Exploring the effects of extracranial injections of botulinum toxin type A on activation and sensitization of central trigeminovascular neurons by cortical spreading depression in male and female rats.

BACKGROUND: OnabotulinumtoxinA (onabotA), is assumed to achieve its therapeutic effect in migraine through blocking activation of unmyelinated meningeal nociceptors and their downstream communications with central dura-sensitive trigeminovascular neurons in the spinal trigeminal nucleus (SPV). The present study investigated the mechanism of action of onabotA by assessing its effect on activation and sensitization of dura-sensitive neurons in the SPV by cortical spreading depression (CSD). It is a follow up to our recent study on onabotA effects on activation and sensitization of peripheral trigeminovascular neurons. METHODS: In anesthetized male and female rats, single-unit recordings were used to assess effects of extracranial injections of onabotA (five injections, one unit each, diluted in 5 µl of saline were made along the lambdoid (two injection sites) and sagittal (two injection sites) suture) vs. vehicle on CSD-induced activation and sensitization of high-threshold (HT) and wide-dynamic range (WDR) dura-sensitive neurons in the SPV. RESULTS: Single cell analysis of onabotA pretreatment effects on CSD-induced activation and sensitization of central trigeminovascular neurons in the SPV revealed the ability of this neurotoxin to prevent activation and sensitization of WDR neurons (13/20 (65%) vs. 4/16 (25%) activated neurons in the control vs. treated groups, p = 0.022, Fisher's exact). By contrast, onabotA pretreatment effects on CSD-induced activation and sensitization of HT neurons had no effect on their activation (12/18 (67%) vs. 4/7 (36%) activated neurons in the control vs. treated groups, p = 0.14, Fisher's exact). Regarding sensitization, we found that onabotA pretreatment prevented the enhanced responses to mechanical stimulation of the skin (i.e. responses reflecting central sensitization) in both WDR and HT neurons. In control but not treated WDR neurons, responses to brush (p = 0.004 vs. p = 0.007), pressure (p = 0.002 vs. p = 0.79) and pinch (p = 0.007 vs. 0.79) increased significantly two hours after CSD. Similarly, in control but not treated HT neurons, responses to brush (p = 0.002 vs. p = 0.79), pressure (p = 0.002 vs. p = 0.72) and pinch (p = 0.0006 vs. p = 0.28) increased significantly two hours after CSD. Unexpectedly, onabotA pretreatment prevented the enhanced responses of both WDR and HT neurons to mechanical stimulation of the dura (commonly reflecting peripheral sensitization). In control vs. treated WDR and HT neurons, responses to dural stimulation were enhanced in 70 vs. 25% (p = 0.017) and 78 vs. 27% (p = 0.017), respectively. CONCLUSIONS: The ability of onabotA to prevent activation and sensitization of WDR neurons is attributed to its preferential inhibitory effects on unmyelinated C-fibers. The inability of onabotA to prevent activation of HT neurons is attributed to its less extensive inhibitory effects on the thinly myelinated Aδ-fibers. These findings provide further pre-clinical evidence about differences and potentially complementary mechanisms of action of onabotA and calcitonin gene-related peptide-signaling neutralizing drugs.

The headache research priorities: Research goals from the American Headache Society and an international multistakeholder expert group.

