Smell-induced gamma oscillations in human olfactory cortex are required for accurate perception of odor identity.

Studies of neuronal oscillations have contributed substantial insight into the mechanisms of visual, auditory, and somatosensory perception. However, progress in such research in the human olfactory system has lagged behind. As a result, the electrophysiological properties of the human olfactory system are poorly understood, and, in particular, whether stimulus-driven high-frequency oscillations play a role in odor processing is unknown. Here, we used direct intracranial recordings from human piriform cortex during an odor identification task to show that 3 key oscillatory rhythms are an integral part of the human olfactory cortical response to smell: Odor induces theta, beta, and gamma rhythms in human piriform cortex. We further show that these rhythms have distinct relationships with perceptual behavior. Odor-elicited gamma oscillations occur only during trials in which the odor is accurately perceived, and features of gamma oscillations predict odor identification accuracy, suggesting that they are critical for odor identity perception in humans. We also found that the amplitude of high-frequency oscillations is organized by the phase of low-frequency signals shortly following sniff onset, only when odor is present. Our findings reinforce previous work on theta oscillations, suggest that gamma oscillations in human piriform cortex are important for perception of odor identity, and constitute a robust identification of the characteristic electrophysiological response to smell in the human brain. Future work will determine whether the distinct oscillations we identified reflect distinct perceptual features of odor stimuli.

Seizure Risk Associated With the Use of Transcranial Magnetic Stimulation for Coma Recovery in Individuals With Disordered Consciousness After Severe Traumatic Brain Injury.

OBJECTIVE: Repetitive Transcranial Magnetic Stimulation (rTMS) is emerging as a promising treatment for persons with disorder of consciousness (DoC) following traumatic brain injury (TBI). Clinically, however, there are concerns about rTMS exacerbating baseline seizure risk. To advance understanding of risks, this article reports evidence of DoC-TBI rTMS-related seizure risk. SETTING: Acute and sub-acute hospitals. PARTICIPANTS: Persons in states of DoC 6.5 months to 15 years after TBI (n = 20) who received active rTMS (n = 17) or placebo rTMS (n = 3). After completing placebo procedures, placebo participants completed active rTMS procedures. These 3 participants are included in the active group. DESIGN: Meta-analysis of data from 3 clinical trials; 2 within-subject, 1 double blind randomized placebo-controlled. Each trial used the same rTMS protocol, provided at least 30 rTMS sessions, and delivered rTMS to the dorsolateral prefrontal cortex. MAIN MEASURES: During each study's rTMS treatment phase, seizure occurrences were compared between active and placebo groups using logistic regression. After stratifying active group by presence/absence of seizure occurrences, sub-groups were compared using contingency chi-square tests of independence and relative risk (RR) ratios. RESULTS: Two unique participants experienced seizures (1 active, 1 placebo). Post seizure, both participants returned to baseline neurobehavioral function. Both participants received antiepileptics during remaining rTMS sessions, which were completed without further seizures. rTMS-related seizure incidence rate is 59 per 1000 persons. Logistic regression revealed no difference in seizure occurrence by treatment condition (active vs placebo) or when examined with seizure risk factors (P > .1). Presence of ventriculoperitoneal shunt elevated seizure risk (RR = 2.0). CONCLUSION: Collectively, findings indicate a low-likelihood that the specified rTMS protocol exacerbates baseline seizure rates in persons with DoC after TBI. In presence of VP shunts, however, rTMS likely elevates baseline seizure risk and mitigation of this increased risk with pharmacological seizure prophylaxis should be considered.

Occipital nerve stimulation in pediatric patients with refractory occipital neuralgia.

PURPOSE: Occipital neuralgia (ON) is a disabling problem within the pediatric population. Many of these patients fail medical therapies and continue to suffer without further surgical management. Occipital nerve stimulation (ONS) is used to treat ON in the adult population leading to a 72-89% reduction in pain; however, there are limited studies regarding its use in the pediatric population. In this study, we examined the outcomes of ONS in pediatric patients with medically refractory ON. METHODS: We performed a chart review of pediatric patients at our institution who have undergone ONS for the same indications. RESULTS: We identified 3 patients at our institution who underwent ONS trial and/or permanent implantation for ON. One patient had complete pain relief after the trial and declined permanent implantation. The other patient had fewer attacks compared to his pre-trial baseline and controlled them by adjusting his permanent implant stimulation settings. The last patient had near complete relief of her symptoms and no longer required any pain medication. CONCLUSION: Our study highlights the paucity of studies evaluating the utility of ONS in the pediatric ON population. Limited data from both the literature and our institution's experience reveal that pediatric patients may benefit from trial and/or permanent implantation of ONS for medically refractory ON pain.

