A Novel Closed-Loop Electrical Brain Stimulation Device Featuring Wireless Low-Energy Ultrasound Power and Communication.

OBJECTIVES: This study aimed to indicate the feasibility of a prototype electrical neuromodulation system using a closed-loop energy-efficient ultrasound-based mechanism for communication, data transmission, and recharging. MATERIALS AND METHODS: Closed-loop deep brain stimulation (DBS) prototypes were designed and fabricated with ultrasonic wideband (UsWB) communication technology and miniaturized custom electronics. Two devices were implanted short term in anesthetized Göttingen minipigs (N = 2). Targeting was performed using preoperative magnetic resonance imaging, and locations were confirmed postoperatively by computerized tomography. DBS systems were tested over a wide range of stimulation settings to mimic minimal, typical, and/or aggressive clinical settings, and evaluated for their ability to transmit data through scalp tissue and to recharge the DBS system using UsWB. RESULTS: Stimulation, communication, reprogramming, and recharging protocols were successfully achieved in both subjects for amplitude (1V-6V), frequency (50-250 Hz), and pulse width (60-200 µs) settings and maintained for ≥six hours. The precision of pulse settings was verified with <5% error. Communication rates of 64 kbit/s with an error rate of 0.05% were shown, with no meaningful throughput degradation observed. Time to recharge to 80% capacity was <9 minutes. Two DBS systems also were implanted in the second test animal, and independent bilateral stimulation was successfully shown. CONCLUSIONS: The system performed at clinically relevant implant depths and settings. Independent bilateral stimulation for the duration of the study with a 4F energy storage and full rapid recharge were achieved. Continuous function extrapolates to six days of continuous stimulation in future design iterations implementing application specific integrated circuit level efficiency and 15F storage capacitance. UsWB increases energy efficiency, reducing storage requirements and thereby enabling device miniaturization. The device can enable intelligent closed-loop stimulation, remote system monitoring, and optimization and can serve as a power/data gateway to interconnect the intrabody network with the Internet of Medical Things.

Outcome differences between males and females undergoing deep brain stimulation for treatment-resistant depression: systematic review and individual patient data meta-analysis.

BACKGROUND: Treatment-resistant depression (TRD) occurs more commonly in women. Deep brain stimulation (DBS) is an emerging treatment for TRD, and its efficacy continues to be explored. However, differences in treatment outcomes between males and females have yet to be explored in formal analysis. METHODS: A PRISMA-compliant systematic review of DBS for TRD studies was conducted. Patient-level data were independently extracted by two authors. Treatment response was defined as a 50 % or greater reduction in depression score. Percent change in depression scores by gender were evaluated using random-effects analyses. RESULTS: Of 737 records, 19 studies (129 patients) met inclusion criteria. The mean reduction in depression score for females was 57.7 % (95 % CI, 64.33 %-51.13 %), whereas for males it was 35.2 % (95 % CI, 45.12 %-25.23 %) (p < 0.0001). Females were more likely to respond to DBS for TRD when compared to males (OR = 2.44, 95 % CI 1.06, 1.95). These differences varied in significance when stratified by DBS anatomical target, age, and timeframe for responder classification. LIMITATIONS: Studies included were open-label trials with small sample sizes. CONCLUSIONS: Our findings suggest that females with TRD respond at higher rates to DBS treatment than males. Further research is needed to elucidate the implications of these results, which may include connectomic sexual dimorphism, depression phenotype variations, or unrecognized symptom reporting differences. Methodological standardization of outcome scales, granular demographic data, and individual subject outcomes would allow for more robust comparisons between trials.

Noradrenaline tracks emotional modulation of attention in human amygdala.