OBJECTIVE: To identify and disseminate research priorities for the headache field that should be areas of research focus during the next 10 years. BACKGROUND: Establishing research priorities helps focus and synergize the work of headache investigators, allowing them to reach the most important research goals more efficiently and completely. METHODS: The Headache Research Priorities organizing and executive committees and working group chairs led a multistakeholder and international group of experts to develop headache research priorities. The research priorities were developed and reviewed by clinicians, scientists, people with headache, representatives from headache organizations, health-care industry representatives, and the public. Priorities were revised and finalized after receiving feedback from members of the research priorities working groups and after a public comment period. RESULTS: Twenty-five research priorities across eight categories were identified: human models, animal models, pathophysiology, diagnosis and management, treatment, inequities and disparities, research workforce development, and quality of life. The priorities address research models and methods, development and optimization of outcome measures and endpoints, pain and non-pain symptoms of primary and secondary headaches, investigations into mechanisms underlying headache attacks and chronification of headache disorders, treatment optimization, research workforce recruitment, development, expansion, and support, and inequities and disparities in the headache field. The priorities are focused enough that they help to guide headache research and broad enough that they are widely applicable to multiple headache types and various research methods. CONCLUSIONS: These research priorities serve as guidance for headache investigators when planning their research studies and as benchmarks by which the headache field can measure its progress over time. These priorities will need updating as research goals are met and new priorities arise.

Versatility of OnabotulinumtoxinA in Aesthetic Medicine.

BACKGROUND: OnabotulinumtoxinA is an injectable product that was introduced into medicine in the 1970s and has been the subject of thousands of clinical and nonclinical publications. OBJECTIVE: To review the data related to the versatility of onabotulinumtoxinA in medical aesthetics. METHODS: PubMed was searched to identify literature evaluating the effects of onabotulinumtoxinA, with preference given to randomized, placebo-controlled trials and safety meta-analyses. RESULTS: OnabotulinumtoxinA is effective and safe across multiple facial indications, racial and ethnic groups, age groups, genders, and facial line severities. Patient-reported outcomes have been prioritized in aesthetic clinical trials and indicate high patient satisfaction and appearance-related psychological outcomes. Integrated safety meta-analysis and immunogenicity analyses have documented acceptable adverse event rates and low immunogenicity of onabotulinumtoxinA. CONCLUSION: OnabotulinumtoxinA is a versatile aesthetic product supported by a strong literature base and positive physician and patient-reported outcomes that reflect a meaningful impact on patient's quality of life.

Update on Non-Interchangeability of Botulinum Neurotoxin Products.

The growing use of botulinum neurotoxins (BoNTs) for medical and aesthetic purposes has led to the development and marketing of an increasing number of BoNT products. Given that BoNTs are biological medications, their characteristics are heavily influenced by their manufacturing methods, leading to unique products with distinct clinical characteristics. The manufacturing and formulation processes for each BoNT are proprietary, including the potency determination of reference standards and other features of the assays used to measure unit potency. As a result of these differences, units of BoNT products are not interchangeable or convertible using dose ratios. The intrinsic, product-level differences among BoNTs are compounded by differences in the injected tissues, which are innervated by different nerve fiber types (e.g., motor, sensory, and/or autonomic nerves) and require unique dosing and injection sites that are particularly evident when treating complex therapeutic and aesthetic conditions. It is also difficult to compare across studies due to inherent differences in patient populations and trial methods, necessitating attention to study details underlying each outcome reported. Ultimately, each BoNT possesses a unique clinical profile for which unit doses and injection paradigms must be determined individually for each indication. This practice will help minimize unexpected adverse events and maximize efficacy, duration, and patient satisfaction. With this approach, BoNT is poised to continue as a unique tool for achieving individual goals for an increasing number of medical and aesthetic indications.

Racial and Socioeconomic Disparities in Laminoplasty Versus Laminectomy With Fusion in Patients With Cervical Spondylosis.

