A review of the holy Quran listening and its neural correlation for its potential as a psycho-spiritual therapy.

Since its revelation over 14 centuries ago, the Holy Quran is considered as scriptural divine words of Islam, and it is believed to promote psycho-spiritual therapeutic benefits to its reciter and/or listener. In this context, the listening of rhythmic Quranic verses among Muslims is often viewed as a form of unconventional melodic vocals, with accompanied anecdotal claims of the 'Quranic chills' pleasing effect. However, compared to music, rhythm, and meditation therapy, information on the neural basis of the anecdotal healing effects of the Quran remain largely unexplored. Current studies in this area took the leads from the low-frequency neuronal oscillations (i.e., alpha and theta) as the neural correlates, mainly using electroencephalography (EEG) and/or magnetoencephalography (MEG). In this narrative review, we present and discuss recent work related to these neural correlates and highlight several methodical issues and propose recommendations to progress this emerging transdisciplinary research. Collectively, evidence suggests that listening to rhythmic Quranic verses activates similar brain regions and elicits comparable therapeutic effects reported in music and rhythmic therapy. Notwithstanding, further research are warranted with more concise and standardized study designs to substantiate these findings, and opens avenue for the listening to Quranic verses as an effective complementary psycho-spiritual therapy.

Goofballing of Opioid and Methamphetamine: The Science Behind the Deadly Cocktail.

Globally, millions of people suffer from various substance use disorders (SUD), including mono-and polydrug use of opioids and methamphetamine. Brain regions such as the cingulate cortex, infralimbic cortex, dorsal striatum, nucleus accumbens, basolateral and central amygdala have been shown to play important roles in addiction-related behavioral changes. Clinical and pre-clinical studies have characterized these brain regions and their corresponding neurochemical changes in numerous phases of drug dependence such as acute drug use, intoxication, craving, withdrawal, and relapse. At present, many studies have reported the individual effects of opioids and methamphetamine. However, little is known about their combined effects. Co-use of these drugs produces effects greater than either drug alone, where one decreases the side effects of the other, and the combination produces a prolonged intoxication period or a more desirable intoxication effect. An increasing number of studies have associated polydrug abuse with poorer treatment outcomes, drug-related deaths, and more severe psychopathologies. To date, the pharmacological treatment efficacy for polydrug abuse is vague, and still at the experimental stage. This present review discusses the human and animal behavioral, neuroanatomical, and neurochemical changes underlying both morphine and methamphetamine dependence separately, as well as its combination. This narrative review also delineates the recent advances in the pharmacotherapy of mono- and poly drug-use of opioids and methamphetamine at clinical and preclinical stages.

Mitragynine (Kratom)-Induced Cognitive Impairments in Mice Resemble Δ9-THC and Morphine Effects: Reversal by Cannabinoid CB1 Receptor Antagonism.

Kratom is a widely abused plant-based drug preparation with a global interest in recent years, well beyond its native grounds in Southeast Asia. Mitragynine, its major psychoactive constituent is known to exhibit opioid-like behavioral effects with resultant neuroplasticity in the brain reward system. Its chronic administration is associated with cognitive impairments in animal studies. However, the underlying molecular mechanism for such a deficit remains elusive. In this study, the involvement of cannabinoid type-1 (CB1) receptors in cognitive deficits after chronic mitragynine exposures was investigated for 28 days (with incremental dose sensitization from 1 to 25 mg/kg) in adult male Swiss albino mice using the IntelliCage® system. Chronic high-dose mitragynine exposure (5-25 mg/kg, intraperitoneal [i.p.]), but not low-dose exposure (1-4 mg/kg, i.p.), induced hyperlocomotion, potentiated the preference for sucrose reward, increased resistance to punishment, and impaired place learning and its reversal. Comparable deficits were also observed after chronic treatments with Δ-9-tetrahydrocannabinol (THC, 2 mg/kg, i.p.) or morphine (5 mg/kg, subcutaneous). Mitragynine-, morphine-, and THC-induced learning and memory deficits were reversed by co-treatment with the CB1 receptor antagonist, NIDA-41020 (10 mg/kg, i.p.). A significant upregulation of CB1 receptor expression was found in the hippocampal CA1 region and ventral tegmental area after chronic high-dose mitragynine and morphine, whereas a downregulation was observed after chronic THC. In conclusion, the present study suggests a plausible role of the CB1 receptor in mediating the dose-dependent cognitive deficits after chronic high-dose mitragynine exposure. This also highlights the potential of CB1 receptor antagonism in ameliorating the cognitive deficits associated with long-term kratom/mitragynine consumption in humans.

