Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder.

OBJECTIVES: Endoxifen is a protein kinase C inhibitor. The objective of the present phase III study was to demonstrate the safety and efficacy of endoxifen in treating bipolar I disorder (BPD I) patients. METHODS: A multicenter, double-blind, active-controlled study was conducted using a daily dose of 8 mg endoxifen compared to 1000 mg divalproex, the current standard treatment, in patients with BPD I acute manic episodes with/without mixed features. The primary endpoint of our study was the mean change in total Young Mania Rating Scale (YMRS) score at day 21. RESULTS: Endoxifen (n = 116) significantly (p < 0.0001) reduced total YMRS score (from 33.1 to 17.8. A significant (p < 0.001) improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score was observed for endoxifen (4.8 to 2.5). Early time to remission of the disease was observed with endoxifen compared to divalproex. None of the patients required rescue medication and there was no drug-associated withdrawals. Changes in Clinical Global Impressions-Bipolar Disorder and Clinical Global Impression-Severity of Illness scores showed that treatment with endoxifen was well-tolerated. CONCLUSIONS: Endoxifen at a low daily dose of 8 mg was as efficacious and safe in patients with BPD I acute manic episodes with/without mixed features.

Evidence of neuroplasticity with robotic hand exoskeleton for post-stroke rehabilitation: a randomized controlled trial.

BACKGROUND: A novel electromechanical robotic-exoskeleton was designed in-house for the rehabilitation of wrist joint and Metacarpophalangeal (MCP) joint. OBJECTIVE: The objective was to compare the rehabilitation effectiveness (clinical-scales and neurophysiological-measures) of robotic-therapy training sessions with dose-matched conventional therapy in patients with stroke. METHODS: A pilot prospective parallel randomized controlled study at clinical settings was designed for patients with stroke within 2 years of chronicity. Patients were randomly assigned to receive an intervention of 20 sessions of 45 min each, five days a week for four weeks, in Robotic-therapy Group (RG) (n = 12) and conventional upper-limb rehabilitation in Control-Group (CG) (n = 11). We intended to evaluate the effects of a novel exoskeleton based therapy on the functional rehabilitation outcomes of upper-limb and cortical-excitability in patients with stroke as compared to the conventional-rehabilitation. Clinical-scales- Modified Ashworth Scale, Active Range of Motion, Barthel-Index, Brunnstrom-stage and Fugl-Meyer (FM) scale and neurophysiological measures of cortical-excitability (using Transcranial Magnetic Stimulation) -Motor Evoked Potential and Resting Motor threshold, were acquired pre- and post-therapy. RESULTS: No side effects were noticed in any of the patients. Both RG and CG showed significant (p < 0.05) improvement in all clinical motor-outcomes except Modified Ashworth Scale in CG. RG showed significantly (p < 0.05) higher improvement over CG in Modified Ashworth Scale, Active Range of Motion and Fugl-Meyer scale and FM Wrist-/Hand component. An increase in cortical-excitability in ipsilesional-hemisphere was found to be statistically significant (p < 0.05) in RG over CG, as indexed by a decrease in Resting Motor Threshold and increase in the amplitude of Motor Evoked Potential. No significant changes were shown by the contralesional-hemisphere. Interhemispheric RMT-asymmetry evidenced significant (p < 0.05) changes in RG over CG indicating increased cortical-excitability in ipsilesional-hemisphere along with interhemispheric changes. CONCLUSION: Robotic-exoskeleton training showed improvement in motor outcomes and cortical-excitability in patients with stroke. Neurophysiological changes in RG could most likely be a consequence of plastic reorganization and use-dependent plasticity. Trial registry number: ISRCTN95291802.

Effectiveness and Predictors of Response to 1-Hz Repetitive Transcranial Magnetic Stimulation in Patients With Obsessive-Compulsive Disorder.