STUDY DESIGN: A retrospective cohort study using prospectively collected data. OBJECTIVE: The aim of this study was to investigate preoperative differences in racial and socioeconomic factors in patients undergoing laminoplasty (LP) versus laminectomy and fusion (LF) for degenerative cervical myelopathy (DCM). SUMMARY OF BACKGROUND DATA: DCM is prevalent in the United States, requiring surgical intervention to prevent neurological degeneration. While LF is utilized more frequently, LP is an emerging alternative. Previous studies have demonstrated similar neurological outcomes for both procedures. However, treatment selection is primarily at the discretion of the surgeon and may be influenced by social determinants of health that impact surgical outcomes. MATERIALS AND METHODS: The Quality Outcome Database (QOD), a national spine registry, was queried for adult patients who underwent either LP or LF for the management of DCM. Covariates associated with socioeconomic status, pain and disability, and demographic and medical history were collected. Multivariate logistic regression was performed to assess patient factors associated with undergoing LP versus LF. RESULTS: Of 1673 DCM patients, 157 (9.4%) underwent LP and 1516 (90.6%) underwent LF. A significantly greater proportion of LP patients had private insurance (P<0.001), a greater than high school level education (P<0.001), were employed (P<0.001), and underwent primary surgery (P<0.001). LP patients reported significantly lower baseline neck/arm pain and Neck Disability Index (P<0.001). In the multivariate regression model, lower baseline neck pain [odds ratio (OR)=0.915, P=0.001], identifying as non-Caucasian (OR=2.082, P<0.032), being employed (OR=1.592, P=0.023), and having a greater than high school level education (OR=1.845, P<0.001) were associated with undergoing LP rather than LF. CONCLUSIONS: In DCM patients undergoing surgery, factors associated with patients undergoing LP versus LF included lower baseline neck pain, non-Caucasian race, higher education, and employment. While symptomatology may influence the decision to choose LP over LF, there may also be socioeconomic factors at play. The trend of more educated and employed patients undergoing LP warrants further investigation.

Early ambulation after fibular free flap surgery is associated with reduced length of stay, increased mobility independence, and discharge to home.

BACKGROUND: Fibula free flaps (FFF) are one of the most common bony flaps utilized. This paper describes a quality improvement project aimed at increasing early ambulation. METHODS: A review of FFF patients at an academic hospital was completed (2014-2023). In 2018, an institutional change to encourage early ambulation without placement of a boot was made. Changes in hospital disposition and physical therapy outcomes were evaluated. RESULTS: A total of 168 patients underwent FFF reconstruction. There was a statistically significant lower length of stay in Group 2 (early ambulation, no boot) (8.1 vs. 9.4; p = 0.04). A higher rate of discharge to a skilled nursing facility was noted in Group 1 (delayed ambulation with boot) (21.3% vs. 11.9%; p = 0.009). A higher proportion of patients in Group 2 demonstrated independence during bed mobility, transfers, and gait (p < 0.05). CONCLUSIONS: Early ambulation without boot placement after FFF is associated with decreased length of hospital stay, improved disposition to home and physical therapy outcomes.

Modulation of locomotion and motor neuron response by the cohesive effect of acute and chronic feeding states and acute d-amphetamine treatment in zebrafish larvae.

Amphetamine (AMPH) increases locomotor activities in animals, and the locomotor response to AMPH is further modulated by caloric deficits such as food deprivation and restriction. The increment in locomotor activity regulated by AMPH-caloric deficit concomitance can be further modulated by varying feeding schedules (e.g. acute and chronic food deprivation and acute feeding after chronic food deprivation). However, the effects of different feeding schedules on AMPH-induced locomotor activity are yet to be explicated. Here, we have explored the stimulatory responses of acutely administered d-amphetamine in locomotion under systematically varying feeding states (fed/sated and food deprivation) and schedules (chronic and acute) in zebrafish larvae. We used wild-type and transgenic[Tg(mnx1:GCaMP5)] zebrafish larvae and measured swimming activity and spinal motor neuron activity in vivo in real-time in time-elapsed and cumulative manner pre- and post-AMPH treatment. Our results showed that locomotion and motor neuron activity increased in both chronic and acute food deprivation post-AMPH treatment cumulatively. A steady increase in locomotion was observed in acute food-deprivation compared to an immediate abrupt increase in chronic food-deprivation state. The ad libitum-fed larvae exhibited a moderate increase both in locomotion and motor neuron activity. Conversely to all other caloric states, food-sated (acute feeding after chronic food deprivation) larvae moved moderately less and exhibited a mild decrease in motor neuron activity after AMPH treatment. These results point to the importance of the feeding schedule in modulating amphetamine's characteristic stimulatory response on behavior and motor neurons.

