Prevalence of and Annual Conversion Rates to Mild Cognitive Impairment and Dementia: Prospective, Longitudinal Study of an Essential Tremor Cohort.

OBJECTIVE: Despite recent attention to cognitive impairment in essential tremor, few studies examine rates of conversion to diagnoses of mild cognitive impairment and dementia. Development of dementia in essential tremor is associated with loss of functional ability and a doubling of mortality rate. This prospective, longitudinal study comprehensively reports the prevalence and incidence of, and the annual rates of conversion to, mild cognitive impairment and dementia in an essential tremor cohort. METHODS: Patients underwent detailed cognitive assessments and were assigned diagnoses of normal cognition, mild cognitive impairment, or dementia. There were 222 patients at baseline (mean age = 79.3 ± 9.7 years), and 177 patients participated in follow-up evaluations at 18, 36, 54, and 72 months (mean years of observation = 5.1 ± 1.7). Data were compared to those of historical controls and Parkinson disease patients. RESULTS: The cumulative prevalence of dementia and average annual conversion rate of mild cognitive impairment to dementia were 18.5% and 12.2%, nearly three times higher than rates in the general population, and approximately one half the magnitude of those reported for Parkinson disease patients. The cumulative prevalence of mild cognitive impairment (26.6%) was almost double that of the general population, but less than that in Parkinson disease populations. INTERPRETATION: We present the most complete exposition of the longitudinal trajectory of cognitive impairment in an essential tremor cohort yet presented. The prevalence of and conversion rates to dementia in essential tremor fall between those associated with the natural course of aging and the more pronounced rates observed in Parkinson disease. ANN NEUROL 2024;95:1193-1204.

Classification of Parkinson's disease and essential tremor based on balance and gait characteristics from wearable motion sensors via machine learning techniques: a data-driven approach.

BACKGROUND: Parkinson's disease (PD) and essential tremor (ET) are movement disorders that can have similar clinical characteristics including tremor and gait difficulty. These disorders can be misdiagnosed leading to delay in appropriate treatment. The aim of the study was to determine whether balance and gait variables obtained with wearable inertial motion sensors can be utilized to differentiate between PD and ET using machine learning. Additionally, we compared classification performances of several machine learning models. METHODS: This retrospective study included balance and gait variables collected during the instrumented stand and walk test from people with PD (n = 524) and with ET (n = 43). Performance of several machine learning techniques including neural networks, support vector machine, k-nearest neighbor, decision tree, random forest, and gradient boosting, were compared with a dummy model or logistic regression using F1-scores. RESULTS: Machine learning models classified PD and ET based on balance and gait characteristics better than the dummy model (F1-score = 0.48) or logistic regression (F1-score = 0.53). The highest F1-score was 0.61 of neural network, followed by 0.59 of gradient boosting, 0.56 of random forest, 0.55 of support vector machine, 0.53 of decision tree, and 0.49 of k-nearest neighbor. CONCLUSIONS: This study demonstrated the utility of machine learning models to classify different movement disorders based on balance and gait characteristics collected from wearable sensors. Future studies using a well-balanced data set are needed to confirm the potential clinical utility of machine learning models to discern between PD and ET.

Deep brain stimulation of the centromedian thalamic nucleus for essential tremor: a case report.

The centromedian nucleus (CM) of the thalamus is an important site with anatomical connections to different cortical and subcortical motor areas; however, its role in tremor disorders is not clear, although deep brain stimulation (DBS) of the CM has been described to be effective in the treatment of parkinsonian tremor. We report a case of a patient with medication-refractory essential tremor (ET) who had excellent tremor suppression with DBS of the CM. The CM and the nearby region should be explored as a potential target for the treatment of ET and other forms of tremor.

Pimavanserin for psychosis in Parkinson's disease dementia: Subgroup analysis of the HARMONY Trial.

