Consensus Paper: Cerebellum and Ageing.

Given the key roles of the cerebellum in motor, cognitive, and affective operations and given the decline of brain functions with aging, cerebellar circuitry is attracting the attention of the scientific community. The cerebellum plays a key role in timing aspects of both motor and cognitive operations, including for complex tasks such as spatial navigation. Anatomically, the cerebellum is connected with the basal ganglia via disynaptic loops, and it receives inputs from nearly every region in the cerebral cortex. The current leading hypothesis is that the cerebellum builds internal models and facilitates automatic behaviors through multiple interactions with the cerebral cortex, basal ganglia and spinal cord. The cerebellum undergoes structural and functional changes with aging, being involved in mobility frailty and related cognitive impairment as observed in the physio-cognitive decline syndrome (PCDS) affecting older, functionally-preserved adults who show slowness and/or weakness. Reductions in cerebellar volume accompany aging and are at least correlated with cognitive decline. There is a strongly negative correlation between cerebellar volume and age in cross-sectional studies, often mirrored by a reduced performance in motor tasks. Still, predictive motor timing scores remain stable over various age groups despite marked cerebellar atrophy. The cerebello-frontal network could play a significant role in processing speed and impaired cerebellar function due to aging might be compensated by increasing frontal activity to optimize processing speed in the elderly. For cognitive operations, decreased functional connectivity of the default mode network (DMN) is correlated with lower performances. Neuroimaging studies highlight that the cerebellum might be involved in the cognitive decline occurring in Alzheimer's disease (AD), independently of contributions of the cerebral cortex. Grey matter volume loss in AD is distinct from that seen in normal aging, occurring initially in cerebellar posterior lobe regions, and is associated with neuronal, synaptic and beta-amyloid neuropathology. Regarding depression, structural imaging studies have identified a relationship between depressive symptoms and cerebellar gray matter volume. In particular, major depressive disorder (MDD) and higher depressive symptom burden are associated with smaller gray matter volumes in the total cerebellum as well as the posterior cerebellum, vermis, and posterior Crus I. From the genetic/epigenetic standpoint, prominent DNA methylation changes in the cerebellum with aging are both in the form of hypo- and hyper-methylation, and the presumably increased/decreased expression of certain genes might impact on motor coordination. Training influences motor skills and lifelong practice might contribute to structural maintenance of the cerebellum in old age, reducing loss of grey matter volume and therefore contributing to the maintenance of cerebellar reserve. Non-invasive cerebellar stimulation techniques are increasingly being applied to enhance cerebellar functions related to motor, cognitive, and affective operations. They might enhance cerebellar reserve in the elderly. In conclusion, macroscopic and microscopic changes occur in the cerebellum during the lifespan, with changes in structural and functional connectivity with both the cerebral cortex and basal ganglia. With the aging of the population and the impact of aging on quality of life, the panel of experts considers that there is a huge need to clarify how the effects of aging on the cerebellar circuitry modify specific motor, cognitive, and affective operations both in normal subjects and in brain disorders such as AD or MDD, with the goal of preventing symptoms or improving the motor, cognitive, and affective symptoms.

Effects of a 10-week musical instrument training on cognitive function in healthy older adults: implications for desirable tests and period of training.

Introduction: Previous studies have shown that musical instrument training programs of 16 or more weeks improve verbal memory (Logical Memory Test delayed recall), processing speed (Digit Symbol Coding Test), and executive function (Trail Making Test Part B) of musically untrained healthy older adults. However, it is unclear whether shorter-period instrument training can yield similar effects. We sought to (1) verify those results and (2) clarify if intervention effects could be detected using other measures such as reaction time. Methods: Healthy older adults (mean age = 73.28 years) were pseudo-randomly assigned to an untrained control group (n = 30) or an intervention group (n = 30) that received a weekly 10-session musical instrument training program (using melodica). We conducted neuropsychological tests on which intervention effects or association with musical training were reported in previous studies. We newly included two reaction time tasks to assess verbal working memory (Sternberg task) and rhythm entrainment (timing task). Intervention effects were determined using a "group × time" analysis of variance (ANOVA). Results: The intervention effects were detected on the reaction time in Sternberg task and phonological verbal fluency. Although intervention effects had been reported on Logical Memory test, Digit Symbol Coding Test and Trail Making Test in previous studies with longer training periods, the present study did not show such effects. Instead, the test-retest practice effect, indicated by significant improvement in the control group, was significant on these tests. Discussion: The present results indicated the usefulness of working memory assessments (Verbal Fluency Test and Sternberg task) in detecting the effects of short-term melodica training in healthy older adults. The practice effect detected on those three tasks may be due to the shorter interval between pre- and post-intervention assessments and may have obscured intervention effects. Additionally, the findings suggested the requirement for an extended interval between pre- and post-tests to capture rigorous intervention effects, although this should be justified by a manipulation of training period.

