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A team of clinical researchers at Lund University found that electromagnetic radiation, such as that used in GSM-900 mobile telephones, at low non-thermal power values (<2 W/kg), causes users' blood albumin to leak through the blood-brain barrier "BBB" into in the brain tissue. The neurosurgeons: Leif Salford MD, PhD, professor emeritus, Henrietta Nittby MD, PhD,Neuropathologist: Arne Brun MD, PhD, professor emeritus.Medical physicist: Bertil RR Persson PhD, MDhc, professor emeritus.. Jacob Eberhardt PhD, Electrical engineer: Lars Malmgren Tech. Dr.The BBB is supposed to protect the brain from unwanted and toxic molecules that are potentially in the blood to transfer into the brain tissue. However, after exposing rats to radiation from cell phones, albumin from the blood leaks into the brain and accumulates in neurons and glial cells.In late 2023, it came to my attention that Arendash in the USA, in order to treat patients with Alzheimer's disease, had used a similar microwave pulse train and non-thermal SAR levels as we used in our studies of the BBB leakage of blood-Albumin.Concerns were raised that albumin leakage in the BBB after many years of intensive mobile phone use could promote the development of autoimmune and neurodegenerative diseases such as Alzheimer's. At Christmas time in 2023 it came to my attention that Arendash and coworkers already in 2010 reported that treatment with GSM-900 electromagnetic fields protects against and reverses cognitive decline in mice with Alzheimer's disease (Arendash et al., 2010).Arendash's report indicates that prolonged exposure to non-thermal levels of microwave radiation directly associated with GSM-900 cell phone use confers cognitive benefits. They observed both cognitive protective and ameliorating effects of such exposure in both normal mice and transgenic mice designed to develop Alzheimer's-like impairment.Arendash and colleagues used similar 900 MHz GSM modulated microwaves at non-thermal SAR levels in a clinical

The insula is an intriguing target for pain modulation. Unfortunately, it lies deep to the cortex making spatially specific noninvasive access difficult. Here, we leverage the high spatial resolution and deep penetration depth of low-intensity focused ultrasound (LIFU) to nonsurgically modulate the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact heat–evoked potentials, as well as autonomic measures including heart-rate variability (HRV). In a within-subjects, repeated-measures, pseudo-randomized trial design, 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, electrodermal, electrocardiography and EEG recording. Low-intensity focused ultrasound was delivered to the AI (anterior short gyrus), PI (posterior longus gyrus), or under an inert Sham condition. The primary outcome measure was pain rating. Low-intensity focused ultrasound to both AI and PI similarly reduced pain ratings but had differential effects on EEG activity. Low-intensity focused ultrasound to PI affected earlier EEG amplitudes, whereas LIFU to AI affected later EEG amplitudes. Only LIFU to the AI affected HRV as indexed by an increase in SD of N-N intervals and mean HRV low-frequency power. Taken together, LIFU is an effective noninvasive method to individually target subregions of the insula in humans for site-specific effects on brain biomarkers of pain processing and autonomic reactivity that translates to reduced perceived pain to a transient heat stimulus.

The insula is an intriguing target for pain modulation. Unfortunately, it lies deep to the cortex making spatially specific noninvasive access difficult. Here, we leverage the high spatial resolution and deep penetration depth of low-intensity focused ultrasound (LIFU) to nonsurgically modulate the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact heat–evoked potentials, as well as autonomic measures including heart-rate variability (HRV). In a within-subjects, repeated-measures, pseudo-randomized trial design, 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, electrodermal, electrocardiography and EEG recording. Low-intensity focused ultrasound was delivered to the AI (anterior short gyrus), PI (posterior longus gyrus), or under an inert Sham condition. The primary outcome measure was pain rating. Low-intensity focused ultrasound to both AI and PI similarly reduced pain ratings but had differential effects on EEG activity. Low-intensity focused ultrasound to PI affected earlier EEG amplitudes, whereas LIFU to AI affected later EEG amplitudes. Only LIFU to the AI affected HRV as indexed by an increase in SD of N-N intervals and mean HRV low-frequency power. Taken together, LIFU is an effective noninvasive method to individually target subregions of the insula in humans for site-specific effects on brain biomarkers of pain processing and autonomic reactivity that translates to reduced perceived pain to a transient heat stimulus.

Functional ultrasound is by now a well-established technique in the neuroscience community to measure brain activity. However, the transcranial application of functional ultrasound on humans, with the exception of the acoustic windows in the skull, remains a huge challenge because of the properties of the cranial bone the acoustic waves will reflect, refract, attenuate or will cause aberration. Therefore, the signal-to-noise ratio (SNR) of the incoming signal is too low for transcranial functional ultrasound (TCfUS). This thesis tries to overcome the SNR problem of TCfUS with the design of a 64-channel ultrasound acquisition system that is focused on achieving the highest SNR possible. This is achieved by placing the analog front-end (AFE) chips as near to the transducer elements as possible and by oversampling the incoming signal with a factor of 25, a theoretical increase of 15 dB of the signal-to-quantization-noise ratio over the current state-of-the-art is estimated. The proposed design is a receive-only system where the transmission of the ultrasound pulses is carried out by a separate ultrasound system. The design splits the acquisition system into a front-end and a back-end subsystem, where the front-end system is implemented using four AFE58JD48 analog front-end chips from Texas Instruments. From here the data samples are transported over fiber optics to the back-end subsystem, which consists of a VCK190 FPGA board from Xilinx, where the samples are processed and/or transported to a workstation for storage. Because the system organization differentiates from more conventional research ultrasound systems, a trade-off is introduced between processing and throughput, resulting in three processing configurations for the FPGA with each a different focus: raw RF data sampling, real-time processing, and hardware processing. Due to time and resource constraints, no measurements and results are available on the SNR and decimation. However, a theoretical exploration h, https://ultrasoundbrainimaging.com/ Website CUBE https://neuro.nl/ Website department of Neuroscience at Erasmus MC https://neurocomputinglab.com/ Website Neuro Computing Lab, Computer Science

Human learning is supported by multiple neural mechanisms that maturate at different rates and interact in mostly cooperative but also sometimes competitive ways. We tested the hypothesis that mature cognitive mechanisms constrain implicit statistical learning mechanisms that contribute to early language acquisition. Specifically, we tested the prediction that depleting cognitive control mechanisms in adults enhances their implicit, auditory word-segmentation abilities. Young adults were exposed to continuous streams of syllables that repeated into hidden novel words while watching a silent film. Afterward, learning was measured in a forced-choice test that contrasted hidden words with nonwords. The participants also had to indicate whether they explicitly recalled the word or not in order to dissociate explicit versus implicit knowledge. We additionally measured electroencephalography during exposure to measure neural entrainment to the repeating words. Engagement of the cognitive mechanisms was manipulated by using two methods. In experiment 1 (n = 36), inhibitory theta-burst stimulation (TBS) was applied to the left dorsolateral prefrontal cortex or to a control region. In experiment 2 (n = 60), participants performed a dual working-memory task that induced high or low levels of cognitive fatigue. In both experiments, cognitive depletion enhanced word recognition, especially when participants reported low confidence in remembering the words (i.e., when their knowledge was implicit). TBS additionally modulated neural entrainment to the words and syllables. These findings suggest that cognitive depletion improves the acquisition of linguistic knowledge in adults by unlocking implicit statistical learning mechanisms and support the hypothesis that adult language learning is antagonized by higher cognitive mechanisms.

