Single neurons in the thalamus and subthalamic nucleus process cardiac and respiratory signals in humans.

Visceral signals are constantly processed by our central nervous system, enable homeostatic regulation, and influence perception, emotion, and cognition. While visceral processes at the cortical level have been extensively studied using non-invasive imaging techniques, very few studies have investigated how this information is processed at the single neuron level, both in humans and animals. Subcortical regions, relaying signals from peripheral interoceptors to cortical structures, are particularly understudied and how visceral information is processed in thalamic and subthalamic structures remains largely unknown. Here, we took advantage of intraoperative microelectrode recordings in patients undergoing surgery for deep brain stimulation (DBS) to investigate the activity of single neurons related to cardiac and respiratory functions in three subcortical regions: ventral intermedius nucleus (Vim) and ventral caudalis nucleus (Vc) of the thalamus, and subthalamic nucleus (STN). We report that the activity of a large portion of the recorded neurons (about 70%) was modulated by either the heartbeat, the cardiac inter-beat interval, or the respiration. These cardiac and respiratory response patterns varied largely across neurons both in terms of timing and their kind of modulation. A substantial proportion of these visceral neurons (30%) was responsive to more than one of the tested signals, underlining specialization and integration of cardiac and respiratory signals in STN and thalamic neurons. By extensively describing single unit activity related to cardiorespiratory function in thalamic and subthalamic neurons, our results highlight the major role of these subcortical regions in the processing of visceral signals.

Case report - Asterixis Post High Frequency Focused-Ultrasound Thalamotomy.

Background: High frequency focused ultrasound is used for treatment of essential tremor. Side effects associated with the procedure may resolve over time. We report a case of negative myoclonus, which has not been reported with this procedure. Case report: A 73-year-old left-handed man underwent focused ultrasound thalamotomy for treatment of essential tremor. Immediately post procedure he was noted to have negative myoclonus in the treated limb. This side effect resolved over the course of 6 months. Discussion: Although asterixis has been associated with thalamic infarcts in the past, this has not yet been reported in the literature with MRgFUS procedure and is a novel observation. Occupational and physical therapy may be considered to address this side effect. It is important to counsel patients about the rare occurrence of this complication of therapy but also its potential for complete resolution over time.

Transcranial magnetic stimulation, deep brain stimulation, and other forms of neuromodulation for substance use disorders: Review of modalities and implications for treatment.

Given the high prevalence of individuals diagnosed with substance use disorder, along with the elevated rate of relapse following treatment initiation, investigating novel approaches and new modalities for substance use disorder treatment is of vital importance. One such approach involves neuromodulation which has been used therapeutically for neurological and psychiatric disorders and has demonstrated positive preliminary findings for the treatment of substance use disorder. The following article provides a review of several forms of neuromodulation which warrant consideration as potential treatments for substance use disorder. PubMed, PsycINFO, Ovid MEDLINE, and Web of Science were used to identify published articles and clinicaltrials.gov was used to identify currently ongoing or planned studies. Search criteria for Brain Stimulation included the following terminology: transcranial direct current stimulation, transcranial magnetic stimulation, theta burst stimulation, deep brain stimulation, vagus nerve stimulation, trigeminal nerve stimulation, percutaneous nerve field stimulation, auricular nerve stimulation, and low intensity focused ultrasound. Search criteria for Addiction included the following terminology: addiction, substance use disorder, substance-related disorder, cocaine, methamphetamine, amphetamine, alcohol, nicotine, tobacco, smoking, marijuana, cannabis, heroin, opiates, opioids, and hallucinogens. Results revealed that there are currently several forms of neuromodulation, both invasive and non-invasive, which are being investigated for the treatment of substance use disorder. Preliminary findings have demonstrated the potential of these various neuromodulation techniques in improving substance treatment outcomes by reducing those risk factors (e.g. substance craving) associated with relapse. Specifically, transcranial magnetic stimulation has shown the most promise with several well-designed studies supporting the potential for reducing substance craving. Deep brain stimulation has also shown promise, though lacks well-controlled clinical trials to support its efficacy. Transcranial direct current stimulation has also demonstrated promising results though consistently designed, randomized trials are also needed. There are several other forms of neuromodulation which have not yet been investigated clinically but warrant further investigation given their mechanisms and potential efficacy based on findings from other studied indications. In summary, given promising findings in reducing substance use and craving, neuromodulation may provide a non-pharmacological option as a potential treatment and/or treatment augmentation for substance use disorder. Further research investigating neuromodulation, both alone and in combination with already established substance use disorder treatment (e.g. medication treatment), warrants consideration.

Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: a double-blind, randomised controlled trial.

BACKGROUND: Chronic cluster headache is the most disabling form of cluster headache. The mainstay of treatment is attack prevention, but the available management options have little efficacy and are associated with substantial side-effects. In this study, we aimed to assess the safety and efficacy of sphenopalatine ganglion stimulation for treatment of chronic cluster headache. METHODS: We did a randomised, sham-controlled, parallel group, double-blind, safety and efficacy study at 21 headache centres in the USA. We recruited patients aged 22 years or older with chronic cluster headache, who reported a minimum of four cluster headache attacks per week that were unsuccessfully controlled by preventive treatments. Participants were randomly assigned (1:1) via an online adaptive randomisation procedure to either stimulation of the sphenopalatine ganglion or a sham control that delivered a cutaneous electrical stimulation. Patients and the clinical evaluator and surgeon were masked to group assignment. The primary efficacy endpoint, which was analysed with weighted generalised estimated equation logistic regression models, was the difference between groups in the proportion of stimulation-treated ipsilateral cluster attacks for which relief from pain was achieved 15 min after the start of stimulation without the use of acute drugs before that timepoint. Efficacy analyses were done in all patients who were implanted with a device and provided data for at least one treated attack during the 4-week experimental phase. Safety was assessed in all patients undergoing an implantation procedure up to the end of the open-label phase of the study, which followed the experimental phase. This trial is registered with ClinicalTrials.gov, number NCT02168764. FINDINGS: Between July 9, 2014, and Feb 14, 2017, 93 patients were enrolled and randomly assigned, 45 to the sphenopalatine ganglion stimulation group and 48 to the control group. 36 patients in the sphenopalatine ganglion stimulation group and 40 in the control group had at least one attack during the experimental phase and were included in efficacy analyses. The proportion of attacks for which pain relief was experienced at 15 min was 62·46% (95% CI 49·15-74·12) in the sphenopalatine ganglion stimulation group versus 38·87% (28·60-50·25) in the control group (odds ratio 2·62 [95% CI 1·28-5·34]; p=0·008). Nine serious adverse events were reported by the end of the open-label phase. Three of these serious adverse events were related to the implantation procedure (aspiration during intubation, nausea and vomiting, and venous injury or compromise). A fourth serious adverse event was an infection that was attributed to both the stimulation device and the implantation procedure. The other five serious adverse events were unrelated. There were no unanticipated serious adverse events. INTERPRETATION: Sphenopalatine ganglion stimulation seems efficacious and is well tolerated, and potentially offers an alternative approach to the treatment of chronic cluster headache. Further research is need to clarify its place in clinical practice. FUNDING: Autonomic Technologies.

A High Definition Noninvasive Neuromuscular Electrical Stimulation System for Cortical Control of Combinatorial Rotary Hand Movements in a Human With Tetraplegia.

OBJECTIVE: Paralysis resulting from spinal cord injury (SCI) can have a devastating effect on multiple arm and hand motor functions. Rotary hand movements, such as supination and pronation, are commonly impaired by upper extremity paralysis, and are essential for many activities of daily living. In this proof-of-concept study, we utilize a neural bypass system (NBS) to decode motor intention from motor cortex to control combinatorial rotary hand movements elicited through stimulation of the arm muscles, effectively bypassing the SCI of the study participant. We describe the NBS system architecture and design that enabled this functionality. METHODS: The NBS consists of three main functional components: 1) implanted intracortical microelectrode array, 2) neural data processing using a computer, and, 3) a noninvasive neuromuscular electrical stimulation (NMES) system. RESULTS: We address previous limitations of the NBS, and confirm the enhanced capability of the NBS to enable, in real-time, combinatorial hand rotary motor functions during a functionally relevant object manipulation task. CONCLUSION: This enhanced capability was enabled by accurate decoding of multiple movement intentions from the participant's motor cortex, interleaving NMES patterns to combine hand movements, and dynamically switching between NMES patterns to adjust for hand position changes during movement. SIGNIFICANCE: These results have implications for enabling complex rotary hand functions in sequence with other functionally relevant movements for patients suffering from SCI, stroke, and other sensorimotor dysfunctions.