Sensory computations in the cuneate nucleus of macaques.

Tactile nerve fibers fall into a few classes that can be readily distinguished based on their spatiotemporal response properties. Because nerve fibers reflect local skin deformations, they individually carry ambiguous signals about object features. In contrast, cortical neurons exhibit heterogeneous response properties that reflect computations applied to convergent input from multiple classes of afferents, which confer to them a selectivity for behaviorally relevant features of objects. The conventional view is that these complex response properties arise within the cortex itself, implying that sensory signals are not processed to any significant extent in the two intervening structures-the cuneate nucleus (CN) and the thalamus. To test this hypothesis, we recorded the responses evoked in the CN to a battery of stimuli that have been extensively used to characterize tactile coding in both the periphery and cortex, including skin indentations, vibrations, random dot patterns, and scanned edges. We found that CN responses are more similar to their cortical counterparts than they are to their inputs: CN neurons receive input from multiple classes of nerve fibers, they have spatially complex receptive fields, and they exhibit selectivity for object features. Contrary to consensus, then, the CN plays a key role in processing tactile information.

Case-based explanation of standard work tools for selective dorsal rhizotomy for cerebral palsy.

OBJECTIVE: Spasticity is a challenging feature of cerebral palsy (CP) that may be managed with selective dorsal rhizotomy (SDR). Although standard work tools (SWTs) have recently been utilized to inform a standard of care for neurosurgical procedures, no SWTs for SDR have been previously described. The authors present the multidisciplinary approach SWTs for SDR used at their institutions to promote consistency in the field and minimize complication rates. METHODS: A multidisciplinary approach was used to define all steps in the SDR pathway. Preoperative, intraoperative, and postoperative workflows were synthesized, with specific efforts to improve mobility through inpatient rehabilitation and minimize infection. RESULTS: The SWTs have been implemented at two institutions for 7 years. An illustrative case of a patient aged 3 years 10 months with a history of premature birth at 29 weeks, spastic-diplegic CP, right-sided periventricular leukomalacia, and developmental delay who underwent L2-S1 SDR is presented. CONCLUSIONS: The authors detail SWTs for SDR developed by a multidisciplinary team with specific steps at all points in the patient pathway. The illustrative case emphasizes that SWTs may help ensure the safety of SDR while maximizing its long-term efficacy for individuals with CP.

Anticipation-induced delta phase reset improves human olfactory perception.

Anticipating an odor improves detection and perception, yet the underlying neural mechanisms of olfactory anticipation are not well understood. In this study, we used human intracranial electroencephalography (iEEG) to show that anticipation resets the phase of delta oscillations in piriform cortex prior to odor arrival. Anticipatory phase reset correlates with ensuing odor-evoked theta power and improvements in perceptual accuracy. These effects were consistently present in each individual subject and were not driven by potential confounds of pre-inhale motor preparation or power changes. Together, these findings suggest that states of anticipation enhance olfactory perception through phase resetting of delta oscillations in piriform cortex.

Artifacts Can Be Deceiving: The Actual Location of Deep Brain Stimulation Electrodes Differs from the Artifact Seen on Magnetic Resonance Images.

