Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Preventive Effect of Maternal Forced Exercise on Offspring Pain Perception and Intensity: The Role of 5-HT2 and D2 Receptors

Background: Many previous studies showed that maternal forced exercise can reduce some central disorders in offsprings, but its clear mechanism remains unclear. In this study, the role of 5-HT2 and D2 receptors in neuroprotective effects of maternal forced exercise in offspring neurodevelopment and effect on some behaviors were evaluated. Materials and Methods: Forty-eight pregnant rats were trained by forced exercise, and some behavioral assays in their offspring were performed in the presence and absence of 5-HT2 and D2 receptor antagonists in various experimental groups. Results: Our data showed that maternal forced exercise caused increase in latency of pain perception in offsprings in hot plate test, writhing test (WT), and tail flick test. Furthermore, a decrease in intensity was shown by WT. On the other hand, treatment of mothers by forced exercise in combination with 5-HT2 and D2 receptor antagonists could inhibit these effects of forced exercise and cause disturbances in pain perception and intensity. Conclusion: Our data suggested that maternal forced exercise causes protective effects on offspring pain perception and intensity, and in this effect, 5-HT2 and D2 receptors are probably involved

Attenuation of morphine withdrawal signs, blood cortisol and glucose level with forced exercise in comparison with clonidine

Background: Morphine withdrawal usually results in undesired outcomes , despite partial benefits of alternative medication such as methadone, because of the lack of mental sedation during the withdrawal period, may not lead to the desired result. In this study, forced exercise by treadmill is used to manage morphine dependence in animal model. Materials and Methods: Forty adult male mice were divided into 5 groups, from which 4 groups became dependent by increasing daily doses of morphine for 6 days (20-45 mg/kg, SC). Afterwards, the animals were treated for 21 days by either of the following protocol: Positive control (dependent) received once daily 45 mg/kg of morphine sulfate (SC) for 21 day, group under treatment by clonidine (0.4 mg/kg, SC) for 21 day group under treatment by forced exercise by treadmill for 21 day, group under treatment by combination of clonidine (0.4 mg/kg, SC) and forced exercise by treadmill for 21day and the negative control group(independent) received saline injection like other groups. Each of this administration was injected at 8 AM. Finally, in the test day (day 28), all animals received a single dose of naloxone (3 mg/kg, SC) at 8 AM and then were observed for withdrawal signs, and Total Withdrawal Score (TWS) was determined as described previously. After withdrawal sign evaluation for evaluation of stress level of dependent mice, blood cortisol and glucose level were measured in non-fasting situations well. Results: This study showed that TWS significantly decreased in all treatment groups in comparison with positive control group (P < 0.001). Moreover, blood cortisol and glucose level significantly decreased in group under treatment by clonidine (0.4 mg/kg) and group under treatment by combination of clonidine (0.4 mg/kg) and forced exercise by treadmill groups in comparison with control positive (dependent) (P < 0.05). Conclusion: This study suggested that forced exercise can be useful as adjunct therapy in dependent people and can ameliorate side effects and stress situation of withdrawal syndrome periods

Attenuation of Morphine Physical Dependence and Blood Levels of Cortisol by Central and Systemic Administration of Ramelteon in Rat

Background: Chronic administration of morphine cause physical dependence but the exact mechanism of this phenomenon remains unclear. The aim of this study is the assessment of systemic and intracerebroventricular (icv) administration of ramelteon (a melatonin receptor agonist) on morphine physical dependence. Methods: 88 adult male rats were divided into 2 major groups, namely “systematic” and “central” administration of ramelteon. In the first category, systemic administration of ramelteon at various dosages (10, 20, and 40 mg/kg) was assessed on dependent animals and withdrawal signs were compared with positive (received morphine and saline as systemic administration), negative control (saline) and group under treatment by ramelteon (40 mg/kg) groups. In the second category, central administration of ramelteon at various dosages (25, 50, or 100 μg,) was assessed on dependent animals and withdrawal signs were compared with the positive control (received morphine and saline as icv) and negative control (saline) groups, and the group under treatment by ramelteon (50 μg/5 μl/rat). On the test day, all animals received naloxone (3 mg/kg) and were observed for withdrawal signs. Total withdrawal score (TWS) was also determined. Finally, to evaluate the stress level of dependent rats, blood cortisols were measured. Results: Central administration of ramelteon in all doses and systemic administration in high doses attenuate withdrawal syndrome in comparison with the dependent positive control group (P<0.05). Both central and systemic administrations of ramelteon can attenuate the blood cortisol level in comparison with the dependent positive control group (P<0.05). Conclusion: In conclusion, we found that central administration of ramelteon attenuated morphine withdrawal symptoms and cortisol level as a stress marker

Possible Role of Cyclic AMP Response Element Binding/Brain-Derived Neurotrophic Factor Signaling Pathway in Mediating the Pharmacological Effects of Duloxetine against Methamphetamine Use-Induced Cognitive Impairment and Withdrawal-Induced Anxiety and Depression in Rats

