Attenuated vagally-mediated heart rate variability at rest and in response to postural maneuvers in patients with generalized anxiety disorder.

BACKGROUND: Altered heart rate variability (HRV), an index of autonomic nervous system function, has been reported in generalized anxiety disorder (GAD), but the results have been mixed. Thus, the present study, using a large sample size and better methodology, aims to examine whether GAD is associated with impaired HRV, both at rest and in response to posture challenges. METHODS: In total, 1832 participants were recruited in this study, consisting of 682 patients with GAD (including 326 drug- and comorbidity-free GAD patients) and 1150 healthy controls. Short-term HRV was measured during the supine-standing-supine test (5-min per position). Propensity score matching (PSM), a relatively novel method, was used to control for potential confounders. RESULTS: After PSM algorithm, drug- and comorbidity-free GAD patients had reductions in resting (baseline) high-frequency power (HF), an index for parasympathetic modulation, and increases in the low-frequency/HF ratio (LF/HF), an index for sympathovagal balance as compared to matched controls. Furthermore, the responses of HF and LF/HF to posture changes were all attenuated when compared with matched controls. Effect sizes, given by Cohen's d, for resting HF and HF reactivity were 0.42 and 0.36-0.42, respectively. CONCLUSIONS: GAD is associated with altered sympathovagal balance, characterized by attenuation in both resting vagal modulation and vagal reactivity, with an almost medium effect size (Cohen's d ≈ 0.4), regardless of medication use or comorbidity status.

Sex-specific pathways among tri-allelic serotonin transporter polymorphism, trait neuroticism and generalized anxiety disorder.

Background: Neuroticism personality trait is recognized as an important endophenotypic predictor of generalized anxiety disorder (GAD). Furthermore, endophenotype-based pathway approaches have recently been shown to have greater advantages for gene-finding strategies than traditional case-control studies. In the present study, in addition to conventional case-control methods, we used pathway analyses to test whether the tri-allelic serotonin transporter promoter polymorphism (combining 5-HTTLPR and rs25531) is associated with risk of GAD through its effects on trait neuroticism. Methods: We included 2236 Han Chinese adults in this study, including 736 patients with GAD and 1500 healthy participants. We genotyped the 5-HTTLPR and rs25531 polymorphisms using the polymerase chain reaction restriction fragment length polymorphism method. We used the Neuroticism scale of the Maudsley Personality Inventory (MPI) short version (MPI-Neuroticism) to measure participants' tendency toward neuroticism. Results: Using endophenotype-based path analyses, we found significant indirect effects of the tri-allelic genotype on risk of GAD, mediated by MPI-Neuroticism in both men and women. Compared to women carrying the S'S' genotype, women carrying the L' allele had higher levels of MPI-Neuroticism, which in turn were associated with higher risk of GAD. Men, however, showed the opposite pattern. Using traditional case-control comparisons, we observed that the effect of tri-allelic genotype on GAD was significant, but only in women. Limitations: Participants were restricted to Han Chinese, and we used only 1 questionnaire to assess neuroticism. Conclusion: These findings are the first to show that the triallelic 5-HTTLPR polymorphism is associated with elevated risk of GAD, and that this effect is mediated via increased trait neuroticism, a sex-dependent risk pathway.

Disproportionate Reduction of Serotonin Transporter May Predict the Response and Adherence to Antidepressants in Patients with Major Depressive Disorder: A Positron Emission Tomography Study with 4-[18F]-ADAM.

BACKGROUND: Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). This study aimed to examine whether the pretreatment of SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with treatment outcomes to SERT-targeted antidepressants. METHODS: We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. All the patients with MDD had HDRS scores of 18 or more. RESULTS: Pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3. Nonresponders and dropout patients showed a proportionate reduction in SERT binding in the terminal projection regions and midbrain compared to healthy controls. In contrast, a disproportionate reduction in SERT binding in the terminal projection regions relative to midbrain was observed in responders. CONCLUSIONS: The results of this study suggested that a disproportionate reduction in SERT binding between terminal projection regions and midbrain may predict better treatment outcomes in patients with MDD.

Assessment of psychiatrists' preparedness in managing disaster-related psychiatric disorders: a survey in Taiwan from post-graduate medical education perspective.