The IntelliCage System: A Review of Its Utility as a Novel Behavioral Platform for a Rodent Model of Substance Use Disorder.

The use of animal models for substance use disorder (SUD) has made an important contribution in the investigation of the behavioral and molecular mechanisms underlying substance abuse and addiction. Here, we review a novel and comprehensive behavioral platform to characterize addiction-like traits in rodents using a fully automated learning system, the IntelliCage. This system simultaneously captures the basic behavioral navigation, reward preference, and aversion, as well as the multi-dimensional complex behaviors and cognitive functions of group-housed rodents. It can reliably capture and track locomotor and cognitive pattern alterations associated with the development of substance addiction. Thus, the IntelliCage learning system offers a potentially efficient, flexible, and sensitive tool for the high-throughput screening of the rodent SUD model.

Elevated Circulating Microparticle Subpopulations in Incidental Cerebral White Matter Hyperintensities: A Multimodal Study.

Asymptomatic (or "silent") manifestations of cerebral small vessel disease (CSVD) are widely recognized through incidental findings of white matter hyperintensities (WMHs) as a result of magnetic resonance imaging (MRI). This study aims to examine the potential associations of surrogate markers for the evaluation of white matter integrity in CSVD among asymptomatic individuals through a battery of profiling involving QRISK2 cardiocerebrovascular risk prediction, neuroimaging, neurocognitive evaluation, and microparticles (MPs) titers. Sixty asymptomatic subjects (mean age: 39.83 ± 11.50 years) with low to moderate QRISK2 scores were recruited and underwent neurocognitive evaluation for memory and cognitive performance, peripheral venous blood collection for enumeration of selected MPs subpopulations, and 3T MRI brain scan with specific diffusion MRI (dMRI) sequences inclusive of diffusion tensor imaging (DTI). WMHs were detected in 20 subjects (33%). Older subjects (mean age: 46.00 ± 12.00 years) had higher WMHs prevalence, associated with higher QRISK2 score and reduced processing speed. They also had significantly higher mean percentage of platelet (CD62P)- and leukocyte (CD62L)-derived MPs. No association was found between reduced white matter integrity-especially at the left superior longitudinal fasciculus (LSLF)-with age and neurocognitive function; however, LSLF was associated with higher QRISK2 score, total MPs, and CD62L- and endothelial cell-derived MPs (CD146). Therefore, this study establishes these multimodal associations as potential surrogate markers for "silent" CSVD manifestations in the well-characterized cardiocerebrovascular demographic of relatively young, neurologically asymptomatic adults. Furthermore, to the best of our knowledge, this study is the first to exhibit elevated MP counts in asymptomatic CSVD (i.e., CD62P and CD62L), which warrants further delineation.

Effective Connectivity for Default Mode Network Analysis of Alcoholism.

Introduction: With the recent technical advances in brain imaging modalities such as magnetic resonance imaging, positron emission tomography, and functional magnetic resonance imaging (fMRI), researchers' interests have inclined over the years to study brain functions through the analysis of the variations in the statistical dependence among various brain regions. Through its wide use in studying brain connectivity, the low temporal resolution of the fMRI represented by the limited number of samples per second, in addition to its dependence on brain slow hemodynamic changes, makes it of limited capability in studying the fast underlying neural processes during information exchange between brain regions. Materials and Methods: In this article, the high temporal resolution of the electroencephalography (EEG) is utilized to estimate the effective connectivity within the default mode network (DMN). The EEG data are collected from 20 subjects with alcoholism and 25 healthy subjects (controls), and used to obtain the effective connectivity diagram of the DMN using the Partial Directed Coherence algorithm. Results: The resulting effective connectivity diagram within the DMN shows the unidirectional causal effect of each region on the other. The variations in the causal effects within the DMN between controls and alcoholics show clear correlation with the symptoms that are usually associated with alcoholism, such as cognitive and memory impairments, executive control, and attention deficiency. The correlation between the exchanged causal effects within the DMN and symptoms related to alcoholism is discussed and properly analyzed. Conclusion: The establishment of the causal differences between control and alcoholic subjects within the DMN regions provides valuable insight into the mechanism by which alcohol modulates our cognitive and executive functions and creates better possibility for effective treatment of alcohol use disorder.

