Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice.

Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.

Reduced Prefrontal-Thalamic Theta Flow During Working Memory Retrieval in APP/PS1 Mice.

Background: Working memory deficits in Alzheimer's disease (AD) are linked to impairments in the retrieval of stored memory information. However, research on the mechanism of impaired working memory retrieval in Alzheimer's disease is still lacking. Objective: The medial prefrontal cortex (mPFC) and mediodorsal thalamus (MD) are involved in memory retrieval. The purpose of this study is to investigate the functional interactions and information transmission between mPFC and MD in the AD model. Methods: We recorded local field potentials from mPFC and MD while the mice (APP/PS1 transgenic model and control) performed a T-maze spatial working memory task. The temporal dynamics of oscillatory activity and bidirectional information flow between mPFC and MD were assessed during the task phases. Results: We mainly found a significant decrease in theta flow from mPFC to MD in APP/PS1 mice during retrieval. Conclusions: Our results indicate an important role of the mPFC-MD input for retrieval and the disrupted information transfer from mPFC to MD may be the underlying mechanism of working memory deficits in APP/PS1 mice.

Hippocampal-prefrontal high-gamma flow during performance of a spatial working memory.

Working memory refers to a system that provides temporary storage and manipulation of the information necessary for complex cognitive tasks. The prefrontal cortex (PFC) and hippocampus (HPC) are major structures contributing to working memory. Accumulating evidence suggests that the HPC-PFC interactions are critical for the successful execution of working memory tasks. Nevertheless, the directional information transmission within the HPC-PFC pathway remains unclear. Using simultaneous multi-electrode recordings, we recorded local field potentials (LFPs) from the medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) while the rats performed a spatial working memory task in a Y-maze. The directionality of functional interactions between mPFC and vHPC was assessed using the phase-slope index (PSI). Our findings revealed a frequency-specific oscillatory synchrony in the two regions during the spatial working memory task. Furthermore, an increased high-gamma flow from vHPC to mPFC manifested exclusively during correctly performed trials, not observed during incorrect ones. This suggests that the enhanced high-gamma flow reflects behavioral performance in working memory. Consequently, our results indicate an major role of directional frequency-specific communication in the hippocampal-frontal circuit during spatial working memory, providing a potential mechanism for working memory.

Decreased phase information transfer from the mPFC to the BLA: During exploratory behavior in CUMS rats.

Introduction: Depression is a mental disorder characterized by aberrant exploratory behavior. Environmental factors, such as chronic stress, are commonly used to induce depression-like behavior in rodent models. The medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA) are crucial sites in subjects with chronic stress-induced depression. The transmission of amplitude information from the mPFC to the BLA was abated during exploratory behavior in depressive rats; however, the nature of the phase interaction between these two sites remains unknown. Methods: We used chronic unpredictable mild stress (CUMS) to model depression in rats and acquired local field potentials (LFPs) via multiple electrodes implanted in the mPFC and the BLA while rats (both the control and CUMS groups, respectively) were allowed to explore freely in an open field. The weighted phase lag index (WPLI) within the mPFC and the BLA and phase transfer entropy (PTE) from the mPFC to BLA were computed for two groups of rats (control and CUMS rats) to quantify the phase information transmission. Results: Rats subjected to CUMS showed a decrease in exploratory behavior. The WPLI within the mPFC and the BLA showed strikingly higher phase synchrony at theta frequencies (4-12 Hz) than other frequency bands during exploratory behavior in both the control and CUMS groups. The results of theta PTE from the mPFC to BLA showed that PTE was significantly decreased in the CUMS group compared with the control group. Discussions: These findings demonstrated that attenuated phase information transfer might restrain exploratory behavior in CUMS rats.

Directional prefrontal-thalamic information flow is selectively required during spatial working memory retrieval.

Introduction: Spatial working memory is a kind of short-term memory that allows temporarily storing and manipulating spatial information. Evidence suggests that spatial working memory is processed through three distinctive phases: Encoding, maintenance, and retrieval. Though the medial prefrontal cortex (mPFC) and mediodorsal thalamus (MD) are involved in memory retrieval, how the functional interactions and information transfer between mPFC and MD remains largely unclear. Methods: We recorded local field potentials (LFPs) from mPFC and MD while mice performed a spatial working memory task in T-maze. The temporal dynamics of functional interactions and bidirectional information flow between mPFC and MD was quantitatively assessed by using directed transfer function. Results: Our results showed a significantly elevated information flow from mPFC to MD, varied in time and frequency (theta in particular), accompanying successful memory retrieval. Discussion: Elevated theta information flow, a feature that was absent on error trials, indicates an important role of the directional information transfer from mPFC to MD for memory retrieval.