INTRODUCTION: Pimavanserin is FDA-approved to treat Parkinson's disease (PD) psychosis. We analyzed the effect of pimavanserin on psychosis in the PD dementia (PDD) subgroup from the phase 3 HARMONY trial. METHODS: This subgroup analysis included PDD patients enrolled in an international, multicenter, randomized discontinuation study of pimavanserin for dementia-related psychosis. PDD patients with moderate-to-severe psychosis, age 50-90 years, received pimavanserin 34 mg/day for 12 weeks (open-label period). Those with a sustained psychosis response to pimavanserin at weeks 8 and 12 were randomized during the double-blind period to continue pimavanserin or receive placebo. Primary efficacy endpoint was time to psychosis relapse as measured by the SAPS-H + D and CGI-I. Safety was assessed, as were effects on motor symptoms and cognitive abilities using the ESRS-A and MMSE. RESULTS: 392 patients were enrolled in HARMONY (mean age: 72.6 years; 38.8 % female): 59 had PDD; 49/59 remained on pimavanserin during the open-label period (safety analysis set), and 36/49 were randomized to pimavanserin (n = 16) or placebo (n = 20) in the double-blind phase (intent-to-treat analysis set). Risk of psychosis relapse was lower with pimavanserin 34 mg compared with placebo in the double-blind phase (HR = 0.052; 95 % CI 0.016-0.166; 1-sided nominal p < 0.001). During the open-label period, 46.9 % experienced a treatment-emergent adverse event; event incidence was similar across arms in the double-blind period. Pimavanserin did not adversely affect motor or cognitive function in either treatment phase. CONCLUSIONS: Pimavanserin significantly reduced risk of psychosis relapse in patients with PDD, was well tolerated, and did not worsen motor or cognitive function.

WHIGET and TETRAS Ratings of Action Tremor in Patients with Essential Tremor: Substantial Association and Agreement.

Background: Evaluating tremor severity is a critical component of diagnosing and clinically managing patients with essential tremor (ET). We examined the comparability of tremor severity ratings derived from two frequently used tremor rating scales: the Washington Heights-Inwood Genetic Study of Essential Tremor (WHIGET) rating scale and the Tremor Research Group Essential Tremor Rating Scale (TETRAS). Methods: A trained assistant administered and videotaped a neurological examination, including eight items assessing upper limb action tremor (arms outstretched, arms in the wingbeat position, finger-nose-finger maneuver, and drawing of Archimedes spirals). An experienced movement disorders neurologist reviewed the videos and assigned WHIGET and TETRAS ratings. We calculated associations between TETRAS and WHIGET ratings using Spearman rank order correlations. Subsequently, we collapsed these ratings into four tremor severity categories (absent, mild, moderate, severe) and then two broader tremor severity categories (absent/mild, moderate/severe). We calculated weighted Kappa coefficients to assess agreement between category assignments based on the TETRAS and the WHIGET. Results: Spearman's r' s were significant for all items (p's ≤ 0.001, mean r = 0.89). Weighted Kappa's revealed substantial to near perfect agreement for all eight items (mean k = 0.86, range = 0.64 to 1.00). Conclusion: Analyses revealed substantial strength of association and substantial to near perfect agreement between items rated with the WHIGET and TETRAS scales. These data indicated that ratings provided by each scale are highly comparable.

Longitudinal prognosis of Parkinson's outcomes using causal connectivity.

Despite the prevalence of Parkinson's disease (PD), there are no clinically-accepted neuroimaging biomarkers to predict the trajectory of motor or cognitive decline or differentiate Parkinson's disease from atypical progressive parkinsonian diseases. Since abnormal connectivity in the motor circuit and basal ganglia have been previously shown as early markers of neurodegeneration, we hypothesize that patterns of interregional connectivity could be useful to form patient-specific predictive models of disease state and of PD progression. We use fMRI data from subjects with Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), idiopathic PD, and healthy controls to construct predictive models for motor and cognitive decline and differentiate between the four subgroups. Further, we identify the specific connections most informative for progression and diagnosis. When predicting the one-year progression in the MDS-UPDRS-III1* and Montreal Cognitive assessment (MoCA), we achieve new state-of-the-art mean absolute error performance. Additionally, the balanced accuracy we achieve in the diagnosis of PD, MSA, PSP, versus healthy controls surpasses that attained in most clinics, underscoring the relevance of the brain connectivity features. Our models reveal the connectivity between deep nuclei, motor regions, and the thalamus as the most important for prediction. Collectively these results demonstrate the potential of fMRI connectivity as a prognostic biomarker for PD and increase our understanding of this disease.