Child Developmental MRI (CDM) project: protocol for a multi-centre, cross-sectional study on elucidating the pathophysiology of attention-deficit/hyperactivity disorder and autism spectrum disorder through a multi-dimensional approach.

INTRODUCTION: Neuroimaging studies on attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have demonstrated differences in extensive brain structure, activity and network. However, there remains heterogeneity and inconsistency across these findings, presumably because of the diversity of the disorders themselves, small sample sizes, and site and parameter differences in MRI scanners, and their overall pathogenesis remains unclear. To address these gaps in the literature, we will apply the travelling-subject approach to correct site differences in MRI scanners and clarify brain structure and network characteristics of children with ADHD and ASD using large samples collected in a multi-centre collaboration. In addition, we will investigate the relationship between these characteristics and genetic, epigenetic, biochemical markers, and behavioural and psychological measures. METHODS AND ANALYSIS: We will collect resting-state functional MRI (fMRI) and T1-weighted and diffusion-weighted MRI data from 15 healthy adults as travelling subjects and 300 children (ADHD, n=100; ASD, n=100; and typical development, n=100) with multi-dimensional assessments. We will also apply data from more than 1000 samples acquired in our previous neuroimaging studies on ADHD and ASD. ETHICS AND DISSEMINATION: The study protocol has been approved by the Research Ethics Committee of the University of Fukui Hospital (approval no: 20220601). Our study findings will be submitted to scientific peer-reviewed journals and conferences.

Dismantling cognitive-behavioural therapy components for attention-deficit hyperactivity disorder in adolescents and adults: protocol for a network meta-analysis.

INTRODUCTION: Cognitive-behavioural therapy (CBT) consists of multiple treatment techniques for each treatment model and is tailored to the patient's characteristics. Randomised controlled trials (RCTs) have reported that CBT is effective for attention-deficit/hyperactivity disorder (ADHD); however, which CBT components are effective is unknown. In order to provide the best treatment technique, it is important to know which therapeutic component or combination thereof is more effective and what the specific effect size is. METHODS AND ANALYSIS: We will perform component network meta-analysis (cNMA). The search will include studies published from database inception up to 31 March 2022, in English. The electronic databases of MEDLINE (via PubMed), EMBASE, PsycINFO, ClinicalTrials.gov and Cochrane Library will be searched. We will systematically identify all RCTs in the treatment of ADHD between the ages of 10 and 60 years, comparing interventions composed of various CBT components with controlled interventions. We will perform pairwise and network meta-analysis with random effects to estimate summary ORs and standardised mean differences. We will assess the risk of bias in selected studies using the Cochrane risk of bias tool. ETHICS AND DISSEMINATION: Since we will review published papers, ethical approval is not required. The results from this cNMA will provide a panorama of the CBT-based ADHD studies. The results of this study will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022323898.

Impact of Early-Commenced and Continued Sports Training on the Precuneus in Older Athletes.

Intervention studies on sedentary older adults have demonstrated that commencing physical exercise at an older age has a positive effect on brain structure. Although this suggests that older athletes with lifelong sports training have larger gray matter volume (GMV) in some brain regions compared to age-matched non-athletes, evidence in the literature is scarce. Moreover, it remains unclear whether a larger GMV is associated with training intensity or period of training in life. To address these gaps in the literature, we compared regional brain GMV between 24 older athletes (mean age, 71.4 years; age at the commencement of sports training, 31.2 years, continuous sports training, 40.0 years; current training time, 7.9 h/week) and 24 age-matched non-athletes (mean age, 71.0 years). The period of sports training and the current training time of the athletes were assessed. Both groups were evaluated for physical activity intensity as well as cognitive and motor performance. Although no group differences were noted in cognitive and motor performance, athletes reported higher physical activity intensity than non-athletes. Whole-brain structural analysis revealed a significantly larger GMV in several brain regions in athletes. Notably, the GMV of the precuneus in athletes was positively correlated with earlier commencement of sports training and training duration but was negatively correlated with current training time. Our findings demonstrate that early-commenced and continued sports training predicts structural maintenance of the precuneus in old age. Our results also suggest that excessive training time in old age may have a negative impact on the GMV of the precuneus; thereby delineating how the precuneus is associated with lifelong sports training in older athletes.