While noninvasive brain stimulation is convenient and cost effective, its utility is limited by the substantial distance between scalp electrodes and their intended neural targets in the head. The tympanic membrane, or eardrum, is a thin flap of skin deep in an orifice of the head that may serve as a port for improved efficiency of noninvasive stimulation. Here we chose the cochlea as a target because it resides in the densest bone of the skull and is adjacent to many deep-brain-stimulation structures. We also tested the hypothesis that noninvasive electric stimulation of the cochlea may restore neural activities that are missing in acoustic stimulation. We placed an electrode in the ear canal or on the tympanic membrane in 25 human adults (10 females) and compared their stimulation efficiency by characterizing the electrically-evoked auditory sensation. Relative to ear canal stimulation, tympanic membrane stimulation was four times more likely to produce an auditory percept, required eight times lower electric current to reach the threshold and produced two-to-four times more linear suprathreshold responses. We further measured tinnitus suppression in 14 of the 25 subjects who had chronic tinnitus. Compared with ear canal stimulation, tympanic membrane stimulation doubled both the probability (22% vs. 55%) and the amount (-15% vs. -34%) of tinnitus suppression. These findings extended previous work comparing evoked perception and tinnitus suppression between electrodes placed in the ear canal and on the scalp. Together, the previous and present results suggest that the efficiency of conventional scalp-based noninvasive electric stimulation can be improved by at least one order of magnitude via tympanic membrane stimulation. This increased efficiency is most likely due to the shortened distance between the electrode placed on the tympanic membrane and the targeted cochlea. The present findings have implications for the management of tinnitus by offering a potential

Introduction The management of recurrent craniopharyngioma is complex with limited data to guide decision-making. Some reports suggest reoperation should be avoided due to an increased complication profile, while others have demonstrated that safe reoperation can be performed. For other types of skull base lesions, maximal safe resection followed by adjuvant therapy has replaced radical gross total resection due to the favorable morbidity profiles. Methods Seventy-one patients underwent resection over a 9-year period for craniopharyngioma and were retrospectively reviewed. Patients were separated into primary resection and reoperation cohorts and stratified by surgical approach (endonasal vs. cranial) and survival analyses were performed based on cohort and surgical approach. Results Fifty patients underwent primary resection, while 21 underwent reoperation for recurrence. Fifty endonasal transsphenoidal surgeries and 21 craniotomies were performed. Surgical approaches were similarly distributed across cohorts. Subtotal resection was achieved in 83% of all cases. There were no differences in extent of resection, visual outcomes, subsequent neuroendocrine function, and complications across cohorts and surgical approaches. The median time to recurrence was 87 months overall, and there were no differences by cohort and approach. The 5-year survival rate was 81.1% after reoperation versus 93.2% after primary resection. Conclusion Compared with primary resection, reoperation for craniopharyngioma recurrence is associated with similar functional and survival outcomes in light of individualized surgical approaches. Maximal safe resection followed by adjuvant radiotherapy for residual tumor likely preserves vision and endocrine function without sacrificing overall patient survival.

Functional ultrasound is by now a well-established technique in the neuroscience community to measure brain activity. However, the transcranial application of functional ultrasound on humans, with the exception of the acoustic windows in the skull, remains a huge challenge because of the properties of the cranial bone the acoustic waves will reflect, refract, attenuate or will cause aberration. Therefore, the signal-to-noise ratio (SNR) of the incoming signal is too low for transcranial functional ultrasound (TCfUS). This thesis tries to overcome the SNR problem of TCfUS with the design of a 64-channel ultrasound acquisition system that is focused on achieving the highest SNR possible. This is achieved by placing the analog front-end (AFE) chips as near to the transducer elements as possible and by oversampling the incoming signal with a factor of 25, a theoretical increase of 15 dB of the signal-to-quantization-noise ratio over the current state-of-the-art is estimated. The proposed design is a receive-only system where the transmission of the ultrasound pulses is carried out by a separate ultrasound system. The design splits the acquisition system into a front-end and a back-end subsystem, where the front-end system is implemented using four AFE58JD48 analog front-end chips from Texas Instruments. From here the data samples are transported over fiber optics to the back-end subsystem, which consists of a VCK190 FPGA board from Xilinx, where the samples are processed and/or transported to a workstation for storage. Because the system organization differentiates from more conventional research ultrasound systems, a trade-off is introduced between processing and throughput, resulting in three processing configurations for the FPGA with each a different focus: raw RF data sampling, real-time processing, and hardware processing. Due to time and resource constraints, no measurements and results are available on the SNR and decimation. However, a theoretical exploration h, https://ultrasoundbrainimaging.com/ Website CUBE https://neuro.nl/ Website department of Neuroscience at Erasmus MC https://neurocomputinglab.com/ Website Neuro Computing Lab, Computer Science

BackgroundIntracranial atherosclerotic disease (ICAD) is a common cause of ischemic stroke with a high risk of clinical stroke recurrence. Multiple mechanisms may underlie cerebral ischemia in this condition. The study's objective is to discern the mechanisms of recurrent ischemia in ICAD through imaging biomarkers of impaired antegrade flow, poor distal perfusion, abnormal vasoreactivity, and artery-to-artery embolism.MethodsThis prospective multicenter observational study enrolled patients with recent (≤21 days) ischemic stroke or transient ischemic attack (TIA) caused by ICAD with 50-99% stenosis treated medically. We obtained baseline quantitative MRA (QMRA), perfusion MRI (PWI), transcranial Doppler vasoreactivity (VMR), and emboli detection studies (EDS). The primary outcome was ischemic stroke in the territory of the stenotic artery within 1 year of follow-up; secondary outcomes were TIA at 1 year and new infarcts in the territory on MRI at 6-8 weeks.ResultsAmongst 102 of 105 participants with clinical follow-up (mean 253±131 days), the primary outcome occurred in 8.8% (12.7/100 patient-years), while 5.9% (8.5/100 patient-years) had a TIA. A new infarct in the territory of the symptomatic artery was noted in 24.7% at 6-8 weeks. A low flow state on QMRA was noted in 25.5%, poor distal perfusion on PWI in 43.5%, impaired vasoreactivity on VMR in 67.5%, and microemboli on EDS in 39.0%. No significant association was identified between these imaging biomarkers and primary or secondary outcomes.ConclusionsDespite intensive medical management in ICAD, there is a high risk of clinical cerebrovascular events at 1 year and an even higher risk of new imaging-evident infarcts in the subacute period after index stroke. Hemodynamic and plaque instability biomarkers did not identify a higher risk group. Further work is needed to identify mechanisms of ischemic stroke and infarct recurrence and their consequence on long-term physical and cognitive outcomes.Trial registratio

Background The primary aim of this study was to characterize the middle cerebral artery blood velocity (MCAv) dynamic response to an acute bout of exercise in humans at 3- and 6-months poststroke. As a secondary objective, we grouped individuals according to the MCAv dynamic response to the exercise bout as responder or nonresponder. We tested whether physical activity, aerobic fitness, and exercise mean arterial blood pressure differed between groups. Methods and Results Transcranial Doppler ultrasound measured MCAv during a 90-second baseline followed by a 6-minute moderate intensity exercise bout. Heart rate, mean arterial blood pressure, and end-tidal CO2 were additional variables of interest. The MCAv dynamic response variables included the following: baseline, time delay, amplitude, and time constant. Linear mixed model revealed no significant differences in our selected outcomes between 3- and 6-months poststroke. Individuals characterized as responders demonstrated a faster time delay, higher amplitude, and reported higher levels of physical activity and aerobic fitness when compared with the nonresponders. No between-group differences were identified for baseline, time constant, or exercise mean arterial blood pressure. In the nonresponders, we observed an immediate rise in MCAv following exercise onset followed by an immediate decline to near baseline values, while the responders showed an exponential rise until steady state was reached. Conclusions The MCAv dynamic response profile has the potential to provide valuable information during an acute exercise bout following stroke. Individuals with a greater MCAv response to the exercise stimulus reported statin use and regular participation in exercise.

PurposeThe mechanisms of brain metastasis are incompletely understood. Circulating tumor cells travel to the right heart and through the pulmonary circulation, where they may become lung metastases, and can circulate further to the left heart and brain. In patients who develop brain metastases without lung involvement, we hypothesized that cancer cells may travel directly from the right atrium to left atrium via a patent foramen ovale (PFO), akin to paradoxical embolism. If the prevalence of PFO is greater in these individuals compared to the general population (20-30%), PFO may play a role in brain metastasis, and prophylactic closure may provide benefit. Accordingly, we investigated the prevalence of PFO in patients with brain metastases without prior lung involvement.MethodsWe prospectively identified patients with brain metastases from a non-lung primary cancer with no preceding or concurrent lung involvement. Nine eligible participants underwent a transcranial Doppler study with intravenous agitated saline to assess for PFO.ResultsAmong nine participants, primary cancers were breast (n = 6), upper gastrointestinal (n = 2), and thyroid (n = 1). A positive bubble study was identified in 2/9 (22.2%) participants: one female with breast cancer and one male with duodenal adenocarcinoma. No participants developed lung metastases on subsequent chest imaging.ConclusionIn this prospective pilot study, we found a similar prevalence of PFO in patients who developed brain metastases without preceding lung involvement compared to estimates for the general population. Through a larger study is needed, the development of brain metastases in these individuals may primarily reflect tumor-specific biological factors diecting metastasis organotropism.

