Protocol for combined N-of-1 trials to assess cerebellar neurostimulation for movement disorders in children and young adults with dyskinetic cerebral palsy.

BACKGROUND: Movement and tone disorders in children and young adults with cerebral palsy are a great source of disability. Deep brain stimulation (DBS) of basal ganglia targets has a major role in the treatment of isolated dystonias, but its efficacy in dyskinetic cerebral palsy (DCP) is lower, due to structural basal ganglia and thalamic damage and lack of improvement of comorbid choreoathetosis and spasticity. The cerebellum is an attractive target for DBS in DCP since it is frequently spared from hypoxic ischemic damage, it has a significant role in dystonia network models, and small studies have shown promise of dentate stimulation in improving CP-related movement and tone disorders. METHODS: Ten children and young adults with DCP and disabling movement disorders with or without spasticity will undergo bilateral DBS in the dorsal dentate nucleus, with the most distal contact ending in the superior cerebellar peduncle. We will implant Medtronic Percept, a bidirectional neurostimulator that can sense and store brain activity and deliver DBS therapy. The efficacy of cerebellar DBS in improving quality of life and motor outcomes will be tested by a series of N-of-1 clinical trials. Each N-of-1 trial will consist of three blocks, each consisting of one month of effective stimulation and one month of sham stimulation in a random order with weekly motor and quality of life scales as primary and secondary outcomes. In addition, we will characterize abnormal patterns of cerebellar oscillatory activity measured by local field potentials from the intracranial electrodes related to clinical assessments and wearable monitors. Pre- and 12-month postoperative volumetric structural and functional MRI and diffusion tensor imaging will be used to identify candidate imaging markers of baseline disease severity and response to DBS. DISCUSSION: Our goal is to test a cerebellar neuromodulation therapy that produces meaningful changes in function and well-being for people with CP, obtain a mechanistic understanding of the underlying brain network disorder, and identify physiological and imaging-based predictors of outcomes useful in planning further studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT06122675, first registered November 7, 2023.

Evaluating the Presence of a Stage IV Low-Grade Well-Differentiated Neuroendocrine Tumor of the Ileocecum: A Case Report with Evaluation of Staging Protocol of Neuroendocrine Tumors and Treatment Options Based on Current Available Evidence.

Neuroendocrine tumors (NET) are rare neoplasms that can originate throughout the human body. An initial treatment option includes upfront surgical resection of the primary tumor (pT) if the tumor can be localized. Current systemic therapy options following resection of the pT or with evidence of metastatic disease include somatostatin analogs, evorlimus, peptide receptor radionuclide therapy, cytotoxic chemotherapy, and interferon alpha among other less common therapy options. We present a case of a patient with a NET that originated in the ileocecal region. The patient underwent upfront surgical resection with a right hemicolectomy due to the location of the tumor. The pT was notable for extensive invasion into the visceral peritoneum and metastasis to nearby lymph nodes. However, despite being diagnosed as a stage IV NET, the Ki67 index was less than 1%, categorizing it as a low-grade well-differentiated tumor. Following resection of the tumor, there was no evidence of metastasis to the liver on the follow-up magnetic resonance imaging and recurrent somatostatin receptor overexpressing neoplasm on the Gallium-68 DOTATE PET/CT scan. Due to the juxtaposition of the low grade of the tumor and the high staging, several different treatment options were discussed with the main distinction being whether to base these options off of the stage or the grade of the tumor in the case. Low-grade well-differentiated NET have a good prognosis. On the other hand, stage IV NET and tumors that have metastasized to nearby lymph nodes and organs have an increased likelihood to reoccur and worse outcomes. Recommendations for NET based on current evidence have a lack of clarity in terms of when to undergo observation versus systemic therapy.

The whore gaze as the world burns: A conversation between PJ Starr, Monica Jones, The Incredible, Edible, Akynos and Bambi Katsura.

This illustrated conversation between The Incredible, Edible, Akynos, Monica Jones, PJ Starr and Bambi Katsura unpacks how we use media to continue our sex worker activism during the multiple pandemics of COVID-19, police violence and environmental disasters. We each bring our histories and theoretical innovations to the table including the framework of the 'Whore Gaze' developed by PJ, Monica's approach to documentary that ensures trans people narrate their own lives, Akynos' scripted film series Chronicles of a Black Heaux that may re-imagine the 'melomentary form' for sex worker representation and Bambi's experience as a filmmaker and curator. In our conversation, we discuss how we use film, photography, film festivals, animation and other forms for our activism to promote social justice. We also describe how we are systematically unlearning the codes of representation of research and human rights documentation, so that we can create materials that are accessible to our communities, to people with disabilities and be freed from the dead-end of respectability politics.