Long-term outcomes of spinal cord stimulation with paddle leads in the treatment of complex regional pain syndrome and failed back surgery syndrome.

INTRODUCTION: Spinal cord stimulation (SCS) is frequently used to treat chronic, intractable back, and leg pain. Implantation can be accomplished with percutaneous leads or paddle leads. Although there is an extensive literature on SCS, the long-term efficacy, particularly with paddle leads, remains poorly defined. Outcome measure choice is important when defining therapeutic efficacy for chronic pain. Numerical rating scales such as the NRS-11 remain the most common outcome measure in the literature, although they may not accurately correlate with quality of life improvements and overall satisfaction. METHODS: We reviewed the medical records of patients with failed back surgery syndrome (FBSS) or complex regional pain syndrome (CRPS) implanted with SCS systems using paddle leads between 1997 and 2008 at the Cleveland Clinic with a minimum six-month follow-up. Patients were contacted to fill out a questionnaire evaluating outcomes with the NRS-11 as well as overall satisfaction. RESULTS: A total of 35 eligible patients chose to participate. More than 50% of the patients with CRPS reported greater than 50% pain relief at a mean follow-up of 4.4 years. Approximately 30% of the FBSS patients reported a 50% or greater improvement at a mean follow-up of 3.8 years. However, 77.8% of patients with CRPS and 70.6% of patients with FBSS indicated that they would undergo SCS surgery again for the same outcome. CONCLUSION: Patients with CRPS and FBSS have a high degree of satisfaction, indexed as willingness to undergo the same procedure again for the same outcome at a mean follow-up of approximately four years. The percentage of satisfaction with the SCS system is disproportionally greater than the percentage of patients reporting 50% pain relief, particularly among patients with FBSS. This suggests that the visual analog scale may not be the optimal measure to evaluate long-term outcomes in this patient population.

Sphenopalatine ganglion interventions: technical aspects and application.

Recent research has highlighted the important role of the sphenopalatine ganglion (SPG) in cerebrovascular autonomic physiology and in the pathophysiology of cluster and migraine headaches as well as conditions of stroke and cerebral vasospasm. The relatively accessible location of the SPG within the pterygopalatine fossa and the development of options for minimally invasive approaches to the SPG make it an attractive target for neuromodulation approaches. The obvious advantage of SPG stimulation compared to ablative procedures on the SPG such as radiofrequency destruction and stereotactic radiosurgery is its reversibility and adjustable features. The on-going design of strategies for transient and continuous SPG stimulation on as needed basis using implantable SPG stimulators is an exciting new development which is expected to expand the clinical versatility of this technique.

Addressing neurological disorders with neuromodulation.

Neurological disorders are becoming increasingly common in developed countries as a result of the aging population. In spite of medications, these disorders can result in progressive loss of function as well as chronic physical, cognitive, and emotional disability that ultimately places enormous emotional and economic on the patient, caretakers, and the society in general. Neuromodulation is emerging as a therapeutic option in these patients. Neuromodulation is a field, which involves implantable devices that allow for the reversible adjustable application of electrical, chemical, or biological agents to the central or peripheral nervous system with the objective of altering its functioning with the objective of achieving a therapeutic or clinically beneficial effect. It is a rapidly evolving field that brings together many different specialties in the fields of medicine, materials science, computer science and technology, biomedical, and neural engineering as well as the surgical or interventional specialties. It has multiple current and emerging indications, and an enormous potential for growth. The main challenges before it are in the need for effective collaboration between engineers, basic scientists, and clinicians to develop innovations that address specific problems resulting in new devices and clinical applications.

Treatment of chronic pain with neurostimulation.