OBJECTIVE: The present study aimed to assess the effectiveness of repetitive transcranial magnetic stimulation (rTMS) treatment targeting either supplementary motor area (SMA) or orbitofrontal cortex (OFC) among patients with OCD in real-world clinical practice settings. Also, the present study explored for potential predictors of response to rTMS treatment. METHODS: Retrospective review and analysis of records of 79 patients with medication-refractory OCD, all of whom had received 20 sessions of 1-Hz rTMS as part of routine clinical care. Of 79 patients, 46 received rTMS over the bilateral SMA and 33 over the left OFC. A reduction of 25% and 35% in Yale-Brown Obsessive Compulsive Scale (YBOCS) scores was used to classify outcome as partial and complete response, respectively. Statistical analysis was done using SPSS version 23.0. RESULTS: There was a significant decrease in mean YBOCS score from baseline to end of treatment (7.68 ± 5.62; t = 12.14, P < 0.001). Forty-five patients (57%) met criteria for partial response, of which 32 patients (40.5%) showed complete response. There was no significant difference in outcomes between patients receiving rTMS over SMA or OFC. Binary logistic regression analysis revealed presence of comorbid depression and higher baseline YBOCS score to be associated with lesser likelihood of response to rTMS. CONCLUSIONS: This study provided evidence for overall effectiveness of adjunctive 1-Hz rTMS treatment over either SMA or OFC in patients with medication-refractory OCD, and reported comorbid depression and higher pretreatment YBOCS scores as potential predictors of poor response to rTMS.

The Effect of Low-Frequency Repetitive Transcranial Magnetic Stimulation at Orbitofrontal Cortex in the Treatment of Patients With Medication-Refractory Obsessive-Compulsive Disorder: A Retrospective Open Study.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a chronic debilitating psychiatric disorder, with significant proportion of patients failing to respond with current first-line treatments. The present study assesses the safety and effectiveness of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) over left-orbitofrontal cortex (Lt-OFC) as a potential augmentation strategy in treatment of patients with medication-refractory OCD in real-world clinical setting. The present report also aims to examine the factors affecting response to rTMS and the durability of effects produced by rTMS over 1 month of follow-up period. METHODS: Retrospective review and analysis of clinical case files of 25 patients with medication-refractory OCD, all of whom had received 20 sessions of LF-rTMS over Lt-OFC as part of routine clinical care. A reduction of 25% and 35% in Yale-Brown Obsessive Compulsive Scale scores was used to determine the proportion of partial and complete responders, respectively. RESULTS: There was a significant decrease in mean Yale-Brown Obsessive Compulsive Scale score at the end of 20 sessions of rTMS compared with baseline (7.04 ± 5.07; P < 0.001), with no further significant change during the subsequent 1-month follow-up period (0.20 ± 1.38; P = 0.47). Thirteen patients (52%) met criteria for partial response, of which 11 patients (44%) showed complete response. Furthermore, higher number of failed medication trials was found to be significantly associated with greater chances of nonresponse to rTMS treatment. CONCLUSIONS: There is a role of applying LF-rTMS over Lt-OFC as an augmentation strategy in ameliorating clinical symptoms among patients with medication-refractory OCD.

Cathodal neuromodulation of dominant temporoparietal cortex with transcranial direct current stimulation for tinnitus: A case series.

There is scant literature on the effectiveness of using transcranial direct current stimulation (tDCS) as an intervention modality for managing tinnitus. The current case series reflects the use of tDCS as an effective intervention for tinnitus while inhibiting the dominant temporoparietal cortex and simultaneous stimulating the non-dominant dorsolateral prefrontal cortex.

Effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) in patients with comorbid panic disorder and major depression.

OBJECTIVE: To explore the role of dorsolateral prefrontal cortex (DLPFC) stimulation in the treatment of panic disorder with comorbid depression. METHODS: The present study reports findings from retrospective analysis of 13 treatment-resistant patients diagnosed with comorbid panic disorder and depression, given 20 sessions of high-frequency transcranial magnetic stimulation (rTMS) over left-DLPFC over a period of 1 month. RESULTS: There was a significant reduction in both the panic and depressive symptom severity, assessed by applying Panic Disorder Severity Scale (PDSS) and Hamilton Depression Rating Scale (HDRS) at baseline and after 20 sessions of rTMS. There was a 38% and 40% reduction of PDSS and HDRS scores, respectively, in the sample. The changes in PDSS and HDRS scores were not significantly correlated (ρ = -0.103, p = 0.737). CONCLUSIONS: High-frequency rTMS delivered at left-DLPFC may have a potential role in treatment of comorbid panic disorder and depression. Future studies done on a larger sample in a controlled environment are required to establish its role.

Effective concentration ratio driven phase engineering of MBE-grown few-layer MoTe2.