NeuroDAC: an open-source arbitrary biosignal waveform generator.

Objective.Researchers are developing biomedical devices with embedded closed-loop algorithms for providing advanced adaptive therapies. As these devices become more capable and algorithms become more complex, tasked with integrating and interpreting multi-channel, multi-modal electrophysiological signals, there is a need for flexible bench-top testing and prototyping. We present a methodology for leveraging off-the-shelf audio equipment to construct a biosignal waveform generator capable of streaming pre-recorded biosignals from a host computer. By re-playing known, well-characterized, but physiologically relevant real-world biosignals into a device under test, researchers can evaluate their systems without the need for expensivein vivoexperiments.Approach.An open-source design based on the proposed methodology is described and validated, the NeuroDAC. NeuroDAC allows for 8 independent channels of biosignal playback using a simple, custom designed attenuation and buffering circuit. Applications can communicate with the device over a USB interface using standard audio drivers. On-board analog amplitude adjustment is used to maximize the dynamic range for a given signal and can be independently tuned for each channel.Main results.Low noise component selection yields a no-signal noise floor of just 5.35 ± 0.063. NeuroDAC's frequency response is characterized with a high pass -3 dB rolloff at 0.57 Hz, and is capable of accurately reproducing a wide assortment of biosignals ranging from EMG, EEG, and ECG to extracellularly recorded neural activity. We also present an application example using the device to test embedded algorithms on a closed-loop neural modulation device, the Medtronic RC+S.Significance.By making the design of NeuroDAC open-source we aim to present an accessible tool for rapidly prototyping new biomedical devices and algorithms than can be easily modified based on individual testing needs.ClinicalTrials.gov Identifiers: NCT04281134, NCT03437928, NCT03582891.

Subthalamic nucleus deep brain stimulation in primary cervical dystonia.

OBJECTIVES: The globus pallidus internus (GPi) has been the primary target for deep brain stimulation (DBS) to treat severe medication-refractory dystonia. Some patients with primary cervical or segmental dystonia develop subtle bradykinesia occurring in previously nondystonic body regions during GPi DBS. Subthalamic nucleus (STN) DBS may provide an alternative target choice for treating dystonia, but has only been described in a few short reports, without blinded rating scales, statistical analysis, or detailed neuropsychological studies. METHODS: In this prospective pilot study, we analyzed the effect of bilateral STN DBS on safety, efficacy, quality of life, and neuropsychological functioning in 9 patients with medically refractory primary cervical dystonia. Severity of dystonia was scored by a blinded rater (unaware of the patient's preoperative or postoperative status) using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) preoperatively and 3, 6, and 12 months postsurgery. Lead location, medications, and adverse events were also measured. RESULTS: STN DBS was well-tolerated with no serious adverse effects. The TWSTRS total score improved (p < 0.001) from a mean (±SEM) of 53.1 (±2.57), to 19.6 (±5.48) at 12 months. Quality of life measures were also improved. STN DBS induced no consistent neuropsychological deficits. Several patients reported depression in the study and 3 had marked weight gain. No patients developed bradykinetic side effects from stimulation, but all patients developed transient dyskinetic movements during stimulation. CONCLUSIONS: This prospective study showed that bilateral STN DBS resulted in improvement in dystonia and suggests that STN DBS may be an alternative to GPi DBS for treating primary cervical dystonia. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that bilateral subthalamic nucleus deep brain stimulation results in significant improvement in cervical dystonia without bradykinetic side effects.

Physiological identification of the human pedunculopontine nucleus.

BACKGROUND: The pedunculopontine nucleus (PPN) is a brainstem structure with widespread connections to the basal ganglia. Despite the recent introduction of PPN deep brain stimulation (DBS) for the treatment of gait disorders, little is known about its physiology in humans. METHODS: Single unit discharge characteristics of neurons in the PPN region were analysed in four patients and PPN local field potentials (LFP) in one patient, recorded during the course of DBS implantation. Two patients had Parkinson disease, and two had non-sinemet responsive parkinsonism. Cell locations were plotted in the coordinate system of a human brainstem atlas. RESULTS: Fifty-six units in the PPN region were studied, of which 32 mapped to within PPN boundaries. The mean (SD) discharge rate of neurons in the PPN was 23.2 (15.6) Hz. Spontaneous neuronal firing rate and burst discharge rate were significantly different between neurons in the region dorsal to PPN and those in the PPN. Responses to passive movement of contralateral and ipsilateral limbs were found. Theta and beta band oscillations were present in the PPN LFP. CONCLUSION: PPN discharge characteristics may prove useful in the electrophysiological identification of PPN during DBS implantation surgery.