Dopamine neuron activity evoked by sucrose and sucrose-predictive cues is augmented by peripheral and central manipulations of glucose availability.

Food deprivation drives eating through multiple signals and circuits. Decreased glucose availability (i.e., cytoglucopenia) drives eating and also increases the value of sucrose. Ventral tegmental area (VTA) dopamine neurons (DANs) contribute to the evaluation of taste stimuli, but their role in integrating glucoprivic signals remains unknown. We monitored VTA DAN activity via Cre-dependent expression of a calcium indicator with in vivo fibre photometry. In ad libitum fed rats, intraoral sucrose evoked a phasic increase in DAN activity. To manipulate glucose availability, we administered (intraperitoneal, lateral or fourth ventricular) the antiglycolytic agent 5-thio-D-glucose (5TG), which significantly augmented the phasic DAN activity to sucrose. 5TG failed to alter DAN activity to water or saccharin, suggesting the response was selective for caloric stimuli. 5TG enhancement of sucrose-evoked DAN activity was stronger after fourth ventricular administration, suggesting a critical node of action within the hindbrain. As 5TG also increases blood glucose, in a separate study, we used peripheral insulin, which stimulates eating, to decrease blood glucose-which was associated with increased DAN activity to intraoral sucrose. DAN activity developed to a cue predictive of intraoral sucrose. While 5TG augmented cue-evoked DAN activity, its action was most potent when delivered to the lateral ventricle. Together, the studies point to central glucose availability as a key modulator of phasic DAN activity to food and food-cues. As glucose sensing neurons are known to populate the hypothalamus and brainstem, results suggest differential modulation of cue-evoked and sucrose-evoked DAN activity.

A framework to explain the in-match decision-making of elite Australian football coaches.

The ability to make effective decisions is an important function of any football coach, whether during training, team selection, match-day performance or post-match player evaluation. It is not yet known how elite Australian football coaches make decisions during matches, in time-constrained but well-resourced environments. This study is the first to explore the decision-making of elite Australian football coaches during matches, in pursuit of identifying opportunities to improve the translation and implementation of research findings into the competitive match environment. Using semi-structured interviews and thematic analysis, a six-stage framework of the decision-making of elite Australian football coaches during matches was developed. The stages include (1) Opportunity trigger, (2) Understand the opportunity, (3) Determine the need for action, (4) Explore options, (5) Take action and (6) Evaluate the decision. Coaches relied on subjective and objective sources of information and consulted with assistant coaches, performance analysts, and sport scientists. The findings enable researchers to ensure future interventions to improve decision-making during matches are well integrated. They also provide an opportunity for coaches to reflect on their own decision-making process, identifying targeted areas for improvement in their own practice.

Real time prediction of match outcomes in Australian football.

This study aimed to determine whether machine learning models based on technical performance and not score margin could be used to predict end-of-match outcome of Australian football matches in real-time. If efficacious, these models could be used to generate insights about team performance and support the decision-making of coaches during matches. A database of 168 team technical performance indicators from 829 Australian Football League matches played between 2017 and 2021 was used. Two feature sets (data-driven and data-informed) were used to train and evaluate six models (generalised linear model, random forest and adaboost) on match outcome prediction (Win/Loss) over 120 epochs (a representation of normalised time during each match). All models performed well (mean classification accuracy = 73.5-75.8%) in comparison with a benchmark score-based model (mean classification accuracy = 77.4%). Data-informed feature sets performed better than data-driven in most cases. Classification accuracy was low at the start of a match (45.7-48.8%) but increased to a peak near the end of a match (87.2-92.7%). These findings suggest that any of the employed models can be used to formulate in-match decision support. The model which is best in practice will depend on factors such as time-cost trade-off, feasibility and the perceived value of its suggestions.