Deep Brain Stimulation for the Treatment of Hemichorea: Case Series and Literature Review.

Background: Hemichorea (HC) and its severe form hemiballismus (HB) are rare movement disorders which can be medically refractory to treatments and may need surgical intervention. Case Report: We report 3 patients with HC-HB who had meaningful clinical improvement with unilateral deep brain stimulation (DBS) of the globus pallidus interna (GPi). We identified 8 prior cases of HC-HB treated with GPi-DBS, and a majority of these patients experienced significant improvement in their symptoms. Discussion: GPi-DBS can be considered in medically refractory HC-HB in carefully selected patients. However, data is limited to small case series and further studies are needed.

Cognitive task-related oscillations in human internal globus pallidus and subthalamic nucleus.

Recently it has been acknowledged that the basal ganglia nuclei play a major role in cognitive control; however, the contribution by their network remains unclear. Previous studies have demonstrated the role of the subthalamic nucleus (STN) in cognitive processing and suggested that its connections to cortical and other associated regions regulate response inhibition during conflict conditions. By contrast, the role of the internal globus pallidus (GPi) as the output nucleus before the thalamic relay has not yet been investigated during cognitive processing. We recorded local field potentials (LFPs) from externalized deep brain stimulation (DBS) electrodes implanted bilaterally in the GPi (n = 9 participants with dystonia) and STN (n = 8 participants with Parkinson's disease (PD)) during a primed flanker task. Both dystonia (GPi group) and PD participants (STN group) responded faster to the congruent trials than the incongruent trials. Overall, the dystonic GPi group was significantly faster than the PD STN group. LFPs showed elevated cue-triggered theta (3-7 Hz) power in GPi and STN groups in a similar way. Response-triggered LFP beta power (13-25 Hz) was significantly increased in the GPi group compared to the STN group. Results demonstrate that GPi activity appears to be critical in the cognitive processing of action selection and response during the presence of conflict tasks similar to the STN group.

Telemedicine and Deep brain stimulation - Current practices and recommendations.

The use of telemedicine in the management of chronic neurological conditions including movement disorders has expanded over time. In addition to enabling remote access to specialized care, telemedicine has also been shown to reduce caregiver burden and to improve patient satisfaction. With the COVID-19 pandemic, implementation of telehealth for patients with movement disorders, particularly those with more severe mobility issues, has increased rapidly. Although telemedicine care has been shown to be effective for patients with various movement disorders, its utilization for patients with device aided therapies such as deep brain stimulation (DBS) is limited due to challenges related to adjusting these devices remotely and to the lack of consensus recommendations for using telemedicine in this patient population. Thus, guidelines for telemedicine and DBS will assist clinicians on the appropriate implementation of telemedicine to provide care to DBS patients. Optimizing the use of telemedicine for DBS will expand this type of therapy to remote locations with limited access to programming expertise, and also reduce the need for patient travel. Telemedicine is particularly important during the ongoing pandemic due to infection risk and limited access to clinic visits. In this article we review the currently available and emerging strategies for telemedicine and remote care for DBS. We then outline common principles and recommendations for telemedicine care in patients with DBS, review patient selection and best practices. Finally, we briefly discuss the current state of reimbursement for DBS telemedicine visits.

Surgical Treatment of Parkinson's Disease: Devices and Lesion Approaches.

Surgical treatments have transformed the management of Parkinson's disease (PD). Therapeutic options available for the management of PD motor complications include deep brain stimulation (DBS), ablative or lesioning procedures (pallidotomy, thalamotomy, subthalamotomy), and dopaminergic medication infusion devices. The decision to pursue these advanced treatment options is typically done by a multidisciplinary team by considering factors such as the patient's clinical characteristics, efficacy, ease of use, and risks of therapy with a goal to improve PD symptoms and quality of life. DBS has become the most widely used surgical therapy, although there is a re-emergence of interest in ablative procedures with the introduction of MR-guided focused ultrasound. In this article, we review DBS and lesioning procedures for PD, including indications, selection process, and management strategies.

The Pseudodystonia of Paroxysmal Sympathetic Hyperactivity: A Reversible Post-Anoxic Complication.

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Copulatory Dyskinesia: Pathognomonic Manifestation of Tardive Dyskinesia.