Background: Disaster-related psychiatric disorders (DRPD) present a significant challenge to mental health professionals, yet there is a notable lack of emphasis on the preparedness of psychiatrists in managing these conditions within post-graduate medical education. Methods: This study utilized a questionnaire to collect data from psychiatrists, focusing on their prior involvement in managing DRPD, perceived competence, medication preferences, and factors influencing their experiences in handling such disorders. Analysis included distribution and ranking of variables, alongside cross-analysis examining associations between demographic factors (age, gender, hospital levels, years of practice, board certification) and treatment experiences, as well as readiness for in-hospital or outside-hospital mobilization in DRPD management. Results: One hundred and three Taiwanese psychiatrists participated in the study, with the majority reporting involvement in managing DRPD (71.8%), particularly in post-traumatic stress disorder (PTSD) and depression. Antidepressants, specifically serotonin selective reuptake inhibitors, were commonly preferred for DRPD treatment, including PTSD and depression. Psychiatrists aged over 40, with more than 10 years of practice, and hold the board-certified status, showed greater experiences for outside- or inside- the hospital mobilization in DRPD management. Conclusion: Findings suggest that within post-graduate medical education, Taiwanese psychiatrists demonstrate significant experience, willingness, and capacity to effectively manage DRPD. However, there is a need to integrate comprehensive training on disaster psychiatry into post-graduate psychiatric education programs to further enhance preparedness and optimize outcomes in managing these challenging conditions.

Acute Mountain Sickness and the Risk of Subsequent Psychiatric Disorders-A Nationwide Cohort Study in Taiwan.

We aim to explore if there is a relationship between acute mountain sickness (AMS) and the risk of psychiatric disorders in Taiwan by using the National Health Insurance Research Database for to the rare studies on this topic. We enrolled 127 patients with AMS, and 1270 controls matched for sex, age, monthly insured premiums, comorbidities, seasons for medical help, residences, urbanization level, levels of care, and index dates were chosen from 1 January 2000 to 31 December 2015. There were 49 patients with AMS and 140 controls developed psychiatric disorders within the 16-year follow-up. The Fine-Gray model analyzed that the patients with AMS were prone to have a greater risk for the development of psychiatric disorders with an adjusted sub-distribution hazard ratio (sHRs) of 10.384 (95% confidence interval [CI]: 7.267-14.838, p < 0.001) for psychiatric disorders. The AMS group was associated with anxiety disorders, depressive disorders, bipolar disorder, sleep disorders, posttraumatic stress disorder/acute stress disorder, psychotic disorder, and substance-related disorder (SRD). The relationship between anxiety, depression, sleep disorders, SRD, and AMS still persisted even after we excluded the psychiatric disorders within the first five years after AMS. There was an association between AMS and the rising risk of psychiatric disorders in the 16 years of long-term follow-up research.

Midazolam-Induced Parasomnia as Online-Shopping Behaviors.

OBJECTIVES: The objective of this study was to report a case of sleep online shopping. METHODS: A single case study of midazolam-induced sleep online shopping behavior in a 35-year-old woman with posttraumatic stress disorder and bipolar II disorder was performed. RESULTS: The Naranjo score was 7, which supported the probability of midazolam-induced sleep online shopping behaviors. CONCLUSIONS: To the best of our knowledge, this is the first case report of parasomnia as online-shopping behaviors, induced by midazolam, in a patient with posttraumatic stress disorder and bipolar disorder. This case could serve as a reminder for the clinicians prescribing midazolam as a hypnotic for insomnia for their patients.