The noradrenaline (NA) system is one of the brain's major neuromodulatory systems; it originates in a small midbrain nucleus, the locus coeruleus (LC), and projects widely throughout the brain.1,2 The LC-NA system is believed to regulate arousal and attention3,4 and is a pharmacological target in multiple clinical conditions.5,6,7 Yet our understanding of its role in health and disease has been impeded by a lack of direct recordings in humans. Here, we address this problem by showing that electrochemical estimates of sub-second NA dynamics can be obtained using clinical depth electrodes implanted for epilepsy monitoring. We made these recordings in the amygdala, an evolutionarily ancient structure that supports emotional processing8,9 and receives dense LC-NA projections,10 while patients (n = 3) performed a visual affective oddball task. The task was designed to induce different cognitive states, with the oddball stimuli involving emotionally evocative images,11 which varied in terms of arousal (low versus high) and valence (negative versus positive). Consistent with theory, the NA estimates tracked the emotional modulation of attention, with a stronger oddball response in a high-arousal state. Parallel estimates of pupil dilation, a common behavioral proxy for LC-NA activity,12 supported a hypothesis that pupil-NA coupling changes with cognitive state,13,14 with the pupil and NA estimates being positively correlated for oddball stimuli in a high-arousal but not a low-arousal state. Our study provides proof of concept that neuromodulator monitoring is now possible using depth electrodes in standard clinical use.

Combined Responsive Neurostimulation and Focal Resection for Super Refractory Status Epilepticus: A Systematic Review and Illustrative Case Report.

OBJECTIVE: Super-refractory status epilepticus (SRSE) is a neurologic emergency with high mortality and morbidity. Although medical algorithms typically are effective, when they do fail, options may be limited, and neurosurgical intervention should be considered. METHODS: We report a case of SRSE treated acutely with responsive neurostimulation (RNS) and focal surgical resection after intracranial monitoring. We also conducted a systematic review of the literature for neurosurgical treatment of SRSE (e.g., neurostimulation). Only published manuscripts were considered. RESULTS: Our patient's seizure semiology consisted of left facial twitching with frequent evolution to bilateral tonic-clonic convulsions. Stereoelectroencephalography and grid monitoring identified multiple seizure foci. The patient underwent right RNS placement with cortical strip leads over the lateral primary motor and premotor cortex as well as simultaneous right superior temporal and frontopolar resection. Status epilepticus resolved 21 days after surgical resection and placement of the RNS. The systematic review revealed 15 case reports describing 17 patients with SRSE who underwent acute neurosurgical intervention. There were 3 patients with SRSE with RNS placement as a single modality, all of whom experienced cessation of SE. Four patients with SRSE received vagus nerve stimulation (3 as a single modality and 1 with combined corpus callosotomy), of whom 1 had SE recurrence at 2weeks. Two patients with SRSE received deep brain stimulation, and the remaining 8 underwent surgical resection; none had recurrence of SE. CONCLUSIONS: RNS System placement with or without resection can be a viable treatment option for select patients with SRSE. Early neurosurgical intervention may improve seizure outcomes and reduce complications.

Complete seizure-free rates following interventional treatment of intracranial arteriovenous malformations: a systematic review and meta-analysis.