An open-source platform for head-fixed operant and consummatory behavior.

Head-fixed behavioral experiments in rodents permit unparalleled experimental control, precise measurement of behavior, and concurrent modulation and measurement of neural activity. Here, we present OHRBETS (Open-Source Head-fixed Rodent Behavioral Experimental Training System; pronounced 'Orbitz'), a low-cost, open-source platform of hardware and software to flexibly pursue the neural basis of a variety of motivated behaviors. Head-fixed mice tested with OHRBETS displayed operant conditioning for caloric reward that replicates core behavioral phenotypes observed during freely moving conditions. OHRBETS also permits optogenetic intracranial self-stimulation under positive or negative operant conditioning procedures and real-time place preference behavior, like that observed in freely moving assays. In a multi-spout brief-access consumption task, mice displayed licking as a function of concentration of sucrose, quinine, and sodium chloride, with licking modulated by homeostatic or circadian influences. Finally, to highlight the functionality of OHRBETS, we measured mesolimbic dopamine signals during the multi-spout brief-access task that display strong correlations with relative solution value and magnitude of consumption. All designs, programs, and instructions are provided freely online. This customizable platform enables replicable operant and consummatory behaviors and can be incorporated with methods to perturb and record neural dynamics in vivo.

Early development history of Botox (onabotulinumtoxinA).

The development of Botox (onabotulinumtoxinA) began in the 1970s as Dr. Scott was attempting to identify an injectable substance that would weaken the extraocular eye muscles in patients with strabismus as an alternative to muscle surgery. This search led to botulinum toxin type A, which was tested and developed over the next 15 years. As botulinum toxin type A moved from an experimental drug to a product in need of licensing by the Food and Drug Administration (FDA), the first manufacturing methods and quality control procedures were developed for Oculinum, the botulinum toxin type A product that would eventually be sold to Allergan and become known as Botox.

Botox (onabotulinumtoxinA) mechanism of action.

Studies in the 1920s found that botulinum neurotoxin type A (BoNT/A) inhibited the activity of motor and parasympathetic nerve endings, confirmed several decades later to be due to decreased acetylcholine release. The 1970s were marked by studies of cellular mechanisms aided by use of neutralizing antibodies as pharmacologic tools: BoNT/A disappeared from accessibility to neutralizing antibodies within minutes, although it took several hours for onset of muscle weakness. The multi-step mechanism was experimentally confirmed and is now recognized to consist broadly of binding to nerve terminals, internalization, and lysis or cleavage of a protein (SNAP-25: synaptosomal associated protein-25 kDa) that is part of the SNARE (Soluble NSF Attachment protein REceptor) complex needed for synaptic vesicle docking and fusion. Clinical use of the BoNT/A product onabotulinumtoxinA was based on its ability to reduce muscle contractions via inhibition of acetylcholine from motor terminals. Sensory mechanisms of onabotulinumtoxinA have now been identified, supporting its successful treatment of chronic migraine and urgency in overactive bladder. Exploration into migraine mechanisms led to anatomical studies documenting pain fibers that send axons through sutures of the skull to outside the head-a potential route by which extracranial injections could affect intracranial processes. Several clinical studies have also identified benefits of onabotulinumtoxinA in major depression, which have been attributed to central responses induced by feedback from facial muscle and skin movement. Overall, the history of BoNT/A is distinguished by basic science studies that stimulated clinical use and, conversely, clinical observations that spurred basic research into novel mechanisms of action.

The pluripotential evolution and journey of Botox (onabotulinumtoxinA).

