An update on advanced therapies for Parkinson's disease: From gene therapy to neuromodulation.

Advanced Parkinson's disease (PD) is characterized by increasingly debilitating impaired movements that include motor fluctuations and dyskinesias. At this stage of the disease, pharmacological management can result in unsatisfactory clinical benefits and increase the occurrence of adverse effects, leading to the consideration of advanced therapies. The scope of this review is to provide an overview of currently available therapies for advanced PD, specifically levodopa-carbidopa intestinal gel, continuous subcutaneous apomorphine infusion, radiofrequency ablation, stereotactic radiosurgery, MRI-guided focused ultrasound, and deep brain stimulation. Therapies in clinical trials are also discussed, including novel formulations of subcutaneous carbidopa/levodopa, gene-implantation therapies, and cell-based therapies. This review focuses on the clinical outcomes and adverse effects of the various therapies and also considers patient-specific characteristics that may influence treatment choice. This review can equip providers with updated information on advanced therapies in PD to better counsel patients on the available options.

Utilization of epilepsy surgery in the United States: A study of the National Inpatient Sample investigating the roles of race, socioeconomic status, and insurance.

BACKGROUND: Epilepsy is estimated to affect 70 million people worldwide and is medically refractory in 30% of cases. METHODS: This is a retrospective cross-sectional study using a US database from 2012 to 2014 to identify patients aged ≥18 years admitted to the hospital with epilepsy as the primary diagnosis. The sampled population was weighted using Healthcare Cost and Utilization Project guidelines. Procedural ICD-9 codes were utilized to stratify the sampled population into two cohorts: resective surgery and implantation or stimulation procedure. RESULTS: Query of the database yielded 152,925 inpatients, of which 8535 patients underwent surgical intervention. The nonprocedural group consisted of 76,000 White patients (52.6%) and 28,390 Black patients (19.7%) while the procedural group comprised 5550 White patients (64%) and 730 Black patients (8.6%) (P < 0.001). Patients with Medicare were half as likely to receive a surgical procedure (14.8% vs. 28.4%) while patients with private insurance were twice as likely to receive a procedure (53.4% vs. 29.3%), both were statistically significant (P < 0.01). Those in the lowest median household income quartile by zip code (<$40,000) were 68% less likely to receive a procedure (21.5% vs. 31.4%) while the highest income quartile was 133% more likely to receive a procedure (26.1% vs. 19.5%). Patients from rural and urban nonteaching hospitals were, by a wide margin, less likely to receive a surgical procedure. CONCLUSION: We demonstrate an area of need and significant improvement at institutions that have the resources and capability to perform epilepsy surgery. The data show that institutions may not be performing enough epilepsy surgery as a result of racial and socioeconomic bias. Admissions for epilepsy continue to increase without a similar trend for epilepsy surgery despite its documented effectiveness. Race, socioeconomic status, and insurance all represent significant barriers in access to epilepsy surgery. The barriers can be remedied by improving referral patterns and implementing cost-effective measures to improve inpatient epilepsy services in rural and nonteaching hospitals.

National Resident Matching Program Performance Among US MD and DO Seniors in the Early Single Accreditation Graduate Medical Education Era.

INTRODUCTION: As of the 2020 National Resident Matching Program (NRMP), nearly all applicants are evaluated together for graduate medical education (GME) candidacy. We set out to characterize US MD and DO Senior residency match performance in the single-accreditation GME era. METHODS: A retrospective study was conducted in 2021 utilizing data collected from the 2018 and 2020 NRMP Charting Outcomes in the Match publications aggregated and subdivided into three groups based on competitiveness: low (LC), moderate (MC), and high (HC). Nonparametric analysis was performed using Chi square or Fisher exact tests if counts were less than five. Significance was determined at p < 0.05. RESULTS: A total of 46,853 candidates were included, with 36,194 (77.3%) US MD and 10,659 (22.7%) DO Seniors. Match rates for US DO Seniors were lower than US MD Seniors across all competitiveness strata (p < 0.0001). Research item production, national licensing examination scores, and mean number of contiguous programs ranked were lower for matched US DO Seniors compared to matched US MD Seniors, with significant differences depending on competitiveness group. CONCLUSIONS: With recent changes to GME and its application process, understanding how various groups compare will be increasingly important. US DO Seniors have lower first-rank match rates for all specialty competitiveness levels. This may be due to lower research output or nuanced specialty selection. This study could aid GME stakeholders to more effectively allocate resources and better prepare residency candidates.