Cerebral Blood Flow Velocity waveforms acquired via Transcranial Doppler (TCD) can provide evidence for cerebrovascular occlusion and stenosis. Thrombolysis in Brain Ischemia (TIBI) flow grades are widely used for this purpose, but require subjective assessment by expert evaluators to be reliable. In this work we seek to determine whether TCD morphology can be objectively assessed using an unsupervised machine learning approach to waveform categorization. TCD beat waveforms were recorded at multiple depths from the Middle Cerebral Arteries of 106 subjects; 33 with Large Vessel Occlusion (LVO). From each waveform, three morphological features were extracted, quantifying onset of maximal velocity, systolic canopy length, and the number/prominence of peaks/troughs. Spectral clustering identified groups implicit in the resultant three-dimensional feature space, with gap statistic criteria establishing the optimal cluster number. We found that gap statistic disparity was maximized at four clusters, referred to as flow types I, II, III, and IV. Types I and II were primarily composed of control subject waveforms, whereas types III and IV derived mainly from LVO patients. Cluster morphologies for types I and IV aligned clearly with Normal and Blunted TIBI flows, respectively. Types II and III represented commonly observed flow-types not delineated by TIBI, which nonetheless deviate from normal and blunted flows. We conclude that important morphological variability exists beyond that currently quantified by TIBI in populations experiencing or at-risk for acute ischemic stroke, and posit that the observed flow-types provide the foundation for objective methods of real-time automated flow type classification.

Interactive behaviors rely on the operation of several processes allowing the control of actions, including their selection, withholding and abortion. The corticospinal tract provides a unique route through which brain circuits can exert such control over bodily motor acts. In humans, the activity of the corticospinal tract can be probed through the quantification of motor-evoked potentials, which can be elicited in targeted effectors by applying single-pulse transcranial magnetic stimulation (TMS) over the contralateral primary motor cortex. Using this approach, a compendium of studies has shown that the corticospinal tract exhibits dynamic increases and decreases in excitability during action selection, withholding and stopping, reflecting the implementation of the underlying control processes at the motor level. In this review, we highlight neural data from TMS studies revealing the causal role played by multiple intra-cortical, trans-cortical and subcortico-cortical circuits in these changes in corticospinal excitability. An emerging picture is that these distributed circuits cooperate through a parallel brain architecture to tune corticospinal excitability in a continuous and dynamic way, helping to determine what, when and whether actions must be executed, depending on the state of the external world.

Sickle cell disease (SCD) is characterized by deoxygenation-induced polymerization of hemoglobin in red blood cells, leading to hemolytic anemia, vaso-occlusion, and the development of multiple clinical complications. To characterize the clinical burden associated with differences in hemoglobin concentration and hemolysis measures, a systematic literature review of MEDLINE, EMBASE, and related meta-analyses was undertaken. For quantitative analyses related to hemoglobin concentration, pooled results were analyzed using random effects models to control for within-and between-study variability. To derive risk ratios associated with hemoglobin concentration change, we combined ratios of means from select studies, which reported hazard and odds ratios in meta-analyses for hemoglobin concentration-related outcomes and changes between groups. Forty-one studies were identified for inclusion based on relating hemoglobin concentration to clinical outcomes. Meta-analyses demonstrated that mean hemoglobin concentration was significantly lower in patients with cerebrovascular disease (0.4 g/dL), increased transcranial Doppler velocity in cerebral arteries (0.6 g/dL), albuminuria (0.6 g/dL), elevated estimated pulmonary artery systolic pressure (0.9 g/dL), and in patients that subsequently died (0.6 g/dL). In a risk reduction meta-analysis, modeled increased hemoglobin concentrations of 1 g/dL or greater resulted in decreased risk of negative clinical outcomes of 41% to 64%. In conclusion, chronic anemia is associated with worse clinical outcomes in individuals with SCD and even modest increases in hemoglobin concentration may be beneficial in this patient population. This systematic review has been registered on Prospero (Registration number CRD42018096860; https://www.crd.york.ac.uk/prospero/).

Sickle cell disease (SCD) is characterized by deoxygenation-induced polymerization of hemoglobin in red blood cells, leading to hemolytic anemia, vaso-occlusion, and the development of multiple clinical complications. To characterize the clinical burden associated with differences in hemoglobin concentration and hemolysis measures, a systematic literature review of MEDLINE, EMBASE, and related meta-analyses was undertaken. For quantitative analyses related to hemoglobin concentration, pooled results were analyzed using random effects models to control for within-and between-study variability. To derive risk ratios associated with hemoglobin concentration change, we combined ratios of means from select studies, which reported hazard and odds ratios in meta-analyses for hemoglobin concentration-related outcomes and changes between groups. Forty-one studies were identified for inclusion based on relating hemoglobin concentration to clinical outcomes. Meta-analyses demonstrated that mean hemoglobin concentration was significantly lower in patients with cerebrovascular disease (0.4 g/dL), increased transcranial Doppler velocity in cerebral arteries (0.6 g/dL), albuminuria (0.6 g/dL), elevated estimated pulmonary artery systolic pressure (0.9 g/dL), and in patients that subsequently died (0.6 g/dL). In a risk reduction meta-analysis, modeled increased hemoglobin concentrations of 1 g/dL or greater resulted in decreased risk of negative clinical outcomes of 41% to 64%. In conclusion, chronic anemia is associated with worse clinical outcomes in individuals with SCD and even modest increases in hemoglobin concentration may be beneficial in this patient population. This systematic review has been registered on Prospero (Registration number CRD42018096860; https://www.crd.york.ac.uk/prospero/).

The leptomeningeal collateral status is an independent predictor of stroke outcome. By means of optical coherent tomography angiography to compare two mouse strains with different extent of native leptomeningeal collateralization, we determined the spatiotemporal dynamics of collateral flow and downstream hemodynamics following ischemic stroke. A robust recruitment of leptomeningeal collateral flow was detected immediately after middle cerebral artery (MCA) occlusion in C57BL/6 mice, with continued expansion over the course of seven days. In contrast, little collateral recruitment was seen in Balb/C mice during- and one day after MCAO, which coincided with a greater infarct size and worse functional outcome compared to C57BL/6, despite a slight improvement of cortical perfusion seven days after MCAO. Both strains of mice experienced a reduction of blood flow in the penetrating arterioles (PA) by more than 90% 30-min after dMCAO, although the decrease of PA flow was greater and the recovery was less in the Balb/C mice. Further, Balb/C mice also displayed a prolonged greater heterogeneity of capillary transit time after dMCAO in the MCA territory compared to C57BL/6 mice. Our data suggest that the extent of native leptomeningeal collaterals affects downstream hemodynamics with a long lasting impact in the microvascular bed after cortical stroke.

RationaleIntracranial atherosclerotic disease (ICAD) is the most common cause of ischemic stroke with the highest rate of recurrence, despite aggressive medical management. Diverse mechanisms may be responsible for ICAD-related cerebral ischemia, with potential therapeutic implications. Here we present the rationale, design and methods of the Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease (MyRIAD) study. The aim of MyRIAD is to determine the mechanisms of stroke in ICAD through physiologic imaging biomarkers that evaluate impaired antegrade flow, poor distal perfusion, abnormal vasoreactivity, artery to artery embolism, and their interaction.Methods and designThis is a prospective observational study of patients with recently symptomatic (<21 days) ICAD with 50-99% stenosis treated medically and monitored for up to 1 year. An estimated 110 participants are recruited at 10 sites to identify the association between the presence of each mechanism of ischemia and recurrent stroke. The primary outcome is ischemic stroke in the territory of the symptomatic artery. Secondary outcomes include new cerebral infarction on MRI at 6-8 weeks and recurrent TIA in the territory of the symptomatic artery.DiscussionMyRIAD is positioned to define the role of specific mechanisms of recurrent ischemia in patients with symptomatic ICAD. This knowledge will allow the development and implementation of effective and specific treatments for this condition.

Delayed cerebral ischemia (DCI) is the leading cause of mortality and disability in patients who survived the initial bleed of subarachnoid hemorrhage. Currently available guidelines are based on expert opinions derived from small observational studies due to the lack of randomized controlled trials. In this review, we will review some of the available literature and describe our local protocols for prophylaxis, risk stratification, monitoring in patients at risk, including multimodal invasive monitoring, and interventions measures in patients with DCI. These protocols are largely in line with the current guidelines but are deemed to evolve as ongoing and future trials provide stronger evidence to support interventions., SCOPUS: re.j, info:eu-repo/semantics/published

Objective: To quantitatively compare different microsurgical and endoscopic approaches to the middle cranial fossa in a preclinical setting with a novel, computer-based research method. Methods: Different approaches were performed bilaterally in 5 head and neck specimens that underwent high-resolution computed tomography scans: 5 transcranial anterolateral (supraorbital, mini-pterional, pterional, pterional-transzygomatic, fronto-temporal-orbito-zygomatic) without and with anterior clinoidectomy; 2 transcranial lateral (subtemporal and subtemporal-transzygomatic); 2 endoscopic transnasal (transpterygoid, transpterygoid to infratemporal fossa); 2 endoscopic transorbital (superior eyelid and inferolateral), and endoscopic transmaxillary. A dedicated navigation system was used to quantify surgical working volumes and exposure of different areas of the middle cranial fossa (ApproachViewer, part of GTx-Eyes II, University Health Network, Toronto, Canada). Statistical analysis was performed using a mixed linear model with bootstrap resampling. Results: Endoscopic transnasal and fronto-temporal-orbito-zygomatic approaches with anterior clinoidectomy showed the largest surgical volumes. Endoscopic approaches allowed a wider exposure of medial anatomical surfaces (e.g., the petrous apex) compared with transcranial ones. Transcranial approaches with larger craniotomies allowed the widest exposure of superomedial anatomical structures (e.g., roof of cavernous sinus). The resection of the zygomatic arch allowed exposure of more medial surfaces with an inferior to superior trajectory. Conclusions: This study implemented a novel neuronavigation-based research method to quantitatively compare different approaches to the middle cranial fossa; its results might guide, after consideration of clinical implications, the choice of the neurosurgical approach to different areas of this complex skull base region.