Chronic pain conditions are a complex and multifactorial problem generally requiring a multidisciplinary-type approach. The central nervous system at some point clearly becomes involved in the processing of these painful conditions with an integration of complex changes in neurophysiology and behavior. Many ablative techniques have been employed in the past to interrupt these signals. However, the results were often temporary and symptoms tended to recur. The more modern approach has suggested that modulation of the nervous elements may be a more resilient approach for treating such chronic pain disorders. We are realizing that many of these pain conditions are also dynamic and evolving, and as such need a similar treatment modality. Neurostimulation, thus, provides the ability of therapeutically dosing electrical current in a variety of pulse forms, amplitudes, pulse widths, and frequencies, to affect that system. Furthermore, it is not destructive, it is reversible, and it can be remotely adjusted and programmed over time; clear advantages to previous surgical therapies. This chapter reports on the current evidence for the use of neurostimulation (i.e. spinal cord stimulation, motor cortex stimulation and deep brain stimulation) in the treatment of chronic pain conditions.

Failure modes of spinal cord stimulation hardware.

OBJECT: Epidural spinal cord stimulation (SCS) is effective at treating refractory pain. The failure modes of the implanted hardware, however, have not been well studied. A better understanding of this could aid in improving the current procedure or designing future devices. METHODS: The authors reviewed electronic charts and operative reports of 289 patients who had undergone SCS implantation between 1998 and 2002 at the Cleveland Clinic Foundation. Data were collected on demographics, type of hardware, date of implantation procedure, indication for treatment, time to failure, and failure mode. Data were then analyzed to identify significant differences. A total of 577 procedures were performed, 43.5% of which involved revision or removal of SCS hardware. The most common indication was complex regional pain syndrome 1, and this was followed by failed-back surgery syndrome. The median number of procedures per patient was two. Approximately 80% of all leads were the percutaneous type. The majority (62%) of leads were placed in the thoracic region, and 33.5% of all leads required revision. Poor pain relief coverage was the most common indication for revision. Surgically implanted leads broke twice as often as percutaneous leads. In 46% of the patients, hardware revision was required, and multiple revisions were necessary in 22.5%. Three-way ANOVA revealed significant differences in failure mode rates according to location (cervical compared with thoracic, p = 0.037) and failure modes (p = 0.019). Laminotomy leads tended to break and migrate sooner than percutaneous leads. Thoracic leads became infected sooner than cervical leads. CONCLUSIONS: The results of this analysis of SCS hardware failures may be used as a basis for refining surgical technique and designing the next generation of SCS hardware.

Anatomy and physiology of the basal ganglia: implications for deep brain stimulation for Parkinson's disease.

Central to surgical management of movement disorders is an understanding of the anatomy and physiology of the basal ganglia. The basal ganglia have been a target for neuromodulation surgery since Russell Meyers' pioneering works in the late 1930s. With the development of deep brain stimulation as the gold standard of surgical intervention for movement disorders, there has been a concomitant evolution in the understanding of the role the basal ganglia plays in the genesis of normal and abnormal motor behaviors. The fundamental concept of the cortico-striato-pallido-thalamocortical loop will be explored in the context of deep brain stimulation. The current targets for deep brain stimulation for Parkinson's disease, the subthalamic nucleus, the globus pallidus internus, and the ventral intermediate nucleus, will be discussed in the framework of the current physiological and anatomical models of Parkinson's disease (PD). Finally, the current understandings of the mechanisms underpinning the beneficial effects of deep brain stimulation for PD will be discussed.

Temporal excitation properties of paresthesias evoked by thalamic microstimulation.

OBJECTIVE: The neuronal elements mediating the effects of deep brain stimulation (DBS) are unknown. The objective was to determine the strength-duration properties of the neuronal elements that mediate paresthesias evoked by thalamic microstimulation. METHODS: The strength-duration properties of the neuronal elements causing paresthesias were measured using intraoperative microstimulation of the human thalamus. The sample included both concordant (reported in the same region as the mapped sensory receptive fields) and discordant paresthesias (reported in a region different than the mapped sensory receptive fields). RESULTS: There were no significant differences between the chronaxies of concordant and discordant paresthesias. There was no significant correlation between chronaxie and rheobase for concordant paresthesias, but a strong negative correlation existed for discordant paresthesias. CONCLUSIONS: Chronaxies did not distinguish the neuronal elements mediating concordant and discordant paresthesias, but correlations between chronaxie and rheobase suggest that concordant paresthesias were produced by activation of local cells while discordant paresthesias were caused by activation of axons of passage. SIGNIFICANCE: The similarity between the strength-duration properties of paresthesias evoked by thalamic stimulation, tremor reduction evoked by thalamic DBS, and EMG responses to thalamic DBS does not mean that these effects are caused by the same neural elements.