The polymorphic nature of ultrathin transition metal dichalcogenide (TMDC) materials makes the phase engineering of these materials an interesting field of investigation. Understanding the phase-controlling behavior of different growth parameters is crucial for obtaining large-area growth of a desirable phase. Here, we report a detailed study on the effect of growth parameters for engineering different phases of few-layer MoTe2 on sapphire using molecular beam epitaxy (MBE). Our study shows that the 2H phase of MoTe2 is stabilized in a certain regime of the flux ratio and growth temperature, while on both the lower, as well as, the higher sides of this regime, the 1T' phase is favored. The combined effect of growth parameters is explained using the effective concentration ratio of Te and Mo at the growth surface, which is found to be the primary factor governing the phase selectivity in few-layer MoTe2. XPS and KPFM investigations show the contribution of excess carrier doping in driving the phase change. The effect of the sapphire substrate on the crystallinity and phase-dependent morphological features has also been studied. This knowledge of versatile and controlled phase engineering of few-layer MoTe2 paves the way for fabricating large-scale hetero-phase-based metal-semiconductor heterostructures for future electronic and optoelectronic device applications.

Film thickness-induced optical and electrical modifications in large-area few-layer 2H-MoSe2 grown by MBE.

Here, we report on a detailed study of film thickness-induced effects on optical and electrical characteristics of ultra-thin MoSe2 films grown using molecular beam epitaxy (MBE) on a c-plane sapphire substrate. The layer-dependent optical and electrical responses are investigated for MoSe2 films with different thicknesses (1, 2, 4 and 7 layers). Spectroscopic ellipsometry (SE) reveals significant variation in optical constants with film thickness in the spectral range of 5.04 eV to 0.73 eV. As the thickness increases from 1 layer to 7 layers, the band gap of the materials also changes from 1.62 eV to 1.19 eV. The layer-dependent band diagram analysis shows that the conduction band to Fermi level energy gap changes from 0.50 eV to 0.40 eV as the film thickness changes from 1 layer to 7 layers, making thicker films more n-type than thinner ones. I-V measurement shows an increase in current from the order of 10-9 to 10-5 ampere at a voltage of 3 V as the film thickness increases from 1 layer to 7 layers, which is explained by the corresponding change in the band diagram and supported by a temperature-dependent I-V study. The findings of the study offer a pathway to tune the optical and electrical characteristics of MoSe2 by controlling the layer number which can be valuable for its electronic and optoelectronic device applications.

Cortical intermittent theta burst stimulation on gait pathomechanics and urinary tract dysfunction in incomplete spinal cord injury patients: Protocol for a randomized controlled trial.

Gait impairment and neurogenic bladder are co-existing common findings in incomplete spinal cord injury (iSCI). Repetitive transcranial magnetic stimulation (rTMS), evident to be a promising strategy adjunct to physical rehabilitation to regain normal ambulation in SCI. However, there is a need to evaluate the role of Intermittent theta burst stimulation (iTBS), a type of patterned rTMS in restoring gait and neurogenic bladder in SCI patients. The aim of the present study is to quantify the effect of iTBS on spatiotemporal, kinetic, and kinematic parameters of gait and neurogenic bladder dyssynergia in iSCI. After maturing all exclusion and inclusion criteria, thirty iSCI patients will be randomly divided into three groups: Group-A (sham), Group-B (active rTMS) and Group-C (active iTBS). Each group will receive stimulation adjunct to physical rehabilitation for 2 weeks. All patients will undergo gait analysis, as well assessment of bladder, electrophysiological, neurological, functional, and psychosocial parameters. All parameters will be assessed at baseline and 6th week (1st follow-up). Parameters except urodynamics and gait analysis will also be assessed after the end of the 2 weeks of the intervention (post-intervention) and at 12th week (2nd follow-up). Appropriate statistical analysis will be done using various parametric and non-parametric tests based on results.

Restoring initial steps by intermittent theta burst stimulation in complete spinal cord injury patient: a case report.

INTRODUCTION: Spinal cord injury (SCI) causes damage to neurons and results in motor and sensory dysfunction. Intermittent theta burst stimulation (iTBS) has been used to induce neuronal and synaptic plasticity by applying a magnetic field in the brain. The plasticity induced in the cortex has an imperative role in the recovery of motor and sensory functioning. However, the effect of iTBS in complete SCI patients is still elusive. CASE PRESENTATION: We report here the case of a 27-year-old female who sustained an L1 complete spinal cord injury (SCI) with an ASIA score of A. The patient lost all the sensory and motor functions below the level of injury. Intermittent theta burst stimulation (iTBS) was administered at 80% of the resting motor threshold over the M1 motor cortex, along with intensive rehabilitation training to promote sensorimotor function. DISCUSSION: There was a partial recovery in functional, electrophysiological, and neurological parameters. The case report also demonstrates the safety and efficacy of iTBS in complete SCI patients. No adverse event has been observed in the patient during intervention sessions.