Background: Copulatory or pelvic thrusting dyskinesia is a subtype of tardive dyskinesia (TD) which is caused by exposure to dopamine blocking agents. Phenomenology shown: A man exhibiting rhythmic, stereotypical pelvic thrusting movements. Educational value: Recognition of copulatory dyskinesia as a distinctive iatrogenic disorder helps prevent unnecessary investigations and guides the implementation of corrective strategies.

Does post-operative symptomatic lead edema associated with subthalamic DBS implantation impact long-term clinical outcomes?

INTRODUCTION: Post-operative, non-hemorrhagic, non-infectious symptomatic delayed edema around the DBS lead is an uncommon complication of DBS surgery. We investigated whether this complication impacts clinical outcomes or has long-term sequelae. METHODS: All Parkinson's disease (PD) patients with subthalamic nucleus (STN) DBS implantation who developed delayed symptomatic lead edema were identified. UPDRS part III motor, Parkinson's Disease Questionnaire (PDQ-39) total and MoCA scores were analyzed to assess motor outcome, quality of life and cognitive status at 1 year. RESULTS: A total of 260 patients underwent 482 STN lead placements. Of these, 16 patients (20 leads, 4.1% of total 482 leads) developed this delayed complication. None of the patients had edema on immediate post-operative scan. Patients presented with varied symptoms including speech difficulty (n = 8), mild confusion (n = 6), headaches (n = 4), gait difficulty (n = 4) and seizures (n = 3). The mean duration for the diagnosis was 5.8 days after lead implantation and the mean duration for which follow-up CT scans reported complete/near complete resolution or improvement of edema was 4.7 weeks (range 2-10 weeks). At 1-year post-DBS, UPDRS motor scores improved significantly (42.5%, p < .001); quality of life improved, but the change was not statistically significant (21.3%, p = .197). There was no decline in cognitive function at 1 year (26.6 vs 26.4, p = .567). No long-term complication related to lead edema occurred in these patients. CONCLUSION: Symptomatic lead edema after DBS surgery is an uncommon complication which typically resolves over time. In our series, there were no long-term sequelae of this complication and clinical outcomes were comparable to that reported in the literature.

Clinical outcomes of globus pallidus deep brain stimulation for Parkinson disease: a comparison of intraoperative MRI- and MER-guided lead placement.

OBJECTIVE: Deep brain stimulation (DBS) lead placement is increasingly performed with the patient under general anesthesia by surgeons using intraoperative MRI (iMRI) guidance without microelectrode recording (MER) or macrostimulation. The authors assessed the accuracy of lead placement, safety, and motor outcomes in patients with Parkinson disease (PD) undergoing DBS lead placement into the globus pallidus internus (GPi) using iMRI or MER guidance. METHODS: The authors identified all patients with PD who underwent either MER- or iMRI-guided GPi-DBS lead placement at Emory University between July 2007 and August 2016. Lead placement accuracy and adverse events were determined for all patients. Clinical outcomes were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part III motor scores for patients completing 12 months of follow-up. The authors also assessed the levodopa-equivalent daily dose (LEDD) and stimulation parameters. RESULTS: Seventy-seven patients were identified (MER, n = 28; iMRI, n = 49), in whom 131 leads were placed. The stereotactic accuracy of the surgical procedure with respect to the planned lead location was 1.94 ± 0.21 mm (mean ± SEM) (95% CI 1.54-2.34) with frame-based MER and 0.84 ± 0.007 mm (95% CI 0.69-0.98) with iMRI. The rate of serious complications was similar, at 6.9% for MER-guided DBS lead placement and 9.4% for iMRI-guided DBS lead placement (RR 0.71 [95% CI 0.13%-3.9%]; p = 0.695). Fifty-seven patients were included in clinical outcome analyses (MER, n = 16; iMRI, n = 41). Both groups had similar characteristics at baseline, although patients undergoing MER-guided DBS had a lower response on their baseline levodopa challenge (44.8% ± 5.4% [95% CI 33.2%-56.4%] vs 61.6% ± 2.1% [95% CI 57.4%-65.8%]; t = 3.558, p = 0.001). Greater improvement was seen following iMRI-guided lead placement (43.2% ± 3.5% [95% CI 36.2%-50.3%]) versus MER-guided lead placement (25.5% ± 6.7% [95% CI 11.1%-39.8%]; F = 5.835, p = 0.019). When UPDRS III motor scores were assessed only in the contralateral hemibody (per-lead analyses), the improvements remained significantly different (37.1% ± 7.2% [95% CI 22.2%-51.9%] and 50.0% ± 3.5% [95% CI 43.1%-56.9%] for MER- and iMRI-guided DBS lead placement, respectively). Both groups exhibited similar reductions in LEDDs (21.2% and 20.9%, respectively; F = 0.221, p = 0.640). The locations of all active contacts and the 2D radial distance from these to consensus coordinates for GPi-DBS lead placement (x, ±20; y, +2; and z, -4) did not differ statistically by type of surgery. CONCLUSIONS: iMRI-guided GPi-DBS lead placement in PD patients was associated with significant improvement in clinical outcomes, comparable to those observed following MER-guided DBS lead placement. Furthermore, iMRI-guided DBS implantation produced a similar safety profile to that of the MER-guided procedure. As such, iMRI guidance is an alternative to MER guidance for patients undergoing GPi-DBS implantation for PD.