Quercetin ameliorates memory impairment by inhibiting abnormal microglial activation in a mouse model of paradoxical sleep deprivation.

Paradoxical sleep deprivation (PSD) is prevalent in modern society, and impaired memory is one of its serious consequences. The pathogenic mechanism is still unclear, and the therapeutic strategies for PSD are limited. Here, we found that quercetin treatment ameliorated memory impairments caused by PSD in a dose-dependent manner in an animal model. Quercetin could restore the dynamic changes of the gamma band while the animals performed novel object recognition (NOR) tasks as determined by electroencephalogram analysis. Morphological analysis showed that quercetin, by targeting the hippocampal CA1 region, strikingly ameliorated the overactivation of microglia induced by PSD. Mechanistically, quercetin inhibited the toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa-b (NF-κB) cascade, which is critical for abnormal microglial activation following PSD stress. Our results provided experimental evidence for the therapeutic effects of quercetin on PSD-related memory impairments by suppressing TLR4/MyD88/NF-κB signaling that mediated abnormal microglia activation in the hippocampus.

Behavioral state-dependent oscillatory activity in prefrontal cortex induced by chronic social defeat stress.

Chronic stress contributes to the onset and exacerbation of major depressive disorder (MDD) through the oscillatory activity in the prefrontal cortex (PFC). However, the oscillations on which chronic social stress converges to yield the behavioral state of social avoidance are largely unknown. Here, we use a chronic social defeat stress model and in vivo electrophysiological recordings to uncover a novel neurophysiological measure that predicts the social behavioral state in stressed animals. First, in this study, we find that chronic social defeat stress model induces depression-like behaviors (anhedonia and social avoidance). Second, we find statistically significant differences in PFC oscillatory activity across different frequency ranges in social behavioral state, and the oscillatory activity correlates with stress-induced behavioral state. Finally, we show that the social behavioral states are accurately decoded from the oscillatory activity based on machine learning. Together, these results demonstrate that naturally occurring differences in PFC oscillation underlie the social behavioral state that accompanies the emergence of stress-induced behavioral dysfunction.

Lactobacillus rhamnosus GG colonization in early life regulates gut-brain axis and relieves anxiety-like behavior in adulthood.

Evidence reveals that gut dysbiosis is involved in bidirectional interactions in gut-brain axis and participates in the progress of multiple disorders like anxiety. Gut microbes in early life are crucial for establishment of host health. We aimed to investigate whether early life probiotics Lactobacillus rhamnosus GG (LGG) colonization could relieve anxiety in adulthood through regulation of gut-brain axis. Live or fixed LGG was gavaged to C57BL/6 female mice from day 18 of pregnancy until natural birth, and newborn mice from day 1 to day 5 respectively. In this study, we found that live LGG could be effectively colonized in the intestine of offspring. LGG colonization increased intestinal villus length and colonic crypt depth, accompanied with barrier function protection before weaning. Microbiota composition by 16S rRNA sequencing showed that some beneficial bacteria, such as Akkermansia and Bifidobacteria, were abundant in LGG colonization group. The protective effect of LGG on gut microbiota persisted from weaning to adulthood. Intriguingly, behavioral results assessed by elevated plus mazed test and open field test demonstrated relief of anxiety-like behavior in adult LGG-colonized offspring. Mechanically, LGG colonization activated epithelial growth factor receptor (EGFR) and enhanced serotonin transporter (SERT) expression and modulated serotonergic system in the intestine, and increased brain-derived neurotrophic factor and γ-aminobutyric acid receptor levels in the hippocampus and amygdala. Blocking EGFR blunted LGG-induced the increased SERT and zonula occludens-1 expression. Collectively, early life LGG colonization could protect intestinal barrier of offspring and modulate gut-brain axis in association with relief of anxiety-like behavior in adulthood.

Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures.