Seizures are common presenting symptoms of intracranial arteriovenous malformations (AVMs). This systematic review and meta-analysis aims to assess the current evidence regarding complete seizure freedom rates following surgical resection, stereotactic radiosurgery (SRS), and/or endovascular embolization of intracranial AVMs. A systematic review of PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Included manuscripts were methodically scrutinized for quality, spontaneous AVM-associated or hemorrhage-associated seizures, complete seizure-free rates following each interventional treatment, follow-up duration; determination methods of seizure outcomes, and average time-to-onset of recurrent seizures after each treatment. Manuscripts that described patients with nondisabling seizures or reduced seizure frequency in their seizure-free calculations were excluded. Seizure freedom rates following surgical resection, SRS, and endovascular embolization were compared via random-effect analysis. Thirty-four studies with a total of 1765 intracranial AVM patients presenting with spontaneous AVM-associated seizures and 408 patients presenting with hemorrhage-associated seizures were qualitatively analyzed. For patients presenting with AVM-associated seizures, the complete seizure-free rates were 73.0% (321/440 patients; 95% CI 68.8-77.1%) following surgical resection, 60.5% (376/622 patients; 95% CI 56.6-64.3%) following SRS, and 44.6% (29/65 patients; 95% CI 32.5-56.7%) following endovascular embolization alone. For patients presenting with either AVM-associated or hemorrhage-associated seizures, the complete seizure-free rates were 73.0% (584/800 patients; 95% CI 69.9-76.1%) following surgical resection, 46.4% (572/1233 patients; 95% CI 43.6-49.2%) following SRS, and 44.6% (29/65 patients; 95% CI 32.5-56.7%) following embolization. For patients presenting with either AVM-associated or hemorrhage-associated seizures, the overall improvements in seizure outcomes regardless of complete seizure freedom were 82.6% (661/800 patients; 95% CI 80.0-85.3%), 70.6% (870/1233 patients; 95% CI 68.0-73.1%), and 70.8% (46/65 patients; 95% CI 59.7-81.1%) following surgical resection, SRS, and embolization, respectively. No study reported information about the time-to-onset for recurrent seizures in any patient following treatment, as seizure outcomes were only described at the last follow-up visit. The available data suggests that surgical resection results in the highest rate of complete seizure freedom. The rate of seizure improvement following surgery increased further to 82.3% when including patients who had improved seizure frequency without achieving true seizure freedom. Complete seizure-free rates following SRS or embolization were more ambiguous and lower when compared to surgical resection. There is a need for high quality studies evaluating AVM treatment modalities and clearly defined seizure outcomes, as the current literature consists mostly of heterogenous patient populations.

Peripheral Nerve Stimulation for Refractory Trigeminal Pain: Recent Single-Institution Case Series With Long-Term Follow-Up and Review of the Literature.

BACKGROUND: Peripheral neurostimulation (PNS) for medically refractory trigeminal pain is an emerging alternative to traditional surgical approaches, with safety and efficacy demonstrated in several retrospective series and a prospective trial currently in progress. Many existing studies suffer from relatively small numbers and short or inconsistent follow-up, making balanced treatment assessment difficult. MATERIALS AND METHODS: Consecutive cases of trial and permanent placement of trigeminal branch stimulation electrodes by a single surgeon from May 2014 through January 2019 were retrospectively reviewed from a prospectively collected database, following the PROCESS guidelines for surgical case series. Outcomes were assessed at six months and at last follow-up. RESULTS: Ninteen patients underwent trial electrode placement, with 15 patients undergoing permanent system placement. The most common diagnoses were idiopathic trigeminal neuralgia Type 2 (N = 8) and trigeminal neuropathic pain (N = 7). Median follow-up was 14 months (range 6-58 months). At last follow-up, 12 of 15 implanted patients (80%) were still receiving stimulation, with mean (median) pain reduction of 52.3% (47.5%). Infection and revision rates were high, although erosion and migration, which have typically plagued trigeminal PNS surgery, did not occur. Implanted systems were well-tolerated, with excellent cosmetic outcomes and high patient satisfaction that proved durable over long follow-up. CONCLUSIONS: We present a single-institution series of PNS for complex craniofacial pain involving the trigeminal nerve. The procedure is safe, effective and durable over at least one year in the large majority of a well-selected patient population.

Altered expression of signaling pathways regulating neuronal excitability in hippocampal tissue of temporal lobe epilepsy patients with low and high seizure frequency.