Commemorating the 40-Year Journey of the School of Medical Sciences, Universiti Sains Malaysia

@#The School of Medical Sciences of Universiti Sains Malaysia (USM) is the launching pad for this journal. From the school’s humble beginning at the USM Main Campus in Pulau Pinang, Malaysia, it has grown in stature at its current location in the USM Health Campus, Kubang Kerian, Kelantan, Malaysia. Commemorating its 40th anniversary, this editorial aims to recollect, although not exhaustively, the wealth of returns for the USM, as well as for the nation, which the school has managed to deliver in that period. Resolute to its vision and mission, this article highlights the outstanding accomplishments in various core aspects of the school’s academic, research and professional growth as we continually strive to train globally competitive and compassionate medical graduates, medical specialists and scientists, skilled to serve nation’s needs and broader markets worldwide. Currently guided by the Malaysian Higher Education Blueprint (2015–2025), the school shall remain ingenious in its duties in the many more years to come, as we head for a world-class trajectory.

Tualang Honey Reduced Neuroinflammation and Caspase-3 Activity in Rat Brain after Kainic Acid-Induced Status Epilepticus.

The protective effect of tualang honey (TH) on neuroinflammation and caspase-3 activity in rat cerebral cortex, cerebellum, and brainstem after kainic acid- (KA-) induced status epilepticus was investigated. Male Sprague-Dawley rats were pretreated orally with TH (1.0 g/kg body weight) five times at 12 h intervals. KA (15 mg/kg body weight) was injected subcutaneously 30 min after last oral treatment. Rats were sacrificed at 2 h, 24 h, and 48 h after KA administration. Neuroinflammation markers and caspase-3 activity were analyzed in different brain regions 2 h, 24 h, and 48 h after KA administration. Administration of KA induced epileptic seizures. KA caused significant (p < 0.05) increase in the level of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß), glial fibrillary acidic protein (GFAP), allograft inflammatory factor 1 (AIF-1), and cyclooxygenase-2 (COX-2) and increase in the caspase-3 activity in the rat cerebral cortex, cerebellum, and brainstem at multiple time points. Pretreatment with TH significantly (p < 0.05) reduced the elevation of TNF-α, IL-1ß, GFAP, AIF-1, and COX-2 level in those brain regions at multiple time points and attenuated the increased caspase-3 activity in the cerebral cortex. In conclusion, TH reduced neuroinflammation and caspase-3 activity after kainic acid- (KA-) induced status epilepticus.

An In-Laboratory Validity and Reliability Tested System for Quantifying Hand-Arm Tremor in Motions.

Despite the advancement of the tremor assessment systems, the current technology still lacks a method that can objectively characterize tremors in relative segmental movements. This paper presents a measurement system, which quantifies multi-degrees-of-freedom coupled relative motions of hand-arm tremor, in terms of joint angular displacement. In-laboratory validity and reliability tests of the system algorithm to provide joint angular displacement was carried out by using the two-degrees-of-freedom tremor simulator with incremental rotary encoder systems installed. The statistical analyses show that the developed system has high validity results and comparable reliability performances using the rotary encoder system as the reference. In the clinical trials, the system was tested on 38 Parkinson's disease patients. The system readings were correlated with the observational tremor ratings of six trained medical doctors. The moderate to very high clinical correlations of the system readings in measuring rest, postural and task-specific tremors add merits to the degree of readiness of the developed tremor measurement system in a routine clinical setting and/or intervention trial for tremor amelioration.

Short-term and long-term survival probabilities among first-ever ischaemic and haemorrhagic stroke patients at a hospital in the suburban east coast of Peninsular Malaysia.