Risk of Psychiatric Disorders in Multiple Sclerosis: A Nationwide Cohort Study in an Asian Population.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease that can damage neurons in the brain and spinal cord and is associated with several psychiatric disorders. However, few studies have evaluated the risk of psychiatric disorders in patients with MS by using a nationwide database. This study investigated the association between MS and the risk of psychiatric disorders. METHODS: Using data from the Taiwan National Health Insurance Research Database from 2000 to 2015, we identified 1066 patients with MS. After adjustment for confounding factors, Fine and Gray's competing risk model was used to compare the risk of psychiatric disorders during 15 years of follow-up. RESULTS: Of the patients with MS, 531 (4622.86 per 105 person years) developed psychiatric disorders; by contrast, 891 of the 3198 controls (2485.31 per 105 person years) developed psychiatric disorders. Fine and Gray's competing risk model revealed an adjusted hazard ratio (HR) of 5.044 (95% confidence interval = 4.448-5.870, p < 0.001) after adjustment for all the covariates. MS was associated with depression, anxiety, bipolar disorder, sleep disorders, schizophrenia, schizophreniform disorder, and other psychotic disorders (adjusted HR: 12.464, 4.650, 6.987, 9.103, 2.552, 2.600, 2.441, and 2.574, respectively; all p < 0.001). Some disease-modifying drugs were associated with a lower risk of anxiety or depression. CONCLUSION: Patients with MS were determined to have a higher risk of developing a wide range of psychiatric disorders.

N-methyl d-aspartate receptors are involved in the induction, but not expression stage of amphetamine sensitization in schedule-induced polydipsia in rats.

1. The aim of the present study was to examine the role of dopaminergic and glutamatergic receptors on different stages of the amphetamine (AMPH) sensitized effect in schedule-induced polydipsia (SIP) in rats. 2. Three experiments were designed to evaluate the roles of DAD2 receptor antagonist haloperidol (HAL) and glutamatergic N-methyl d-aspartate receptor antagonist MK-801 on both the induction and the expression stage of AMPH sensitization in SIP rats. First, the induction of AMPH sensitization in the SIP model was tested again to confirm previous findings. Second, HAL or MK-801 was co-administered with AMPH on five consecutive days and their effect on induction was examined 14 days after withdrawal. Finally, HAL or MK-801 was co-administered with AMPH on the final day of testing in SIP rats in which AMPH sensitization had been established previously. 3. The present results showed that HAL and MK-801 affected the effect of AMPH differently during the process of sensitization. Whereas HAL influenced the sensitization during both the induction and the expression phases, MK-801 affected only the induction phase; thus, once the sensitization had been established, MK-801 had no further influence. 4. These results suggest that the SIP model could be considered useful for the study of sensitization. In addition, the induction and expression of AMPH sensitization is influenced differently by the dopaminergic and glutamatergic systems.

Association between traumatic spinal cord injury and affective and other psychiatric disorders-A nationwide cohort study and effects of rehabilitation therapies.

BACKGROUND: This study aimed to investigate the association between traumatic spinal cord injury (TSCI) and the risk of affective and other psychiatric disorders, and the role of the rehabilitation therapies. METHODS: In this population-based, retrospective cohort study, we used Taiwan's National Health Insurance Research Database to analyze the patients who were newly diagnosed with TSCI between 2000 and 2015 were included, with a 1:3 ratio by age, sex, and index year matched in the non-TSCI comparison group, for the risk of affective and other psychiatric disorders. RESULTS: In total, 5375 out of 16,151 patients with TSCI developed psychiatric disorders, and 1467 out of 48,543 patients in the non-TSCI group developed psychiatric disorders (2930.88 vs 2823.29 per 100,000 persons/year). The Kaplan-Meier analysis showed that the TSCI cohort had a significantly higher risk of psychiatric disorders (log-rank, p < 0.001). Fine and Gray's survival analysis revealed that the adjusted hazard ratio was 1.977 (95% CI: 1.914-2.042, p < 0.001). Rehabilitation therapies, including physical and occupational therapies, within 90 days after the injury, was associated with a lowered risk of psychiatric disorders, including anxiety, depression, and bipolar disorder, in the TSCI cohort (adjusted HR = 0.702 [95% CI: 0.661-0.746, p < 0.001]). In the subgroups with low, medium, and high intensity, rehabilitation therapies were associated with a lowered risk of psychiatric disorders. CONCLUSIONS: TSCI was associated with the risk of affective and other psychiatric disorders, and rehabilitation therapies were associated with a lowered risk of these in the TSCI cohort.

Age-dependent association of polymorphisms in the promoter and 5'-untranslated region of the norepinephrine transporter gene with generalized anxiety disorder.