The evaluation of frequency and predictors of delirium and its short-term and long-term outcomes in hospitalized older adults'.

BACKGROUND: Delirium is a common complication in hospitalized older adults with multifactorial etiology and poor health outcomes. AIM: To determine the frequency and predictors of delirium and its short-term and long-term outcomes in hospitalized older adults. METHODS: A prospective observational study was performed in patients aged ≥60 years consecutively admitted to geriatric ward. Potential risk factors were assessed within 24 hours of hospital admission. Delirium screening was performed on admission and daily thereafter throughout the hospital stay using Confusion Assessment Method (CAM). Patients were followed up at 1-year post-discharge. RESULTS: The study included 200 patients with mean age 73.1 ± 8.83 years. Incidence and prevalence rate of delirium were 5% and 20% respectively. Multivariable regression analysis revealed emergency admission (OR= 5.12 (1.94-13.57), p=0.001), functional dependency (Katz index of Independence in Activities of Daily Living (Katz-ADL) score <5) 2 weeks before admission (OR= 3.08 (1.30-7.33), p=0.011) and more psychopathological symptoms (higher Brief Psychiatric Rating Scale (BPRS) total score) (OR=1.12 (1.06-1.18), p=0.001) to be independently associated with delirium. Patients in delirium group had significantly high in-hospital mortality (OR= 5.02 (2.12-11.8), p=0.001) and post-discharge mortality (HR= 2.02 (1.13-3.61), p=0.017) and functional dependency (Katz-ADL score <5) (OR= 5.45 (1.49-19.31), p=0.01) at 1-year follow up. CONCLUSION: Delirium is quite frequent in geriatric inpatients and is associated with high in-hospital and post-discharge mortality risk and long-term functional dependency. Emergency admission, pre-hospitalization functional dependency, and more general psychopathological symptoms are independently associated factors. Hence, earliest identification and treatment with early implementation of rehabilitation services is warranted.

Prevalence of depression among type 2 diabetes compared to healthy non diabetic controls.

AIMS: Successful diabetes management depends on patient behaviour. Diabetes is a significant risk factor for depression which itself is a risk factor for poor metabolic control. Data on this association is scarce from India--which is fast becoming the diabetes capital of the world. This study was done to see the prevalence of depression in adult patients with type 2 diabetes diagnosed within the previous 5 years and treated with oral hypoglycaemic agents compared to healthy persons without diabetes. Also, to evaluate Becks depression inventory (BDI) in terms of Mini International Neuropsychiatric Interview (MINI) as a tool to assess depression in diabetes. METHODS: Patients with diabetes within 5 year of diagnosis and on oral anti-diabetic drugs were included. Controls were healthy relatives of these patients without diabetes. These patients underwent clinical examination, biochemical tests, assessment of depression by BDI and MINI BDI and MINI were used to assess depression in controls as well. Prevalence of depression was found in both groups and compared. BDI was evaluated considering the MINI as gold standard in detecting depression in diabetes. RESULTS: The prevalence of co-morbid depression was 27.05% according to the MINI. In the non-diabetic healthy patient relatives, this was 11.11%. Those having depression had a lower educational attainment and a higher prevalence of retinopathy, compared to subjects without depression. The relative risk for the diabetics to have co-morbid depression was 2.97 (95% confidence interval 1.41-6.24). The BDI score with best sensitivity and specificity for diagnosing depression in diabetes was > or = 21. For healthy controls, a score of > or = 14 had best sensitivity and specificity. Diabetic patients had a higher score of BDI even without a diagnosis of depression on the MINI. CONCLUSION: Prevalence of depression was 27.05% diabetic patients and 11.11% healthy controls. A BDI score of 21 had the best sensitivity and specificity for diagnosing depression in adult type 2 diabetic patients. BDI can be used as a simple screening tool for the detection of depression in diabetic patients.

Novel intervention of high-frequency repetitive transcranial magnetic stimulation in patients with somatic symptom disorder and its safety and outcome.

Somatic Symptom disorders (SSDs) are characterised by the presence of persistent somatic symptoms associated with excessive thoughts, feelings and behaviours related to the symptoms. However, current treatment modalities are non-specific with modest effects. We aim to explore the safety and outcome of high-frequency transcranial magnetic stimulation at medial Prefrontal Cortex in ten such patients. Patient Health Questionnaire-15, Hamilton Rating Scale for Depression and Hamilton Anxiety Rating Scale were applied to ten patients with Somatic Symptom Disorder. 15 sessions of 15Hz TMS using a double cone coil with 2500 pulses/session were administered. All patients completed their sessions except one. Eight of the nine patients reported significant improvement with a reduction of 33%-80% from their baseline PHQ-15 scores. One patient reported significant adverse effects. Double cone coil TMS at medial Prefrontal Cortex appears to be a safe therapeutic intervention with potentially good outcomes in SSDs.