Safety and tolerability of putaminal AADC gene therapy for Parkinson disease.

BACKGROUND: In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial. METHODS: Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [(18)F]fluoro-L-m-tyrosine (FMT) were performed as a measure of gene expression. RESULTS: The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased "on" time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort. CONCLUSION: This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson's Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.

Results from a phase I safety trial of hAADC gene therapy for Parkinson disease.

BACKGROUND: In a primate model of Parkinson disease (PD), intrastriatal infusion of an adeno-associated viral (AAV) vector containing the human aromatic l-amino acid decarboxylase (hAADC) gene results in robust gene expression. After gene transfer, low doses of systemically administered l-dopa are converted to dopamine in the transduced striatal neurons, resulting in behavioral improvement without the side effects typically associated with higher doses of l-dopa. These studies led to the initiation of a phase I safety trial. Here we report the findings for the first cohort of five patients. METHODS: Patients with moderate to advanced PD received bilateral infusion of a low dose of the AAV-hAADC vector into the putamen. PET scans using the AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT), were performed at baseline and at 1 and 6 months after infusion as an in vivo measure of gene expression. RESULTS: PET results showed an average 30% increase in FMT uptake (K(i)(c)) in the putamen after gene transfer. Preliminary analysis of clinical data indicates a modest improvement, but absence of a control and the nonblinded analyses make interpretation difficult. CONCLUSIONS: Thus far, this gene therapy approach has been well tolerated and shows PET evidence of sustained gene expression. These initial findings demonstrate the safety of the therapy; higher doses of adeno-associated viral vector containing the human aromatic l-amino acid decarboxylase gene in the next cohort of patients may further increase dopamine production in the putamen and provide more profound clinical benefit.

Electrophysiological localization of the substantia nigra in the parkinsonian nonhuman primate.

During ablative surgery and implantation of deep-brain stimulators for the treatment of movement disorders, electrophysiological techniques are often used for localization of subcortical targets. New restorative therapies for Parkinson disease, aimed at delivering drugs or cells to the substantia nigra (SN), are becoming available. Therefore, precise surgical approaches to the dopaminergic cell-containing region of the SN are required to avoid damage to nearby structures such as the corticospinal tract and subthalamic nucleus. In a study conducted in nonhuman primates, the authors evaluated the utility and accuracy of electrophysiological techniques in localizing the SN. Three adult rhesus monkeys were used as hosts for intranigral cell transplants. The monkeys were rendered hemiparkinsonian by intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. With the aid of stereotactic guidance, chronic recording chambers were placed on the skull of each monkey and directed at the SN. In each monkey, 20 to 40 trajectories were explored with a microelectrode. Spontaneous and movement-related single-unit activities were recorded in the SN, pars reticulata, subthalamic nucleus, globus pallidus, striatum, thalamus, and red nucleus. Motor and ocular responses to microstimulation in the subthalamic area were noted. Using the electrophysiological and stereotactic information that was obtained, three-dimensional maps of the nigral complex were constructed to infer the location of the SN pars compacta. The maps were subsequently used to guide intranigral placement of fetal dopaminergic cells. Accurate delivery was verified by histological analysis. Based on the characteristic electrophysiological properties of the SN and surrounding structures in the parkinsonian state, microelectrode recording techniques may be used to ensure accurate placement of cell transplantation in the intranigral region.

Deep brain stimulation for advanced Parkinson's disease.

Deep brain stimulation (DBS) is a new and promising technique for the treatment of movement disorders. Medically intractable Parkinson's disease (PD) is one of the most common indications for DBS. There are three possible subcortical targets for PD, depending on the symptomatology (i.e., the motor subdivision of the thalamus, the globus pallidus internus, the subthalamic nucleus [STN]). Thalamic stimulation has been well established as a safe and effective treatment for essential tremor and the tremor associated with PD. Globus pallidus internus and STN DBS are being investigated for the treatment of all the cardinal signs of PD. This article describes the pathophysiology of PD, the surgical treatment history of PD, surgical techniques used for DBS implants, and the role the perioperative nurse has in the care of the patients undergoing these procedures.