INTRODUCTION: Deep brain stimulation (DBS) is a common treatment for a variety of neurological and psychiatric disorders. Recent studies have highlighted the role of neuroimaging in localizing the position of electrode contacts relative to target brain areas in order to optimize DBS programming. Among different imaging methods, postoperative magnetic resonance imaging (MRI) has been widely used for DBS electrode localization; however, the geometrical distortion induced by the lead limits its accuracy. In this work, we investigated to what degree the difference between the actual location of the lead's tip and the location of the tip estimated from the MRI artifact varies depending on the MRI sequence parameters such as acquisition plane and phase encoding direction, as well as the lead's extracranial configuration. Accordingly, an imaging technique to increase the accuracy of lead localization was devised and discussed. METHODS: We designed and constructed an anthropomorphic phantom with an implanted DBS system following 18 clinically relevant configurations. The phantom was scanned at a Siemens 1.5 Tesla Aera scanner using a T1MPRAGE sequence optimized for clinical use and a T1TSE sequence optimized for research purposes. We varied slice acquisition plane and phase encoding direction and calculated the distance between the caudal tip of the DBS lead MRI artifact and the actual tip of the lead, as estimated from MRI reference markers. RESULTS: Imaging parameters and lead configuration substantially altered the difference in the depth of the lead within its MRI artifact on the scale of several millimeters - with a difference as large as 4.99 mm. The actual tip of the DBS lead was found to be consistently more rostral than the tip estimated from the MR image artifact. The smallest difference between the tip of the DBS lead and the tip of the MRI artifact using the clinically relevant sequence (i.e., T1MPRAGE) was found with the sagittal acquisition plane and anterior-posterior phase encoding direction. DISCUSSION/CONCLUSION: The actual tip of an implanted DBS lead is located up to several millimeters rostral to the tip of the lead's artifact on postoperative MR images. This distance depends on the MRI sequence parameters and the DBS system's extracranial trajectory. MRI parameters may be altered to improve this localization.

Variations in Determining Actual Orientations of Segmented Deep Brain Stimulation Leads Using the DiODe Algorithm: A Retrospective Study Across Different Lead Designs and Medical Institutions.

INTRODUCTION: Directional deep brain stimulation (DBS) leads have become widely used in the past decade. Understanding the asymmetric stimulation provided by directional leads requires precise knowledge of the exact orientation of the lead in respect to its anatomical target. Recently, the DiODe algorithm was developed to automatically determine the orientation angle of leads from the artifact on postoperative computed tomography (CT) images. However, manual DiODe results are user-dependent. This study analyzed the extent of lead rotation as well as the user agreement of DiODe calculations across the two most common DBS systems, namely, Boston Scientific's Vercise and Abbott's Infinity, and two independent medical institutions. METHODS: Data from 104 patients who underwent an anterior-facing unilateral/bilateral directional DBS implantation at either Northwestern Memorial Hospital (NMH) or Albany Medical Center (AMC) were retrospectively analyzed. Actual orientations of the implanted leads were independently calculated by three individual users using the DiODe algorithm in Lead-DBS and patients' postoperative CT images. The deviation from the intended orientation and user agreement were assessed. RESULTS: All leads significantly deviated from the intended 0° orientation (p < 0.001), regardless of DBS lead design (p < 0.05) or institution (p < 0.05). However, the Boston Scientific leads showed an implantation bias toward the left at both institutions (p = 0.014 at NMH, p = 0.029 at AMC). A difference of 10° between at least two users occurred in 28% (NMH) and 39% (AMC) of all Boston Scientific and 76% (NMH) and 53% (AMC) of all Abbott leads. CONCLUSION: Our results show that there is a significant lead rotation from the intended surgical orientation across both DBS systems and both medical institutions; however, a bias toward a single direction was only seen in the Boston Scientific leads. Additionally, these results raise questions into the user error that occurs when manually refining the orientation angles calculated with DiODe.

An Initial miRNA Profile of Persons With Persisting Neurobehavioral Impairments and States of Disordered Consciousness After Severe Traumatic Brain Injury.

OBJECTIVE: To examine the merits of using microRNAs (miRNAs) as biomarkers of disorders of consciousness (DoC) due to traumatic brain injury (TBI). SETTINGS: Acute and subacute beds. PARTICIPANTS: Patients remaining in vegetative and minimally conscious states (VS, MCS), an average of 1.5 years after TBI, and enrolled in a randomized clinical trial ( n = 6). Persons without a diagnosed central nervous system disorder, neurotypical controls ( n = 5). DESIGN: Comparison of whole blood miRNA profiles between patients and age/gender-matched controls. For patients, correlational analyses between miRNA profiles and measures of neurobehavioral function. MAIN MEASURES: Baseline measures of whole blood miRNAs isolated from the cellular and fluid components of blood and measured using miRNA-seq and real-time polymerase chain reaction (RT-PCR). Baseline neurobehavioral measures derived from 7 tests. RESULTS: For patients, relative to controls, 48 miRNA were significantly ( P < .05)/differentially expressed. Cluster analysis showed that neurotypical controls were most similar to each other and with 2 patients (VS: n = 1; and MCS: n = 1). Three patients, all in MCS, clustered separately. The only female in the sample, also in MCS, formed an independent group. For the 48 miRNAs, the enriched pathways identified are implicated in secondary brain damage and 26 miRNAs were significantly ( P < .05) correlated with measures of neurobehavioral function. CONCLUSIONS: Patients remaining in states of DoC an average of 1.5 years after TBI showed a different and reproducible pattern of miRNA expression relative to age/gender-matched neurotypical controls. The phenotypes, defined by miRNA profiles relative to persisting neurobehavioral impairments, provide the basis for future research to determine the miRNA profiles differentiating states of DoC and the basis for future research using miRNA to detect treatment effects, predict treatment responsiveness, and developing targeted interventions. If future research confirms and advances reported findings, then miRNA profiles will provide the foundation for patient-centric DoC neurorehabilitation.