Despite recent advances in our understanding of synaptic transmission associated with epileptogenesis, the molecular mechanisms that control seizure frequency in patients with temporal lobe epilepsy (TLE) remain obscure. RNA-Seq was performed on hippocampal tissue resected from 12 medically intractable TLE patients with pre-surgery seizure frequencies ranging from 0.33 to 120 seizures per month. Differential expression (DE) analysis of individuals with low (LSF, mean = 4 seizure/month) versus high (HSF, mean = 60 seizures/month) seizure frequency identified 979 genes with ≥2-fold change in transcript abundance (FDR-adjusted p-value ö0.05). Comparisons with post-mortem controls revealed a large number of downregulated genes in the HSF (1676) versus LSF (399) groups. More than 50 signaling pathways were inferred to be deactivated or activated, with Signal Transduction as the central hub in the pathway network. While neuroinflammation pathways were activated in both groups, key neuronal system pathways were systematically deactivated in the HSF group, including calcium, CREB and Opioid signaling. We also infer that enhanced expression of a signaling cascade promoting synaptic downscaling may have played a key role in maintaining a higher seizure threshold in the LSF cohort. These results suggest that therapeutic approaches targeting synaptic scaling pathways may aid in the treatment of seizures in TLE.

Placement and Anchoring of Trigeminal Neurostimulation Electrodes: Technical Report.

BACKGROUND: Peripheral neurostimulation (PNS) for medically refractory trigeminal and craniofacial pain is an emerging alternative to traditional surgical approaches. Technical problems with craniofacial PNS have included electrode migration and erosion, limiting the utility and cost-effectiveness of this procedure. OBJECTIVE: To review our institutional surgical technique for trigeminal PNS implantation, focusing on a novel technique for electrode anchoring. METHODS: Consecutive cases of permanent craniofacial PNS placement by a single surgeon over 36 months were reviewed for surgical technique and technical outcomes. Electrodes were placed percutaneously with open anchoring to the pericranium at a separate parietal incision. RESULTS: Sixteen systems (53 electrodes) were implanted in 14 patients. Median follow-up was 13 months (range, 5-29 months). Electrode placement was successful in all cases with no intraoperative complications. There was 1 lead migration (6.3% per patient; 1.8% per lead) and no cases of erosion. Two patients (14.3%) required explant for infection, 1 of whom was successfully reimplanted. Three patients (21.4%) underwent surgical revision other than for infection. CONCLUSIONS: We present an improved method for craniofacial PNS surgery which introduces a separate incision for electrode anchoring at the parietal boss. This technique simplifies the procedure and greatly reduces rates of erosion and migration, improving patient comfort and satisfaction.

Closed Loop Deep Brain Stimulation for PTSD, Addiction, and Disorders of Affective Facial Interpretation: Review and Discussion of Potential Biomarkers and Stimulation Paradigms.

The treatment of psychiatric diseases with Deep Brain Stimulation (DBS) is becoming more of a reality as studies proliferate the indications and targets for therapies. Opinions on the initial failures of DBS trials for some psychiatric diseases point to a certain lack of finesse in using an Open Loop DBS (OLDBS) system in these dynamic, cyclical pathologies. OLDBS delivers monomorphic input into dysfunctional brain circuits with modulation of that input via human interface at discrete time points with no interim modulation or adaptation to the changing circuit dynamics. Closed Loop DBS (CLDBS) promises dynamic, intrinsic circuit modulation based on individual physiologic biomarkers of dysfunction. Discussed here are several psychiatric diseases which may be amenable to CLDBS paradigms as the neurophysiologic dysfunction is stochastic and not static. Post-Traumatic Stress Disorder (PTSD) has several peripheral and central physiologic and neurologic changes preceding stereotyped hyper-activation behavioral responses. Biomarkers for CLDBS potentially include skin conductance changes indicating changes in the sympathetic nervous system, changes in serum and central neurotransmitter concentrations, and limbic circuit activation. Chemical dependency and addiction have been demonstrated to be improved with both ablation and DBS of the Nucleus Accumbens and as a serendipitous side effect of movement disorder treatment. Potential peripheral biomarkers are similar to those proposed for PTSD with possible use of environmental and geolocation based cues, peripheral signs of physiologic arousal, and individual changes in central circuit patterns. Non-substance addiction disorders have also been serendipitously treated in patients with OLDBS for movement disorders. As more is learned about these behavioral addictions, DBS targets and effectors will be identified. Finally, discussed is the use of facial recognition software to modulate activation of inappropriate responses for psychiatric diseases in which misinterpretation of social cues feature prominently. These include Autism Spectrum Disorder, PTSD, and Schizophrenia-all of which have a common feature of dysfunctional interpretation of facial affective clues. Technological advances and improvements in circuit-based, individual-specific, real-time adaptable modulation, forecast functional neurosurgery treatments for heretofore treatment-resistant behavioral diseases.