ASH1L, a histone methyltransferase, is identified as a top-ranking risk factor for autism spectrum disorder (ASD), however, little is known about the biological mechanisms underlying the link of ASH1L haploinsufficiency to ASD. Here we show that ASH1L expression and H3K4me3 level are significantly decreased in the prefrontal cortex (PFC) of postmortem tissues from ASD patients. Knockdown of Ash1L in PFC of juvenile mice induces the downregulation of risk genes associated with ASD, intellectual disability (ID) and epilepsy. These downregulated genes are enriched in excitatory and inhibitory synaptic function and have decreased H3K4me3 occupancy at their promoters. Furthermore, Ash1L deficiency in PFC causes the diminished GABAergic inhibition, enhanced glutamatergic transmission, and elevated PFC pyramidal neuronal excitability, which is associated with severe seizures and early mortality. Chemogenetic inhibition of PFC pyramidal neuronal activity, combined with the administration of GABA enhancer diazepam, rescues PFC synaptic imbalance and seizures, but not autistic social deficits or anxiety-like behaviors. These results have revealed the critical role of ASH1L in regulating synaptic gene expression and seizures, which provides insights into treatment strategies for ASH1L-associated brain diseases.

Translational relevance of behavioral, neural, and electroencephalographic profiles in a mouse model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a severe, long-term psychological disorder triggered by distressing events. The neural basis and underlying mechanisms of PTSD are not completely understood. Therefore, it is important to determine the pathology of PTSD using reliable animal models that mimic the symptoms of patients. However, the lack of evidence on the clinical relevance of PTSD animal models makes it difficult to interpret preclinical studies from a translational perspective. In this study, we performed a comprehensive screening of the behavioral, neuronal, glial, and electroencephalographic (EEG) profiles in the single prolonged stress and electric foot shock (SPS&S) mouse model. Based on the clinical features of PTSD, we observed fearful and excessive responses to trauma-related environments in the SPS&S mouse model that lasted longer than 14 days. The mice exhibited a defective and strong resistance to the extinction of fear memories caused by auditory cues and also showed enhanced innate fear induced by visual stimuli with concomitant phobias and anxiety. Furthermore, neurons, astrocytes, and microglia in PTSD-related brain regions were activated, supporting abnormal brain activation and neuroimmune changes. EEG assessment also revealed decreased power and impaired coupling strength between cortical regions. These results demonstrated that the SPS&S mouse model recapitulates the behavioral symptoms as well as neural and EEG profiles of PTSD patients, justifying the preclinical use of this mouse model.

Information transmission in mPFC-BLA network during exploratory behavior in the open field.

Exploratory behavior plays a fundamental role in motivation, learning, and well-being of organisms. The open field test (OFT) is a classic method to investigate the exploratory behavior in rodents, also a widely adopted and pharmacologically validated procedure for evaluating anxiety and depression. Several lines of evidence have shown that medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) play crucial roles in anxiety-like or depression-like exploratory behavior. However, the dynamic characterization of the mPFC-BLA network in exploratory behavior is less well understood. Therefore, this study aimed to investigate the information transmission mechanism in the mPFC-BLA network during exploratory behavior. Local field potentials (LFPs) from mPFC and BLA were simultaneously recorded while the rats performed the OFT. Directed transfer function (DTF), which was derived from Granger causal connectivity analysis, was applied to measure the functional connectivity among LFPs. Information flow (IF) was calculated to explore the dynamics of information transmission in the mPFC-BLA network. Our results revealed that, for both mPFC and BLA, the theta-band functional connectivity in periphery was significantly higher than that in center of the open field. The IF from BLA to mPFC in the open field task was significantly higher than that from mPFC to BLA. These results suggest that the functional connectivity and IF in the mPFC-BLA network are related to the exploratory behavior, and information transmission from BLA to mPFC could be predominant for exploratory behavior.

Neural circuits and activity dynamics underlying sex-specific effects of chronic social isolation stress.