BACKGROUND: Norepinephrine transporter (NET), which regulates synaptic norepinephrine for noradrenergic signaling, is involved in the pathogenesis of anxiety, while expression of the NET gene differs at different ages. Here, we examine whether genetic variants in the NET gene are associated, in an age-specific manner, with increased risk of generalized anxiety disorder (GAD), one of the most disabling anxiety disorders. METHODS: Three common single-nucleotide polymorphisms (SNPs) in the promoter (rs168924: A/G; rs2242446: T/C) and 5'-untranslated region (5'-UTR) (rs2397771: G/C) of the NET gene were genotyped in 2,317 Han-Chinese participants (791 GAD patients and 1,526 controls; age: 20-65). Potential confounding factors, such as gender, stress levels and psychiatric comorbidities, were included as covariates. RESULTS: An interaction between age and NET genotypes and haplotypes was found for the risk of GAD. In the younger participants, rs168924 minor allele G homozygotes had the lowest incidence of GAD; however, older subjects displayed an inverse pattern, with homozygous G/G carriers presenting the highest prevalence of GAD. Additionally, younger individuals carrying 2 copies of the GGT haplotype composed of rs2397771-rs168924-rs2242446 had the lowest rate of GAD. However, those with 2 copies of the same haplotype exhibited the highest risk of GAD in the older groups. LIMITATIONS: Only 3 common SNPs in the promoter and 5'-UTR of the NET gene were analyzed. CONCLUSIONS: Our findings are the first to demonstrate that potentially functional SNPs in the NET promoter and 5'-UTR are associated with an increased risk of GAD, and that such associations are determined in an age-specific way.

BDNF Val66Met polymorphism to generalized anxiety disorder pathways: Indirect effects via attenuated parasympathetic stress-relaxation reactivity.

The valine66methionine (Val66Met) polymorphism (rs6265) of the brain-derived neurotrophic factor (BDNF) gene has been shown to influence autonomic arousal pathways, which in turn predict elevated syndromal anxiety in healthy humans. We examined whether the BDNF variant is associated with an increased risk of generalized anxiety disorder (GAD), one of the most prevalent anxiety disorders, through altering parasympathetic stress/relaxation reactivity. A total of 2,250 Han Chinese adults (750 GAD patients and 1,500 healthy controls) were included in the genotyping. High-frequency heart rate variability, an index of vagal (parasympathetic) activity, was measured during the supine-standing-supine test (5 min in each position); vagal withdrawal and vagal activation were calculated as baseline supine minus standing and recovery supine minus standing, respectively. Analysis of healthy participants indicated that Val/Val homozygotes displayed significantly blunted vagal withdrawal and vagal activation compared with Met allele carriers. After analyzing the entire sample, these effects remained significant. Furthermore, both attenuated vagal response patterns were found to be significantly associated with a higher incidence of GAD. Lastly, the path analysis identified a significant indirect effect of BDNF on the risk of GAD via diminishing vagal response to either orthostatic stress or supine relaxation. Even when further testing the subsample comprising only comorbidity- and medication-free GAD patients and healthy controls to minimize the confounding bias, the results still remained. Our findings demonstrate that individuals carrying the BDNF Val/Val genotype, compared to Met-carriers, may be at higher risk of GAD due to blunted vagal reactivity in response to both stress and relaxation. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Role of dopaminergic DAD1 and DAD2 receptors in the sensitization of amphetamine-suppressed schedule-induced polydipsia in rats.

Effects of dopaminergic D1 (DAD1) and D2 (DAD2) receptors were examined in the sensitization of amphetamine (AMPH)-suppressed schedule-induced polydipsia (SIP). After training under a fixed-interval 60 sec schedule of food presentation in the presence of a water tube, rats received injections of different doses of AMPH 10 min prior to the test. It was found that AMPH at 2.0 mg/kg significantly to reduced licks and water intake during the SIP. The AMPH-suppressed SIP manifested again following 5-days of pretreatment with a sub-threshold dosage of AMPH (1.0 mg/kg) and a period of withdrawal. The role of dopaminergic D1 and D2 receptors was then examined by introducing D1 or D2 antagonist during the 5-days repeated injections of a sub-threshold dosage of AMPH. Results showed that DAD1 antagonist SCH23390 had little effect on the sensitization. However pretreatment with DAD2 antagonist haloperidol (HAL) prevented the sensitization to AMPH in the long-term rather than short-term withdrawal conditions. It is suggested that SIP could be a useful paradigm to study AMPH sensitization in rats and the involvement of dopamine receptors might be different.