Background: Duloxetine is used for treating depression and anxiety. The current study evaluated the effects of duloxetine against methamphetamine withdrawal-induced anxiety, depression, and motor disturbances and methamphetamine use-induced cognitive impairments. Materials and Methods: Ninety-six adult male rats were used for two independent experiments. Each experiment consisted of Groups 1 and 2 which received normal saline (0.2 ml/rat) and methamphetamine (10 mg/kg) respectively, Groups 3, 4, and 5 received both methamphetamine and duloxetine at doses of 5, 10, and 15 mg/kg, respectively. Groups 6, 7, and 8 received 5, 10, and 15 mg/kg of duloxetine, respectively. All administrations were performed for 21 days. In experiment 1, elevated plus maze (EPM), open-field test (OFT), forced swim test (FST), and tail suspension test (TST) were used to examine anxiety and depression in animals during withdrawal period. In experiment 2, Morris water maze (MWM) test was used to assess the effect of methamphetamine use followed by duloxetine treatment, on learning and memory. In the experiments, the expression of cyclic AMP response element binding (CREB) and brain-derived neurotrophic factor (BDNF) proteins were evaluated using enzyme-linked immunosorbent assay. Results: In the first experiment, duloxetine at all doses attenuated methamphetamine withdrawal induced-depression, anxiety, and motor disturbances in FST, OFT, EPM, and TST. In the second experiment, duloxetine at all doses attenuated methamphetamine use-induced cognitive impairment in MWM. In both experiments, duloxetine activated cAMP, CREB, and BDNF proteins' expression in methamphetamine-treated rats. Conclusions: Duloxetine can protect the brain against methamphetamine withdrawal-induced mood and motor disturbances and can also inhibit methamphetamine-induced cognitive impairment, possibly via cAMP/CREB/BDNF signaling pathway

Neuroprotective Effects of Forced Exercise and Bupropion on Chronic Methamphetamine-induced Cognitive Impairment via Modulation of cAMP Response Element-binding Protein/Brain-derived Neurotrophic Factor Signaling Pathway, Oxidative Stress, and Inflammatory Biomarkers in Rats

Background: Forced exercise can act as non-pharmacologic neuroprotective agent. In current study, we tried the involved molecular mechanisms of protective effects of forced exercise against methamphetamine induced neurodegeneration. Materials and Methods: Forty adult male rats were divided to Group 1 and 2 which received normal saline and methamphetamine (10 mg/kg) respectively for 30 days. Groups 3, 4 and 5 were treated with methamphetamine for first 15 days and then were treated by forced exercise, bupropion (20 mg/kg/day) or combination of them for the following 15 days. Between 26th and 30th days, Morris Water Maze (MWM) was used to evaluate the cognition. On day 31, hippocampus was isolated from each rat and oxidative, antioxidant and inflammatory factors also the level of total and phosphorylated forms of cAMP response element-binding protein (CREB) and brain derived neurotrophic factor (BDNF) proteins were also evaluated. Results: Chronic abuse of methamphetamine could decreases cognition and increase malondialdehyde (MDA), Tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β), while caused decreases in superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities all these changes was significant (P < 0.001) in compared to control group while treatment with bupropion, forced exercise and bupropion in combination with forced exercise could prevent all these malicious effects of methamphetamine (P < 0.001). Bupropion, forced exercise and bupropion in combination with forced exercise could activate CREB (both forms) and activates BDNF proteins' expression with P < 0.001 in methamphetamine treated rats. Conclusions: P-CREB/BDNF signaling pathways might have critical role in forced exercise protective effects against methamphetamine induced neurodegeneration

Attenuation of Withdrawal Signs, Blood Cortisol, and Glucose Level with Various Dosage Regimens of Morphine after Precipitated Withdrawal Syndrome in Mice

Morphine withdrawal usually results in unsuccessful outcomes. Despite partial benefits from alternative substances such as methadone, its use may not lead to the desired result due to the lack of mental tranquility during the withdrawal period. In this study, by means of an animal model, morphine itself was used to manage morphine dependence. Forty mice were divided into 5 groups, in which 4 groups became dependent by increasing daily doses of morphine for 7 days (15-45 mg/kg). Afterwards, the animals received morphine for 14 days by either of the following regimens: • Once daily 45 mg/kg (positive controls) • Increasing the interval (each time 6 hours longer than the previous interval) • Irregular interval in every 36, 12 and 24 hours until the 21th day • 12, 24, 36 hours decreasing doses (each time 2.5 mg/kg less than the former dosage). Negative controls received saline solution only. On day 22, total withdrawal index (TWI) was determined by injecting 3 mg/kg of naloxone. Thereafter, blood samples were taken for the measurement of cortisol and glucose levels. TWI significantly decreased in all test groups in comparison with the positive control animals (P<0.001). Cortisol levels significantly decreased when either the dosage or the administration frequencies were decreased on a regular and gradual basis (P<0.005). Blood glucose levels significantly decreased in animals that received decreasing doses of morphine (P<0.005). This study suggests that no other measures may be required in clinical practice except for changing the dosage regimen of morphine for the cessation of self-administration