A high-resolution fast spin-echo inversion-recovery sequence for preoperative localization of the internal globus pallidus.

A fast spin-echo inversion-recovery (FSE-IR) sequence is described for its utility regarding surgical planning for patients with Parkinson's disease (PD) who are undergoing microelectrode-guided internal globus pallidus (GPi) ablation. Images from thirty-seven adult patients with PD were reviewed and visualization of the GPi, globus pallidus externa (GPe), and the intervening lamina was noted. High-resolution images were acquired from all patients despite the external hardware and the patients' movement disorder. In all cases, the conventional surgical trajectory, determined indirectly by a fixed measurement from the anteroposterior commissure line, was modified by the ability to visualize the GPi and optic tract directly. This sequence facilitated accurate stereotactic targeting.

Porcine xenografts in Parkinson's disease and Huntington's disease patients: preliminary results.

The observation that fetal neurons are able to survive and function when transplanted into the adult brain fostered the development of cellular therapy as a promising approach to achieve neuronal replacement for treatment of diseases of the adult central nervous system. This approach has been demonstrated to be efficacious in patients with Parkinson's disease after transplantation of human fetal neurons. The use of human fetal tissue is limited by ethical, infectious, regulatory, and practical concerns. Other mammalian fetal neural tissue could serve as an alternative cell source. Pigs are a reasonable source of fetal neuronal tissue because of their brain size, large litters, and the extensive experience in rearing them in captivity under controlled conditions. In Phase I studies porcine fetal neural cells grafted unilaterally into Parkinson's disease (PD) and Huntington's disease (HD) patients are being evaluated for safety and efficacy. Clinical improvement of 19% has been observed in the Unified Parkinson's Disease Rating Scale "off" state scores in 10 PD patients assessed 12 months after unilateral striatal transplantation of 12 million fetal porcine ventral mesencephalic (VM) cells. Several patients have improved more than 30%. In a single autopsied PD patient some porcine fetal VM cells were observed to survive 7 months after transplantation. Twelve HD patients have shown a favorable safety profile and no change in total functional capacity score 1 year after unilateral striatal placement of up to 24 million fetal porcine striatal cells. Xenotransplantation of fetal porcine neurons is a promising approach to delivery of healthy neurons to the CNS. The major challenges to the successful use of xenogeneic fetal neuronal cells in neurodegenerative diseases appear to be minimizing immune-mediated rejection, management of the risk of xenotic (cross-species) infections, and the accurate assessment of clinical outcome of diseases that are slowly progressive.

Health care reform and the new economy.

The objectives and assumptions of health care reform have changed repeatedly during the past century and may now be entering a new historical phase as a result of the "new economy" rooted in information technology. In a high-growth context, proponents of reform may no longer feel obliged to bundle expanded coverage with tighter cost containment. At the same time, the new digital environment may facilitate innovations intended to inform and expand consumer choice and to improve quality. The new environment elevates "transparency" to a guiding principle. Health informatics has long been peripheral to reform and must now become more central.

Peer review of teaching: instituting a program in a college of nursing.

Institutions of higher education can lose sight of the importance of teaching. Teaching, in some settings, needs to be restored to its place of primacy in the faculty role and its quality needs to be evaluated. The American Association for Higher Education (AAHE) national project, "From Idea to Prototype: The Peer Review of Teaching," is an attempt to accomplish that purpose. Involvement in the AAHE national peer review project has been the impetus for the Kent State University College of Nursing to initiate a faculty-developed program of peer review. The program has been well received primarily because it was owned and controlled by the faculty. Its voluntary nature, administrative sanction, and strong support have contributed to its success. Faculty explored many possible methods to accomplish peer review. However, the use of a task force, classroom and clinical observations, and teaching circles have been the approaches best suited to this particular departmental culture.

Intranigral transplantation of fetal substantia nigra allograft in the hemiparkinsonian rhesus monkey.