Management strategies for patients with neurologic stimulators during nonneurologic surgery: an update and review.

PURPOSE OF REVIEW: The goal of this review is to summarize the perioperative management of noncardiac implanted electrical devices (NCIEDs) and update the anesthesiologist on current recommendations for management when a NCIED is encountered during a nonneurosurgical procedure. RECENT FINDINGS: Indications for NCIEDs continue to expand, and increasing numbers of patients with NCIEDs are presenting for nonneurosurgical procedures. Recent case reports demonstrate that NCIEDs may meaningfully affect perioperative management including use of electrocautery and neuromonitoring. This review highlights the importance of evaluating NCIED function (including lead impedance) prior to surgery, provides an update on the MRI compatibility and safety of these devices, and reviews the management of patients with altered respiratory drive because of vagal nerve stimulators. SUMMARY: As the prevalence of NCIEDs in patients presenting for surgery increases, anesthesiologists will likely encounter these devices more frequently. To provide a well tolerated anesthetic, anesthesiologists should recognize the concerns associated with NCIEDs and how best to address them perioperatively.

Ethical considerations in the surgical and neuromodulatory treatment of epilepsy.

Surgical resection and neuromodulation are well-established treatments for those with medically refractory epilepsy. These treatments entail important ethical considerations beyond those which extend to the treatment of epilepsy generally. In this paper, the authors explore these unique considerations through a framework that relates foundational principles of bioethics to features of resective epilepsy surgery and neuromodulation. The authors conducted a literature review to identify ethical considerations for a variety of epilepsy surgery procedures and to examine how foundational principles in bioethics may inform treatment decisions. Healthcare providers should be cognizant of how an increased prevalence of somatic and psychiatric comorbidities, the dynamic nature of symptom burden over time, the individual and systemic barriers to treatment, and variable sociocultural contexts constitute important ethical considerations regarding the use of surgery or neuromodulation for the treatment of epilepsy. Moreover, careful attention should be paid to how resective epilepsy surgery and neuromodulation relate to notions of patient autonomy, safety and privacy, and the shared responsibility for device management and maintenance. A three-tiered approach-(1) gathering information and assessing the risks and benefits of different treatment options, (2) clear communication with patient or proxy with awareness of patient values and barriers to treatment, and (3) long-term decision maintenance through continued identification of gaps in understanding and provision of information-allows for optimal treatment of the individual person with epilepsy while minimizing disparities in epilepsy care.

Cross-Sectional Analysis of US Health Insurance Payer Policies for Humanitarian Device Exemption Indications for Deep Brain Stimulation.

BACKGROUND: The US Food and Drug Administration (FDA) has granted deep brain stimulation (DBS) approval under the humanitarian device exemption (HDE) pathway for both dystonia and obsessive-compulsive disorder (OCD). However, recent reports from the community of functional neurosurgeons suggest that insurance authorization remains a disproportionate barrier to OCD DBS implantation despite both conditions having similar support from the FDA. This cross-sectional study of health insurance policies quantifies the current payer landscape for these two interventions. OBJECTIVES: The aim of this study was to quantify the current payer policy coverage of DBS under HDE status for OCD as compared to DBS for dystonia for eligible patients in the US insurance market. METHODS: A commercial health insurance policy database was queried for documentation on DBS for dystonia and OCD. Results were individually analyzed for payer policy coverage statements on DBS for either dystonia or OCD and categorized as unique or nonunique policies. Unique policy positions were then coded for the geographic region, whether coverage was offered, and guidelines cited as evidence and justification. RESULTS: From the 80 policies in the database, there were 34 unique policies addressing DBS for either dystonia or OCD representing coverage of all 50 states. Of the 34 unique policies, 3 (9%) covered DBS for OCD, while 32 (94%) covered dystonia. Only 2 policies covered neither intervention. CONCLUSIONS: In spite of similar levels of support from the FDA, DBS for OCD has less support from insurance companies on a national level. This study begins to quantify the disparity noted by functional neurosurgeons in recent literature.