Age-specific associations among functional COMT Val158Met polymorphism, resting parasympathetic nervous control and generalized anxiety disorder.

The functional Val158Met polymorphism (rs4680) of the Catechol-O-Methyltransferase (COMT) gene has been implicated in generalized anxiety disorder (GAD); however, the underlying neural mechanisms remain unexamined. Recent evidence reveals that low resting parasympathetic (vagal) control is an endophenotypic predictor of anxiety, while the effect of COMT rs4680 differs at different ages. Thus, we examined whether the COMT Val158Met variant could increase the risk of GAD through decreased resting parasympathetic nervous control in an age-specific manner. COMT rs4680 polymorphism was genotyped in 1,655 Han Chinese adults (1,142 healthy subjects and 513 patients with GAD; age: 20-65). High-frequency power (HF) of heart rate variability (HRV) was used to measure resting state parasympathetic nervous regulation. Non-genetic factors, such as gender, smoking status, medication use and comorbidity conditions, were treated as covariates. After adjusting for relevant covariates, there was a significant age x COMT genotype interaction on resting HF of HRV. In younger adults, Met allele carriers had a significantly lower HF index; however, older adults exhibited the opposite pattern, with Val/Val homozygotes exhibiting decreased HF values. Moreover, reduced HF-HRV is associated with increased risk of GAD. Finally, pathway analysis revealed a significant indirect effect of COMT on the risk of GAD via reduced resting HF-HRV, in the aforementioned age-dependent manner. Our findings are the first to demonstrate that COMT Val158Met polymorphism is associated with risk of GAD via reduced resting parasympathetic nervous control, an age-specific risk pathway.

Subchronic administration of aripiprazole improves fear extinction retrieval of Pavlovian conditioning paradigm in rats experiencing psychological trauma.

People may suffer from an intruded fear memory when the attributable traumatic events no longer exist. This is of highly clinical relevance to trauma-induced mental disorders, such as posttraumatic stress disorder (PTSD). Mechanism underlying PTSD largely lies in the abnormal process of fear extinction and a functional imbalance within amygdala associated fear circuit areas. Previous evidence suggested central dopamine plays a key role in the regulation of the fear memory process, yet it remains unclear whether the intervention of dopamine modulators would be beneficial for the fear extinction abnormalities. The present study examined the performance of Pavlovian conditioned fear and the changes of dopamine profiles following a subchronic 14-day regimen of aripiprazole (a partial agonist of dopamine D2 receptors to normalize the condition caused by dopamine imbalance) in rats previously experienced a psychologically traumatic procedure of single prolonged stress (SPS). The results demonstrated that aripiprazole at 5.0 mg/kg reversed the SPS-impaired fear memory dysfunction and the SPS-reduced dopamine efflux in the amygdala. The present study suggests a therapeutic potential of subchronic treatment with aripiprazole in managing patients suffered from fear extinction problem.

Hyperbaric oxygenation reduces overexpression of c-Fos and oxidative stress in the brain stem of experimental endotoxemic rats.