Location of the active contact within the subthalamic nucleus (STN) in the treatment of idiopathic Parkinson's disease.

BACKGROUND: Chronic electrical stimulation of the subthalamic nucleus (STN) has been shown to be safe and effective in the treatment of medically refractory idiopathic Parkinson's disease. The clinically most relevant location of stimulation within the physiologically defined STN has not been confirmed. We reviewed the locations of active electrical contacts in 33 patients who underwent simultaneous bilateral STN deep brain stimulator (DBS) implantation. METHODS: The location of the microelectrode-defined dorsal STN border was compared to the location of the center of the active contact(s) employed in achieving optimal clinical results 6 to 18 months postoperatively. Furthermore, the location of this optimal contact was determined with respect to each individual patient's midcommissural point. Bilateral monopolar stimulation was employed in 30 patients using quadripolar DBS electrodes. RESULTS: After a minimum follow-up period of 6 months, the motor subscores (UPDRS Part III) in the postoperative on-stimulation/off-medication state were 64 +/- 18% (mean +/- SD) improved as compared to the preoperative off-medication state (p < 0.01). Additionally, an improvement of 53 +/- 38% was noted when comparing the postoperative on-stimulation/on-medication state to the preoperative on-medication state (p < 0.01). On average, the center of the optimal contact was 13.3 mm lateral, 0.5 mm posterior, 0.1 mm inferior to the mid-commissural point and was 0.1 +/- 2.1 mm dorsal to the physiologically defined dorsal STN border. CONCLUSIONS: While the achieved clinical results are comparable to those published in the literature, it appears that monopolar electrical stimulation at the anterior dorsolateral border of the STN yields optimal clinical results. Further studies are crucial in determining the precise mechanism of various modes of DBS in an effort to maximize clinical outcome.

Deep brain stimulation for psychiatric disorders.

Over the last decade, deep brain stimulation (DBS) has revolutionized the practice of neurosurgery, particularly in the realm of movement disorders. It is no surprise that DBS is now being studied in the treatment of refractory psychiatric disease. Deep brain stimulation has inherent advantages over previous lesioning procedures. It is fully reversible, and stimulation can be adjusted according to a patient's changing symptoms and disease progression. Coupled with the fact that the stimulation can generally be turned on or off without the patient's awareness, DBS provides a unique opportunity for double-blinding studies. To undertake DBS for psychiatric conditions, appropriate surgical targets must be chosen. What is most strongly supported is the role of cortico-striato-thalamocortical (CSTC) loops in the pathophysiology of psychiatric symptoms. Recent functional imaging studies have consistently found evidence that corroborate this model of psychiatric symptom pathogenesis. Based on the psychiatric and cognitive effects seen in recent movement disorder surgery, it is apparent that modulation of neural systems subserving psychiatric phenomenon can be accomplished by DBS. The few published studies on DBS for obsessive-compulsive disorder (OCD) suggest that this can be done safely. While efficacy data are still uncertain, initial data are promising.

Neurostimulation system used for deep brain stimulation (DBS): MR safety issues and implications of failing to follow safety recommendations.

The use of magnetic resonance imaging (MRI) in patients with neurostimulation systems used for deep brain stimulation requires the utmost care, and no individual should undergo an MR examination in the absence of empirical evidence that the procedure can be performed safely. The risks of performing MRI in patients with neurostimulators include those associated with heating, magnetic field interactions, induced currents, and the functional disruption of these devices. The exact safety recommendations for the particular neurostimulation system with regard to the pulse generator, leads, electrodes, operational conditions for the device, the positioning of these components, and the MR system conditions must be carefully followed for MRI. As highlighted by 2 recent accidents, the failure to strictly follow safety recommendations (eg, use a 1.5-T MR system with a send/receive head radiofrequency coil only; limit the specific absorption rate to 0.4 W/kg; etc.) may result in serious, temporary, or permanent injury to the patient including the possibility of transient dystonia, paralysis, coma, or even death.

Deep brain stimulation for movement disorders.