Ethical Considerations in the Implantation of Neuromodulatory Devices.

OBJECTIVES: Neuromodulatory devices are increasingly used by neurosurgeons to manage a variety of chronic conditions. Given their potential benefits, it is imperative to create clear ethical guidelines for the use of these devices. We present a tiered ethical framework for neurosurgeon recommendations for the use of neuromodulatory devices. MATERIALS AND METHODS: We conducted a literature review to identify factors neurosurgeons should consider when choosing to offer a neuromodulatory device to a patient. RESULTS: Neurosurgeons must weigh reductions in debilitating symptoms, improved functionality, and preserved quality of life against risks for intraoperative complications and adverse events due to stimulation or the device itself. Neurosurgeons must also evaluate whether patients and families will maintain responsibility for the management of neuromodulatory devices. Consideration of these factors should occur on an axis of resource allocation, ranging from provision of neuromodulatory devices to those with greatest potential benefit in resource-limited settings to provision of neuromodulatory devices to all patients with indications in contexts without resource limitations. Neurosurgeons must also take action to promote device effectiveness throughout the duration of care. CONCLUSIONS: Weighing risks and benefits of providing neuromodulatory devices and assessing ability to remain responsible for the devices on the level of the individual patient indicate which patients are most likely to achieve benefit from these devices. Consideration of these factors on an axis of resource allocation will allow for optimal provision of neuromodulatory devices to patients in settings of varied resources. Neurosurgeons play a primary role in promoting the effectiveness of these devices.

Increased Subthalamic Nucleus Deep Brain Stimulation Amplitude Impairs Inhibitory Control of Eye Movements in Parkinson's Disease.

BACKGROUND AND OBJECTIVES: Bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) can have detrimental effects on eye movement inhibitory control. To investigate this detrimental effect of bilateral STN DBS, we examined the effects of manipulating STN DBS amplitude on inhibitory control during the antisaccade task. The prosaccade error rate during the antisaccade task, that is, directional errors, was indicative of impaired inhibitory control. We hypothesized that as stimulation amplitude increased, the prosaccade error rate would increase. MATERIALS AND METHODS: Ten participants with bilateral STN DBS completed the antisaccade task on six different stimulation amplitudes (including zero amplitude) after a 12-hour overnight withdrawal from antiparkinsonian medication. RESULTS: We found that the prosaccade error rate increased as stimulation amplitude increased (p < 0.01). Additionally, prosaccade error rate increased as the modeled volume of tissue activated (VTA) and STN overlap decreased, but this relationship depended on stimulation amplitude (p = 0.04). CONCLUSIONS: Our findings suggest that higher stimulation amplitude settings can be modulatory for inhibitory control. Some individual variability in the effect of stimulation amplitude can be explained by active contact location and VTA-STN overlap. Higher stimulation amplitudes are more deleterious if the active contacts fall outside of the STN resulting in a smaller VTA-STN overlap. This is clinically significant as it can inform clinical optimization of STN DBS parameters. Further studies are needed to determine stimulation amplitude effects on other aspects of cognition and whether inhibitory control deficits on the antisaccade task result in a meaningful impact on the quality of life.

Encoding of limb state by single neurons in the cuneate nucleus of awake monkeys.