Reduction of methylphenidate induced anxiety, depression and cognition impairment by various doses of venlafaxine in rat

Background: Methylphenidate (MPH) is a neural stimulant agent, which its neurochemical and behavioral effect remain unclear. Venlafaxine is a serotonin-norepinephrine reuptake inhibitor antidepressant, which was used for management of depression and anxiety. In this study, protective effects of venlafaxine on MPH induced anxiety, depression and cognition impairment were investigated. Methods: Forty-eight adult male rats were divided randomly to 5 groups. Group 1, received normal saline (0.2 ml/rat) for 21 days and served as control group. Group 2, received MPH (10 mg/kg) for 21 days. Groups, 3, 4, 5 and 6 concurrently were treated by MPH (10 mg/kg) and venlafaxine at doses of 25, 50, 75 and 100 mg/kg respectively for 21 days. On day 22, elevated plus maze (EPM), open field test (OFT), forced swim test (FST) and tail suspension test (TST) were used to investigate the level of anxiety and depression in animals. In addition, between days 17 and 21, Morris water maze (MWM) was used to evaluate the effect of MPH on spatial learning and memory. Results: MPH caused depression and anxiety in a dose-dependent manner in FST, OFT, EPM and TST, which were significantly different compared with control group. Furthermore, MPH can significantly attenuate the motor activity in OFT. Venlafaxine in all doses can attenuate MPH induced anxiety, depression and motor activity alterations. MPH also can disturb learning and memory in MWM, but venlafaxine did not alter this effect of MPH. Conclusions: We conclude that venlafaxine can be protective in the brain against MPH induced anxiety and depression

Kefir protective effects against nicotine cessation-induced anxiety and cognition impairments in rats

Background: Nicotine as one of the potent psychostimulant drugs is characterized by its parasympathomimetic activity. Upon the abrupt discontinuation of nicotine intake, a number of symptoms such as anxiety, depression and cognition impairment develop. Kefir as a food supplement is rich in tryptophan. In this study, we have evaluated the effects of Kefir on nicotine cessation-induced anxiety, depression and cognition impairment. Materials and Methods: Forty adult male rats were divided into four groups. All the groups received 6 mg/kg/day of nicotine for 17 days and then the negative control groups got 5 mg/kg/day of normal saline. The positive control groups were given 40 mg/kg/day of Sertraline HCl for 7 days. The group treated with Cow Milk Kefir (CMK) and Soy Milk Kefir (SMK) received 5 mg/kg/day for 7 days. On the 25 th day, Elevated Plus Maze (EPM), Open Field Test (OFT) and Forced Swim Test (FST) were used to investigate anxiety and depression. In addition, Moris Water Maze was applied to evaluate learning and memory in the animals between the 20 th and 25 th days. Results: The results showed that administration of CMK, SMK and Sertraline had higher anti-depression and anxiolytic effects on nicotine withdrawal-induced depression and anxiety in rats (P < 0.05). Moreover, CMK and SMK improved learning and memory impairment results in the nicotine withdrawal period (P < 0.05). Conclusion: This study revealed that Kefir had a potential effect on the treatment of nicotine cessation-induced depression, anxiety and cognition impairment in the animal model. Kefir may be useful for adjunct therapy for nicotine abandonment treatment protocols

Study of the effects of controlled morphine administration for treatment of anxiety, depression and cognition impairment in morphine-addicted rats

Background: Morphine dependency usually results in undesired outcomes such as anxiety, depression, and cognitive alterations. In this study, morphine was used to manage morphine dependence-induced anxiety, depression, and learning and memory disturbances. Materials and Methods: Forty rats were divided equally into five groups. Group 1 received saline for 21 days. Groups 2–5 were dependent by increasing administration of morphine (15–45 mg/kg) for 7 days. For the next 14 days, morphine was administered as the following regimen: Group 2: once daily; 45 mg/kg (positive controls), Group 3: the same dose with an increasing interval (6 h longer than the previous intervals each time), Group 4: the same dose with an irregular intervals (12, 24, 36 h intervals interchangeably), and Group 5: decreasing doses once daily (every time 2.5 mg/kg less than the former dosage). On days 22–26, elevated plus maze (EPM), open field test (OFT), forced swim test (FST), and tail suspension test (TST) were performed to investigate anxiety level and depression in animals. Between 17th and 21st days, Morris water maze (MWM) was used to evaluate the spatial learning and memory. Results: Chronic morphine administration caused depression and anxiety as observed by FST, EPM, and TST and decreased motor activity in OFT and caused impairment in learning and memory performance in MWM. Treatment with our protocol as increasing interval, irregular interval, and decreasing dosage of morphine caused marked reduction in depression, anxiety, and improved cognition performance compared with positive control group; and attenuated motor deficits in morphine-dependent rats, remarkably. Conclusions: Change in dosage regimens of morphine can reduce morphine-induced anxiety, depression, and cognitive impairments