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.

Adaptive Deep Brain Stimulation in Parkinson's Disease: A Delphi Consensus Study.

Importance: If history teaches, as cardiac pacing moved from fixed-rate to on-demand delivery in in 80s of the last century, there are high probabilities that closed-loop and adaptive approaches will become, in the next decade, the natural evolution of conventional Deep Brain Stimulation (cDBS). However, while devices for aDBS are already available for clinical use, few data on their clinical application and technological limitations are available so far. In such scenario, gathering the opinion and expertise of leading investigators worldwide would boost and guide practice and research, thus grounding the clinical development of aDBS. Observations: We identified clinical and academically experienced DBS clinicians (n=21) to discuss the challenges related to aDBS. A 5-point Likert scale questionnaire along with a Delphi method was employed. 42 questions were submitted to the panel, half of them being related to technical aspects while the other half to clinical aspects of aDBS. Experts agreed that aDBS will become clinical practice in 10 years. In the present scenario, although the panel agreed that aDBS applications require skilled clinicians and that algorithms need to be further optimized to manage complex PD symptoms, consensus was reached on aDBS safety and its ability to provide a faster and more stable treatment response than cDBS, also for tremor-dominant Parkinson's disease patients and for those with motor fluctuations and dyskinesias. Conclusions and Relevance: Despite the need of further research, the panel concluded that aDBS is safe, promises to be maximally effective in PD patients with motor fluctuation and dyskinesias and therefore will enter into the clinical practice in the next years, with further research focused on algorithms and markers for complex symptoms.

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.

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.

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.

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.

Pre- and postoperative MR evaluation of stereotactic pallidotomy.

PURPOSE: Stereotactic pallidotomy, which has evolved as a result of technological advances in high-resolution MR imaging and microelectrode electrophysiological recording, is becoming a major form of treatment for patients with Parkinson disease in whom medical therapy has failed. We describe the location and appearance of the pallidotomy lesion on high-resolution MR images. METHODS: MR images in 83 patients (60 men and 23 women) who underwent stereotactic pallidotomy were reviewed retrospectively. The prepallidotomy screening study included standard spin-echo and gradient-echo sequences. After placement of a stereotactic headframe, volume-acquisition T1-weighted spoiled gradient-echo images were acquired for target localization in the posteroventral internal globus pallidus. One to three days after the pallidotomy, volume-acquisition T1-weighted and standard spin-echo sequences were obtained. In 16 patients, turbo spin-echo inversion recovery images also were obtained before and after surgery. The diameter, signal intensity, and location of the lesions relative to the midcommissural point and the intercommissural line were noted. RESULTS: The average lesion volume was 118 mm3 while that of the lesion-edema complex was 420 mm3. The midportion of the lesion was located on average 3.5 mm anterior to the midcommissural point, 21 mm lateral to the middle of the third ventricle, and 1.2 mm inferior to the intercommissural line. Signal intensity of the lesions varied, but all had a rim of edema. Forty-two patients had edema extending into the optic tract, four had increased signal in the ipsilateral basal ganglia on T2-weighted images, and seven had hemorrhage involving the ipsilateral caudate, internal capsule, and putamen. All patients experienced some improvement in contralateral bradykinesia, rigidity, and dystonia. CONCLUSION: The acute pallidotomy lesion is invariably located within the posteroventral internal globus pallidus, is usually hyperintense centrally on T1-weighted and turbo spin-echo inversion recovery MR images, and has a thin rim of edema. Edema extending into the ipsilateral optic tract was a common finding, but this series of patients evinced no visual changes.

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.

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.

Ablative surgery and deep brain stimulation for Parkinson's disease.

Surgical options for Parkinson's disease (PD) are rapidly expanding and include ablative procedures, deep brain stimulation, and cell transplantation. The target nuclei for ablative surgery and deep brain stimulation are the motor thalamus, the globus pallidus, and the subthalamic nucleus. Multiple factors have led to the resurgence of interest in the surgical treatment of PD: 1) recognition that long-term medical therapy for PD is often unsatisfactory, with patients eventually suffering from drug-induced dyskinesias, motor fluctuations, and variable responses to medication; 2) greater understanding of the pathophysiology of PD, providing a better scientific rationale for some previously developed procedures and suggesting new targets; and 3) use of improved techniques, such as computed tomography- and magnetic resonance imaging-guided stereotaxy and single-unit microelectrode recording, making surgical intervention in the basal ganglia more precise. We review the present status of ablative surgery and deep brain stimulation for PD, including theoretical aspects, surgical techniques, and clinical results.

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.

Neurotransmitter release from hair cells and its blockade by glutamate-receptor antagonists.