The cuneate nucleus (CN) is among the first sites along the neuraxis where proprioceptive signals can be integrated, transformed, and modulated. The objective of the study was to characterize the proprioceptive representations in CN. To this end, we recorded from single CN neurons in three monkeys during active reaching and passive limb perturbation. We found that many neurons exhibited responses that were tuned approximately sinusoidally to limb movement direction, as has been found for other sensorimotor neurons. The distribution of their preferred directions (PDs) was highly nonuniform and resembled that of muscle spindles within individual muscles, suggesting that CN neurons typically receive inputs from only a single muscle. We also found that the responses of proprioceptive CN neurons tended to be modestly amplified during active reaching movements compared to passive limb perturbations, in contrast to cutaneous CN neurons whose responses were not systematically different in the active and passive conditions. Somatosensory signals thus seem to be subject to a "spotlighting" of relevant sensory information rather than uniform suppression as has been suggested previously.NEW & NOTEWORTHY The cuneate nucleus (CN) is the somatosensory gateway into the brain, and only recently has it been possible to record these signals from an awake animal. We recorded single CN neurons in monkeys. Proprioceptive CN neurons appear to receive input from very few muscles, and their sensitivity to movement changes reliably during reaching relative to passive arm perturbations. Sensitivity is generally increased, but not exclusively so, as though CN "spotlights" critical proprioceptive information during reaching.

Seizure outcome in patients with cavernous malformation after early surgery.

OBJECTIVE: To describe seizure outcome and complications in patients with cavernous malformations (CM) undergoing early versus late surgery. METHODS: A database was created for all CM patients who presented with seizure referred to the neurosurgical clinic at an academic center. A telephone survey and chart review were conducted to evaluate for preoperative and postoperative seizure frequency. Postoperative seizure-free outcome of patients who had ≤2 preoperative seizures versus those that had >2 preoperative seizures was compared. RESULTS: A total of 35 CM patients were included for analysis. Nineteen patients had ≤2 preoperative seizures and 16 patients had >2 preoperative seizures, six of them drug resistant for over two years. Among the ≤2 seizure group, 15 had only a single seizure before surgical resection. 94.7% of patients with ≤2 preoperative seizures and 62.5% of patients with >2 preoperative seizures were seizure free one year following surgical resection (p = 0.019). 78.9% of patients with ≤2 preoperative seizures and 25% of patients with >2 preoperative seizures were able to wean off AEDs (p < 0.001). Among those patients who had a single preoperative seizure, 100% of patients were seizure free at one year. CONCLUSIONS: Early surgical resection for CM patients who present after a CM-related seizure is an effective, well tolerated treatment and has good chance to offer seizure freedom without the need for long-term antiepileptic medications. Outcome for patients operated with only one or two preoperative seizures may lead to better results than patients who delay the procedure.

Prospective Evaluation of the Time Course of White Matter Edema Associated with Implanted Deep Brain Stimulation Electrodes.

INTRODUCTION: Deep brain stimulation (DBS) is commonly used in the treatment of medically refractory movement disorders. There have been several reports in the literature of edema developing around the implanted electrode. Most of these studies have been retrospective, suggesting that the time course and incidence of this edema are underestimated. An understanding of the incidence and time course of edema related to DBS leads is important to allow clinicians to better assess the correct course of action when edema following DBS implantation is observed. METHODS: We examined both the time course and prevalence of edema following DBS implantation by obtaining a series of postoperative MRI scans from patients who underwent DBS surgery. Edema volume was quantified by a single neuroradiologist, measuring the peri-electrode T2 signal change. RESULTS: We examined postoperative MRIs in thirteen patients with fifteen DBS electrode implants. Eleven patients exhibited white matter edema on at least 1 postoperative MRI, with none being symptomatic. Edema was completely resolved in 4 of the electrode implants through postoperative day 70, with the remaining cases still exhibiting edema at the last imaged time point. DISCUSSION/CONCLUSION: In this study, we obtained a regimented series of postoperative MRIs in an effort to determine the time course and incidence of edema. Our results show that edema following DBS implant is not rare, is often asymptomatic, and may resolve over many weeks.

Factors Associated With Implantable Pulse Generator Site Pain: A Multicenter Cross-Sectional Study.