Impact of Long-Rope Jumping on Monoamine and Attention in Young Adults.

Previous research has shown that rope jumping improves physical health; however, little is known about its impact on brain-derived monoamine neurotransmitters associated with cognitive regulation. To address these gaps in the literature, the present study compared outcomes between 15 healthy participants (mean age, 23.1 years) after a long-rope jumping exercise and a control condition. Long-rope jumping also requires co-operation between people, attention, spatial cognition, and rhythm sensation. Psychological questionnaires were administered to both conditions, and Stroop task performance and monoamine metabolite levels in the saliva and urine were evaluated. Participants performing the exercise exhibited lower anxiety levels than those in the control condition. Saliva analyses showed higher 3-methoxy-4-hydroxyphenylglycol (a norepinephrine metabolite) levels, and urine analyses revealed higher 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindoleacetic acid (a serotonin metabolite) levels in the exercise condition than in the control. Importantly, urinary 5-hydroxyindoleacetic acid level correlated with salivary and urinary 3-methoxy-4-hydroxyphenylglycol levels in the exercise condition. Furthermore, cognitive results revealed higher Stroop performance in the exercise condition than in the control condition; this performance correlated with salivary 3-methoxy-4-hydroxyphenylglycol levels. These results indicate an association between increased 3-methoxy-4-hydroxyphenylglycol and attention in long-rope jumping. We suggest that long-rope jumping predicts central norepinephrinergic activation and related attention maintenance.

Draft Genome Sequence of Neisseria mucosa Strain HSUH001, Isolated from an Aggressive Periodontal Lesion.

We report the draft genome sequence (143 contigs, with a total length of 2,424,805 bp and an N 50 value of 36,066 bp) of a bacterium isolated from an aggressive periodontal lesion in a patient. We assigned strain HSUH001 to Neisseria mucosa through a multilocus sequence analysis.

Musical instrument training program improves verbal memory and neural efficiency in novice older adults.

Previous studies indicate that musical instrument training may improve the cognitive function of older adults. However, little is known about the neural origins of training-related improvement in cognitive function. Here, we assessed the effects of instrumental training program on cognitive functions and neural efficiency in musically naïve older adults (61-85 years old). Participants were assigned to either the intervention group, which received a 4-month instrumental training program using keyboard harmonica, or a control group without any alternative training. Cognitive measurements and functional magnetic resonance imaging during visual working memory (VWM) task were administered before and after the intervention in both groups. Behavioral data revealed that the intervention group significantly improved memory performance on the test that measures verbal recall compared to the control group. Neuroimaging data revealed that brain activation in the right supplementary motor area, left precuneus, and bilateral posterior cingulate gyrus (PCgG) during the VWM task decreased after instrumental training only in the intervention group. Task-related functional connectivity (FC) analysis revealed that the intervention group showed decreased FC between the right PCgG and left middle temporal gyrus, and between the left putamen and right superior temporal gyrus (lPu-rSTG) during a VWM task after the intervention. Furthermore, a greater improvement in memory performance in the intervention group was associated with a larger reduction in lPu-rSTG FC, which might be interpreted as improved neural efficiency. Our results indicate that the musical instrument training program may contribute to improvements in verbal memory and neural efficiency in novice older adults.

Neural Advantages of Older Musicians Involve the Cerebellum: Implications for Healthy Aging Through Lifelong Musical Instrument Training.

This study compared 30 older musicians and 30 age-matched non-musicians to investigate the association between lifelong musical instrument training and age-related cognitive decline and brain atrophy (musicians: mean age 70.8 years, musical experience 52.7 years; non-musicians: mean age 71.4 years, no or less than 3 years of musical experience). Although previous research has demonstrated that young musicians have larger gray matter volume (GMV) in the auditory-motor cortices and cerebellum than non-musicians, little is known about older musicians. Music imagery in young musicians is also known to share a neural underpinning [the supramarginal gyrus (SMG) and cerebellum] with music performance. Thus, we hypothesized that older musicians would show superiority to non-musicians in some of the abovementioned brain regions. Behavioral performance, GMV, and brain activity, including functional connectivity (FC) during melodic working memory (MWM) tasks, were evaluated in both groups. Behaviorally, musicians exhibited a much higher tapping speed than non-musicians, and tapping speed was correlated with executive function in musicians. Structural analyses revealed larger GMVs in both sides of the cerebellum of musicians, and importantly, this was maintained until very old age. Task-related FC analyses revealed that musicians possessed greater cerebellar-hippocampal FC, which was correlated with tapping speed. Furthermore, musicians showed higher activation in the SMG during MWM tasks; this was correlated with earlier commencement of instrumental training. These results indicate advantages or heightened coupling in brain regions associated with music performance and imagery in musicians. We suggest that lifelong instrumental training highly predicts the structural maintenance of the cerebellum and related cognitive maintenance in old age.