To assess the mechanism by which glutamate-receptor antagonists block afferent discharge at the hair cell synapse, we examined the effects of these and other agents on sound-evoked excitatory post-synaptic potentials (EPSPs) and on spontaneous miniature post-synaptic potentials (MEPSPs) in auditory-nerve fibers of the goldfish (Carassius auratus) saccule. A quantal analysis of synaptic transmission under conditions in which the probability of transmitter release was reduced by cobalt, an agent that can block transmitter release, supports Furukawa's (Jpn. J. Physiol. 36, 1059-1077, 1986) conclusion that transmitter release at this synapse is quantal. Cobalt reduced the rate of occurrence of spontaneous MEPSPS without reducing their amplitude. The glutamate-receptor antagonists, gamma-D-glutamyl glycine (DGG) and 5-aminophosphonovaleric acid (APV) both reduced the amplitude of sound-evoked EPSPs much more than that of the spontaneous MEPSPs. The glutamate-receptor agonists, L-glutamate, kainate, and quisqualate, produced a depolarization of the afferent nerve fiber, a decrease in the amplitude of the EPSP and an increased tendency for an EPSP to generate an action potential.

Pituitary apoplexy following cardiopulmonary bypass: considerations for a staged cardiac and neurosurgical procedure.

Pituitary apoplexy in a pre-existing pituitary tumor can result in serious and permanent neurologic deficits following cardiac surgical procedures. Several factors related to the altered physiology of cardiopulmonary bypass (CPB) contribute separately or in combination to the development of this syndrome. Over the last year we have encountered two such cases in whom emergency and prompt decompression of the adenoma resulted in an improvement of the initial clinical presentation but nevertheless persistence of residual and devastating ocular manifestations. In the literature six similar cases have been reported following cardiac surgical procedures, with similar outcomes. In this report we describe our experience and management of these two patients, and that published in the literature. We propose a possible role for a staged cardiac and neurosurgical procedure as a prophylactic measure in patients with known pituitary tumor. The role of cerebral monitoring is also discussed.

Deep brain stimulation for movement disorders.

Chronic deep brain stimulation (DBS) is a promising technique for the treatment of movement disorders. Thalamic stimulation is now an established surgical procedure for parkinsonian and essential tremor. Pallidal and subthalamic stimulation are under active investigation as treatments for Parkinson's disease. Although high-frequency DBS at these sites has similar behavioral effects as lesioning, the physiologic mechanisms underlying the beneficial effect of DBS is not well understood and may be extremely complex. DBS offers a potential advantage over ablative therapy because stimulation-induced complications are reversible, and the stimulation parameters are adjustable to minimize complications and maximize therapeutic effects. With this added safety, bilateral stimulation or use of a stimulator following a prior procedure may be preferable to bilateral ablative procedures.

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.

Posterior ventral pallidotomy: techniques and theoretical considerations.

1. Microeletrode mapping of the pallidum and adjacent structures allows for precise target identification and localization of critical structures, i.e., optic tract, internal capsule, and external pallidum, which must be spared from lesioning. 2. Microelectrode mapping has provided physiologic-anatomic correlation of determining the optimal target location as related to clinical outcome and has helped to refine the role of stimulation as a tool for target localization. 3. The improved accuracy of this technique should result in more accurate lesion placement which should improve long-term outcome and decrease morbidity.

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.

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.

The shape factor in radial keratotomy.

The corneal contour as defined by the shape factor was found by photokeratoscopy both before and after radial keratotomy to reduce myopia. In 51 eyes with mean pre-operative myopia of -5.67 DS there was a mean reduction of -5.23 DS, and the shape factor became negative in all cases. A relationship was found between the pre-operative myopia and the shape factor, and the size of optical zone to be left untouched when attempting to achieve emmetropia. The importance of taking shape factor into account when forming the surgical plan was made apparent by retrospective study of the surgery performed.

Effects of calcitonin gene-related peptide and efferent nerve stimulation on afferent transmission in the lateral line organ.

1. Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide immunolocalized in efferent fibers innervating hair-cell organs, including the lateral line organ of Xenopus laevis. CGRP, applied in nanomolar concentrations, increased the spontaneous discharge rate in afferent fibers innervating hair cells of the lateral line organ. 2. The increase in spontaneous discharge rate with application of CGRP was associated with an increase in the rate of occurrence of spontaneous excitatory postsynaptic potentials (EPSPs) and with little change in the amplitude of the EPSPs. 3. Prolonged (several hundred seconds) application of CGRP produced an increase in afferent fiber discharge rate that returned to control values in the continued presence of the peptide. 4. Efferent fibers were electrically stimulated to look for a non-cholinergic effect on spontaneous afferent discharge that might be attributed to CGRP. Electrical stimulation of the efferent fibers produced a rapid (100 ms) suppression of discharge rate followed by a rapid (100 ms) increase in discharge rate. However, both the rapid suppression and rapid excitation were likely to be mediated by the release of acetylcholine, because they were blocked by the application of the cholinergic blocking agents curare and atropine as well as by strychnine. 5. In almost one-half of the preparations examined, electrical stimulation of efferent fibers also produced a slowly developing increase in afferent discharge that could persist for several minutes after termination of the shocks. 6. This slow excitation by efferent stimulation was not blocked by concentrations of curare that blocked the rapid effects of efferent stimulation. Thus the slow effect is likely to be mediated by a receptor different from that for the rapid cholinergic effects. One possibility is that the excitation is mediated by the release of CGRP from the efferent nerve fibers.