Clinical use of onabotulinumtoxinA evolved based on strategic, hypothesis-driven applications, as well as serendipitous observations by physicians and patients. The success of onabotulinumtoxinA in blepharospasm and strabismus led to its study in other head and neck dystonias, followed by limb dystonia, tremor, and spasticity. The aesthetic use of onabotulinumtoxinA followed initial reports from patients of improved facial lines after injections for facial dystonias and hemifacial spasm. Although patients with dystonias and spasticity regularly reported that their local pain improved after injections, onabotulinumtoxinA was not systematically explored for chronic migraine until patients began reporting headache improvements following aesthetic injections. Clinicians began assessing onabotulinumtoxinA for facial sweating and hyperhidrosis based on its inhibition of acetylcholine from sympathetic cholinergic nerves. Yet another line of research grew out of injections for laryngeal dystonia, whereby clinicians began to explore other sphincters in the gastrointestinal tract and eventually to treatment of pelvic sphincters; many of these sphincters are innervated by autonomic nerves. Additional investigations in other autonomically mediated conditions were conducted, including overactive bladder and neurogenic detrusor overactivity, achalasia, obesity, and postoperative atrial fibrillation. The study of onabotulinumtoxinA for depression also grew out of the cosmetic experience and the observation that relaxing facial muscle contractions associated with negative emotions may improve mood. For approved indications, the safety profile of onabotulinumtoxinA has been demonstrated in the formal development programs and post-marketing reports. Over time, evidence has accumulated suggesting clinical manifestations of systemic effects, albeit uncommon, particularly with high doses and in vulnerable populations. Although onabotulinumtoxinA is approved for approximately 26 indications across multiple local regions, there are 15 primary indication uses that have been approved in most regions, including the United States, Europe, South America, and Asia. This review describes many uses for which AbbVie has not sought and/or received regulatory approval and are mentioned for historical context only.

Treatment of strabismus and blepharospasm with Botox (onabotulinumtoxinA): Development, insights, and impact.

Strabismus, deviation of the ocular alignment, can adversely affect quality of life and activities of daily living. Surgery was the prior standard of care for strabismus, but up to 40% of patients required additional surgeries. This need for more effective and less invasive treatment, along with the convergence of other events such as the development of electromyography, purification of botulinum toxin A, and the finding that injection of botulinum toxin type A could paralyze the hind limbs of chicks, led Dr. Alan Scott to investigate injection of his formulation for strabismus. The positive results of initial trials in monkeys segued to human trials with observations of alignment improvements and few adverse events. The success of botulinum toxin type A in the treatment of strabismus led to interest in its use to treat other skeletal muscles, particularly in blepharospasm, a type of focal dystonia involving eyelid spasms and involuntary eye closure that lacked an effective pharmacological treatment. Patient groups helped to increase awareness of this novel treatment, and results from clinical trials confirmed its effectiveness. Dr. Scott's formulation, then known as Oculinum, received its first Food and Drug Administration approvals in 1989 for strabismus and blepharospasm. Allergan acquired Oculinum in 1991, renaming it Botox. These initial uses led to its application in a myriad of other indications as outlined in other articles of this supplement.

Treatment of cervical dystonia with Botox (onabotulinumtoxinA): Development, insights, and impact.

Cervical dystonia (CD), the most common focal dystonia encountered in neurologic practice, is a chronic disorder in which the muscles of the neck involuntarily contract and cause abnormal postures and movements of the head, neck, and shoulders. Treatment of CD prior to botulinum toxin was unsatisfactory, as existing therapies often did not improve symptoms. The use of botulinum toxin for CD grew out of its success in treating blepharospasm, another type of focal dystonia. On the basis of results from a double-blind, placebo-controlled trial, onabotulinumtoxinA was approved in 2000 in the US for the treatment of CD in adults in order to alleviate abnormal head position and neck pain. A subsequent large observational trial further demonstrated the effectiveness of onabotulinumtoxinA for CD, showing improvements in various rating scales, physician-reported measures, and profound positive effects on patient quality of life, including in amelioration of pain and improvements in work productivity. In addition, onabotulinumtoxinA treatment also reduced the complications of CD, as patients no longer develop contractures (permanent muscle and tendon shortening from prolonged untreated dystonia), which markedly limited the range of neck motion. The onset of onabotulinumtoxinA treatment also accompanied advances in understanding the functional anatomy of neck muscles, basal ganglia physiology, and video and other recording technology. Following the success of onabotulinumtoxinA in the treatment of CD, its use has been expanded into numerous other therapeutic indications, and these advances stimulated educational and training programs by various neurologic and other medical societies.