How neuropsychiatric comorbidity, modulatory indication, demographics, and other factors impact deep brain stimulation inpatient outcomes in the United States: A population-based study of 27,956 patients.

OBJECTIVE: To determine how neuropsychiatric comorbidity, modulatory indication, demographics, and other characteristics affect inpatient deep brain stimulation (DBS) outcomes. METHODS: This is a retrospective study of 45 months' worth of data from the National Inpatient Sample. Patients were aged ≥ 18 years old and underwent DBS for Parkinson Disease (PD), essential tremor (ET), general dystonia and related disorders, other movement disorder (non-PD/ET), or obsessive-compulsive disorder (OCD) at a US hospital. Primary endpoints were prolonged length of stay (PLOS), high-end hospital charges (HEHCs), unfavorable disposition, and inpatient complications. Logistic models were constructed with odds ratios under 95% confidence intervals. A p-value of 0.05 determined significance. RESULTS: Of 214,098 records, there were 27,956 eligible patients. Average age was 63.9 ± 11.2 years, 17,769 (63.6%) were male, and 10,182 (36.4%) patients were female. Most of the cohort was White (51.1%), Medicare payer (64.3%), and treated at a large-bed size (80.7%), private non-profit (76.9%), and metro-teaching (94.0%) hospital. Neuropsychiatric comorbidity prevalence ranged from 29.9% to 47.7% depending on indication. Compared with PD, odds of complications and unfavorable disposition were significantly higher with other movement disorders and dystonia, whereas OCD conferred greater risk for HEHCs (p < 0.05). Patients with ET had favorable outcomes. Neuropsychiatric comorbidity, Black race, and Charlson Comorbidity Index > 0 were significantly associated with unfavorable outcomes (p < 0.05). CONCLUSION: The risk of adverse inpatient outcomes for DBS in the United States is independently correlated with non-PD/ET disorders, neuropsychiatric comorbidity, and non-White race, reflecting the heterogeneity and infancy of widespread DBS for these patients.

Inflammatory Markers in Severity of Intracerebral Hemorrhage II: A Follow Up Study.

Introduction Spontaneous intracerebral hemorrhage (ICH) results in significant morbidity and mortality. The pathogenesis of brain injury after ICH is thought to be due to mechanical damage followed by ischemic, cytotoxic, and inflammatory changes in the underlying and surrounding tissue. Various inflammatory and non-inflammatory biomarkers have been studied as predictors and potential therapeutic targets for intracerebral hemorrhage. Our prior study showed an association with low vascular endothelial growth factor (VEGF) levels and increased mortality. This current study looks to expand on our prior results and will look at the relationship between tumor necrosis factor alpha (TNFα), C-reactive protein (CRP), VEGF, Homocysteine (Hcy), and CRP to albumin ratio (CAR) in predicting outcomes and severity in spontaneous intracerebral hemorrhage. Methods We conducted a retrospective chart review of patients with spontaneous intracerebral hemorrhage with TNFα, CRP, VEGF, Hcy levels drawn on admission. Albumin and CRP levels on admission were used to calculate CAR. Ninety-nine patients were included in the study. Primary outcomes included death, early neurologic decline (END), and hemorrhage size. Secondary outcomes included late neurologic decline (LND), Glasgow Coma Scale (GCS) on admission, GCS on discharge, ICH score, change in hemorrhage size, need for surgical intervention, and length of ICU stay. Results A total of 99 patients were included in this study, with 42% requiring surgical intervention and an overall mortality of 16%. Basal ganglia hemorrhage was seen in 41% of patients. Hcy and CAR were significantly correlated with ICH size in basal ganglia patients (r-=0.36, p=0.03; r=0.43, p=0.03, respectively). CAR was significantly correlated with ICH score (r=0.33, p=0.007874). Admission VEGF levels less than 45 pg/ml had 8.4-fold increase in mortality (odds ratio [OR] 8.4545, p=0.0488). Patients with TNFα levels greater than 1.40 pg/ml had a 4.1-fold increase in mortality (OR 4.1, p=0.04) Conclusion Our study demonstrated that low levels (<45 pg/ml) of VEGF were associated with an 8.4-fold increase in mortality, supporting the neuroprotective effect of this protein. Elevated Hcy and CAR levels were associated with an increase in hemorrhage size in patients with basal ganglia hemorrhages. TNFα levels greater than 1.40 pg/ml were associated with a 4.1-fold increase in mortality, and this together with CAR being correlated with increased hemorrhage size and ICH score further demonstrate the inflammatory consequences after intracerebral hemorrhage. Future studies directed at lowering CRP, TNFα, and Hcy and/or increasing VEGF in intracerebral hemorrhage patients are needed and may be beneficial.

