Biology subjects

Lim, W.

Publications and source records attributed to Lim, W..

6 recordsLinked to original sources

bioRxiv2018

Cluster Burst Synchronization in A Scale-Free Network of Inhibitory Bursting Neurons

We consider a scale-free network of inhibitory Hindmarsh-Rose (HR) bursting neurons, and investigate coupling-induced burst synchronization by varying the average coupling strength J0. When passing a lower threshold [Formula], a transition from desynchronization to 3-cluster burst synchronization occurs due to a constructive role of inhibition to favor the cluster burst synchronization. For this case, the whole population is segregated into 3 clusters, and HR neurons in each cluster exhibit burst synchronization. However, as J0 is increased and passes an intermediate threshold [Formula], HR neurons begin to make intermittent hoppings between the 3 clusters. Due to the intermittent intercluster hoppings, the 3 clusters are integrated into a single one. In spite of break-up of the 3 clusters, burst synchronization persists in the whole population, which is well visualized in the raster plot of burst onset times where bursting stripes (composed of burst onset times and indicating burst synchronization) appear successively. With further increase in J0, intercluster hoppings are intensified, and bursting stripes also become smeared more and more due to a destructive role of inhibition to spoil the burst synchronization. Eventually, when passing a higher threshold [Formula] a transition to desynchronization occurs via complete overlap between the bursting stripes. Finally, we also investigate the effects of stochastic noise on both 3-cluster burst synchronization and intercluster hoppings.\n\nPACS numbers: 87.19.lm, 87.19.lc

neuroscience↗

bioRxiv2018

Complementary topology of maintenance and manipulation brain networks in working memory

Working memory (WM) is assumed to consist of a process that sustains memory representations in an active state (maintenance) and a process that operates on these activated representations (manipulation). Prior fMRI studies have examined maintenance and manipulation in separate task conditions, whereas in real life these processes operate simultaneously. In the current study, the neural mechanisms of maintenance and manipulation were disentangled during the same task by parametrically varying these processes. During fMRI, participants maintained consonant letters in WM while sorting them in alphabetical order. Maintenance was investigated by varying the number of letters held in WM and manipulation by varying the number of moves required to sort the list alphabetically. The study yielded three main findings. First, the degree of both maintenance and manipulation demand had significant effects on behavior that were associated with different cortical regions: maintenance was associated with bilateral prefrontal and left parietal cortex, and manipulation with right parietal activity, a link that is consistent with the role of parietal cortex in symbolic computations. Second, univariate fMRI and tractography based on diffusion-weighted imaging showed that maintenance and manipulation regions are supported by two dissociable structural networks. Finally, maintenance and manipulation functional networks became increasingly segregated with increasing demand, possibly reflecting the protection of information held in WM from interference generated by manipulation operations. These results represent a novel approach to study the brain as an adaptive system that coordinates multiple ongoing cognitive processes.\n\nSignificance StatementDespite the importance of working memory (WM) in everyday life, little is known about how the brain is able to simultaneously maintain and manipulate information stored in short-term memory buffers. We examined evidence for two distinct, concurrent cognitive functions supporting maintenance and manipulation abilities by testing brain activity as participants performed a WM alphabetization task. We found behavioral and neural evidence in support of dissociable cognitive functions associated with these two operations. Furthermore, we found that connectivity between these networks was increasingly segregated as difficulty increased, and that this effect was positively related to individual WM ability. These results provide evidence that network segregation may act as a protective mechanism to enable successful performance under increasing WM demand.

neuroscience↗

bioRxiv2018

Effect of Inhibitory Spike-Timing-Dependent Plasticity on Fast Sparsely Synchronized Rhythms in A Small-World Neuronal Network

We consider the Watts-Strogatz small-world network (SWN) consisting of inhibitory fast spiking Izhikevich interneurons. This inhibitory neuronal population has adaptive dynamic synaptic strengths governed by the inhibitory spike-timing-dependent plasticity (iSTDP). In previous works without iSTDP, fast sparsely synchronized rhythms, associated with diverse cognitive functions, were found to appear in a range of large noise intensities for fixed strong synaptic inhibition strengths. Here, we investigate the effect of iSTDP on fast sparse synchronization (FSS) by varying the noise intensity D. We employ an asymmetric anti-Hebbian time window for the iSTDP update rule [which is in contrast to the Hebbian time window for the excitatory STDP (eSTDP)]. Depending on values of D, population-averaged values of saturated synaptic inhibition strengths are potentiated [long-term potentiation (LTP)] or depressed [long-term depression (LTD)] in comparison with the initial mean value, and dispersions from the mean values of LTP/LTD are much increased when compared with the initial dispersion, independently of D. In most cases of LTD where the effect of mean LTD is dominant in comparison with the effect of dispersion, good synchronization (with higher spiking measure) is found to get better via LTD, while bad synchronization (with lower spiking measure) is found to get worse via LTP. This kind of Matthew effect in inhibitory synaptic plasticity is in contrast to that in excitatory synaptic plasticity where good (bad) synchronization gets better (worse) via LTP (LTD). Emergences of LTD and LTP of synaptic inhibition strengths are intensively investigated via a microscopic method based on the distributions of time delays between the pre- and the post-synaptic spike times. Furthermore, we also investigate the effects of network architecture on FSS by changing the rewiring probability p of the SWN in the presence of iSTDP.

neuroscience↗

bioRxiv2018

Burst Synchronization in A Scale-Free Neuronal Network with Inhibitory Spike-Timing-Dependent Plasticity