The low cost, simple, noninvasive, and continuous measurement of cerebral blood flow velocity (CBFV) by transcranial Doppler is becoming a common clinical tool for the assessment of cerebral hemodynamics. CBFV monitoring can also help with noninvasive estimation of intracranial pressure and evaluation of mild traumatic brain injury. Reliable CBFV waveform analysis depends heavily on its accurate beat-to-beat delineation. However, CBFV is inherently contaminated with various types of noise/artifacts and has a wide range of possible pathological waveform morphologies. Thus, pulse onset detection is in general a challenging task for CBFV signal. In this paper, we conducted a comprehensive comparative analysis of three popular pulse onset detection methods using a large annotated dataset of 92,794 CBFV pulses-collected from 108 subarachnoid hemorrhage patients admitted to UCLA Medical Center. We compared these methods not only in terms of their accuracy and computational complexity, but also for their sensitivity to the selection of their parameters values. The results of this comprehensive study revealed that using optimal values of the parameters obtained from sensitivity analysis, one method can achieve the highest accuracy for CBFV pulse onset detection with true positive rate (TPR) of 97.06% and positive predictivity value (PPV) of 96.48%, when error threshold is set to just less than 10 ms. We conclude that the high accuracy and low computational complexity of this method (average running time of 4ms/pulse) makes it a reliable algorithm for CBFV pulse onset detection.

Over 50% of patients who rapidly ascend to extreme altitudes develop various symptoms known as acute mountain sickness (AMS), which rarely can be life threatening. It is unclear why some patients are more susceptible to AMS than others. Our objective was to determine whether patent foramen ovale (PFO) is a risk factor for AMS. Subjects who had hiked to altitudes above 10,000' (∼3,000 meters) on the John Muir Trail in California were recruited. Participants completed a questionnaire and 2-physician adjudication was performed in regard to AMS status. A transcranial Doppler with agitated saline contrast injection was performed to evaluate the presence or absence of PFO. The primary outcome was the development of AMS. From 2016 to 2018, 137 hikers were recruited into the study. There was a higher prevalence of PFO in hikers with AMS 15 of 24 (63%) compared with hikers without AMS 44 of 113 (39%); p = 0.034. In the multivariate model, the presence of a PFO significantly increased the risk for developing AMS: odds ratio 4.15, 95% confidence intervals 1.14 to 15.05; p = 0.030. In conclusion, hikers with a PFO had significantly higher risk of developing AMS relative to hikers without a PFO. Clinicians should consider PFO a risk factor in patients who plan to hike to high altitudes.

Over 50% of patients who rapidly ascend to extreme altitudes develop various symptoms known as acute mountain sickness (AMS), which rarely can be life threatening. It is unclear why some patients are more susceptible to AMS than others. Our objective was to determine whether patent foramen ovale (PFO) is a risk factor for AMS. Subjects who had hiked to altitudes above 10,000' (∼3,000 meters) on the John Muir Trail in California were recruited. Participants completed a questionnaire and 2-physician adjudication was performed in regard to AMS status. A transcranial Doppler with agitated saline contrast injection was performed to evaluate the presence or absence of PFO. The primary outcome was the development of AMS. From 2016 to 2018, 137 hikers were recruited into the study. There was a higher prevalence of PFO in hikers with AMS 15 of 24 (63%) compared with hikers without AMS 44 of 113 (39%); p = 0.034. In the multivariate model, the presence of a PFO significantly increased the risk for developing AMS: odds ratio 4.15, 95% confidence intervals 1.14 to 15.05; p = 0.030. In conclusion, hikers with a PFO had significantly higher risk of developing AMS relative to hikers without a PFO. Clinicians should consider PFO a risk factor in patients who plan to hike to high altitudes.

BACKGROUND AND PURPOSE:Individuals with migraine are at higher risk for stroke, but the mechanism has not been established. On the basis of the association between migraine and intracardiac right-to-left shunt, it has been proposed that stroke in migraineurs could be caused by a paradoxical embolus passing through a patent foramen ovale (PFO) or pulmonary arteriovenous malformation. The aim of this study was to determine the prevalence of PFO with right-to-left shunt in patients who presented with cryptogenic stroke and had a history of migraine. METHODS:Patients between 18 and 60 years old who presented with an ischemic stroke were characterized based on ASCOD phenotyping (atherosclerosis; small-vessel disease; cardiac pathology; other causes; dissection). A migraine diagnosis was identified by reviewing physician notes, and frequent aura was defined if present in at least 50% of attacks. A PFO with right-to-left shunt diagnosis was identified by the presence of a positive bubble contrast study with either transcranial Doppler, transthoracic, or transesophageal echocardiography. RESULTS:Of the 712 patients who presented with ischemic stroke, 127 (18%) were diagnosed as cryptogenic; 68 patients had adequate testing for PFO and a documented migraine history. The prevalence of PFO in patients with cryptogenic stroke without migraine was elevated (59%) compared with the general population (18%). Patients with both cryptogenic stroke and migraine had a higher prevalence of PFO (79%). In patients with cryptogenic stroke who had migraine with frequent aura, the prevalence of PFO was 93%. Only 5 patients (4%) had a history compatible with migrainous infarction. CONCLUSIONS:In patients with cryptogenic stroke who have migraine, there is a high prevalence (79%) of PFO with right-to-left shunt. The timing of the stroke in migraineurs is usually not related to a migraine attack. These observations are consistent with the hypothesis that the mechanism of stroke in migraineurs i

BACKGROUND AND PURPOSE:Individuals with migraine are at higher risk for stroke, but the mechanism has not been established. On the basis of the association between migraine and intracardiac right-to-left shunt, it has been proposed that stroke in migraineurs could be caused by a paradoxical embolus passing through a patent foramen ovale (PFO) or pulmonary arteriovenous malformation. The aim of this study was to determine the prevalence of PFO with right-to-left shunt in patients who presented with cryptogenic stroke and had a history of migraine. METHODS:Patients between 18 and 60 years old who presented with an ischemic stroke were characterized based on ASCOD phenotyping (atherosclerosis; small-vessel disease; cardiac pathology; other causes; dissection). A migraine diagnosis was identified by reviewing physician notes, and frequent aura was defined if present in at least 50% of attacks. A PFO with right-to-left shunt diagnosis was identified by the presence of a positive bubble contrast study with either transcranial Doppler, transthoracic, or transesophageal echocardiography. RESULTS:Of the 712 patients who presented with ischemic stroke, 127 (18%) were diagnosed as cryptogenic; 68 patients had adequate testing for PFO and a documented migraine history. The prevalence of PFO in patients with cryptogenic stroke without migraine was elevated (59%) compared with the general population (18%). Patients with both cryptogenic stroke and migraine had a higher prevalence of PFO (79%). In patients with cryptogenic stroke who had migraine with frequent aura, the prevalence of PFO was 93%. Only 5 patients (4%) had a history compatible with migrainous infarction. CONCLUSIONS:In patients with cryptogenic stroke who have migraine, there is a high prevalence (79%) of PFO with right-to-left shunt. The timing of the stroke in migraineurs is usually not related to a migraine attack. These observations are consistent with the hypothesis that the mechanism of stroke in migraineurs i