Movement disorders remain the primary indication for the use of intracranial neurostimulation techniques. This review will discuss the history of this technology as well as the mechanisms of action, current clinical indications, and future prospects for the treatment of movement disorders.

Precentral stimulation for chronic pain.

A decade of clinical experience has suggested that precentral stimulation is an option for patients with deafferentation as well as other chronic pain syndromes. Permanent complications are uncommon. More scientific evidence is warranted to understand the precise mechanisms for this treatment modality. A larger organized clinical trial is desired to establish the efficacy of precentral stimulation.

Mechanisms and the current state of deep brain stimulation in neuropsychiatry.

Deep brain stimulation (DBS) is established as a therapy for movement disorders, and it is an investigational treatment in other neurologic conditions. DBS precisely targets neuroanatomical targets deep within the brain that are proposed to be centrally involved in the pathophysiology of some neuropsychiatric illnesses. DBS is nonablative, offering the advantages of reversibility and adjustability. This might permit therapeutic effectiveness to be enhanced or side effects to be minimized. Preclinical and clinical studies have shown effects of DBS locally, at the stimulation target, and at a distance, via actions on fibers of passage or across synapses. Although its mechanisms of action are not fully elucidated, several effects have been proposed to underlie the therapeutic effects of DBS in movement disorders, and potentially in other conditions as well. The mechanisms of action of DBS are the focus of active investigation in a number of clinical and preclinical laboratories. As in severe movement disorders, DBS may offer a degree of hope for patients with intractable neuropsychiatric illness. It is already clear that research intended to realize this potential will require a very considerable commitment of resources, energy, and time across disciplines including psychiatry, neurosurgery neurology, neuropsychology, bioengineering, and bioethics. These investigations should proceed cautiously.

Subthalamic nucleus deep brain stimulus evoked potentials: physiological and therapeutic implications.

The effect of subthalamic nucleus (STN) stimulation on cortical electroencephalographic activity was examined in 10 patients with Parkinson's disease and 4 patients with epilepsy. Evoked potentials were created by time-locking electroencephalography to the onset of electrical stimulation delivered through the lead implanted in the STN of patients who had previously undergone deep brain stimulation (DBS) surgery. The effect of different patterns of stimulation on the evoked response, including single- and paired-pulse as well as burst stimulation, was explored. Cortical evoked potentials to single pulses were observed with latencies as short as 1 to 2 msec after a single pulse of stimulation, with activity continuing, in some cases, for up to 400 msec. Paired-pulse experiments revealed refractory periods on the order of 0.5 msec, suggesting that stimulation of axons contributed to the generation of at least some portion of the evoked potential waveform. Evoked potentials were also present in response to 100-msec bursts of stimulation, with some evidence that the potential was initiated within the burst artifact. The potential implications of the types of responses observed as well as potential applications are discussed.

Subthalamic nucleus stimulation in patients with a prior pallidotomy.

OBJECT: A substantial number of patients with Parkinson disease (PD) who have undergone unilateral stereotactic pallidotomy ultimately develop symptom progression, becoming potential candidates for further surgical treatment. Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) has been shown to be effective in the treatment of a subset of patients with refractory PD. Microelectrode recording is performed to help localize the STN and guide final placement of the electrode. Potential alterations in physiological features of the STN after pallidotomy may complicate localization of this structure in this group of patients. METHODS: Bilateral STN DBS surgery guided by microelectrode recording was performed in six patients who had undergone previous unilateral pallidotomies. Physiologically obtained parameters of the STN, including trajectory length, mean firing rate, cell number, and cell density were calculated. These data were compared with those from the side without prior pallidotomy within each patient, as well as with those from our series of 49 subthalamic nuclei explored in 26 patients who had not undergone prior pallidotomy but who underwent bilateral STN stimulator placement. In all patients, analysis of STN cellular activity on the side ipsilateral to the pallidotomy demonstrated a lower mean firing frequency than on the contralateral, intact side. The physiological features on the intact side were not significantly different from those found in our series of patients who had not undergone prior pallidotomy. CONCLUSIONS: Physicians who perform STN surgery in patients with prior pallidotomy should be aware of the electrophysiological differences between the STN that had undergone pallidotomy and the one that had not, to avoid prolonging recording time to search for the typical STN. The implications of these findings for the current models of information processing in the basal ganglia are discussed.