AIM: This study aimed to determine the 28-day, 1-year, and 5-year survival probabilities in first-ever stroke patients in a relatively understudied setting: a suburban hospital that serves a predominantly rural population in the east coast of Peninsular Malaysia. METHODS AND RESULTS: A retrospective record review was conducted among 432 first-ever stroke patients admitted to the Hospital Universiti Sains Malaysia, Kelantan, Malaysia. Data from between January 1, 2005 and December 31, 2011, were extracted from the medical records. The Kaplan-Meier product limit estimator was applied to determine the 28-day, 1-year, and 5-year survival probabilities. Log-rank test was used to test the equality of survival time between different groups. A total of 101 patients died during the study period. The 28-day, 1-year, and 5-year survival probabilities were 78.0% (95% confidence interval [CI]: 73.5-81.9), 74.2% (95% CI: 69.4-78.4), and 70.9% (95% CI: 65.1-75.9), respectively. There were significant differences in the survival time based on the types of stroke, Glasgow Coma Scale, hyperlipidaemia, atrial fibrillation, fasting blood glucose, and diastolic blood pressure. CONCLUSION: This study, though retrospective, highlights several clinical parameters that influenced the survival probabilities among first-ever stroke patients managed in a suburban setting in Malaysia, and compared them to those reported in more urban regions. Our data emphasise the need for wider establishment of specialized stroke units and teams, as well as for prospective multi-centre studies on first-ever stroke patients to better inform the development of stroke care provision in Malaysia.

Tualang Honey Protects the Rat Midbrain and Lung against Repeated Paraquat Exposure.

Paraquat (PQ) is a dopaminergic neurotoxin and a well-known pneumotoxicant that exerts its toxic effect via oxidative stress-mediated cellular injuries. This study investigated the protective effects of Tualang honey against PQ-induced toxicity in the midbrain and lungs of rats. The rats were orally treated with distilled water (2 mL/kg/day), Tualang honey (1.0 g/kg/day), or ubiquinol (0.2 g/kg/day) throughout the experimental period. Two weeks after the respective treatments, the rats were injected intraperitoneally with saline (1 mL/kg/week) or PQ (10 mg/kg/week) once per week for four consecutive weeks. After four weekly exposures to PQ, the glutathione peroxidase activity and the number of tyrosine-hydroxylase immunopositive neurons in the midbrain were significantly decreased in animals from group PQ (p < 0.05). The lungs of animals from group PQ showed significantly decreased activity of superoxide dismutase and glutathione-S-transferase. Treatment with Tualang honey ameliorated the toxic effects observed in the midbrain and lungs. The beneficial effects of Tualang honey were comparable to those of ubiquinol, which was used as a positive control. These findings suggest that treatment with Tualang honey may protect against PQ-induced toxicity in the rat midbrain and lung.

Effect of tualang honey against KA-induced oxidative stress and neurodegeneration in the cortex of rats.

BACKGROUND: Administration of KA on rodents has resulted in seizures, behavioral changes, oxidative stress, and neuronal degeneration on selective population of neurons in the brain. The present study was undertaken to investigate the extent of neuroprotective effect conferred by Malaysian Tualang Honey (TH), an antioxidant agent, in the cerebral cortex of rats against KA-induced oxidative stress and neurodegeneration in an animal model of KA-induced excitotoxicity. METHODS: Male Sprague-Dawley rats were randomly divided into five groups: Control, KA-treated group, TH + KA-treated group, aspirin (ASP; anti-inflammatory agent) + KA-treated group and topiramate (TPM; antiepileptic agent) + KA-treated group. The animals were pretreated orally with drinking water, TH (1.0g/kg BW), ASP (7.5mg/kg BW) or TPM (40mg/kg BW), respectively, five times at 12 h intervals. KA (15mg/kg BW) was injected subcutaneously 30 min after last treatment to all groups except the control group (normal saline). Behavioral change was observed using an open field test (OFT) to assess the locomotor activity of the animals. Animals were sacrificed after 2 h, 24 h and 48 h of KA administration. RESULTS: KA significantly inflicted more neuronal degeneration in the piriform cortex and heightened the predilection to seizures as compared with the control animals. Pretreatment with TH reduced the KA-induced neuronal degeneration in the piriform cortex but failed to prevent the occurrence of KA-induced seizures. In the OFT, KA-induced animals showed an increased in locomotor activity and hyperactivity and these were attenuated by TH pretreatment. Furthermore, TH pretreatment significantly attenuated an increase of thiobarbituric acid reactive substances level and a decrease of total antioxidant status level enhanced by KA in the cerebral cortex. CONCLUSION: These results suggest that pretreatment with TH has a therapeutic potential against KA-induced oxidative stress and neurodegeneration through its antioxidant effect.