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease patients over 75 years of age.

INTRODUCTION: Deep brain stimulation (DBS) is an effective therapy for Parkinson's disease (PD). However, its effect in older patients is not extensively studied, as they are often excluded from DBS surgery due to concerns of complications or reduced benefit. We assessed clinical outcomes after subthalamic nucleus (STN) DBS in older patients (age > 75 years) with PD. METHODS: All PD patients above 75 years who underwent STN-DBS between 1999 and 2015 were included. Unified Parkinson's Disease Rating Scale (UPDRS) scores and Parkinson's Disease Questionnaire (PDQ-39) scores were assessed up to 4 years after surgery. Other measures included were complications/adverse events, levodopa equivalent dose, and cognitive function. RESULTS: A total of 30 patients underwent 52 lead placements. Mean age at surgery was 77.5 years (range 75.0-84.5 years). Post-DBS, motor scores improved by 30.8% after 1-year and 27.3% after a mean of 2.5 years (p < .001). All motor sub-scores improved, however axial signs did not change over time. OFF time and dyskinesia duration reduced significantly (p < .001), whereas quality of life, activities of daily living and cognitive function did not significantly change. The following adverse events were noted: transient post-operative confusion (36% of patients), gait difficulty (13.3% of patients), hemorrhage (3.8% of leads), personality changes (3.3% of patients), lead revision (1.9% of leads), seizure (1.9% of leads), and infection (1.9% of leads). CONCLUSIONS: STN-DBS improves motor outcomes in patients over 75 years of age; however, there was no change in quality of life. Although post-surgical transient confusion was common, there were no serious adverse events and the incidence of other complications was typical for DBS surgery.

Clinical outcomes of pallidal deep brain stimulation for dystonia implanted using intraoperative MRI.

OBJECTIVE: Lead placement for deep brain stimulation (DBS) using intraoperative MRI (iMRI) relies solely on real-time intraoperative neuroimaging to guide electrode placement, without microelectrode recording (MER) or electrical stimulation. There is limited information, however, on outcomes after iMRI-guided DBS for dystonia. The authors evaluated clinical outcomes and targeting accuracy in patients with dystonia who underwent lead placement using an iMRI targeting platform. METHODS: Patients with dystonia undergoing iMRI-guided lead placement in the globus pallidus pars internus (GPi) were identified. Patients with a prior ablative or MER-guided procedure were excluded from clinical outcomes analysis. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores and Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores were assessed preoperatively and at 6 and 12 months postoperatively. Other measures analyzed include lead accuracy, complications/adverse events, and stimulation parameters. RESULTS: A total of 60 leads were implanted in 30 patients. Stereotactic lead accuracy in the axial plane was 0.93 ± 0.12 mm from the intended target. Nineteen patients (idiopathic focal, n = 7; idiopathic segmental, n = 5; DYT1, n = 1; tardive, n = 2; other secondary, n = 4) were included in clinical outcomes analysis. The mean improvement in BFMDRS score was 51.9% ± 9.7% at 6 months and 63.4% ± 8.0% at 1 year. TWSTRS scores in patients with predominant cervical dystonia (n = 13) improved by 53.3% ± 10.5% at 6 months and 67.6% ± 9.0% at 1 year. Serious complications occurred in 6 patients (20%), involving 8 of 60 implanted leads (13.3%). The rate of serious complications across all patients undergoing iMRI-guided DBS at the authors' institution was further reviewed, including an additional 53 patients undergoing GPi-DBS for Parkinson disease. In this expanded cohort, serious complications occurred in 11 patients (13.3%) involving 15 leads (10.1%). CONCLUSIONS: Intraoperative MRI-guided lead placement in patients with dystonia showed improvement in clinical outcomes comparable to previously reported results using awake MER-guided lead placement. The accuracy of lead placement was high, and the procedure was well tolerated in the majority of patients. However, a number of patients experienced serious adverse events that were attributable to the introduction of a novel technique into a busy neurosurgical practice, and which led to the revision of protocols, product inserts, and on-site training.