Need to rethink tDCS protocols for the treatment of alcohol use disorder: Insights from a randomized sham-controlled clinical trial among detoxified inpatients.

OBJECTIVES: Alcohol use disorder (AUD) is a chronic disorder with various health problems. Reduced functioning of the Dorsolateral Prefrontal Cortex (DLPFC) is associated with impaired regulation of alcohol-seeking behaviors and increased cravings in individuals with AUD. This study aimed to investigate whether 10 add-on sessions of tDCS, over the left DLPFC in detoxified inpatients with AUD could reduce cravings and increase abstinence rates at three months. METHODS: Detoxified inpatients with AUD were randomly assigned to either treatment as usual (TAU) plus ten sessions of active tDCS over left DLPFC, or TAU plus ten sessions of sham tDCS treatment twice daily for five consecutive days. RESULTS: The results from the generalized linear mixed model (GLMM) revealed that time had a significant effect on OCDS scores, but neither treatment nor interaction between these two factors had a significant effect on OCDS scores The Chi-square test in the intention- to- treat analysis did not show a significant difference in complete abstinence rates between the active treatment group and the sham treatment group. CONCLUSIONS: we found that adding ten sessions of active tDCS over left DLPFC tDCS to the treatment as usual for AUD did not result in improved abstinence rates or reduced craving.

Longitudinal assessment of disability amongst patients of bipolar and unipolar depressive disorders presenting to a tertiary care center in North India.

OBJECTIVES: To assess and compare the changes in disability scores associated with Bipolar Depression (BD) and Unipolar Depression (UD) over 1 year. METHODS: A longitudinal study was taken up in adults diagnosed with unipolar or bipolar depressive disorder with current depressive episode. Diagnosis was made according to Schedule for Clinical Assessment in Neuropsychiatry. Severity scoring was done using Hamilton's Depression (HAM-D) rating scale and Hamilton's Anxiety (HAM-A) rating scale. Disability was assessed using Indian Disability Evaluation and Assessment Scale (IDEAS) and London handicap Scale (LHS) at baseline, 6 and 12 months. RESULTS: Sixty participants were recruited (42 UD and 18 BD). No significant differences were seen in socio-demographic parameters, except higher education levels and males being overrepresented in UD. Significant differences at baseline were seen in HAM-D (p = .001) and HAM-A (p = .003) scores. The extent of disability was seen to correlate with severity of illness only in case of BD at baseline. No significant differences were seen in the IDEAS scores at baseline. IDEAS score improved at each follow-up assessment (p < .001). LHS showed significant improvement over time in UD (p < .001), but not BD (p = .076). Percentage individuals meeting cut-off for benchmark disability (>40%) were comparable at baseline but were significantly more in the BD at 12-months (p = .049). CONCLUSION AND IMPLICATIONS: Disability in psychiatry occurs equally amongst unipolar and bipolar depressive disorders and tends to improve over time, although the level of improvement may differ. It may not always correspond to severity of illness. These factors should be considered while certifying disability.

Individualized closed-loop TMS synchronized with exoskeleton for modulation of cortical-excitability in patients with stroke: a proof-of-concept study.