Difficult Vascular Access Anatomy Associated with Decreased Success of Revascularization in Emergent Thrombectomy.

BACKGROUND: Thrombectomy has become established as a successful treatment strategy for ischemic stroke, and consequently, more patients are undergoing this procedure. Due to comorbid conditions, chronic disease states, and advanced age, many patients have anatomy which complicates revascularization, specifically difficult aortic arch anatomy, or tortuous common and internal artery anatomy, or both. METHODS: In the present study, these unfavorable anatomic parameters were analyzed for 53 patients undergoing acute thrombectomy for ischemic stroke. Statistical analysis was performed and the outcome TICI scores were compared. 26 of the patients analyzed had features of difficult femoral access. RESULTS: Difficult arch anatomy was associated with unsuccessful revascularization (p = 0.03, Fisher's exact) with only 53% of patients with this feature having favorable TICI scores. Difficult common carotid access was also associated with unsuccessful revascularization (p = 0.004, Fisher's exact) with 38% success. There was a trend toward significance for unsuccessful revascularization for difficult internal carotid artery access (p = 0.06, Fisher's exact). CONCLUSION: Any combination of the aforementioned anatomic parameters was associated with the decreased success of treatment which was an independent predictor in multivariate analysis (p = 0.009). As difficult access anatomy is commonly encountered in patients undergoing emergent thrombectomy, it is important for the treating physician to be prepared and to adapt access strategies to increase the likelihood of successful revascularization.

Sacroiliac Fusion: Another "Magic Bullet" Destined for Disrepute.

Pain related to joint dysfunction can be treated with joint fusion; this is a long-standing principle of musculoskeletal surgery. However, pain arising from the sacroiliac (SI) joint is difficult to diagnose. Several implant devices are available that promote fusion by simply crossing the joint space. Evidence establishing outcomes is misleading because of vague diagnostic criteria, flawed methodology, bias, and limited follow-up. Because of nonstandardized indications and historically inferior reconstruction techniques, SI joint fusion should be considered unproven. The indications and procedure in their present form are unlikely to stand up to close scrutiny or weather the test of time.

Measuring Quality of Neurosurgical Care: Readmission Is Affected by Patient Factors.

OBJECTIVE: The Hospital Readmission Reduction Program section of the Patient Protection and Affordable Care Act uses readmission rates as a proxy for measuring quality of care. Multiple studies have demonstrated that readmission rates are highly imprecise proxies for quality of care because readmission rates contain large amounts of statistical noise and are dependent on disease type, insurance type, severity, population, and a multitude of other factors. The current study was conducted to investigate characteristics associated with readmission and the quality of neurosurgical care. METHODS: Admissions data were gleaned from the University Health System Consortium database for neurosurgical patient (both cranial and spine) readmissions to assess patient-related factors relating to readmission from January 2011 to December 2014. RESULTS: Among 257,212 admissions for neurosurgical disease analyzed, patients with Medicaid and private payers as a primary insurance source had increased rates of readmission (odds ratio for readmission of 1.38 and 1.17, respectively) compared with patients with Medicare or other primary insurers. Patients with greater severity of disease and emergent or urgent admission also had statistically significant rates of readmission. CONCLUSIONS: The findings suggest that readmission is affected by patient factors that are beyond the control of treating physicians. These findings also suggest that readmission rates may not be a good proxy for measurement of quality of care in neurosurgical patients.