Current clinical protocols for fetal cell transplantation for Parkinson's disease (PD) have focused on restoring dopamine in the striatum. However, there are now a number of human transplant recipients who have had robust innervation of the striatum by dopaminergic grafts (documented by positron emission tomography or by autopsy), but only a partial improvement in parkinsonian motor signs. Thus, there is a need for improved transplant strategies. In animal models of PD, there is recent evidence that restoring dopamine in the substantia nigra, instead of or in addition to the striatum, may be important to correct abnormal motor behavior. This pilot study examined the morphological features and behavioral effects of fetal dopaminergic neuronal allografts placed into the substantia nigra of three 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated hemiparkinsonian rhesus monkeys. We show that grafts can survive in host substantia nigra. Characteristics of the graft-host interface were variable. In one animal, reinnervation of host substantia nigra was observed, and this animal showed behavioral improvement in a reach-and-retrieval task.

Comparison of MPTP-induced changes in spontaneous neuronal discharge in the internal pallidal segment and in the substantia nigra pars reticulata in primates.

The basal ganglia are currently viewed as components of segregated corticosubcortical reentrant circuits. One of these circuits, the "motor" circuit, is critically involved in the development of parkinsonian motor signs. Current pathophysiologic models postulate that parkinsonism is associated with increased activity in the basal ganglia output nuclei. The neuronal activity in the motor portion of one of these output nuclei, the internal segment of the globus pallidus (GPi), has been characterized in detail in intact and parkinsonian animals, but the neuronal activity in the second major basal ganglia output nucleus, the substantia nigra pars reticulata (SNr), has received far less attention. This study in primates represents a comparison of the effects of parkinsonism, induced by injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on the neuronal discharge in the GPi and SNr. These electrophysiologic recording experiments were carried out in three African green and two rhesus monkeys. One hundred and twenty-four neurons were recorded in the GPi before treatment with MPTP, and 93 neurons thereafter. In the SNr, 55 cells were recorded before treatment with MPTP, and 41 cells thereafter. MPTP induced a non-significant increase in the average discharge rate and a significant decrease in the median interspike interval length (ISI) in the GPi (by 13%), whereas no changes were detected in either parameter in the SNr. The average ISI distributions were markedly asymmetric in both structures, and could be modeled by a logarithmic normal distribution. With the MPTP treatment, the mode of the ISI distribution fell by 24% in the GPi (P< or =0.01), whereas it did not change significantly in the SNr. An algorithm that detects burst discharges in the raw ISI data (based on the method by Legendy and Salcman) detected a significant increase in the proportion of action potentials that participated in bursts of discharge in both structures (increase by 257% in the GPi, and by 67% in the SNr). Power spectral and autocorrelation analysis revealed that treatment with MPTP increased the proportion of cells with oscillatory burst patterns at 3-8 Hz in both structures (from 0.8% to 27% of all neurons in the GPi, and from none to 10% in the SNr). The results show that neuronal discharge in the SNr is affected in parkinsonism, but that the changes in the SNr are less pronounced then those seen in the GPi.

Magnetic resonance imaging-based stereotactic localization of the globus pallidus and subthalamic nucleus.

OBJECTIVE: To optimize the accuracy of initial stereotactic targeting for movement disorders surgery, we performed stereotactic localization of the internal segment of the globus pallidus (GPi) and subthalamic nucleus (STN) using magnetic resonance imaging protocols in which the borders of these nuclei were directly visualized. METHODS: Fifty-one consecutive cases using the pallidal target and six using the subthalamic target were studied. Localization of these nuclei was performed using the Leksell stereotactic head frame and inversion recovery sequences (GPi) or T2-weighted spin echo sequences (STN). Targeting accuracy and individual variation in the spatial coordinates of these structures were independently measured by identification of nuclear boundaries during multiple microelectrode penetrations. RESULTS: The lateral and vertical coordinates of an atlas-defined point in the GPi, with respect to the line between the anterior and posterior commissures, was highly variable. Initial targeting the GPi based on direct visualization of the target boundaries (external medullary lamina and optic tract) resulted in greater precision than would be expected using fixed anterior and posterior commissure-based coordinates. Initial targeting the STN using magnetic resonance imaging was sufficiently precise to place the initial microelectrode penetration within STN in all six cases. CONCLUSION: Magnetic resonance imaging-based initial stereotactic targeting of the GPi, based on direct visualization of the target boundaries, is useful to improve target accuracy over that of purely indirect anterior and posterior commissure-based targeting methods. Initial targeting of the STN was reliably accomplished by direct visualization. However, there remains sufficient variability that the final target location in both GPi and STN required electrophysiological mapping in all cases.