Amantadine extended-release capsules for levodopa-induced dyskinesia in patients with Parkinson's disease.

Levodopa-induced dyskinesia (LID) is a common motor complication in patients with Parkinson's disease on chronic levodopa therapy. The management of LID is important as dyskinesia can be disabling and impair quality of life. Currently, there are limited treatment options for the medical management of LID. Amantadine extended-release capsules (Gocovri™) is the first medication that received US Food and Drug Administration approval for the treatment of LID. The following is a review of the pharmacodynamics, efficacy and safety profile, and current state of treatment of amantadine for LID.

Deep Brain Stimulation and Sleep-Wake Disturbances in Parkinson Disease: A Review.

Sleep-wake disturbances are common non-motor manifestations in Parkinson Disease (PD). Complex pathophysiological changes secondary to neurodegeneration in combination with motor symptoms and dopaminergic medications contribute to development of sleep-wake disturbances. The management of sleep complaints in PD is important as this symptom can affect daily activities and impair quality of life. Deep brain stimulation (DBS) is an effective adjunctive therapy for management of motor symptoms in PD. However, its effect on non-motor symptoms including sleep-wake disturbances is not widely understood. In this article, we reviewed studies assessing the effect of DBS at various therapeutic targets on sleep-wake disturbances. Of the studies examining the role of DBS in sleep-wake disturbances, the effect of subthalamic nucleus stimulation is most widely studied and has shown improvement in sleep quality, sleep efficiency, and sleep duration. Although, studies investigating changes in sleep with stimulation of thalamus, globus pallidus interna, and pedunculopontine nucleus are limited, they support the potential for modulation of sleep-wake centers with DBS at these sites. The mechanism by which DBS at different anatomical targets affects sleep-wake disturbances in PD is unclear and may involves multiple factors, including improved motor symptoms, medication adjustment, and direct modulation of sleep-wake centers.

Psychodynamic Psychotherapy for Functional (Psychogenic) Movement Disorders.

OBJECTIVE: As the literature for the treatment of functional (psychogenic) movement disorders (FMD) is sparse, we assessed clinical outcomes in patients with FMD who underwent treatment with psychodynamic psychotherapy (PDP). METHODS: A retrospective analysis of the data of patients with FMD who were referred for PDP from 2008-2014 at Emory University Medical Center was performed. RESULTS: Thirty patients were included, mean age at presentation was 50 years (SD 13.9) and majority were female (27/30). Most common movement disorder was involuntary shaking/jerky movements (50%) and tremor (43%). Mean duration of symptoms was 3.2 years and mean number of PDP visits was 4.9. PDP lead to good outcomes in 10, modest in 8, and poor in 9. Three patients lost to follow up. Mean duration of symptoms between two groups (good vs. poor) was not statistically significant (p = 0.11), mean number of PDP visits showed a trend towards significance (p = 0.053). In all cases of good outcomes precipitants of the movement disorder were identified and a majority (60%) was receptive of the diagnosis and had good insight. CONCLUSION: PDP lead to improvement in 60% of the patients which is encouraging as the treatment is challenging. This study supports heterogeneous causes of FMD including varied roles of past/recent events and demonstrates importance of psychological approaches such as PDP. Treatment with PDP should be considered in some patients with FMD but predicting who will respond remains a challenge. Further long term prospective studies with large sample size and placebo control are needed.