BACKGROUND: Sepsis-associated brain dysfunction (SABD) is associated with high morbidity and mortality. The pathophysiology of SABD is multifactorial. One hypothesis is that impaired cerebral autoregulation (CAR) may result in brain hypoperfusion and neuronal damage leading to SABD. METHODS: We studied 100 adult patients with sepsis (July 2012-March 2017) (age = 62 [52-71] years; Acute Physiology and Chronic Health Evaluation II score on admission = 21 [15-26]). Exclusion criteria were acute or chronic intracranial disease, arrhythmias, extracorporeal membrane oxygenation, and known intra- or extracranial supra-aortic vessel disease. The site of infection was predominantly abdominal (46%) or pulmonary (28%). Transcranial Doppler was performed, insonating the left middle cerebral artery with a 2-MHz probe. Middle cerebral artery blood flow velocity (FV) and arterial blood pressure (ABP) signals were recorded simultaneously; Pearson's correlation coefficient (mean flow index [Mxa]) between ABP and FV was calculated using MATLAB. Impaired CAR was defined as Mxa > 0.3. RESULTS: Mxa was 0.29 [0.05-0.62]. CAR was impaired in 50 patients (50%). In a multiple linear regression analysis, low mean arterial pressure, history of chronic kidney disease and fungal infection were associated with high Mxa. SABD was diagnosed in 57 patients (57%). In a multivariable analysis, altered cerebral autoregulation, mechanical ventilation and history of vascular disease were independent predictors of SABD. CONCLUSIONS: Cerebral autoregulation was altered in half of the patients with sepsis and was associated with the development of SABD. These findings support the concept that cerebral hypoxia could contribute to the development of SABD., SCOPUS: ar.j, info:eu-repo/semantics/published

Recent advancement in brain-machine-interface (BMI) technology has made tremendous impact on both clinical treatment and neuroscience research. It enables neural scientists to record and study signals fired by an individual neuron. To decode simple actions such as open and close a hand or rudimentary movements of an arm, signals from close to a hundred neurons must be examined [Hochberg06]. The large amount of collected neural data must be transmitted out of the skull to an external processer to translate into action or to be analyzed. To minimize the risk of infection to the patients, wireless data transmission is the preferred option. A next-generation 1024-channel implanted neural recorder that uses 20KS/s 8b Analog-to-Digital Converter (ADC) to capture neural signals can generate up to 164Mb/s data, which imposes a stringent requirement on the communication throughput of the implanted wireless transmitter (TX). In addition, TX power consumption must be kept as low as possible for longer battery life or safe wireless power delivery, while the power consumption of the external receiver (RX) chip outside the skull can be relaxed. The current state-of-the-art implantable transmitters that use backscattering, pulse harmonic modulation (PHM), or ultra-wide-band (UWB) communication suffer either from limited throughput or low TX energy efficiency. Although other techniques such as ultrasound have the potential to achieve ultra-low power, they suffer from low data-rate (tens to hundreds of Kb/s) and severe loss through the skull bone. To overcome these issues, inductive coupling technique is adopted in this work. The proposed transmitter only consists of an inductor driver, which significantly simplifies the TX architecture and lowers power. Inter-symbol-interference (ISI) caused by the ringing of the coupled inductors is alleviated by series de-Q resistors. To further reduce power, the entire TX uses a single 0.5V supply. To generate low jitter TX clock under such low

Recent advancement in brain-machine-interface (BMI) technology has made tremendous impact on both clinical treatment and neuroscience research. It enables neural scientists to record and study signals fired by an individual neuron. To decode simple actions such as open and close a hand or rudimentary movements of an arm, signals from close to a hundred neurons must be examined [Hochberg06]. The large amount of collected neural data must be transmitted out of the skull to an external processer to translate into action or to be analyzed. To minimize the risk of infection to the patients, wireless data transmission is the preferred option. A next-generation 1024-channel implanted neural recorder that uses 20KS/s 8b Analog-to-Digital Converter (ADC) to capture neural signals can generate up to 164Mb/s data, which imposes a stringent requirement on the communication throughput of the implanted wireless transmitter (TX). In addition, TX power consumption must be kept as low as possible for longer battery life or safe wireless power delivery, while the power consumption of the external receiver (RX) chip outside the skull can be relaxed. The current state-of-the-art implantable transmitters that use backscattering, pulse harmonic modulation (PHM), or ultra-wide-band (UWB) communication suffer either from limited throughput or low TX energy efficiency. Although other techniques such as ultrasound have the potential to achieve ultra-low power, they suffer from low data-rate (tens to hundreds of Kb/s) and severe loss through the skull bone. To overcome these issues, inductive coupling technique is adopted in this work. The proposed transmitter only consists of an inductor driver, which significantly simplifies the TX architecture and lowers power. Inter-symbol-interference (ISI) caused by the ringing of the coupled inductors is alleviated by series de-Q resistors. To further reduce power, the entire TX uses a single 0.5V supply. To generate low jitter TX clock under such low

BackgroundThe reproducibility of transcranial Doppler (TCD) ultrasound measurements in Sturge-Weber syndrome (SWS) and TCD's ability to predict neurological progression is unknown.MethodsIn 14 individuals with SWS, TCD measured mean flow velocity, pulsatility index, peak systolic velocity, and end-diastolic velocity in the middle, posterior, and anterior cerebral arteries of the affected and unaffected hemisphere. TCD was performed either once (n = 5) or twice in one day (n = 9). We assessed the reproducibility of the measurements performed twice on the same day on subjects and compared the TCD measurements to previously published age-matched controls. Clinically obtained neuroimaging was scored for extent and severity of SWS brain involvement. Patients were prospectively assigned SWS neuroscores.ResultsMiddle cerebral artery velocity (r = 0.79, P = 0.04, n = 7), posterior cerebral artery velocity (r = 0.90, P = 0.04, n = 5), and anterior cerebral artery pulsatility index (r = 0.82, P = 0.02, n = 7) were reproducible TCD measurements comparing same-day percent side-to-side differences. In subjects with SWS, affected and unaffected mean peak systolic velocity and end-diastolic velocity in the middle, posterior, and anterior cerebral arteries were globally lower compared with age-matched control subjects. Subjects with the lowest affected middle cerebral artery velocity had the greatest worsening in the total neurological score between time 1 and 2 (r = -0.73, P = 0.04, n = 8) and the most severe magnetic resonance imaging involvement of the affected frontal lobe (r = -0.82, P = 0.007, n = 9).ConclusionsTCD may be a reliable measure with potential clinical value, indicating that blood flow may be globally decreased in SWS patients with unilateral brain involvement.

Once deemed benign, patent foramen ovale (PFO)-mediated right-to-left shunting has now been linked to stroke, migraine, and hypoxemia. Contrast transesophageal echocardiography is considered the standard technique for identifying a PFO, allowing visualization of the atrial septal anatomy and differentiation from non-PFO right-to-left shunts. Transthoracic echocardiography is the most common method for PFO imaging, being cost-effective, but has the lowest sensitivity. Transcranial Doppler is highly sensitive but is unable to differentiate cardiac from pulmonary shunts; it is the best method to quantitate shunt severity, being more sensitive than transthoracic or transesophageal echocardiography so is our preferred screening method for PFO.

Transcranial Doppler (TCD) screening rates remain low among children with sickle cell disease (SCD). We assessed TCD screening rates and missed opportunities for TCD screening. Children 2 to 16 years old with SCD enrolled in Michigan Medicaid for ≥1 year (2007-2011) were identified through newborn screening. Receipt of TCD screening and presence of a missed opportunity (≥1 SCD-related outpatient visit, no TCD screening) were identified through administrative claims. Potential correlates of missed opportunities included SCD-related health services, comorbidities, and demographics. Logistic regression with generalized estimating equations modeled associations between a missed opportunity and correlates. Overall, 353 children contributed 1066 person-years. TCD screening was low yearly (10%-32%); missed opportunities occurred in 73% of the person-years. Increasing age (odds ratio [OR] = 1.11; confidence interval CI = 1.07, 1.15), previous TCD screening (OR = 0.26; CI = 0.16, 0.41), and 4 to 5 (OR = 0.48; CI = 0.26, 0.87) or ≥6 outpatient visits (OR = 0.26; CI = 0.14, 0.49) were associated with a missed opportunity. Reduction of missed opportunities is a potential strategy to increase TCD screening rates.

In children with Sickle Cell Disease, the combination of risk stratification with Transcranial Doppler Ultrasound (TCD) and selective chronic red cell transfusion (CRCT-the STOP Protocol) is one of the most effective stroke prevention strategies in medicine. How fully it is being implemented is unclear. Nineteen of 26 sites that conducted the two pivotal clinical trials (STOP and STOP II) participated in Post STOP, a comprehensive medical records review assessing protocol implementation in the 10-15 years since the trials ended. Professional abstractors identified medical records in the Post STOP era in 2851 (74%) of the 3,840 children who took part in STOP and/or STOP II, and documented TCD rescreening, maintenance of CRCT in those at risk, and stroke. Among 1,896 children eligible for TCD rescreening (target group), evidence of any rescreening was found in 1,090 (57%). There was wide site variation in TCD rescreening ranging from 18% to 91% of eligible children. Both younger age and having a conditional TCD during STOP/II were associated with a higher likelihood of having a TCD in Post STOP. Sixty eight new abnormal, high risk cases were identified. Despite clear evidence of benefit the STOP protocol is not fully implemented even at experienced sites. Site variation suggests that system improvements might remove barriers to implementation and result in even greater reduction of ischemic stroke in children with SCD. Am. J. Hematol. 91:1191-1194, 2016. © 2016 Wiley Periodicals, Inc.