Generalized Dystonia Treated With Deep Brain Stimulator: An Institutional Single Surgeon Experience.

Introduction Dystonia can cause severe disability when left untreated. Once a patient has exhausted medical management, surgical intervention may be the only treatment option. Although not curative, deep brain stimulation has been shown to be beneficial for patients affected by this condition. Our study sought to review patients undergoing deep brain stimulation for medically refractory dystonia to assess outcomes. Methods Our institution's operative database was reviewed retrospectively for all patients undergoing deep brain stimulator placement over the last six years. These medical records were reviewed for the severity of dystonia preoperatively and followed postoperatively for 24 months, focusing on the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). Patients with less than two-year postoperative follow-up were excluded from the study. The patients were further stratified by age into Group A, consisting of patients less than 40 years old, and Group B, patients greater than or equal to 40 years old. Other attributes such as age, sex, age of disease onset, disease duration at the time of surgery, genetic tests for dystonia-related genes, and any complication associated with surgery were also reviewed. Results Four hundred fifty-five operative cases for deep brain stimulator placement were reviewed, and 16 patients met inclusion criteria for the study. The mean age for our patient cohort was 43.75 years, with four males and 12 females. The average time from the age of disease onset to time of surgery was 9.7 years for Group A and 10.8 years for Group B; the overall average was 10.3 years. All patients had globus pallidus interna (GPi) as their surgical target. The first incidence of a statistically significant decrease in BFMDRS score was noted at three months postoperatively (p<0.001) when compared to preoperative values. Fourteen patients in our cohort underwent preoperative genetic testing for DYT gene mutations, out of which four were found to have a mutation. Conclusion Our review of outcomes for primary generalized dystonia at our institution found that deep brain stimulator targeting the GPi is safe and effective. We found an overall 88% response rate with younger patients (< 40-year-old) showing a better response at two years than older patients.

Pneumocephalus causing oculomotor nerve palsy: A case report.

BACKGROUND: Pneumocephalus, the presence of gas or air within the intracranial cavity, is a common finding after cranial procedures, though patients often remain asymptomatic. Rare cases of cranial nerve palsies in patients with pneumocephalus have been previously reported. However, only two prior reports document direct unilateral compression of the third cranial nerve secondary to pneumocephalus, resulting in an isolated deficit. CASE DESCRIPTION: A 26-year-old male developed a unilateral oculomotor (III) nerve palsy after repair of a cerebrospinal fluid leak. The pneumocephalus was treated with a combination of an epidural drain, external ventricular drain (EVD), and high-flow oxygen. Following treatment, repeat computed tomography imaging of the head demonstrated that the pneumocephalus was progressively resorbed and the patient's deficit resolved. CONCLUSION: In rare cases, isolated cranial nerve palsies, specifically of the third cranial nerve, can result from pneumocephalus following cranial procedures. Acute cranial nerve palsy secondary to pneumocephalus will often resolve without intervention as the air is resorbed, but direct decompression with an epidural drain and an EVD may expedite the resolution of deficits.