OBJECTIVE: Septic encephalopathy is associated with an increased mortality rate in septic patients. We have previously shown that a peripheral lipopolysaccharide (LPS) injection induces neuronal activation in the brain-stem nuclei of rats. Nitric oxide (NO) and superoxide are involved in LPS-induced brain damage. Hyperbaric oxygenation (HBO) provides protective effects against systemic oxidative stress and mortality in animals with septic shock. We examined the effects of HBO on neuronal activation and oxidative stress in the brain-stem nuclei of LPS-treated rats. DESIGN AND INTERVENTIONS: Wistar rats were randomly distributed into six groups for the following treatments:(a) normal saline injection (NS); (b) HBO; (c) LPS; (d) LPS-HBO; (e) LPS-aminoguanidine (AG, an inhibitor of inducible nitric oxide synthase); or (f) hydralazine (HYD, a direct vasodilator). The HYD induces prolonged hypotension and was used as a comparison for LPS stimulation. The AG was used as a comparison for HBO treatment. Two HBO sessions were administered, 1 and 4[Symbol: see text]h after LPS. RESULTS: HBO and AG significantly reversed the overproduction of c-Fos induced by LPS in the brain stems of rats, with greater reversal in the nucleus tractus solitarii (NTS) by HBO. Although AG did not reduce the superoxide level, HBO significantly abolished superoxide production and NADPH diaphorase expression in the brain stems of LPS-treated rats. The HYD induced much lower c-Fos expression in the brain-stem nuclei than that in LPS-treated animals and caused no significant increase in NADPH diaphorase expression or superoxide formation. CONCLUSION: HBO protects against endotoxin-related neuronal activation and oxidative stress in the brain-stem nuclei of rats.

Effects of haloperidol and risperidone on cerebrohemodynamics in drug-naive schizophrenic patients.

BACKGROUND: Use of antipsychotics may be associated with cerebrovascular adverse events in psychotic patients. In this study, the effects of haloperidol and risperidone on the cerebral hemodynamics and the possible relationships between antipsychotics and cerebrovascular risks tendency were evaluated by Transcranial Doppler ultrasonography (TCD). METHODS: Twenty drug-nai ve schizophrenic patients and 20 normal control subjects were included. The patients were divided into haloperidol- and risperidone-treated groups and received treatment for 8 weeks double-blindly. The subjects' cerebral blood flow mean velocities (MV) and pulsatility index (PI) were measured weekly by TCD. The Positive and Negative Syndrome Scale for schizophrenia (PANSS) was used to assess the patients' psychopathological symptoms. RESULTS: Increased MV and decreased PI were found significantly in drug-nai ve schizophrenic patients than normal subjects before treatment (p<0.01). The decreased PI could be normalized after 8 weeks of antipsychotic treatment, while the increased MV could not. Treatment with haloperidol could significantly increase the PI than the treatment with risperidone (p<0.01) throughout the treatment course. The PANSS scores of both groups were significantly improved (p<0.05) at the endpoints of treatment. CONCLUSIONS: Our findings indicate that haloperidol may affect the cerebral hemodynamics in drug-naive schizophrenics more prominently than that of risperidone via TCD monitoring.

Importance of intervention timing in the effectiveness of antipsychotics.

The use of early pharmacological intervention in treating young patients with schizophrenia is a debating issue for psychiatrists. However, on the basis of developmental theory, early antipsychotic intervention can be beneficial in terms of protecting neurons from further deterioration. This study investigated whether the initiation of second-generation antipsychotic (SGA) treatment at a younger age can effectively reverse schizophrenia-relevant behavioral and neurochemical features, namely acoustic prepulse inhibition (PPI) and accumbal dopamine (DA) efflux, respectively. Risperidone (RIS, 1mg/kg/day) or olanzapine (OLA, 2.5mg/kg/day) was administered for 6weeks in rats subjected to isolation rearing (IR) in adolescence or young adulthood. Behavioral testing was performed at 3 and 5 (for locomotor activity) and 2 and 4 (for PPI) weeks after the initiation of the pharmacological regimen. An additional PPI test was performed 6weeks after the initiation of the pharmacological regimen to assess the acute add-on effect of RIS or OLA. Dopamine (DA) efflux of the nucleus accumbens was evaluated through in vivo microdialysis at the end of the study, for measuring both the baseline levels after the chronic regimen and the responsiveness to acute add-on RIS or OLA treatment. Our results demonstrated that the effects of SGAs on PPI and accumbal DA efflux were dissociated. Specifically, RIS intervention was more beneficial for adolescent than young adult IR rats in restoring their PPI deficit, whereas OLA was age-independently effective in stimulating the accumbal DA efflux. Both PPI and accumbal DA could be employed to reflect IR-induced abnormalities, in which accumbal DA appeared to be more suitable in depicting the long-term effect of IR, whereas PPI might be a more accurate biological index for revealing the advantages of early RIS intervention.