Treatment of glabellar lines with Botox (onabotulinumtoxinA): Development, insights, and impact.

OnabotulinumtoxinA is an injectable medication that produces muscle relaxation through local chemical denervation at the neuromuscular junction. Discovery of onabotulinumtoxinA's aesthetic benefits occurred serendipitously in the 1980s at the intersection of several medical disciplines, including ophthalmology, neurology, otolaryngology, and dermatology. Patients receiving onabotulinumtoxinA for blepharospasm, hemifacial spasm, and dystonia noticed their periorbital wrinkles disappearing, particularly frown lines between the eyebrows called glabellar lines (GL). Aesthetic use of onabotulinumtoxinA necessitated rigorous training programs and vigilant monitoring by Allergan. Approval for the GL indication was based on 2 similarly designed, double-blind, randomized, multicenter clinical studies. Subjects with moderate to severe GL receiving onabotulinumtoxinA achieved significantly greater improvement in GL severity than those receiving placebo. In subsequent studies, more than 80% of subjects were satisfied with onabotulinumtoxinA treatment through day 60, and many reported looking approximately 4 years younger at weeks 4 and 12 than at baseline. OnabotulinumtoxinA has a rapid onset of action, and peak effect occurs between 30 and 60 days. The median duration of response for dynamic GL in the initial studies was 120 days and response progressively improved with subsequent treatments. OnabotulinumtoxinA was well tolerated, and the 2 most common adverse events, headache and blepharoptosis, tended to decrease in frequency with repeat treatment. The novel use of onabotulinumtoxinA for treating GL was an important step in addressing the clinical need for a noninvasive, straightforward, office-based procedure for facial lines that also left patients extremely satisfied with its treatment effects and represented the beginning of its widespread use for numerous aesthetic indications.

Treatment of crow's feet lines and forehead lines with Botox (onabotulinumtoxinA): Development, insights, and impact.

Extrinsic and age-related intrinsic factors contribute to the development of facial lines, including lateral canthal lines (called crow's feet lines [CFL]) and horizontal forehead lines (FHL). OnabotulinumtoxinA is a highly effective treatment for facial lines that inhibits acetylcholine release at the neuromuscular junction. This temporary chemical denervation leads to localized muscle relaxation and subsequent wrinkle reduction. Early studies of onabotulinumtoxinA treatment for facial neuronal disorders such as dystonia documented improvements in FHL and CFL. After the neurotoxin was approved for treating frown lines (glabellar lines [GL]), individuals requested treatment for other rhytids, and physicians continued assessing use in new areas. Once onabotulinumtoxinA was in clinical trial development, its efficacy and safety for CFL and FHL were successively evaluated as required by the US Food and Drug Administration and by key global health authorities, including those in the European Union, Japan, and China. Allergan, collaborating with leading physicians, established clinical programs that included novel safety and efficacy measures to meet regulatory requirements. Global, phase 3, randomized, controlled studies of CFL and FHL met rigorous primary endpoints. Some countries mandated clinical trial data beyond US and European regulations, and Allergan conducted 11 studies in total, fulfilling diverse regulatory and study population data requirements. Adverse events associated with local spread, including brow and eyelid ptosis, diplopia, headache, and eyelid sensory disorder, were infrequent and well tolerated. Consequently, onabotulinumtoxinA treatment of upper facial lines is now established globally as a highly effective, minimally invasive treatment for patients to achieve a natural appearance and look younger.