Effect of ramosetron, a 5-HT3 receptor antagonist on the severity of seizures and memory impairment in electrical amygdala kindled rats

The entorhinal cortex (EC) plays a pivotal role in epileptogenesis and seizures. EC expresses high density of serotonergic receptors, especially 5-HT3 receptors. Cognitive impairment is common among people with epilepsy. The present study investigated the role of 5-HT3 receptor on the severity of seizures and learning and memory impairment by electrical kindling of amygdala in rats. The amygdala kindling was conducted in a chronic kindling manner in male Wistar rats. In fully kindled animals, ramosetron (as a potent and selective 5-HT3 receptor antagonist) was microinjected unilaterally (ad doses of 1, 10 or 100 µg/0.5 µl) into the EC 5 min before the novel object recognition (NOR) and Y-maze tests or kindling stimulations. Applying ramosetron at the concentration of 100 μg/0.5 µl (but not at 1 and 10 µg/0.5 µl) reduced afterdischarge (AD) duration and increased stage 4 latency in the kindled rats. Moreover, the obtained data from the NOR test showed that treatment by ramosetron (10 and 100 µg/0.5 µl) increased the discrimination index in the fully kindled animals. Microinjection of ramosetron (10 and 100 µg/0.5 µl) in fully kindled animals reversed the kindling induced changes in the percentage of spontaneous alternation in Y-maze task. The findings demonstrated an anticonvulsant role for a selective 5-HT3 receptor antagonist microinjected into the EC, therefore, suggesting an excitatory role for the EC 5-HT3 receptors in the amygdala kindling model of epilepsy. This anticonvulsive effect was accompanied with a restoring effect on cognitive behavior in NOR and Y-maze tests.

The hippocampus as a sorter and reverberatory integrator of sensory inputs

In entorhinal-hippocampal networks, the trisynaptic pathway, including the CA3 recurrent circuit, processes episodes of context and space. Recurrent connectivity can generate reverberatory activity, an intrinsic activity pattern of neurons that occurs after sensory inputs have ceased. However, the role of reverberatory activity in memory encoding remains incompletely understood. Here we demonstrate that in mice, synchrony between conditioned stimulus (CS) and unconditioned stimulus (US)-responsible cells occurs during the reverberatory phase, lasting for approximately 15 s, but not during CS and US inputs, in the CA1 and the reverberation is crucial for the linking of CS and US in the encoding of delay-type cued-fear memory. Retrieval-responsive cells developed primarily during the reverberatory phase. Mutant mice lacking N-methyl-D-aspartate receptors (NRs) in CA3 showed a cued-fear memory impairment and a decrease in synchronized reverberatory activities between CS- and US-responsive CA1 cells. Optogenetic CA3 silencing at the reverberatory phase during learning impaired cued-fear memory. Our findings suggest that reverberation recruits future retrieval-responsive cells via synchrony between CS- and US-responsive cells. The hippocampus uses reverberatory activity to link CS and US inputs, and avoid crosstalk during sensory inputs.

Theta Oscillation and Functional Connectivity Alterations Related to Cerebral Small Vessel Disease with Working Memory Impairment

Background Impaired working memory (WM) is an important clinical symptom of cognitive dysfunction associated with cerebral small vessel disease (CSVD). Theta oscillations play an important role in the regulation of learning, WM and synaptic plasticity. Therefore, we speculate that theta oscillation may play an important role in the process of working memory impairment in CSVD. Methods Seventy-eight patients with CSVD (mean age 66.18 ± 1.42) and 49 healthy controls (HCs) (mean age 66.53 ± 1.3) were recruited to perform the WM task. Neural oscillations and functional connectivity during the encoding, maintenance, and retrieval phases of WM were evaluated during performance of WM test. Results Compared with the control group, the working memory behavior of the CSVD group showed a significantly longer reaction time and lower accuracy rate. The energy density and functional connection (FC) strength of the theta band in frontal region of the CSVD group were significantly lower than those of the control group, and the theta oscillation in the retrieval phase was significantly higher than that in the coding phase. However, there was no significant change in FC strengths among three phases. Both in the two groups, the FC was significantly positively correlated with accuracy and negatively correlated with reaction time (RT). Conclusion Our results indicated that CSVD patients have significant working memory impairment, and the lack of theta oscillation in the frontal region and the abnormal functional connection of the brain network may be one of its potential neurophysiological mechanisms.