Pentobarbital Coma With Therapeutic Hypothermia for Treatment of Refractory Intracranial Hypertension in Traumatic Brain Injury Patients: A Single Institution Experience.

Introduction Traumatic brain injury (TBI) results in primary and secondary brain injuries. Secondary brain injury can lead to cerebral edema resulting in increased intracranial pressure (ICP) secondary to the rigid encasement of the skull. Increased ICP leads to decreased cerebral perfusion pressure which leads to cerebral ischemia. Refractory intracranial hypertension (RICH) occurs when ICP remains elevated despite first-tier therapies such as head elevation, straightening of the neck, analgesia, sedation, paralytics, cerebrospinal fluid (CSF) drainage, mannitol and/or hypertonic saline administration. If unresponsive to these measures, second-tier therapies such as hypothermia, barbiturate infusion, and/or surgery are employed. Methods This was a retrospective review of patients admitted at Arrowhead Regional Medical Center from 2008 to 2019 for severe TBI who developed RICH requiring placement into a pentobarbital-induced coma with therapeutic hypothermia. Primary endpoints included mortality, good recovery which was designated at Glasgow outcome scale (GOS) of 4 or 5, and improvement in ICP (goal is <20 mmHg). Secondary endpoints included complications, length of intensive care unit (ICU) stay, length of hospital stay, length of pentobarbital coma, length of hypothermia, need for vasopressors, and decompressive surgery versus no decompressive surgery. Results Our study included 18 patients placed in pentobarbital coma with hypothermia for RICH. The overall mortality rate in our study was 50%; with 60% mortality in pentobarbital/hypothermia only group, and 46% mortality in surgery plus pentobarbital/hypothermia group. Maximum ICP prior to pentobarbital/hypothermia was significantly lower in patients who had a prior decompressive craniectomy than in patients who were placed into pentobarbital/hypothermia protocol first (28.3 vs 35.4, p<0.0238). ICP was significantly reduced at 4 hours, 8 hours, 12 hours, 24 hours, and 48 hours after pentobarbital and hypothermia treatment. Initial ICP and maximum ICP prior to pentobarbital/hypothermia was significantly correlated with mortality (p=0.022 and p=0.026). Patients with an ICP>25 mmHg prior to pentobarbital/hypothermia initiation had an increased risk of mortality (p=0.0455). There was no statistically significant difference in mean ICP after 24 hours after pentobarbital/hypothermia protocol in survivors vs non-survivors. Increased time to reach 33°C was associated with increased mortality (r=0.47, p=0.047); with a 10.5-fold increase in mortality for >7 hours (OR 10.5, p=0.039). Conclusion Prolonged cooling time >7 hours was associated with a 10.5-fold increase in mortality and ICP>25 mmHg prior to initiation of pentobarbital and hypothermia is suggestive of a poor response to treatment. We recommend patients with severe TBI who develop RICH should first undergo a 12 x 15 cm decompressive hemicraniectomy because they have better survival and are more likely to have ICP <25 mmHg as the highest elevation of ICP if the ICP were to become and stay elevated again. Pentobarbital and hypothermia should be initiated if the ICP becomes elevated and sustained above 20 mmHg with a prior decompressive hemicraniectomy and refractory to other medical therapies. However, our data suggests that patients are unlikely to survive if there ICP does not decrease to less than 15mmHg at 8 and 12 hours after pentobarbital/hypothermia and remain less than 20 mmHg within first 48 hours.

Primary Angiitis of the Central Nervous System Presenting as a Cerebral Mass Lesion: A Case Report and Literature Review.