On resident duty hour restrictions and neurosurgical training: review of the literature.

Within neurosurgery, the national mandate of the 2003 duty hour restrictions (DHR) by the Accreditation Council for Graduate Medical Education (ACGME) has been controversial. Ensuring the proper education and psychological well-being of residents while fulfilling the primary purpose of patient care has generated much debate. Most medical disciplines have developed strategies that address service needs while meeting educational goals. Additionally, there are numerous studies from those disciplines; however, they are not specifically relevant to the needs of a neurosurgical residency. The recent implementation of the 2011 DHR specifically aimed at limiting interns to 16-hour duty shifts has proven controversial and challenging across the nation for neurosurgical residencies--again bringing education and service needs into conflict. In this report the current literature on DHR is reviewed, with special attention paid to neurosurgical residencies, discussing resident fatigue, technical training, and patient safety. Where appropriate, other specialty studies have been included. The authors believe that a one-size-fits-all approach to residency training mandated by the ACGME is not appropriate for the training of neurosurgical residents. In the authors' opinion, an arbitrary timeline designed to limit resident fatigue limits patient care and technical training, and has not improved patient safety.

Surgical anatomy of the minimally invasive lateral lumbar approach.

The lateral lumbar interbody fusion approach (LLIF), which encompasses the extreme lateral interbody fusion or direct lateral interbody fusion techniques, has gained popularity as an alternative to traditional posterior approaches. With rapidly expanding applications, this minimally invasive surgery (MIS) approach is now utilized in basic degenerative pathologies as well as complex lumbar degenerative deformities and tumors. Given the intimate relationship of the psoas muscle, and hence the lumbar plexus, to this MIS approach, several authors have examined the surgical anatomy of this approach. Understanding this regional neural anatomy is imperative given the potential for serious injuries to both the motor and sensory nerves of the lumbar plexus. In this review, we critically and comprehensively discuss all published studies detailing the surgical anatomy of the lateral lumbar approach with respect to the MIS LLIF techniques. This is a timely review given the rapidly growing number of surgeons utilizing this technique.

Knockdown of tropomyosin-related kinase B receptor expression in the nucleus accumbens shell prevents intermittent social defeat stress-induced cross-sensitization to amphetamine in rats.

The nucleus accumbens (NAc) is a critical brain region for the rewarding effects of drugs of abuse. Brain-derived neurotrophic factor (BDNF) can facilitate stress- and drug-induced neuroadaptation in the mesocorticolimbic system. BDNF-containing projections to the NAc originate from the ventral tegmental area (VTA) and the prefrontal cortex, and BDNF release activates tropomyosin-related kinase B (TrkB). In this study, we examined the necessity for BDNF-TrkB signaling in the NAc shell during social defeat stress-induced cross-sensitization to amphetamine. Adeno-associated virus expressing short hairpin RNA directed against TrkB (AAV-shTrkB) was infused bilaterally into the NAc shell to knock down TrkB, whereas AAV-GFP (green fluorescent protein) was used as the control virus. Rats were exposed to intermittent social defeat stress or handling procedures; amphetamine challenge was given at 10 days after the last defeat and locomotor activity was measured. Stressed rats that received the control virus showed cross-sensitization to amphetamine compared with the handled rats. In contrast, NAc TrkB knockdown prevented social defeat stress-induced cross-sensitization. TrkB knockdown in the NAc was found to reduce the level of phospho-extracellular signal-regulated kinase 1 in this region. NAc TrkB knockdown also prevented stress-induced elevation of BDNF and the glutamate receptor type 1 (GluA1) subunit of AMPA receptor in the VTA, as well as ΔFosB expression in the NAc. These findings indicated that BDNF-TrkB signaling in the NAc shell was required for social defeat stress-induced cross-sensitization. NAc TrkB-BDNF signaling also appeared to be involved in the regulation of GluA1 in the VTA, as well as in the NAc ΔFosB accumulation that could trigger cross-sensitization after social defeat stress.