We are concerned about burst synchronization (BS), related to neural information processes in health and disease, in the Barabasi-Albert scale-free network (SFN) composed of inhibitory bursting Hindmarsh-Rose neurons. This inhibitory neuronal population has adaptive dynamic synaptic strengths governed by the inhibitory spike-timing-dependent plasticity (iSTDP). In previous works without considering iSTDP, BS was found to appear in a range of noise intensities for fixed synaptic inhibition strengths. In contrast, in our present work, we take into consideration iSTDP and investigate its effect on BS by varying the noise intensity. Our new main result is to find occurrence of a Matthew effect in inhibitory synaptic plasticity: good BS gets better via LTD, while bad BS get worse via LTP. This kind of Matthew effect in inhibitory synaptic plasticity is in contrast to that in excitatory synaptic plasticity where good (bad) synchronization gets better (worse) via LTP (LTD). We note that, due to inhibition, the roles of LTD and LTP in inhibitory synaptic plasticity are reversed in comparison with those in excitatory synaptic plasticity. Moreover, emergences of LTD and LTP of synaptic inhibition strengths are intensively investigated via a microscopic method based on the distributions of time delays between the preand the post-synaptic burst onset times. Finally, in the presence of iSTDP we investigate the effects of network architecture on BS by varying the symmetric attachment degree l* and the asymmetry parameter {Delta}l in the SFN.

neuroscience↗

bioRxiv2018

A systematic study of repetitive transcranial magnetic stimulation to enhance working memory manipulation abilities

A core element of human working memory (WM) is the ability to perform mental operations on information that is stored in a flexible, limited capacity buffer. Given the profound importance of such WM manipulation (WM-M) abilities, there is a concerted effort aimed at developing approaches to improve them. Past research has identified neural substrates of WM-M centered in the dorsolateral prefrontal cortex (DLPFC), thereby providing a plausible and accessible target for noninvasive neuromodulatory stimulation that can be used to alter cortical excitability and potentially lead to facilitation of WM-M. In the current study, 5Hz online repetitive transcranial magnetic stimulation (rTMS), applied over the left DLPFC, was used to test the hypothesis that active rTMS would lead to significant improvements in memory recall accuracy compared to sham stimulation, and that these effects would be most pronounced in the WM-M conditions with the highest cognitive demand (registered Clinical Trial: #NCT02767323). Participants performed a delayed response alphabetization task with three individually-titrated levels of difficulty during active and sham rTMS. Analyses revealed that active rTMS led to numerically greater accuracy relative to sham stimulation for the hardest condition; however, this effect did not survive Bonferroni correction over all task conditions. Despite the lack of robust, study-wise significant effects, when considered in isolation, the magnitude of behavioral improvement in the hardest condition was negatively correlated with parametric difficulty-related fMRI activity in the targeted brain region, suggesting that individuals with less activation benefit more from rTMS. The present findings therefore suggest evidence towards the hypothesis that active rTMS can enhance performance during difficult memory manipulation conditions; however, firm conclusions cannot be drawn given the lack of overall significant effects. These findings are discussed in the context of individualized targeting and other factors that might moderate rTMS effects.

neuroscience↗

bioRxiv2018

Addressing the Most Neglected Diseases through an Open Research Model: the Discovery of Fenarimols as Novel Drug Candidates for Eumycetoma

Eumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungus Madurella mycetomatis. A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, therefore, an urgent need to find more effective drugs for the treatment of this disease. In this study, we screened 800 diverse drug-like molecules and identified 215 molecules that were active in vitro. Minimal inhibitory concentrations were determined for the 13 most active compounds. One of the most potent compounds, a fenarimol analogue for which a large analogue library is available, led to the screening of an additional 35 compounds for their in vitro activity against M. mycetomatis hyphae, rendering four further hit compounds. To assess the in vivo potency of these hit compounds, a Galleria mellonella larvae model infected with M. mycetomatis was used. Several of the compounds identified in vitro demonstrated promising efficacy in vivo in terms of prolonged larval survival and/or reduced fungal burden. The results presented in this paper are the starting point of an Open Source Mycetoma (MycetOS) approach in which members of the global scientific community are invited to participate and contribute as equal partners. We hope that this initiative, coupled with the promising new hits we have reported, will lead to progress in drug discovery for this most neglected of neglected tropical diseases.\n\nAuthor summaryMycetoma is a poverty-associated disease that was recently recognised as a neglected tropical disease by the World Health Organisation (WHO). This disease can be caused by either bacteria (actinomycetoma) or fungi (eumycetoma). The most common causative agent of mycetoma is the fungus Madurella mycetomatis. Actinomycetoma can be easily treated, but for eumycetoma, the current and only antifungal drug used is only able to successfully treat 30% of patients. Treatment often involves prolonged medication use and amputation of the affected area. This disease is disfiguring and is a social stigma for patients in endemic countries. To improve treatment for patients, we have looked at over 800 diverse drug-like molecules and compounds in hope to develop new drugs in this study. We have identified 215 compounds with activity against M. mycetomatis in vitro and several in vivo with our Galleria mellonella larvae model. We have chosen an open source approach with this study and placed our findings in an online database and made it available to the public. We invite the global scientific community to participate in our study and contribute as equal partners as long as an open source approach is held in hopes to fast track and boost drug discovery for Eumycetoma.

pharmacology and toxicology↗