Primary angiitis of the central nervous system (PACNS) is a rare form of vasculitis and is confined entirely to the central nervous system (CNS)without systemic involvement. We report a rare case of PACNS in a 39-year-old female with new onset seizures and a right frontal enhancing mass. Initially the patient was thought to have a high-grade glioma and thus underwent a right frontal craniotomy for resection of right frontal mass. Intraoperatively, two fresh tissue samples were sent for intraoperative consultation. Sample 1 showed predominantly necrotic tissue and scant glial cells while sample 2 revealed glial tissue favoring gliosis versus low-grade neoplasm with necrosis and a few acute inflammatory cells. Final pathological diagnosis was consistent with PACNS. Postoperatively, the patient recovered well from surgery with no neurological deficits and was discharged on postoperative day 3. Two weeks after surgery the patient was started on cyclophosphamide and prednisone by Rheumatology. At one month follow up, the patient remained asymptomatic and seizure free.

The Unsuccessful Twiddler: A Case of Twiddler's Syndrome Without Deep Brain Stimulator Lead Breakage.

The authors present the case of a 78-year-old right-handed female with a past medical history of Parkinson's disease, treated with implantation of a left-sided subthalamic nucleus St. Jude Medical Infinity® (Abbott Medical, Austin, TX) deep brain stimulator, who presented with lead-associated discomfort, or "bowstringing". Further investigation by chest X-ray revealed an extensive case of distal lead coiling. However, it was surprising that, despite the extensive coiling, the lead stayed intact without hardware failure as proven by patient remaining asymptomatic from her Parkinson's disease and intraoperative impedance testing demonstrating normal results. After revision surgery, the patient remained asymptomatic. Due to paucity of cases of this disease in the literature, specific predictive risk factors are not known, but certain patient characteristics may help take precautions.

Resolution of tardive tremor after bilateral subthalamic nucleus deep brain stimulation placement.

BACKGROUND: Tardive tremor (TT) is an underrecognized manifestation of tardive syndrome (TS). In our experience, TT is a rather common manifestation of TS, especially in a setting of treatment with aripiprazole, and is a frequent cause of referrals for the evaluation of idiopathic Parkinson disease. There are reports of successful treatment of tardive orofacial dyskinesia and dystonia with deep brain stimulation (DBS) using globus pallidus interna (GPi) as the primary target, but the literature on subthalamic nucleus (STN) DBS for tardive dyskinesia (TD) is lacking. To the best of our knowledge, there are no reports on DBS treatment of TT. CASE DESCRIPTION: A 75-year-old right-handed female with the medical history of generalized anxiety disorder and major depressive disorder had been treated with thioridazine and citalopram from 1980 till 2010. Around 2008, she developed orolingual dyskinesia. She was started on tetrabenazine in June 2011. She continued to have tremors and developed Parkinsonian gait, both of which worsened overtime. She underwent DBS placement in the left STN in January 2017 with near-complete resolution of her tremors. She underwent right STN implantation in September 2017 with similar improvement in symptoms. CONCLUSION: While DBS-GPi is the preferred treatment in treating oral TD and dystonia, DBS-STN could be considered a safe and effective target in patients with predominating TT and/or tardive Parkinsonism. This patient saw a marked improvement in her symptoms after implantation of DBS electrodes, without significant relapse or recurrence in the years following implantation.

Infections in Deep Brain Stimulator Surgery.