Exposure to prolonged stress in critical developmental periods induces heightened vulnerability to psychiatric disorders, which may have sex-specific consequences. Here we investigate the neuronal circuits mediating behavioral changes in mice after chronic adolescent social isolation stress. Escalated aggression is exhibited in stressed males, while social withdrawal is shown in stressed females. In vivo multichannel recordings of free-moving animals indicate that pyramidal neurons in prefrontal cortex (PFC) from stressed males exhibit the significantly decreased spike activity during aggressive attacks, while PFC pyramidal neurons from stressed females show a blunted increase of discharge rates during sociability tests. Chemogenetic and electrophysiological evidence shows that PFC hypofunctioning and BLA principal neuron hyperactivity contribute to the elevated aggression in stressed males, while PFC hypofunctioning and VTA dopamine neuron hypoactivity contribute to the diminished sociability in stressed females. These results establish a framework for understanding the circuit and physiological mechanisms underlying sex-specific divergent effects of stress.

Electrical Stimulation of the Motor Cortex or Paretic Muscles Improves Strength Production in Stroke Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: Transcranial direct current stimulation (tDCS) and functional electrical stimulation (FES) are two widely applied methods of electrical stimulation for motor recovery among stroke patients. This systematic review and meta-analysis investigated the efficacy of tDCS and FES for strength production in stroke patients. TYPE: Systematic review. LITERATURE SURVEY: Studies that explored the effects of tDCS or FES on the strength production of paralyzed muscles in stroke patients were retrieved on a comprehensive set of three databases: (1) Google Scholar, (2) PubMed, and (3) the Cochrane Database of Systematic Reviews until July 2019. METHODOLOGY: Systematic study retrieval led to the inclusion of 15 studies that reported on strength production effects after tDCS and FES interventions among stoke patients. A sham control group and randomization were used in each study. The 15 studies included 20 comparisons with sham controls, 7 of which involved tDCS and 13 of which involved FES. SYNTHESIS: Random-effects models showed that strength production was improved after tDCS (effect size [ES] = 0.52, 95% confidence interval [CI] = 0.35-0.69, P < .001, Z = 6.05) and FES (ES = 0.47, 95% CI = 0.16-0.78, P < .003, Z = 2.99). Additionally, tDCS was shown to improve strength production in the acute (ES = 0.52, 95% CI = 0.24-0.80, P < .001, Z = 3.65), subacute (ES = 0.85, 95% CI = 0.37-1.32, P < .001, Z = 3.51), but not chronic (ES = 0.06, 95% CI = -0.47-0.60, P = .82, Z = 0.23) phases of stroke recovery. Out of the 13 studies involving FES, 12 investigated strength production in the chronic phase and one investigated in the acute phase, showing a positive effect in these two stages. CONCLUSIONS: The results of the meta-analysis showed that tDCS and FES successfully improved strength production in stroke patients.

Decreased Phase-Amplitude Coupling Between the mPFC and BLA During Exploratory Behaviour in Chronic Unpredictable Mild Stress-Induced Depression Model of Rats.

Depression is a common neuropsychiatric illness observed worldwide, and reduced interest in exploration is one of its symptoms. The control of dysregulated medial prefrontal cortex (mPFC) over the basolateral amygdala (BLA) is related to depression. However, the oscillation interaction in the mPFC-BLA circuit has remained elusive. Therefore, this study used phase-amplitude coupling (PAC), which provides complicated forms of information transmission by the phase of low-frequency rhythm, modulating the amplitude of high-frequency rhythm, and has a potential application for the treatment of neurological disease. The chronic unpredictable mild stress (CUMS) was used to prepare the rat models of depression. Moreover, multichannel in vivo recording was applied to obtain the local field potentials (LFPs) of the mPFC, the BLA in rats in control, and CUMS groups, while they explored the open field. The results showed prominent coupling between the phase of theta oscillation (4-12 Hz) in the mPFC and the amplitude of high-gamma oscillation (70-120 Hz) in the BLA. Compared to the control group, this theta-gamma PAC was significantly decreased in the CUMS group, which was accompanied by the diminished exploratory behaviour. The results indicate that the coupling between the phase of theta in the mPFC and the amplitude of gamma in the BLA is involved in exploratory behaviour, and this decreased coupling may inhibit exploratory behaviour of rats exposed to CUMS.

Reduced Information Transmission of Medial Prefrontal Cortex to Basolateral Amygdala Inhibits Exploratory Behavior in Depressed Rats.