Chronic mitragynine (kratom) enhances punishment resistance in natural reward seeking and impairs place learning in mice.

Kratom (Mitragyna speciosa) is a widely abused herbal drug preparation in Southeast Asia. It is often consumed as a substitute for heroin, but imposing itself unknown harms and addictive burdens. Mitragynine is the major psychostimulant constituent of kratom that has recently been reported to induce morphine-like behavioural and cognitive effects in rodents. The effects of chronic consumption on non-drug related behaviours are still unclear. In the present study, we investigated the effects of chronic mitragynine treatment on spontaneous activity, reward-related behaviour and cognition in mice in an IntelliCage® system, and compared them with those of morphine and Δ-9-tetrahydrocannabinol (THC). We found that chronic mitragynine treatment significantly potentiated horizontal exploratory activity. It enhanced spontaneous sucrose preference and also its persistence when the preference had aversive consequences. Furthermore, mitragynine impaired place learning and its reversal. Thereby, mitragynine effects closely resembled that of morphine and THC sensitisation. These findings suggest that chronic mitragynine exposure enhances spontaneous locomotor activity and the preference for natural rewards, but impairs learning and memory. These findings confirm pleiotropic effects of mitragynine (kratom) on human lifestyle, but may also support the recognition of the drug's harm potential.

Kainic Acid-Induced Excitotoxicity Experimental Model: Protective Merits of Natural Products and Plant Extracts.

Excitotoxicity is well recognized as a major pathological process of neuronal death in neurodegenerative diseases involving the central nervous system (CNS). In the animal models of neurodegeneration, excitotoxicity is commonly induced experimentally by chemical convulsants, particularly kainic acid (KA). KA-induced excitotoxicity in rodent models has been shown to result in seizures, behavioral changes, oxidative stress, glial activation, inflammatory mediator production, endoplasmic reticulum stress, mitochondrial dysfunction, and selective neurodegeneration in the brain upon KA administration. Recently, there is an emerging trend to search for natural sources to combat against excitotoxicity-associated neurodegenerative diseases. Natural products and plant extracts had attracted a considerable amount of attention because of their reported beneficial effects on the CNS, particularly their neuroprotective effect against excitotoxicity. They provide significant reduction and/or protection against the development and progression of acute and chronic neurodegeneration. This indicates that natural products and plants extracts may be useful in protecting against excitotoxicity-associated neurodegeneration. Thus, targeting of multiple pathways simultaneously may be the strategy to maximize the neuroprotection effect. This review summarizes the mechanisms involved in KA-induced excitotoxicity and attempts to collate the various researches related to the protective effect of natural products and plant extracts in the KA model of neurodegeneration.

Time course of motor and cognitive functions after chronic cerebral ischemia in rats.

Cerebral ischemia is one of the leading causes of death and long-term disability in aging populations, due to the frequent occurrence of irreversible brain damage and subsequent loss of neuronal function which lead to cognitive impairment and some motor dysfunction. In the present study, the real time course of motor and cognitive functions were evaluated following the chronic cerebral ischemia induced by permanent, bilateral occlusion of the common carotid arteries (PBOCCA). Male Sprague Dawley rats (200-300g) were subjected to PBOCCA or sham-operated surgery and tested 1, 2, 3 and 4 weeks following the ischemic insult. The results showed that PBOCCA significantly reduced step-through latency in a passive avoidance task at all time points when compared to the sham-operated group. PBOCCA rats also showed significant increase in escape latencies during training in the Morris water maze, as well as a reduction of the percentage of times spend in target quadrant of the maze at all time points following the occlusion. Importantly, there were no significant changes in locomotor activity between PBOCCA and sham-operated groups. The BDNF expression in the hippocampus was 29.3±3.1% and 40.1±2.6% on day 14 and 28 post PBOCCA, respectively compared to sham-operated group. Present data suggest that the PBOCCA procedure effectively induces behavioral, cognitive symptoms associated with cerebral ischemia and, consequently, provides a valuable model to study ischemia and related neurodegenerative disorder such as Alzheimer's disease and vascular dementia.