INTRODUCTION: Deep brain stimulation has emerged as an effective treatment for movement disorders such as Parkinson's disease, dystonia, and essential tremor with estimates of >100,000 deep brain stimulators (DBSs) implanted worldwide since 1980s. Infections rates vary widely in the literature with rates as high as 25%. Traditional management of infection after deep brain stimulation is systemic antibiotic therapy with wound incision and debridement (I&D) and removal of implanted DBS hardware. The aim of this study is to evaluate the infections occurring after DBS placement and implantable generator (IPG) placement in order to better prevent and manage these infections. MATERIALS/METHODS: We conducted a retrospective review of 203 patients who underwent implantation of a DBS at a single institution. For initial electrode placement, patients underwent either unilateral or bilateral electrode placement with implantation of the IPG at the same surgery and IPG replacements occurred as necessary. For patients with unilateral electrodes, repeat surgery for placement of contralateral electrode was performed when desired. Preoperative preparation with ethyl alcohol occurred in all patients while use of intra-operative vancomycin powder was surgeon dependent. All patients received 24 hours of postoperative antibiotics. Primary endpoint was surgical wound infection or brain abscess located near the surgically implanted DBS leads. Infections were classified as early (<90 days) or late (>90 days). Infectious organisms were recorded based on intra-operative wound cultures. Number of lead implantations, IPG replacements and choice of presurgical, intra-operative, and postsurgical antibiotics were recorded and outcomes compared. RESULTS: Two hundred and three patients underwent 391 electrode insertions and 244 IPG replacements. Fourteen patients developed an infection (10 early versus 4 late); 12 after implantation surgery (3%) and 2 after IPG replacement surgery (0.8%). No intracranial abscesses were found. Most common sites were the chest and connector. Staphylococcus aureus (MSSA) was the most common organism. Intra-operative vancomycin powder did not decrease infection risk. Vancomycin powder use was shown to increase risk of infection after electrode implantation surgery (Relative Risk 5.5080, p = 0.02063). Complete hardware removal occurred in eight patients, one patient had electrode only removal, three patients with I&D and no removal of hardware, and two patients with removal of IPG and extensor cables only. All patients were treated with postoperative intravenous antibiotics and no recurrent infections were found in patients with hardware left in place. DISCUSSION/CONCLUSION: Infections after DBS implantation and IPG replacement occurred in 3% and 0.8% of patients respectively in our study which is lower than reported historically. Early infections were more common. No intracranial infections were found. Intra-operative use of vancomycin was not shown to decrease risk of infection after electrode implantation surgery or IPG replacement. However, in our study it was shown to increase risk of infection after electrode implantation surgery. Treatment includes antibiotic therapy and debridement with or without removal of hardware. DBS hardware can be safely left in place in select patients who may have significant adverse effects if it is removed.

Safety of the transventricular approach to deep brain stimulation: A retrospective review.

BACKGROUND: Anatomically, deep brain stimulation (DBS) targets such as the ventral intermediate and subthalamic nucleus are positioned such that the long axis of the nucleus is often most accessible through a transventricular trajectory. We hypothesize that using this trajectory does not place patients at increased risk of neurologic complications. METHODS: A series of 206 patients at a single institution between 2000 and 2017 were reviewed. All patients had a confirmed transventricular trajectory and their clinical course was reviewed to assess neurologic complication rates in the postoperative period. RESULTS: The average length of hospital stay was 2.4 days. The most common neurologic complication was altered mental status in 1.2% of cases (four patients). This was followed by seizure in 0.6% of cases (two patients). No patients had ischemic stroke or postoperative hemiparesis. There were two mortalities in this series, one with lobar hemorrhage contralateral from the surgical site and one with a thalamic hemorrhage. There was only one confirmed intraventricular hemorrhage postoperatively; however, this was clinically asymptomatic. CONCLUSION: Although the total incidence of intraventricular or intracerebral hemorrhage cannot be reliably assessed from this data set, the low incidence of neurologic complications challenges the notion that DBS electrode trajectories that transgress the ventricle significantly increase the risk of complications.

Diagnosis of Rhinocerebral Mucormycosis by Treatment of Cavernous Right Internal Carotid Artery Occlusion With Mechanical Thrombectomy: Special Case Presentation and Literature Review.