BackgroundTranscranial Doppler (TCD) with agitated saline has been shown to be an alternative for the detection of right-to-left shunts (RLS) with similar diagnostic accuracies as transesophageal echocardiography (TEE). It is hypothesized that the addition of blood to agitated saline increases the sensitivity of TCD for the detection of RLS. The aim of this meta-analysis was to determine whether agitated saline with blood increases the sensitivity of TCD for the detection of RLS compared to agitated saline alone and other contrast agents.MethodA systematic review of Medline, Cochrane, and Embase was performed to look for all prospective studies assessing intracardiac RLS using TCD compared with TEE as the reference; both tests were performed with a contrast agent and a maneuver to provoke RLS in all studies.ResultsA total of 27 studies (29 comparisons) with 1,968 patients met the inclusion criteria. Of 29 comparisons, 10 (35%) used echovist contrast during TCD, 4 (14%) used a gelatin-based solution, 12 (41%) used agitated saline, and 3 (10%) utilized 2 different contrast agents. The addition of blood to agitated saline improved the sensitivity of TCD to 100% compared to agitated saline alone (96% sensitivity, P = 0.161), echovist (94% sensitivity, P = 0.044), and gelatin-based solutions (93% sensitivity, P = 0.041).ConclusionThe addition of blood to agitated saline improves the sensitivity of TCD for the detection of RLS to 100% when compared to other conventional contrast agents; these findings support the addition of blood to agitated saline during TCD bubble studies.

Transcranial Doppler (TCD) screening rates remain low among children with sickle cell disease (SCD). We assessed TCD screening rates and missed opportunities for TCD screening. Children 2 to 16 years old with SCD enrolled in Michigan Medicaid for ≥1 year (2007-2011) were identified through newborn screening. Receipt of TCD screening and presence of a missed opportunity (≥1 SCD-related outpatient visit, no TCD screening) were identified through administrative claims. Potential correlates of missed opportunities included SCD-related health services, comorbidities, and demographics. Logistic regression with generalized estimating equations modeled associations between a missed opportunity and correlates. Overall, 353 children contributed 1066 person-years. TCD screening was low yearly (10%-32%); missed opportunities occurred in 73% of the person-years. Increasing age (odds ratio [OR] = 1.11; confidence interval CI = 1.07, 1.15), previous TCD screening (OR = 0.26; CI = 0.16, 0.41), and 4 to 5 (OR = 0.48; CI = 0.26, 0.87) or ≥6 outpatient visits (OR = 0.26; CI = 0.14, 0.49) were associated with a missed opportunity. Reduction of missed opportunities is a potential strategy to increase TCD screening rates.

In children with Sickle Cell Disease, the combination of risk stratification with Transcranial Doppler Ultrasound (TCD) and selective chronic red cell transfusion (CRCT-the STOP Protocol) is one of the most effective stroke prevention strategies in medicine. How fully it is being implemented is unclear. Nineteen of 26 sites that conducted the two pivotal clinical trials (STOP and STOP II) participated in Post STOP, a comprehensive medical records review assessing protocol implementation in the 10-15 years since the trials ended. Professional abstractors identified medical records in the Post STOP era in 2851 (74%) of the 3,840 children who took part in STOP and/or STOP II, and documented TCD rescreening, maintenance of CRCT in those at risk, and stroke. Among 1,896 children eligible for TCD rescreening (target group), evidence of any rescreening was found in 1,090 (57%). There was wide site variation in TCD rescreening ranging from 18% to 91% of eligible children. Both younger age and having a conditional TCD during STOP/II were associated with a higher likelihood of having a TCD in Post STOP. Sixty eight new abnormal, high risk cases were identified. Despite clear evidence of benefit the STOP protocol is not fully implemented even at experienced sites. Site variation suggests that system improvements might remove barriers to implementation and result in even greater reduction of ischemic stroke in children with SCD. Am. J. Hematol. 91:1191-1194, 2016. © 2016 Wiley Periodicals, Inc.

BackgroundTranscranial Doppler (TCD) with agitated saline has been shown to be an alternative for the detection of right-to-left shunts (RLS) with similar diagnostic accuracies as transesophageal echocardiography (TEE). It is hypothesized that the addition of blood to agitated saline increases the sensitivity of TCD for the detection of RLS. The aim of this meta-analysis was to determine whether agitated saline with blood increases the sensitivity of TCD for the detection of RLS compared to agitated saline alone and other contrast agents.MethodA systematic review of Medline, Cochrane, and Embase was performed to look for all prospective studies assessing intracardiac RLS using TCD compared with TEE as the reference; both tests were performed with a contrast agent and a maneuver to provoke RLS in all studies.ResultsA total of 27 studies (29 comparisons) with 1,968 patients met the inclusion criteria. Of 29 comparisons, 10 (35%) used echovist contrast during TCD, 4 (14%) used a gelatin-based solution, 12 (41%) used agitated saline, and 3 (10%) utilized 2 different contrast agents. The addition of blood to agitated saline improved the sensitivity of TCD to 100% compared to agitated saline alone (96% sensitivity, P = 0.161), echovist (94% sensitivity, P = 0.044), and gelatin-based solutions (93% sensitivity, P = 0.041).ConclusionThe addition of blood to agitated saline improves the sensitivity of TCD for the detection of RLS to 100% when compared to other conventional contrast agents; these findings support the addition of blood to agitated saline during TCD bubble studies.

The aim of this study was to assess transcranial Doppler (TCD) as a screening test for pulmonary arteriovenous malformation (PAVM) in patients with hereditary hemorrhagic telangiectasia (HHT). This retrospective study included suspected patients with HHT who were screened for PAVM with a TCD and a chest computed tomography (CT) study. The results of TCD and CT were compared to evaluate the usefulness of TCD for detecting PAVM. A TCD Spencer grade ≥3 was defined as positive for a significant right-to-left shunt (RLS). The diameter of the pulmonary arteries feeding the PAVM was measured by calipers from the CT study. In 86 subjects from 74 families with HHT, the sensitivity of TCD for identifying a PAVM at rest was 98% and post-Valsalva was 100%. Specificity was 58% and 35%, respectively, presumably due to pulmonary shunts too small to recognize on CT. Of the patients with HHT who were referred for embolization therapy for their PAVMs, all 20 had TCD grade ≥3. In patients who were diagnosed with a PAVM by chest CT, patients with TCD grade ≥5 had a significantly larger sum of artery diameters feeding the PAVMs compared to those with grade ≤4 (5.0 ± 3.2 mm vs 2.6 ± 1.9 mm, p = 0.01). In conclusion, a TCD examination for evaluating RLS is sensitive for identifying PAVM in patients with HHT and is useful in quantitating the degree of RLS flow. The sensitivity of the TCD examination makes it a useful screening test without radiation in HHT subjects to determine which patients need to undergo CT evaluation to identify PAVMs.