Anxiolytic-like effects of mitragynine in the open-field and elevated plus-maze tests in rats.

The effects of mitragynine on anxiety-related behaviours in the open-field and elevated plus-maze tests were evaluated. Male Sprague-Dawley rats were orally treated with mitragynine (10, 20 and 40 mg/kg) or diazepam (10 mg/kg) 60 min before behavioural testing. Mitragynine doses used in this study were selected on the basis of approximately human equivalent doses with reference to our previous literature reports. Acute administration of mitragynine (10, 20 and 40 mg/kg) or diazepam (10 mg/kg) increased central zone and open arms exploration in the open-field and elevated plus-maze tests respectively. These anxiolytic-like effects of mitragynine were effectively antagonized by intraperitoneal administration of naloxone (2 mg/kg), flumazenil (10 mg/kg), sulpiride (0.5 mg/kg) or SCH 23390 (0.02 mg/kg) 15 min before mitragynine treatments. These findings reveal that the acute administration of mitragynine produces anxiolytic-like effects and this could be possibly attributed to the interactions among opioidergic, GABAergic and dopaminergic systems in brain regions involved in anxiety.

Better Glasgow outcome score, cerebral perfusion pressure and focal brain oxygenation in severely traumatized brain following direct regional brain hypothermia therapy: A prospective randomized study.

BACKGROUND: Induced hypothermia for treatment of traumatic brain injury is controversial. Since many pathways involved in the pathophysiology of secondary brain injury are temperature dependent, regional brain hypothermia is thought capable to mitigate those processes. The objectives of this study are to assess the therapeutic effects and complications of regional brain cooling in severe head injury with Glasgow coma scale (GCS) 6-7. MATERIALS AND METHODS: A prospective randomized controlled pilot study involving patients with severe traumatic brain injury with GCS 6 and 7 who required decompressive craniectomy. Patients were randomized into two groups: Cooling and no cooling. For the cooling group, analysis was made by dividing the group into mild and deep cooling. Brain was cooled by irrigating the brain continuously with cold Hartmann solution for 24-48 h. Main outcome assessments were a dichotomized Glasgow outcome score (GOS) at 6 months posttrauma. RESULTS: A total of 32 patients were recruited. The cooling-treated patients did better than no cooling. There were 63.2% of patients in cooling group attained good GOS at 6 months compared to only 15.4% in noncooling group (P = 0.007). Interestingly, the analysis at 6 months post-trauma disclosed mild-cooling-treated patients did better than no cooling (70% vs. 15.4% attained good GOS, P = 0.013) and apparently, the deep-cooling-treated patients failed to be better than either no cooling (P = 0.074) or mild cooling group (P = 0.650). CONCLUSION: Data from this pilot study imply direct regional brain hypothermia appears safe, feasible and maybe beneficial in treating severely head-injured patients.

Neuroscience 101 for School Pupils: ‘The Brain Apprentice’ Project

Community engagement efforts in brains and neurosciences projects involving higher education institutions are currently sporadic in Malaysia and likely to contribute the apparent lack of neuroscience awareness in the society. In this paper, we highlight ‘The Brain Apprentice’ project as a knowledge transfer effort to raise neuroscience awareness using school-centred neuroscience clubs. These groups promote the appreciation of neuroscience beyond conventional classroom approaches and the training of neuroscience graduate interns as student facilitators in the teaching and learning of neuroscience. The Brain Apprentice was delivered through the establishment of two school-based neuroscience clubs, Sekolah Kebangsaan Kubang Kerian 3 (primary level) and Sekolah Menengah Sains Tengku Muhammad Faris Petra (secondary level). The teaching and learning of neuroscience was delivered through practical sessions and competitions. Questionnaires were collected from the students based on the following four domains: general satisfaction, impact of knowledge transfer, satisfaction with graduate interns, and knowledge and practical relevance of neuroscience. The National Brain Bee championship has resulted in the first Malaysia representative competing at the International Brain Bee 2012. Students, who had participated as neuroscience club members were exposed to the basic principles of neuroscience, which boosted their interest in science and neuroscience. The graduate interns had also been provided with opportunities to hone in their soft skills and be involved in community-engagement efforts. This project offered a suitable model of community-engagement in raising awareness about and the profile of neuroscience both in terms of knowledge exposure and from the perspective of career options in the field.