Potential Role of Neuroactive Tryptophan Metabolites in Central Fatigue: Establishment of the Fatigue Circuit.

Central fatigue leads to reduced ability to perform mental tasks, disrupted social life, and impaired brain functions from childhood to old age. Regarding the neurochemical mechanism, neuroactive tryptophan metabolites are thought to play key roles in central fatigue. Previous studies have supported the "tryptophan-serotonin enhancement hypothesis" in which tryptophan uptake into extensive brain regions enhances serotonin production in the rat model of exercise-induced fatigue. However, serotonin was transiently released after 30 minutes of treadmill running to exhaustion, but this did not reflect the duration of fatigue. In addition, as the vast majority of tryptophan is metabolized along the kynurenine pathway, possible involvement of the tryptophan-kynurenine pathway in the mechanism of central fatigue induction has been pointed out. More recently, our study demonstrated that uptake of tryptophan and kynurenine derived from the peripheral circulation into the brain enhances kynurenic acid production in rat brain in sleep deprivation-induced central fatigue, but without change in serotonin activity. In particular, dynamic change in glial-neuronal interactive processes within the hypothalamus-hippocampal circuit causes central fatigue. Furthermore, increased tryptophan-kynurenine pathway activity in this circuit causes reduced memory function. This indicates a major potential role for the endogenous tryptophan-kynurenine pathway in central fatigue, which supports the "tryptophan-kynurenine enhancement hypothesis." Here, we review research on the basic neuronal mechanism underlying central fatigue induced by neuroactive tryptophan metabolites. Notably, these basic findings could contribute to our understanding of latent mental problems associated with central fatigue.

Tryptophan circuit in fatigue: From blood to brain and cognition.

Brain tryptophan and its neuroactive metabolites play key roles in central fatigue. However, previous brain function analysis targets may have included both glia and neurons together. Here, we clarified the fatigue-cognitive circuit of the central-peripheral linkage, including the role of glial-neuronal interaction in cognition. Using a rat model of central fatigue induced by chronic sleep disorder (CFSD), we isolated presynaptic terminals and oligodendrocytes. Results showed that compared to control group, presynaptic levels of tryptophan, kynurenine, and kynurenic acid, but not serotonin, in the CFSD group were higher in the hypothalamus and hippocampus. Moreover, CFSD group had higher oligodendrocytic levels of tryptophan, and impaired spatial cognitive memory accuracy and increased hyperactivity and impulsivity. These findings suggest that dynamic change in glial-neuronal interactions within the hypothalamus-hippocampal circuit causes central fatigue, and increased tryptophan-kynurenic acid pathway activity in this circuit causes reduced cognitive function. Additionally, CFSD group had 1.5 times higher plasma levels of tryptophan and kynurenine. Furthermore, in rats undergoing intraperitoneal administration of kynurenine (100mg/kg) versus vehicle, kynurenine-treated rats showed enhanced production of kynurenic acid in the hippocampus, with suppressed recall of retained spatial cognitive memory. The study revealed that uptake of periphery-derived kynurenine and tryptophan into the brain enhances kynurenic acid production in the brain, and the three factors produce amplification effect involved in the role of central-peripheral linkage in central fatigue, triggering cognitive dysfunction.

Tryptophan and kynurenic Acid may produce an amplified effect in central fatigue induced by chronic sleep disorder.

Tryptophan (TRP) and its neuroactive metabolite, kynurenic acid (KYNA), are thought to play key roles in central fatigue, but the specifics are still unknown. To clarify their roles in the brain, we developed a rat model of central fatigue induced by chronic sleep disorder (CFSD) by disturbing the sleep-wake cycle. Results showed that while 5-hydroxytryptamine (5-HT) concentration did not differ between control and CFSD groups, levels of TRP and KYNA in the CFSD group were about 2 and 5 times higher in the hypothalamus, and 2 and 3.5 times higher in the hippocampus, respectively. Moreover, CFSD-induced fatigue led to abnormal running performance (via treadmill test) and social interaction (via social-interaction test). These results support a TRP-KYNA hypothesis in central fatigue in which increased TRP concentration in the brain and subsequently synthesized KYNA may produce an amplified effect on central fatigue, with enhanced concentrations being a possible mechanism by which social-interaction deficits are generated.