Background: Mucormycosis is a rapidly progressive, angioinvasive fungal infection that has a predilection for the paranasal sinuses and adjacent mucosa. Rhinocerebral mucormycosis (RCM) is the most common form and is known to invade the skull base and its associated blood vessels-leading to mycotic aneurysms, ischemic infarcts, and intracerebral hemorrhage. There are documented cases of mechanical thrombectomy in ischemic stroke due to RCM, however, there are no known cases that were diagnosed primarily by histological and pathological analysis of the embolus. We present a case of treatment of large vessel occlusion that led to the diagnosis and treatment of RCM. Case Presentation: A 21 year-old male inmate with history of type 1 diabetes presented with generalized weakness, abdominal pain, right eye blindness, and ophthalmoplegia after an assault in prison. He underwent treatment for diabetic ketoacidosis, but subsequently developed left hemiplegia and was found to have complete occlusion of his right internal carotid artery. He underwent successful mechanical thrombectomy and pathological analysis of the embolus revealed a diagnosis of mucormycosis. He completed a course of amphotericin B, micafungin, and posaconazole. With the aid of acute rehabilitation he achieved a modified Rankin score of 2. Discussion: We review the pathogenesis, diagnosis, and treatment of RCM. A comprehensive multidisciplinary approach is critical in the management of this often-fatal disease. Early diagnosis and treatment are essential in RCM as delaying treatment by more than 6 days significantly increases mortality. Treatment includes surgical debridement and intravenous antifungal therapy (amphotericin B + micafungin or caspofungin) for a minimum of 6-8 weeks.

Scalable, Modular Three-Dimensional Silicon Microelectrode Assembly via Electroless Plating.

We devised a scalable, modular strategy for microfabricated 3-D neural probe synthesis. We constructed a 3-D probe out of individual 2-D components (arrays of shanks bearing close-packed electrodes) using mechanical self-locking and self-aligning techniques, followed by electroless nickel plating to establish electrical contact between the individual parts. We detail the fabrication and assembly process and demonstrate different 3-D probe designs bearing thousands of electrode sites. We find typical self-alignment accuracy between shanks of <0.2° and demonstrate orthogonal electrical connections of 40 µm pitch, with thousands of connections formed electrochemically in parallel. The fabrication methods introduced allow the design of scalable, modular electrodes for high-density 3-D neural recording. The combination of scalable 3-D design and close-packed recording sites may support a variety of large-scale neural recording strategies for the mammalian brain.

Automated in vivo patch-clamp evaluation of extracellular multielectrode array spike recording capability.

Much innovation is currently aimed at improving the number, density, and geometry of electrodes on extracellular multielectrode arrays for in vivo recording of neural activity in the mammalian brain. To choose a multielectrode array configuration for a given neuroscience purpose, or to reveal design principles of future multielectrode arrays, it would be useful to have a systematic way of evaluating the spike recording capability of such arrays. We describe an automated system that performs robotic patch-clamp recording of a neuron being simultaneously recorded via an extracellular multielectrode array. By recording a patch-clamp data set from a neuron while acquiring extracellular recordings from the same neuron, we can evaluate how well the extracellular multielectrode array captures the spiking information from that neuron. To demonstrate the utility of our system, we show that it can provide data from the mammalian cortex to evaluate how the spike sorting performance of a close-packed extracellular multielectrode array is affected by bursting, which alters the shape and amplitude of spikes in a train. We also introduce an algorithmic framework to help evaluate how the number of electrodes in a multielectrode array affects spike sorting, examining how adding more electrodes yields data that can be spike sorted more easily. Our automated methodology may thus help with the evaluation of new electrode designs and configurations, providing empirical guidance on the kinds of electrodes that will be optimal for different brain regions, cell types, and species, for improving the accuracy of spike sorting. NEW & NOTEWORTHY We present an automated strategy for evaluating the spike recording performance of an extracellular multielectrode array, by enabling simultaneous recording of a neuron with both such an array and with patch clamp. We use our robot and accompanying algorithms to evaluate the performance of multielectrode arrays on supporting spike sorting.

Inflammatory Markers and Severity of Intracerebral Hemorrhage.