Depression is a mental and neurological disease that reduces the desire for exploration. Dysregulation of the information transmission between medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) is associated with depression. However, which direction of information transmission (mPFC-BLA or BLA-mPFC) related to the decline of exploratory interests in depression is unclear. Therefore, it is important to determine what specific changes occur in mPFC and BLA information transmission in depressed rats during exploratory behavior. In the present study, local field potentials (LFPs) were recorded via multi-electrodes implanted in the mPFC and BLA for the control and depression groups of rats when they were exploring in an open field. The theta band was determined to be the characteristic band of exploratory behavior. The direct transfer function (DTF) was used to calculate the mPFC and BLA bidirectional information flow (IF) to measure information transmission. Compared with the control group, the theta IF of mPFC-BLA in the depression group was significantly reduced, and there was no significant difference in theta IF of BLA-mPFC between the two groups. Our results indicated that the reduction of mPFC-BLA information transmission can inhibit the exploratory behavior of depressed rats.

[Connectivity pattern of action potentials causal network in prefrontal cortex during anxiety].

Anxiety disorder is a common emotional handicap, which seriously affects the normal life of patients and endangers their physical and mental health. The prefrontal cortex is a key brain region which is responsible for anxiety. Action potential and behavioral data of rats in the elevated plus maze (EPM) during anxiety (an innate anxiety paradigm) can be obtained simultaneously by using the in vivo and in conscious animal multi-channel microelectrode array recording technique. Based on maximum likelihood estimation (MLE), the action potential causal network was established, network connectivity strength and global efficiency were calculated, and action potential causal network connectivity pattern of the medial prefrontal cortex was quantitatively characterized. We found that the entries (44.13±6.99) and residence period (439.76±50.43) s of rats in the closed arm of the elevated plus maze were obviously higher than those in the open arm [16.50±3.25, P<0.001; (160.23±48.22) s, P<0.001], respectively. The action potential causal network connectivity strength (0.017 3±0.003 6) and the global efficiency (0.044 2±0.012 8) in the closed arm were both higher than those in the open arm (0.010 4±0.003 2, P<0.01; 0.034 8±0.011 4, P<0.001), respectively. The results suggest that the changes of action potential causal network in the medial prefrontal cortex are related to anxiety state. These data could provide support for the study of the brain network mechanism in prefrontal cortex during anxiety.

Electroencephalography and Functional Magnetic Resonance Imaging-Guided Simultaneous Transcranial Direct Current Stimulation and Repetitive Transcranial Magnetic Stimulation in a Patient With Minimally Conscious State.

OBJECTIVE: A minimally conscious state (MCS) is characterized by discernible behavioral evidence of consciousness that cannot be reproduced consistently. This condition is highly challenging to treat. Recent studies have demonstrated the potential therapeutic effect of non-invasive brain stimulation in patients with MCS. In one patient in an MCS, we delivered simultaneous transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) based on an individual brain network analysis and evaluated the therapeutic effect. METHODS: The directional transfer function (DTF) was calculated based on electroencephalograph (EEG) analysis. Global brain connectivity was calculated based on functional magnetic resonance imaging (fMRI) analysis. By referring to the EEG and fMRI results, we identified inferior parietal lobes (IPLs) as targets. In the 2-week treatment period, 14 sessions were applied to the identified bilateral parietal regions. Simultaneous 1.5-mA anodal tDCS and 5-Hz rTMS were delivered for 20 min per hemisphere in each session. Clinical evaluation scores were recorded weekly throughout the treatment. A second patient given the routine treatment was evaluated as a control. RESULTS: The clinical scores of patient 1 with MCS improved after 2 weeks of stimulation treatment, and the effect lasted for up to 1 month. EEG analysis showed a significant increase (p < 0.001) in the DTF value in the gamma band in a bilateral set of posterior regions, and fMRI showed a trend toward normalized activity in the IPLs. The clinical scores of patient 2 with coma did not improve much after 2 weeks of routine treatment. The EEG analysis showed a significant increase (p = 0.021) in the DTF value in the gamma band in a bilateral set of posterior regions. CONCLUSION: The application of EEG and fMRI to characterize the functional connectivity features of the network in an MCS patient provided a reasonable and accurate stimulation target and verified the changes in functional connectivity resulting from stimulation.

Design and preparation of mesoporous silica carriers with chiral structures for drug release differentiation.