Background: Repetitive TMS is used in stroke rehabilitation with predefined passive low and high-frequency stimulation. Brain State-Dependent Stimulation (BSDS)/Activity-Dependent Stimulation (ADS) using bio-signal has been observed to strengthen synaptic connections. Without the personalization of brain-stimulation protocols, we risk a one-size-fits-all approach. Methods: We attempted to close the ADS loop via intrinsic-proprioceptive (via exoskeleton-movement) and extrinsic-visual-feedback to the brain. We developed a patient-specific brain stimulation platform with a two-way feedback system, to synchronize single-pulse TMS with exoskeleton along with adaptive performance visual feedback, in real-time, for a focused neurorehabilitation strategy to voluntarily engage the patient in the brain stimulation process. Results: The novel TMS Synchronized Exoskeleton Feedback (TSEF) platform, controlled by the patient's residual Electromyogram, simultaneously triggered exoskeleton movement and single-pulse TMS, once in 10 s, implying 0.1 Hz frequency. The TSEF platform was tested for a demonstration on three patients (n = 3) with different spasticity on the Modified Ashworth Scale (MAS = 1, 1+, 2) for one session each. Three patients completed their session in their own timing; patients with (more) spasticity tend to take (more) inter-trial intervals. A proof-of-concept study on two groups-TSEF-group and a physiotherapy control-group was performed for 45 min/day for 20-sessions. Dose-matched Physiotherapy was given to control-group. Post 20 sessions, an increase in ipsilesional cortical-excitability was observed; Motor Evoked Potential increased by ~48.5 µV at a decreased Resting Motor Threshold by ~15.6%, with improvement in clinical scales relevant to the Fugl-Mayer Wrist/Hand joint (involved in training) by 2.6 units, an effect not found in control-group. This strategy could voluntarily engage the patient. Conclusion: A brain stimulation platform with a real-time two-way feedback system was developed to voluntarily engage the patients during the brain stimulation process and a proof-of-concept study on three patients indicates clinical gains with increased cortical excitability, an effect not observed in the control-group; and the encouraging results nudge for further investigations on a larger cohort.

Low-Frequency Repetitive Transcranial Magnetic Stimulation for Chronic Tension-Type Headache: A Randomized Controlled Study.

BACKGROUND: Nearly 1-3% of the population is affected by chronic tension-type headaches (CTTH). However, it is still difficult to treat owing to the lack of knowledge of the disease's pathophysiology. Available literature suggests a role for pericranial muscle activity and abnormal modulation of central pain. Repetitive transcranial magnetic stimulation (rTMS) therapy done at the dorsolateral prefrontal cortex (DLPFC) can help modulate pericranial muscle overactivity and central pain modulation in subjects with CTTH. AIM: This randomized controlled study aimed to assess the effect of rTMS used in the low-frequency dorsolateral prefrontal cortex on pain and muscle activity in subjects with a chronic tension-type headache. MATERIALS AND METHODS: The present randomized controlled clinical study was commenced in a health care center on 20 subjects with chronic tension-type headaches who were given either sham or low-frequency repetitive transcranial magnetic stimulation at the right dorsolateral prefrontal cortex. The therapy effect was evaluated statistically using Welch's corrected t-test. RESULTS: The study results depicted that daily use of rTMS therapy for two weeks led to a considerable reduction in the intensity of the pain, the activity of pericranial muscles, and headache impact, along with an increase in the nociceptive excitability thresholds in subjects with CTTH, with p=0.001 compared to the sham group. CONCLUSION: Considering its limitations, the present study depicts that rTMS is an efficacious management tool for reducing pain associated with CTTH and can serve as the cornerstone for additional investigations.

Role of nuclear energy in carbon mitigation to achieve United Nations net zero carbon emission: evidence from Fourier bootstrap Toda-Yamamoto.

In this communication, the time series data of three major countries USA, France, and Japan from 1965 to 2020 for CO2 emission, GDP, and nuclear energy (NE) are evaluated. It also analyzed and validated the EKC hypothesis while using nuclear energy for electricity generation. Fourier ARDL is used to investigate the hypothesis criteria, and the Fourier bootstrap Toda-Yamamoto (FBTY) causality test is used for causal linkage between the variables as well as the wavelet coherence; it is also presented the time and frequency dependency of the variables. The CO2 mitigation by using the NE is also assessed for all three countries and assessed that the France, Japan, and USA mitigated the CO2 per year is 0.0463 million metric ton (MMT), 0.0239 and 0.0728 MMT per year respectively. Similar to that the SO2 is reduced by using the NE is 24.322, 43.527, and 132.592 MMT/year, and NOx is reduced by approximately 0.2847, 0.147, and 0.4478 MMT/year by France, Japan, and USA respectively by applying the NE for power generation. The evidence of the EKC, Fourier bootstrap and Toda-Yamamoto clarifies the important role of nuclear energy in terms of carbon mitigation to achieve UN net zero carbon emission by 2050. Hence, in order to meet the UN target of net zero carbon emission by 2050, the USA and Japan should increase the production of nuclear energy as France meets its 74.1% energy demand through NE by validating the EKC hypothesis; on the other hand, all the three countries should increase the production of tidal energy due to their geographical location as tides are much more predictable than wind and sun keeping in consideration to the expenses incurred and a full proof plan for disposing NE residuals in a safe place as NE residuals are highly radioactive and contains traces of thorium and uranium.