbic regions, but rather interferes with sensory processing which in turn reduces sensory-limbic connectivity, leading to deactivation of affective regions.

Sleep disturbances are very common in tinnitus sufferers with a high prevalence ranging from 50% to 77%. Untreated sleep disturbances and tinnitus can cause brain shrinkage and lead to cognitive impairments in late adulthood. Until now, non-pharmacological treatments are very few for older patients suffering from sleep disturbances and chronic tinnitus. Even though clinical trials of transcranial magnetic stimulation (TMS) have shown positive results in the treatment of either sleep disturbances or chronic tinnitus, the results are highly varied due to the superficial cortical target. Compared to TMS, focused low-intensity transcranial ultrasound stimulation (TUS) is a newly developed modality of non-invasive brain stimulation that offers promising therapeutic effects by transmitting acoustic energy into deep brain structures with a high spatial resolution (i.e., sub-millimeter), which sparks interest in managing the comorbidities in ageing populations. Chinese individuals between the ages of 60 and 90 years, who are right-handed and have sleep disturbances and chronic tinnitus, will participate in this pilot randomized clinical trial (RCT). Eligible participants will be randomly assigned to two treatment groups (1:1 ratio): low-intensity TUS or sham TUS (i.e., placebo-controlled group). Each group will consist of 15 participants. Before the treatment, high-resolution T1-weighted magnetic resonance imaging (MRI) data will be used to create a computational head model for each participant. The head model will help identify the treatment target of the left hippocampus. The treatments schedule contains six sessions of low-intensity TUS, three times per week, lasting two weeks. Each session of treatment lasts for 80 seconds. Throughout the study, outcome measurements will be conducted at four time points, including baseline, 2nd week, 6th week, and 12th week. The primary outcomes include subjective sleep quality and severity of tinnitus. The secondary measurements include actigraphy, tinnitus handicap inventory and glymphatic function. Participants' adherence to the program and any adverse event will be closely monitored throughout the duration of the clinical trial. It is expected that a 2-week treatment of low-intensity TUS will show significant enhancement in sleep quality and the severity of tinnitus symptoms compared to sham TUS. This proposed clinical trial will provide high-level and valuable clinical evidence that could inform the effect size and personalized modeling of focused low-intensity TUS for different types of brain diseases. ClinicalTrials.gov Identifier: NCT06776705.

Adult neurogenesis, the generation of new neurons throughout life, occurs in the subventricular zone of the dentate gyrus in the human hippocampal formation. It has been shown in rodents that adult hippocampal neurogenesis is needed for pattern separation, the ability to differentially encode small changes derived from similar inputs, and recognition memory, as well as the ability to recognize previously encountered stimuli. Improved hippocampus-dependent cognition and cellular readouts of adult hippocampal neurogenesis have been reported in daily energy restricted and intermittent fasting adult mice. Evidence that nutrition can significantly affect brain structure and function is increasing substantially. This randomized intervention study investigated the effects of intermittent and continuous energy restriction on human hippocampal neurogenesis-related cognition, which has not been reported previously. Pattern separation and recognition memory were measured in 43 individuals with central obesity aged 35–75 years, before and after a four-week dietary intervention using the mnemonic similarity task. Both groups significantly improved pattern separation (P = 0.0005), but only the intermittent energy restriction group had a significant deterioration in recognition memory. There were no significant differences in cognitive improvement between the two diets. This is the first human study to investigate the association between energy restriction with neurogenesis-associated cognitive function. Energy restriction may enhance hippocampus-dependent memory and could benefit those in an ageing population with declining cognition. This study was registered on ClinicalTrials.gov (NCT02679989) on 11 February 2016.

Background Cortico-hippocampal functional networks, specifically the anterior-temporal (AT) and posterior-medial (PM) systems, are crucial for memory and highly vulnerable to aging and Alzheimer’s disease (AD). While modifiable cardiovascular risk factors may offer prevention opportunities to preserve brain aging, their effects on AT/PM functional connectivity remain unknown. This study aims to investigate these associations in older adults, considering major risk categories and exploring potential interactions with protective lifestyle habits and AD risk factors. Methods One hundred thirty-one community-dwelling cognitively unimpaired adults aged 65 + were selected from the Age-Well trial, a French monocentric population-based study conducted from 2016 to 2020. Resting-state fMRI and cardiovascular risk assessments were performed at baseline and 18-month follow-up. Functional connectivity within the AT and PM networks was derived from seed-based analyses using the perirhinal and parahippocampal cortices as individual seeds, respectively. Generalized additive and linear mixed models assessed the effects of cardiovascular risk factors on AT/PM functional connectivity, including interactions with protective lifestyle habits and AD risk factors. Results Baseline mean age was 69 (65–84) years, with 63.5% women. Higher abdominal fat (95% CI: -0.00118, -0.00005; F  = 5.39; P  =.02), higher LDL cholesterol (95% CI: -0.01642, -0.00345; F  = 10.40; P  =.001), longer smoking duration (95% CI: NA; F  = 3.89; P  =.03) and greater alcohol consumption (95% CI: -0.01134, -0.00045; F  = 4.66; P  =.02) were consistently associated with lower PM connectivity, collectively explaining 11.4% of the variance. However, only LDL cholesterol survived multiple comparisons, possibly reflecting a more direct involvement in cardiovascular mechanisms affecting functional connectivity. No association was found with AT connectivity. Exploratory analyses showed that these relationships were independent of cerebral Aβ-positivity or APOE-ε4 carrier status and were unaffected by physical activity and Mediterranean diet when considered separately. Discussion This study highlights converging associations between higher cardiovascular risk factors and lower functional connectivity in cognitively unimpaired older adults, specifically affecting the PM—but not AT—network, and independent of AD risk. Targeting these specific modifiable factors may prevent age-related network alterations to promote cognitive health in aging. Trial registration information The Age-Well trial was registered with ClinicalTrials.gov on November 25, 2016 (identifier: NCT02977819).