In this study, twisted rod-like chiral mesoporous silicas (CMSs) with discriminating chiral characteristics (D/L) were designed and biomimetic synthesized by using L- and d-alanine derivatives as templates, and employed as poorly water-soluble chiral drug ibuprofen (IBU) carriers. The morphology and mesoscopic characteristics of CMSs were determined by transmission electron microscope (TEM) and small-angle X-ray scattering (SAXS). Meanwhile, the physicochemical properties of CMSs before and after drug loading were systematically characterized by infrared spectroscopy (IR), nitrogen adsorption, X-ray diffraction (XRD), differential scanning calorimetry (DSC) and induced circular dichroism (ICD). The results suggested that, the CMSs exhibited local chiral characteristics, which were successfully endowed by the alanine-derivative surfactants templates with a reversal of chirality. The crystalline state of IBU was effectively converted to amorphous state after being incorporated into CMSs, and the drug delivery systems shared the chiral characteristic of carriers. Besides, in vitro drug release experiments were respectively performed in simulated gastric fluid (SGF, pH 1) and simulated intestinal fluid (SIF, pH 6.8) medium, and the results demonstrated that both l-CMS and d-CMS could improve the dissolution of IBU in SGF medium, which could be explained by the amorphization of IBU. Particularly, due to the different pore geometry of these two materials, CMSs with different chirality (D/L) could be applied as carriers to accomplish drug release differentiation.

Information transmission in HPC-PFC network for spatial working memory in rat.

Spatial working memory is a short-term system for the temporary holding and manipulation of spatial information. Evidence shows that the hippocampus (HPC) and prefrontal cortex (PFC) play important roles in spatial working memory. Though the communication between HPC and PFC is recognized as essential for successful execution of spatial working memory tasks, the directional information transmission in the HPC-PFC network is largely unclear. Therefore, in the present study, neuronal activity was recorded from rat ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC) while the rats performed a spatial working memory task in Y-maze. Then the causality connectivity among the spikes from recorded neurons was estimated using the maximum likelihood estimation and the information flow in the vHPC-mPFC network was calculated to investigate the functional dynamics of the vHPC-mPFC information transmission. Our results showed the increased bidirectional information flow in the vHPC-mPFC network during the spatial working memory task. Both directions of information flow were observed only on trials in which the animal subsequently made the correct response, indicating that the increase in information flow predicted memory accuracy. Furthermore, the information flow from vHPC to mPFC was remarkably higher and preceded that from mPFC to vHPC. These findings suggest that the direct vHPC-mPFC information transmission may be predominant for spatial working memory in rat.

Contact Angle Measurements: an Alternative Approach Towards Understanding the Mechanism of Increased Drug Dissolution from Ethylcellulose Tablets Containing Surfactant and Exploring the Relationship Between Their Contact Angles and Dissolution Behaviors.

The addition of surfactant in tablet was a well-defined approach to improve drug dissolution rate. While the selected surfactant played a vital role in improving the wettability of tablet by medium, it was equally important to improve the dissolution rate by permeation effect due to production of pores or the reduced inter-particle adhesion. Furthermore, understanding the mechanism of dissolution rate increased was significant. In this work, contact angle measurement was taken up as an alternative approach for understanding the dissolution rate enhancement for tablet containing surfactant. Ethylcellulose, as a substrate, was used to prepare tablet. Four surfactants, sodium dodecyl sulfate (SDS), sodium dodecylbenzenesulfonate (SDBS), dodecyltrimethylammonium bromide (DTAB), and sodium lauryl sulfonate (SLS), were used. Berberine hydrochloride, metformin hydrochloride, and rutin were selected as model drugs. The contact angle of tablet in the absence and presence of surfactant was measured to explore the mechanism. The dissolution test was investigated to verify the mechanism and to establish a correlation with the contact angle. The result showed that the mechanism was the penetration effect rather than the wetting effect. The dissolution increased with a reduction in the contact angle. DTAB was found to obtain the highest level of dissolution enhancement and the lowest contact angle, while SDS, SDBS, and SLS were found to be the less effective in both dissolution enhancement and contact angle decrease. Therefore, contact angle was a good indicator for dissolution behavior besides exploring the mechanism of increased dissolution, which shows great potential in formula screening.