Characterization of cognitive impairment in adult polyglucosan body disease

Adult polyglucosan body disease (APBD) is a rare but probably underdiagnosed autosomal recessive neurodegenerative disorder due to pathogenic variants in GBE1. The phenotype is characterized by neurogenic bladder dysfunction, spastic paraplegia, and axonal neuropathy. Additionally, cognitive symptoms and dementia have been reported in APBD but have not been studied systematically. Using exome sequencing, we identified two previously unreported bi-allelic missense GBE1 variants in a patient with severe memory impairment along with the typical non-cognitive symptoms. We were able to confirm a reduction of GBE1 activity in blood lymphocytes. To characterize the neuropsychological profile of patients suffering from APBD, we conducted a systematic review of cognitive impairment in this rare disease. Analysis of 24 cases and case series (in total 58 patients) showed that executive deficits and memory impairment are the most common cognitive symptoms in APBD.

A 12-month Randomised Pilot Trial of the Alzheimer’s and Music Therapy Study: A Feasibility Assessment of Music Therapy and Physical Activity in Patients with Mild-to-Moderate Alzheimer’s Disease

Background: The Alzheimer’s and Music Therapy (ALMUTH) study is the first randomised controlled trial (RCT) design with 12 months of active non-pharmacological therapy (NPT) implementing music therapy (MT) and physical activity (PA) for participants with Alzheimer’s disease (AD). The aim of the present article is to retrospectively examine the inclusion of mild-to-moderate Alzheimer’s Disease patients into the main ALMUTH study protocol and to determine if continued inclusion of AD patients is warranted. Methods: The randomised pilot trial was conducted as a parallel three-arm RCT, reflecting the experimental design of the ALMUTH study. The trial was conducted in Bergen, Norway and randomisation (1:1:1) was performed by an external researcher. The study was open label and the experimental design features two active NPTs: MT and PA, and a passive control (no intervention, CON) in Norwegian speaking patients with AD who still live at home and could provide informed consent. Sessions were offered one time per week (up to 90 minutes) up to 40 sessions over the period of 12 months. Baseline and follow-up tests included a full neuropsychological test battery and three magnetic resonance imaging (MRI) measurements (structural, functional, and diffusion weighted imaging). Feasibility outcomes were assessed and were determined as feasible if they met the target criteria. Results: 18 participants with a diagnosis of mild-to-moderate AD were screened, randomised, and tested at baseline and after a 12-month follow-up interval. Participants were divided into three groups: MT (n=6), PA (n=6), and CON (n=6). Results of the study revealed that the ALMUTH protocol in patients with AD is not feasible. Adherence to protocol was poor (50% attended sessions), the presence of 50% attrition rates, 50% retention rates, insufficient and costly recruitment, issues with study fidelity, and many issues raised by staff. Recruitment status is still ongoing and the main study has been expanded to include milder forms of memory impairment. No adverse events were reported by the patients or their caregivers. Conclusions: The pilot trial was not deemed feasible in patients exclusively with AD. To mitigate this, the ALMUTH study has expanded the recruitment criteria to include participants with milder forms of memory impairment (pre-AD) in addition to expanding the neuropsychological test battery. The ALMUTH study is currently ongoing. Trial Registration: Norsk Forskningsråd (NFR) funded. Regional Committees for Medical and Health Research Ethics (REC-WEST: reference number 2018/206). ClinicalTrials.gov: NCT03444181 (registered retrospectively 23 February 2018, https://clinicaltrials.gov/ct2/show/NCT03444181).

BDNF Val66Met gene polymorphism modulates brain activity following rTMS-induced memory impairment

The BDNF Val66Met gene polymorphism is a relevant factor explaining inter-individual differences to TMS responses in studies of the motor system. However, whether this variant also contributes to TMS-induced memory effects, as well as their underlying brain mechanisms, remains unexplored. In this investigation, we applied rTMS during encoding of a visual memory task either over the left frontal cortex (LFC; experimental condition) or the cranial vertex (control condition). Subsequently, individuals underwent a recognition memory phase during a functional MRI acquisition. We included 43 young volunteers and classified them as 19 Met allele carriers and 24 as Val/Val individuals. The results revealed that rTMS delivered over LFC compared to vertex stimulation resulted in reduced memory performance only amongst Val/Val allele carriers. This genetic group also exhibited greater fMRI brain activity during memory recognition, mainly over frontal regions, which was positively associated with cognitive performance. We concluded that BDNF Val66Met gene polymorphism, known to exert a significant effect on neuroplasticity, modulates the impact of rTMS both at the cognitive as well as at the associated brain networks expression levels. This data provides new insights on the brain mechanisms explaining cognitive inter-individual differences to TMS, and may inform future, more individually-tailored rTMS interventions.