TCD apnea test kao neinvazivna i bezbedna neuroultrasonografska metoda pruža korisne informacije o vazomotornoj reaktivnosti (VMR) u procesu indirektnog sagledavanja funkcionisanja moždane autoregulacije. Vazomotorna reaktivnosti podrazumeva sposobnost dilatacije ili konstrikcije moždanih arteriola nastale kao odgovor na određeni vazoaktivni stimulus, najčešće ugljen dioksid. Cilj ove doktorske disertacije bio je ispitivanje i analiziranje promene karotidne hemodinamike kod bolesnika sa ishemijskim moždanim udarom (IMU) ili tranzitornim ishemijskim atakom (TIA) i simptomatskom karotidnom stenozom u preoperativnom i tromesečnom postoperativnom periodu, kao i procena revaskularizacionog efekta karotidne endarterektomije (KEA).U istraživanje je uključeno 60 hospitalizovanih bolesnika koji su doživeli prvi IMU i TIA u zoni vaskularizacije arterije cerebri anterior (ACA) i arterije cerebri medije (ACM), svi sa karotidnom stenozom, ACI ≥70%. Bolesnici su bili hospitalizovani na Klinici za neurologiju, Kliničkog Centra Vojvodine, Klinici za kardiovaskularnu hirurgiju, Instituta za kardiovaskularne bolesti Vojvodine i Klinici za vaskularnu hirurgiju, u Novom Sadu. U odnosu na kliničke manifestacije bolesni i su podeljeni u tri grupe: bolesnici sa TIA i amaurosis fugax, sa parcijalnim infarktom u zoni ACA ili ACM i sa lakunarnim infarktom. Istraživanje je analiziralo uticaj promenljivih i nepromenljivih vaskularnih faktora rizika na pojavu IMU i TIA, ali i na VMR, procenjivanu kroz indeks zadržavanja daha (Breath Holding Index, BHI) ipsilateralno i kontralateralno u odnosu na karotidnu stenozu. Analizirana je povezanost stepena karotidne stenoze sa vrednostima BHI preoperativno, povezanost BHI sa težinom kliničke slike, uticaj kolateralnog krvotoka na VMR, distribucija BHI u pojedinim tipovima IMU i TIA kao i komparacija BHI u pre i u postoperativnom periodu od 30 i 90 dana. Na osnovu sprovedenog istraživanja, došlo se do zaključaka da je redukovana VMR preoperativna karakte, TCD apnea test, as a noninvasive and safe neuroultrasonographic method, provides useful information about vasomotor reactivity (VMR) in the indirect evaluation of cerebral autoregulation. Vasomotor reactivity is the ability of cerebral arterioles to constrict or to dilate in response to a vasoactive stimulus, mainly carbon dioxide. The aim of this doctoral thesis was to investigate and analyze changes in carotid hemodynamics in patients with ischemic stroke (IS) or transient ischemic attack (TIA) and symptomatic carotid stenosis in the preoperative and three-month postoperative period as well as the assessment of revascularisation effect of carotid endarterectomy (CEA). The study included 60 hospitalized patients who experienced a first ischemic stroke or TIA in the vasularisation area of anterior cerebral artery (ACA) and middle cerebral artery (MCA), all with carotid stenosis ≥70% ACI. Patients were hospitalized at the Clinic of Neurology, Clinical Center of Vojvodina, Department of Cardiovascular Surgery, Institute of Cardiovascular Diseases and the Department of Vascular Surgery in Novi Sad. Considering clinical manifestations of stroke, the patients were divided into three groups: patients with TIA and amaurosis fugax, with partial infarction in area ACA or ACM and with lacunar infarct. The study analyzed the impact of variabile and unvariable vascular risk factors on the incidence of ischemic stroke and TIA, but also on VMR, evaluated through Breath Holding Index (Breath Holding Index, BHI) on the ipsilateral and contralateral side from carotid stenosis. We analysed the correlation between the degree of carotid stenosis with preoperative values of BHI, BHI correlation to the severity of clinical findings, the impact of collateral circulation to the VMR, distribution of BHI in certain types of ischemic stroke and TIA as well as comparison of BHI in the pre and postoperative period of 30 and 90 days. On the basis of this research came the conclusion that reduced

Otkrivanje embolusa u cerebralnoj cirkulaciji na egzaktan način moguće je samo upotrebom transkranijalnog doplera. Istraživanje je obuhvatilo 150 ispitanika, obolelih od akutnog ishemijskog cerebrovaskularnog događaja (ishemijskog moždanog udara i tranzitornog ishemijskog ataka) u zoni vaskularizacije a. cerebri medie (ACM), a lečenih na Klinici za neurologiju, Kliničkog centra Vojvodine. Ciljevi istraživanja su obuhvatili određivanje prevalence i frekvence MES kod bolesnika sa akutnim ishemijskim cerebrovaskularnim događajem (TIA, IMU) tokom serijskog monitoringa, utvrđivanje povezanost pojave MES u odnosu na etiologiju ishemijske epizode, procenjivanje efekata terapije (antiagregacione i antikoagulantne) na pojavu MES tokom serijskog monitoringa, i utvrđivanje prediktivnog značaja MES na dalji tok bolesti tj, rani povratni embolizam unutra tri meseca. Utvrdili smo da se mikroembolusi kao markeri aktivne embolizacije mogu registrovati primenom transkranijalnog doplera u akutnoj fazi moždanog udara u određenoj meri. U ispitivanom uzorku metodom transkranijalne detekcije kod 52 (34,7%) bolesnika je registrovana pojava cerebralnih mikroembolusa. Ovi ispitanici su činili MES (+) grupu pacijenata. Kod 98 (65,3%) bolesnika nisu registrovani ES, oni su činili MES (-) grupu pacijenata. Detekcija je vršena u prvih 72h od vremena nastanka IMU ili TIA. Zaključili smo da se serijskim monitoringom registruje smanjenje prevalence i frekvence embolijskih signala. Utvrdili smo da su starija životna dob, hipertenzija i dijabetes statistički značajno povezani sa pojavom mikroembolusnih signala. Najveća zastupljenost mikroembolusa registrovana je u aterotrombotičnom podtipu ishemijskog moždanog udara. Utvrđen je prediktivni značaj aterosklerotske bolesti velikih krvnih sudova na pojavu MES. Registrovana je statistički značajno češća pojava MES kod simptomatske karotidne stenoze, visokog stepena (70-90%), neravne i ulcerisane površine plaka. Nije utvrđena statistički značajna povezano, Detection of emboli in the cerebral circulation to the exact way it is possible only by using transcranial doppler. The study included 150 patients of acute ischemic cerebrovascular events (ischemic stroke and TIA) in a zone of vascularization a. cerebri media (ACM), and treated at the Clinic of Neurology, Clinical Center of Vojvodina Research objectives included the determination of the prevalence and frequency of MES in patients with acute ischemic cerebrovascular accident (TIA, IMU) during serial monitoring, establishing the link between the appearance MES in relation to the etiology of ischemic episodes, assessing the effects of therapy (antiplatelet and anticoagulant) on the occurrence of MES during serial monitoring and determine the predictive value MES in the further course of the disease, ie. return early embolism within three months. We have found that microemboli as markers of active embolization can register by using transcranial Doppler in the acute phase of stroke in certain extent. In the examined sample using transcranial detection with 52 (34.7%) patients the occurrence of cerebral microemboli is registered. These respondents are accounted for MES (+) group of patients. With 98 patients (65.3%) is not registered EC, they account for MES (-) group of patients. Detection was performed during 72 hours from the time of occurrence of ischemic stroke or TIA. We concluded that serial monitoring registers decrease in prevalence and frequency of embolic signals. We found that older age, hypertension, and diabetes are significantly associated with the appearance of microembolic signals. The highest incidence of microemboli was registered in atherothrombotic ischemic stroke subtype. It is determined the predictive significance of atherosclerotic disease of large blood vessels on the occurrence of MES. More common MES is significantly registered with symptomatic carotid stenosis, greater degree (70-90%), uneven surfaces and ulcerated plaque. There was no statis

ObjectiveWe explored factors that may influence physician adherence to transcranial Doppler (TCD) screening guidelines among children with sickle cell disease.MethodsPediatric hematologists, neurologists, and primary care physicians (n = 706) responded to a mailed survey in May 2012 exploring factors hypothesized to influence physician adherence to TCD screening guidelines: physician (internal) barriers and physician-perceived external barriers. Responses were compared by specialty using chi-square tests.ResultsAmong 276 physicians (44%), 141 currently treated children with sickle cell disease; 72% recommend screening. Most primary care physicians (66%) did not feel well informed regarding TCD guidelines, in contrast to neurologists (25%) and hematologists (6%, P < .0001). Proportion of correct answers on knowledge questions was low (13%-35%). Distance to a vascular laboratory and low patient adherence were external barriers to receipt of TCD screening.ConclusionsAdditional research regarding physicians' lack of self-efficacy and knowledge of recommendations could help clarify their role in recommendation of TCD screening.