OBJECTIVES: Implantable pulse generator (IPG) site pain following neuromodulation procedures is a recognized complication. The site of the IPG placement varies depending on the neuromodulation type and physician preference. The incidence of IPG site pain as a function of the site of IPG implantation has not been studied systematically. MATERIALS AND METHODS: We performed a multicenter cross-sectional survey of the incidence, severity, and quality of IPG site pain, location of the IPG, the pain management needs, functional impairment, and cosmetic appearance related to the IPG placement. Contingency table analysis was conducted for categorical variables, and logistic regression analysis and linear regression model was used. RESULTS: The survey response rate was 60.5% (n = 510). Overall, 31.0% of patients reported pain at the IPG site in the last 72 hours with 31.4% reporting moderate to severe pain and 7.6% reporting severe pain. Older age was inversely associated with IPG-related pain (OR = 0.97, 95% CI = 0.96-0.99, p = 0.001). IPG implantation site did not have a statistically significant interaction with IPG site pain (p > 0.05). The most important factor for IPG site-associated pain was having a spinal cord stimulator implanted as compared to a deep brain stimulator, or sacral nerve stimulator. Most subjects reported no functional impairment related to IPG site pain (91%), found the IPG site pain as expected (80%), and found IPG site cosmetic appearance as expected (96%). CONCLUSIONS: The incidence of IPG site pain is an important complication of invasive neuromodulation. The anatomic location of the IPG placement does not appear to affect the incidence or severity of IPG site pain. However, the presence of a pre-implant chronic pain disorder does appear to affect the frequency and severity of IPG site pain.

A Pilot Trial Examining the Merits of Combining Amantadine and Repetitive Transcranial Magnetic Stimulation as an Intervention for Persons With Disordered Consciousness After TBI.

OBJECTIVE: Report pilot findings of neurobehavioral gains and network changes observed in persons with disordered consciousness (DoC) who received repetitive transcranial magnetic stimulation (rTMS) or amantadine (AMA), and then rTMS+AMA. PARTICIPANTS: Four persons with DoC 1 to 15 years after traumatic brain injury (TBI). DESIGN: Alternate treatment-order, within-subject, baseline-controlled trial. MAIN MEASURES: For group and individual neurobehavioral analyses, predetermined thresholds, based on mixed linear-effects models and conditional minimally detectable change, were used to define meaningful neurobehavioral change for the Disorders of Consciousness Scale-25 (DOCS) total and Auditory-Language measures. Resting-state functional connectivity (rsFC) of the default mode and 6 other networks was examined. RESULTS: Meaningful gains in DOCS total measures were observed for 75% of treatment segments and auditory-language gains were observed after rTMS, which doubled when rTMS preceded rTMS+AMA. Neurobehavioral changes were reflected in rsFC for language, salience, and sensorimotor networks. Between networks interactions were modulated, globally, after all treatments. CONCLUSIONS: For persons with DoC 1 to 15 years after TBI, meaningful neurobehavioral gains were observed after provision of rTMS, AMA, and rTMS+AMA. Sequencing and combining of treatments to modulate broad-scale neural activity, via differing mechanisms, merits investigation in a future study powered to determine efficacy of this approach to enabling neurobehavioral recovery.

Amygdala-stimulation-induced apnea is attention and nasal-breathing dependent.

OBJECTIVE: Evidence suggests that disordered breathing is critically involved in Sudden Unexpected Death in Epilepsy (SUDEP). To that end, evaluating structures that are activated by seizures and can activate brain regions that produce cardiorespiratory changes can further our understanding of the pathophysiology of SUDEP. Past preclinical studies have shown that electrical stimulation of the human amygdala induces apnea, suggesting a role for the amygdala in controlling respiration. In this study, we aimed to both confirm these findings in a larger group of patients with intractable temporal lobe epilepsy (TLE) and also further explore the anatomical and cognitive properties of this effect. METHODS: Seven surgical TLE patients had depth electrodes implanted in the amygdala that were used to deliver electrical stimulation during functional mapping preceding resection. Real-time respiratory monitoring was performed in each patient to confirm apnea. RESULTS: Our data confirm that amygdala stimulation reliably induces apnea (occurring in all 7 patients) and further suggest that apnea can be overcome by instructing the patient to inhale, and can be prevented entirely by breathing through the mouth before electrical stimulation. Finally, stimulation-induced apnea occurred only when stimulating the medial-most amygdalar contacts located in the central nucleus. INTERPRETATION: These findings confirm a functional connection between the amygdala and respiratory control in humans. Moreover, they suggest specific amygdalar nuclei may be critical in mediating this effect and that attentional state is critical to apnea mediated by amygdala activation-perhaps alluding to future development of strategies for the prevention of SUDEP. Ann Neurol 2018;83:460-471.