Background and purpose The pathogenesis of brain injury after intracerebral hemorrhage is thought to be due to mechanical damage followed by ischemic, cytotoxic, and inflammatory changes in the underlying and surrounding tissue.In recent years, there has been a greater research interest into the various inflammatory biomarkers and growth factors that are secreted during intracerebral hemorrhage. The biomarkers investigated in this study are tumor necrosis factor alpha (TNF alpha), C-reactive protein (CRP), homocysteine (Hcy), and vascular endothelial growth factor (VEGF). The aim of this study was to further investigate the effects of these biomarkers in predicting the acute severity outcome of intracerebral hemorrhage (ICH). Methods We conducted a retrospective chart review of patients with spontaneous ICH with TNF alpha, CRP, VEGF, and Hcy levels drawn on admission. Forty-two patients with spontaneous ICH with at least one of the above labs were included in the study. Primary outcomes included death, Glasgow Coma Scale (GCS) on admission, early neurologic decline (END), and hemorrhage size. Secondary outcomes included GCS on discharge, ICH score, functional outcome risk stratification scale of intracerebral hemorrhage (FUNC score), change in hemorrhage size, need for surgical intervention, and length of intensive care unit (ICU) stay. Results Forty-two patients with spontaneous intracerebral hemorrhage (ICH) were analyzed, 12 patients (28.5%) required surgical intervention, and four patients (9.5%) died. Only low VEGF serum values were found to predict mortality. TNF alpha, CRP, Hcy, and VEGF levels in our patients with ICH were not found to predict early neurologic decline and were not correlated with GCS on admission, initial hemorrhage size, change in hemorrhage size, need for surgical intervention, ICH score, FUNC score, midline shift, and length of ICU stay. CRP and Hcy were elevated in 58% and 31% of patients tested, respectively. GCS on admission and ICH score were significantly associated with mortality. Conclusion After careful statistical review of the data obtained from this patient population, only low VEGF values were found to be a significant predictor of mortality. However, elevated CRP and Hcy levels were associated with a non-significant trend in hemorrhage size and mortality suggesting that CRP and Hcy-lowering therapies may decrease hemorrhagic stroke risk and severity.

Heterogeneous neural amplifier integration for scalable extracellular microelectrodes.

We here demonstrate multi-chip heterogeneous integration of microfabricated extracellular recording electrodes with neural amplifiers, highlighting a path to scaling electrode channel counts without the need for more complex monolithic integration. We characterize the noise and impedance performance of the heterogeneously integrated neural recording electrodes, and analyze the design parameters that enable the low-voltage neural input signals to co-exist with the high-frequency and high-voltage digital outputs on the same silicon substrate. This heterogeneous integration approach can enable future scaling efforts for microfabricated neural probes, and provides a design path for modular, fast, and independent scaling innovations in recording electrodes and neural amplifiers.

Close-Packed Silicon Microelectrodes for Scalable Spatially Oversampled Neural Recording.

OBJECTIVE: Neural recording electrodes are important tools for understanding neural codes and brain dynamics. Neural electrodes that are closely packed, such as in tetrodes, enable spatial oversampling of neural activity, which facilitates data analysis. Here we present the design and implementation of close-packed silicon microelectrodes to enable spatially oversampled recording of neural activity in a scalable fashion. METHODS: Our probes are fabricated in a hybrid lithography process, resulting in a dense array of recording sites connected to submicron dimension wiring. RESULTS: We demonstrate an implementation of a probe comprising 1000 electrode pads, each 9 × 9 µm, at a pitch of 11 µm. We introduce design automation and packaging methods that allow us to readily create a large variety of different designs. SIGNIFICANCE: We perform neural recordings with such probes in the live mammalian brain that illustrate the spatial oversampling potential of closely packed electrode sites.

A direct-to-drive neural data acquisition system.

Driven by the increasing channel count of neural probes, there is much effort being directed to creating increasingly scalable electrophysiology data acquisition (DAQ) systems. However, all such systems still rely on personal computers for data storage, and thus are limited by the bandwidth and cost of the computers, especially as the scale of recording increases. Here we present a novel architecture in which a digital processor receives data from an analog-to-digital converter, and writes that data directly to hard drives, without the need for a personal computer to serve as an intermediary in the DAQ process. This minimalist architecture may support exceptionally high data throughput, without incurring costs to support unnecessary hardware and overhead associated with personal computers, thus facilitating scaling of electrophysiological recording in the future.