ObjectivesTo assess the presence of right-to-left shunting (RLS) in patients with obstructive sleep apnea (OSA), and compare clinical characteristics and parameters of the sleep studies of patients with and without RLS.BackgroundThe most common cause of RLS is due to intermittent flow through a patent foramen ovale (PFO). PFO occurs more frequently in patients with OSA and may be involved in the exacerbation of OSA.MethodsPatients with an abnormal polysomnogram seen at UCLA-Santa Monica Sleep Medicine Clinic were enrolled. A diagnosis of RLS was made using a transcranial Doppler (TCD) bubble study. Gender and age-matched controls were drawn from patients referred for cardiac catheterization who underwent a TCD. The frequency of RLS in OSA patients and the controls was evaluated. Clinical characteristics and polysomnogram parameters were compared between OSA patients with and without a RLS.ResultsA total of 100 OSA patients and 200 controls participated in the study. The prevalence of RLS was higher in patients with OSA compared to the control group (42% versus 19%; p < 0.0001). Patients with OSA and a RLS had a lower apnea-hypopnea index (AHI), less obstructive apnea, and fewer hypopnea episodes than patients with OSA without a RLS. The baseline and nadir SpO2 were similar in both groups and did not correlate with the level of RLS assessed by TCD. The degree of desaturation for a given respiratory disturbance, as measured by oxygen desaturation index (ODI)/AHI ratio, was higher in OSA patients with RLS versus OSA patients without RLS (0.85 ± 0.07 versus 0.68 ± 0.04; p < 0.0001).ConclusionRLS, most commonly due to a PFO, occurs 2.2 times more frequently in OSA patients compared to a control population that was matched for age and gender. The severity of sleep apnea is not greater in OSA patients who have a PFO. However, patients with OSA and a PFO are more likely to become symptomatic at a younger age with an equivalent decrease in nocturnal SpO2, and have grea

Nervous stimulation with electric methods not only has a long history in the treatment of many conditions but also in the last two decades has been used increasingly as a powerful functional brain mapping tool alongside other imaging techniques. This technology has been used to record the stimulation-evoked activity of the stimulated location. This research describes work surrounding a novel technique for brain and nervous stimulation using the electric field as the medium; particularly transcranial brain stimulation by an electric field and its possible advantages compared to relatively similar techniques. This thesis discusses our knowledge regarding brain electrical activities as they relate to this project. We will present discoveries concerning the role of electric fields in the brain and the effects of external electric fields on neuronal function. Then we discuss our new prototype, its design, and some results from simulations. Our device aims at introducing the use of electric fields in modifying the functional activity of the brain in a precise and accurate manner, one that surpasses that of other current methods, minimizing some of the side effects, and maximizing effectiveness in altering desired brain function.The goal in this thesis is to demonstrate the potential that this technology can provide us. We show that in theory this device could be used as a very high-resolution brain stimulation device. we leave the speculation about impacts of this device in the medical world to the readers imagination.

Recent in vivo modulation of region-specific brain activity suggests that Low Intensity Focused Ultrasound (LIFU) may be a non-invasive alternative therapy for drug-delivery applications and the treatment of neurological diseases, including epilepsy and Parkinson’s disease.Despite these recent successes, failure to reproduce published results continues to plague the field due to the limited understanding of cellular mechanisms that underlie neuromodulation and the impact of skull on targeting accuracy. The objective of this thesis is to help bridge these knowledge gaps and better understand non-invasive transcranial focused ultrasound modulation. While hypotheses exist explaining the mechanism underlying ultrasound modulation, they largely remain untested. It has been suggested that mechanical perturbation of cellular membranes with embedded protein channels using ultrasound has an impact on ion channel kinetics, resulting in depolarization, and ultimately, increased neural activity. In particular, this thesis investigates the hypothesis explaining the mechanical perturbation as a result of pure acoustic radiation forces using simplified in vitro models, including Large-Conductance Mechanosensitive Channels (MscL) and non-mechanically stimulated channels. The outcome revealed an increase in efflux through proteoliposomes regardless of the channel type except at the highest concentration of mechanosensitive channel (MS) model where a lowering efflux trend was noticed. These unexpected results suggest that focused ultrasound does not modulate the gating of ion channels, but instead effects the permeability of the membrane itself or protein-membrane interface. Also a dual effect of membrane stretch enhancement and pore formation is observed only at high MS channel concentration.In addition, to prepare for in vivo efficacy studies, the present dissertation characterizes the ultrasonic beam scatter and focal shifts that occur as ultrasound passes through a rat skull for

Nervous stimulation with electric methods not only has a long history in the treatment of many conditions but also in the last two decades has been used increasingly as a powerful functional brain mapping tool alongside other imaging techniques. This technology has been used to record the stimulation-evoked activity of the stimulated location. This research describes work surrounding a novel technique for brain and nervous stimulation using the electric field as the medium; particularly transcranial brain stimulation by an electric field and its possible advantages compared to relatively similar techniques. This thesis discusses our knowledge regarding brain electrical activities as they relate to this project. We will present discoveries concerning the role of electric fields in the brain and the effects of external electric fields on neuronal function. Then we discuss our new prototype, its design, and some results from simulations. Our device aims at introducing the use of electric fields in modifying the functional activity of the brain in a precise and accurate manner, one that surpasses that of other current methods, minimizing some of the side effects, and maximizing effectiveness in altering desired brain function.The goal in this thesis is to demonstrate the potential that this technology can provide us. We show that in theory this device could be used as a very high-resolution brain stimulation device. we leave the speculation about impacts of this device in the medical world to the readers imagination.

Recent in vivo modulation of region-specific brain activity suggests that Low Intensity Focused Ultrasound (LIFU) may be a non-invasive alternative therapy for drug-delivery applications and the treatment of neurological diseases, including epilepsy and Parkinson’s disease.Despite these recent successes, failure to reproduce published results continues to plague the field due to the limited understanding of cellular mechanisms that underlie neuromodulation and the impact of skull on targeting accuracy. The objective of this thesis is to help bridge these knowledge gaps and better understand non-invasive transcranial focused ultrasound modulation. While hypotheses exist explaining the mechanism underlying ultrasound modulation, they largely remain untested. It has been suggested that mechanical perturbation of cellular membranes with embedded protein channels using ultrasound has an impact on ion channel kinetics, resulting in depolarization, and ultimately, increased neural activity. In particular, this thesis investigates the hypothesis explaining the mechanical perturbation as a result of pure acoustic radiation forces using simplified in vitro models, including Large-Conductance Mechanosensitive Channels (MscL) and non-mechanically stimulated channels. The outcome revealed an increase in efflux through proteoliposomes regardless of the channel type except at the highest concentration of mechanosensitive channel (MS) model where a lowering efflux trend was noticed. These unexpected results suggest that focused ultrasound does not modulate the gating of ion channels, but instead effects the permeability of the membrane itself or protein-membrane interface. Also a dual effect of membrane stretch enhancement and pore formation is observed only at high MS channel concentration.In addition, to prepare for in vivo efficacy studies, the present dissertation characterizes the ultrasonic beam scatter and focal shifts that occur as ultrasound passes through a rat skull for

ObjectiveWe explored factors that may influence physician adherence to transcranial Doppler (TCD) screening guidelines among children with sickle cell disease.MethodsPediatric hematologists, neurologists, and primary care physicians (n = 706) responded to a mailed survey in May 2012 exploring factors hypothesized to influence physician adherence to TCD screening guidelines: physician (internal) barriers and physician-perceived external barriers. Responses were compared by specialty using chi-square tests.ResultsAmong 276 physicians (44%), 141 currently treated children with sickle cell disease; 72% recommend screening. Most primary care physicians (66%) did not feel well informed regarding TCD guidelines, in contrast to neurologists (25%) and hematologists (6%, P < .0001). Proportion of correct answers on knowledge questions was low (13%-35%). Distance to a vascular laboratory and low patient adherence were external barriers to receipt of TCD screening.ConclusionsAdditional research regarding physicians' lack of self-efficacy and knowledge of recommendations could help clarify their role in recommendation of TCD screening.

ObjectivesTo assess the presence of right-to-left shunting (RLS) in patients with obstructive sleep apnea (OSA), and compare clinical characteristics and parameters of the sleep studies of patients with and without RLS.BackgroundThe most common cause of RLS is due to intermittent flow through a patent foramen ovale (PFO). PFO occurs more frequently in patients with OSA and may be involved in the exacerbation of OSA.MethodsPatients with an abnormal polysomnogram seen at UCLA-Santa Monica Sleep Medicine Clinic were enrolled. A diagnosis of RLS was made using a transcranial Doppler (TCD) bubble study. Gender and age-matched controls were drawn from patients referred for cardiac catheterization who underwent a TCD. The frequency of RLS in OSA patients and the controls was evaluated. Clinical characteristics and polysomnogram parameters were compared between OSA patients with and without a RLS.ResultsA total of 100 OSA patients and 200 controls participated in the study. The prevalence of RLS was higher in patients with OSA compared to the control group (42% versus 19%; p < 0.0001). Patients with OSA and a RLS had a lower apnea-hypopnea index (AHI), less obstructive apnea, and fewer hypopnea episodes than patients with OSA without a RLS. The baseline and nadir SpO2 were similar in both groups and did not correlate with the level of RLS assessed by TCD. The degree of desaturation for a given respiratory disturbance, as measured by oxygen desaturation index (ODI)/AHI ratio, was higher in OSA patients with RLS versus OSA patients without RLS (0.85 ± 0.07 versus 0.68 ± 0.04; p < 0.0001).ConclusionRLS, most commonly due to a PFO, occurs 2.2 times more frequently in OSA patients compared to a control population that was matched for age and gender. The severity of sleep apnea is not greater in OSA patients who have a PFO. However, patients with OSA and a PFO are more likely to become symptomatic at a younger age with an equivalent decrease in nocturnal SpO2, and have grea